Kv1.3 potassium channel blockade as an approach to insulin resistance

Diabetes mellitus is a devastating metabolic disease caused by either insulin deficiency or resistance and characterised by abnormal glucose, protein and lipid metabolism. It affects > 150 million people worldwide, 14 million in the US alone (90% Type II and 10% Type I) where it accounts for approximately 15% of healthcare expenditure. Insulin resistance is a cardinal feature of Type II diabetes. The molecular mechanisms that mediate insulin resistance are under intense scrutiny, and a major goal of this effort is to uncover potential therapeutic targets. Recent data indicate that the voltage-gated potassium channel, Kv1.3, is an important regulator of peripheral insulin sensitivity and glucose metabolism. Indeed, Kv1.3 channel inhibition increases insulin sensitivity by decreasing inflammatory cytokines and by facilitating the translocation of GLUT4 to the plasma membrane. In light of these novel findings, the author believes that Kv1.3 is a promising target for the development of drugs useful in the management of insulin resistance and diabetes.     

Multiple lung nodules in a woman with a history of melanoma

A 61-year-old Caucasian female presented with a 6-week history of dry persistent cough. She had no shortness of breath, chest pain, fever, chills, or weight loss. She had been diagnosed with melanoma on the left thigh 6 months earlier. It was a spindle cell variant, Clark's grade III, with maximal thickness of 0.5 mm. At the time of diagnosis of melanoma, there was no evidence of metastasis on chest radiographs or computed tomography (CT) of the abdomen and pelvis. Treatment of her melanoma was limited to surgical excision with no subsequent radiation or chemotherapy. Other significant past medical history included hypertension, hypothyroidism, and bilateral breast augmentation. She had a 40 pack-year history of smoking.     

Evaluation of the smallest detectable difference in outcome or process variables in ankylosing spondylitis

OBJECTIVE: To evaluate the smallest detectable difference (SDD) of symptomatic outcome or process variables in ankylosing spondylitis (AS) patients from various countries. METHODS: Thirty consecutive AS patients with axial involvement were recruited from 1 center in each of 4 countries (Spain, Morocco, France, The Netherlands), for a total of 120 patients. Fourteen variables were studied in 6 domains: pain (3 variables), stiffness (1 variable), function (2 variables), spinal mobility (3 variables), patient global assessment (4 variables), and the domain of enthesiopathy (1 variable). All patients were evaluated twice within a 1-week period during which no clinical or therapeutic change occurred. Intracenter reliability was evaluated using the intraclass correlation coefficient (ICC). The SDD was determined using the Bland-Altman method. RESULTS: Of the 14 variables evaluated in the 120 patients (82% males, 42 +/- 12 years old, with a mean disease duration of 17 +/- 13 years), only the SDD for the variable occiput-to-wall distance showed statistically significant difference among centers. For the entire group, the SDD, expressed as percentage of the range of the variable, varied from 10% (Mander enthesis index) to 39% (spinal pain at night last week). The intraobserver reliability was good (ICC > 0.80) except for the variables morning stiffness and modified Schober test (ICCs of 0.76 and 0.60, respectively). CONCLUSION: This study suggests that the evaluation of AS patients is homogenous and reliable in different centers of different European and North African countries. Evaluation of the SDD of the symptomatic outcome or process variables is a starting point to determine the minimum clinically important difference, permitting the presentation of results of clinical studies on an individual basis.     

MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation

MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression primarily through translational repression. In erythropoietic (E) culture of cord blood CD34+ progenitor cells, the level of miR 221 and 222 is gradually and sharply down-modulated. Hypothetically, this decline could promote erythropoiesis by unblocking expression of key functional proteins. Indeed, (i) bioinformatic analysis suggested that miR 221 and 222 target the 3' UTR of kit mRNA; (ii) the luciferase assay confirmed that both miRs directly interact with the kit mRNA target site; and (iii) in E culture undergoing exponential cell growth, miR down-modulation is inversely related to increasing kit protein expression, whereas the kit mRNA level is relatively stable. Functional studies show that treatment of CD34+ progenitors with miR 221 and 222, via oligonucleotide transfection or lentiviral vector infection, causes impaired proliferation and accelerated differentiation of E cells, coupled with down-modulation of kit protein: this phenomenon, observed in E culture releasing endogenous kit ligand, is magnified in E culture supplemented with kit ligand. Furthermore, transplantation experiments in NOD-SCID mice reveal that miR 221 and 222 treatment of CD34+ cells impairs their engraftment capacity and stem cell activity. Finally, miR 221 and 222 gene transfer impairs proliferation of the kit+ TF-1 erythroleukemic cell line. Altogether, our studies indicate that the decline of miR 221 and 222 during exponential E growth unblocks kit protein production at mRNA level, thus leading to expansion of early erythroblasts. Furthermore, the results on kit+ erythroleukemic cells suggest a potential role of these miRs in cancer therapy.     

Dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated fatty acids, attenuates colonic inflammation in rats with DSS-induced colitis

Previous studies proposed a protective role of the dietary intake of (n-3) PUFA in human inflammatory bowel disease (IBD), but almost no studies have been performed using olive oil. The aims of the present study were to test the beneficial effects of an olive oil-based diet with or without fish oil, rich in (n-3) PUFA, in the dextran sodium sulfate (DSS) model of rat colitis and to elucidate the mechanisms involved in their potential beneficial effects, with special attention to the production of some of the mediators involved in the intestinal inflammatory response, such as leukotriene B(4) (LTB(4)), tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO). Rats were fed the different diets for 2 wk before colitis induction and thereafter until colonic evaluation 15 d later. Colitic rats fed the olive oil-based diet had a lower colonic inflammatory response than those fed the soybean oil diet, and this beneficial effect was increased by the dietary incorporation of (n-3) PUFA. A restoration of colonic glutathione levels and lower colonic NO synthase expression occurred in all colitic rats fed an olive oil diet compared with the control colitic group that consumed the soybean oil diet. However, (n-3) PUFA incorporation into an olive oil diet significantly decreased colonic TNFalpha and LTB(4) levels compared with colitic rats that were not supplemented with fish oil. These results affirm the benefits of an olive oil diet in the management of IBD, which are further enhanced by the addition of (n-3) PUFA.     

Community care for people with disability: blurring boundaries between formal and informal caregivers

Health care for individuals with disability is increasingly shifting from institutional settings to the "community," with assistance by those in the formal sector. In this article, the authors examine 5 case studies illustrating interactions and relationships between people with disability and their caregivers, using qualitative data collected as part of a community study of disability conducted in a medium-sized city in the northeastern United States. Employing the task specificity framework, they explore the implications of using either formal care providers to fill needs that are more typically met by family and friends or family caregivers to provide care that is best provided by the formal sector. Although our narratives illustrate the negative implications of mismatched care substitution, we conclude that the framework is less applicable to emerging systems of community care.     

Stroke and ischemic heart disease mortality trends in Brazil from 1979 to 1996

Stroke and ischemic heart disease (IHD) mortality rates were analyzed in Brazilian subjects older than 30 years of age from 1979 to 1996. Population estimates were based on census surveys. Mortality data were obtained from the Ministry of Health. For stroke, the age-adjusted death rate (ADR) dropped from 200 to 164 and from 168 to 130 deaths/100,000 population in men and women, respectively (p < 0.001), in the interval study. For IHD, the ADR dropped from 194 to 164 and from 119 to 105 deaths/100,000 population in men and women, respectively (p < 0.001), in the same time period. Mortality from stroke and IHD combined was greater in men for all age groups (p < 0.001). Stroke was the most frequent cause of death in both women and men except for men aged between 40 and 69 years, in whom IHD was more common. Stroke and IHD were the main causes of death in the Brazilian population.     

Vein versus polytetrafluoroethylene in above-knee femoropopliteal bypass grafting: five-year results of a randomized controlled trial

OBJECTIVE: Controversy still exists whether polytetrafluoroethylene is equivalent to vein as bypass graft material for the above-knee femoropopliteal bypass. Therefore, a prospective randomized trial was performed to compare vein with polytetrafluoroethylene for femoropopliteal bypasses with the distal anastomosis above the knee. METHODS: Between January 1993 and December 1996, 151 above-knee femoropopliteal bypasses were performed. The indications for operation were severe claudication in 120 cases, rest pain in 20 cases, and ulceration in 11 cases. After randomization, 75 reversed saphenous venous bypasses and 76 polytetrafluoroethylene bypasses were performed. RESULTS: No perioperative mortality was seen, and 5% of the patients had minor infections of the wound, not resulting in loss of the bypass, the limb, or life. After 5 years, 38% of the patients had died and 7% were lost to follow-up. Only once was the saphenous vein necessary for coronary artery bypass grafting. Primary patency rates after 5 years were 75.6% for venous bypass grafts and 51.9% for polytetrafluoroethylene grafts (P =.035). Secondary patency rates were 79.7% for vein and 57.2% for polytetrafluoroethylene bypasses (P =.036). In the venous group, 14 bypasses failed, leading to five new bypasses. In the polytetrafluoroethylene group, 29 bypasses failed, leading to 16 reinterventions. For these 16 new bypasses, in four cases, the ipsilateral preserved saphenous vein was used. In both groups, one above-knee amputation and one below-knee amputation had to be performed. CONCLUSION: We conclude after 5 years of follow-up of this randomized controlled trial that a bypass with saphenous vein has better patency rates at all intervals and needs fewer reoperations. Saphenous vein should be the graft material of choice for above-knee femoropopliteal bypasses and should not be preserved for reinterventions. Polytetrafluoroethylene is an acceptable alternative if the saphenous vein is not available.     

Adherence among women with HIV infection in Puerto Rico: the potential use of modified directly observed therapy (MDOT) among pregnant and postpartum women

Women are the fastest growing segment of the adult population acquiring HIV, and most women infected with HIV are in their reproductive years. The success of HAART is highly dependent upon the ability and willingness of the individual to adhere to complex antiretroviral regimens. Improved adherence among HIV-infected pregnant women will delay disease progression in the mother and should also reduce HIV transmission to the baby. Modified directly observed therapy (MDOT), may benefit this population. MDOT has been shown to be an acceptable and feasible intervention among HIV substance users; however, no-one has yet evaluated the use of MDOT in pregnant and postpartum women. Based on semi-structured interviews with 17 Latina women with HIV infection, we explored women's adherence patterns and barriers to adherence and their perceptions of a hypothetical MDOT program. The vast majority of women positively appraised the MDOT program as an effective means to increase and reinforce adherence to demanding drug regimens. Respondents cited the face-to-face contact, the supportive nature of the relationship, and the practical approach of the program as the primary reasons for the effectiveness of MDOT. Results indicate that MDOT could be an acceptable intervention for pregnant and postpartum Latina women to improve adherence to HAART.