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Tumor-grade hyperprolactinemia induced by multiple medications in the setting of renal failure.

OBJECTIVE: To describe a patient with galactorrhea and severe hyperprolactinemia in whom workup revealed a nontumoral mechanism. METHODS: We present the medical history of a woman with long-standing diabetes in whom bilateral galactorrhea and hyperprolactinemia developed. In addition, the details of her clinical course and management are reviewed. RESULTS: A 33-year-old woman with diabetes, end-stage renal disease, and gastroparesis was admitted to the hospital because of intractable nausea and vomiting. Several months before admission, she had been noted to have galactorrhea and irregular menses. Routine medications included captopril, verapamil, furosemide, prochlorperazine, metoclopramide, cisapride, and Ortho-Novum. Laboratory evaluation showed normal thyroid function, increased serum prolactin levels (up to 1,197 ng/mL), and normal findings on magnetic resonance imaging of the pituitary. Electrophoresis of the patient's serum on a protein A Sepharose column showed no evidence of macro-prolactinemia. Orally administered medications were discontinued, and the patient was given total parenteral nutrition. These measures resulted in a decrease of 300 ng/mL in serum prolactin levels in 4 days. The prolactin levels eventually normalized after withdrawal of verapamil, prochlorperazine, and metoclopramide. CONCLUSION: A modest increase in serum prolactin level often can be produced by a variety of medications, but gross hyperprolactinemia of 200 ng/mL or higher usually raises suspicion of an underlying prolactin-secreting tumor. This case report demonstrates that conventional limits for nontumoral hyperprolactinemia can be exceeded by concurrent exposure to multiple lactotropic medications in the setting of renal failure.

Journal Article↗

[Bacterial vaginosis. Epidemiology and risk factors].

Bacterial vaginosis (BV) is a change in vaginal ecosystem where lactobacilli dominate, flora is absent or greatly reduced, and replaced with a mixed, predominantly anaerobic flora, consisting of Gardnerella vaginalis, Mycoplasma hominis, Mobiluncus spp, Bacteroides spp, Prevotela spp, Peptostreptococcus spp, Fusobacterium spp and Porphyromonas spp. The concentration of bacteria increases from 100 to 1000 fold in women with BV compared to healthy women. BV has been formerly known as nonspecific vaginitis, Haemophilus vaginitis, Corynebacterium vaginitis, Gardnerella vaginitis and anaerobic vaginintis. BV is the most prevalent form of vaginal disturbances in reproductive age women. The average incidence of BV varies: 10-35% in patients visiting gynaecological wards, 10-30% in patients visiting obstetric wards and 20-60% in patients visiting services of sexually transmitted diseases. A typical clinical symptom of BV is malodorous vaginal discharge. However, more than 50% of all women with BV are asymptomatic. BV has been associated with many gynaecological and obstetric complications such as cervicitis, salpingitis, endometritis, postoperative infections, urinary tract infections, pelvic inflammatory disease, mild abnormal Pap smear results and possible link with cervical intraepithelial neoplasia, preterm delivery, premature rupture of the membranes, chorioamnionitis and postpartum endometritis. Factors that increase the risk of BV are multiple partners, exposure to semen, prior trichomoniasis, intrauterine device usage, smoking, indigent population and frequent use of scented soap. Diagnosis of BV is established by Amsel's criteria of which three of four are the following: presence of homogeneous discharge, vaginal fluid pH > 4.5, positive amine test and microscopic analysis of Gram stained smear of vaginal discharge where "clue" cells (epithelial vaginal cells covered with mass of adherent bacteria, mostly coccobacilli) should be detected. The treatment of patients with BV consist of metronidazole or clindamycin, per os or intravaginally. The treatment of asymptomatic women and male sex partners of women with BV is controversial. The aim of the study was to establish the occurrence rate of BV in our women and potential factors increasing the risk of BV. We examined 166 women at the Institute of Microbiology and Immunology, University School of Medicine, Belgrade. Diagnosis of BV was established by Amsel's criteria. Each woman filled in a special questionnaire. Pregnant women were excluded. BV was diagnosed in 25% (33/166) of women. BV was more common among women with multiple partners. The most prevalent clinical symptom of BV was malodorous vaginal discharge. Vaginal symptoms became more evident after intercourse. Taking into consideration the occurrence rate of BV and its connection with numerous gynaecological and obstetric sequelae, and taking into account that the diagnosis of BV is quick, simple and inexpensive, we suggest that the examination of BV in women becomes a usual procedure.

Adult↗

Efficient naked plasmid cotransfection of lung grafts by extended lung/plasmid exposure time.

BACKGROUND: Multiple gene cotransfection may be an effective strategy to modulate concurrent pathologic events after lung transplantation. We investigated in vivo naked plasmid lung cotransfection during cold preservation and the role of lung parenchyma/naked plasmid exposure time. METHODS: F344 rats underwent left main bronchus instillation of pCF1-CAT (chloramphenicol acetyl transferase) (130 microg) +/- pCF1-beta-Gal (beta-galactosidase) (130 microg) in saline. Part Ia: 4 degrees C preservation versus cotransfection. Lung isografts (4 groups, n = 8) were stored after transfection for 1 (2 groups: one received only pCF1-CAT), 6, and 18 hours. Recipient sacrifice was after 48 hours. Part Ib: 4 degrees C preservation versus transgene expression. Rats were sacrificed 48 hours after transfection in a nontransplant setting (2 groups, n = 8; one received only pCF1-CAT). In a third group (n = 8) lungs were harvested 24 hours after transfection, stored for 18 hours, and recipients were sacrificed after 24 hours. The CAT and beta-Gal enzymatic-linked immunosorbent assays were performed. Part II: Lung/plasmid exposure time. In three groups (n = 6) after pCF1-CAT transfection the left main bronchus was not clamped, clamped for 10 minutes, or clamped for 1 hour. Sacrifice was after 48 hours. RESULTS: Part Ia: Lung CAT protein was (in picograms per 100 microg of total protein): median, 42 (range, 25 to 95) after 1 hour (only CAT); 67 (19 to 296) after 1 hour, 32 (6 to 157) after 6 hours; and 9 (5 to 243) after 18 hours. Lung beta-Gal protein was (in picograms per 100 microg of total protein): median, 20 (range, 5 to 353) after 1 hour; 17 (6 to 157) after 6 hours; 4 (1 to 74) after 18 hours (1 hour versus 18 hours, p = 0.04 for both proteins). CAT and beta-Gal production were significantly correlated (p = 0.0001, r = 0.924). Part Ib: Lung CAT protein was (in picograms per 100 microg of total protein): median, 2 (range, 0.6 to 10) no transplant, only CAT; 7 (0.3 to 13) no transplant; 3 (0.9 to 14) transplant. Part II: Left lung CAT protein was (in picograms per 100 microg of total protein): median, 31 (range, 6 to 83) no clamp; 74 (25 to 430) 10 minutes of clamp; 111 (30 to 263) 1 hour of clamp. Right lung CAT protein was (in picograms per 100 microg of total protein): median, 0.06 (range, 0 to 0.9) no clamp; 1 (0 to 6) 10 minutes of clamp; 1 (0 to 18) 1 hour of clamp. CONCLUSIONS: Efficient lung isograft endobronchial cotransfection results from using naked plasmid. Cold preservation affects transfection efficiency but not transgene expression. Lung parenchyma/naked plasmid exposure time determines transfection efficiency.

Animals↗

The relationship of pregnancy to the use of highly active antiretroviral therapy.

OBJECTIVE: Public health agencies have recommended that the criteria for the use of highly active antiretroviral therapy should not be modified because of pregnancy. However, little information has been published with regard to the degree to which these recommendations are being followed. We report here the frequency of highly active antiretroviral therapy use among pregnant women in the Women's Interagency HIV Study and compare the frequencies of its use by pregnant women meeting published criteria for implementing highly active antiretroviral therapy and its use by nonpregnant women meeting the same criteria. STUDY DESIGN: From October 1994 through November 1995, a total of 2059 human immunodeficiency virus type 1-seropositive women were enrolled in a cohort study. Participants were evaluated at baseline and at 6-month intervals with standardized interview instruments. In addition to a general physical examination at each visit, patients had a urine pregnancy test performed and were asked about current pregnancies, pregnancies since the last visit, and which antiretroviral medications they had used since the last visit. Highly active antiretroviral therapy was defined according to 1997 National Institutes of Health guidelines. RESULT: At each calendar interval after October 1996, a greater proportion of nonpregnant women than pregnant women reported the use of highly active antiretroviral therapy. The use of monotherapy declined for both groups during the course of multiple calendar periods (P <.01), although the use of monotherapy remained higher among the pregnant women. In any given calendar period, pregnant women meeting published criteria for highly active antiretroviral therapy use were slightly less likely than similar nonpregnant women to receive highly active antiretroviral therapy (odds ratio, 0.28-0.98). Because of the sample size these differences reached significance in only one calendar period (P =.02). With time pregnant women did demonstrate an increase in the percentage receiving highly active antiretroviral therapy. In nearly all calendar periods a larger percentage of pregnant than nonpregnant women were receiving a regimen that included zidovudine. CONCLUSIONS: Highly active antiretroviral therapy is being received by an increasing percentage of women who meet published criteria for its use, and pregnancy is a relatively small impediment to its use. Further efforts are needed to bolster the use of highly active antiretroviral therapy by all appropriate candidates and to ensure equal access to this therapy for pregnant women. Because of the increasingly frequent use of highly active antiretroviral therapy during pregnancy, ongoing efforts are needed to monitor any long-term effects of in utero exposure to multiple antiretroviral agents.

Anti-HIV Agents↗

Induction of oxidative stress in erythrocytes of male rats subchronically exposed to a mixture of eight metals found as groundwater contaminants in different parts of India.

Exposure of animals and humans to different metal components through contaminated drinking water can result in a wide range of adverse clinical conditions. Toxicological consequences arising from the concurrent repeated exposure to multiple metal contaminants are not known. The purpose of the present study was to evaluate the oxidative stress-inducing potential of a mixture of eight metals (arsenic, cadmium, lead, mercury, chromium, nickel, manganese, iron), representative of groundwater contamination in different areas of India, in erythrocytes of male rats subchronically exposed to environmentally relevant doses via drinking water. The selection of these metals, as determined by literature survey of groundwater contamination in India, was primarily based on the frequency of their occurrence and contamination level above World Health Organization maximum permissible limit (MPL) in drinking water. Male albino Wistar rats were exposed to the metal mixture at 0, 1, 10, and 100 times the mode concentrations (the most frequently occurring concentration) of the individual metals in drinking water for 90 days. In addition, one group of rats was also exposed to the mixture at a concentration equal to the MPL of individual components. The oxidative stress in erythrocytes was evaluated by assessing the magnitude of malondialdehyde production and reduced glutathione (GSH) content and the activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione reductase (GR) after 30, 60, and 90 days of exposure. MPL and 1x dose levels did not cause any changes. The mixture at 10x and 100x doses caused dose- and time-dependent effects. After 30 days, the 10x dose did not cause any changes except increase in SOD activity. The 100x dose increased the activities of SOD, catalase and GR and the GSH level, but caused no alterations in lipid peroxidation (LPO) and GPx activity. After 60 days, the 10x dose did not cause any changes. The 100x dose increased LPO and decreased all the antioxidant parameters, except GSH. After 90 days, both 10x and 100x levels elevated LPO. The 10x dose decreased GSH level and activities of SOD and catalase, but not of GPx and GR, whereas the 100x dose decreased all the antioxidative systems. Overall, the present study demonstrates that the subchronic exposure of male rats to the mixture of metals via drinking water results in induction of oxidative stress and concomitant reduction in antioxidative defense system in erythrocytes at 10 and 100 times the mode concentrations of the individual metals in contaminated groundwater.

Administration, Oral↗

Transient induction of the MRP/GS-X pump and gamma-glutamylcysteine synthetase by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea in human glioma cells.

Treatment of human glioma A172 cells with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), an alkylating antitumor agent the primary target of which has been thought to be DNA, resulted in elevated expression of mRNA for multidrug resistance-associated protein (MRP) within the first 2 h and then a decrease in expression 24 h after the treatment. Western blot analyses revealed that levels of MRP in these ACNU-treated cells paralleled mRNA levels. Membrane vesicles prepared from ACNU-treated cells also displayed elevated transport activities for leukotriene C4, a known substrate for MRP. Gamma-glutamylcysteine synthetase (gamma-GCS) mRNA expression was coinduced with MRP by ACNU. Because gamma-GCS is the rate-limiting enzyme involved in the de novo biosynthesis of glutathione, increases in glutathione were also transiently induced by ACNU. These results demonstrate for the first time that the expression of functional MRP and gamma-GCS can be transiently coinduced by ACNU. Multiple short exposures (1 h) of ACNU following a long duration (1 week) of drug-free conditions resulted in the development of an ACNU-resistant population (designated A172R) that overexpressed MRP/gamma-GCS mRNA and had elevated transport activities for leukotriene C4. A172R exhibited cross-resistance to the antitumor drug doxorubicin and heavy metal sodium arsenate but not to cisplatin. Our results also demonstrate that intermittent treatments of human glioma cells with ACNU can lead to the development of MRP-related multidrug resistance. These results, taken together, reveal a possible new mechanism of the development of drug resistance for the antitumor nitrosoureas.

ATP-Binding Cassette Transporters↗

Truncal site and detoxifying enzyme polymorphisms significantly reduce time to presentation of further primary cutaneous basal cell carcinoma.

Basal cell carcinoma (BCC) is the commonest cancer in Caucasians. Its incidence is rising and many patients develop multiple primary tumours at separate sites. Factors determining time between first primary tumour presentation and the next new primary lesion are unclear. We used Cox's proportional hazards model to study, in 856 Caucasians, the influence of tumour site, individual characteristics and polymorphism in glutathione S-transferase (GSTM1, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) loci on time to next primary tumour presentation. More than one tumour at first presentation (P <0.0001, hazard ratio 2.72) and GSTT1 null (P = 0.028, hazard ratio 1.74) were associated with decreased time to next primary tumour presentation. Significant two-factor interactions, corrected for number of tumours at presentation, were identified between a truncal tumour at first presentation and each of male gender, GSTM1 null and CYP2D6 EM (P <0.003, hazard ratios 3.09-3.82). In each of these cases, all patients with the risk combination demonstrated further separate tumours within 5 years of first presentation. Thus, patients with a truncal tumour at first presentation, especially males and those presenting with more than one lesion have a significantly decreased time to presentation of further tumours and should receive more meticulous follow-up. Polymorphism in GSTM1 and CYP2D6 also influences the rate of new primary tumour accrual giving insights into the link between ultraviolet exposure and multiple tumour development.

Aged↗

US adult attitudes and practices regarding smoking restrictions and child exposure to environmental tobacco smoke: changes in the social climate from 2000-2001.

OBJECTIVE: A substantial proportion of homes and automobiles serve as settings for environmental tobacco smoke (ETS) exposure, and many public settings that children frequent are still not smoke-free. Tobacco control efforts are attempting to increase smoking bans. The objective of this study was to describe the knowledge, attitudes, and practices of smokers and nonsmokers regarding smoking bans and child ETS exposure in multiple public and private settings and to report changes from 2000-2001. METHODS: Cross-sectional data from the annual Social Climate Survey of Tobacco Control were analyzed for changes in knowledge, attitudes, and practices regarding tobacco. These data were collected via automated, random-digit-dialing telephone surveys that were conducted in the summers of 2000 and 2001. The samples were weighted by race and gender to be representative of the US population. RESULTS: Response rates for eligible adults actually contacted were 1501 (75%) of 1876 in 2000 and 3002 (84%) of 3566 in 2001. The majority of adults, both smokers and nonsmokers, support smoking bans in a wide variety of places. The percentage of all respondents reporting the presence of smoking bans in several public and private places increased from 2000-2001: the household (69%-74%), in the presence of children (84%-88%), convenience stores (68%-74%), fast-food restaurants (52%-58%), and non-fast-food restaurants (25%-28%). Support for smoking bans also increased in shopping malls (71%-75%), fast-food restaurants (77%-80%), and indoor sporting events (78%-80%). There were no significant changes in support for smoking bans in convenience stores, restaurants, or outdoor parks. Adults' knowledge of the harm caused by tobacco was unchanged, with the vast majority of adults recognizing the dangers of exposure to ETS from parental smoking (95%) and exposure to ETS in cars (77%). CONCLUSIONS: Small improvements in adult attitudes and practices regarding children's ETS exposure occurred from 2000-2001. However, a significant number of adults in the United States still report ignorance of the harmful effects of child ETS exposure, and there was no improvement in reported knowledge in this 1-year period. In contrast, a growing majority of smokers and nonsmokers favor restrictions on smoking in public settings, suggesting that states and communities have public support for broad public smoking restriction policies. There are significant roles that pediatricians can play in preventing children's ETS exposure, through both patient and family education and by moving smoking restriction policies forward on their community's agenda.

Adult↗

Long-term exposure to particulate matter and all-cause and cause-specific mortality in an analysis of multiple Asian cohorts.

BACKGROUND: Exposure to ambient air pollution is associated with a significant number of deaths. Much of the evidence associating air pollution with adverse effects is from North American and Europe, partially due to incomplete data in other regions limiting location specific examinations. The aim of the current paper is to leverage satellite derived air quality data to examine the relationship between ambient particulate matter and all-cause and cause-specific mortality in Asia. METHODS: Six cohorts from the Asia Cohort Consortium provided residential information for participants, recruited between 1991 and 2008, across six countries (Bangladesh, India, Iran, Japan, South Korea, and Taiwan). Ambient particulate material (PM2&#xb7;5) levels for the year of enrolment (or 1998 if enrolled earlier) were assigned utilizing satellite and sensor-based maps. Cox proportional models were used to examine the association between ambient air pollution and all-cause and cause-specific mortality (all cancer, lung cancer, cardiovascular and lung disease). Models were additionally adjusted for urbanicity (representing urban and built characteristics) and stratified by smoking status in secondary analyses. Country-specific findings were pooled via random-effects meta-analysis. FINDINGS: More than 300,000 participants across six cohorts were included, representing more than 4-million-person years. A positive relationship was observed between a 5&#xa0;&#xb5;g/m (Dockery et al., 1993) increase in PM2&#xb7;5 and cardiovascular mortality (HR: 1&#xb7;06, 95&#xa0;% CI: 0.99, 1&#xb7;13). The additional adjustment for urbanicity resulted in increased associations between PM2.5 and mortality outcomes, including all-cause mortality (1&#xb7;04, 95&#xa0;% CI: 0&#xb7;97, 1&#xb7;11). Results were generally similar regardless of whether one was a current, never, or ex-smoker. INTERPRETATION: Using satellite and remote sensing technology we showed that associations between PM2.5 and all-cause and cause-specific Hazard Ratios estimated are similar to those reported for U.S. and European cohorts. FUNDING: This project was supported by the Health Effects Institute. Grant number #4963-RFA/18-5. Specific funding support for individual cohorts is described in the Acknowledgements.

Humans↗

Responses to panic induction procedures in subjects with multiple chemical sensitivity/idiopathic environmental intolerance: understanding the relationship with panic disorder.

Idiopathic environmental intolerance (IEI), also known as multiple chemical sensitivity, is a clinical description for a cluster of symptoms of unknown etiology that have been attributed by patients to multiple environmental exposures when other medical explanations have been excluded. Because allergy has not been clearly demonstrated and current toxicological paradigms for exposure-symptom relationships do not readily accommodate IEI, psychogenic theories have been the focus of a number of investigations. A significantly higher lifetime prevalence of major depression, mood disorders, anxiety disorders, and somatization disorder has been reported among patients with environmental illness compared with that in controls. Symptoms often include anxiety, lightheadedness, impaired mentation, poor coordination, breathlessness (without wheezing), tremor, and abdominal discomfort. Responses to intravenous sodium lactate challenge or single-breath inhalation of 35% carbon dioxide versus a similar breath inhalation of clean air have shown a greater frequency of panic responses in subjects with IEI than in control subjects, although such responses did not occur in all subjects. Preliminary genetic findings suggest an increased frequency of a common genotype with panic disorder patients. The panic responses in a significant proportion of IEI patients opens a therapeutic window of opportunity. Patients in whom panic responses may at least be a contributing factor to their symptoms might be responsive to intervention with psychotherapy to enable their desensitization or deconditioning of responses to odors and other triggers, and/or may be helped by anxiolytic medications, relaxation training, and counseling for stress management.

Administration, Inhalation↗

In vitro maintenance and retroviral transduction of human myeloma cells in long-term marrow cultures.

One objective of clinical gene marking trials in multiple myeloma (MM) is to determine the extent to which relapse after stem cell transplant is attributable to contamination of the autograft with myeloma cells. A requirement in these studies is ex vivo genetic marking of malignant cells present in autografts which are derived from patients exposed to significant prior chemotherapy. We evaluated gene marking of cloonogenic myeloma cells in marrow aspirates from 14 patients with MM. To effect gene transfer we utilized a long-term marrow culture (LTMC) system previously shown to facilitate gene transfer into a spectrum of hematopoietic progenitor and stem cells. Transduction of cells in LTMC was performed by multiple supernatant exposure. At LTMC initiation and after 21 days of culture malignant cells were assessed by morphology, flow cytometry, and polymerase chain reaction (PCR). The mean number of day 21 LTMC adherent layer-derived granulocyte/macrophage progenitors as a percentage of the original inoculum was within the normal range for this technique. The efficiency of transduction of normal hematopoietic progenitors as determined by the number of colonies positive for proviral DNA by PCR, G418 resistance, and X-gal staining was also within the expected range; 65%, 44% and 23%, respectively. Thus, there was no evidence that prior chemotherapy exposure or malignant cell contamination compromised cell survival or gene transfer efficiency in LTMC. All patients retained plasma cells in LTMCs for the duration of the 21-day culture period. Molecular analysis confirmed the persistence of clonal IgVH gene rearrangements in day 21 LTMC-derived DNA from 6 of 12 informative patients (50%). PCR using allele-specific primers when available confirmed the specificity of IgVH rearrangements for the myeloma clone. In 2 of the 14 patients, expansion of clonogenic cells was demonstrated in LTMC. In both cases there was strong evidence for transfer of reporter genes (neo and LacZ) into the myeloma clone: morphologically abnormal G418-resistant colonies demonstrated intense staining for beta-galactosidase, and cytospin preparations showed 100% plasma cells with monoclonal heavy and light chain restriction. In one patient, individual colonies positive for beta-galactosidase bore a cytogenetic abnormality characteristic of the patient's myeloma clone. PCR of DNA from pooled plasma cell colonies using tumor-specific CDR3 primers was positive. Our results demonstrate the maintenance of myeloma cells in vitro for up to 21 days in LTMC. They further illustrate that these cells can be genetically marked using transduction protocols currently being tested in clinical trials of hematopoietic cell gene transfer.

Antineoplastic Agents, Alkylating↗

Effect of prenatal exposure to ethanol on the development of cerebral cortex: I. Neuronal generation.

Prenatal exposure to ethanol causes profound disruptions in the development of the cerebral cortex. Therefore, the effect of in utero ethanol exposure on the generation of neurons was determined. Pregnant rats were fed a liquid diet in which ethanol constituted 37.5% of the total caloric content (Et) or pair-fed an isocaloric control diet (Ct) from gestational day (GD) 6 to the day of birth. The time of origin of cortical neurons was determined in the mature pups of females injected with [3H]thymidine on one day during the period from GD 10 to the day of birth. The brains were processed by standard autoradiographic techniques. Ethanol exposure produced multiple defects in neuronal ontogeny. The period of generation was 1-2 days later for Et-treated rats than for rats exposed prenatally to either control diet. Moreover, the generation period was 1-2 days longer in Et-treated rats. The numbers of neurons generated on a specific day was altered; from GD 12-19 significantly fewer neurons were generated in Et-treated rats than in Ct-treated rats, whereas after GD 19 more neurons were born. The distribution of neurons generated on a specific day was disrupted; most notable was the distribution of late-generated neurons in deep cortex of Et-treated rats rather than in superficial cortex as they are in controls. Cortical neurons in Et-treated rats tended to be smaller than in Ct-treated rats, particularly early generated neurons in deep cortex. The late-generated neurons in Et-treated rats were of similar size to those in Ct-treated rats despite their abnormal position in deep cortex. Neurons in Ct-treated rats tended to be rounder than those in Et-treated rats which were more polarized in the radial orientation. A proliferation index, which was based on the amount of autoradiographic signal over each labeled neuron, indicated that an additional, late surge in proliferative activity occurred in Et-treated rats on GD 20-21. The amount of [3H]thymidine incorporated each day was determined by biochemical analyses. In Ct-treated rats, incorporation increased to a maximum on GD 17 and decreased thereafter. In Et-treated rats, there were two maxima, the first on GD 18 and the second on GD 20. These data fully support the findings of the autoradiographic analyses. The present data show that neuronal generation is profoundly affected by ethanol. Such disturbances result from ethanol-induced abnormalities in neuronal proliferation and migration.

Animals↗

Multiple myeloma among Danish women: employment history and workplace exposures.

To investigate the role of employment history and workplace exposures as risk factors for multiple myeloma among women, a population-based case-control study using the Danish Cancer Registry data linkage system was conducted. All cases of myeloma diagnosed in Danish women between 1970 and 1984 (1,010 cases) and 4,040 age-matched women alive at the time of case-diagnosis were identified. Industrial histories from 1964 forward were obtained from the nationwide Pension Fund for 363 cases and 1,517 controls, and the most recent occupation on the tax record was available for 607 cases and 2,596 controls. Using industry/occupational-code combinations for the cases and controls who had industry employment, Danish industrial hygienists assessed the likelihood of exposure to 47 workplace substances. An increased myeloma risk (odds ratio [OR] = 1.2, 95 percent confidence interval [CI] = 1.0-1.5) was seen for women not in the Pension Fund, but who had an occupational title coded as 'Mrs/homemaker.' Nonsignificantly elevated risks of 1.3 or greater were observed for employment in: production of agricultural products; orchards/nurseries; spinning/weaving; other textile and plastics manufacturing; hotel, entertainment, and social services industries. Elevated, but nonsignificant risks were observed for possible and probable exposure to exhaust fumes, formaldehyde, wood dust, animals or animal products, and pesticides. The strongest association with myeloma was employment in the agricultural industry (OR = 1.5, CI = 0.8-2.8), however, the number of women who worked on family farms was unknown and could not be included in this risk estimate.

Adult↗

Comparison of the use of standardized diagnostic criteria and intuitive clinical diagnosis in the diagnosis of common viral warts (verrucae vulgaris).

OBJECTIVE: To assess the diagnostic value of standardized diagnostic criteria compared with the clinical intuitive diagnosis for verrucae vulgaris. DESIGN: A blind comparison with cross-over of experienced dermatologists using either intuitive clinical diagnosis or else recording the presence of standardized diagnostic criteria in verrucae vulgaris. SETTING: Clinical outpatient department in a major teaching hospital. PATIENTS: Fifteen patients aged 6 to 60 years with 21 verrucae vulgaris and 24 control lesions. INTERVENTION: Dermatologists examined the lesions and recorded either the diagnosis by the usual clinical intuitive method or else whether standardized diagnostic criteria were present in the lesion of each patient. Each dermatologist did 1 only of the 2 methods for each lesion with the other doing the alternative method for the same lesion, neither of them having previously been aware of any of the diagnoses. MAIN OUTCOME MEASURE: The sensitivity, specificity, and positive predictive, negative predictive, and relative values for each diagnostic approach were compared. RESULTS: Use of intuitive clinical diagnosis resulted in 100% specificity, sensitivity, and positive predictive, negative predictive, and relative values for both the verrucae vulgaris and the control lesions. Recording the presence of the diagnostic criteria reduced to a varying extent all the parameters of diagnostic accuracy with site--fingers and hands, elbows, and knees--being the most efficacious of the criteria. CONCLUSIONS: These data indicate that care is required in relying too much on standardized criteria as the basis for clinical diagnosis, even for a lesion as simple as a wart. They also reinforce the value of clinical experience obtained from repeated exposure to multiple variants of a disease in the traditional bedside teaching model.

Adolescent↗

Primary basal cell carcinoma of the caruncle.

Basal cell carcinomas (BCCs) of the caruncle are rare. We report a case of a primary BCC of the caruncle in a 74-year-old man who was seen with a medial interpalpebral lesion. He had a history of sun exposure and multiple malignant neoplasms of the skin. The lesion was excised and histological examination showed a BCC of the caruncle. The clinical history, examination findings, and histological features are given.

Aged↗

Treatment of von Willebrand's disease and hypofibrinogenemia with single donor cryoprecipitate from plasma exchange donation.

Conventional replacement therapy for hypofibrinogenemia and von Willebrand's disease requires multiple donor exposures and a correspondingly high risk of blood-borne infection. We describe the collection and successful use of cryoprecipitate derived from a single donor by plasma exchange donation to support such patients through major hemostatic stresses. The father of an epileptic patient with von Willebrand's disease produced cryoprecipitate containing 23,546 units of von Willebrand factor (vWF) in nine desmopressin-stimulated donations; this provided total factor replacement for neurosurgery to remove a seizure focus. The average yield was 2,616 units per donation and the average VWF concentration in cryoprecipitate was 17.7 units/ml. The husband of a hypofibrinogenemic patient with a history of postpartum hemorrhage provided cryoprecipitate containing 13.4 g of fibrinogen in five donations; this supported his wife through parturition without recourse to other blood products. The average yield was 2.7 g per donation, and the average fibrinogen concentration was 15.3 g/liter. Plasma exchange donation is a practical alternative source for cryoprecipitate. It can provide vWF and fibrinogen that carry a reduced risk of infectious disease transmission.

Adult↗

Analysis of the flagellar bending waves of ejaculated ram sperm.

The variability of flagellar movement, illustrated by the highly heterogeneous nature of the ejaculated sperm population of the ram, was analyzed by the use of a stroboscopic technique and an adapted microphotographic 24 X 36 camera system. The multiple-moving-exposures (MME) records give very distinct successive sequences of the flagellar beats and are particularly suitable for the analysis of bend development and propagation along the tail. With this technique, the parameters of the flagellar bending waves of ejaculated ram sperm have been determined. Most of the sperm have planar flagellar beatings; few are rolling under the conditions of observation. The trajectories of the gametes are mostly linear; nevertheless, some have circular paths. The analysis of bending has been focused on two examples for which the difference in the progressiveness ratio was maximum. The circular pathways for ram spermatozoa are linked to an asymmetry between principal and reverse bend probably induced by differences in wave propagation evidenced along the flagellum. A typical sperm flagellar movement may be related either to the conditions of the observations or to some differences in the maturation process of the sperm.

Animals↗

Clorazepate kinetics in treated epileptics.

Clorazepate is decarboxylated to form desmethyldiazepam and is a convenient way of administering it. Its kinetics were investigated in epileptic patients after single oral and multiple oral doses. Peak serum concentrations of demethyldiazepam occurred in 0.5 to 1 hr. There appeared to be a brief lag before rapid absorption. Because of the rapid absorption with resulting high serum levels, daily doses should be divided. Serum concentration/time curves were best fitted by the two-compartment open model. The apparent t1/2 of the distribution phase was 1.28 +/- 0.44 hr and the t1/2 of the disposition phase was 40.8 +/- 9.96 hr. Serum concentrations rose after meals. Whole body apparent volume of distribution (VB/F) was 1.63 +/- 0.24 L/kg. Total plasma clearance was 34.4 +/- 7.2 ml/min, which is greater than clearance levels for desmethyldiazepam in normals and reflects the greater hepatic metabolism which occurs in treated epileptics. The discrepancy illustrates the hazards of extrapolating data collected in normals to patients with multiple drug exposures.

Adult↗