Prolonged antiretroviral therapy initiated at seroconversion is associated with a polyfunctional HIV-1-specific T-cell profile comparable to that of long-term non-progressors (LTNPs)

Background: Early initiation of antiretroviral therapy (ART) may dramatically curtail cumulative immunological damage allowing maximal levels of immune preservation/reconstitution and induce an immunovirological status similar to that of HIV-1 LTNPs with low viral reservoirs and polyfunctional HIV-1 specific T cell responses.Methods: We performed a cross-sectional study of an HIV-1 seroconverter cohort on long-term ART (LTTS) and compared it to one of LTNPs. Inclusion criteria for 20 LTTS were: (a) ?4 years ART; (b) long-term aviremia and (c) absence of treatment failure and for 15 LTNPs: (a) ?7 years of documented HIV-1 infection; (b) <1000 HIV-1 RNA copies/mL and ?500 CD4+ T-cells/mm3 in >90% of measurements; (d) absence of AIDS-defining conditions; (e) ART-naı¨ve except for temporary ART for prevention of MTCT. In both cohorts, we analysed residual viral replication and reservoirs in peripheral blood, as measured by cellassociated HIV-1 RNA and DNA in PBMCs, respectively and used polychromatic flow cytometry to analyse HIV-1-specific CD4+ and CD8+ T-cell functional profile in terms of cytokine production using IFN-c, IL-2, TNF-a production.Results: Cell-associated DNA [47.7 (4.8-583.2) in LTTS and 19.7 (0.5-295.5) in LTNPS, p=0.10], and RNA [3.9 (0-36) and 5.8 (0-10.3), respectively] were shown to be similarly low in both cohorts. We identified 103 CD8 T cell epitope-specific responses, all subjects responding to ?1 epitope. Mean responding number of responding epitopes per patient was 2 and 4 in LTTS and LTNPS, respectively. Mean% of cytokine-secreting CD8 T cells was 0.37% and 0.50% (p=0.06), of these 43% and 39% (p=0.12) were secreting simultaneously IFN-c, IL-2 and TNF-a. Respective values for CD4 T cells were 0.28% and 0.33% (p=0.28) of which 33% and 30% (0.32) were secreting these 3 cytokines simultaneously.Conclusions: Long-term aviremia after very early ART initiation is associated with low levels of reservoirs saturation ad residual replication. Although less broad CD8 T cell responses were found in LTTS, HIV-1 specific CD4 and CD8 T cell responses showed similar magnitude and functional profile in the 2 cohorts. Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs. (BHIVA Research Award Winner 2008: Anna Garcia-Diaz.)

Bisphosphonate-related osteonecrosis of the jaws: how to manage cancer patients.

Bisphosphonate related osteonecrosis of the jaw (BRONJ) is defined as exposed necrotic bone appearing in the jaws of patients treated by systemic IV or oral BPs never irradiated in the head and neck area and that has persisted for more than 8 weeks. More than 90% of cases of osteonecrosis of the jaw have been in patients with cancer who received IV-BPs. The estimate of cumulative incidence of BRONJ in cancer patients with IV-BPs ranges from 0.8% to 18.6%. The pathogenesis of BRONJ appeared related to the potent osteoblast-inhibiting properties of BPs which act by blocking osteoclast recruitment, decreasing osteoclast activity and promoting osteoclast apoptosis. Dental extractions are the most potent local risk factor. Cancer patients wearing a denture could also be at increased risk of BRONJ. Non-healing mucosal breaches caused by dentures could be a portal for the oral flora to access bone, while the oral mucosa of patients on IV-BPs could also be defective. Whether periodontal disease is a risk factor for BRONJ remains controversial. Preventive measures are fundamental. Nevertheless, some teams have questioned its cost-effectiveness. The perceived limitations of surgical therapy of BRONJ led to the restriction of aggressive surgery to symptomatic patients with stage 3 BRONJ. The evidence-based literature on BRONJ is growing but there are still many controversial aspects.

Non-tuberculous mycobacteria I: one year clinical isolates identification in Tertiary Hospital Aids Reference Center, Rio de Janeiro, Brazil, in pre highly active antiretroviral therapy era

The aim of this study was to determine the prevalence of non-tuberculous mycobacteria (NTM) isolates at University Hospital, Reference Center for Aids in Rio de Janeiro, Brazil, during one year. We used standard biochemical tests for species identification and IS1245 PCR amplification was applied as a Mycobacterium avium specific identification marker. Four hundred and four specimens from 233 patients yielded acid-fast bacilli growth. M. tuberculosis was identified in 85% of the patients and NTM in 15%. NTM disseminated infection was a common event correlated with human immunodeficiency virus (HIV) infected patients and only in HIV negative patients the source of NTM was non sterile site. M. avium complex (MAC) was biochemically identified in 57.8% (49/83) of NTM isolates, most of them from sterile sites (75.5%), and in 94% (46/49) the IS 1245 marker specific for M. avium was present. Twenty NTM strains showed a MAC biochemical pattern with the exception of a urease-positive (99% of MAC are urease-negative), however IS1245 was detected in 96% of the strains leading to their identification as M. avium. In this group differences in NTM source was not significant. The second most frequently isolated NTM was identified as M. scrofulaceum (7.2%), followed by M. terrae (3.6%), M. gordonae (2.4%), M. chelonae (1.2%), M. fortuitum (1.2%) and one strain which could not be identified. All were IS1245 negative except for one strain identified as M. scrofulaceum. It is interesting to note that non-sterile sites were the major source of these isolates (92.8%). Our finding indicated that M. avium is still the major atypical species among in the MAC isolates recovered from Brazilian Aids patients without highty active antiretroviral therapy schema. Some discrepancies were seen between the identification methods and further investigations must be done to better characterize NTM isolates using other phenotypic and genotypic methods.

Manual therapy followed by specific active exercises versus a placebo followed by specific active exercises on the improvement of functional disability in patients with chronic non specific low back pain: a randomized controlled trial.

BACKGROUND: Recent clinical recommendations still propose active exercises (AE) for CNSLBP. However, acceptance of exercises by patients may be limited by pain-related manifestations. Current evidences suggest that manual therapy (MT) induces an immediate analgesic effect through neurophysiologic mechanisms at peripheral, spinal and cortical levels. The aim of this pilot study was first, to assess whether MT has an immediate analgesic effect, and second, to compare the lasting effect on functional disability of MT plus AE to sham therapy (ST) plus AE. METHODS: Forty-two CNSLBP patients without co-morbidities, randomly distributed into 2 treatment groups, received either spinal manipulation/mobilization (first intervention) plus AE (MT group; n = 22), or detuned ultrasound (first intervention) plus AE (ST group; n = 20). Eight therapeutic sessions were delivered over 4 to 8 weeks. Immediate analgesic effect was obtained by measuring pain intensity (Visual Analogue Scale) before and immediately after the first intervention of each therapeutic session. Pain intensity, disability (Oswestry Disability Index), fear-avoidance beliefs (Fear-Avoidance Beliefs Questionnaire), erector spinae and abdominal muscles endurance (Sorensen and Shirado tests) were assessed before treatment, after the 8th therapeutic session, and at 3- and 6-month follow-ups. RESULTS: Thirty-seven subjects completed the study. MT intervention induced a better immediate analgesic effect that was independent from the therapeutic session (VAS mean difference between interventions: -0.8; 95% CI: -1.2 to -0.3). Independently from time after treatment, MT + AE induced lower disability (ODI mean group difference: -7.1; 95% CI: -12.8 to -1.5) and a trend to lower pain (VAS mean group difference: -1.2; 95% CI: -2.4 to -0.30). Six months after treatment, Shirado test was better for the ST group (Shirado mean group difference: -61.6; 95% CI: -117.5 to -5.7). Insufficient evidence for group differences was found in remaining outcomes. CONCLUSIONS: This study confirmed the immediate analgesic effect of MT over ST. Followed by specific active exercises, it reduces significantly functional disability and tends to induce a larger decrease in pain intensity, compared to a control group. These results confirm the clinical relevance of MT as an appropriate treatment for CNSLBP. Its neurophysiologic mechanisms at cortical level should be investigated more thoroughly. TRIAL REGISTRATION: Trial registration number: NCT01496144.

Healthy child, healthy future - Speech and language therapy: Factsheet for parents 2. Helping your young non-fluent child

This factsheet outlines how parents can help their child speak more fluently, without stammering.

Surgical outcomes following repeat non-penetrating glaucoma filtration surgery at a tertiary referral centre

Purpose:To determine the surgical outcomes of patients undergoing repeat deep sclerectomies with collagen implant (DSCI) at a tertiary referral centre. Methods:The medical notes of 208 patients undergoing multiple DSCI were reviewed. Those undergoing repeat DSCI were identified and post operative data for each DSCI were analysed. Group A: the first DSCI; group B: second DSCI; group C: third DSCI. Results:Mean age was 66.8 ±13.0 years. At 12 months, percentage of mean IOP reduction in groups were 18%, 24% and 17% respectively. Mean interval to starting glaucoma medications, re-operation, mitomycin injection and goniopuncture all decreased as the number of operations increased. There was a significant reduction in complete success rates between groups A and B and groups B and C. Few minor complications were observed in all 3 groups. Conclusions:Despite the possibility of bleb independent outflow pathways in patients undergoing non-penetrating surgery, there are significantly reduced success rates in eyes undergoing repeat DSCI. This has important implications for the choice of subsequent operations in patients who have failed non-penetrating filtration surgery.

Clinical characteristics and outcome of patients admitted to a medico- surgical ICU requiring non invasive ventilation (NIV) for hypercapnic respiratory failure

Introduction Because it decreases intubation rate and mortality, NIV has become first-line treatment in case of hypercapnic acute respiratory failure (HARF). Whether this approach is equally successful for all categories of HARF patients is however debated. We assessed if any clinical characteristics of HARF patients were associated with NIV intensity, success, and outcome, in order to identify prognostic factors. Methods Retrospective analysis of the clinical database (clinical information system and MDSi) of patients consecutively admitted to our medico-surgical ICU, presenting with HARF (defined as PaCO2 > 50 mmHg), and receiving NIV between May 2008 and December 2010. Demographic data, medical diagnoses (including documented chronic lung disease), reason for ICU hospitalization, recent surgical interventions, SAPS II and McCabe scores were extracted from the database. Total duration of NIV and the need for tracheal intubation during the 5 days following the first hypercapnia documentation, as well as ICU, hospital and one year mortality were recorded. Results are reported as median [IQR]. Comparisons were carried out with Chi2 or Kruskal-Wallis tests, p<0.05 (*). Results Two hundred and twenty patients were included. NIV successful patients received 16 [9-31] hours of NIV for up to 5 days. Fifty patients (22.7%) were intubated 11 [2-34] hours after HARF occurence, after having receiving 10 [5-21] hours of NIV. Intubation was correlated with increased ICU (18% vs. 6%, p<0.05) and hospital (42% vs. 31%, p>0.05) mortality. SAPS II score was related to increasing ICU (51 [29-74] vs. 23 [12-41]%, p<0.05), hospital (37% [20-59] vs 20% [12-37], p<0.05) and one year mortality (35% vs 20%, p<0.05). Surgical patients were less frequent among hospital fatalities (28.8% vs. 46.3%, p<0.05, RR 0.8 [0-6-0.9]). Nineteen patients (8.6%) died in the ICU, 73 (33.2%) during their hospital stay and 108 (49.1%) were dead one year after HARF. Conclusion The practice to start NIV in all suitable patients suffering from HARF is appropriate. NIV can safely and appropriately be used in patients suffering from HARF from an origin different from COPD exacerbation. Beside usual predictors of severity such as severity score (SAPS II) appear to be associated with increased mortality. Although ICU mortality was low in our patients, hospital and one year mortality were substantial. Surgical patients, although undergoing a similar ICU course, had a better hospital and one year outcome.

Healthy child, health future - Speech and language therapy: Factsheet for parents 2. Helping your young non-fluent child

This factsheet outlines how parents can help their child speak more fluently, without stammering.

Second non-breast primary cancer following adjuvant therapy for early breast cancer: a report from the International Breast Cancer Study Group.

The incidence of second non-breast primary cancer following adjuvant treatment was evaluated using data from patients enrolled from 1978 to 1999 in four International Breast Cancer Study Group (IBCSG) trials. The occurrence of these tumours as sites of the first failure was assessed separately for two treatment comparisons: toremifene versus tamoxifen for 5 years in 1035 patients in IBCSG Trials 12-93 and 14-93 with a median follow-up of 8 years and endocrine therapy (toremifene or tamoxifen) versus chemo-endocrine therapy (CMF or AC plus toremifene or tamoxifen) in 1731 patients from IBCSG Trials III, VII and 12-93, with a combined median follow-up of 14 years. No significant differences in second non-breast primary tumours were observed in either comparison. In particular, the incidences of second primary uterine tumours with toremifene and tamoxifen were similar and no significant increase of secondary leukaemias was observed with chemo-endocrine therapy compared with endocrine therapy.

Early and Prolonged Antiretroviral Therapy Is Associated with an HIV-1-Specific T-Cell Profile Comparable to That of Long-Term Non-Progressors.

Background: Intervention with antiretroviral treatment (ART) and control of viral replication at the time of HIV-1 seroconversion may curtail cumulative immunological damage. We have therefore hypothesized that ART maintenance over a very prolonged period in HIV-1 seroconverters could induce an immuno-virological status similar to that of HIV-1 long-term non-progressors (LTNPs).Methodology/Principal Findings: We have investigated a cohort of 20 HIV-1 seroconverters on long-term ART (LTTS) and compared it to one of 15 LTNPs. Residual viral replication and reservoirs in peripheral blood, as measured by cell-associated HIV-1 RNA and DNA, respectively, were demonstrated to be similarly low in both cohorts. These two virologically matched cohorts were then comprehensively analysed by polychromatic flow cytometry for HIV-1-specific CD4(+) and CD8(+) T-cell functional profile in terms of cytokine production and cytotoxic capacity using IFN-gamma, IL-2, TNF-alpha production and perforin expression, respectively. Comparable levels of highly polyfunctional HIV-1-specific CD4(+) and CD8(+) T-cells were found in LTTS and LTNPs, with low perforin expression on HIV-1-specific CD8+ T-cells, consistent with a polyfunctional/non-cytotoxic profile in a context of low viral burden.Conclusions: Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs, strengthening the recent emphasis on the positive impact of early treatment initiation and paving the way for further interventions to promote virological control after treatment interruption.

Acute haematogenous prosthetic joint infection: prospective evaluation of medical and surgical management

The optimum treatment for prosthetic joint infections has not been clearly defined. We report our experience of the management of acute haematogenous prosthetic joint infection (AHPJI) in patients during a 3-year prospective study in nine Spanish hospitals. Fifty patients, of whom 30 (60%) were female, with a median age of 76 years, were diagnosed with AHPJI. The median infection-free period following joint replacement was 4.9 years. Symptoms were acute in all cases. A distant previous infection and/or bacteraemia were identified in 48%. The aetiology was as follows: Staphylococcus aureus, 19; Streptococcus spp., 14; Gram-negative bacilli, 12; anaerobes, two; and mixed infections, three. Thirty-four (68%) patients were treated with a conservative surgical approach (CSA) with implant retention, and 16 had prosthesis removal. At 2-year follow-up, 24 (48%) were cured, seven (14%) had relapsed, seven (14%) had died, five (10%) had persistent infection, five had re-infection, and two had an unknown evolution. Overall, the treatment failure rates were 57.8% in staphylococcal infections and 14.3% in streptococcal infections. There were no failures in patients with Gram-negative bacillary. By multivariate analysis, CSA was the only factor independently associated with treatment failure (OR 11.6; 95% CI 1.29-104.8). We were unable to identify any factors predicting treatment failure in CSA patients, although a Gram-negative bacillary aetiology was a protective factor. These data suggest that although conservative surgery was the only factor independently associated with treatment failure, it could be the first therapeutic choice for the management of Gram-negative bacillary and streptococcal AHPJI, and for some cases with acute S. aureus infections.

Correcting non cephalic presentation with moxibustion: study protocol for a multi-centre randomised controlled trial in general practice.

BACKGROUND Non cephalic presentation in childbirth involves various risks to both the mother and the foetus. The incidence in Spain is 3.8% of all full-term pregnancies. The most common technique used to end the gestation in cases of non cephalic presentation is that of caesarian section, and although it provokes a lower rate of morbi-mortality than does vaginal delivery in such situations, there remains the possibility of traumatic injury to the foetal head and neck, while maternal morbidity is also increased. The application of heat (moxibustion) to an acupuncture point, in order to correct non cephalic presentation, has been practised in China since ancient times, but as yet there is insufficient evidence of its real effectiveness. METHODS/DESIGN The experimental design consists of a multi-centre randomised controlled trial with three parallel arms, used to compare real moxibustion, sham moxibustion and the natural course of events, among pregnant women with a non cephalic presentation and a gestational duration of 33-35 weeks (estimated by echography). The participants in the trial will be blinded to both interventions. The results obtained will be analyzed by professionals, blinded with respect to the allocation to the different types of intervention. In addition, we intend to carry out a economic analysis. DISCUSSION This trial will contribute to the development of evidence concerning moxibustion in the correction of non cephalic presentations. The primary outcome variable is the proportion of cephalic presentations at term. As secondary outcomes, we will evaluate the proportion of cephalic presentations at week 38 of gestation, determined by echography, together with the safety of the technique, the specificity of moxibustion and the control of the blinding process. This study has been funded by the Health Ministry of the Andalusian Regional Government. TRIAL REGISTRATION Current Controlled Trials ISRCTN10634508.

Disseminated Rhizopus microsporus infection cured by salvage allogeneic hematopoietic stem cell transplantation, antifungal combination therapy, and surgical resection.

O. Lebeau, C. Van Delden, J. Garbino, J. Robert, F. Lamoth, J. Passweg, Y. Chalandon. Disseminated Rhizopus microsporus infection cured by salvage allogeneic hematopoietic stem cell transplantation, antifungal combination therapy, and surgical resection. Transpl Infect Dis 2010. All rights reserved Abstract: Invasive Zygomycetes infection complicating prolonged neutropenia is associated with high mortality in the absence of immune recovery. We report a patient who developed disseminated zygomycosis due to Rhizopus microsporus during induction chemotherapy for acute myeloid leukemia. Rescue allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed as her only chance of cure of this infection and to treat refractory leukemia. Posaconazole combined with liposomal amphotericin B contained the zygomycosis during prolonged neutropenia due to allo-HSCT followed by intense immunosuppression for grade IV acute graft-versus-host disease. Surgical removal of all infected sites after immune recovery, with prolonged posaconazole treatment, ultimately cured the infection. New combination antifungal therapies might sufficiently control disseminated zygomycosis to allow allo-HSCT to be performed, assuring life-saving immune recovery. Surgery appears to be necessary for definite cure of these infections.

Successful surgical resection in non-lesional operculo-insular epilepsy without intracranial monitoring.

Pre-operative assessment and surgical management of patients with non-lesional extratemporal epilepsy remain challenging due to a lack of precise localisation of the epileptic zone. In most cases, invasive recording with depth or subdural electrodes is required. Here, we describe the case of 6.5-year-old girl who underwent comprehensive non-invasive phase I video-EEG investigation for drug-resistant epilepsy, including electric source and nuclear imaging. Left operculo-insular epilepsy was diagnosed. Post-operatively, she developed aphasia which resolved within one year, corroborating the notion of enhanced language plasticity in children. The patient remained seizure-free for more than three years.

Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma.

We present the long-term results of 18 chemotherapy relapsed indolent (N = 12) or transformed (N = 6) NHL patients of a phase II anti-CD20 (131)I-tositumomab (Bexxar) therapy study. The biphasic therapy included two injections of 450 mg unlabelled antibody combined with (131)I-tositumomab once as dosimetric and once as therapeutic activity delivering 75 or 65 cGy whole-body radiation dose to patients with normal or reduced platelet counts, respectively. Two patients were not treated due to disease progression during dosimetry. The overall response rate was 81% in the 16 patients treated, including 50% CR/CRu and 31% PR. Median progression free survival of the 16 patients was 22.5 months. Median overall survival has not been reached after a median observation of 48 months. Median PFS of complete responders (CR/CRu) has not been reached and will be greater than 51 months. Short-term side effects were mainly haematological and transient. Among the relevant long-term side effects, one patient previously treated with CHOP chemotherapy died from secondary myelodysplasia. Four patients developed HAMA. In conclusion, (131)I-tositumomab RIT demonstrated durable responses especially in those patients who achieved a complete response. Six of eight CR/CRu are ongoing after 46-70 months.