Long-term caloric restriction reduces metabolic rate and heart rate under cool and thermoneutral conditions in FBNF1 rats.

The long-term metabolic and cardiovascular responses to caloric restriction (CR) are poorly understood. We examined the responses to one year of CR in FBNF1 rats housed in cool (COOL; T(a)=15 °C) or thermoneutral (TMN; T(a)=30 °C) conditions. Rats were acclimated to COOL or TMN for 2 months, instrumented for cardiovascular telemetry and studied in calorimeters. Baseline caloric intake, oxygen consumption (VO(2)), mean arterial blood pressure (MAP), and heart rate (HR) were determined prior to assignment to ad lib (AL) or CR groups (30-40% CR) within each T(a) (n = 8). Groups of rats were studied after 10 weeks CR, one year CR, and after 4 days of re-feeding. Both 10 weeks and one year of CR reduced HR and VO(2) irrespective of T(a). Evaluation of the relationship between metabolic organ mass (liver, heart, brain, and kidney mass) and energy expenditure revealed a clear shift induced by CR to reduce expenditure per unit metabolic mass in both COOL and TMN groups. Re-feeding resulted in prompt elevations of HR and VO(2) to levels observed in control rats. These findings are consistent with the hypothesis that long term CR produces sustained reductions in metabolic rate and heart rate in rats.

Vagal tone dominates autonomic control of mouse heart rate at thermoneutrality.

It is generally accepted that cardiac sympathetic tone dominates the control of heart rate (HR) in mice. However, we have recently challenged this notion given that HR in the mouse is responsive to ambient temperature (T(a)) and that the housing T(a) is typically 21-23 degrees C, well below the thermoneutral zone ( approximately 30 degrees C) of this species. To specifically test the hypothesis that cardiac sympathetic tone is the primary mediator of HR control in the mouse, we first examined the metabolic and cardiovascular responses to rapid changes in T(a) to demonstrate the sensitivity of the mouse cardiovascular system to T(a). We then determined HR in 1) mice deficient in cardiac sympathetic tone ("beta-less" mice), 2) mice deficient in cardiac vagal tone [muscarinic M(2) receptor (M(2)R(-/-)) mice], and 3) littermate controls. At a T(a) of 30 degrees C, the HR of beta-less mice was identical to that of wild-type mice (351 +/- 11 and 363 +/- 10 beats/min, respectively). However, the HR of M(2)R(-/-) mice was significantly greater (416 +/- 7 beats/min), demonstrating that vagal tone predominates over HR control at this T(a). When these mice were calorically restricted to 70% of normal intake, HR fell equally in wild-type, beta-less, and M(2)R(-/-) mice (DeltaHR = 73 +/- 9, 76 +/- 3, and 73 +/- 7 beats/min, respectively), suggesting that the fall in intrinsic HR governs bradycardia of calorically restricted mice. Only when the T(a) was relatively cool, at 23 degrees C, did beta-less mice exhibit a HR (442 +/- 14 beats/min) that was different from that of littermate controls (604 +/- 10 beats/min) and M(2)R(-/-) mice (602 +/- 5 beats/min). These experiments conclusively demonstrate that in the absence of cold stress, regulation of vagal tone and modulation of intrinsic rate are important determinants of HR control in the mouse.

Electrophysiological and behavioral phenotype of insulin receptor defective mice.

The olfactory bulb expresses one of the highest levels of insulin found in the brain. A high level of expression of the concomitant insulin receptor (IR) kinase is also retained in this brain region, even in the adult. We have previously demonstrated in a heterologous system that insulin modulates the voltage-dependent potassium channel, Kv1.3, through tyrosine phosphorylation of three key residues in the amino and carboxyl terminus of the channel protein. Phosphorylation also induces current suppression of the Kv1.3-contributed current in cultured olfactory bulb neurons (OBNs) of rodents. In order to explore the behavioral importance of this kinase-induced modulation of the channel for the olfactory ability of the animal, mice with a targeted-gene deletion of the insulin receptor were electrophysiologically and behaviorally characterized. Mice heterozygous for the insulin receptor kinase (IR+/-) gene performed the same as wild-type (+/+) mice when challenged with a traditional, non-learning-based task to test gross anosmia. There was also no significant difference across the two genotypes in tests designed to measure exploratory behavior or in a battery of systems physiology experiments designed to assess metabolic energy usage (locomotion, ingestive behaviors, weight, oxygen consumption, and respiratory quotient). Object memory recognition tests suggest that IR+/- mice have an impairment in recognition of familiarized objects; IR+/- mice demonstrate poor performance for both short-term (1 h) and long-term (24 h) memory tests in comparison to that of wild-type mice. Electrophysiological experiments indicate that mitral cell neurons cultured from both heterozygous and homozygous-null mice (IR+/- and IR-/-) have an decreased peak current amplitude compared with that recorded for wild-type (+/+) animals matched for days in vitro (DIV). These data indicate that the loss of one allele of the IR kinase gene modifies the electrical phenotype of the mitral cell neurons in the olfactory bulb without a change in gross olfactory ability. Given our findings that there are no significant changes in metabolic balance of the IR (+/-) mice but some impairment in memory retention, future experiments testing for specific olfactory behaviors or functional deficits in IR-/+ mice models of diabetes will need to either be tasks that do not require learning or will require a different model (such as diet-induced diabetes) that may evoke a stronger phenotype.

Homeostatic responses to caloric restriction: influence of background metabolic rate.

The biological responses to caloric restriction (CR) are generally examined in rats with elevated metabolic rates due to being housed at ambient temperatures (T(a)) below the zone of thermoneutrality. We determined the physiological and behavioral responses to 2 wk of 30-40% CR in male FBNF1 rats housed in cool (T(a) = 12 degrees C) or thermoneutral (TMN; T(a) = 30 degrees C) conditions. Rats were instrumented with telemetry devices and housed continuously in home-cage calorimeters for the entire experiment. At baseline, rats housed in cool T(a) had reduced rate of weight gain; thus a mild CR (5%) group at thermoneutrality for weight maintenance was also studied. Rats housed in cool T(a) exhibited elevated caloric intake (cool = 77 +/- 1; TMN = 54 +/- 2 kcal), oxygen consumption (Vo(2); cool = 9.9 +/- 0.1; TMN = 5.5 +/- 0.1 ml/min), mean arterial pressure (cool = 103 +/- 1; TMN = 80 +/- 2 mmHg), and heart rate (cool = 374 +/- 3; TMN = 275 +/- 4 beats/min). Cool-CR rats exhibited greater CR-induced weight loss (cool = -62 +/- 3; TMN = -42 +/- 3 g) and reductions in Vo(2) (cool = -2.6 +/- 0.1; TMN = -1.5 +/- 0.1 ml/min) but similar CR-induced reductions in heart rate (cool = -59 +/- 1; TMN= -51 +/- 7 beats/min). CR had no effect on arterial blood pressure or locomotor activity in either group. Unexpectedly, weight maintenance produced significant reductions in Vo(2) and heart rate. At thermoneutrality, a single day of refeeding effectively abolished CR-induced reductions in Vo(2) and heart rate. The results reveal that rats with low or high baseline metabolic rate exhibit comparable compensatory reductions in Vo(2) and heart rate and suggest that T(a) can be used to modulate the metabolic background on which the more prolonged effects of CR can be studied.

Long-Evans and Sprague-Dawley rats exhibit divergent responses to refeeding after caloric restriction.

Mature male Sprague-Dawley (SD) and Long-Evans (LE) rats were instrumented with telemetry transmitters for measurement of heart rate (HR) and housed in room calorimeters for assessment of food intake and oxygen consumption (Vo(2)) at standard laboratory temperatures (23 degrees C) to examine physiological responses to caloric restriction (CR; 60% of baseline ad libitum calories for 2 wk) and refeeding. Ad libitum controls had stable food intake (84-88 kcal/day) and gained weight at rates of 3-4 g/day. Groups from both strains assigned to CR exhibited similar patterns of weight loss and reductions in Vo(2) and HR. Upon refeeding, SD rats exhibited a mild, transient hyperphagic response (1 day) accompanied by sustained suppression of Vo(2) and HR that remained evident 8 days after refeeding. In contrast, LE rats exhibited sustained daily hyperphagia that persisted 8 days after refeeding and was accompanied by a complete restoration of HR and Vo(2). The lower HR and Vo(2) observed during refeeding in SD rats were not due to reduced locomotor activity. The results reveal a strain-dependent divergent response to recovery from CR. We conclude that during recovery from CR, homeostatic stimulation of appetite or suppression of energy expenditure may occur selectively to restore body weight.

Adaptive thermogenesis is intact in B6 and A/J mice studied at thermoneutrality.

To investigate mechanisms of resistance to obesity, the physiologic responses to short-term moderate fat feeding were studied at ambient temperature (T(a)) = 23 degrees C and thermonuetrality (T(a) = 30 degrees C) in mice susceptible (B6) or resistant (A/J) to obesity. We hypothesized that A/J mice would exhibit greater adaptive thermogenic responses to consumption of moderate-fat diets, and that this response would be attenuated in thermoneutral conditions due to reduced activity of brown adipose tissue (BAT). B6 and A/J mice were adapted to either T(a) = 23 degrees C or T(a) = 30 degrees C, implanted with telemetry devices, housed in metabolic chambers for measurement of food intake, oxygen consumption (Vo(2)), and heart rate (HR), and studied before and during 1 week of consuming a diet containing 32% of calories from fat. Access to 32% fat diet resulted in increased caloric intake in both strains, but caloric intake for A/J mice returned to baseline levels within 72 hours, while B6 mice remained hyperphagic. Both strains exhibited increased light-phase Vo(2) indicative of adaptive thermogenesis; however, there was no strain difference in light-phase Vo(2) during the 1-week feeding trial. Surprisingly, T(a) had no effect on diet-induced thermogenesis in either mouse strain. Moderate high-fat feeding produced mild tachycardia that was similar in B6 and A/J mice and more clearly evident at thermonuetrality. We conclude that adaptive thermogenic responses are intact in both mouse strains studied at thermoneutrality, suggesting a minimal role for BAT in the initial metabolic response to hyperphagia. Furthermore, the results suggest that differences in control of caloric intake, rather than capacity for adaptive thermogenesis, may contribute to the relative susceptibility to obesity in A/J and B6 mice.

Kv1.3 channel gene-targeted deletion produces "Super-Smeller Mice" with altered glomeruli, interacting scaffolding proteins, and biophysics.

Mice with gene-targeted deletion of the Kv1.3 channel were generated to study its role in olfactory function. Potassium currents in olfactory bulb mitral cells from Kv1.3 null mice have slow inactivation kinetics, a modified voltage dependence, and a dampened C-type inactivation and fail to be modulated by activators of receptor tyrosine signaling cascades. Kv1.3 deletion increases expression of scaffolding proteins that normally regulate the channel through protein-protein interactions. Kv1.3-/- mice have a 1,000- to 10,000-fold lower threshold for detection of odors and an increased ability to discriminate between odorants. In accordance with this heightened sense of smell, Kv1.3-/- mice have glomeruli or olfactory coding units that are smaller and more numerous than those of wild-type mice. These data suggest that Kv1.3 plays a far more reaching role in signal transduction, development, and olfactory coding than that of the classically defined role of a potassium channel-to shape excitability by influencing membrane potential.

Effect of transdermal oestradiol on the haemostatic balance of menopausal women.

OBJECTIVE: To determine the effect of transdermal oestrogen replacement therapy on the haemostatic balance of menopausal women. DESIGN: Open, parallel group, prospective study. SETTING: Three hospital-based menopause clinics. SUBJECTS: Fifty-two postmenopausal women receiving transdermal hormone replacement therapy (Estrapak 50) for 6 months. Comparison group of 48 untreated postmenopausal women studied in parallel. MAIN OUTCOME MEASURES: Changes in platelet number, plasma concentrations of coagulation factors and their natural inhibitors, fibrinolytic activity, and rheological parameters. RESULTS: Estrapak 50 had no significant thrombophilic effect on any of the outcome measures. CONCLUSION: The haemostatic balance and thus the risk of thrombosis would not appear to be upset by this dose of transdermal oestrogen.

A multivariate investigation of postpartum mood disturbance.

The interrelationships of 'blues' and later postpartum depression with a number of biochemical, medical, and psychosocial variables have been examined in 52 subjects. The two syndromes shared only an impressive association with a prior history of gynaecological problems. Puerperal 'blues' was characterised in addition by associations with primiparity, tearfulness during pregnancy, and reduced plasma total tryptophan in the early puerperium. Depressive symptomatology up to nine months postpartum was related to an excess of male births and to an altered pattern of decline of non-esterified fatty acids immediately postpartum. In each case, the 'risk' variables were statistically independent and combined linearly. Stepwise discriminant analysis successfully discriminated 'blues' and depression from their respective non-cases. 'Blues and postpartum depression were only weakly related and, apart from gynaecological history, each was associated with separate and independent causative factors.

Sterilisation.

PIP: The discussion identifies some of the issues in counseling for sterilization and outlines the information which the counselor should make available to the couple. The most appropriate person to counsel a couple about sterilization is usually their general practitioner. He/she already will have some background knowledge about the couple, which will shorten the information-gathering part of the counseling process and help in understanding the problems the couple may experience in reaching their decision. Wherever the couple is seen, more than 1 consultation may be necessary. The basic requirement for counseling is an unhurried and nonthreatening atmosphere. Except in the unusual but increasing case of the man or woman without permanent partner, it is mandatory to see the couple together. This may seem obvious, yet many sterilizations (particularly for women) are still being carried out after a consultation with only 1 partner. Even though the counselor may already know the couple well, it is worth reviewing certain features of their situation. Age has been considered 1 of the most important factors in deciding whether to "allow" a sterilization. There is some disagreement among surgeons and gynecologists about this, so it is important to know what is available locally. If the couple have children and the vast majority of those requesting sterilization do, the age of these may be insignificant. Pregnancy is not a good time to make irreversible decisions, so immediate postpartum sterilization should probably be avoided except where the couple's decision predates the pregnancy. In the years since the liberalization of the divorce laws in the US, there has been a steady increase in the frequency of 2nd and 3rd marriages. In view of this, careful consideration should be given as to whether vasectomy, or female sterilization is appropriate. A high percentage of those who request a reversal of sterilization had their operation at a time when their relationship was unstable or had recently broken up, suggesting that some attempt should be made to assess the stability of the relationship. Many will choose sterilization as a last resort, having failed to find a reversible method of contraception which suits them. This is reasonable if all the possibilities have been explored, but many women who are happy on the combined oral contraceptive are being encouraged to change this for a sterilization at an unnecessarily early age. Couples need to know what is involved in sterilization, and the counselor requires local knowledge for this. In addition to knowing the technical details of the operation and understanding that its effects are only on fertility, there are a number of other points that should be discussed. These include: the failure rate, the reversibility of sterilization, the need for at least 2 sperm-free postoperative samples of seminal fluid before vasectomy can be considered effective, and the possibility of regretting the decision.^ieng