HIV-1 evades virus-specific IgG2 and IgA responses by targeting systemic and intestinal B cells via long-range intercellular conduits.

Contact-dependent communication between immune cells generates protection but also facilitates viral spread. Here we found that macrophages formed long-range actin-propelled conduits in response to negative factor (Nef), a human immunodeficiency virus type 1 (HIV-1) protein with immunosuppressive functions. Conduits attenuated immunoglobulin G2 (IgG2) and IgA class switching in systemic and intestinal lymphoid follicles by shuttling Nef from infected macrophages to B cells through a guanine-exchange factor-dependent pathway involving the amino-terminal anchor, central core and carboxy-terminal flexible loop of Nef. By showing stronger virus-specific IgG2 and IgA responses in patients with Nef-deficient virions, our data suggest that HIV-1 exploits intercellular 'highways' as a 'Trojan horse' to deliver Nef to B cells and evade humoral immunity systemically and at mucosal sites of entry.

Posterior cranial vault distraction osteogenesis in the immunocompromised patient.

PURPOSE: The treatment of patients with multisuture craniosynostosis is complex and patient-dependent. Cranial distraction osteogenesis is a relatively new procedure for treatment of these patients, with its use increasing in many centers. With this increased use comes an expanding range of indications. Surgical management of multisuture craniosynostosis in therapeutically immunosuppressed patients following a solid organ transplant presents unique challenges. We describe our experience with posterior cranial vault distraction in two patients with multisuture craniosynostosis that had previously undergone organ transplantation. METHODS: Two solid-organ transplant recipient patients with multisuture craniosynostosis were identified. A detailed examination of their medical/transplant history and perioperative details were recorded. RESULTS: The first patient was a 3-year-old girl who received a kidney transplantation in infancy and subsequently presented with a symptomatic Chiari malformation and papilledema. Imaging revealed pansynostosis. She underwent posterior cranial vault distraction extending into a Chiari decompression. Her postoperative course was complicated by distractor site infection at the beginning of consolidation, necessitating early removal of distractors. The second patient was a 2-year-old boy who received a heart transplantation at the age of 3 months and subsequently presented with head shape concerns. Imaging revealed bicoronal and sagittal craniosynostosis. He underwent a posterior cranial vault distraction without complication. Following removal of the distractors, he developed an infection at one of the distractor sites with associated fever and leukocytosis, necessitating washout and drain placement. Both patients achieved successful cranial vault expansion with distraction osteogenesis and at a 2-year follow-up do not have evidence of elevated intracranial pressure. CONCLUSIONS: Immunosuppressive therapy has the potential to inhibit wound healing and place patients at risk for wound infection. Although we have demonstrated successful cranial vault expansion with distraction in two immunosuppressed children, extra care must be taken with these patients when placing semi-buried hardware. Specifically, prompt identification and proactive management of potential infectious complications is critical to applying this technique safely in these patients.

Source-space EEG neurofeedback links subjective experience with brain activity during effortless awareness meditation.

BACKGROUND: Meditation is increasingly showing beneficial effects for psychiatric disorders. However, learning to meditate is not straightforward as there are no easily discernible outward signs of performance and thus no direct feedback is possible. As meditation has been found to correlate with posterior cingulate cortex (PCC) activity, we tested whether source-space EEG neurofeedback from the PCC followed the subjective experience of effortless awareness (a major component of meditation), and whether participants could volitionally control the signal. METHODS: Sixteen novice meditators and sixteen experienced meditators participated in the study. Novice meditators were briefly trained to perform a basic meditation practice to induce the subjective experience of effortless awareness in a progressively more challenging neurofeedback test-battery. Experienced meditators performed a self-selected meditation practice to induce this state in the same test-battery. Neurofeedback was provided based on gamma-band (40-57Hz) PCC activity extracted using a beamformer algorithm. Associations between PCC activity and the subjective experience of effortless awareness were assessed by verbal probes. RESULTS: Both groups reported that decreased PCC activity corresponded with effortless awareness (P<0.0025 for each group), with high median confidence ratings (novices: 8 on a 0-10 Likert scale; experienced: 9). Both groups showed high moment-to-moment median correspondence ratings between PCC activity and subjective experience of effortless awareness (novices: 8, experienced: 9). Both groups were able to volitionally control the PCC signal in the direction associated with effortless awareness by practicing effortless awareness meditation (novices: median % of time=77.97, P=0.001; experienced: 89.83, P<0.0005). CONCLUSIONS: These findings support the feasibility of using EEG neurofeedback to link an objective measure of brain activity with the subjective experience of effortless awareness, and suggest potential utility of this paradigm as a tool for meditation training.

Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice.

Humans with ALS and transgenic rodents expressing ALS-associated superoxide dismutase (SOD1) mutations develop spontaneous blood-spinal cord barrier (BSCB) breakdown, causing microvascular spinal-cord lesions. The role of BSCB breakdown in ALS disease pathogenesis in humans and mice remains, however, unclear, although chronic blood-brain barrier opening has been shown to facilitate accumulation of toxic blood-derived products in the central nervous system, resulting in secondary neurodegenerative changes. By repairing the BSCB and/or removing the BSCB-derived injurious stimuli, we now identify that accumulation of blood-derived neurotoxic hemoglobin and iron in the spinal cord leads to early motor-neuron degeneration in SOD1(G93A) mice at least in part through iron-dependent oxidant stress. Using spontaneous or warfarin-accelerated microvascular lesions, motor-neuron dysfunction and injury were found to be proportional to the degree of BSCB disruption at early disease stages in SOD1(G93A) mice. Early treatment with an activated protein C analog restored BSCB integrity that developed from spontaneous or warfarin-accelerated microvascular lesions in SOD1(G93A) mice and eliminated neurotoxic hemoglobin and iron deposits. Restoration of BSCB integrity delayed onset of motor-neuron impairment and degeneration. Early chelation of blood-derived iron and antioxidant treatment mitigated early motor-neuronal injury. Our data suggest that BSCB breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BSCB integrity during an early disease phase retards the disease process.

Development, manufacturing and characterization of a highly purified, liquid immunoglobulin g preparation from human plasma.

BACKGROUND: The use of plasma-derived immunoglobulin G (IgG) is increasing, and the number of diseases, including immunodeficiencies, neurological diseases and autoimmune conditions, treated with intravenous IgG (IVIG) is expanding. Consequently, there is a great need for high-yield production processes for plasma-derived IgG. The aim of this work was to develop a high-yield process leading to a highly purified, liquid, ready-to-use IgG for intravenous use. METHODS: Plasma from healthy, voluntary, non-remunerated donors was fractionated by ethanol precipitation. IgG was extracted from fraction II + III using a phosphate/acetate buffer, pH 4, and purified by chromatography. RESULTS: Precipitation with 6% polyethylene glycol at pH 7 removed high molecular-weight contaminating proteins, aggregates and contaminating viruses. Ion exchange chromatography at pH 5.7 on serially connected anion and cation exchange columns allowed for elution of IgG from the cation exchange column in good yield and high purity. Further safety was achieved by solvent/detergent treatment and repeated ion exchange chromatography. The product consisted of essentially only IgG monomers and dimers, and had a high purity with very low levels of IgM and IgA. CONCLUSION: A process providing highly purified IVIG in good yield was developed.

Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis.

The blood-brain barrier and blood-spinal cord barrier (BSCB) limit the entry of plasma components and erythrocytes into the central nervous system (CNS). Pericytes play a key role in maintaining blood-CNS barriers. The BSCB is damaged in patients with amyotrophic lateral sclerosis (ALS). Moreover, transgenic ALS rodents and pericyte-deficient mice develop BSCB disruption with erythrocyte extravasation preceding motor neuron dysfunction. Here, we studied whether BSCB disruption with erythrocyte extravasation and pericyte loss are present in human ALS. We show that 11 of 11 cervical cords from ALS patients, but 0 of 5 non-neurodegenerative disorders controls, possess perivascular deposits of erythrocyte-derived hemoglobin and hemosiderin typically 10-50 µm in diameter suggestive of erythrocyte extravasation. Immunostaining for CD235a, a specific marker for erythrocytes, confirmed sporadic erythrocyte extravasation in ALS, but not controls. Quantitative analysis revealed a 3.1-fold increase in perivascular hemoglobin deposits in ALS compared to controls showing hemoglobin confined within the vascular lumen, which correlated with 2.5-fold increase in hemosiderin deposits (r = 0.82, p < 0.01). Spinal cord parenchymal accumulation of plasma-derived immunoglobulin G, fibrin and thrombin was demonstrated in ALS, but not controls. Immunostaining for platelet-derived growth factor receptor-ß, a specific marker for CNS pericytes, indicated a 54 % (p < 0.01) reduction in pericyte number in ALS patients compared to controls. Pericyte reduction correlated negatively with the magnitude of BSCB damage as determined by hemoglobin abundance (r = -0.75, p < 0.01). Thus, the BSCB disruption with erythrocyte extravasation and pericyte reductions is present in ALS. Whether similar findings occur in motor cortex and affected brainstem motor nuclei remain to be seen.

Seasoned adaptive antibody immunity for highly pathogenic pandemic influenza in humans.

Fundamentally new approaches are required for the development of vaccines to pre-empt and protect against emerging and pandemic influenzas. Current strategies involve post-emergent homotypic vaccines that are modelled upon select circulating 'seasonal' influenzas, but cannot induce cross-strain protection against newly evolved or zoonotically introduced highly pathogenic influenza (HPI). Avian H5N1 and the less-lethal 2009 H1N1 and their reassortants loom as candidates to seed a future HPI pandemic. Therefore, more universal 'seasoned' vaccine approaches are urgently needed for heterotypic protection ahead of time. Pivotal to this is the need to understand mechanisms that can deliver broad strain protection. Heterotypic and heterosubtypic humoral immunities have largely been overlooked for influenza cross-protection, with most 'seasoned' vaccine efforts for humans focussed on heterotypic cellular immunity. However, 5 years ago we began to identify direct and indirect indicators of humoral-herd immunity to protein sites preserved among H1N1, H3N2 and H5N1 influenzas. Since then the evidence for cross-protective antibodies in humans has been accumulating. Now proposed is a rationale to stimulate and enhance pre-existing heterotypic humoral responses that, together with cell-mediated initiatives, will deliver pre-emptive and universal human protection against emerging epidemic and pandemic influenzas.

Electromagnetic interference complicating Impella® use during pediatric ablation.

In children, the Impella® is most commonly used in the setting of cardiogenic shock. There are few reported cases of Impella® use in pediatric patients undergoing ablation; description of troubleshooting techniques may improve success rates. We describe a pediatric patient with tachycardia-induced cardiomyopathy due to incessant ectopic atrial tachycardia whose ablation was notable for significant electromagnetic interference (EMI) from the Impella® leading to incomplete mapping. This case highlights the need for multidisciplinary planning and consideration of possible EMI with the use of magnet-based electroanatomic mapping systems as well as troubleshooting techniques to reduce the impact of EMI.

Serological Immunity to Smallpox in New South Wales, Australia.

The re-emergence of smallpox is an increasing and legitimate concern due to advances in synthetic biology. Vaccination programs against smallpox using the vaccinia virus vaccine ceased with the eradication of smallpox and, unlike many other countries, Australia did not use mass vaccinations. However, vaccinated migrants contribute to population immunity. Testing for vaccinia antibodies is not routinely performed in Australia, and few opportunities exist to estimate the level of residual population immunity against smallpox. Serological data on population immunity in Australia could inform management plans against a smallpox outbreak. Vaccinia antibodies were measured in 2003 in regular plasmapheresis donors at the Australian Red Cross Blood Service from New South Wales (NSW). The data were analysed to estimate the proportion of Australians in NSW with detectable serological immunity to vaccinia. The primary object of this study was to measure neutralising antibody titres against vaccinia virus. Titre levels in donor samples were determined by plaque reduction assay. To estimate current levels of immunity to smallpox infection, the decline in geometric mean titres (GMT) over time was projected using two values for the antibody levels estimated on the basis of different times since vaccination. The results of this study suggest that there is minimal residual immunity to the vaccinia virus in the Australian population. Although humoral immunity is protective against orthopoxvirus infections, cell-mediated immunity and immunological memory likely also play roles, which are not quantified by antibody levels. These data provide an immunological snapshot of the NSW population, which could inform emergency preparedness planning and outbreak control, especially concerning the stockpiling of vaccinia vaccine.

Possible clearance of transfusion-acquired nef/LTR-deleted attenuated HIV-1 infection by an elite controller with CCR5 Δ32 heterozygous and HLA-B57 genotype.

BACKGROUND: Subject C135 is one of the members of the Sydney Blood Bank Cohort, infected in 1981 through transfusion with attenuated nef/3' long terminal repeat (LTR)-deleted HIV-1, and has maintained undetectable plasma viral load and steady CD4 cell count, in the absence of therapy. Uniquely, C135 combines five factors separately associated with control of viraemia: nef/LTR-deleted HIV-1, HLA-B57, HLA-DR13, heterozygous CCR5 Δ32 genotype and vigorous p24-stimulated peripheral blood mononuclear cell (PBMC) proliferation. Therefore, we studied in detail viral burden and immunological responses in this individual. METHODS: PBMC and gut and lymph node biopsy samples were analysed for proviral HIV-1 DNA by real-time and nested PCRs, and nef/LTR alleles by nested PCR. HIV-specific antibodies were studied by Western blotting, and CD4+ and CD8+ T lymphocyte responses were measured by proliferation and cytokine production in vitro. RESULTS: PBMC samples from 1996, but not since, showed amplification of nef alleles with gross deletions. Infectious HIV-1 was never recovered. Proviral HIV-1 DNA was not detected in recent PBMC or gut or lymph node biopsy samples. C135 has a consistently weak antibody response and a substantial CD4+ T cell proliferative response to a previously described HLA-DR13-restricted epitope of HIV-1 p24 in vitro, which augmented a CD8+ T cell response to an immunodominant HLA-B57-restricted epitope of p24, while his T cells show reduced levels of CCR5. CONCLUSIONS: Subject C135's early PCR and weak antibody results are consistent with limited infection with a poorly replicating nef/LTR-deleted strain of HIV-1. With his HLA-B57-restricted gag-specific CD8 and helper HLA-DR13-restricted CD4 T cell proliferative responses, C135 appears to have cleared his HIV-1 infection 37 years after transfusion.

Mechanisms of HIV non-progression; robust and sustained CD4+ T-cell proliferative responses to p24 antigen correlate with control of viraemia and lack of disease progression after long-term transfusion-acquired HIV-1 infection.

BACKGROUND: Elite non-progressors (plasma viral load < 50 copies/ml while antiretroviral naive) constitute a tiny fraction of HIV-infected individuals. After 12 years follow-up of a cohort of 13 long-term non-progressors (LTNP) identified from 135 individuals with transfusion-acquired HIV infection, 5 remained LTNP after 23 to 26 years infection, but only 3 retained elite LTNP status. We examined the mechanisms that differentiated delayed progressors from LTNP in this cohort. RESULTS: A survival advantage was conferred on 12 of 13 subjects, who had at least one host genetic factor (HLA, chemokine receptor or TLR polymorphisms) or viral attenuating factor (defective nef) associated with slow progression. However, antiviral immune responses differentiated the course of disease into and beyond the second decade of infection. A stable p24-specific proliferative response was associated with control of viraemia and retention of non-progressor status, but this p24 response was absent or declined in viraemic subjects. Strong Gag-dominant cytotoxic T lymphocyte (CTL) responses were identified in most LTNP, or Pol dominant-CTL in those with nef-defective HIV infection. CTL were associated with control of viraemia when combined with p24 proliferative responses. However, CTL did not prevent late disease progression. Individuals with sustained viral suppression had CTL recognising numerous Gag epitopes, while strong but restricted responses to one or two immunodominant epitopes was effective for some time, but failed to contain viraemia over the course of this study. Viral escape mutants at a HLA B27-restricted Gag-p24 epitope were detected in only 1 of 3 individuals, whereas declining or negative p24 proliferative responses occurred in all 3 concurrent with an increase in viraemia. CONCLUSION: Detectable viraemia at study entry was predictive of loss of LTNP status and/or disease progression in 6 of 8, and differentiated slow progressors from elite LTNP who retained potent virological control. Sustained immunological suppression of viraemia was independently associated with preserved p24 proliferative responses, regardless of the strength and breadth of the CTL response. A decline in this protective p24 response preceded or correlated with loss of non-progressor status and/or signs of disease progression.

Pathogenicity and immunogenicity of attenuated, nef-deleted HIV-1 strains in vivo.

In efforts to develop an effective vaccine, sterilizing immunity to primate lentiviruses has only been achieved by the use of live attenuated viruses carrying major deletions in nef and other accessory genes. Although live attenuated HIV vaccines are unlikely to be developed due to a myriad of safety concerns, opportunities exist to better understand the correlates of immune protection against HIV infection by studying rare cohorts of long-term survivors infected with attenuated, nef-deleted HIV strains such as the Sydney blood bank cohort (SBBC). Here, we review studies of viral evolution, pathogenicity, and immune responses to HIV infection in SBBC members. The studies show that potent, broadly neutralizing anti-HIV antibodies and robust CD8+ T-cell responses to HIV infection were not necessary for long-term control of HIV infection in a subset of SBBC members, and were not sufficient to prevent HIV sequence evolution, augmentation of pathogenicity and eventual progression of HIV infection in another subset. However, a persistent T-helper proliferative response to HIV p24 antigen was associated with long-term control of infection. Together, these results underscore the importance of the host in the eventual outcome of infection. Thus, whilst generating an effective antibody and CD8+ T-cell response are an essential component of vaccines aimed at preventing primary HIV infection, T-helper responses may be important in the generation of an effective therapeutic vaccine aimed at blunting chronic HIV infection.

Phenotype and envelope gene diversity of nef-deleted HIV-1 isolated from long-term survivors infected from a single source.

BACKGROUND: The Sydney blood bank cohort (SBBC) of long-term survivors consists of multiple individuals infected with attenuated, nef-deleted variants of human immunodeficiency virus type 1 (HIV-1) acquired from a single source. Long-term prospective studies have demonstrated that the SBBC now comprises slow progressors (SP) as well as long-term nonprogressors (LTNP). Convergent evolution of nef sequences in SBBC SP and LTNP indicates the in vivo pathogenicity of HIV-1 in SBBC members is dictated by factors other than nef. To better understand mechanisms underlying the pathogenicity of nef-deleted HIV-1, we examined the phenotype and env sequence diversity of sequentially isolated viruses (n = 2) from 3 SBBC members. RESULTS: The viruses characterized here were isolated from two SP spanning a three or six year period during progressive HIV-1 infection (subjects D36 and C98, respectively) and from a LTNP spanning a two year period during asymptomatic, nonprogressive infection (subject C18). Both isolates from D36 were R5X4 phenotype and, compared to control HIV-1 strains, replicated to low levels in peripheral blood mononuclear cells (PBMC). In contrast, both isolates from C98 and C18 were CCR5-restricted. Both viruses isolated from C98 replicated to barely detectable levels in PBMC, whereas both viruses isolated from C18 replicated to low levels, similar to those isolated from D36. Analysis of env by V1V2 and V3 heteroduplex tracking assay, V1V2 length polymorphisms, sequencing and phylogenetic analysis showed distinct intra- and inter-patient env evolution. CONCLUSION: Independent evolution of env despite convergent evolution of nef may contribute to the in vivo pathogenicity of nef-deleted HIV-1 in SBBC members, which may not necessarily be associated with changes in replication capacity or viral coreceptor specificity.

pH dependence of cyanide and imidazole binding to the heme domains of Sinorhizobium meliloti and Bradyrhizobium japonicum FixL.

Equilibrium and kinetic properties of cyanide and imidazole binding to the heme domains of Sinorhizobium meliloti and Bradyrhizobium japonicum FixL (SmFixLH and BjFixLH) have been investigated between pH5 and 11. KD determinations were made at integral pH values, with the strongest binding at pH9 for both ligands. KD for the cyanide complexes of BjFixLH and SmFixLH is 0.15±0.09 and 0.50±0.20µM, respectively, and 0.70±0.01mM for imido-BjFixLH. The association rate constants are pH dependent with maximum values of 443±8 and 252±61M(-1)s(-1) for cyano complexes of BjFixLH and SmFixLH and (5.0±0.3)×10(4) and (7.0±1.4)×10(4)M(-1)s(-1) for the imidazole complexes. The dissociation rate constants are essentially independent of pH above pH5; (1.2±0.3)×10(-4) and (1.7±0.3)×10(-4)s(-1) for the cyano complexes of BjFixLH and SmFixLH, and (73±19) and (77±14) s(-1) for the imidazole complexes. Two ionizable groups in FixLH affect the rate of ligand binding. The more acidic group, identified as the heme 6 propionic acid, has a pKa of 7.6±0.2 in BjFixLH and 6.8±0.2 in SmFixLH. The second ionization is due to formation of hydroxy-FixLH with pKa values of 9.64±0.05 for BjFixLH and 9.61±0.05 for SmFixLH. Imidazole binding is limited by the rate of heme pocket opening with maximum observed values of 680 and 1270s(-1) for BjFixLH and SmFixLH, respectively.

GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration.

The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimer's disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here we show that GLUT1 deficiency in mice overexpressing amyloid ß-peptide (Aß) precursor protein leads to early cerebral microvascular degeneration, blood flow reductions and dysregulation and BBB breakdown, and to accelerated amyloid ß-peptide (Aß) pathology, reduced Aß clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimer's disease cerebrovascular degeneration, neuropathology and cognitive function, suggesting that GLUT1 may represent a therapeutic target for Alzheimer's disease vasculo-neuronal dysfunction and degeneration.

Association of Fc gamma receptor IIA polymorphisms with acute renal-allograft rejection.

Acute rejection is a leading cause of early renal-allograft failure. The human Fc gamma receptor IIA (FcgammaRIIA) forms an essential link between the humoral branch and the effector cells of the immune system. In this study, we examined FcgammaRIIA genotypes in renal-allograft recipients (rejectors) with acute graft rejection and in a number of control groups to investigate a possible association between FcgammaRIIA polymorphism and acute renal-allograft rejection. The distribution of the genotypes in the study patient group differed from the control groups. The frequency of homozygosity for FcagammaRIIA-R/R131 in the rejectors was significantly higher than that in the recipients (nonrejectors) with well-functioning renal allografts and in blood donors (P< 0.05). In comparison with the control groups, the rejectors displayed a higher R131 allele frequency (P< 0.05) and a lower H131 allele frequency (P< 0.05). These results reveal a significant association between FcgammaRIIA-R/R131 and acute renal-graft rejection, and it is likely that FcgammaRIIA polymorphisms could be useful markers for potential risk of rejection.

Correlates of antiviral immune restoration in acute and chronic HIV type 1 infection: sustained viral suppression and normalization of T cell subsets.

Highly active antiretroviral therapy (HAART) has suppressed viral replication and facilitated normalization of T cell subsets, resulting in restoration of immunity against opportunistic pathogens. Induction of full immune restoration in chronically infected individuals, including HIV-specific helper T cell responses, is considered a priority, particularly if immunological control of HIV is to be achieved. Regimens containing dual protease inhibitors (PIs) have provided greater suppression of viremia than single-PI regimens. We therefore conducted a prospective analysis of factors associated with immune restoration after 3 years of therapy in two cohorts of acutely and chronically HIV-infected patients, comparing dual- versus single-PI regimens. Earlier and more durable returns of p24-specific proliferation were demonstrated in patients receiving dual-PI compared with single-PI regimens. Individuals with restored p24 responses had larger reductions in total HIV-specific cytotoxic T lymphocytes (CTLs) associated with stronger viral suppression, but Gag-specific CTLs remained higher, demonstrating that Gag-specific helper T cell responses were a critical component of functional immune restoration. On examination of clinical factors associated with immune restoration, we demonstrated that decreasing activation of CD8+ T cells (%CD8+ CD38+) and increasing proportions of CD4+ T cells were independently associated with restoration of p24 responses. Minimal immune activation, resulting from maximal suppression of viral replication, was required for long-term restoration and maintenance of Gag-specific T cell responses. This study uniquely demonstrates that dual-PI regimens are superior in achieving these levels of virological control and immune restoration in both chronic and acute infection, compared with single-PI or non-PI regimens.

ROHHADNET syndrome presenting as major behavioral changes in a 5-year-old obese girl.

Behavioral issues are a frequent problem in the pediatric population. Often, these are evaluated and considered to be psychiatric in origin. We report on a pediatric patient who presented with severe behavioral disturbance and developed organic symptoms including hypoventilation and dysautonomia and who was ultimately diagnosed with ROHHADNET syndrome, a syndrome of rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation associated with a neuroendocrine tumor. Autopsy findings revealed novel findings of the syndrome, including hypothalamic encephalitis.

A randomized clinical trial of the immunogenicity of 7-valent pneumococcal conjugate vaccine compared to 23-valent polysaccharide vaccine in frail, hospitalized elderly.

BACKGROUND: Elderly people do not mount strong immune responses to vaccines. We compared 23-valent capsular polysaccharide (23vPPV) alone versus 7-valent conjugate (PCV7) vaccine followed by 23vPPV 6 months later in hospitalized elderly. METHODS: Participants were randomized to receive 23vPPV or PCV7-23vPPV. Antibodies against serotypes 3, 4, 6A, 6B, 9V, 14, 18C, 19A, 19F, 23F were measured by enzyme-linked immunosorbent (ELISA) and opsonophagocytic (OPA) assays at baseline, 6 months and 12 months. RESULTS: Of 312 recruited, between 40% and 72% of subjects had undetectable OPA titres at baseline. After one dose, PCV7 recipients had significantly higher responses to serotypes 9V (both assays) and 23F (OPA only), and 23vPPV recipients had significantly higher responses to serotype 3 (ELISA), 19F and 19A (OPA only). In subjects with undetectable OPA titres at baseline, a proportionately greater rise in OPA titre (P<0.01) was seen for all serotypes after both vaccines. The GMT ratio of OPA was significantly higher at 12 months in the PCV7-23vPPV group for serotypes 6A, 9V, 18C and 23F. OPA titre levels for these serotypes increased moderately after 6 months, whereas immunity waned in the 23vPPV only arm. CONCLUSION: We did not show overwhelming benefit of one vaccine over the other. Low baseline immunity does not preclude a robust immune response, reiterating the importance of vaccinating the frail elderly. A schedule of PCV7-23vPPV prevents waning of antibody, suggesting that both vaccines could be useful in the elderly. Follow up studies are needed to determine persistence of immunity. TRIAL REGISTRATION: The Australian Clinical Trials Registry ACTRN12607000387426.

Symptom response following acute bouts of exercise in concussed and non-concussed individuals - a systematic narrative review.

BACKGROUND: Athletes suspected of being concussed are frequently evaluated on the side-line for self-reported symptoms which guide subsequent management and return-to-play decisions. Concussion-like symptoms have been shown to be influenced by prior participation in physical activity; however, the potential contribution of acute exercise on symptoms is not well understood. OBJECTIVE: The purpose of this study was to systematically review the literature in order to further understand the acute effects of exercise on documented self-reported symptoms in both concussed and non-concussed individuals. DESIGN: Systematic narrative review. METHODS: Nine electronic databases were systematically searched using keywords and MeSH terms that included; self-reported symptoms, sports-related concussion, brain concussion, exercise and athletic injuries. In addition, an extensive search of the grey literature was conducted. RESULTS: Of the 785 articles retrieved, only five met the inclusion criteria comprising a total of 295 concussed and non-concussed participants. In general, the mean symptom scores increased from pre-exercise to post-exercise levels immediately following acute bouts of exercise in both concussed and non-concussed individuals. CONCLUSION: Although the symptom scores increased following exercise in both concussed and non-concussed participants, this increase was only maintained for a relatively short duration. Thus, the application to real world situation is still to be established.