Microglia mediate the early-life programming of adult glucose control.

Mammalian glucose homeostasis is, in part, nutritionally programmed during early neonatal life, a critical window for the formation of synapses between hypothalamic glucoregulatory centers. Although microglia are known to prune synapses throughout the brain, their specific role in refining hypothalamic glucoregulatory circuits remains unknown. Here, we show that microglia in the mediobasal hypothalamus (MBH) of mice actively engage in synaptic pruning during early life. Microglial phagocytic activity is induced following birth, regresses upon weaning from maternal milk, and is exacerbated by feeding dams a high-fat diet while lactating. In particular, we show that microglia refine perineuronal nets (PNNs) within the neonatal MBH. Indeed, transiently depleting microglia before weaning (P6-16), but not afterward (P21-31), remarkably increased PNN abundance in the MBH. Furthermore, mice lacking microglia only from P6-16 had glucose intolerance due to impaired glucose-responsive pancreatic insulin secretion in adulthood, a phenotype not seen if microglial depletion occurred after weaning. Viral retrograde tracing revealed that this impairment is linked to a reduction in the number of neurons in specific hypothalamic glucoregulatory centers that synaptically connect to the pancreatic ß-cell compartment. These findings show that microglia facilitate synaptic plasticity in the MBH during early life through a process that includes PNN refinement, to establish hypothalamic circuits that regulate adult glucose homeostasis.

MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice.

The maternal perinatal environment modulates brain formation, and altered maternal nutrition has been linked to the development of metabolic and psychiatric disorders in the offspring. Here, we showed that maternal high-fat diet (HFD) feeding during lactation in mice elicits long-lasting changes in gene expression in the offspring's dopaminergic circuitry. This translated into silencing of dopaminergic midbrain neurons, reduced connectivity to their downstream targets, and reduced stimulus-evoked dopamine (DA) release in the striatum. Despite the attenuated activity of DA midbrain neurons, offspring from mothers exposed to HFD feeding exhibited a sexually dimorphic expression of DA-related phenotypes, i.e., hyperlocomotion in males and increased intake of palatable food and sucrose in females. These phenotypes arose from concomitantly increased spontaneous activity of D1 medium spiny neurons (MSNs) and profoundly decreased D2 MSN projections. Overall, we have unraveled a fundamental restructuring of dopaminergic circuitries upon time-restricted altered maternal nutrition to induce persistent behavioral changes in the offspring.

The optimized effective potential with finite temperature.

The optimized effective potential (OEP) method provides an additional level of exactness in the computation of electronic structures, e.g. the exact exchange energy can be used. This extra freedom is likely to be important in moving density functional methods beyond traditional approximations such as the local density approximation. We provide a new density-matrix-based derivation of the gradient of the Kohn-Sham energy with respect to the effective potential. This gradient can be used to iteratively minimize the energy in order to find the OEP. Previous work has indicated how this can be done in the zero temperature limit. This paper generalizes the previous results to the finite temperature regime. Equating our gradient to zero gives a finite temperature version of the OEP equation.

Writing a coding success story: best practices and beyond. Panel discussion.

What are the cornerstones of a thriving coding department? How can you ensure your coding team is built on a foundation of education, compliance, and satisfaction? We spoke with several coding managers to collect solutions and guidance for common coding challenges.

["A male view?" Texts on feminism film theory]. / "Ist der Blick männlich?" Texte zur feministischen Filmtheorie.

The author traces the course taken by psychoanalytically oriented feminist film theory from its beginnings in the late seventies. She situates its origins in the Anglo-American debate about the exclusion of female subjectivity from the cinema and the new awareness of the problem of the cinematic mise-en-scène of the gaze, of "visual pleasure". First, massive criticism was levelled at the exclusively male/patriarchal gaze of the viewer, then emphasis centred around the specifically female gaze as a category in aesthetic theory. Ultimately, psychoanalytic feminist film theory has turned its attention to films for women, melodrams and early movies in an attempt to capture the respective historical forms of female subjectivity that they reflect.

The spectrum of peripheral neuropathy associated with ARC and AIDS.

Peripheral neuropathy is increasingly recognized as a complication of the Acquired Immune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC), but the varied clinical features have been incompletely described. Thirty homosexual men with peripheral neuropathy were evaluated in this study. Twenty-one had ARC and nine had AIDS. Four distinct clinical syndromes were recognized: distal sensorimotor polyneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), mononeuropathy multiplex, and progressive polyradiculopathy. Four patients with clinical, electrophysiologic, and histologic evidence of CIDP and severe progressive weakness improved with plasma exchange, three regaining normal function.

Antibody-mediated peripheral neuropathies associated with ARC and AIDS: successful treatment with plasmapheresis.

Peripheral neuropathy is increasingly recognized in patients with AIDS as well as AIDS-related complex (ARC). Thirty homosexual men with polyneuropathy were evaluated in this study. Twenty-one had ARC and nine had AIDS. We observed three distinct clinical syndromes: distal sensorimotor polyneuropathy, chronic inflammatory demyelinating polyrediculoneuropathy (CIDP), and mononeuropathy multiplex. Circulating antibodies to peripheral nerve tissues were found in all patients. In six patients, treatment with plasma exchange was undertaken because of severe, progressive weakness. Four patients with clinical, electrophysiologic, and histologic evidence of CIDP improved with plasma exchange, three regaining normal function. These results suggest that the peripheral neuropathy associated with ARC and AIDS is immunologically mediated and that plasma exchange is an effective treatment in a subgroup of patients with this disorder.

Risk of AIDS-related virus (human immunodeficiency virus) transmission through apheresis procedures.

Since exposure to blood products occurs on a daily basis during hemapheresis, the acquired immunodeficiency syndrome (AIDS) epidemic has a serious impact both for patients undergoing apheresis procedures as well as for health professionals working in the field. We studied serum samples from 110 patients who underwent therapeutic plasmapheresis for a variety of diseases not related to AIDS for the presence of antibodies to human immunodeficiency virus (HIV). Exchange fluids used in the majority of the patients were plasma protein fraction and 5% human albumin. Four patients received only fresh-frozen plasma. Fifty-five patients also received IV gammaglobulin. The follow-up period exceeded 24 months. All patients who did not belong to any known high-risk group for AIDS were negative for HIV antibodies prior to treatment and remained negative at last follow-up. Seven patients were homosexual men. All seven were seropositive prior to plasmapheresis and remained so throughout the treatment period. Seven health professional working in a busy haemapheresis unit were followed for 2 1/2 years. All remain HIV seronegative with normal immune function. These data indicate that transmission of HIV is unlikely through haemapheresis procedures.

Left heart function in chronic obstructive lung disease.

In patients with varying degrees of chronic obstructive pulmonary disease (COPD), simultaneous measurements of central hemodynamics and left ventricular radionuclide ventriculograms at rest and during exercise were made. In 21 of these patients, satisfactory echocardiograms could be performed. In seven of the patients, arterial blood pressure at rest was increased. Decreased compliance of the left ventricle was thought to be present in patients with COPD and additional arterial hypertension. The left ventricular ejection fraction (LVEF) at rest was in the high normal range in all patients. During exercise, no further increase was observed. This pattern of LVEF response seems to be typical in patients with COPD. Because the highest values were observed in the more severe COPD and right ventricular hypertrophy, it is unlikely that an impairment of left ventricular function is caused by COPD. In five of 27 patients, an abnormal decrease of LVEF and regional hypokinesis occurred during exercise, thus suggesting additional coronary heart disease. The fact that at least 30% of the patients with COPD suffered from arterial hypertension and 20% of the patients exhibited unexpected ischemia detected by regional hypokinesis in RNV during exercise, but not in the ECG, may be of practical relevance. Coronary angiography was not indicated because most of these patients were over 65 and the factor limiting the working capacity was ventilatory impairment and not angina pectoris, in all patients. For this reason, a diagnostic uncertainty remains with regard to additional coronary heart disease in the older patients with advanced chronic obstructive pulmonary disease.

The use of plasmapheresis, lymphocytapheresis, and staph protein-A immunoadsorption as an immunomodulatory therapy in patients with AIDS and AIDS-related conditions.

Circulating immune complexes, autoantibodies, and suppressor factors to normal lymphoproliferation may play an important role in the induction and maintenance of the cellular immunodeficiency characteristic for the acquired immunodeficiency syndrome (AIDS) and its related conditions. In order to explore the possibility that the removal of circulating humoral factors may have an immunomodulatory effect in patients with AIDS and AIDS-related conditions (ARC), we used apheresis procedures to treat patients with different clinical presentations of AIDS and ARC. Five patients with AIDS and opportunistic infections were treated with plasmapheresis. Four patients with AIDS and Kaposi's sarcoma without opportunistic infections were treated with staph protein-A immunoadsorption and two patients with ARC and peripheral neuropathy were treated with lymphoplasmapheresis. The treatments were tolerated well by all patients. Effective removal of circulating humoral immune factors was observed in all three groups. No significant clinical benefit was seen in the patients with AIDS and opportunistic infections treated with plasmapheresis. Partial tumor responses were observed in three of the four patients with AIDS related Kaposi's sarcoma treated with staph protein-A plasma perfusion, and resolution of neurologic symptoms was seen in both patients with ARC and peripheral neuropathy treated with lymphoplasmapheresis. Our preliminary results suggest that lymphoplasmapheresis may be an effective treatment modality for patients with ARC related peripheral neuropathy, that protein-A immunoadsorption is well tolerated by patients with AIDS-related Kaposi's sarcoma, and that this treatment has antitumor and immunomodulatory effects in these patients.

Pulmonary gas exchange and central hemodynamics at rest and during exercise in patients with chronic obstructive pulmonary disease.

Right-heart catheterization and ergometry with arterial and mixed venous blood gas analysis were performed in 27 patients with a wide range of chronic obstructive pulmonary diseases. The purpose of the examination was to evaluate the risk in patients for lung surgery or to detect additional heart diseases. Patients who developed exertional hypoxia (group 1) were compared with others who did not (group 2). In all patients the steady-state maximal workload was determined by ventilatory dysfunction. Both groups had normal values for mixed venous pO2 and normal increase of the circulatory parameters during exercise. The patients with exertional hypoxia differed from the others in that they showed no decrease of venous admixture and alveolar-arterial oxygen gradient. In addition, these patients had increasing pCO2 values at rest compared with exercise, indicating alveolar hypoventilation and ventilation-perfusion mismatching. Because of the good correlation of the absolute values of FEV1 (forced expiratory volume in 1 s) with pulmonary artery pressures, parameters of gas exchange and working capacity, this lung function parameter seems to have a central role in predicting the functional state of patients with chronic obstructive disease. Ergometry and blood gas analysis should be performed in addition because these values cannot be predicted with the calculated postoperative FEV1.

Limitations of radionuclide ventriculography in the non-invasive diagnosis of coronary artery disease. A correlation with right heart haemodynamic values during exercise.

A consecutive series of 56 patients with chest pain but no evidence of previous myocardial infarction was prospectively studied by radionuclide ventriculography to determine the value of global and regional radionuclide indices in detecting coronary artery disease. The results were correlated with the clinical judgment of chest pain, the results of the exercise electrocardiogram, and the right heart haemodynamic measurements during exercise. As a result of the criteria for entry, the study group was representative of the population seen in such a clinical setting. Only 25% of patients had coronary artery disease. The predictive power of radionuclide ventriculography was limited. The conventionally used criterion that normal subjects have an increase in left ventricular ejection fraction of at least 5% with exercise provided only 78% sensitivity and 57% specificity. Fourier analysis and visual interpretation of radionuclide studies wrongly diagnosed three out of 10 patients with extensive disease requiring surgery. These results suggest that radionuclide ventriculography is of limited value in the non-invasive diagnosis of coronary artery disease.

Acquired immunodeficiency syndrome (AIDS)--apheresis and operative risks.

The removal of immune complexes, autoantibodies and suppressor factors from the circulation of patients with AIDS and AIDS related conditions by plasmapheresis and selective immunoadsorption may play a role as a therapeutic modality in these disorders. Lymphocytapheresis may also be of potential use in AIDS related conditions with presumed autoimmune basis. Perfusion of plasma over immobilized protein A columns is being evaluated as a possible immunomodulatory and antitumor therapy in patients with AIDS related Kaposi's sarcoma. Although apheresis procedures as a therapeutic modality in AIDS related conditions are still at the experimental stage, preliminary results are encouraging. The possible transmission of the disease by blood products presents a health hazard to health workers involved in the field of apheresis. Since the mode of transmission of the disease appears to be similar to hepatitis B, strict hepatitis B precautions should be enforced in every case in which AIDS suspected blood is being processed.

Extracorporeal perfusion of plasma over immobilized protein A in a patient with Kaposi's sarcoma and acquired immunodeficiency.

Plasma of a homosexual man with Kaposi's sarcoma and acquired immunodeficiency was perfused over a protein A column using a continuous-flow plasma-cell separator. Three liters of plasma was perfused during each procedure and returned to the patient at a plasma flow rate of 10-20 ml/min. Three treatments were performed over a 1-week period. Transient removal of IgG, immune complexes, antilymphocyte antibodies, and serum blocking factors to mitogenic lymphocyte stimulation was observed during each treatment. Although no striking regression occurred, microscopic examination of sarcomatous lesions revealed decrease of tumor cell density and collagen proliferation within the tumor. Immunohistochemical deposition of C3 was observed in the tumor lesions after treatment. Side effects from the treatment included a mild drop of systolic blood pressure, sinus tachycardia, and a decrease in platelet count.

Mechanism of action of narcotics in the production of menstrual dysfunction in women.

The ability of morphine to block ovulation in animals prompted investigation of the frequency and mechanisms of menstrual abnormalities in women addicted to narcotic analgesics. Menstrual histories obtained from 76 former heroin addicts receiving daily methadone maintenance revealed that more than one-half of these women had experienced menstrual abnormalities while taking heroin or methadone. In order to determine the specific physiologic effects of narcotic analgesics on reproductive function, detailed endocrinologic studies were carried out in seven of these patients who complained of amenorrhea or irregular menses while receiving methadone. Four of the seven women manifested abnormalities of the control of gonadotropin secretion. Three of these four failed to exhibit cyclic gonadotropin release, as evidenced by an absence of increased levels of follicular phase follicle-stimulating hormone, midcycle gonadotropin peaks or luteal phase progesterone increments. In the fourth patient a prolonged follicular phase (30 days) of the menstrual cycle was detected. One of these four patients also had low basal gonadotropin levels and failed to exhibit luteinizing hormone increments greater than control levels in response to ethinyl estradiol (positive feedback). The remaining three women exhibited normal patterns of gonadotropin secretion during the observation period. In these women, menstrual bleeding occurred in response to withdrawal from luteal phase (10 to 20 ng/ml) progesterone levels and to exogenous ethinyl estradiol, suggesting normal uterine responsivity to progesterone and estrogen. Although not documented, it is likely that oligo-ovulation was the cause of the irregular menses in these three patients. Amenorrhea is commonly associated with methadone ingestion or heroin addiction and appears to be related to an alteration of the hypothalamic mechanisms controlling gonadotropin secretion. Tolerance to these effects of methadone may develop after chronic ingestion.