Glucagon-like peptide-1 receptor activation antagonizes voltage-dependent repolarizing K(+) currents in beta-cells: a possible glucose-dependent insulinotropic mechanism

Glucagon-like peptide-1 (GLP-1) acts through its G-protein-coupled receptor to enhance glucose-stimulated insulin secretion from pancreatic beta-cells. This is believed to result from modulation of at least two ion channels: ATP-sensitive K(+) (K(ATP)) channels and voltage-dependent Ca(2+) channels. Here, we report that GLP-1 receptor signaling also regulates the activity of beta-cell voltage-dependent K(+) (K(V)) channels, themselves potent glucose-dependent regulators of insulin secretion. GLP-1 receptor activation with exendin 4 (10(-8) mol/l) in rat beta-cells antagonized K(V) currents by 43.3 +/- 6.3%, whereas the GLP-1 receptor antagonist exendin 9-39 had no effect. The effect of GLP-1 receptor activation on K(V) currents could be replicated (current reduction of 55.7 +/- 6.0%) by G-protein activation with GMP-PNP (10 nmol/l). The cAMP pathway antagonist Rp-cAMPS (100 micro mol/l) prevented current inhibition by exendin 4, implicating cAMP signaling in GLP-1 receptor modulation of beta-cell K(V) currents. Finally, exendin 4 (10(-8) mol/l) increased the amplitude (130 +/- 5.7%) and duration (285 +/- 15.9%) of the beta-cell depolarization response to current injection, independent of any effect on K(ATP) or Ca(2+) channels. The present results demonstrate that GLP-1 receptor signaling can antagonize beta-cell repolarization by reducing voltage-dependent K(+) currents, an effect likely to contribute to GLP-1's glucose-dependent insulinotropic effect.     

Diagnosis of breast cancer in women age 40 and younger: delays in diagnosis result from underuse of genetic testing and breast imaging

Background

The impact of newer breast imaging technologies and genetic testing on the detection of breast cancer in women age 40 and younger remains unknown.

Methods

A records review identified 628 women age 40 and younger diagnosed with breast cancer from 1996 to 2008. Patient and tumor characteristics, means of diagnosis, imaging results, and genetic testing were examined.

Results

Tumors were first detected by self-examination in 71%, with a median invasive tumor size of 2.0 cm. Imaging performed at or after diagnosis visualized most tumors; mammography visualized 86%, magnetic resonance imaging (MRI) visualized 96%, and mammography plus MRI visualized more than 98% of tumors. For 81% of patients, the mammogram at diagnosis was their first mammogram. Although 50% had a family history of breast or ovarian cancer, few underwent genetic testing before their cancer diagnosis; 61 of 247 (25%) ultimately tested had a BRCA mutation.

Conclusions

Better use of genetic testing, mammography, and MRI could improve breast cancer detection in young women.     

One-year outcomes of tension-free vaginal tape (TVT) mid-urethral slings in overweight and obese women

Introduction  The purpose of this study was to assess the impact of body mass index (BMI) on tension-free vaginal tape (TVT) success rates, patient satisfaction, and complications 1 year following surgery. Methods  Baseline and 1-year postsurgery outcomes were abstracted, including Urogenital Distress Inventory (UDI-6) scores, Incontinence Impact Questionnaire (IIQ-7) scores, and patient satisfaction ratings. Multivariable logistic and linear regression analyses were performed to examine relationships between outcomes and BMI. Results  Subjects (N = 195) with a mean age of 59.3 ± 12.6 were included. There was significant improvement within each group (all p values <0.01) in total UDI-6 and IIQ-7 scores from baseline to 1 year postsurgery; all groups had high patient satisfaction. No differences in improvement or complications rates were observed among the BMI cohorts (all p values >0.05). Conclusion  Differential counseling of overweight or obese women regarding outcomes of the TVT procedure is not supported by these results; longer follow-up is warranted. Poster presentation Annual Meeting of the Society of Gynecologic Surgeons, April 2009. Partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases DK068389 to HER.     

Association of Body Composition and Physical Activity with Proximal Femur Geometry in Middle-Aged and Elderly Afro-Caribbean Men:

Osteoporotic fractures are less prevalent in African Americans than in caucasians, possibly because of differences in bone structural strength. Bone structural adaptation can be attributed to changes in load, crudely measured as lean and fat mass throughout life. The purpose of this analysis was to describe the associations of leg lean mass, total body fat mass, and hours walked per week with femoral bone mineral density (BMD) and bone geometry in a cross-sectional sample of 1,748 men of African descent between the ages of 40 and 79 years. BMD, section modulus (Z), cross-sectional area (CSA), and subperiosteal width were measured from dual energy X-ray absortiometry (DXA) scans using the hip structural analysis (HSA) program. Multiple linear regression models explained 35% to 48% of the variance in bending (Z) and axial (CSA) strength at the femoral neck and shaft. Independent of all covariates including total body fat mass, one standard deviation increase in leg lean mass was significantly associated with a 5% to 8% higher Z, CSA, and BMD (P < 0.010) at the neck and shaft. The number of hours walked per week was not a strong or consistent independent predictor of bone geometry or BMD. We have shown that weight is the strongest independent predictor of femur BMD and geometric strength although the effect appears to be mediated by lean mass since leg lean mass fraction and total body fat mass fraction had significant and opposing effects at the narrow neck and shaft in this group of middle aged and elderly men.     

Retroperitoneal approach to aortic surgery

The retroperitoneal approach has been recently advocated as an alternate approach to abdominal aortic surgery rather than the traditional transperitoneal approach. A comparative analysis of these two approaches was undertaken to clarify the differences. From June 1984 through June 1986, 172 patients underwent elective infrarenal abdominal aortic surgery on the Vascular Surgery Service at Eastern Virginia Medical School. One hundred nineteen were operated through a transperitoneal approach, and 53 through a retroperitoneal approach. The two groups were similar relative to age, sex, indications, risk factors and operations performed. The groups were then analyzed relative to operating time, blood transfusion, fluid replacement, ileus, morbidity, length of hospital stay, American Society of Anesthesiologists classification, and mortality. Significant differences were found: retroperitoneal patients had shorter operating time, shorter ileus, fewer cardiac complications, and shorter hospitalization than transperitoneal patients. This retrospective evaluation supports the conclusion that the retroperitoneal approach to abdominal aortic surgery is safe and beneficial in most patients. The retroperitoneal approach should therefore be given consideration in routine aortic surgery.     

Testicular metastasis as the first manifestation of colon carcinoma

Metastatic carcinoma to the testes is uncommon, and it is most often found incidentally at autopsy or after orchiectomy for prostatic carcinoma. One of the rarest causes of testicular tumor is metastasis from another primary site. It is even more unusual when the metastasis to the testicle is the first manifestation of the tumor. We report a case of asymptomatic colon carcinoma presenting as metastases to the testis and epididymis, which was diagnosed after biopsy of testicular nodules. Although nonlymphomatous cancer presenting as an intrascrotal mass is extremely rare, seldom detected clinically and almost never the first sign of disease, it should be considered a possibility, even in the young adult who presents with a mass involving the testicle or epididymis.     

"Stem cell" origin of the hematopoietic defect in dyskeratosis congenita

We have used the long-term bone marrow culture (LTBMC) system to analyze hematopoiesis in three patients with dyskeratosis congenita (DC), two of whom had aplastic anemia, and the third had a normal blood count (apart from mild macrocytosis) and normal BM cellularity. Hematopoiesis was severely defective in all three patients, as measured by a low incidence of colony-forming cells and a low level of hematopoiesis in LTBMC. The function of the marrow stroma was normal in its ability to support the growth of hematopoietic progenitors from normal marrows seeded onto them in all three cases, but the generation of hematopoietic progenitors from patients marrow cells inoculated onto normal stromas was reduced, thus suggesting the defect to be of stem cell origin. The parents and unaffected brother of one of the families have also been studied in LTBMC and all showed normal hematopoietic and stromal cell function. From this study we speculate that there are some similarities between DC and the defect in the W/Wv mouse.     

Regeneration of the thymus in old male rats treated with a stable analogue of LHRH

It has been shown that the thymus can be regenerated in intact old rats by implanting s.c. a stable analogue of LHRH. Old male rats were given s.c. implants of osmotic pumps containing a solution in citrate buffer of the analogue which was given at a rate of 1 microgram/h for 28 days. Some animals were given pumps containing buffer alone, and another group of rats was orchidectomized. The animals were killed after 28 days and the tissues weighed and taken for histology. Serum testosterone was measured by radioimmunoassay. Sham-treated rats had small fatty thymuses, which were poorly organized with a very narrow band of cortex. Animals treated with the analogue of LHRH and those which had been orchidectomized had relatively large thymuses which were multi-lobed in drug-treated rats, and atrophied accessory sex organs. The testes were grossly atrophied in analogue-treated rats. Histologically, the thymus looked healthy, having a wide, thymocyte-filled cortex and a clearly defined corticomedullary junction. Serum testosterone concentrations were similar in orchidectomized and analogue-treated rats. It is concluded that it is possible to regenerate the thymus in old rats treated with an analogue of LHRH, but the effect is accompanied by chemical castration. It is also clear that the old pituitary gland is susceptible to the desensitizing action of an LHRH analogue.     

Physician practices in the prevention of venous thromboembolism

OBJECTIVE: To determine the rate of use of prophylaxis for venous thromboembolism in high-risk hospital patients. DESIGN: A retrospective medical record review. SETTING: A community-wide study in 16 short-stay hospitals in central Massachusetts. PATIENTS: A total of 2017 patients with multiple risk factors for venous thromboembolism. MEASUREMENTS AND MAIN RESULTS: On the basis of age, length of hospitalization, and the presence of at least one additional major risk factor, 17% of 151,349 discharges (25,410 patients) were identified as being at high risk for venous thromboembolism. Eight percent of these discharges were randomly selected for medical record review. Prophylaxis for venous thromboembolism was received by 32% of these high-risk patients. Prophylaxis use among the 16 study hospitals varied widely, ranging from 9% to 56%, and was higher in teaching hospitals than in nonteaching hospitals (44% compared with 19%; P less than 0.001). One or more of the following methods of prophylaxis was used: low-dose heparin (78%), intermittent calf compression (13%), warfarin (12%), and inferior vena caval filter (3%). Use of prophylaxis increased with the number of risk factors identified (P less than 0.001). CONCLUSION: Prophylaxis for venous thromboemobolism is underused, particularly in nonteaching hospitals.