Response to treatment with rosiglitazone in familial partial lipodystrophy due to a mutation in the LMNA gene

Background Familial partial lipodystrophy (FPLD) is a monogenic form of diabetes characterised by a dominantly inherited disorder of adipose tissue associated with the loss of subcutaneous fat from the limbs and trunk, with excess fat deposited around the face and neck. The lipodystrophy causes severe insulin resistance, resulting in acanthosis nigricans, diabetes, dyslipidaemia, and increased risk of cardiovascular disease. Preliminary results from animals and man suggest that increasing subcutaneous fat by treatment with thiazolidinediones should improve insulin resistance and the associated features of this syndrome. Case report We report a 24-year-old patient with FPLD caused by a mutation in the LMNA gene (R482W) treated with 12 months of rosiglitazone. Subcutaneous fat increased following rosiglitazone treatment as demonstrated by a 29% generalised increase in skin-fold thickness. Leptin levels increased from 5.8 to 11.2 ng/ml. Compared with treatment on Metformin, there was an increase in insulin sensitivity (HOMA S% 17.2–31.6) but no change in glycaemic control. The lipid profile worsened during the follow-up period. Conclusion This initial case suggests that, for modification of cardiovascular risk factors, there are no clear advantages in treating patients with FPLD with rosiglitazone despite increases in subcutaneous adipose tissue. Larger series will be needed to identify moderate beneficial effects and treatment may be more effective in patients with generalised forms of lipodystrophy.     

A microwave technique for double indirect immunostaining of human brain tissue cultures with mouse monoclonal antibodies.

The use of 2 monoclonal antibodies during double immunohistochemistry would enable the use of a greater variety of antibody combinations. Here, we demonstrate a simple, cost effective method of double indirect immunostaining of cultured cells using primary antibodies from the same species. This method uses microwaving of cell samples immediately after the application of the first secondary antibody, and significantly reduces the level of nonspecific staining. This technique does not elute the antibodies, nor raise the sample temperature above 37 degrees C.     

The presence of the casein kinase II phosphorylation sites of Vpu enhances the CD4(+) T cell loss caused by the simian-human immunodeficiency virus SHIV(KU-lbMC33) in pig-tailed macaques

The simian-human immunodeficiency virus (SHIV)/ macaque model for human immunodeficiency virus type 1 has become a useful tool to assess the role of Vpu in lentivirus pathogenesis. In this report, we have mutated the two phosphorylated serine residues of the HIV-1 Vpu to glycine residues and have reconstructed a SHIV expressing this nonphosphorylated Vpu (SHIV(S52,56G)). Expression studies revealed that this protein was localized to the same intracellular compartment as wild-type Vpu. To determine if this virus was pathogenic, four pig-tailed macaques were inoculated with SHIV(S52,56G) and virus burdens and circulating CD4(+) T cells monitored up to 1 year. Our results indicate that SHIV(S52,56G) caused rapid loss in the circulating CD4(+) T cells within 3 weeks of inoculation in one macaque (CC8X), while the other three macaques developed no or gradual numbers of CD4(+) T cells and a wasting syndrome. Histological examination of tissues revealed that macaque CC8X had lesions in lymphoid tissues (spleen, lymph nodes, and thymus) that were typical for macaques inoculated with pathogenic parental SHIV(KU-1bMC33) and had no lesions within the CNS. To rule out that macaque CC8X had selected for a virus in which there was reversion of the glycine residues at positions 52 and 56 to serine residues and/or compensating mutations occurred in other genes associated with CD4 down-regulation, sequence analysis was performed on amplified vpu sequences isolated from PBMC and from several lymphoid tissues at necropsy. Sequence analysis revealed a reversion of the glycine residues back to serine residues in this macaque. The other macaques maintained low virus burdens, with one macaque (P003) developing a wasting syndrome between months 9 and 11. Histological examination of tissues from this macaque revealed a thymus with severe atrophy that was similar to that of a previously reported macaque inoculated with a SHIV lacking vpu (Virology 293, 2002, 252). Sequence analysis revealed no reversion of the glycine residues in the vpu sequences isolated from this macaque. These results contrast with those from four macaques inoculated with the parental pathogenic SHIV(KU-1bMC33), all of which developed severe CD4(+) T cell loss within 1 month after inoculation. Taken together, these results indicate that casein kinase II phosphorylation sites of Vpu contributes to the pathogenicity of the SHIV(KU-1bMC33) and suggest that the SHIV(KU-1bMC33)/pig-tailed macaque model will be useful in analyzing amino acids/domains of Vpu that contribute to the pathogenesis of HIV-1.     

The effects of calcium and magnesium on inhibitory junctional transmission in smooth muscle of guinea pig small intestine

Summary The membrane potential of smooth muscle cells in the circular layer of the guinea pig ileum was recorded using intracellular electrodes. Transmural stimulation, in the presence of atropine, caused a transient hyperpolarization, an inhibitory junction potential (IJP). IJP's are thought to result from the action of transmitter released from intramural inhibitory nerves. It has been reported that, in the guinea pig jejunum, the amplitude of the IJP resulting from field stimulation is not altered by changes in the calcium and magnesium ion concentration in the bathing solution. Experiments reported here have shown that the IJP amplitude decreased markedly on reducing the calcium ion concentration and or increasing the magnesium ion concentration. Indirect evidence is presented suggesting that the decrease in amplitude of the IJP is due to a decrease in the amount of transmitter released.     

Perceived Confidentiality Risks of Mobile Technology-Based Ecologic Momentary Assessment to Assess High-Risk Behaviors Among Rural Men Who Have Sex with Men

Archives of Sexual Behavior - Although men who have sex with men (MSM) within rural communities are disproportionately impacted by HIV, limited HIV research and programmatic resources are directed...     

Localization of the nonpalpable colonic lesion with intraoperative ultrasound

Localization of an nonpalpable colonic lesion at the time of colectomy usually requires intraoperative colonoscopy. The use of ultrasound to locate the lesion has not been described. A soft bowel clamp is placed above the expected location of the lesion and a catheter placed in the anus. Saline is then instilled into the colon and rectum. The lesion is located by ultrasound scan of the fluid filled colon with the probe placed on the serosal surface. Refinement of the technique was performed on resected colonic specimens. An in vivo trial was then performed with rapid and accurate localization of the lesion for resection. Intraoperative ultrasound of the colon can accurately localize nonpalpable colonic lesions and is an alternative to currently available techniques of localization. Received: 10 December 1997/Accepted: 11 March 1998     

AAV-mediated delivery of the caspase inhibitor XIAP protects against cisplatin ototoxicity.

HYPOTHESIS: Delivery of the gene encoding X-linked inhibitor of apoptosis (XIAP) using an adeno-associated viral (AAV) vector can protect against cisplatin-mediated ototoxicity. BACKGROUND: Cisplatin is a widely used chemotherapeutic agent with significant ototoxic side effects. One possible mechanism of toxicity is apoptotic death of many cochlear cell types. Acute treatment with inhibitors of caspases- enzymes critical for apoptosis- has been shown to prevent hearing loss in vivo, but is too short-acting for therapeutic use. Gene therapy provides a specific and chronic means of delivering potential therapeutic gents. Introducing an anti-apoptotic gene into the cochlea could provide long-term prophylaxis against the ototoxic effects of cisplatin. METHOD: Two groups of rats were treated with unilateral injection into the round window of AAV harboring a gene encoding either XIAP or green fluorescent protein (GFP). After at least two months of gene expression, auditory-brainstem-response (ABR) threshold shifts and outer-hair-cell (OHC) number were measured in these two groups of animals after 72-hour treatment with cisplatin. RESULTS: Consistent with previous reports, uninjected and AAV.GFP-injected ears displayed profound ABR threshold elevations and OHC loss after cisplatin treatment. Ears that had been injected with AAV encoding XIAP, however, were significantly protected from these effects: cisplatin-induced ABR-threshold shift and hair-cell loss were attenuated by as much as 78% and 45%, respectively, when compared with contralateral (untreated) ears. CONCLUSION: XIAP delivery to the cochlea can protect against the audiometric changes and hair-cell loss associated with cisplatin ototoxicity. The efficacy, specificity, and duration of the protective effects make this a potentially attractive therapeutic paradigm.     

VERIDICAL AND FALSE MEMORIES IN HEALTHY OLDER ADULTS AND IN DEMENTIA OF THE ALZHEIMER'S TYPE

Five groups of participants (young, healthy old, healthy old-old, very mild Dementia of the Alzheimer's Type, Mild Dementia of the Alzheimer's Type) studied and were tested on six 12-item lists of words selected from the DRM (Deese, 1959; Roediger & McDermott, 1995) materials. These lists of words strongly converged semantically on a nonpresented critical word. The results indicated that both veridical recall and recognition performance decreased both as a function of age of the participants and as a function of dementia severity. However, the recall and recognition of the highly related nonpresented items actually increased as a function of age, and only slightly decreased as a function of DAT. When false memory was considered as a proportion of veridical memory, there was a clear increase as a function of both age of the participants and as a function of disease severity. The results are discussed in terms of (a) age and DAT-related changes in attention and memory performance, and (b) the underlying mechanisms that produce false memories in the DRM paradigm.     

Postoperative complications: does intensive care unit staff nursing make a difference?

OBJECTIVE: The purpose of this study was to examine the association between intensive care unit nurse (ICU) staffing and the likelihood of complications for patients undergoing abdominal aortic surgery. DESIGN: The study is a retrospective review of hospital discharge data linked to data on ICU organizational characteristics. SETTING: Research took place in ICUs in non-federal, short-stay hospitals in Maryland. PATIENTS: Study included 2606 patients undergoing abdominal aortic surgery in Maryland between January 1994 and December 1996. Outcome Measures: Outcome measures included cardiac, respiratory, and other complications. RESULTS: Cardiac complications occurred in 13% of patients, respiratory complications occurred in 30%, and other complications occurred in 8% of patients. Multiple logistic regression revealed a statistically significant increased likelihood of respiratory complications (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.50-3.60) in abdominal aortic surgery patients cared for in ICUs with low- versus high-intensity nurse staffing, an increased likelihood of cardiac complications (OR, 1.78; CI, 1.16-2.72) and other complications (OR, 1.74; CI, 1.15-2.63) in ICUs with medium- versus high-intensity nurse staffing, after controlling for patient and organizational characteristics. CONCLUSIONS: Within the range of ICU nurse staffing levels present in Maryland hospitals, decreased nurse staffing was significantly associated with an increased risk of complications in patients undergoing abdominal aortic surgery.