The diagnostic accuracy of truncated cardiovascular MR protocols for detecting non-ischemic cardiomyopathies.

Cardiovascular magnetic resonance imaging is one of the most important diagnostic modalities in the evaluation of cardiomyopathies. However, significant limitations are the complex and time-consuming workflows and the need of contrast agents. The aim of this multi-center retrospective study was to assess workflows and diagnostic value of a short, contrast agent-free cardiac magnetic resonance protocol. 160 patients from Heidelberg, Germany and 119 patients from Montreal, Canada with suspected cardiomyopathy and 20 healthy volunteers have been enrolled. Scans were performed at a 1.5Tesla or 3Tesla scanner in Heidelberg and at a 3Tesla scanner in Montreal. We used single-slice T1 map only. A stepwise analysis of images has been performed. The possible differential diagnosis after each step has been defined. T1-values and color-encoded T1 maps significantly contributed to the differential diagnosis in 54% of the cases (161/299); the final diagnosis has been done without late gadolinium enhancement images in 83% of healthy individuals, in 99% of patients with dilated cardiomyopathy, in 93% of amyloidosis patients, in 94% of patients with hypertrophic cardiomyopathy and in 85% of patients with hypertensive heart disease, respectively. Comparing the scan time with (48 ± 7 min) vs. without contrast agent (23 ± 5 min), significant time saving could be reached by the short protocol. Subgroup analysis showed the most additional diagnostic value of T1 maps in amyloidosis and hypertrophic cardiomyopathy or in confirmation of normal findings. In patients with unclear left ventricular hypertrophy, a short, non-contrast protocol can be used for diagnostic decision-making, if the quality of the T1 map is diagnostic, even if only one slice is available.

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity.

Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells to vorinostat-induced apoptosis. A synthetic lethal functional screen using a whole-genome protein-coding RNAi library was used to identify genes that when knocked down cooperated with vorinostat to induce tumor cell apoptosis in otherwise resistant cells. Through iterative screening, we identified 10 vorinostat-resistance candidate genes that sensitized specifically to vorinostat. One of these vorinostat-resistance genes was GLI1, an oncogene not previously known to regulate the activity of HDACi. Treatment of vorinostat-resistant cells with the GLI1 small-molecule inhibitor, GANT61, phenocopied the effect of GLI1 knockdown. The mechanism by which GLI1 loss of function sensitized tumor cells to vorinostat-induced apoptosis is at least in part through interactions with vorinostat to alter gene expression in a manner that favored apoptosis. Upon GLI1 knockdown and vorinostat treatment, BCL2L1 expression was repressed and overexpression of BCL2L1 inhibited GLI1-knockdown-mediated vorinostat sensitization. Taken together, we present the identification and characterization of GLI1 as a new HDACi resistance gene, providing a strong rationale for development of GLI1 inhibitors for clinical use in combination with HDACi therapy.

Diabetes myonecrosis - A rare complication.

We report a patient with very rare complication of poorly controlled diabetes. Diabetes myonecrosis is a self-limiting condition with unclear pathogenesis and it most commonly affects the quadriceps muscle. Physicians should consider this diagnosis in diabetic patients presenting with sudden onset, non-traumatic muscular pain.

Dietary fat and sleep duration in Chinese men and women.

BACKGROUND: Many recent studies have highlighted the complex interaction between sleep duration, food intake and metabolic balance. Although a causal link is yet to be established, emerging evidence suggests that short sleep duration may alter the balance between energy intake and energy expenditure. Thus far, most research has focussed on the link between sleep duration and carbohydrate metabolism. The role of sleep duration in fat intake and vice versa remains relatively unknown. OBJECTIVE: The aim of this analysis was to determine whether there exists a significant association between sleep duration and fat intake. DESIGN: Data from 2828 adults living in Jiangsu province, China, collected during a national survey of nutrition and health conducted in 2002. RESULTS: The analysis showed a statistically significant association between sleep duration and fat and carbohydrate intake but not protein or fasting blood glucose. Those who slept for less than 7 h a day had significantly higher (P=0.005) percentage of energy from fat intake than those who slept for 7-9 h per day. Analysis of the influence of high fat intake upon sleep demonstrated a trend to reduced sleep duration between the highest and lowest quartiles of fat intake (P=0.056). CONCLUSIONS: To our knowledge, this is the first data from a large cross-sectional study to show an association between decreased sleep duration and increased fat intake in humans. Given the trend towards decreased sleep duration in modern societies and the parallel obesity epidemic, the significance of this association warrants more research.

Acute effects of sildenafil on the electroretinogram and multifocal electroretinogram.

PURPOSE: To evaluate the acute effects of sildenafil (Viagra; Pfizer, Inc, New York, New York) on the electroretinogram and multifocal electroretinogram. METHODS: Eighteen healthy individuals (ages 21-49 years) were studied; 14 were given 200 mg sildenafil orally and four were given only water. All subjects were tested before sildenafil and 1 hour after sildenafil (or water) with a desaturated Panel D-15 color test, a full-field standard electroretinogram, and a multifocal electroretinogram using the VERIS system; five subjects were also tested 5 hours after sildenafil. RESULTS: Responses from the subjects who received sildenafil were compared with those from the control subjects. At 1 hour after sildenafil, photopic single-flash waveforms were attenuated by 9% and scotopic maximal response amplitudes were increased slightly. Photopic and 30-Hz flicker electroretinogram responses were delayed; multifocal electroretinogram waveforms were delayed (5%-9%) and attenuated (14%-22%) across the posterior pole. These changes did not resolve by 5 hours. Nine of the subjects who had received sildenafil (64%) reported visual or systemic symptoms, including one who reported bluish vision. Ten of those subjects (71%) showed a slight increase in color test errors 1 hour after sildenafil. CONCLUSIONS: For at least 5 hours after taking 200 mg of sildenafil, cone function was slightly depressed in the macula and periphery, as measured by full-field electroretinogram and multifocal electroretinogram recordings. However, the affected electroretinogram and multifocal electroretinogram parameters still remained within normal limits.

Acute effects of sildenafil (viagra) on blue-on-yellow and white-on-white Humphrey perimetry.

OBJECTIVE: To study the effects of sildenafil on blue-on-yellow and white-on-white Humphrey visual field (HVF). MATERIALS AND METHODS: Healthy subjects, ages 20 to 38 years, were prospectively randomized to active drug (n = 5) or placebo (n = 3) groups. Blue-on-yellow and white-on-white HVF testing was performed before and 1 hour after masked dosing of sildenafil 200 mg or placebo. Changes in mean deviation (MD) were compared between groups. RESULTS: Three of three placebo and four of five sildenafil subjects had no change on HVF. One of five sildenafil subjects had a decrease in MD of 17.9 dB and 4.7 dB on blue-on-yellow and white-on-white HVF testing, respectively. This subject reported more systemic side effects than other subjects. CONCLUSIONS: Sildenafil has no effect on HVF testing in most persons; however, sildenafil caused an acute abnormality of HVF testing in one subject, who experienced pronounced non-visual systemic symptoms; this effect was greater on blue-on-yellow than white-on-white HVF.

Induction of tubuloreticular structures in cultured human endothelial cells by recombinant interferon alfa and beta.

Tubuloreticular structures were induced in human umbilical vein endothelial cells cultured in media containing recombinant interferon alfa and beta but not in media containing recombinant interferon gamma or other agents that induce interferon, such as 5-bromodeoxyuridine or polyinosinicpolycytidylic acid. Recombinant interferon beta induced tubuloreticular structures in endothelial cells at a lower concentration and in a greater percentage of cell sections than recombinant interferon alfa. This report of tubuloreticular structures being induced in vitro in nonlymphoid cells provides evidence that interferon is the substance that causes the formation of tubuloreticular structures in endothelial cells in vivo.

Tubuloreticular structures and cylindrical confronting cisternae: a review.

Tubuloreticular structures (TRS) and cylindrical confronting cisternae (CCC) are unique subcellular structures that arise from the membranes of the rough endoplasmic reticulum of a variety of cell types. In vivo, they occur most frequently in endothelial cells and lymphocytes from patients with autoimmune diseases and viral infections; they are seen in these cells in almost all acquired immunodeficiency syndrome (AIDS) patients. The inducer(s) of TRS and CCC in vivo is (are) not firmly established. However, clinical and experimental studies indicate that the occurrence of these structures in these diseases is directly related to the endogenous elevation of alpha- and beta-interferon but not to gamma-interferon. Although CCC have been seen and reported to occur in human and primate cells since the late 1970s, their presence did not arouse much clinical and scientific interest until 1983 when they were observed in lymph node tissues of AIDS patients. The nature and pathogenesis of TRS and CCC are obscure. Through the years, many hypotheses have been proposed. They range from suggestions of these structures being incomplete viral particles to being nothing more than accumulated proteins; and from reference to these structures as specific markers for diseases to a generalized cell reaction to certain biological stimuli. In vitro investigations with lymphoblastoid cell lines have contributed a great deal in illuminating the potential clinical significance and the in vivo inducer(s) of TRS and CCC. Both the TRS and CCC are now known to be induced in vitro by alpha- and beta-interferon in some lymphoblastoid cell lines. However, only TRS and not CCC are induced in healthy donor lymphocytes and endothelial cells. Isolation of TRS and CCC using the lymphoblastoid cell system will help clarify the nature, the pathogenesis, and the importance of TRS and CCC in human diseases.

Induction of cylindrical confronting cisternae (AIDS inclusions) in Daudi lymphoblastoid cells by recombinant alpha-interferon.

Cylindrical confronting cisternae (CCC), also known as test-tube and ring-shaped forms, are frequently present in the cytoplasm of lymphocytes and occasionally in other cells from patients with acquired immunodeficiency syndrome (AIDS). Recent data indicate that the presence of these cisternae and tubuloreticular structures (TRS) in lymphocytes from patients at risk for AIDS is predictive of the development of this syndrome. CCC are formed by an alteration of the membranes of the rough endoplasmic reticulum, but the mechanism by which they are formed or demonstration of their induction by specific agents has not been previously reported. We cultured Daudi lymphoblastoid cells in medium containing recombinant alpha-interferon and induced the formation of both TRS and CCC. The number of CCC formed in Daudi cells was directly proportional to the concentration of interferon used and the length of culture. CCC were in direct continuity with TRS, which were induced in cells by interferon at an earlier time. The percentage of cell sections containing TRS stayed the same or decreased somewhat after 72 hours of culture, whereas the number of CCC increased. Our results indicate that CCC could be present in various cells from patients with AIDS and other diseases as a result of elevated interferon levels in these conditions.