Gonadal steroids influence neurophysin II distribution in the forebrain of normal and mutant mice

The distribution of arginine vasopressin-associated neurophysin (neurophysin II) immunoreactivity was investigated in normal and mutant house mice during development and after various gonadal steroid manipulations. During postnatal development of normal mice dense networks of neurophysin II immunoreactivity in the lateral septal nucleus and lateral habenular nucleus appeared earlier in male than in female mice, with an adult pattern of immunoreactivity being attained by 8 weeks and 12 weeks of age, respectively. The neurophysin II immunoreactivity in the male was denser than that in female mice. After gonadectomy of adult normal mice there was a gradual loss of neurophysin II immunoreactivity in the lateral septum and lateral habenula over a period of 15 weeks. In hypogonadal mice, a mutant in which gonadal development is arrested postnatally due to a deficiency in hypothalamic gonadotrophin releasing hormone, no immunoreactive neurophysin II could be detected in the lateral septum or lateral habenula. A pattern of neurophysin II immunoreactivity similar to that in normal control mice was observed in hypogonadal mice which had been implanted for 4 weeks with silicone elastomer capsules containing testosterone or oestradiol-17 beta, but not 5 alpha-dihydrotestosterone or progesterone. Stimulation of gonadal development and endogenous steroid production in hypogonadal mice by third ventricular grafts of preoptic area tissue from normal neonatal animals also produced a normal pattern of neurophysin II immunoreactivity in the lateral septum and lateral habenula. In the androgen-insensitive testicular feminized mouse immunoreactive neurophysin II was undetectable in the lateral septum and lateral habenula. Treatment of testicular feminized mice with oestradiol-17 beta, but not progesterone, produced a normal pattern of neurophysin II immunoreactivity. The main immunohistological findings were confirmed by radioimmunoassay of tissue extracts which showed that the concentration of arginine vasopressin in lateral septum was far greater in normal males than females and was undetectable in hypogonadal mice; no oxytocin could be detected in the septum of normal or hypogonadal mice. These results show that the expression of neurophysin II immunoreactivity in the lateral septum and lateral habenula of the mouse brain is dependent on the presence of aromatizeable androgens or oestrogens.     

Immunoglobulin class-specific antibody response in serum, spleen, lungs, and bronchoalveolar washings after primary and secondary sendai virus infection of germfree mice.

Immunoglobulin class-specific antibodies were measured by a solid-phase radioimmunoassay in serum, bronchoalveolar washings (BAW), lung cell lysates, and spleen cell lysates in germfree mice after intranasal (i.n.) and intraperitoneal (i.p.) primary and secondary 10(5), 10(4), and 10(3) mean tissue culture infective doses (TCID(50)) of live parainfluenza 1 (Sendai) virus. The earliest antibody detected in lungs after i.n. virus challenge was immunoglobulin G (IgG), followed by IgM and, lastly, IgA. The local IgA response after both primary and secondary i.n. virus challenge was lowest after the severest infection. It is suggested that the delayed appearance of IgA antibody and the lower response after severe lung damage may be related to a temporary local secretory component-producing cell deficiency. The lungs were a major source of serum IgG antibody after both primary and secondary i.n. virus challenge. Only IgG and IgM antibodies were detectable in lung cell lysates after the i.n. 10(3) TCID(50) secondary response. A secondary response was detected in IgG, IgA, and IgM after secondary i.n. challenge with the other two doses. The lung response to all of primary and secondary i.p. doses of virus was exclusively IgG and IgM. Calculation of radioimmunoassay antibody per microgram of IgG, IgA, and IgM in serum and BAW after both i.n. and i.p. virus challenges showed that, when BAW antibody was present, the ratio in BAW was always higher than that in serum. This finding in the i.n. mice, together with the presence of IgA antibody-containing cells in the lungs, strongly indicates local manufacture and secretion of IgA antibodies in these animals and suggests that the same conclusion could apply to local IgG and IgM antibodies after both i.n. and i.p. challenges.     

Making access to health care more equal: the role of general medical services

The Resource Allocation Working Party (RAWP) recognised the need to consider both health authority and primary care services in achieving its objective. RAWP and the subsequent Advisory Group on Resource Allocation (AGRA) found (but did not publish) considerable variation in resources used by both services but could not find a clear relation between them. Statistics provided by the DHSS were used to compare spending by 80 area health authorities in 1980-1 with expenditure per head on general medical services by their corresponding family practitioner committees. There was considerable variation in the provision of resources for both services and no clear relation between the variations in spending on each service. Only 40 of the 80 areas had both health authority and family practitioner committee spending levels within 10% of "target." Subregional inequalities in resources tend to be related to variations in admission rates, which in turn are related to general practitioners' referral behaviour. These results emphasise the importance of finding out more about inequalities in the provision of general medical services and their relation to the use of hospital services. They also suggest that RAWP's aim of equality of opportunity of access to health care resources may be achieved only if general medical services are brought into the equation as well.     

Effects of the Family Check-Up 4 Health on Parenting and Child Behavioral Health: A Randomized Clinical Trial in Primary Care

The Family Check-Up 4 Health (FCU4Health) is an adaptation of the Family Check-Up (FCU) for delivery in primary care settings. While maintaining the original FCU’s focus on parenting and child behavioral health, we added content targeting health behaviors. This study evaluated whether the adapted FCU maintained positive effects on parenting (positive behavior support, limit setting, parental warmth) and child behavioral health (self-regulation, conduct problems, emotional problems). Pediatric (6–12 years) primary care patients with a BMI?≥?85^th%ile (n?=?240) were recruited from primary care clinics in Phoenix. Children were 75% Latino, 49% female, and 73% Medicaid recipients. This type 2 effectiveness-implementation hybrid trial compared families randomized to FCU4Health (n?=?141) or usual care (n?=?99). FCU4Health was delivered over a period of 6 months. This study focuses on a priori secondary outcomes included parenting and child behavioral health targets of the original FCU, assessed at baseline and 3, 6, and 12 months. Significant improvements were found for the FCU4Health condition, compared to usual care, in parenting from baseline to the 3-month assessment [β?=?.17 (.01; .32)]. Parenting predicted improvements in child self-regulation at 6-months [β?=?.17 (.03; .30)], which in turn predicted reductions in conduct problems [β?=?? .38 (? .51; ? .23)] and emotional problems [β?=?? .24 (? .38; ? .09)] at 12 months. Ethnicity and language of delivery (English or Spanish) did not moderate these effects. The FCU4Health can improve parenting and child behavioral health outcomes when delivered in primary care.

Trial Registration Trial registration number: NCT03013309 ClinicalTrials.gov

     

Drugs acting on the heart: heart failure and coronary insufficiency

Heart failure (HF) and coronary insufficiency are common amongst surgical and critical care patients. Both are chronic conditions interrupted by acute episodes. HF activates neurohormonal mechanisms that worsen renal and cardiac function. Acute heart failure (AHF) commonly presents with dyspnoea as a consequence of systolic and/or diastolic dysfunction. Goals of treatment are symptom relief to maintain tissue perfusion and optimize cardiac function. Diuretics and vasodilators are used early; positive inotropic drugs are reserved for when other treatment has failed. Chronic heart failure (CHF) is treated using changes in lifestyle and drugs to manage symptoms. ACE inhibitors and beta-blockers are effective in systolic heart failure and are associated with improved mortality. HF with preserved ejection fraction (HFPEF) is less responsive to drug therapy, though outcomes are better than for systolic HF. Coronary insufficiency occurs because of an imbalance of myocardial oxygen balance, leading to symptoms of ischaemic heart disease (IHD). Treatment goals are maintaining coronary blood flow and reducing myocardial oxygen demand. Beta-blockers and anti-platelet drugs improve outcomes; modern anti-platelets are more effective but are associated with risks of haemorrhage. Statins are effective for primary and secondary prevention of myocardial infarction; they have additional anti-inflammatory properties.     

Erbium-YAG and holmium-YAG laser ablation of bone

Results are presented for the latent heat of ablation of bone using an erbium-YAG laser operating at 2.9m, and a holmium-YAG laser operating at 2.1m. The values are 8.2±1.0 kJ cm^–3 and 18±2.0 kJ cm^–3, respectively. Secondary damage to surrounding tissue is found to extend approximately 5m with the erbium laser and is greatly increased to 80m with significant charring in the case of holmium. These secondary damage zones are much smaller than those produced by the CO₂ laser.     

Enhancement of the response to purinergic agonists in P2Y1 transfected 1321N1 cells by antagonists suramin and PPADS

1. We have previously shown that both suramin and pyridoxal-phosphate-6-azophenyl-2′, 4′ disulphonic acid (PPADS) act as antagonists at transfected P2Y₁ receptors. Here we show that under certain experimental conditions these two P2 antagonists can enhance the response to agonists acting at these receptors.
2. The expression of either P2Y₁ or P2Y₂ receptors in 1321N1 human astrocytoma cells results, on a change of medium, in an elevation of basal (no added agonist) accumulation of [³H]-inositol(poly)phosphates([³H]-InsP_x) compared to cells not expressing these receptors. This elevation is much greater in P2Y₁ transfectants than in P2Y₂ transfectants.
3. Both PPADS and suramin reduced this basal level of [³H]-InsP_x accumulation in the P2Y₁ expressing cells.
4. When a protocol was used which required changing the culture medium, antagonists were added at a concentration which reduced the basal accumulation by about 50%, there was a significant stimulation in response to increasing concentrations of 2-methylthioadenosine 5′-triphosphate (2MeSATP), in the absence of antagonists there was no significant effect of the agonist.
5. However, when 2MeSATP was added in the absence of a change of medium and with no antagonist present, there was a several fold increase in [³H]-InsP_x accumulation. These results show that a release of endogenous agonist activity (possibly ATP/ADP) from the P2Y₁ expressing cells can create conditions in which a response to an agonist such as 2MeSATP can only be seen in the presence of a competitive antagonist.

     

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

Elderly men living alone: are they at high nutritional risk?

This review article investigates the influence of living arrangements on the dietary intake and nutritional status of elderly men. Elderly men living alone have been identified as a group particularly at risk of poor dietary habits, however available evidence is inconsistent. Data from the United States suggests that low income elderly men living alone are at high risk of an inadequate dietary intake, and that a low energy intake is the most important predictor of a poor quality diet in this group. In Australia, older men living with a spouse have a better quality diet (higher nutrient density) than those living alone or with a person or persons other than a spouse, particularly regarding fruit and vegetable intake; differences in nutrient intake are not explained by lower energy intakes. In contrast, older men in European countries who live alone appear to have a more favourable dietary intake as compared to their counterparts in other living arrangements. Information on the association between living arrangements and household food security in the elderly in developing countries is sparse, however single living among older men is rare and the ethos of the extended family appears to remain intact. The inconsistencies in the apparent level of nutritional risk associated with living alone in elderly men in different countries necessitates the development and validation of screening programmes and nutrition services which are country-specific.     

Combined finasteride and flutamide therapy in men with advanced prostate cancer

Objectives

To evaluate the efficacy of combined finasteride and flutamide therapy in men with advanced prostate cancer by determining (1 ) the short-term tolerability of finasteride monotherapy and its effect on serum prostate-specific antigen (PSA) and hormone (testosterone, dihydrotestosterone) levels, and (2) the effects of the addition of flutamide on tolerability and on serum PSA and hormone levels.

Methods

Thirteen hormone-naive men with advanced prostate cancer (4 with Stage D2, 1 with Stage D1, 1 with Stage DO, 7 with rising PSA levels after radical prostatectomy [n = 2]or definitive radiation therapy [n = 5]) were initially treated with 5 mg finasteride daily. Flutamide (250 mg three times a day) was added after serum PSA levels stabilized.

Results

Finasteride alone (median 5 weeks) had no significant effect on serum PSA levels (P>0.05). Combined finasteride and flutamide resulted in a mean 91% reduction in serum PSA levels, with 85% of men achieving a nadir serum PSA level of less than 4.0 ng/mL and 46% achieving undetectable levels (0.2 ng/mL or less). Finasteride alone had no significant effect on serum testosterone levels (P>0.05) but did result in a mean 74% reduction in serum dihydrotestosterone levels. Combined finasteride and flutamide resulted in a mean 56% increase in serum testosterone levels but had no additional effect on serum dihydrotestosterone levels (P>0.05). Side effects occurred in 85% (gynecomastia or breast tenderness in 62% [8 of 13]and diarrhea in 23% [3 of 13]) of men on combined therapy. Potency was preserved in 66%. Combined finasteride and flutamide therapy was withdrawn from 15% (2 of 13) because of flutamide-induced diarrhea and from 23% (3 of 13) because of disease progression. All remaining patients (8 of 13) have serum PSA levels below 4.0 ng/mL and 4 of these 8 have undetectable levels. These men have received combined finasteride and flutamide for a median 11 months (range 6 to 19).

Conclusions

Finasteride monotherapy is inadequate therapy for advanced prostate cancer, but combined finasteride and flutamide may be a reasonable alternative for men with advanced prostate cancer who refuse conventional hormone therapy.