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Recent studies have reported that founder viruses play unique roles in establishing HIV-1 infection. Understanding the biological and immunological features of envelope glycoproteins (Env) from such viruses may facilitate the development of effective vaccines against HIV-1. In this report, we evaluated the immunogenicity of gp120 immunogens from two pairs of clade B and two pairs of clade C mother-to-child transmitted (MTCT) HIV-1 variants that had various levels of sensitivity to broadly neutralizing monoclonal antibodies. Individual gp120 DNA and protein vaccines were produced from each of the eight MTCT Env antigens included in the current study. Rabbits were immunized with these gp120 immunogens by the DNA prime-protein boost approach. High level Env-specific antibody responses were elicited by all MTCT gp120 immunogens. However, their abilities to elicit neutralizing antibody (NAb) responses differed and those from relatively neutralization-resistant variants tended to be more effective in eliciting broader NAb. Results of this pilot study indicated that not all MTCT Env proteins have the same potential to elicit NAb. Understanding the mechanism(s) behind such variation may provide useful information in formulating the next generation of HIV vaccines.

BACKGROUND AND OBJECTIVES: Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL).

METHODS: The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m(2) of doxorubicin in 30 mg/m(2) doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function.

RESULTS: A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with >/=1 echocardiogram >/=3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event-free survival rates did not differ between the 2 groups (continuous-infusion, 83% versus bolus-infusion, 78%; P = .24).

CONCLUSIONS: In survivors of childhood high-risk ALL, continuous-infusion doxorubicin, compared with bolus-infusion, provided no long-term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion.

OBJECTIVE:Historically, many children and adolescents with sickle cell disease (SCD) were underweight. Treatment advances like hydroxyurea have been associated with improved growth. We hypothesized that increased hemoglobin (Hb) levels would be associated with increased weight status of children with SCD.

METHODS:Investigators at 6 institutions conducted a retrospective chart review of all patients aged 2 to 19 years of age for the calendar years 2007-2009. Height, weight, baseline Hb levels, demographic information, and select comorbidities were recorded from the most recent clinic visit. Overweight and obesity were defined as >/=85th and >/=95th BMI percentiles for age and gender, respectively, and underweight was defined as sample, 22.4% were overweight or obese, whereas only 6.7% were underweight. Overweight or obese status was associated with sickle genotypes other than Hb SS or Hb Sbeta0 disease, and were associated with higher baseline Hb levels. Underweight individuals were more likely to be male, older, and have had at least 1 SCD-related complication. After adjusting for demographic factors, any SCD-related complication, SCD-directed treatments, and obesity-related conditions, there was a 36% increased odds of overweight/obesity for each 1 g/dL increase in baseline Hb levels.

CONCLUSIONS:Nearly one-quarter of children and adolescents with SCD in New England are overweight or obese. Longitudinal studies are needed to determine the impact of elevated BMI on the morbidity and mortality of both children and adults with SCD.

How best to support change in health-related behaviors is an important public health challenge. The role of mindfulness training in this process has received limited attention. We sought to explore whether mindfulness training is associated with changes in health-related behaviors. The Health Behaviors Questionnaire was used to obtain self-reported dietary behaviors, drinking, smoking, physical activity and sleep quality before and after attendance at an eight-week Mindfulness-Based Stress Reduction program. T-test for paired data and chi-square were used to compare pre-post intervention means and proportions of relevant variables with p = .05 as level of significance. Participants (n = 174; mean age 47 years, range: 19-68; 61 % female) reported significant improvements in dietary behaviors and sleep quality. Partial changes were seen in drinking and physical activity, and no change in smoking. In conclusion, mindfulness training promotes favorable changes in selected health-related behaviors deserving further study through randomized controlled trials.

BACKGROUND: The Veterans Health Administration has implemented patient to clinical team electronic asynchronous secure messaging (SM). This disruptive technology has the potential to support continuous, coordinated quality care, but limited evidence supports this connection.

OBJECTIVES: The objective of this paper is to (1) measure SM implementation and identify facility characteristics associated with higher rates of adoption and (2) understand the association of SM use and noncontinuity care [ie, urgent care (UC)] utilization rates.

MEASURES: We conducted a retrospective cohort study of 132 VA facilities implementing SM in primary care. We used a combination of cross-sectional survey data on predictors of SM implementation and longitudinal data (July 2010-June 2012) on use of SM and UC.

RESULTS: Human resources (coordinator and staff/volunteer availability to directly assist Veterans), computer resources (computers and computer rooms for Veterans), and leadership support for coordinators were associated with increased SM adoption rates. Higher SM use was associated with lower UC rates; early adopters of SM achieved a greater decrease in UC utilization over time than later adopters.

CONCLUSIONS: In this exploratory analysis of early SM implementation in VA, we found a path of associations linking SM and reductions in UC utilization. These results suggest a need for further examination of the relationship between SM and its effects on health care utilization patterns.

The global pandemic of obesity in children and adolescents has resulted in a new expression of diabetes mellitus designated as double diabetes. The entity encompasses the autoimmune load of Type 1 Diabetes and the metabolic load of Type 2 Diabetes. There is no consensus on the best therapeutic modality for this new expression of diabetes mellitus. Optimal therapeutic options must address the coexistence of both metabolic and autoimmune components of diabetes mellitus in the patient. There have also been calls to revise the current classification of diabetes mellitus to take into account the surging prevalence of double diabetes in children and adolescents.

The annual incidence of traumatic spinal cord injury worldwide is estimated to be 35 patients per million. Nonmissile penetrating spinal injuries most commonly occur in the thoracic region, and the majority has neurologic deficits on admission. The management of patients who lack neurologic deficits is controversial due to the risk of neurologic status alteration intraoperatively. However, failure to intervene increases the risk of infection, delayed onset of neurologic deficits, and worsening functional outcome.A 17-year-old boy presented with an intradural T7-T8 knife penetration injury to the spinal cord with no neurologic deficit. Rapid surgical intervention was critical because the knife was lodged between the 2 hemispheres of the spinal cord. The patient was intubated in the lateral position, transferred to the prone position on a Jackson table, and underwent surgical decompression with laminectomy 1 level above and below the injury site, removal of the knife blade in the original path of trajectory, and repair of the dural tear with a collagen matrix. The patient sustained no neurologic sequelae from the penetrating knife injury. He was able to ambulate at discharge and had no complications. To our knowledge, this is the only report of a patient with intradural spinal cord penetration by a foreign object (knife blade) presenting with a normal neurologic preoperative examination that persisted throughout the course of postoperative care.

BACKGROUND: Management of patients with severe acute cholecystitis (AC) remains controversial. In settings where laparoscopic cholecystectomy (LC) can be technically challenging or medical risks are exceedingly high, surgeons can choose between different options, including LC conversion to open cholecystectomy or surgical cholecystostomy tube (CCT) placement, or initial percutaneous CCT. We reviewed our experience treating complicated AC with CCT at a tertiary-care academic medical center.

STUDY DESIGN: All adult patients (n = 185) admitted with a primary diagnosis of AC and who received CCT from 2002 to 2010 were identified retrospectively through billing and diagnosis codes.

RESULTS: Mean patient age was 71 years and 80% had >/=1 comorbidity (mean 2.6). Seventy-eight percent of CCTs were percutaneous CCT placement and 22% were surgical CCT placement. Median length of stay from CCT insertion to discharge was 4 days. The majority (57%) of patients eventually underwent cholecystectomy performed by 20 different surgeons in a median of 63 days post-CCT (range 3 to 1,055 days); of these, 86% underwent LC and 13% underwent open conversion or open cholecystectomy. In the radiology and surgical group, 50% and 80% underwent subsequent cholecystectomy, respectively, at a median of 63 and 60 days post-CCT. Whether surgical or percutaneous CCT placement, approximately the same proportion of patients (85% to 86%) underwent LC as definitive treatment.

CONCLUSIONS: This 9-year experience shows that use of CCT in complicated AC can be a desirable alternative to open cholecystectomy that allows most patients to subsequently undergo LC. Additional studies are underway to determine the differences in cost, training paradigms, and quality of life in this increasingly high-risk surgical population. rights reserved.

OBJECTIVES: Many medical schools are currently undergoing curriculum reform. When considering the means by which students will be evaluated in a revised curriculum, the need to reduce the prevalences of depression and anxiety associated with academic stress must be weighed against the importance of academic outcomes. Pass/fail evaluation, as compared with tiered grading, is commonly presented as a means to adequately assess student performance while minimising stress and anxiety. The purpose of this literature review was to determine the impact of pass/fail grading on medical student well-being and academic outcomes.

METHODS: A systematic search was performed of the available literature published between January 1980 and August 2010, using the PubMed, Ovid Medline, Ovid PsycINFO and ERIC databases. Eligible papers assessed the impact of pass/fail grading on medical student well-being, academic outcomes or both. Academic outcomes included but were not limited to objective measures, such as performance on the US Medical Licensing Examination, and subjective measures, such as student desirability by residency programmes. Reference lists in identified papers were searched and all identified papers were run through a citation index.

RESULTS: Four papers met the inclusion criteria for both well-being and academic outcomes. An additional five papers met the inclusion criteria for academic outcomes only. The four papers that focused on well-being reported improvement in specified areas. No significant difference was identified in any of the five papers examining objective academic outcomes or in those papers that examined the quality of residency programmes attained. Results from two studies suggested that some programme directors believe pass/fail grading creates disadvantages for students in attaining a residency, whereas a third study yielded mixed results about its impact on residency attainment.

CONCLUSIONS: Student well-being is enhanced and objective academic performance is not adversely affected by a pass/fail evaluation system, but students' ability to obtain a desired residency programme may be hindered by individual programme directors' preferences for tiered grading systems. There is an overall paucity of literature on this topic and additional study is needed.

OBJECT: Massachusetts' health insurance mandate and subsidized insurance program, Commonwealth Care, have been active for 2 years.

METHODS: The financial impact on the neurosurgery division and demographics of the relevant patient groups were assessed. The billing records of neurosurgical patients from January 2007 to September 2008 were collected and analyzed.

RESULTS: Commonwealth Care comprised 2.2% of neurosurgical inpatients, and these patients did not have significantly different acuity or lengths of stay from the average. Length of stay of MassHealth patients was significantly greater, although acuity was significantly lower than the average. Increased free care reimbursement and increased MassHealth/Commonwealth Care enrollment resulted in a net gain in reimbursement of hospital charges.

CONCLUSIONS: The increased insurance rates have resulted in increased reimbursement for the neurosurgical division.

BACKGROUND: Psychiatric and neuropsychological side effects of subthalamic nucleus (STN) stimulation have been increasingly recognized. Most programming regimens focus on contacts 0 and 1, whereas contact 3, which often is located near or in the zona incerta (ZI), is usually not used. The question of whether ZI stimulation may limit limbic effects has not been answered.

OBJECTIVE: To examine the effects of short-term stimulation near or in the ZI (contact 3) compared with stimulation of the STN using standard trajectories and targeting as measured by limbic and motor functions.

METHODS: Motor and limbic functions of 11 patients with STN DBS were assessed with the Unified Parkinson Disease Rating Scale-3, structured gait video analysis, Visual Analog Scale mood scales, task testing of impulsivity, and facial recognition under routine STN programming and under stimulation in or near the ZI. Postoperative magnetic resonance imaging confirmed the location of contact 3 near or in the ZI.

RESULTS: Data analysis with repeated-measures analysis of variance revealed that motor scores remained stable with both stimulation settings, with specific improvements in finger taps (P = .02) and rapid alternating movements (P = .03) in ZI stimulation. Stimulation near or in the ZI led to a decrease in self- reported anxiety and depression (P = .03 for both) and an improvement in fear recognition (P = .02).

CONCLUSION: We provide preliminary evidence that stimulation in or near the ZI results in maintained motor function while improving self-reported depression and anxiety in patients with bilateral STN DBS. Stimulation in or near the ZI may provide a useful programming setting for patients prone to psychiatric side effects.

The paramedian forehead flap has become the standard of care for major nasal reconstruction. The classic procedure involves a second-stage operation to divide and inset the external pedicle. We present our experience in a clinical series using single-stage forehead flap reconstruction. Our indications include elderly patients, pediatric patients treated during mission trips, and any patient in whom an external pedicle or two-stage procedure is problematic. From 2008 to 2009, 9 patients underwent a single-stage forehead flap. The majority had defects after excision of skin cancer. Our modification involves removal of radix and proximal nasal skin and fat and deepithelialization of the proximal pedicle to allow inset without excess compression or kinking. This modification avoids the sequelae of an external pedicle, which include bleeding, dressings, the inability to wear eyeglasses, and the patient's reluctance to appear in public. It safely provides acceptable results and avoids a mandatory secondary procedure.

STUDY DESIGN: This is a prospective study.

OBJECTIVE: The aim of our study is to identify whether vertebral arteries (VA), normal or aberrant, are routinely described in cervical spine magnetic resonance imaging (MRI) interpretations.

SUMMARY OF BACKGROUND DATA: VA injury is a serious complication of anterior cervical spine surgery. Aberrant VA anatomy is a potential cause of such complications. Therefore, VA anatomy should be evaluated in cervical MRIs.

METHODS: Six neuroradiologists were blinded to the study design and were asked to interpret 79 cervical MRIs. Of these, 39 had aberrant VAs, whereas 40 had normal VAs. Initially, the indications for the study included only a description of patient's symptoms. The radiologists were then given the same MRIs with different indications. This time, the indications included the patient's symptoms, a request for annotations on the VA, and a definition of VA anomaly. All of the MRI interpretations were then evaluated for the frequency and accuracy of VA description.

RESULTS: When the indications for the study did not specifically request a comment on VAs, the VA was never described (0%). When the indications included the specific request and definition, all 6 commented on the VA (100%). Three of the 6 radiologists were 100% accurate in identifying all 40 normal and 39 aberrant VAs, whereas the other 3 identified all 40 normal and 38 of 39 aberrant VAs.

CONCLUSION: This study demonstrates that the VA is not a standard component of cervical spine MRI interpretations. Because of the significant complications related to its injury, VA anatomy, whether normal or variant, needs to be evaluated in cervical MRIs. When ordering a cervical MRI, surgeons should request a description of the VA and any anomalies.

In a previous study, intraforaminal anomalies were found to occur at a rate of 7.6%. This increases the risk of injury to this vessel if the surgeon is unaware of such abnormalities preoperatively. The aim of our retrospective study was to identify patient factors that may predict anomalous intraforaminal vertebral arteries. Patient records were obtained from a previous study. In that study, the records of each consecutive patient who underwent cervical spine magnetic resonance imaging (MRI) for axial neck pain, radiculopathy, or myelopathy between January 2007 and January 2008 were reviewed. The social and medical histories of each patient were evaluated with respect to the presence or absence of an aberrant vertebral artery. We reviewed the medical records of the 250 patients whose MRIs were reviewed in the previous study. Seven patients were excluded for incomplete records. Chi-square and Fisher's exact tests were performed to compare the normal vertebral artery anatomy patients to the aberrant patients. The medical records of 19 patients with aberrant vertebral arteries and 224 patients with normal vertebral arteries were reviewed. The aberrant group was significantly older than the normal group (P=.00015). The only diagnostic condition that represented a statistically significant difference between the 2 groups was incidence of cancer. A relationship may exist between patient age, cancer, and medialization of the vertebral artery. The mechanism of this possible relationship is unclear. Although aberrant vertebral arteries are rare, a surgeon should have raised suspicion of this possibility in patients with a history of cancer.

Vitreoretinal disorders constitute a significant portion of treatable ocular disease. Advances in vitreoretinal surgery have included the development and characterization of suitable substitutes for the vitreous. Air, balanced salt solutions, perfluorocarbons, expansile gases, and silicone oil serve integral roles in modern vitreoretinal surgery. Vitreous substitutes vary widely in their properties, serve different clinical functions, and present different shortcomings. Permanent vitreous replacement has been attempted with collagen, hyaluronic acid, hydroxypropylmethylcellulose, and natural hydrogel polymers. None, however, have proven to be clinically viable. A long-term vitreous substitute remains to be found, and recent research suggests promise in the area of synthetic polymers. Here we review the currently available vitreous substitutes, as well those in the experimental phase. We classify these compounds based on their functionality, composition, and properties. We also discuss the clinical use, advantages, and shortcomings of the various substitutes. In addition we define the ideal vitreous substitute and highlight the need for a permanent substitute with long-term viability and compatibility. Finally, we attempt to define the future role of biomaterials research and the various functions they may serve in the area of vitreous substitutes.

BACKGROUND: Previous studies have demonstrated a correlation between Clostridium difficile anti-toxin A serum antibodies and protection against symptomatic disease and recurrence.

METHODS: A neutralizing monoclonal antibody to C. difficile toxin A (CDA1) developed by MBL and Medarex, Inc. was studied in a phase II, randomized, double-blind, placebo-controlled trial in patients receiving standard of care treatment for C. difficile infection (CDI). Twenty-nine subjects received a single intravenous infusion of 10mg/kg CDA1 and 17 subjects received placebo and were evaluated for recurrence of CDI during the 56-day study period. Serum antibodies against C. difficile toxin A and B were measured by ELISA and cytotoxicity assay at various time points before and after infusion.

FINDINGS: CDI recurrence occurred in 5 of 29 (17%) in the CDA1 group and 3 of 17 (18%) (p=NS) in the placebo group with a trend toward delay in time to recurrence in the group treated with CDA1. The geometric mean concentration of antibody to an epitope of the receptor-binding domain of toxin B (0.300 and 1.20microg/ml, respectively; p=0.02) and geometric mean titer of neutralizing B antibody (8.00 and 100, respectively; p=0.02) at study day 28 were lower for those subjects with recurrence compared to those who did not recur. In addition, a significantly greater proportion of subjects who recurred were infected with the epidemic BI/NAP1/027 strain compared with those that did not recur (88% vs. 22%; p=0.002). Finally, in a multiple logistic regression analysis neutralizing anti-toxin B at day 14 (p<0.001), anti-toxin A at day 28 (p<0.001) and infection with the BI/NAP1/027 strain at enrollment (p=0.002) were all predictive of CDI recurrence.

INTERPRETATION: In this prospective study, lower concentrations of neutralizing anti-toxin B and anti-toxin A antibody and infection with the BI/NAP1/027 strain of C. difficile were significantly associated with recurrence of CDI.

The Health Post of Corte de Pedra is located in a region endemic for American tegumentary leishmaniasis (ATL) in the Brazilian state of Bahia, and it treats 500-1,300 patients annually. To describe temporal changes in the epidemiology of ATL, we reviewed a random sample of 10% of patient charts (N = 1,209) from 1988 to 2008. There was a twofold increase in the number of cases over the 20-year period, with fluctuations in 10-year cycles. Patients were most frequently male, between the ages of 10 and 30 years, and engaged in agricultural labor; 4.3% of patients had mucosal disease, and 2.4% of patients had disseminated disease. Over the study period, the number of disseminated cases increased threefold, the proportion of cases in younger patients and agricultural workers decreased, and the proportion of patients residing in coastal areas increased. ATL is on the rise in Bahia, with a 10-year periodicity and evolving changes in epidemiology and manifestations of disease.

The pathogenesis of nonalcoholic steatohepatitis (NASH) and inflammasome activation involves sequential hits. The inflammasome, which cleaves pro-interleukin-1beta (pro-IL-1beta) into secreted IL-1beta, is induced by endogenous and exogenous danger signals. Lipopolysaccharide (LPS), a toll-like receptor 4 ligand, plays a role in NASH and also activates the inflammasome. In this study, we hypothesized that the inflammasome is activated in NASH by multiple hits involving endogenous and exogenous danger signals.

METHODS: Using mouse models of methionine choline-deficient (MCD) diet-induced NASH and high-fat diet-induced NASH, we found up-regulation of the inflammasome [including NACHT, LRR, and PYD domains-containing protein 3 (NALP3; cryopyrin), apoptosis-associated speck-like CARD-domain containing protein, pannexin-1, and pro-caspase-1] at the messenger RNA (mRNA) level increased caspase-1 activity, and mature IL-1beta protein levels in mice with steatohepatitis in comparison with control livers. There was no inflammasome activation in mice with only steatosis. The MCD diet sensitized mice to LPS-induced increases in NALP3, pannexin-1, IL-1beta mRNA, and mature IL-1beta protein levels in the liver. We demonstrate for the first time that inflammasome activation occurs in isolated hepatocytes in steatohepatitis. Our novel data show that the saturated fatty acid (FA) palmitic acid (PA) activates the inflammasome and induces sensitization to LPS-induced IL-1beta release in hepatocytes. Furthermore, PA triggers the release of danger signals from hepatocytes in a caspase-dependent manner. These hepatocyte-derived danger signals, in turn, activate inflammasome, IL-1beta, and tumor necrosis factor alpha release in liver mononuclear cells.

CONCLUSION: Our novel findings indicate that saturated FAs represent an endogenous danger in the form of a first hit, up-regulate the inflammasome in NASH, and induce sensitization to a second hit with LPS for IL-beta release in hepatocytes. Furthermore, hepatocytes exposed to saturated FAs release danger signals that trigger inflammasome activation in immune cells. Thus, hepatocytes play a key role in orchestrating tissue responses to danger signals in NASH.

AIM: To examine the activation of the Nalp3 inflammasome and its downstream targets following lipopolysaccharide (LPS)-induced stimulation in the liver.

METHODS: Six-to-eight-week-old C57BL/6 chow fed mice were injected intraperitoneally with 0.5 mug/g bodyweight LPS and sacrificed 2, 4, 6, 18 or 24 h later. LPS-induced liver damage was confirmed by a biochemical assay to detect alanine aminotransferase (ALT) levels. To determine if LPS stimulation in the liver led to activation of the inflammasome, real-time quantitative polymerase chain reaction was used to evaluate the mRNA expression of components of the Nalp3 inflammasome. Enzyme-linked immunosorbent assays were used to determine the protein expression levels of several downstream targets of the Nalp3 inflammasome, including caspase-1 and two cytokine targets of caspase-1, interleukin (IL)-1beta and IL-18.

RESULTS: We found that LPS injection resulted in liver damage as indicated by elevated ALT levels. This was associated with a significant increase in both mRNA and protein levels of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha in the liver, as well as increased levels of TNFs in serum. We showed that LPS stimulation led to upregulation of mRNA levels in the liver for all the receptor components of the inflammasome, including Nalp3, Nalp1, pannexin-1 and the adaptor molecule apoptosis-associated speck-like, caspase recruitment domain-domain containing protein. We also found increased levels of mRNA and protein for caspase-1, a downstream target of the inflammasome. In addition, LPS challenge led to increased levels of both mRNA and protein in the liver for two cytokine targets of caspase-1, IL-1beta and IL-18. Interestingly, substantial baseline expression of pre-IL-1beta and pre-IL-18 was found in the liver. Inflammasome and caspase-1 activation was indicated by the significant increase in the active forms of IL-1beta and IL-18 after LPS stimulation.

CONCLUSION: Our results show that the Nalp3 inflammasome is upregulated and activated in the liver in response to LPS stimulation.