Rats with low brain angiotensinogen do not exhibit insulin resistance during early aging

During aging increases in body weight, insulin resistance, and elevated systolic pressure contribute to the development of metabolic syndrome. Long-term systemic blockade of the renin-angiotensin system (RAS) with either an angiotensin (Ang) II type 1 (AT₁) receptor antagonist or angiotensin converting enzyme inhibitor improves insulin sensitivity and decreases risk of new onset (type II) diabetes. However, the role of the brain RAS in mediating development of insulin insensitivity during aging is not known. Therefore, we compared responses to an oral glucose load in transgenic rats with selective antisense suppression of brain angiotensinogen (ASrAogen); (mRen2)27 rats with high brain angiotensin II; and control Hannover Sprague-Dawley (SD) rats, at wk 16 and 68 of age. ASrAogen animals had lower body weight than either SD or (mRen2) 27 rats at both ages (p<0.001). The oral glucose tolerance test at 16 wk in (mRen2)27 animals revealed a higher glucose-insulin index (154,421±11,231 untits; p<0.05) and a lower glucose-insulin index in ASrAogen rats (41,580±10,923 units, p<0.05) compared to SD rats (97,134±19,822 units), suggesting insulin resistance in the (mRen2)27 and enhanced insulin sensitivity in the ASrAogen relative to SD rats. At 68 wk, the glucose-insulin index remained low in the ASrAogen rats as evidence of maintained insulin sensitivity during aging compared with either SD or (mRen2)27 (p<0.05). SD animals do not differ from (mRen2)27 rats at 68 wk indicating the development of a state of relative insulin resistance with increased age in the SD rats. Moreover, there was a positive correlation (r=0.44; p<0.05) between body weight and the glucose-insulin index in SD, but not ASrAogen or (mRen2)27 rats. The relationships between insulin and leptin, insulin and glucose, and leptin and body weight observed in SD rats were absent in ASrAogen and (mRen2)27 rats. We conclude that the glial RAS plays a role in development of insulin resistance as well as influencing weight gain associated with early aging.     

Relationship of Psychosocial Risk Factors, Certain Personality Traits and Myocardial Infarction in Indians: A Case�Ccontrol Study

Objective:

To investigate the relationship of psychosocial factors (lack of social support, stress and subjective well-being) and personality traits with myocardial infarction (MI).

Materials and Methods:

A case–control study involving 100 cases and 100 matched controls was conducted in Lok Nayak Hospital, New Delhi.

Results:

Stress over 1 year was significantly higher in cases (P < 0.001). However, difference was not significant when scores of social support (P = 0.2), Presumptive Stressful Life Event (PSLE) over lifetime (P = 0.058) and subjective well-being (P = 0.987) were compared. MI was significantly associated with hyperactive (P < 0.001), dominant (P = 0.03), egoistic (P < 0.001) and introvert (P < 0.001) personalities.

Conclusion:

Certain personality traits and recent stress may be important risk factors of MI, especially in Indians. The finding may have implications on the preventive strategies planned for MI patients.     

Recombinant human interleukin-11 stimulates multilineage hematopoietic recovery in mice after a myelosuppressive regimen of sublethal irradiation and carboplatin

Interleukin-11 (IL-11) is a novel multifunctional hematopoietic cytokine capable of stimulating cells of the myeloid, lymphoid, erythroid, and megakaryocytic lineages in vitro. We have tested the pleiotropic properties of this cytokine on the hematopoietic recovery of mice after a combined regimen of sublethal irradiation and carboplatin administration. This regimen results in severe myelosuppression, characterized by a prolonged period of thrombocytopenia and severe anemia. Administration of recombinant human IL-11 (rhIL-11; 250 micrograms/kg/d) had multilineage effects on bone marrow and spleen hematopoietic activity, increasing the number of megakaryocyte, erythroid, granulocyte, and macrophage progenitors compared with the vehicle-treated controls. This was reflected in the peripheral circulation by a reduction of both the platelet and hematocrit nadirs and a significantly reduced period of thrombocytopenia and anemia in the rhIL-11-treated mice. The results from this study support the broad spectrum of biologic activities that have been attributed to rhIL-11 in vitro and suggest that this cytokine may be an effective agent in the treatment of myelosuppression associated with cancer chemotherapy and bone marrow transplantation.     

Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells

Patients with solid tumors are increasingly being treated by autologous bone marrow transplantation (BMT). Although response rates appear to be increased, disease recurrence is the commonest cause of treatment failure. Whether relapse is entirely due to residual disease in the patient or arises also from infiltrating malignant cells contained in the autologous marrow transplant has not been resolved. If the latter explanation is correct, then purging would be required as part of the transplantation procedure. We used retrovirally mediated transfer of the neomycin-resistance gene to mark BM harvested from eight patients with neuroblastoma in clinical remission. The marked marrow cells were subsequently reinfused as part of an autologous BMT. At relapse, we sought the marker gene in malignant cell populations. Three patients have relapsed, and in each the marker gene was detected by phenotypic and genetic analyses of resurgent malignant cells at medullary and extramedullary sites. Analysis of neuroblast DNA for discrete marker gene integration sites suggested that at least 200 malignant cells, each capable of tumor formation, were introduced with the autologous marrow transplant and contributed to relapse. Thus, autologous BMTs administered to patients with this solid tumor may contain a multiplicity of malignant cells that subsequently contribute to relapse. The marker-gene technique we describe should permit evaluation of the mechanisms of relapse and the efficacy of purging in patients receiving autologous marrow transplantation for other solid tumors that infiltrate the marrow.     

The role of the adrenal gland in hypertensive transgenic rat TGR(mREN2)27.

The TGR(mREN2)27 is a new monogenetic rat model in hypertension research. As the mouse Ren-2d renin gene is integrated into their genome, they develop fulminant hypertension between 5 and 15 weeks of age, with blood pressure maxima of 300 mm Hg. Their plasma renin-angiotensin system (RAS) is suppressed, but the transgene is highly expressed in the adrenal gland, so we investigated its possible role in steroid metabolism and the pathogenesis of hypertension. During the phase of hypertension development (between 6-18 weeks), the urinary excretion of deoxycorticosterone (DOC), corticosterone (B), 18-hydroxycorticosterone, and aldosterone is 1.5- to 2.5-fold elevated compared with that in Sprague-Dawley (SD) rats (P less than 0.0005) despite the suppressed plasma RAS. Moreover, the adrenal gland in TGR(mREN2)27 shows an increased maximal response to ACTH stimulation in regard to urinary excretion of DOC (after ACTH, 244 +/- 42 ng/24 h in TGR; 62 +/- 10 ng/24 h in SD; P less than 0.0005) and B (after ACTH, 5144 +/- 346 ng/24 h in TGR; 2607 +/- 324 ng/24 h in SD; P less than 0.0005). Additionally, plasma prorenin in TGR was stimulated more than 10-fold, indicating transgene regulation by ACTH. Since spironolactone treatment did not lower the blood pressure in TGR, hypertension solely due to hypermineralocorticoism is unlikely. Our results indicate that the adrenal steroid metabolism is markedly stimulated in young TGR, and the absolute increase in urinary DOC and B after ACTH injections is enhanced, possibly due to a stimulated local intraadrenal RAS.     

Body Mass Index and obesity: Tailoring “cut-off” for an Asian Indian male population

Background: Obesity/overweight is a recognized risk factor for a host of disorders. The disease risk stratification is commonly based on the Quetelets Index (Body Mass Index-BMI), a surrogate measure of fatness. The currently used BMI cut-offs to classify people as overweight or obese in Armed Forces have been defined in studies on Caucasian populations. However, because of differences in body structure and composition in different ethnic, socioeconomic, cultural and regional groups the correspondence between BMI and body fat content varies between populations. We conducted this pilot study in the Indian Navy to define BMI cut-offs for overweight and obesity using body fat content derived from Skin Fold Thickness as the standard.