Pharmacokinetics and drying time of testosterone 2% gel in men with hypogonadism: a multicenter, open-label, single-arm trial.

The objective of this study was to assess drying time after application of testosterone 2% gel (Fortesta Gel, Endo Pharmaceuticals), time needed for serum total testosterone (TT) to reach the eugonadal range (⩾ 300 ng dl(-1)), and time to steady-state serum TT. Thirty-four men with primary or secondary hypogonadism were enrolled in the study; 31 men were included in the pharmacokinetics (PKs) population. Testosterone 2% gel (40 mg) was applied once daily in the morning to the front and inner thighs for 14 days. Median gel drying time was 2.4 min (95% confidence interval (CI), 1.7-3.4 min; n = 31). Serum TT concentrations reached the target eugonadal range with a median time of 2.9 h (95% CI, 1.9-4.3 h; n = 24). Median time to steady-state serum TT concentration was 1.1 days (95% CI, 0.7-3.4 days; n = 31). Six patients (17.6%; n = 34) reported treatment-related adverse events; all were mild. The results from this 14-day PK study in men with hypogonadism suggest that testosterone 2% gel dries, on average, in <3 min after application and that testosterone 2% gel rapidly reaches the target eugonadal range and attains steady-state serum TT concentrations in about 1 day.

The effect of ketamine/xylazine and carbon dioxide on plasma luteinizing hormone releasing hormone and testosterone concentrations in the male Norway rat.

The effect of a commonly used anaesthetic, ketamine/xylazine and/or carbon dioxide (CO(2)) on plasma luteinizing hormone releasing hormone (LHRH) and testosterone concentrations was determined in male Sprague-Dawley rats. These values were compared with values obtained from pre-anaesthetic control samples. Ketamine/xylazine treatment did not significantly affect testosterone concentrations. In contrast, LHRH started to decrease one hour after ketamine/xylazine administration and continued to significantly decrease after 24 h. In addition, in the CO(2) euthanasia-only group, LHRH concentrations were also significantly decreased. These results suggest that ketamine/xylazine anaesthesia followed by CO(2) euthanasia 24 h later is exerting a significant effect on LHRH concentrations 24 h after anaesthetizing, while only having a slight effect on testosterone, and that CO(2) is exerting an immediate significant effect on LHRH. In conclusion, LHRH analysis should be avoided after ketamine/xylazine anaesthesia and CO(2) euthanasia.

Graveyard gleanings: socio-economic, geographical and gender inequalities in health at Tynemouth, UK, 1833-1853.

BACKGROUND: Inequalities in the health of different sections of populations are well recognized but were difficult to demonstrate before death registration was introduced in 1837. In the early years of civil registration, geographical and sex differences in mortality were clearly recognized, as were occupational hazards, but socio-economic differences were barely explored in the Annual Reports of the Registrar General. Tynemouth General Cemetery (TGC) was established in 1833 as a private cemetery with unusually detailed records. METHODS: A total of 2610 records from 1833 to 1853 were analysed. Variables used included sex, dates of death and burial, age at death, depth of burial, cause of death, place of residence and occupation. As no denominator population is available, median age at death has been used for comparisons. RESULTS: Depth of burial relates well to a hierarchy of specific occupations and so is used as a marker for socio-economic status. The median age for the burials was 12 years. People of higher socio-economic status survived longer. The people of North Shields, and especially the males, died younger than those from surrounding areas. Males outnumbered females in most age groups. CONCLUSION: Socio-economic, geographical and gender inequalities in mortality are clearly demonstrable in the early nineteenth century, without the use of registration data.

Monoaminergic substrates underlying cocaine-induced enhancement of somatosensory-evoked discharges in rat barrel field cortical neurons.

Previously, we have described a selective potentiating effect of systemically administered cocaine (0.25-1.0 mg/kg i.v.) on long-latency excitatory responses (E2) of rat "barrel field" cortical neurons to mystacial vibrissae stimulation. The rat trigeminal system receives both norepinephrine (NE) and serotonin (5-HT)-containing afferents, but only minimal input from dopaminergic sources. The goal of the present study was to determine which of these monoamine systems was responsible for the previously observed facilitating action of cocaine on E2 responses of barrel field cortical neurons. Two approaches were used: 1) evaluation of cocaine effects on cortical neuron responses to whisker stimulation in NE- or 5-HT-depleted animals and 2) assessment of the effects of selective monoamine uptake blockers on cortical neuron responses to whisker deflection. Extracellular recordings were obtained from spontaneously active neurons in the barrel field cortex of halothane-anesthetized rats. Spontaneous activity and cellular responses to mechanical displacement of a single whisker were monitored before and after systemic (i.v.) administration of either cocaine or one of the following selective uptake blockers, fluoxetine (5-HT), desipramine (NE) and GBR12909 (dopamine). Cocaine-induced increases in the E2 response were observed in N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4, noradrenergic neurotoxin)-treated animals, but were reduced or abolished in p-chlorophenylalanine-treated (5-HT depletion) rats. Fluoxetine and desipramine, but not GBR12909, produced cocaine-like potentiation of the E2 response to whisker stimulation. These results point to a 5-HT-dependent mechanism as the substrate underlying cocaine's facilitating effects on long-latency somatosensory cortical neuron responses to receptive field stimulation.

Focal increases in [Ca2+]i may account for apparent low Ca2+ sensitivity in swine carotid artery.

Estimates of [Ca2+]i sensitivity in intact smooth muscle are frequently obtained by measuring [Ca2+]i with indicators such as aequorin or Fura-2. We investigated whether focal increases in [Ca2+]i could impair such measures of [Ca2+]i sensitivity. Stimulation of swine carotid artery with 10 microM histamine increased aequorin estimated [Ca2+]i, Fura-2 estimated [Ca2+]i and Ca2+ sensitivity without significantly altering the aequorin/Fura-2 ratio (an estimate of [Ca2+]i homogeneity). Subsequent inhibition of Na+/Ca2+ exchange by replacement of Na+ in the PSS with choline+ significantly increased aequorin-estimated [Ca2+]i but only minimally increased Fura-2 estimated [Ca2+]i, myosin light chain (MLC) phosphorylation and force. This resulted in a large increase in the aequorin/Fura-2 ratio, suggesting an increase in [Ca2+] inhomogeneity. Addition of 100 microM histamine to tissues in the choline+ buffer initially increased both aequorin and Fura-2 estimated [Ca2+]i, but after 10 min exposure both of the [Ca2+]i estimates declined to pre-histamine levels. Histamine addition significantly increased MLC phosphorylation and force, indicating increased Ca2+ sensitivity, but the aequorin/Fura-2 ratio remained elevated and unchanged from pre-histamine values. These data show that under certain conditions, aequorin and Fura-2 can yield widely differing estimates of [Ca2+]i and thus can cause misleading assessments of Ca2+ sensitization mechanisms. These discrepancies may arise from inhomogeneous or focal increases in [Ca2+]i which can be evaluated with the aequorin/Fura-2 ratio.

The role of GABAA receptors in the subsensitivity of Purkinje neurons to GABA in genetic epilepsy prone rats.

The GABA receptor subtype mediating responses of cerebellar Purkinje neurons to the neurotransmitter was evaluated and compared in GEPR-9 vs. nonepileptic, genetic control GEPR-NE rats. Quantitative analysis of responses to microiontophoretically applied GABA, muscimol and baclofen indicated that the inhibitory action of GABA on cerebellar Purkinje neurons was mediated by GABAA receptors since muscimol produced responses similar to those of GABA and baclofen was without substantial electrophysiological action. In addition, Purkinje neurons in GEPR-9 animals showed a similar reduced sensitivity to both GABA and muscimol. Radioligand binding studies using the GABAA receptor selective ligand, [3H]muscimol, and the benzodiazepine receptor selective ligand, [3H]flunitrazepam, were conducted on cerebellar and cortical homogenates from GEPR 9, GEPR-NE and Sprague-Dawley rats. No differences in the Kd or Bmax for these ligands among the three groups studied were observed. The lack of significant changes in the Kd and Bmax for these two ligands in the cerebellum suggests that the mechanism for the observed subsensitivity to GABA in the GEPR 9 rat lies beyond the level of the receptor, perhaps at the signal transduction process for GABA mediated inhibitory responses.

Genistein, a tyrosine kinase inhibitor, reduces Ca2+ mobilization in swine carotid media.

DiSalvo and colleagues (Biochem. Biophys. Res. Commun. 190: 968-974, 1993) found that tyrosine kinase inhibitors reduced force at constant Ca2+ concentrations in permeabilized mesenteric arterioles. These data suggest that tyrosine kinase activation could regulate Ca2+ sensitivity in intact vascular smooth muscle. We tested this hypothesis by examining the effects of the tyrosine kinase inhibitor genistein on intracellular Ca2+ concentration ([Ca2+]i), myosin regulatory light chain (MRLC) phosphorylation, and isometric stress in intact swine carotid media tissues. Pretreatment with 30 microM genistein attenuated histamine-induced increases in [Ca2+]i (estimated using the photoprotein aequorin), MRLC phosphorylation, and stress. The genistein-dependent decrease in [Ca2+]i quantitatively accounted for the decrease in MRLC phosphorylation and stress. There was no measurable change in the Ca2+ dependence of MRLC phosphorylation or the dependence of force on MRLC phosphorylation. Genistein inhibited contractions independently of the source of activator Ca2+. These data suggest that tyrosine kinase(s) may influence force development in the intact swine carotid media by altering [Ca2+]i rather than modulating the Ca2+ sensitivity of MRLC phosphorylation.

Partner notification for HIV infection in the United Kingdom: a look back on seven years experience in Newcastle upon Tyne.

OBJECTIVE: To examine the outcome of partner notification for HIV infection. DESIGN: Retrospective analysis of medical, health adviser and counsellor records. SETTING: Teaching hospital, Newcastle upon Tyne. PATIENTS: All newly diagnosed cases of human immunodeficiency virus (HIV) infection and their sexual partners. MAIN OUTCOME MEASURES: Attendance of contact at genitourinary medicine clinics for counselling and testing. Seropositivity rate of people attending as a result of partner notification. RESULTS: Of the 80 partners attending as a result of partner notification 79 were tested. Twenty-five of these (31.6%) were seropositive. This was 21.9% of our newly diagnosed caseload. Seventy-five attended following patient referral and five as a result of provider referral. Discrepancies between districts in policies of provider referral prevented two partners being notified. CONCLUSIONS: Partner notification is an effective method of ensuring that people with a very high risk of HIV infection have access to counselling and medical care. Complete integration of notification services throughout the UK is required.

Sensitivity of cerebellar Purkinje neurons to neurotransmitters in genetically epileptic rats.

Epilepsy is a state of neuronal hyperactivity which may be caused by an altered relationship between inhibitory and excitatory influences on neurons. We have conducted experiments using microiontophoresis with in situ extracellular recording of anesthetized rat cerebellar Purkinje neuron activity to determine the sensitivity of these neurons to neurotransmitters in a genetic model of epilepsy. Quantitative evaluations of agonist-induced changes in activity were carried out by using poststimulus time histograms. Current-response curves were generated and linear regression analysis was performed to evaluate changes in responsiveness and sensitivity between control and genetically epilepsy-prone-9 rats. The current required to produce 50% inhibition of activity by GABA was 2.6-fold higher in the genetically epilepsy-prone-9 rats compared to control. In contrast, the amount of current required to produce 50% inhibition by norepinephrine was not significantly different between groups. There also was no significant change in cerebellar neuron sensitivity to the excitatory transmitter, glutamate. The lack of an alteration in sensitivity and responsiveness to norepinephrine or glutamate suggests that the hyperexcitability of neurons may be associated with a specific subsensitivity of the GABAergic system. Such a specific subsensitivity to gamma-aminobutyric acid would, therefore, yield a more excitable state of the neuron and may contribute to the development of the hyperactivity observed in epilepsy.