Microglial repopulation reverses cognitive and synaptic deficits in an Alzheimer's disease model by restoring BDNF signaling.

Over the past decade, compelling genetic evidence has highlighted the crucial role of microglial dysregulation in the development of Alzheimer's disease (AD). As resident immune cells in the brain, microglia undergo dystrophy and senescence during the chronic progression of AD. To explore the potential therapeutic benefits of replenishing the brain with new microglia in AD, we utilized the CSF1R inhibitor PLX3397 to deplete existing microglia and induce repopulation after inhibitor withdrawal in 5xFAD transgenic mice. Our findings revealed the remarkable benefits of microglial repopulation in ameliorating AD-associated cognitive deficits, accompanied by a notable elevation in synaptic proteins and an enhancement of hippocampal long-term potentiation (LTP). Additionally, we observed the profound restoration of microglial morphology and synaptic engulfment following their self-renewal. The impact of microglial repopulation on amyloid pathology is dependent on the duration of repopulation. Transcriptome analysis revealed a high resemblance between the gene expression profiles of repopulated microglia from 5xFAD mice and those of microglia from WT mice. Importantly, the dysregulated neurotrophic signaling pathway and hippocampal neurogenesis in the AD brain are restored following microglial replenishment. Lastly, we demonstrated that the repopulation restores the expression of brain-derived neurotrophic factor (BDNF) in microglia, thereby contributing to synaptic plasticity. In conclusion, our findings provide compelling evidence to support the notion that microglial self-renewal confers substantial benefits to the AD brain by restoring the BDNF neurotrophic signaling pathway. Thus, targeted microglial repopulation emerges as a highly promising and novel therapeutic strategy for alleviating cognitive impairment in AD.

Clinical Features of Pituitary Stalk Interruption Syndrome in 114 Cases.

Objective To analyze the clinical characteristics of pituitary stalk interruption syndrome(PSIS). Methods The clinical data including clinical manifestations,laboratory tests,and imaging findings of 114 PSIS patients in our hospital were retrospectively analyzed. Results Of these 114 PSIS patients,102 cases (89.4%) were male. The average age was 21.1?6.1 years. A history of breech delivery was documented in 91 cases (91.9%). Short stature was found in 89 cases (71.8%) and bone age delayed (6.1?5.1) years. Secondary sex characteristics were poor or undeveloped in most patients. The prevalence of deficiencies in growth hormone,gonadotropins,corticotropin,and thyrotropin were 100.0%,94.0%,84.2%,and 74.6%,respectively. Hyperprolactinemia was found in 28.1% of patients. Three or more pituitary hormone abnormalities were found in 105 cases(92.1%). Compared with the 5 cases with history of cephalic delivery,no difference were found in the aspects of height(t=0.297,P=0.634),penile length(t=1.205,P=0.882),testicular volume (U=99.000,P=0.348),growth hormone peak (U=89.000,P=0.186),adrenocorticotropic hormone peak(U=131.000,P=0.967),luteinizing hormone peak(U=98.500,P=0.582),thyroid-stimulating hormone (U=82.000,P=0.162),and the height of anterior pituitary (t=1.676,P=0.107) in the 53 cases with history of breech delivery. Conclusions The clinical manifestations,symptoms,hormone deficiencies were severe in our series. The condition severities were not remarkably different in patients with different delivery ways.

The cutoffs and performance of glycated hemoglobin for diagnosing diabetes and prediabetes in a young and middle-aged population and in an elderly population.

The aims were to compare the appropriate cutoffs of glycated hemoglobin (HbA1c) in a population of varying ages and to evaluate the performance of HbA1c for diagnosing diabetes and prediabetes. A total of 1064 participants in the young and middle-aged group and 1671 in the elderly group were included and underwent HbA1c testing and an oral glucose tolerance test (OGTT). Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated to evaluate the optimal HbA1c cutoffs. Kappa coefficients were used to test for agreement between HbA1c categorization and OGTT-based diagnoses. The optimal HbA1c cutoffs for diagnosing diabetes were 5.7% (39 mmol/mol) in the young and middle-aged group with a sensitivity of 66.7%, specificity of 86.7%, and AUC of 0.821 (95% CI: 0.686, 0.955) and 5.9% (41 mmol/mol) in the elderly group with a sensitivity of 80.4%, specificity of 73.3%, and AUC of 0.831 (0.801, 0.861). The optimal cutoffs for diagnosing prediabetes were 5.6% (38 mmol/mol) and 5.7% (39 mmol/mol) in the young and middle-aged group and in the elderly group, respectively. Agreement between the OGTT-based diagnosis of diabetes or prediabetes and the optimal HbA1c cutoff was low (all kappa coefficients <0.4). The combination of HbA1c and fasting plasma glucose increased diagnostic sensitivities or specificities. In conclusion, age-specific HbA1c cutoffs for diagnosing diabetes or prediabetes were appropriate. Furthermore, the performance of HbA1c for diagnosing diabetes and prediabetes was poor. HbA1c should be used in combination with traditional glucose criteria when detecting and diagnosing diabetes or prediabetes.

Experimental study on neuroendocrinological and immunological characteristics of the military-trained artillerymen.

BACKGROUND: Over one million soldiers were treated for battle- or training-fatigue during World War II. Of all ground combat troops, 37% were discharged for psychiatric reasons due to fatigue. The neuroendocrinological and immunological systems played important roles in the work-related fatigue of military personnel. The aim of this study was to investigate the characteristics of fatigue associated with military operations, and we observed changes in the regulatory functions of the neuroendocrinological and immunological systems that may provide theoretical support for improving the combat effectiveness of armies. METHODS: A total of 240 soldiers from the Field Artillery regiment were selected as subjects. Researchers and subjects received training before participating in the study. Data of the subjects' medical histories, physical examinations, scores on a fatigue assessment scale, and assessments of pituitary-adrenal hormones (adrenal cortical hormone (ACTH), cortical hormone (F), and 24-hour urine-free cortisol (UFC)), pituitary-gonadal hormones (luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, estradiol (E2), and prolactin (PRL)), pituitary-thyroid hormones (thyroid-stimulating hormone (TSH), thyroxine (TT4), triiodothyronine (TT3), free thyroxine (FT4), and free triiodothyronine (FT3)), and cellular immune parameters (CD3(+), CD4(+), CD8(+), CD4(+)/CD8(+), B, and NK cells) were investigated before and after large-scale and high-intensity field exercises. Data were statistically analyzed with Student's t test using SPSS software (version 13.0), and P values < 0.05 were deemed to be significant. RESULTS: After the high-intensity military training, the scores on the fatigue scale reflected significant increases of feeling of unpleasantness among soldiers. Additionally, the symptom checklist showed notable increases in somatization scores and significant decreases in psychoticism scores. After intensive military work, levels of plasma ACTH, F, and UFC of soldiers were decreased (P < 0.01). The level of testosterone decreased significantly after the maneuver ((23.51 ± 6.49) versus (18.89 ± 5.89) nmol/L; P < 0.001), whereas the thyroid function (TT3, FT4, and FT3) was markedly increased after the maneuver (P < 0.01). The number of CD3(+), CD4(+), CD4(+)/CD8(+) cells, and B lymphocytes were decreased (P < 0.05), and NK cells were increased (P < 0.001) after the maneuver. CONCLUSIONS: Following high-intensity military operations, the psychological tolerance of soldiers was depressed. And the hypoadrenocorticism (the functional decreases of hypothalamic-pituitary-gonadal and abnormal pituitary-thyroid axis) contributed to the increased levels of fatigue. Hypoimmunity may increase the susceptibility to diseases after high-intensity military operations.

Correlation between 1,5-anhydroglucitol and glycemic excursions in type 2 diabetic patients.

BACKGROUND: The accurate and comprehensive assessment of glycemic control in patients with diabetes is important for optimizing glycemic management and for formulating personalized diabetic treatment schemes. This study aimed to analyze the correlation between 1,5-anhydroglucitol (1,5-AG) and glycemic excursions in type 2 diabetic patients. METHODS: Seventy-one outpatients with type 2 diabetes mellitus were randomly recruited from Chinese People's Liberation Army General Hospital. Using a continuous glucose monitoring system (CGMS), these patients' blood glucose levels were monitored for three consecutive days to obtain mean blood glucose (MBG) data. Intraday glycemic excursions were evaluated using the mean amplitude of glycemic excursions (MAGE), the largest amplitude of glycemic excursions (LAGE), standard deviation of blood glucose (SDBG) and the M-value. Interday glycemic excursion was assessed by absolute mean of daily difference (MODD). Postprandial glycemic fluctuations were evaluated using postprandial glucose excursions (PPGE) and postprandial incremental area under the curve (iAUC). Fasting venous blood samples were collected to measure serum 1,5-AG, whole-blood hemoglobin A1c (HbA1c) and serum glycated albumin (GA). Clinical markers of glycemia and parameters of glycemic excursions from CGMS were analyzed using the Pearson correlation coefficient and multivariate stepwise regression. RESULTS: Pearson correlation analysis revealed that 1,5-AG was significantly correlated with MAGE, SDBG, M-value, LAGE, PPGE and iAUC (r values were -0.509, -0.430, -0.530, -0.462, -0.416 and -0.435, respectively, P < 0.01), especially in moderately and well-controlled patients, based on defined HbA1c levels. Multivariate stepwise regression analysis revealed a negative correlation between 1,5-AG and the above parameters, but not HbA1c and GA. Finally, HbA1c and GA were positively correlated with MBG and fasting blood glucose (FBG). CONCLUSIONS: 1,5-AG was much better than HbA1c and GA as a marker of glycemic excursions in type 2 diabetic patients. Based on these results 1,5-AG is the best metric for assessing postprandial glucose levels in moderately and well-controlled patients, while HbA1c and GA were superior to 1,5-AG for monitoring MBG and FBG.

[Effects of candesartan on expressions of JAK2 and PTP-1B in adipose tissue of high-fat diet-fed rats].

OBJECTIVE: To observe the effects of candesartan on the expressions of JAK2 and protein tyrosine phosphatase-1B (PTP-1B) in adipose tissue of obese rats induced by high-fat diet. METHODS: A total of 45 male Wistar rats were randomly assigned into 3 groups of normal control (NC group), high fat diet (HF group) and high-fat diet with daily Candesartan treatment (FC group). The rats of FC group were treated with orally taken Candesartan at a dose of 8 mg/kg body weight per day. Blood chemistry and insulin were assayed at Week 16. Euglycemic-hyperinsulinemic clamp technique was performed to evaluate the peripheral insulin resistance. The expressions of JAK2 and PTP-1B in adipose tissue were confirmed by both reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. RESULTS: (1) The body weight and peri-renal fat weight of HF group were significantly higher than those of FC and NC groups (all P < 0.05). (2) total cholesterol (TC) and fasting insulin (FINS) of FC group were lower than those of HF group [TC, FC group: (1.37 ± 0.39) mmol/L vs HF group: (2.01 ± 0.26) mmol/L, P < 0.05; FINS, FC group: (3.03 ± 1.37) mU/L vs HF group: (4.76 ± 2.75) mU/L, P < 0.05] while insulin sensitive index (ISI) and angiotensin II (AngII) of FC group were much higher than those of HF group [ISI, FC group: (58 ± 12) × 10(-3) vs HF group: (29 ± 9) × 10(-3), P < 0.05; AngII, FC group: (61 ± 11) mmol/L vs HF group: (52 ± 10) mmol/L, P < 0.05]. (3) The steady-state glucose infusion rate (SSGIR) of FC group was significantly higher than that of HF group [FC group: (22 ± 5) mg×kg(-1)×min(-1) vs HF group:(14 ± 4) mg×kg(-1)min(-1), P < 0.05]. (4) Both the mRNA and protein expressions of JAK2 and PTP-1B in FC group were significantly lower than those in HF group respectively. CONCLUSION: There are insulin resistance and a high expression of JAK2 and PTP-1B in adipose tissue of obese rats induced by high-fat diet. And both are related with the elevated AngII level. Candesartan can reverse these effects.

[Clinical study of glycated albumin measurement by enzymatic method in type 2 diabetes mellitus].

OBJECTIVE: To evaluate the clinical significance of glycated albumin (GA) measured by enzymatic method and to compare its effect with glycosylated hemoglobin A1c (HbA1c) in type 2 diabetes mellitus (DM). METHODS: 128 type 2 DM patients and 84 normal subjects from the Chinese PLA General Hospital were enrolled for the study. The levels of GA, HbA1c, FBG, PBG in DM patient were detected at baseline and followed visit at 2, 4, 8 weeks after blood glucose management. The levels of GA, HbA1c, FBG, PBG and 75 g OGTT were also detected in above normal subjects. RESULTS: Intra CV and inter CV of enzymatic were (0.74-0.9)% and (0.94-1.49)% respectively. In normal subjects GA was in the range of (9-14)%. At baseline, the GA level was significantly correlated with HbA1c (r = 0.8326, P < 0.01), FBG and 2 hour PBG. After 2, 4, 8 weeks treatment, GA level in DM patients was concomitantly decreased with the improvement of FBG, PBG and HbA1c. At early 2 weeks visit, GA, but not HbA1c, showed significant decrease from its baseline (P < 0.05). CONCLUSION: Enzymatic measuring GA was highly correlated with HbA1c, and changing concomitantly with the decrease of HbA1c, FBG, PBG during the 8 weeks treatment. GA was more sensitive than HbA1c for short-term variations of glycemic control during treatment of diabetic patients. GA can be used as a better index of short term mean level of blood glucose in diabetic patients.

[Candesartan improves insulin resistance induced by high-fat diet in rats].

OBJECTIVE: To investigate the effects of candesartan, an angiotension II type I receptor antagonist, in improvement of insulin resistance (IR) induced by high-fat diet and the possible mechanism thereof. METHODS: 45 male Wistar rats were randomly divided into 3 groups: normal chow group (NC, n = 15) fed with normal diet, high fat diet group (HF, n = 15) fed with high fat diet, and high-fat diet with daily candesartan treatment group (HF + C, n = 15) fed with high fat diet and given orally with candesartan 8 mg/kg per day. Body weight was measured regularly. Four weeks later, oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp technique were performed to estimate the insulin sensitivity. After 12 h fasting blood samples were collected from the abdominal aorta to test the contents of blood glucose, and serum triglyceride (TG), total cholesterol (TC), LDL, HDL, and free fatty acid (FFA). Radioimmunoassay was used to detect the serum insulin. Viscera were taken out. Immunohistochemistry was used to examine the expression of peroxisome proliferation activated receptor (PPAR)-gamma in hepatic and adipose tissues. RESULTS: The body weight 16 weeks later of the HF group was significantly higher than that of the HF + C group (P < 0.01). The liver weight and epididymal and peri-renal fat weights of the HF group were all significantly higher than those of the HF + C group and NC group (all P < 0.01). There was no significant difference in fasting blood sugar among these 3 groups (P > 0.05). The glucose levels 2 h after OGTT in the HF + C group was (6.3 +/- 0.5) mmol/L, significantly lower than that of the HF group [(7.3 +/- 1.2) mmol/L, P < 0.01]. The glucose infusion rate (GIR) of the HF + C group was (22 +/- 5) mmol/L, significantly higher than that of the HF group [(14 +/- 4) mmol/L, P < 0.01]. The PPARgamma expression levels in liver and adipose tissue of the HF + C group were up-regulated significantly compared with those of the HF group. CONCLUSION: Candesartan may improve insulin resistance through promoting the expression of PPARgamma in liver and adipose tissue.

[Symptomatic evaluation of late onset hypogonadism in healthy Chinese men].

OBJECTIVE: To investigate the correlation between the symptoms and serum levels of androgen in healthy Chinese men aged over 40 years, and to work out a new symptomatic inventory for screening late onset hypogonadism (LOH) in Chinese men. METHODS: An 18-item questionnaire was designed and 637 respondents were collected from Beijing, Shanghai, Xi'an and Chongqing. Serum total testosterone, calculated free testosterone, testosterone secretion index and free testosterone index were measured. An analysis of the correlation between symptoms and androgens was performed. RESULTS: The twelve-item symptoms were significantly correlated to 2 or more of the 4 androgens mentioned above, marking up a new symptomatic inventory for screening LOH, with a 70% sensitivity and 46% specificity. CONCLUSION: The new symptomatic inventory is acceptable for the screening purpose. The relatively low specificity may be related to the individual response to the decline of serum androgens and age-related changes of other hormones, such as GH-IGF-1 axis, DHEA, thyroid hormones, melatonin and leptin.

[The relationship between metabolic control and the plasma total homocysteine in type 2 diabetes treated with insulin].

OBJECTIVE: To study the relationship between metabolic control and the plasma total homocysteine (tHcy) in type 2 diabetes treated with insulin. METHODS: A total of 68 patients with type 2 diabetes were recruited. At baseline and the end of 3 month therapy, fasting blood samples were collected for measuring fasting blood glucose (FBG), HbA1c, tHcy and other routine biochemical testing and postprandial blood was collected to measure postprandial blood glucose (PBG). RESULTS: FBG, PBG and HbA1c decreased significantly (P < 0.01) after 3 month intensive insulin therapy. tHcy also decreased, but the decrease did not reach statistic significance (P > 0.05). 7.0% of HbA1c was selected as the cut point judging the level of metabolic control. The HbA1c level was less than 7.0% in 31 (45.6%) patients after insulin treatment alone. In these patients, FBG, PBG and HbA1c significantly decreased, when compared with those of pre-treatment. The plasma tHcy decreased significantly as well. CONCLUSIONS: After insulin treatment, the plasma tHcy decreases when the metabolic control is improved significantly.

[The impact of pioglitazone on plasma homocysteine high-fat diet-induced insulin resistance in rats].

OBJECTIVE: To study the effect of pioglitazone on plasma homocysteine in insulin resistant rats induced by high-fat diet. METHODS: 24 Wistar rats were randomized into 3 groups: a control group (n = 8) was fed with normal feeds. High-fat diet was given to a high-fat group and a pioglitazone group. Pioglitazone (10 mg/kg) was then administered by gavage daily for 11 weeks to the pioglitazone group. At week 11, glucose tolerance test was performed, and serum insulin, fasting glucose and plasma homocysteine were detected. Visceral adipose was weighted and then the ratio of visceral adipose over body weight calculated. RESULTS: Fasting glucose, fasting insulin, insulin resistance index (HOMA IR), and the visceral adipose were significantly different among the 3 groups. Fasting glucose, fasting insulin, HOMA IR, and visceral adipose were all significantly lower in the pioglitazone group than those in the high fat group (P < 0.01). Plasma homocysteine decreased significantly in the pioglitazone-treated rats [(8.8 +/- 1.39) micromol/L] as compared with the other two groups [control group: (9.95 +/- 2.40) micromol/L and high fat group: (35.7 +/- 14.1) micromol/L]. Correlation analysis showed that fasting glucose, fasting insulin, HOMA IR and visceral adipose were all factors influencing the plasma homocysteine. Stepwise regression test showed only fasting glucose (r = 0.504, P = 0.031) and HOMA IR (r = 0.302, P = 0.046) independently affected the level of plasma homocysteine. CONCLUSION: It is concluded that pioglitazone can lower plasma homocysteine in insulin resistant Wistar rats induced by high-fat diet.