GHTD-amide: a naturally occurring beta cell-derived peptide with hypoglycemic activity.

In the early 1970s, a peptide fraction with insulin potentiating activity was purified from human urine but the identity and origins of the active constituent remained unknown. Here we identify the active component and characterize its origins. The active peptide was identified as an alpha amidated tetrapeptide with the sequence GHTD-amide. The peptide was synthesized and tested for stimulation of glycogen synthesis and insulin potentiation by insulin tolerance testing in insulin-deficient rats, which confirmed GHTD-amide as the active peptide. Tissue localization using a peptide-specific anti-serum and epifluorescent and confocal microscopy showed decoration of pancreatic islets but not other tissues. Confocal microscopy revealed co-localization with insulin and immunogold and electron microscopy showed localization to dense core secretory granules. Consistent with these observations GHTD-amide was found in media conditioned by MIN6 islet beta cells. Sequence database searching found no annotated protein in the human proteome encoding a potential precursor for GHTD-amide. We conclude that the insulin potentiating activity originally described in human urine is attributable to the tetrapeptide GHTD-amide. GHTD-amide is a novel peptide produced by pancreatic beta cells and no precursor protein is present in the annotated human proteome. Stimulation of glycogen synthesis and co-localization with insulin in beta cells suggest that GHTD-amide may play a role in glucose homeostasis by enhancing insulin action and glucose storage in tissues.

Intrinsa fails to impress FDA advisory panel.

Female sexual dysfunction (FSD) as a discipline of medicine is not fully recognized by many authorities. Definitions are controversial and data are lacking, yet the public clamors for treatment. The lay press has capitalized on this provocative women's issue, seizing on the public's insatiable desire for new, potentially 'sexy' therapeutic options in this area. Thus, the time was ripe for a potential FSD drug. The sexual medicine community watched with interest as the Food and Drug Administration (FDA) considered the Proctor & Gamble new drug application for Intrinsa (a testosterone patch for hypoactive sexual desire disorder for women who had undergone surgical castration via bilateral oophorectomy). In spite of quality scientific data, Intrinsa was not approved. With this issue of IJIR, a new column, entitled, 'perspective' is provided to the readership. Perspective is an invited opinion or viewpoint that aims to advise and update the medical community on a pertinent or current topic in sexual medicine. Dr Richard Spark, a noted endocrinologist, presents the first of three invited 'perspectives' on Intrinsa and the FDA decision. Dr Spark has authored several manuscripts on the topic of FSD.

Serum androgen levels in healthy premenopausal women with and without sexual dysfunction: Part A. Serum androgen levels in women aged 20-49 years with no complaints of sexual dysfunction.

Androgen insufficiency is a recognized cause of sexual dysfunction in men and women. Age-related decrements in adrenal and gonadal androgen levels also occur naturally in both sexes. At present, it is unclear if a woman's low serum androgen level is a reflection of the expected normal age-related decline or indicative of an underlying androgen-deficient state. We studied premenopausal women with no complaints of sexual dysfunction to help define a normal female androgen profile. In all, 60 healthy, normally menstruating women, ages 20-49 y, were studied. The Abbreviated Sexual Function Questionnaire was administered along with a detailed interview. Radioimmunoassay measurements of morning serum testosterone (T), free testosterone (fT), dehydroepiandrosterone-sulfate (DHEAS), sex hormone-binding globulin (SHBG), and free androgen index (FAI) were measured during days 8-15 of the menstrual cycle. In women 20-49 y old without complaints of sexual dysfunction, serum androgen levels exhibit a progressive stepwise decline. Comparing values obtained in women age 20-29 y to those obtained in women 40-49 y, specific hormone decrements were DHEAS 195.6-140.4 microg/dl, serum T 51.5-33.7 ng/dl, fT 1.51-1.03 pg/ml. SHBG did not change significantly in women in this age group. The FAI reflected the age-related decrease in female androgen levels. The framework for the development of a female androgen profile in women with no complaints of sexual dysfunction has been established, and an age-related decrease in testosterone and its adrenal precursor, DHEAS, has been demonstrated. The FAI mirrors these decreases and its usefulness in clinical practice is confirmed. A precipitous decline in all androgens occurs after the decade of the 20s, yet SHBG does not show a significant change throughout the premenopausal years.

Serum androgen levels in healthy premenopausal women with and without sexual dysfunction: Part B: Reduced serum androgen levels in healthy premenopausal women with complaints of sexual dysfunction.

Androgen insufficiency has been associated with decreased libido and arousal in postmenopausal women, but rarely has been evaluated in healthy premenopausal women. In all, 32 healthy premenopausal women were enrolled in this study, 18 with one or more complaints of sexual dysfunction and 14 without. Assays of ovarian and adrenal androgens were measured before and after ACTH stimulation. The women with complaints of sexual dysfunction had significantly lower adrenal androgens than did the control women. There were no differences in the basal ovarian androgens or cortisol levels. After ACTH, both groups stimulated cortisol as well as adrenal and ovarian androgens. In conclusion, premenopausal women with complaints of sexual dysfunction had lower adrenal androgen precursors and testosterone than age-matched control women without such complaints. Further study is required to determine how lower adrenal androgens contribute to female sexual dysfunction.

Opposing effects of low and high-dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice.

Clozapine is a potent atypical neuroleptic or antipsychotic agent used to relieve symptoms of early-diagnosed schizophrenia. Aside from well-described dopamine and serotonin receptor blockade effects, clozapine may also be neuroprotective through its modulation of the p75 neurotrophin receptor (p75(NTR)) and superoxide dismutase 1 (SOD1) expression. The death-signalling activities of both p75(NTR) and mutant SOD1 are implicated in motor neuron degeneration in humans and transgenic mice with amyotrophic lateral sclerosis (ALS). We therefore investigated the effects of clozapine in cell culture and mouse models of ALS. Clozapine dose-dependently inhibited full-length and cleaved p75(NTR) but not SOD1 protein expression in the motor neuron-like (NSC-34) cell line. Furthermore, low concentrations of clozapine protected NSC-34 cells from paraquat-mediated superoxide toxicity, nerve growth factor (NGF)-induced death signalling, and serum deprivation, whereas high concentrations potentiated death. Systemic thrice-weekly administration of low and high-dose clozapine to mutant superoxide dismutase 1 (SOD1(G93A)) mice produced differential effects on disease onset and survival. Low-dose treatment was associated with delayed locomotor impairment and death, compared to high-dose clozapine, which accelerated paralysis and mortality (P < 0.05). Increased death was not attributable to toxicity, as clozapine-induced agranulocytosis was not detected from blood analysis. High-dose clozapine, however, produced extrapyramidal symptoms in mice manifest by hindlimb rigidity, despite reducing spinal cord p75(NTR) levels overall. These results suggest that although clozapine may exert p75(NTR)-mediated neuroprotective activity in vitro, its profound antagonistic effects on dopaminergic and serotonergic systems in vivo at high doses may exacerbate the phenotype of transgenic ALS mice.

Yohimbine treatment of organic erectile dysfunction in a dose-escalation trial.

Yohimbine has had questionable effects in men with organic erectile dysfunction. We conducted this study to better define the population of men responsive to yohimbine, because tobacco was thought to affect a regimen of yohimbine more than other risk factors. We measured nocturnal penile tumescence with the RigiScan monitor, hormone profiles, answers to the Florida Sexual Health Questionnaire, and clinical responses at baseline and after two different doses of yohimbine in 18 nonsmoking men with erectile dysfunction. Of the 18 men, nine (50%) were successful in completing intercourse in more than 75% of attempts. The yohimbine responders were men with less severe erectile dysfunction as manifested by improved increased rigidity on RigiScan testing, higher Florida Sexual Health Questionnaire scores, and slightly higher levels of serum testosterone. Yohimbine is an effective therapy to treat organic erectile dysfunction in some men with erectile dysfunction.

An epidemic of dengue 3 in far north Queensland, 1997-1999.

OBJECTIVES: To describe an epidemic of dengue type 3 that occurred in far north Queensland in 1997-1999 and its influence on the further development of dengue prevention and control strategies. DESIGN: Epidemiological and laboratory investigation of cases, entomological surveys and phylogenetic analysis of dengue virus isolates. MAIN OUTCOME MEASURES: Numbers and characteristics of confirmed cases; Breteau Index (BI; number of containers breeding Aedes aegypti per 100 premises); effect of control measures on mosquito populations; genetic homology of epidemic virus with other dengue virus isolates. RESULTS: The epidemic lasted 70 weeks and comprised 498 confirmed cases in three towns (Cairns, Port Douglas and Mossman); 101 patients (20%) were admitted to hospital. Median interval between symptom onset and notification was seven days (range, 0-53 days), and cumulative duration of viraemia of public health significance was 2,072 days. BIs in affected areas were high, particularly in Mossman (45) and Port Douglas (31). Control measures significantly reduced mosquito populations (assessed as number of ovitraps containing Ae. aegypti eggs and mean number of eggs per trap [P< 0.05 for both]). However, transmission persisted in several foci, in part due to undetected waterfilled containers breeding Ae. aegypti. The epidemic virus belonged to serotype 3; phylogenetic analysis suggested it was imported from Thailand. CONCLUSIONS: The epidemic had greater morbidity than other recent Queensland epidemics of dengue and was harder to control, necessitating substantial revision of the Dengue Fever Management Plan for North Queensland. The epidemic's severity supports the hypothesis that dengue viruses from South East Asia are more virulent than others.

Loxosceles arizonica bite associated with shock.

Envenomation by the brown recluse spider (Loxosceles reclusa) is associated with shock, significant hemolysis, renal insufficiency, and disseminated intravascular coagulation (DIC). Shock has never been associated with envenomation by L arizonica, a related species indigenous to Arizona, southern California, and northwestern Mexico. We report the case of a 13-year-old girl, bitten by a specimen of L arizonica (the spider was identified by an entomologist), in whom shock and a typical cutaneous lesion developed. She did not experience renal insufficiency or disseminated intravascular coagulation. Infectious causes of shock were excluded. She recovered completely with supportive care.

Intractable hypercalcaemia due to parathyroid hormone-related peptide secretion by a carcinoid tumour.

Hypercalcaemia, a common complication of malignancy, may result from either the lytic effect of multiple osseous metastases or the effect of tumour-derived humoral factors. Excessive secretion of parathyroid hormone-related peptide (PTHrP), a major cause of humoral hypercalcaemia of malignancy, has been incriminated as the cause of hypercalcaemia in patients with lung, breast, renal, head and neck and, occasionally, haematological malignancies. Carcinoid tumours, while frequently the source of ectopic hormone secretion, are infrequently associated with hypercalcaemia. We report the case of a 59-year-old woman with fulminant hypercalcaemia due to excessive PTHrP secretion from a hepatic carcinoid and we present the change in her serum PTHrP concentrations during infusion of a somatostatin analogue.

Towards guidelines for survey research in remote Aboriginal communities.

Based on our experience in developing and evaluating community-based health promotion programs in Aboriginal and Torres Strait Islander communities, we offer guidelines to assist nonindigenous health and public policy professionals whose information gathering in these communities includes the use of unstructured interviewing or survey questionnaires. The guidelines primarily apply to research among mainland remote Aboriginal communities, but are placed in a cultural context such that those dealing with Torres Strait Islanders and rural or urban community Aborigines also may benefit from the guidelines. The major aims of these guidelines are to facilitate communication between interviewers and indigenous interviewees and to ensure that interviewing is done with maximum sensitivity to cultural differences and with minimum discomfort to the respondents.

The effect of PTH antagonist BIM-44002 on serum calcium and PTH levels in hypercalcemic hyperparathyroid patients.

BIM-44002, a pure competitive antagonist of parathyroid hormone (PTH), has a high affinity for the PTH/PTHrP receptor in vitro, and can completely inhibit the actions of a PTH agonist in rats in vivo. Toxicology studies in rats and dogs showed BIM-44002 to be devoid of any adverse effects. Therefore we undertook an investigation to evaluate the potential utility of BIM-44002 in lowering elevated serum calcium in three patients with primary hyperparathyroidism. BIM-44002 was administered by continuous intravenous infusion at dosages of 100 microg/hour (370 nmol/hour) for 12 hours, followed by 200 microg/hour for 12 hours, followed by 400 microg/hour for 12 hours. Vital signs and serum ionized and total calcium were monitored hourly and for 3 hours after cessation of the infusion. Blood for PTH determinations was obtained at the same time points. Serum calcium and PTH did not change during and after the infusion of the antagonist. No subject experienced any adverse reactions to the infusion of the antagonist. We conclude that although the PTH antagonist BIM-44002 was effective both in vitro and in vivo in animals, and it was safe in humans, it was not able to lower serum calcium in patients with hyperparathyroidism. Possible reasons for lack of clinical efficacy are discussed.

Serum lipids and modernization in coastal and highland Papua New Guinea.

Previous studies in Melanesians of Papua New Guinea have documented low serum cholesterol concentrations with no age-related rise and a virtual absence of coronary heart disease. However, because of recent reports of the emergence of coronary heart disease in this population, serum lipid concentrations in adults aged > or = 25 years in three coastal (n = 1,489 and three highland (n = 388) village communities at different stages of modernization were examined as part of a survey undertaken in 1991. Total cholesterol concentrations were clearly higher than were levels recorded in earlier studies. Moreover, age-related increases in total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein cholesterol (HDL cholesterol), and triglycerides (in women) were apparent. Mean total cholesterol levels in an urban community with a high risk of diabetes were similar to those observed in Australians, while HDL cholesterol concentrations were lower. Total cholesterol and LDL cholesterol levels were higher in urban coastal and periurban highland subjects than in their rural counterparts. Prevalence of hypercholesterolemia (> or = 5.2 mmol/liter) varied from 16% in rural highlanders to 56% in urban coastal subjects. Sex, age, village, body mass index, fat distribution, glucose intolerance, physical activity, and an index of relative modernity all contributed to variations in cholesterol and triglyceride concentrations. These results show that Papua New Guineans are by no means protected from dyslipidemia and serve warning that, unless effective preventative strategies can be developed, this and similar rapidly developing populations can expect an increasing incidence of coronary heart disease.

Perinatal tuberculosis and its public health impact: a case report.

Tuberculosis was initially unrecognized in a pregnant 26-year-old woman from Mexico. The diagnosis was first considered in this mother 24 days postpartum, when her newborn was admitted in shock with congenital tuberculosis. Had a high index of suspicion for tuberculosis been present during the early course of the patient's care or had she been tested on a routine basis because she was a member of a high-risk group, the continued exposure of 7 family members and the acute exposure of 293 healthcare workers and newborns in three tertiary-care centers could have been minimized or avoided entirely. We wish to emphasize the often elusive features of this diagnostic setting and the public health consequences of delayed recognition resulting in a massive recall effort. Unfortunately, only two thirds of the exposed infants were successfully recalled and skin tested. We identified one skin test conversion in a health-care worker.

Lack of antibodies to glutamic acid decarboxylase in young adults of the high diabetes prevalence Wanigela people of Papua New Guinea.

Antibodies to glutamic acid decarboxylase (anti-GAD) are common in typical insulin-dependent diabetes mellitus, and also identify a sub-group of older persons who are originally misdiagnosed as having non-insulin-dependent disease (NIDDM). The Wanigela people of Papua New Guinea are highly susceptible to diabetes mellitus, with a prevalence of 20.4% in urbanised young adults aged 25-34 years. On the basis of clinical features including the presence of obesity and relatively high insulin concentrations the Wanigelas have NIDDM. To determine whether anti-GAD is present in this high prevalence form of diabetes, and to investigate whether there might be an autoimmune component to the disease, we measured anti-GAD in 93 newly-diagnosed diabetic subjects aged 25-44 years, and in 40 controls with normal glucose tolerance. There was no difference in mean levels of anti-GAD in diabetic subjects and normal controls. Two subjects had borderline elevated anti-GAD levels: one was a normal control, and the other a diabetic. This study shows that anti-GAD is not present in this (and probably other) high prevalence variant of NIDDM. Moreover, the results suggest strongly that diabetes in the Wanigela people is unlikely to have an autoimmune component to its pathogenesis.

Extraordinary prevalence of non-insulin-dependent diabetes mellitus and bimodal plasma glucose distribution in the Wanigela people of Papua New Guinea.

OBJECTIVE: To determine the current prevalence of impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) in Melanesians of three coastal Papua New Guinean communities, to relate this to previous studies, and to investigate plasma glucose distributions in these populations. DESIGN: Cross-sectional survey, using 75 g oral glucose tolerance tests and World Health Organization criteria. SETTING: Rural Papuan villages of Wanigela and Kalo, and Wanigela people of the urban squatter settlement of Koki, Port Moresby. SUBJECTS: All adults aged 25 years or more living in the three communities were eligible, with response rates of 77.2% (Koki), 88.1% (Wanigela) and 72.5% (Kalo). MAIN OUTCOME MEASURES: Prevalence of abnormal glucose tolerance, risk factor levels, fasting and two-hour plasma glucose concentration. RESULTS: Age-standardised prevalence of NIDDM in Koki Wanigelas was 27.5% in men and 33.0% in women; an additional 20.5% of men and 22.0% of women had IGT. Even in the youngest age group (25-34 years), 36.5% of subjects had abnormal glucose tolerance. The overall prevalences of NIDDM and IGT in rural Wanigelas were 11.7% and 17.0% respectively. In Kalo both were uncommon. The prevalences of IGT and NIDDM in Koki had doubled over a 14-year period. The age-standardised prevalence of abnormal glucose tolerance in the Koki Wanigelas is the second highest in the world after the Arizona Pima Indians, and higher than in Micronesian Nauruans, even though the latter are more obese. Both fasting and two-hour glucose concentrations in all age groups in Koki were clearly bimodal, a mixture of two log-normal distributions. CONCLUSIONS: The Wanigela people of Papua New Guinea have an extra-ordinary susceptibility to glucose intolerance which is exposed after adoption of modern lifestyle habits. A "founder effect" may explain the high frequency of a diabetogenic genotype in this population.

Increasing prevalence of NIDDM in the Pacific island population of Western Samoa over a 13-year period.

OBJECTIVE: A survey of noncommunicable diseases (NCD) in the Pacific island population of Western Samoa in 1978 (n = 1,206) documented a relatively high prevalence of non-insulin-dependent diabetes mellitus (NIDDM) and obesity. A follow-up survey was performed in 1991 (n = 1,776) to assess changes in NCD prevalence and risk factor distribution over 13 years. RESEARCH DESIGN AND METHODS: In both surveys, the same representative villages from one urban and two rural areas were studied, and the survey procedure included an oral glucose tolerance test, anthropometric and blood pressure measurements, and physical activity assessment (1991 only). RESULTS: The age-standardized prevalence of NIDDM in 1991 was 9.5 and 13.4% in Apia (urban) for men and women, respectively. In Poutasi (rural), 5.3% of men and 5.6% of women had NIDDM, and in Tuasivi (rural) the prevalence was 7.0 and 7.5% for men and women, respectively. Age, body mass index (BMI), waist-to-hip circumference ratio, physical inactivity, and family history of diabetes all showed independent association with NIDDM and impaired glucose tolerance. Living in Apia (compared with Poutasi) was also associated with NIDDM. Between 1978 and 1991, the age-standardized prevalence of NIDDM in Apia increased from 8.1 to 9.5% in men and 8.2 to 13.4% in women. In Poutasi, a dramatic increase occurred in prevalence from 0.1 to 5.3% in men, but little change in women was noted (5.4 to 5.6%). In Tuasivi, the increases were 2.3 to 7.0% in men and 4.4 to 7.5% in women. In combined survey areas, increases were observed in the age-standardized prevalence of obesity and mean levels of total cholesterol, fasting triglycerides, and uric acid between surveys as well as a reduction in the prevalence of smoking. CONCLUSIONS: This is the first study using standardized methods to show a dramatic increase in the prevalence of NIDDM in a developing Pacific island population, and it indicates the importance of maintaining and expanding preventive programs for NIDDM and related lifestyle diseases in these populations.