Sequential Broadening of CTL Responses in Early HIV-1 Infection Is Associated with Viral Escape

BACKGROUND: Antigen-specific CTL responses are thought to play a central role in containment of HIV-1 infection, but no consistent correlation has been found between the magnitude and/or breadth of response and viral load changes during disease progression. METHODS AND FINDINGS: We undertook a detailed investigation of longitudinal CTL responses and HIV-1 evolution beginning with primary infection in 11 untreated HLA-A2 positive individuals. A subset of patients developed broad responses, which selected for consensus B epitope variants in Gag, Pol, and Nef, suggesting CTL-induced adaptation of HIV-1 at the population level. The patients who developed viral escape mutations and broad autologous CTL responses over time had a significantly higher increase in viral load during the first year of infection compared to those who did not develop viral escape mutations. CONCLUSIONS: A continuous dynamic development of CTL responses was associated with viral escape from temporarily effective immune responses. Our results suggest that broad CTL responses often represent footprints left by viral CTL escape rather than effective immune control, and help explain earlier findings that fail to show an association between breadth of CTL responses and viral load. Our results also demonstrate that CTL pressures help to maintain certain elements of consensus viral sequence, which likely represent viral escape from common HLA-restricted CTL responses. The ability of HIV to evolve to escape CTL responses restricted by a common HLA type highlights the challenges posed to development of an effective CTL-based vaccine

Identification and structural analysis of the tripartite α-pore forming toxin of Aeromonas hydrophila

The alpha helical CytolysinA family of pore forming toxins (α-PFT) contains single, two, and three component members. Structures of the single component Eschericia coli ClyA and the two component Yersinia enterolytica YaxAB show both undergo conformational changes from soluble to pore forms, and oligomerization to produce the active pore. Here we identify tripartite α-PFTs in pathogenic Gram negative bacteria, including Aeromonas hydrophila (AhlABC). We show that the AhlABC toxin requires all three components for maximal cell lysis. We present structures of pore components which describe a bi-fold hinge mechanism for soluble to pore transition in AhlB and a contrasting tetrameric assembly employed by soluble AhlC to hide their hydrophobic membrane associated residues. We propose a model of pore assembly where the AhlC tetramer dissociates, binds a single membrane leaflet, recruits AhlB promoting soluble to pore transition, prior to AhlA binding to form the active hydrophilic lined pore

ERAS in Spine Surgery

Enhanced recovery after surgery (ERAS) programs afford the opportunity to remedy several challenges within spine surgery. Increasing surgical demand, rising costs, and variability in outcomes favor the need for development of ERAS recommendations in spine surgery. Therefore, official guideline recommendations will likely be published in the coming year. These guidelines were completed following a comprehensive literature search for each of 16 enhanced recovery topics. The majority of interventions remain similar to ERAS recommendations in other subspecialties, consisting primarily of preoperative education and health optimization strategies, multimodal medication protocols during the intraoperative and postoperative periods, and early mobilization with rehabilitation following surgery. Prior to the advent of published ERAS recommendations in spine surgery, several programs have already successfully implemented elements of enhanced recovery for a variety of spine procedures. The success of these programs provides stronger evidence for the utility of ERAS within spine surgery and demonstrates that full implementation of an ERAS program will likely improve recovery for these patients. International and multidisciplinary collaboration will serve to guide ERAS implementation into the future of spine surgery

Tic disorders and ADHD: answers from a world-wide clinical dataset on Tourette syndrome

Abstract Background: Tourette syndrome (TS) is a neurodevelopmental disorder with frequent comorbidity with Attention Deficit-Hyperactivity Disorder (ADHD). The impact of this association is still a matter of debate. Method: Using the TIC database containing 6,805 cases, the clinical differences were ascertained between subjects with and without ADHD. Results: The reported prevalence of ADHD in TS was 55%, within the range of many other reports. If the proband was diagnosed with ADHD, a family history of ADHD was much more likely. ADHD was associated with earlier diagnosis of TS and a much higher rate of anger control problems, sleep problems, specific learning disability, OCD, Oppositional-defiant disorder, mood disorder, social skill deficits, sexually inappropriate behaviour, and self-injurious behaviour. Subjects with seizures and with Developmental Coordination Disorder also had high rates of ADHD. Anxiety disorder, however, was not more frequent. Preliminary data suggest that most behavioural difficulties in ADHD are associated with the Combined or Hyperactive-Impulsive Subtypes of ADHD. Every large site (>200 cases) had a significantly increased rate of anger control problems in cases with ADHD. Conclusion: Subjects with TS have high rates of ADHD and complex associations with other disorders. Clinically the findings confirm other research indicating the importance of ADHD in understanding the behavioural problems often associated with the diagnosis of TS. Additional ADHD comorbidity should be taken into account in diagnosis, management, and training