SUMMARY The concentration of progesterone and oestradiol-17β in peripheral plasma was determined by radioimmunoassay on each day of pregnancy in the mouse. The progesterone concentration, low on days 1 and 2, correlated with the histological development of the corpora lutea. Progesterone levels during the first half of pregnancy rose to a peak on day 6 with a significant decrease (P < 0·02) on day 7. Peripheral progesterone concentration during the second half of pregnancy rose on days 12–13 with a peak on days 14–17, and declined after day 17, 3 days before the onset of parturition. Oestradiol-17β concentrations were high on day 1, declined precipitously to low levels on days 2 and 3 recovering slightly on day 4. The levels then fell and remained low from day 5 to days 15–16, when there was a significant increase in oestradiol-17β concentration which continued until day 20.

Attempts were made to destroy selectively the arcuate nucleus with radiofrequency current in adult female rhesus monkeys as a first step in identifying the areas of the mediobasal hypothalamus (MBH) that are responsible for the neural control of gonadotropin secretion in this species. Extensive or complete destruction of the arcuate region was produced in three animals and in two of these the lesion was confined primarily to the arcuate region and the dorsal aspect of the posterior median eminence. These lesions resulted in the cessation of LH and FSH secretion and blocked the positive feedback action of estradiol on gonadotropin release but did not appear to influence grossly basal thyroid and adrenocortical function, or to abolish GH discharge in response to insulin hypoglycemia. Adenohypophysial infarcts were not observed and exogenous LHRH and TRH induced marked discharges of the appropriate anterior pituitary hormones. In two additional animals with large hypothalamic lesions, destruction of the arcuate region was incomplete. In this group only partial inhibition of gonadotropin secretion was observed. LH and FSH secretion did not appear to be influenced in one animal bearing a large MBH lesion that entirely spared the arcuate region. Although serum prolactin remained at pre-lesion control levels after placement of the two relatively discrete lesions confined to the arcuate region, unambiguous increases in the secretion of this hormone were observed when the area of destruction encompassed tissue anterior and/or dorsal to the arcuate region. These observations suggest that the arcuate region is the primary structure mediating the hypothalamic control of gonadotropin secretion in the rhesus monkey. They also suggest that, in this species, the regions of the MBH involved with the regulation of gonadotropin release and those which control prolactin secretion are anatomically distinct.

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IntroductionRoux-en-Y gastric bypass surgery (RYGB) reduces albuminuria and the long-term incidence of end-stage renal disease in patients with obesity and diabetes. Preclinical modeling in experimental diabetic kidney disease demonstrates that improvements in glomerular structure likely underpin these findings.Research design and methodsIn adult male Zucker diabetic fatty (ZDF) rats, we profiled the effect of RYGB on weight and metabolic control as well biochemical, structural and ultrastructural indices of diabetic renal injury. Furthermore, we sequenced the renal cortical transcriptome in these rats and used bioinformatic pathway analyses to characterize the transcriptional alterations governing the renal reparative response to RYGB.ResultsIn parallel with improvements in weight and metabolic control, RYGB reduced albuminuria, glomerulomegaly, podocyte stress and podocyte foot process effacement. Pathway analysis of RYGB-induced transcriptomic changes in the renal cortex highlighted correction of disease-associated alterations in fibrosis, inflammation and biological oxidation pathways. RYGB reversed disease-associated changes in the expression of transforming growth factor (TGF)-β superfamily genes that strongly correlated with improvements in structural measures of glomerulopathy.ConclusionsImproved glomerular structure in ZDF rats following RYGB is underpinned by pathway level changes, including interruption of the TGF-β-driven early profibrotic programme. Our data provide an important layer of experimental support for clinical evidence demonstrating that RYGB arrests renal damage in patients with obesity and type 2 diabetes.

Obesity is one of the leading preventable causes of cancer; however, little is known about the effects of obesity on anti-tumor immunity. Here, we investigated the effects of obesity on CD8 T cells in mouse models and patients with endometrial cancer. Our findings revealed that CD8 T cell infiltration is suppressed in obesity, which was associated with a decrease in chemokine production. Tumor-resident CD8 T cells were also functionally suppressed in obese mice, which was associated with a suppression of amino acid metabolism. Similarly, we found that a high BMI negatively correlated with CD8 infiltration in human endometrial cancer and that weight loss was associated with a complete pathological response in six of nine patients. Moreover, immunotherapy using anti–PD-1 led to tumor rejection in lean and obese mice and partially restored CD8 metabolism and anti-tumor immunity. These findings highlight the suppressive effects of obesity on CD8 T cell anti-tumor immunity, which can partially be reversed by weight loss and/or immunotherapy.

The corpora lutea (CL) of the cyclic hamster are destroyed between Days 2 and 3 of the 4-day estrous cycle so that only one set is ever present (Day 1 = estrus, Day 4 = proestrus). The possibility that luteal cell death in the cyclic hamster is attributable to apoptosis was explored. The earliest histological signs of structural luteolysis were detected at 0600 h of Day 3 as evidenced by a few scattered luteal cells displaying the characteristic morphology of apoptotic cells and by a massive infiltration of neutrophils. The peaks of neutrophil influx and luteal apoptosis were reached on Day 3, 1200 h, and Day 3, 2400 h, respectively. Thus, the increase in neutrophils occurs before the major onset of luteolysis. By Day 3, 2400 h, the CL had already shrunken one third by weight, and they virtually vanished by the next Day 1. Apoptosis ultimately destroyed luteal endothelial cells, luteal cells, and neutrophils. Electrophoretic analysis of low-molecular weight DNA in luteal cell lysates revealed a definite ladder pattern of oligonucleosomal-length DNA fragments--characteristic of apoptosis--on Day 3 beginning at 1200 h. The pattern was not detectable in CL collected on Day 2. Comparing Day 3 CL collected at 0900-1200 h with those at 1500-1800 h showed that only the latter group exhibited inter-nucleosomal cleavage activity. The minimal number of CL on Day 3, 1500 h, needed to demonstrate DNA laddering was six. In summary, the electrophoretic separation of oligonucleosomal fragments and histology indicated that apoptosis occurs during spontaneous luteal regression on Day 3 of the hamster cycle. The initiation of apoptosis is not apparent until several hours after the onset of functional luteolysis. The rapidity with which apoptosis eliminates the CL over a very precise time schedule makes the cyclic hamster an ideal model to analyze the factors involved in structural luteolysis.

BackgroundThe aim was to study changes in immunohistochemical expression markers of synovial and skin inflammation, clinical outcomes and magnetic resonance imaging (MRI) scores with abatacept treatment in patients with psoriatic arthritis (PsA).MethodsBiological-treatment-naïve PsA patients with active disease including synovitis of a knee were enrolled in this single-centre, crossover study. Patients were randomised to receive intravenous abatacept 3 mg/kg of body weight or placebo infusion on day 1, 15 and 29; thereafter abatacept 10 mg/kg of body weight was administered every 28 days for 5 months. Clinical data were collected at each visit. Synovial biopsy of the involved knee was obtained at baseline and 2 and 6 months. MRI of the same knee and skin biopsy was performed prior to arthroscopy.ResultsFifteen patients were recruited. Significant improvements in the joint-related measures were observed; 90% were European League Against Rheumatism criteria responders and 30% achieved psoriasis area severity index (PASI)50 at 6 months. Reduction in synovitis (P = 0.016) and vascularity (P = 0.039) macroscopic scores consistent with decrease in total MRI score (P = 0.016) were noticed. Abatacept decreased the immunohistological expression of FOXP3+ cells (P = 0.027), specifically the expression of CD4+FOXP3+ regulatory T cells (Tregs) (P = 0.008) in the synovium over 6 months. There was no significant clinical or immunohistological change in any of the skin measures.ConclusionThis is the first study assessing synovial and psoriatic skin immunpathological changes following abatacept treatment in PsA. Reduction in Treg expression in the synovium but not in the psoriatic lesion suggests abnormal Treg function in PsA with differential suppressive capacity in the synovium compared to the lesional skin. The results of this study demonstrate that abatacept 10 mg/kg of body weight might be an effective treatment option for joint disease in patients with PsA.Trial registrationIrish Health Products Regulatory Authority. Trial registration number: CT 900/489/1 – Abatacept (case number: 2077284, EudraCT Number: 2009-017525-19, Protocol number: 77777). Registered on 12 March 2010.

Single iv injections of a rabbit antiserum to synthetic LHRH promptly suppressed serum LH and FSH concentrations in ovariectomized rhesus monkeys. Gonadotropin levels remained depressed for 10-21 days, the approximate duration of enhanced LHRH binding activity in the circulation. Doses of LHRH antiserum sufficient to reduce tonic gonadotropin secretion did not modify the time course or magnitude of estrogen-induced gonadotropin surges. These negative findings, however, cannot be interpreted to signify that such surges are not caused by a release of LHRH.