A multicenter, randomized controlled trial comparing a single intra-articular injection of Gel-200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of osteoarthritis of the knee

Objective To compare the safety and efficacy of a single intra-articular (IA) injection of a new cross-linked hyaluronic acid product, Gel-200, with phosphate buffered saline (PBS, control) in a multi-center randomized controlled trial in patients with symptomatic osteoarthritis (OA) of the knee. Design Patients were randomized 2:1 to receive a single injection of Gel-200 or PBS, after joint aspiration. The primary measure of effectiveness was Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscores by 100-mm Visual Analog Scale (VAS); secondary outcomes included: total WOMAC, physical function, and stiffness subscores; patient and physician global assessments of disease activity, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT–OARSI) strict responders, as well as safety of Gel-200. Results Of 379 patients randomized, safety was evaluated in 377 and efficacy in 375 (98.9% randomized) in the intent-to-treat population. Effectiveness of Gel-200 by WOMAC pain subscores was statistically significant at week 13 (P = 0.037). Mean improvements from baseline in WOMAC pain subscores consistently favored Gel-200 at each visit. Effectiveness of Gel-200 treatment was statistically significant over weeks 3–13 by WOMAC total score, physical function, and physician global evaluations (P \u3c 0.05). The number of “strict” OMERACT–OARSI responders was statistically significant from weeks 6 to 13 (P = 0.022). Adverse events were not significantly different between treatment groups, including serious adverse events considered related to study treatment. Conclusions This trial demonstrated that a single injection of Gel-200 was well tolerated and relieved pain associated with symptomatic OA of the knee over 13 weeks. Trial registration number ClinicalTrials.gov NTC 00449696

Childbearing women of twenty and under are at greater risk than those of twenty-five and over for compromised folate status

This study assessed folate intakes, folate concentrations in plasma and erythrocytes, plasma total homocysteine (tHcy) concentration, and urinary excretion of folate metabolites in Korean women with childbearing potential. A total of 23 women voluntarily participated in this study. Precise dietary intakes for 3 consecutive days were determined by weighing all foods consumed and folate intake was calculated using a computer-aided dietary analysis system. Folate concentration of plasma and erythrocytes was determined by a microbiological method. Plasma tHcy concentration was assayed using an HPLC analysis method. Urine excreted over the same period of time was collected and folate catabolites, para-aminobenzoylglutamate (pABG) and para-acetamidobenzoylglutamate (ApABG), were evaluated using a reverse-phase HPLC method after affinity chromatography. Young women of 20 and under were likely to consume less folate with low energy intake, had lower folate concentration in plasma and erythrocytes, and excreted a lesser amount of ApABG and total folate catabolites than women of 25 years and over. The results of this study confirmed that young Korean women with childbearing potential, especially those under 21 years of age, might be at risk for compromised folate status due to insufficient folate intakes from inadequate energy consumption

Development of a Cryptosporidium oocyst assay using an automated fiber optic-based biosensor

An intestinal protozoan parasite, Cryptosporidium parvum, is a major cause of waterborne gastrointestinal disease worldwide. Detection of Cryptosporidium oocysts in potable water is a high priority for the water treatment industry to reduce potential outbreaks among the consumer populace. Anti-Cryptosporidium oocyst polyclonal and monoclonal antibodies were tested as capture and detection reagents for use in a fiber optic biosensor assay for the detection of Cryptosporidium oocysts. Antibodies were validated using enzyme-linked immunosorbent assays, flow cytometry, Western blotting and fluorescent microscopy. Oocysts could be detected at a concentration of 105 oocysts/ml when the polyclonal antibodies were used as the capture and detection reagents. When oocysts were boiled prior to detection, a ten-fold increase in sensitivity was achieved using the polyclonal antibody. Western blotting and immunofluorescence revealed that both the monoclonal and polyclonal antibodies recognize a large (>300 kDa) molecular weight mucin-like antigen present on the surface of the oocyst wall. The polyclonal antibody also reacted with a small (105 kDa) molecular weight antigen that was present in boiled samples of oocysts. Preliminary steps to design an in-line biosensor assay system have shown that oocysts would have to be concentrated from water samples and heat treated to allow detection by a biosensor assay

Using evidence, expert opinion and epidemiological model to understand pathways to survival and mortality:The Pathways to Survival (PATHS) Tool

BACKGROUND: The reasons why episodes of illness can lead to fatal outcomes in affected persons in low resource settings are numerous and complex. A tool that allows policy makers to better understand those complexities could be useful to improve success of programmes that are implemented globally to reduce mortality. METHODS: We developed a “Pathways to Survival” (PATHS) tool: an epidemiological model using decision trees, available evidence and expert opinion. PATHS visualises the “architecture” of mortality in the population by following the entire population cohort over a certain period of time. It explains how initially healthy persons progress through health systems to lethal outcomes at the end of the specified time period. We developed an illustrative example based on the 136 million newborns and an estimated 907 000 deaths from newborn sepsis in the year 2008. This allowed us to develop an epidemiological model that described pathways to deaths from neonatal sepsis globally in 2010. RESULTS: The model described the “status quo’ situation in 2010 with 907 000 deaths to allow an assessment of the potential impact and feasibility of different interventions and programmes at various level of health systems in reducing this cause of mortality. A useful model should incorporate both a ‘horizontal’ and a ‘vertical’ component. The ‘horizontal’ would track the progress of all neonates globally through time, ie, their first 28 days of life, and separate them into different ‘pathways’ every time a change in their risk of dying from neonatal infection occurs because of their specific contextual circumstances. The ‘vertical’ would track their position within the health systems of their countries and separate them into different categories based on the ability of health system to intervene and reduce their risk of dying. Based on those requirements, PATHS tool was developed which is based on decision trees where different “branches” of the trees are associated with varying case-fatality rates. CONCLUSIONS: The application of the PATHS tool on the example of newborn sepsis revealed that novel diagnostic tests could save many lives, so we should continue to invest in them to improve their validity, deliverability and affordability. However, PATHS showed that investments in better diagnostics have limited impact unless they are coupled with improvements of the context. Programs for parental education improve compliance and care seeking. Promoting legislation change to empower community health workers (CHWs) to actively engage in prevention, diagnosis and care also makes a difference, as well as programs for training CHWs to use diagnostic tests and administer treatments correctly. Care-seeking behaviour can also be improved through programs of conditional cash transfers. Finally, PATHS demonstrated that improving access to primary and secondary health care for everyone is the most powerful contextual change

Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells

CD4+ T cells differentiate into T helper cell subsets in feedforward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naive CD4+ T cells avoid spontaneous engagement of feedforward mechanisms but retain a prepared state. T cells lacking the adaptor molecule LAT demonstrate impaired TCR-induced signals yet cause a spontaneous lymphoproliferative T helper 2 (TH2) cell syndrome in mice. Thus, LAT constitutes an unexplained maintenance cue. Here, we demonstrate that tonic signals through LAT constitutively export the repressor HDAC7 from the nucleus of CD4+ T cells. Without such tonic signals, HDAC7 target genes Nur77 and Irf4 are repressed. We reveal that Nur77 suppresses CD4+ T cell proliferation and uncover a suppressive role for Irf4 in TH2 polarization; halving Irf4 gene-dosage leads to increases in GATA3+ and IL-4+ cells. Our studies reveal that naive CD4+ T cells are dynamically tuned by tonic LAT-HDAC7 signals

IgG autoantibody to brain beta tubulin III associated with cytokine cluster-II discriminate cerebral malaria in central India

We investigated the significance of these self-reactive antibodies in clinically well-defined groups of P. falciparum infected patients manifesting mild malaria (MM), severe non-cerebral malaria (SM), or cerebral malaria (CM) and in control subjects from Gondia, a malaria epidemic site in central India using quantitative immunoprinting and multivariate statistical analyses. A two-fold complete-linkage hierarchical clustering allows classifying the different patient groups and to distinguish the CM from the others on the basis of their profile of IgG reactivity to brain proteins defined by PANAMA Blot. We identified beta tubulin III (TBB3) as a novel discriminant brain antigen in the prevalence of CM. In addition, circulating IgG from CM patients highly react with recombinant TBB3. Overall, correspondence analyses based on singular value decomposition show a strong correlation between IgG anti-TBB3 and elevated concentration of cluster-II cytokine (IFNγ, IL1β, TNFα, TGFβ) previously demonstrated to be a predictor of CM in the same populatio

Assessment of Pneumonia in Older Adults: Effect of Functional Status

Evaluate the effect of preadmission functional status on severity of pneumonia, length of hospital stay (LOS), and all-cause 30-day and 1-year mortality of adults aged 60 and older and to understand the effect of pneumonia on short-term functional impairment. DESIGN : Prospective cohort study. SETTING : University hospital. PARTICIPANTS : One hundred twelve patients with radiograph-proven pneumonia (mean age 74.6) were enrolled. MEASUREMENTS : Functional status and comorbidities were assessed using the Functional Autonomy Measurement System (SMAF) and Charlson Comorbidity Index. Clinical information was used to calculate the Pneumonia Prognostic Index (PPI). RESULTS : Eighty-four (75%) patients were functionally independent (FI) before admission, with a SMAF score of 40 or lower. Dementia and aspiration history were higher in the group that was functionally dependent (FD) before admission ( P <.001). The FI group had less-severe pneumonia per the PPI and shorter mean LOS±standard deviation (5.62±0.51 days) than the FD group (11.42±2.58, P <.004). The FI group had lower 1-year mortality (19/65, 23%) than the FD group (14/28, 50%), and the difference remained significant after adjusting for Charlson Index and severity of illness ( P =.009). All patients lost function after admission, with loss being more pronounced in the FI group (mean change 19.24±12.9 vs 4.72±6.55, P <.001). CONCLUSION : Older adults who were FI before admission were more likely to present with less-severe pneumonia and have a shorter LOS. In addition, further loss of function was common in these patients. Assessment of function before and during hospitalization should be an integral part of clinical evaluation in all older adults with pneumonia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66281/1/j.1532-5415.2006.00797.x.pd

Loss of RAF kinase inhibitor protein is involved in myelomonocytic differentiation and aggravates RAS-driven myeloid leukemogenesis

RAS-signaling mutations induce the myelomonocytic differentiation and proliferation of hematopoietic stem and progenitor cells. Moreover, they are important players in the development of myeloid neoplasias. RAF kinase inhibitor protein (RKIP) is a negative regulator of RAS-signaling. As RKIP loss has recently been described in RAS-mutated myelomonocytic acute myeloid leukemia, we now aimed to analyze its role in myelomonocytic differentiation and RAS-driven leukemogenesis. Therefore, we initially analyzed RKIP expression during human and murine hematopoietic differentiation and observed that it is high in hematopoietic stem and progenitor cells and lymphoid cells but decreases in cells belonging to the myeloid lineage. By employing short hairpin RNA knockdown experiments in CD34+ umbilical cord blood cells and the undifferentiated acute myeloid leukemia cell line HL-60, we show that RKIP loss is indeed functionally involved in myelomonocytic lineage commitment and drives the myelomonocytic differentiation of hematopoietic stem and progenitor cells. These results could be confirmed in vivo, where Rkip deletion induced a myelomonocytic differentiation bias in mice by amplifying the effects of granulocyte macrophage-colony-stimulating factor. We further show that RKIP is of relevance for RAS-driven myelomonocytic leukemogenesis by demonstrating that Rkip deletion aggravates the development of a myeloproliferative disease in NrasG12D-mutated mice. Mechanistically, we demonstrate that RKIP loss increases the activity of the RAS-MAPK/ERK signaling module. Finally, we prove the clinical relevance of these findings by showing that RKIP loss is a frequent event in chronic myelomonocytic leukemia, and that it co-occurs with RAS-signaling mutations. Taken together, these data establish RKIP as novel player in RAS-driven myeloid leukemogenesis