An outbreak of severe iodine-deficiency goitre in a sheep flock in north-east Victoria.

BACKGROUND: Several outbreaks of goitre, considered to be related to iodine deficiency, occurred in sheep flocks throughout Victoria in 2010. OBJECTIVE: We describe one outbreak in Merino-Border Leicester-cross ewes and their lambs in north-east Victoria that appeared to be associated with increased rainfall and pasture growth, particularly during the preceding summer and autumn. RESULTS: The outbreak was characterised by a four-fold increase in neonatal lamb deaths and goitre, alopecia and poor skeletal development in the lambs. Most cases occurred in lambs born to 2-year-old crossbred ewes that had grazed long, lush perennial pastures throughout their entire pregnancy, whereas few cases occurred in mature crossbred or Merino ewes that had grazed shorter, annual pastures on hill country for 3 weeks in late pregnancy but were otherwise managed similarly. CONCLUSION: Existing recommendations for south-eastern Australia are that only spring-lambing ewes in iodine-deficient areas require iodine supplementation to prevent goitre in years with high autumn-winter rainfall. Aspects of this outbreak suggest that ewes lambing at other times of the year and grazing abundant pasture for prolonged periods may also require supplementation to prevent goitre, even if autumn-winter rainfall does not exceed previously established thresholds.

Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial.

CONTEXT: Insomnia is a prevalent health complaint associated with daytime impairments, reduced quality of life, and increased health-care costs. Although it is often self-treated with herbal and dietary supplements or with over-the-counter sleep aids, there is still little evidence on the efficacy and safety of those products. OBJECTIVE: To evaluate the efficacy and safety of a valerian-hops combination and diphenhydramine for the treatment of mild insomnia. DESIGN AND SETTING: Multicenter, randomized, placebo-controlled, parallel-group study conducted in 9 sleep disorders centers throughout the United States. PATIENTS: A total of 184 adults (110 women, 74 men; mean age of 44.3 years) with mild insomnia. INTERVENTIONS: (1) Two nightly tablets of standardized extracts of a valerian (187-mg native extracts; 5-8:1, methanol 45% m/m) and hops (41.9-mg native extracts; 7-10:1, methanol 45% m/m) combination for 28 days (n = 59), (2) placebo for 28 days (n = 65), or (3) 2 tablets of diphenhydramine (25 mg) for 14 days followed by placebo for 14 days (n = 60). OUTCOME MEASURES: Sleep parameters measured by daily diaries and polysomnography, clinical outcome ratings from patients and physicians, and quality of life measures. RESULTS: Modest improvements of subjective sleep parameters were obtained with both the valerian-hops combination and diphenhydramine, but few group comparisons with placebo reached statistical significance. Valerian produced slightly greater, though nonsignificant, reductions of sleep latency relative to placebo and diphenhydramine at the end of 14 days of treatment and greater reductions than placebo at the end of 28 days of treatment. Diphenhydramine produced significantly greater increases in sleep efficiency and a trend for increased total sleep time relative to placebo during the first 14 days of treatment. There was no significant group difference on any of the sleep continuity variables measured by polysomnography. In addition, there was no alteration of sleep stages 3-4 and rapid eye movement sleep with any of the treatments. Patients in the valerian and diphenhydramine groups rated their insomnia severity lower relative to placebo at the end of 14 days of treatment. Quality of life (Physical component) was significantly more improved in the valerian-hops group relative to the placebo group at the end of 28 days. There were no significant residual effects and no serious adverse events with either valerian or diphenhydramine and no rebound insomnia following their discontinuation. CONCLUSIONS: The findings show a modest hypnotic effect for a valerian-hops combination and diphenhydramine relative to placebo. Sleep improvements with a valerian-hops combination are associated with improved quality of life. Both treatments appear safe and did not produce rebound insomnia upon discontinuation during this study. Overall, these findings indicate that a valerian-hops combination and diphenhydramine might be useful adjuncts in the treatment of mild insomnia.

The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead.

BACKGROUND: Thousands of children, especially poor children living in deteriorated urban housing, are exposed to enough lead to produce cognitive impairment. It is not known whether treatment to reduce blood lead levels prevents or reduces such impairment. METHODS: We enrolled 780 children with blood lead levels of 20 to 44 microg per deciliter (1.0 to 2.1 micromol per liter) in a randomized, placebo-controlled, double-blind trial of up to three 26-day courses of treatment with succimer, a lead chelator that is administered orally. The children lived in deteriorating inner-city housing and were 12 to 33 months of age at enrollment; 77 percent were black, and 5 percent were Hispanic. Follow-up included tests of cognitive, motor, behavioral, and neuropsychological function over a period of 36 months. RESULTS: During the first six months of the trial, the mean blood lead level in the children given succimer was 4.5 microg per deciliter (0.2 micromol per liter) lower than the mean level in the children given placebo (95 percent confidence interval, 3.7 to 5.3 microg per deciliter [0.2 to 0.3 micromol per liter]). At 36 months of follow-up, the mean IQ score of children given succimer was 1 point lower than that of children given placebo, and the behavior of children given succimer was slightly worse as rated by a parent. However, the children given succimer scored slightly better on the Developmental Neuropsychological Assessment, a battery of tests designed to measure neuropsychological deficits thought to interfere with learning. All these differences were small, and none were statistically significant. CONCLUSIONS: Treatment with succimer lowered blood lead levels but did not improve scores on tests of cognition, behavior, or neuropsychological function in children with blood lead levels below 45 microg per deciliter. Since succimer is as effective as any lead chelator currently available, chelation therapy is not indicated for children with these blood lead levels.

Chemiluminescent detection of sequential DNA hybridizations to high-density, filter-arrayed cDNA libraries: a subtraction method for novel gene discovery.

A chemiluminescent approach for sequential DNA hybridizations to high-density filter arrays of cDNAs, using a biotin-based random priming method followed by a streptavidin/alkaline phosphatase/CDP-Star detection protocol, is presented. The method has been applied to the Brugia malayi genome project, wherein cDNA libraries, cosmid and bacterial artificial chromosome (BAC) libraries have been gridded at high density onto nylon filters for subsequent analysis by hybridization. Individual probes and pools of rRNA probes, ribosomal protein probes and expressed sequence tag probes show correct specificity and high signal-to-noise ratios even after ten rounds of hybridization, detection, stripping of the probes from the membranes and rehybridization with additional probe sets. This approach provides a subtraction method that leads to a reduction in redundant DNA sequencing, thus increasing the rate of novel gene discovery. The method is also applicable for detecting target sequences, which are present in one or only a few copies per cell; it has proven useful for physical mapping of BAC and cosmid high-density filter arrays, wherein multiple probes have been hybridized at one time (multiplexed) and subsequently "deplexed" into individual components for specific probe localizations.

Recall of a lead-contaminated vitamin and mineral supplement in a clinical trial.

PURPOSE: The Treatment of Lead-exposed Children (TLC) trial tested whether developmental outcome differed between children treated for lead poisoning with succimer or placebo. On 7 July 1997, TLC was informed that the vitamin and mineral supplements it gave to all children were contaminated with about 35 microg of lead per tablet. METHODS: TLC recalled the contaminated supplements and measured the children's exposure. RESULTS: The families of 96% of the children were contacted with 30 days. Among the 571 children to whom the contaminated supplements were dispensed, the mean increase in blood lead was 0.06+/-0.01 micromol/L (1.2+/-0.2 microg/dL); among 78 children to whom they were not, it was 0.09+/-0.03 micromol/L (1.8+/-0.7 microg/dL). There was no evidence of a dose-response relation between estimated supplement consumption and increase in blood lead concentration. CONCLUSIONS: The children's blood lead concentrations were not detectably affected by the contamination. Since the association of cognitive delay with lead exposure is best described for blood lead, we believe that the trial's inference about the effect of drug therapy on lead induced cognitive delay should be unaffected.

Alternative splicing produces a divergent cytoplasmic tail in the human endothelial thromboxane A2 receptor.

Thromboxane A2 (TxA2) causes contraction of vascular smooth muscle and aggregation of platelets; paradoxically, it also induces formation of the vasodilator and antiaggregant prostacyclin by human endothelium. To determine if the molecular structure of the endothelial TxA2 receptor differs from that of the previously characterized receptor from placenta, we isolated a putative TxA2 receptor cDNA from a human endothelial library. The predicted amino acid sequence revealed a structure of 369 amino acids, in which a novel cytoplasmic tail replaced the carboxyl-terminal portion of the previously characterized TxA2 receptor; this divergence in cytoplasmic domains resulted from the nonsplicing of a potential intron in the placenta TxA2 receptor. Northern hybridization reveals that the expression of the TxA2 receptor in endothelial RNA decreases 6-fold following stimulation with an endoperoxide analog. Polymerase chain reaction using oligonucleotide primers specific to each cytoplasmic domain revealed that only the novel receptor was expressed in endothelium, while both receptors were expressed in placenta. Overexpression of the endothelial TxA2 receptor cDNA in Chinese hamster ovary cells conferred the ability to bind a known receptor antagonist and mobilize Ca2+ in response to TxA2 mimetics. This finding of a new TxA2 receptor in endothelium suggests that a family of these receptors may result from alternative splicing of the cytoplasmic (carboxyl) tail.

Differences in the mix of patients among medical specialties and systems of care. Results from the medical outcomes study.

OBJECTIVE: To determine differences in the mix of patients among medical specialties and among organizational systems of care. STUDY DESIGN: Cross-sectional analysis of 20,158 adults (greater than or equal to 18 years of age) who visited providers' offices during 9-day screening periods in 1986. Patient and physician information was obtained by self-administered, standardized questionnaires. SETTING: Offices of 349 physicians practicing family medicine, internal medicine, endocrinology, and cardiology within health maintenance organizations, large multispecialty groups, and solo or small single-specialty group practices in three major US cities. OUTCOME MEASURES: Demographic characteristics, prevalence of chronic disease, disease-specific severity of illness, and functional status and well-being. RESULTS: Among patients with selected physician-reported chronic illnesses (diabetes, hypertension, recent myocardial infarction, or congestive heart failure), increasing levels of severity were associated with decreasing levels of functional status and well-being and with increased hospitalizations, more physician visits, and higher numbers of prescription drugs. Compared with patients of general internists, patients of cardiologists were older (56 vs 47 years, P less than .01), had worse functional status and well-being scores (P less than .01), and carried more chronic diagnoses (mean 1.32 vs 1.02, P less than .01); patients of family practitioners were younger (40 vs 47 years, P less than .01) and more functional (P less than .01), carried fewer chronic diagnoses (0.70 vs 1.02, P less than .01), and (among diabetic patients only) had lower disease-specific severity scores (2.06 vs 2.30 on a five-point scale, P less than .01). Compared with patients in health maintenance organizations, patients visiting solo practitioners under fee-for-service payment were older (50 vs 45 years, P less than .01) and sicker (had worse physical functioning) and had a higher mean number of chronic diagnoses (1.10 vs 0.93, P less than .01). CONCLUSION: Patient mix is related to utilization and differs significantly across medical specialties and systems of care. These differences must be taken into account when interpreting variations in utilization and outcomes across specialties and systems, and when considering alternative policies for payment.

The effect of radiation therapy and hyperthermia on a human prostatic carcinoma cell line grown in athymic nude mice.

The effect of radiation and/or hyperthermia on a human prostatic carcinoma xenograft in athymic nude mice was investigated. A human prostate carcinoma subline (1-LN-PC-3-1A) was inoculated subcutaneously in the thigh of male athymic nude mice. When tumors reached a size of approximately 200 mm.3, they were treated with either radiation (X) or hyperthermia (H) alone, or in combination (X + H). In the combined treatment, hyperthermia was delivered immediately after radiation exposure. Comparison of the time required to reach twice the tumor volume observed at the time of treatment was used to define therapeutic impact on tumor growth. The combined treatment resulted in median tumor volume doubling time of 35.5 days, compared to 18 days and 25.5 days, respectively, for hyperthermia or radiation alone. Analysis of tumor doubling time using a proportional hazards regression indicates that under the conditions of this experiment, the effect of radiation and hyperthermia for 1-LN-PC-3-1A tumors is additive. The impact of this treatment regimen in the management of prostatic cancer requires further investigation.

The effect of hyperthermia on human prostatic carcinoma cell lines: evaluation in vitro.

The effect of hyperthermia on established human prostate carcinoma cell lines (PC-3, DU-145) and related sublines (1-LN, 125-1L) was investigated in vitro. Cells were exposed to heat treatment at 43C or 37C for varying time intervals, (one hr or two hrs) and cell survival was evaluated by the colony formation assay and by measurement of cellular growth rate. While one hr exposure at 43C did show a mean inhibition of colony formation, ranging from 29 to 41%, a statistically significant increase in inhibition rate (p less than 0.001) was observed at two hr exposure, ranging from 57 to 92%. This study is a report of the cytotoxic effect of hyperthermia on established human prostatic tumor cell lines. These in vitro results indicate that hyperthermia may become a potentially useful form of adjunctive therapy for local control of prostatic cancer. However, the temperature and exposure time may have an important impact on cell kill when this new modality for cancer treatment is proposed for a clinical trial.

Cytoplasmic Mg2+ concentration in platelets: implications for determination of Ca2+ with aequorin.

The concentration of cytoplasmic ionized Mg2+ ([Mg2+]i) varies considerably among different cell types. It has not been measured in platelets. Incorrect estimates of this value could markedly affect many intracellular investigations, including calibration of measurements of platelet cytoplasmic ionized Ca2+ concentration ([Ca2+]i) with the photoprotein aequorin and other Ca2+-sensitive probes. [Mg2+]i was measured in washed, gel-filtered human platelets suspended in modified Tyrode buffer by two methods: 31P-nuclear magnetic resonance (NMR) spectroscopy of intact platelets and null-point titration in platelets selectively permeabilized with digitonin. The 31P-NMR spectra demonstrated that the [Mg2+]i, as calculated from the chemical shift values of ATP resonances, was 0.23 +/- 0.02 (SD) mM in unstimulated platelets. The mean [Mg2+]i as determined by null-point titration was 0.3 +/- 0.1 mM (range: 0.1-0.6 mM). When this [Mg2+]i value was used to construct a Ca2+-calibration curve for aequorin, the indicated [Ca2+]i values in resting and stimulated platelets were lower than those obtained from curves based on previously assumed values for [Mg2+]i (1.0-1.25 mM). This finding largely resolves the discrepancy between resting [Ca2+]i as determined by aequorin or by quin2, fura-2, and indo-1.

The efficacy of the addition of nifedipine in patients with mixed angina compared to patients with classic exertional angina: a multicenter, randomized, double-blind, placebo-controlled clinical trial.

Episodes of myocardial ischemia in patients with coronary artery disease may be due to transient increases in coronary vasomotor tone superimposed on a fixed atherosclerotic obstruction. The purpose of this study was to determine whether identification of the clinical pattern of angina could predict the therapeutic response to the addition of nifedipine to a regimen of beta blockers and/or long-acting nitrates. Seventy-two patients with stable exertional angina were divided into two groups: "classic exertional angina" (17 patients), defined as exertional angina with a stable threshold; and "mixed angina" (55 patients), defined as exertional angina provoked by a variable threshold and/or at least two episodes of rest angina within the 3 months prior to screening. Patients were studied with nifedipine and placebo in a 6-week, double-blind, crossover design that used serial anginal diaries, exercise treadmill tests, and 24-hour ambulatory ECG monitoring. In patients with mixed angina, nifedipine reduced the frequency of angina compared to that during placebo treatment (13.1 vs 9.9 episodes/3 weeks, p less than 0.01) and reduced nitroglycerin consumption (11.7 vs 7.5 tablets/3 weeks, p less than 0.05); while in patients with classic exertional angina, nifedipine had no symptomatic effect (7.9 vs 6.8 anginal episodes/3 weeks, NS; 6.4 vs 5.8 nitroglycerin tablets/3 weeks, NS). Patients in both groups experienced a significant decrease in the manifestations of ischemia during exercise testing. Patients with mixed angina experienced a reduction in the daily frequency of painful episodes of ST segment depression during nifedipine treatment compared to placebo (0.6 vs 0.2 episodes, p less than 0.05), but there was no effect on the frequency of episodes of silent ischemia (4.2 vs 3.4 episodes, NS). In patients with classic exertional angina, the addition of nifedipine had no effect on any measure of ambulatory ischemia. We conclude that patients with mixed angina are more likely to benefit symptomatically from the addition of nifedipine therapy than patients with classic exertional angina. The lack of a consistently preferential response to nifedipine in patients with mixed angina, however, suggests that episodic coronary vasoconstriction may not be the only mechanism responsible for ischemia in these patients, and/or that nifedipine may not necessarily provide additional therapeutic benefit beyond that conferred by a regimen of beta blockers and/or nitrates.

Clinical and laboratory studies with cefaclor: efficacy in skin and soft tissue infections.

Clinically relevant, recent isolates of common Gram-positive pathogens were examined for their in vitro susceptibility to cefaclor. Group A streptococci and pneumococci were uniformly sensitive (MICs 0.06--0.12 micrograms/ml) to both cefaclor and cephalothin. Cefaclor was 5--10-fold less active than cephalothin against group B streptococci. S. aureus strains were uniformly more susceptible to cephalothin than to cefaclor, but among isolates from children, almost all were sensitive to the latter drug. In clinical studies of patients with skin and soft tissue infections, cefaclor proved effective. Over 90% of patients with staphylococcal bullous impetigo, streptococcal and mixed streptococcal-staphylococcal forms of pyoderma were cleared after 7--10 day courses of treatment. In addition, twice-daily therapy, examined more recently, proved as effective in these forms of infection as did the conventional dose schedule. No significant adverse reactions were noted. Cefaclor appears to be an effective orally absorbed cephalosporin for common skin and soft tissue infections.

Survey of microorganism for the production of extracellular phytase.

A culture enrichment technique was used to isolate phytase-producing microorganisms. Also, microorganisms from various culture collections were tested for their phytase-producing ability. A number of the Aspergillus niger group produced extracellular phytase which dephosphorylated calcium phytate in acidic solution. A soil isolate, A. ficuum NRRL 3135, produced the most active phytase in a cornstarch-based medium. Production of phytase was strongly repressed by inorganic phosphates and required a high carbon to phosphorus ratio in the medium.