Screening for obstructive sleep apnea on the internet: randomized trial.

BACKGROUND: Obstructive sleep apnea is underdiagnosed. We conducted a pilot randomized controlled trial of an online intervention to promote obstructive sleep apnea screening among members of an Internet weight-loss community. METHODS: Members of an Internet weight-loss community who have never been diagnosed with obstructive sleep apnea or discussed the condition with their healthcare provider were randomized to intervention (online risk assessment+feedback) or control. The primary outcome was discussing obstructive sleep apnea with a healthcare provider at 12 weeks. RESULTS: Of 4700 members who were sent e-mail study announcements, 168 (97% were female, age 39.5 years [standard deviation 11.7], body mass index 30.3 [standard deviation 7.8]) were randomized to intervention (n=84) or control (n=84). Of 82 intervention subjects who completed the risk assessment, 50 (61%) were low risk and 32 (39%) were high risk for obstructive sleep apnea. Intervention subjects were more likely than control subjects to discuss obstructive sleep apnea with their healthcare provider within 12 weeks (11% [9/84] vs 2% [2/84]; P=.02; relative risk=4.50; 95% confidence interval, 1.002-20.21). The number needed to treat was 12. High-risk intervention subjects were more likely than control subjects to discuss obstructive sleep apnea with their healthcare provider (19% [6/32] vs 2% [2/84]; P=.004; relative risk=7.88; 95% confidence interval, 1.68-37.02). One high-risk intervention subject started treatment for obstructive sleep apnea. CONCLUSION: An online screening intervention is feasible and likely effective in encouraging members of an Internet weight-loss community to discuss obstructive sleep apnea with their healthcare provider.

Learning curve for robotic-assisted laparoscopic colorectal surgery.

BACKGROUND: Robotic-assisted laparoscopic surgery (RALS) is evolving as an important surgical approach in the field of colorectal surgery. We aimed to evaluate the learning curve for RALS procedures involving resections of the rectum and rectosigmoid. METHODS: A series of 50 consecutive RALS procedures were performed between August 2008 and September 2009. Data were entered into a retrospective database and later abstracted for analysis. The surgical procedures included abdominoperineal resection (APR), anterior rectosigmoidectomy (AR), low anterior resection (LAR), and rectopexy (RP). Demographic data and intraoperative parameters including docking time (DT), surgeon console time (SCT), and total operative time (OT) were analyzed. The learning curve was evaluated using the cumulative sum (CUSUM) method. RESULTS: The procedures performed for 50 patients (54% male) included 25 AR (50%), 15 LAR (30%), 6 APR (12%), and 4 RP (8%). The mean age of the patients was 54.4 years, the mean BMI was 27.8 kg/m(2), and the median American Society of Anesthesiologists (ASA) classification was 2. The series had a mean DT of 14 min, a mean SCT of 115.1 min, and a mean OT of 246.1 min. The DT and SCT accounted for 6.3% and 46.8% of the OT, respectively. The SCT learning curve was analyzed. The CUSUM(SCT) learning curve was best modeled as a parabola, with equation CUSUM(SCT) in minutes equal to 0.73 × case number(2) - 31.54 × case number - 107.72 (R = 0.93). The learning curve consisted of three unique phases: phase 1 (the initial 15 cases), phase 2 (the middle 10 cases), and phase 3 (the subsequent cases). Phase 1 represented the initial learning curve, which spanned 15 cases. The phase 2 plateau represented increased competence with the robotic technology. Phase 3 was achieved after 25 cases and represented the mastery phase in which more challenging cases were managed. CONCLUSIONS: The three phases identified with CUSUM analysis of surgeon console time represented characteristic stages of the learning curve for robotic colorectal procedures. The data suggest that the learning phase was achieved after 15 to 25 cases.

Hypertensive nephropathy treatment by heart-protecting musk pill: a study of anti-inflammatory therapy for target organ damage of hypertension.

This study was designed to investigate the protective effect of the heart-protecting musk pill (HMP) on inflammatory injury of kidney from spontaneously hypertensive rat (SHR). Male SHRs aged 4 weeks were divided into SHR model group, HMP low-dosage group (13.5 mg/kg), and HMP high-dosage group (40 mg/kg). Age-matched Wistar-Kyoto rats were used as normal control. All rats were killed at 12 weeks of age. Tail-cuff method and enzyme-linked immunosorbent assay were used to determine rat systolic blood pressure and angiotensin II (Ang II) contents, respectively. Renal inflammatory damage was evaluated by the following parameters: protein expressions of inflammatory cytokines, carbonyl protein contents, nitrite concentration, infiltration of monocytes/macrophages in interstitium and glomeruli, kidney pathological changes, and excretion rate of urinary protein. HMP did not prevent the development of hypertension in SHR. However, this Chinese medicinal compound decreased renal Ang II content. Consistent with the change of renal Ang II, all the parameters of renal inflammatory injury were significantly decreased by HMP. This study indicates that HMP is a potent suppressor of renal inflammatory damage in SHR, which may serve as a basis for the advanced preventive and therapeutic investigation of HMP in hypertensive nephropathy.

Progenitor cells as remote "bioreactors": Neuroprotection via modulation of the systemic inflammatory response.

Acute central nervous system (CNS) injuries such as spinal cord injury, traumatic brain injury, autoimmune encephalomyelitis, and ischemic stroke are associated with significant morbidity, mortality, and health care costs worldwide. Preliminary research has shown potential neuroprotection associated with adult tissue derived stem/progenitor cell based therapies. While initial research indicated that engraftment and transdifferentiation into neural cells could explain the observed benefit, the exact mechanism remains controversial. A second hypothesis details localized stem/progenitor cell engraftment with alteration of the loco-regional milieu; however, the limited rate of cell engraftment makes this theory less likely. There is a growing amount of preclinical data supporting the idea that, after intravenous injection, stem/progenitor cells interact with immunologic cells located in organ systems distant to the CNS, thereby altering the systemic immunologic/inflammatory response. Such distant cell "bioreactors" could modulate the observed post-injury pro-inflammatory environment and lead to neuroprotection. In this review, we discuss the current literature detailing the above mechanisms of action for adult stem/progenitor cell based therapies in the CNS.

Multicentric hepatic EBV-associated smooth muscle tumors in an AIDS patient: a case report, investigation of mTOR activation and review of the literature.

Epstein-Barr virus (EBV) - associated smooth muscle tumors (EBV-SMT) are a rare, recently recognized distinct group of mesenchymal tumors that develop exclusively in patients with immunosuppression. It is believed that tumorigenesis is, at least in part, through the activation of the Akt/mammalian target of rapamycin (mTOR) signal pathway. We describe the clinicopathologic and immunohistochemical features of a multifocal hepatic EBV-SMT in a 34-year-old acquired immunodeficiency syndrome (AIDS) patient and investigate the activation status of the mTOR signal pathway in this tumor. In addition, we provide a review of the literature on the clinicopathologic findings of hepatic EBV-SMT in adult AIDS patients, and discuss their biologies and possible therapeutic strategies.

Quality of weight loss advice on internet forums.

BACKGROUND: Adults use the Internet for weight loss information, sometimes by participating in discussion forums. Our purpose was to analyze the quality of advice exchanged on these forums. METHODS: This was a retrospective analysis of messages posted to 18 Internet weight loss forums during 1 month in 2006. Advice was evaluated for congruence with clinical guidelines; potential for causing harm; and subsequent correction when it was contradictory to guidelines (erroneous) or potentially harmful. Message- and forum-specific characteristics were evaluated as predictors of advice quality and self-correction. RESULTS: Of 3368 initial messages, 266 (7.9%) were requests for advice. Of 654 provisions of advice, 56 (8.6%) were erroneous and 19 of these 56 (34%) were subsequently corrected. Forty-three (6.6%) provisions of advice were harmful, and 12 of these 43 (28%) were subsequently corrected. Messages from low-activity forums (fewer messages) were more likely than those from high-activity forums to be erroneous (10.6% vs 2.4%, P < .001) or harmful (8.4% vs 1.2%, P < .001). In high-activity forums, 2 of 4 (50%) erroneous provisions of advice and 2 of 2 (100%) potentially harmful provisions of advice were corrected by subsequent postings. Compared with general weight loss advice, medication-related advice was more likely to be erroneous (P = .02) or harmful (P = .01). CONCLUSIONS: Most advice posted on highly active Internet weight loss forums is not erroneous or harmful. However, clinical and research strategies are needed to address the quality of medication-related advice.

Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms.

OBJECTIVE: This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm in patients with Marfan syndrome, familial thoracic aortic aneurysm, or nonfamilial thoracic aortic aneurysm. BACKGROUND: Thoracic aortic aneurysms are associated with a pathologic lesion termed "medial degeneration," which is described as a noninflammatory lesion. Thoracic aortic aneurysms are a complication of Marfan syndrome and can be inherited in an autosomal dominant manner of familial thoracic aortic aneurysm. METHODS: Full aortic segments were collected from patients undergoing elective repair with Marfan syndrome (n = 5), familial thoracic aortic aneurysm (n = 6), and thoracic aortic aneurysms (n = 9), along with control aortas (n = 5). Immunohistochemistry staining was performed using antibodies directed against markers of lymphocytes and macrophages. Real-time polymerase chain reaction analysis was performed to quantify the expression level of the T-cell receptor beta-chain variable region gene. RESULTS: Immunohistochemistry of thoracic aortic aneurysm aortas demonstrated that the media and adventitia from Marfan syndrome, familial thoracic aortic aneurysm, and sporadic cases had increased numbers of T lymphocytes and macrophages when compared with control aortas. The number of T cells and macrophages in the aortic media of the aneurysm correlated inversely with the patient's age at the time of prophylactic surgical repair of the aorta. T-cell receptor profiling indicated a similar clonal nature of the T cells in the aortic wall in a majority of aneurysms, whether the patient had Marfan syndrome, familial thoracic aortic aneurysm, or sporadic disease. CONCLUSION: These results indicate that the infiltration of inflammatory cells contributes to the pathogenesis of thoracic aortic aneurysms. Superantigen-driven stimulation of T lymphocytes in the aortic tissues of patients with thoracic aortic aneurysms may contribute to the initial immune response.

CART: an Hrs/actinin-4/BERP/myosin V protein complex required for efficient receptor recycling.

Altering the number of surface receptors can rapidly modulate cellular responses to extracellular signals. Some receptors, like the transferrin receptor (TfR), are constitutively internalized and recycled to the plasma membrane. Other receptors, like the epidermal growth factor receptor (EGFR), are internalized after ligand binding and then ultimately degraded in the lysosome. Routing internalized receptors to different destinations suggests that distinct molecular mechanisms may direct their movement. Here, we report that the endosome-associated protein hrs is a subunit of a protein complex containing actinin-4, BERP, and myosin V that is necessary for efficient TfR recycling but not for EGFR degradation. The hrs/actinin-4/BERP/myosin V (CART [cytoskeleton-associated recycling or transport]) complex assembles in a linear manner and interrupting binding of any member to its neighbor produces an inhibition of transferrin recycling rate. Disrupting the CART complex results in shunting receptors to a slower recycling pathway that involves the recycling endosome. The novel CART complex may provide a molecular mechanism for the actin-dependence of rapid recycling of constitutively recycled plasma membrane receptors.

Importance of the ebp (endocarditis- and biofilm-associated pilus) locus in the pathogenesis of Enterococcus faecalis ascending urinary tract infection.

BACKGROUND: We recently demonstrated that the ubiquitous Enterococcus faecalis ebp (endocarditis- and biofilm-associated pilus) operon is important for biofilm formation and experimental endocarditis. Here, we assess its role in murine urinary tract infection (UTI) by use of wild-type E. faecalis OG1RF and its nonpiliated, ebpA allelic replacement mutant (TX5475). METHODS: OG1RF and TX5475 were administered transurethrally either at an ~1 : 1 ratio (competition assay) or individually (monoinfection). Kidney pairs and urinary bladders were cultured 48 h after infection. These strains were also tested in a peritonitis model. RESULTS: No differences were observed in the peritonitis model. In mixed UTIs, OG1RF significantly outnumbered TX5475 in kidneys (P=.0033) and bladders (P< or =.0001). More OG1RF colony-forming units were also recovered from the kidneys of monoinfected mice at the 4 inocula tested (P=.015 to P=.049), and 50% infective doses of OG1RF for kidneys and bladder (9.1x10(1) and 3.5x10(3) cfu, respectively) were 2-3 log(10) lower than those of TX5475. Increased tropism for the kidney relative to the bladder was observed for both OG1RF and TX5475. CONCLUSION: The ebp locus, part of the core genome of E. faecalis, contributes to infection in an ascending UTI model and is the first such enterococcal locus shown to be important in this site.

Role played by serum, a biological cue, in the adherence of Enterococcus faecalis to extracellular matrix proteins, collagen, fibrinogen, and fibronectin.

BACKGROUND: Most previous studies have found that Enterococcus faecalis isolates do not show significant adherence to fibronectin and fibrinogen. METHODS: The influence of various conditions on E. faecalis adherence to extracellular matrix (ECM) proteins was evaluated using a radiolabeled-cell adherence assay. RESULTS: Among the conditions studied, growth in 40% horse serum (a biological cue with potential clinical relevance) elicited adherence of all 46 E. faecalis strains tested to fibronectin and fibrinogen but not to elastin; adherence levels were independent of strain source, and adherence was eliminated by treating cells with trypsin. As previously reported, serum also elicited adherence to collagen. Although prolonged exposure to serum during growth was needed for enhancement of adherence to fibrinogen, brief exposure (<5 >min) to serum had an immediate, although partial, enhancing effect on adherence to fibronectin and, to a lesser extent, collagen; pretreatment of bacteria with chloramphenicol did not decrease this enhanced adherence to fibronectin and collagen, indicating that protein synthesis is not required for the latter effect. CONCLUSION: Taken together, these data suggest that serum components may serve (1) as host environmental stimuli to induce the production of ECM protein-binding adhesin(s), as previously seen with collagen adherence, and also (2) as activators of adherence, perhaps by forming bridges between ECM proteins and adhesins.

Denaturation and unfolding of human anaphylatoxin C3a: an unusually low covalent stability of its native disulfide bonds.

The complement C3a anaphylatoxin is a major molecular mediator of innate immunity. It is a potent activator of mast cells, basophils and eosinophils and causes smooth muscle contraction. Structurally, C3a is a relatively small protein (77 amino acids) comprising a N-terminal domain connected by 3 native disulfide bonds and a helical C-terminal segment. The structural stability of C3a has been investigated here using three different methods: Disulfide scrambling; Differential CD spectroscopy; and Reductive unfolding. Two uncommon features regarding the stability of C3a and the structure of denatured C3a have been observed in this study. (a) There is an unusual disconnection between the conformational stability of C3a and the covalent stability of its three native disulfide bonds that is not seen with other disulfide proteins. As measured by both methods of disulfide scrambling and differential CD spectroscopy, the native C3a exhibits a global conformational stability that is comparable to numerous proteins with similar size and disulfide content, all with mid-point denaturation of [GdmCl](1/2) at 3.4-5M. These proteins include hirudin, tick anticoagulant protein and leech carboxypeptidase inhibitor. However, the native disulfide bonds of C3a is 150-1000 fold less stable than those proteins as evaluated by the method of reductive unfolding. The 3 native disulfide bonds of C3a can be collectively and quantitatively reduced with as low as 1mM of dithiothreitol within 5 min. The fragility of the native disulfide bonds of C3a has not yet been observed with other native disulfide proteins. (b) Using the method of disulfide scrambling, denatured C3a was shown to consist of diverse isomers adopting varied extent of unfolding. Among them, the most extensively unfolded isomer of denatured C3a is found to assume beads-form disulfide pattern, comprising Cys(36)-Cys(49) and two disulfide bonds formed by two pair of consecutive cysteines, Cys(22)-Cys(23) and Cys(56)-Cys(57), a unique disulfide structure of polypeptide that has not been documented previously.

Intra-hippocampal administration of the VEGF receptor blocker PTK787/ZK222584 impairs long-term memory.

A number of studies have established a role for vascular endothelial growth factor (VEGF) in angiogenesis. Recent reports have shown that VEGF overexpression in the hippocampus improves learning and memory and is associated with enhanced neurogenesis. PTK787/ZK222584 (PTK/ZK) is a reported inhibitor of VEGFR signaling that is currently being tested for its effects on lung and colon cancer. However, the influence of this drug on cognition has not been examined. In the present study, we questioned if post-training administration of PTK/ZK influences hippocampus-dependent memory. When administered to rats immediately following massed training in the Morris water maze, PTK/ZK impaired spatial memory retention tested 48 h later. This impairment was evidenced by increased latency to the hidden platform and fewer platform crossings. However, this impairment was not associated with a change in neurogenesis during this time frame. PTK/ZK infusion did not reduce VEGFR or AKT phosphorylation, but increased the phosphorylation of ERK. These studies suggest that VEGFR inhibitors such as PTK/ZK may negatively influence cognition.

Body weight, insulin resistance, and serum adipokine levels 2 years after 2 types of bariatric surgery.

OBJECTIVE: Bariatric surgery reverses obesity-related comorbidities, including type 2 diabetes mellitus. Several studies have already described differences in anthropometrics and body composition in patients undergoing Roux-en-Y gastric bypass compared with laparoscopic adjustable gastric banding, but the role of adipokines in the outcomes after the different types of surgery is not known. Differences in weight loss and reversal of insulin resistance exist between the 2 groups and correlate with changes in adipokines. METHODS: Fifteen severely obese women (mean body mass index [BMI]: 46.7 kg/m(2)) underwent 2 types of laparoscopic weight loss surgery (Roux-en-Y gastric bypass=10, adjustable gastric banding=5). Weight, waist and hip circumference, body composition, plasma metabolic markers, and lipids were measured at set intervals during a 24-month period after surgery. RESULTS: At 24 months, patients who underwent Roux-en-Y were overweight (BMI 29.7 kg/m(2)), whereas patients who underwent gastric banding remained obese (BMI 36.3 kg/m(2)). Patients who underwent Roux-en-Y lost significantly more fat mass than patients who underwent gastric banding (mean difference 16.8 kg, P<.05). Likewise, leptin levels were lower in the patients who underwent Roux-en-Y (P=.003), and levels correlated with weight loss, loss of fat mass, insulin levels, and Homeostasis Model of Assessment 2. Adiponectin correlated with insulin levels and Homeostasis Model of Assessment 2 (r=-0.653, P=.04 and r=-0.674, P=.032, respectively) in the patients who underwent Roux-en-Y at 24 months. CONCLUSION: After 2 years, weight loss and normalization of metabolic parameters were less pronounced in patients who underwent gastric banding compared with patients who underwent Roux-en-Y gastric bypass. Our findings require confirmation in a prospective randomized trial.

Role of NonO-histone interaction in TNFalpha-suppressed prolyl-4-hydroxylase alpha1.

Inflammation is a key process in cardiovascular diseases. The extracellular matrix (ECM) of the vasculature is a major target of inflammatory cytokines, and TNFalpha regulates ECM metabolism by affecting collagen production. In this study, we have examined the pathways mediating TNFalpha-induced suppression of prolyl-4 hydroxylase alpha1 (P4Halpha1), the rate-limiting isoform of P4H responsible for procollagen hydroxylation, maturation, and organization. Using human aortic smooth muscle cells, we found that TNFalpha activated the MKK4-JNK1 pathway, which induced histone (H) 4 lysine 12 acetylation within the TNFalpha response element in the P4Halpha1 promoter. The acetylated-H4 then recruited a transcription factor, NonO, which, in turn, recruited HDACs and induced H3 lysine 9 deacetylation, thereby inhibiting transcription of the P4Halpha1 promoter. Furthermore, we found that TNFalpha oxidized DJ-1, which may be essential for the NonO-P4Halpha1 interaction because treatment with gene specific siRNA to knockout DJ-1 eliminated the TNFalpha-induced NonO-P4Halpha1 interaction and its suppression. Our findings may be relevant to aortic aneurysm and dissection and the stability of the fibrous cap of atherosclerotic plaque in which collagen metabolism is important in arterial remodeling. Defining this cytokine-mediated regulatory pathway may provide novel molecular targets for therapeutic intervention in preventing plaque rupture and acute coronary occlusion.