Diminished renal kallikrein responses to mineralocorticoid stimulation in African Americans: determinants of an intermediate phenotype for hypertension

BACKGROUND: Hypertension is a complex trait with an ill-defined genetic predisposition, in which renal mechanisms seem to be involved even at the early stages. Renal kallikrein excretion is diminished in patients with hypertension, and perhaps even in the early, prehypertensive phases of the syndrome. African Americans, a group at increased risk of developing hypertension, have especially diminished kallikrein expression, coupled with decreased renal excretion of K(+), a known stimulant of kallikrein expression, suggesting an environmental mechanism for their kallikrein deficit. We, therefore, tested whether short-term indirect (K(+)) or direct (fludrocortisone) stimulation of mineralocorticoid activity might be capable of restoring kallikrein excretion in African Americans. METHODS: Nineteen healthy normotensive young men (n = 10 white, n = 9 African Americans) were treated with the following sequence of four oral medications, each for 1 week: placebo, KCl (120 mEq/day), placebo, and the mineralocorticoid fludrocortisone (0.4 mg/day). At each stage, we measured vital signs, excretion of kallikrein, aldosterone and electrolytes, and serum renin. Results were evaluated by two-way, repeated measures ANOVA. RESULTS: African Americans had diminished urinary excretion of not only kallikrein (P =.007), but also K(+) (P <.001) and aldosterone (P =.015). Kallikrein responses to mineralocorticoid stimulation were substantially blunted in African Americans, whether achieved indirectly (by supplemental K(+); P =.019) or directly (by the exogenous mineralocorticoid fludrocortisone; P =.027), despite achievement of substantial increments in K(+) excretion after KCl (P =.002), and multiple other mineralocorticoid effects after fludrocortisone (P =.005). The kallikrein increment after KCl was best predicted by renin activity (P =.001) rather than ethnicity. Potassium chloride did not lower blood pressure (BP) in either group (P >.4). CONCLUSIONS: Restoration of K(+) and aldosterone secretion to levels found in whites does not normalize kallikrein excretion or lower BP in African Americans, at least in the short term. Nor does exogenous mineralocorticoid stimulation fully restore kallikrein expression in African Americans. Therefore, the diminution of kallikrein biosynthesis in African Americans seems to involve mechanisms at or distal to the aldosterone receptor, and perhaps at the level of the kallikrein gene itself.     

Long-Term Improvements in Pulmonary Function 5 Years After Bariatric Surgery

Background

Obesity is associated with reduced pulmonary function. We evaluated pulmonary function and status of asthma and obstructive sleep apnoea syndrome (OSAS) before and 5 years after bariatric surgery.

Methods

Spirometry was performed at baseline and 5 years postoperatively. Information of asthma and OSAS were recorded. Of 113 patients included, 101 had undergone gastric bypass, 10 duodenal switch and 2 sleeve gastrectomy.

Results

Eighty (71 %) patients were women, mean preoperative age was 40 years and preoperative weight was 133 kg in women and 158 kg in men. Five years postoperatively, weight reduction was 31 % (42 kg; p?<?0.001) in women and 24 % (38 kg; p?<?0.001) in men. Forced expiratory volume in 1 s (FEV1) increased 4.1 % (116 ml; p?<?0.001) in women and 6.7 % (238 ml; p?=?0.003) in men. Forced vital capacity (FVC) increased 5.8 % (209 ml; p?<?0.001) in women and 7.6 % (349 ml; p?<?0.001) in men. Gender and weight loss were independently associated with the improvements in FEV1 and FVC. At follow-up, FEV1 had increased 36 % of the difference towards the estimated normal FEV1, and there was a corresponding 70 % recovery of FVC. These improvements occurred despite an expected decline in pulmonary function by age during the study period. Of the asthmatics and OSAS patients, 48 and 80 %, respectively, were without symptoms 5 years postoperatively.

Conclusions

Pulmonary function measured with spirometry was significantly improved 5 years after bariatric surgery, despite an expected age-related decline during this period. Symptoms of asthma and OSAS also improved.     

Solid extraintestinal malignancies in patients with inflammatory bowel disease

Malignancies constitute the second cause of death in patients with inflammatory bowel diseases (IBD), after cardiovascular diseases. Although it has been postulated that IBD patients are at greater risk of colorectal cancer compared to the general population, lately there has been evidence supporting that this risk is diminishing over time as a result of better surveillance, while the incidence of extraintestinal cancers (EICs) is increasing. This could be attributed either to systemic inflammation caused by IBD or to long-lasting immunosuppression due to IBD treatments. It seems that the overall risk of EICs is higher for Crohn’s disease patients and it is mainly driven by skin cancers, and liver-biliary cancers in patients with IBD and primary sclerosing cholangitis. The aims of this review were first to evaluate the prevalence, characteristics, and risk factors of EICs in patients with IBD and second to raise awareness regarding a proper surveillance program resulting in early diagnosis, better prognosis and survival, especially in the era of new IBD treatments that are on the way.     

Morbidity related to the use of a protective stoma in anterior resection for rectal cancer

Objective To evaluate morbidity related to the use of a protective stoma in rectal resection for cancer. Method Seventy‐two patients undergoing anterior rectal resection for cancer combined with a protective stoma (1993–2005) were included. Loop ileostomy was applied in 61 patients, loop colostomy in 10, and end ileostomy in one. Data regarding the primary operation were recorded prospectively, and stoma complications retrospectively. Results Five patients (7%) developed stoma complications immediately after the primary operation, and 14/70 (20%) following hospital discharge. The stoma was closed in 62 (86%) patients after median 4 (range 1–11) months. Five patients (8%) developed complications in hospital after closure. Two patients (3%) died, one of ileal anastomotic leak and one of myocardial infarction. Five patients (8%) had late complications after closure. A total of 19 patients (26%) developed stoma related complications. Eight (11%) of these were reoperated. Premature stoma closure was necessary in two additional patients. Nine patients (13%) ended up with a permanent stoma. Fourteen (19%) patients developed signs of rectal anastomotic failure, six (8%) of whom needed reoperation. One died. Conclusion Significant morbidity is related to the use of defunctioning stomas. A protective stoma cannot always prevent serious complications of a rectal anastomotic leak, and a proportion of the patients will not have the stoma closed.     

Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses

PURPOSE: Saccharomyces cerevisiae, a nonpathogenic yeast, has been used previously as a vehicle to elicit immune responses to foreign antigens, and tumor-associated antigens, and has been shown to reduce tumor burden in mice. Studies were designed to determine if vaccination of human carcinoembryonic antigen (CEA)-transgenic (CEA-Tg) mice (where CEA is a self-antigen) with a recombinant S. cerevisiae construct expressing human CEA (yeast-CEA) elicits CEA-specific T-cell responses and antitumor activity. EXPERIMENTAL DESIGN: CEA-Tg mice were vaccinated with yeast-CEA, and CD4(+) and CD8(+) T-cell responses were assessed after one and multiple administrations or vaccinations at multiple sites per administration. Antitumor activity was determined by tumor growth and overall survival in both pulmonary metastasis and s.c. pancreatic tumor models. RESULTS: These studies demonstrate that recombinant yeast can break tolerance and that (a) yeast-CEA constructs elicit both CEA-specific CD4(+) and CD8(+) T-cell responses; (b) repeated yeast-CEA administration causes increased antigen-specific T-cell responses after each vaccination; (c) vaccination with yeast-CEA at multiple sites induces a greater T-cell response than the same dose given at a single site; and (d) tumor-bearing mice vaccinated with yeast-CEA show a reduction in tumor burden and increased overall survival compared to mock-treated or control yeast-vaccinated mice in both pulmonary metastasis and s.c. pancreatic tumor models. CONCLUSIONS: Vaccination with a heat-killed recombinant yeast expressing the tumor-associated antigen CEA induces CEA-specific immune responses, reduces tumor burden, and extends overall survival in CEA-Tg mice. These studies thus form the rationale for the incorporation of recombinant yeast-CEA and other recombinant yeast constructs in cancer immunotherapy protocols.     

Age for measles immunization seroconversion after measles vaccination at 6-8 months of age--a randomized controlled trial

The objective of the study was to compare the effectiveness of measles vaccine by seroconversion in vaccinated children with non-vaccinated children of 6 to 8 months age group in a city slum community so as to study the feasibility of advancing the age of immunization. Live attenuated lyophilized Schwartz strain of measles vaccine was used. Hemagglutination inhibition (HI) antibody was estimated. Seroconversion was defined as either the conversion of negative to positive or a two fold rise in titre. One hundred and thirty two children completed the study. There was no difference in the age, sex and nutritional status between vaccinated and non-vaccinated groups (p greater than 0.7). The seroconversion rate in the vaccinated group was 65% and in the non-vaccinated group was 26%. The age, sex and nutritional status did not significantly affect the seroconversion. Our data suggest that immunization with measles vaccine may be effective as early as 6 months of age. Immunization at 6 months may be needed at least for children in densely populated areas like cities and towns.     

Expression of P-glycoprotein and cytochrome p450 1A in intertidal fish (Anoplarchus purpurescens) exposed to environmental contaminants

Whether P-glycoproteins (P-gps) like those which confer multidrug resistance in tumor cell lines are important in adaptation to chemicals in natural populations of vertebrates exposed to contaminant mixtures is the focus of this study. P-gp expression was examined in the intertidal fish high cockscomb blenny (Anoplarchus purpurescens) exposed to crude oil or pulp mill effluent. The relationship between P-gp expression and cytochrome p450 1A (CYP1A) induction also was investigated. Immunohistochemical (IHC) analysis revealed that levels of P-gp expression in the bile canaliculi were three- to five-fold greater in oil exposed fish than in control fish. Levels of P-gp expression were highly correlated with hepatic CYP1A levels previously measured in these fish. In fish from sites near pulp mills, P-gp expression in freshly caught fish did not correlate with proximity to pulp mills. However, hepatic P-gp expression levels in freshly caught fish were 14-fold higher than in fish from those sites that were depurated in clean water for 6 weeks. CYP1A levels were also elevated in liver of freshly caught as compared with depurated fish. Expression of neither CYP1A nor P-gp was elevated in depurated fish exposed to sediment and food from within the original pulp mill effluent stream. Depurated fish, which were injected with the aryl hydrocarbon receptor (AHR) agonist ss-naphthoflavone (BNF) showed an expected induction of CYP1A but no induction of P-gp. These results suggest that in blennies, unlike CYP1A, P-gp expression is not regulated by the AHR pathway; although P-gp and CYP1A both may be induced by some compounds in petroleum and unidentified xenobiotics at field sites. While our data indicate that CYP1A and P-gp are not coordinately regulated, these proteins may play complementary roles in cellular detoxification. Thus the elevation of P-gp activity may be an important mechanism of multixenobiotic resistance for organisms, such as intertidal fish, which are commonly exposed to anthropogenic contaminants and naturally occurring toxins.