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Approximately 20% of patients receiving multiple platelet transfusions develop platelet alloantibodies, which can be directed against human leukocyte antigens (HLA) and, to a lesser extent, against human platelet antigens (HPA). These antibodies can lead to the rapid clearance of donor platelets, presumably through IgG-Fc receptor (FcγR)-mediated phagocytosis or via complement activation, resulting in platelet refractoriness. Strikingly, not all patients with anti-HLA or -HPA antibodies develop platelet refractoriness upon unmatched platelet transfusions. Previously, we found that IgG Fc glycosylation of anti-HLA antibodies was highly variable between patients with platelet refractoriness, especially with respect to galactosylation and sialylation of the Fc-bound sugar moiety. Here, we produced recombinant glycoengineered anti-HLA and anti- HPA-1a monoclonal antibodies with varying Fc galactosylation and sialylation levels and studied their ability to activate the classical complement pathway. We observed that anti-HLA monoclonal antibodies with different specificities, binding simultaneously to the same HLA-molecules, or anti-HLA in combination with anti-HPA-1a monoclonal antibodies interacted synergistically with C1q, the first component of the classical pathway. Elevated Fc galactosylation and, to a lesser extent, sialylation significantly increased the complement-activating properties of anti-HLA and anti-HPA-1a monoclonal antibodies. We propose that both the breadth of the polyclonal immune response, with recognition of different HLA epitopes and in some cases HPA antigens, and the type of Fc glycosylation can provide an optimal stoichiometry for C1q binding and subsequent complement activation. These factors can shift the effect of a platelet alloimmune response to a clinically relevant response, leading to complement-mediated clearance of donor platelets, as observed in platelet refractoriness.

Approximately 20% of patients receiving multiple platelet transfusions develop platelet alloantibodies, which can be directed against human leukocyte antigens (HLA) and, to a lesser extent, against human platelet antigens (HPA). These antibodies can lead to the rapid clearance of donor platelets, presumably through IgG-Fc receptor (FcγR)-mediated phagocytosis or via complement activation, resulting in platelet refractoriness. Strikingly, not all patients with anti-HLA or -HPA antibodies develop platelet refractoriness upon unmatched platelet transfusions. Previously, we found that IgG Fc glycosylation of anti-HLA antibodies was highly variable between patients with platelet refractoriness, especially with respect to galactosylation and sialylation of the Fc-bound sugar moiety. Here, we produced recombinant glycoengineered anti-HLA and anti- HPA-1a monoclonal antibodies with varying Fc galactosylation and sialylation levels and studied their ability to activate the classical complement pathway. We observed that anti-HLA monoclonal antibodies with different specificities, binding simultaneously to the same HLA-molecules, or anti-HLA in combination with anti-HPA-1a monoclonal antibodies interacted synergistically with C1q, the first component of the classical pathway. Elevated Fc galactosylation and, to a lesser extent, sialylation significantly increased the complement-activating properties of anti-HLA and anti-HPA-1a monoclonal antibodies. We propose that both the breadth of the polyclonal immune response, with recognition of different HLA epitopes and in some cases HPA antigens, and the type of Fc glycosylation can provide an optimal stoichiometry for C1q binding and subsequent complement activation. These factors can shift the effect of a platelet alloimmune response to a clinically relevant response, leading to complement-mediated clearance of donor platelets, as observed in platelet refractoriness.

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Aims: To determine the global extent of hypoglycaemia experienced by patients with diabetes using insulin, as there is a lack of data on the prevalence of hypoglycaemia in developed and developing countries. Methods: This non-interventional, multicentre, 6-month retrospective and 4-week prospective study using self-assessment questionnaire and patient diaries included 27 585 patients, aged >= 18 years, with type 1 diabetes (T1D; n = 8022) or type 2 diabetes (T2D; n = 19 563) treated with insulin for > 12 months, at 2004 sites in 24 countries worldwide. The primary endpoint was the proportion of patients experiencing at least one hypoglycaemic event during the observational period. Results: During the prospective period, 83.0% of patients with T1D and 46.5% of patients with T2D reported hypoglycaemia. Rates of any, nocturnal and severe hypoglycaemia were 73.3 [95% confidence interval (CI) 72.6-74.0], 11.3 (95% CI 11.0-11.6) and 4.9 (95% CI 4.7-5.1) events/patient-year for T1D and 19.3 (95% CI 19.1-19.6), 3.7 (95% CI 3.6-3.8) and 2.5 events/patient-year (95% CI 2.4-2.5) for T2D, respectively. The highest rates of any hypoglycaemia were observed in Latin America for T1D and Russia for T2D. Glycated haemoglobin level was not a significant predictor of hypoglycaemia. Conclusions: We report hypoglycaemia rates in a global population, including those in countries without previous data. Overall hypoglycaemia rates were high, with large variations between geographical regions. Further investigation into these differences may help to optimize therapy and reduce the risk of hypoglycaemia.

Background RhIG is obtained from hyperimmunized healthy anti-D donors (HIDs) boosted with D+ red blood cells (RBCs). One hypothesis for its mechanism of action is fast clearance of opsonized D+ RBCs through Fcγ receptor (FcγR)III. Levels of immunoglobulin (Ig)G Fc-fucosylation influence interactions with FcγRIII, with less Fc-fucosylation strengthening the interaction. Study Design and Methods Anti-D IgG1 Fc-glycosylation patterns in 93 plasma samples from 28 male and 28 female Dutch HIDs and RhIG were analyzed with mass spectrometry. The Fc-glycosylation profiles of HIDs were evaluated with regard to their immunization history. Results HID sera demonstrated clearly lowered anti-D Fc-fucosylation compared to normal IgG fucosylation (93%); this was more pronounced for female than for male HIDs (47% vs. 65%, p-=-0.001). RhIG preparations from seven manufacturers varied greatly in the level of Fc-fucosylation (56%-91%). The level of fucosylation slightly increased upon repeated immunization, although it remained fairly constant over time. The RhIG from the different manufacturers all demonstrated increased Fc-galactosylation (64%-82%) compared to total IgG (38%-51%). Conclusion RhIG preparations vary in Fc-fucosylation and all demonstrate increased galactosylation. Despite not knowing the exact working mechanism, immunoprophylaxis could perhaps be optimized by selection of donors whose anti-D have low amounts of Fc-fucose, to increase the clearance activity of anti-D preparations, as well as high amounts of galactosylation, for anti-inflammatory effects. Implementing a biologic assay in the standardization of RhIG preparations might be considered.

Incidence of hypoglycemia in a global patient population was assesed. Patients reported the degree and severity of hypoglycemic episodes.

Real world data on hypoglycemia on a global level are lacking, as well as patient's actions following hypoglycemic episodes. Presented are data from global noninterventional HAT study.

Haemolytic disease of the fetus and newborn (HDFN) may occur when maternal IgG antibodies against red blood cells (RBCs), often anti-RhD (anti-D) antibodies, cross the placenta and mediate the destruction of RBCs via phagocytic IgG-Fc-receptors (FcγR). Clinical severity is not strictly related to titre and is more accurately predicted by the diagnostically-applied monocyte-based antibody-dependent cellular cytotoxicity (ADCC), a sensitive test with relatively low specificity. This suggests that other factors are involved in the pathogenesis of HDFN. Binding of IgG to FcγR requires the N-linked glycan at position 297 in the IgG-Fc-region, consisting of several different glycoforms. We therefore systematically analysed IgG-derived glycopeptides by mass spectrometry from 70 anti-D IgG1 antibodies purified from the plasma of alloimmunized pregnant women. This revealed a variable decrease in Fc-fucosylation in the majority of anti-D IgG1 (even down to 12%), whereas the total IgG of these patients remained highly fucosylated, like in healthy individuals (>90%). The degree of anti-D fucosylation correlated significantly with CD16 (FcγRIIIa)-mediated ADCC, in agreement with increased affinity of defucosylated IgG to human FcγRIIIa. Additionally, low anti-D fucosylation correlated significantly with low fetal-neonatal haemoglobin levels, thus with increased haemolysis, suggesting IgG-fucosylation to be an important pathological feature in HDFN with diagnostic potential. © 2014 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Hemifacial microsomia is a congenital malformation in which there is a deficiency in the amount of hard and soft tissue on one side of the face. It is primarily a syndrome of the first branchial arch, involving underdevelopment of the temporomandibular joint, mandibular ramus, masticatory muscles and the ear. The affected ear may have an external soft-tissue malformation in addition to being lower set than on the contra lateral side. Hearing loss may result from underdevelopment of the osseous components of the auditory system and a diminished or absent external auditory meatus. Occasionally, second branchial arch defects involving the facial nerve and facial muscles coexist with Hemifacial microsomia. Radiographic examination in case of Hemifacial microsomia is of limited value because of superimposition of normal and abnormal bony structures. The skeletal and soft-tissue findings of a patient with Hemifacial microsomia who underwent three-dimensional computerized tomography is presented here to improve our knowledge and diagnostic skill of this uncommon entity.

Decalcified Allogenic Bone grafts were implanted in and around eighteen root apices after apicoectomy. The procedure was carried out on eighteen rabbits, dividing them into three groups of six rabbits each. The animals were sacrificed after 48-72 hours, 8-10 days & 8-10 weeks period of interval. Result of the present investigation reveal that DABM grafts stimulate osteogenesis and cementogenesis after the initial phase of inflammation. Tissues simulating bone and cementum appear at the apical end, speculating that the grafts would certainly result in physiological sealing of root apices. The possibility of saving the life of non vital teeth with or without wide apical foramen will enhance in future.

SUMMARY A study was carried out to examine the validity of social dysfunctioning as a measure of severity of illness. Modified version of KAS, R2 inventory was used to measure social functioning. Since there can be no absolute measure of severity of psychiatric illness, the validity was tested through indirect means. It was decided that if the scores on social dysfunctioning were higher amongst the mentally ill compared to normals, higher in Psychotics compared to Neurotics and higher in those assessed by a relative as well as the Consultant Pyshciatrist to be more severely ill than those judged as less severely ill, the validity of social dysfunctioning as a measure of severity of Psychiatric illness would stand established. This was indeed found to be the case in the study which was carried out with 200 consecutive patients from a psychiatric out-patient department and their matched normal controls.

SUMMARY As a part of designing a suitable model for mental health care delivery in rural India, a study of detection and management of priority mental disorders was carried out in 120 villages around rural mental health centre, Sakalwara in Bangalore District. During three and a half year period, the team attempted to manage 51 schizophrenics, 30 acute psychotics, 27 M. D. P. and 268 epileptics in the community with minimum number of drugs. The experiences and outcome of this attempt is presented and discussed here.

SUMMARY A cross sectional epidemiological study of mental morbidity among 1160 postgraduate and research students was done by census method. Goldberg's 60 item GHQ was used as screening tool and a person scoring 12 and above was taken as a case. The response rate was 92.5%. A prevalence rate of 16.63 was found. The relationship between mental morbidity and selected socio-demographic, motivational psychological variables; certain life experiences in the campus was studied. The results are discussed. This study is first of its kind in our country.

There has been an increased influx of probiotic products in the Indian market during the last decade. However, there has been no systematic approach for evaluation of probiotics in food to ensure their safety and efficacy. An initiative was, therefore, taken by the Indian Council of Medical Research (ICMR) along with the Department of Biotechnology (DBT) to formulate guidelines for regulation of probiotic products in the country. These guidelines define a set of parameters required for a product/strain to be termed as 'probiotic'. These include identification of the strain, in vitro screening for probiotic characteristics, animal studies to establish safety and in vivo animal and human studies to establish efficacy. The guidelines also include requirements for labeling of the probiotic products with strain specification, viable numbers at the end of shelf life, storage conditions, etc., which would be helpful to the consumers to safeguard their own interest.

Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition where the alveoli fill with inflammatory cells and blood plasma (edema), impeding oxygen uptake and making it difficult to breathe. Severe inflammation and trauma cause ARDS, which ends in death in an estimated 40% of cases. Transfusion-Related Acute Lung Injury (TRALI) can lead to ARDS, but is a result of blood transfusion in two steps: (1) systemic underlying inflammation in the patient and (2), transfusion of biological response modifiers or matching antibodies to HLA and HNA. The exact mechanisms behind the pathologies are not yet clear and to date there is no effective treatment. ARDS and TRALI both have strong immunological profiles and result in destruction of the barrier between the blood circulation and lung tissue, which can result in long-term or permanent damage in survivors. Throughout the cardiovascular system, this barrier consists of so-called endothelial cells. Endothelial cells determine which plasma proteins and immune cells are allowed to pass from the blood to the tissue and actively counteract leakage during these processes. Endothelial cells are affected by signals from the rest of the body, such as blood pressure or stress signals from surrounding cells, which changes their barrier and signal function. In this thesis, we have investigated various factors that can affect barrier function and trans-endothelial migration of immune cells in endothelial cells, to better understand when and how it becomes dysregulated, and where one can possibly intervene to counteract edema and damage in ARDS and TRALI.