Aluminum phosphide (celphos) poisoning in children: A 5-year experience in a tertiary care hospital from northern India

Background:

Aluminum phosphide (ALP) (celphos) is an agricultural pesticide commonly implicated in poisoning. Literature pertaining to the clinical manifestations and treatment outcome of its poisoning among children is limited.

Materials and Methods:

A retrospective chart review was conducted of the medical records of 30 children aged less than 14 years admitted to pediatric intensive care unit (PICU) of a tertiary care hospital in northern India. Demographic, clinical, and laboratory parameters were recorded. The outcome was categorized into “survivors” and “nonsurvivors.”

Results:

The Mean (SD) age of the enrolled children [19 males (63.3%)] was 8.55 (3.07) years. Among the 30 children, 14 (46.67%) were nonsurvivors and the rest 16 (53.33%) were survivors. Nonsurvivors had ingested significantly higher doses of ALP (P < 0.001), and showed higher time lag to PICU transfer (P 0.031), presence of abnormal radiological findings on chest skiagram (P = 0.007), and a higher Pediatric Risk of Mortality (PRISM) III score (P < 0.001) at admission. Use of magnesium sulfate was associated significantly with survival [odds ratio (OR) (95% CI): 0.11 (0.02-0.66); P 0.016].

Conclusion:

The present study highlights that survival among children with ALP poisoning is predicted by dose of ALP ingestion, time lag to medical attention, and higher PRISM score at admission. Use of magnesium sulfate could be associated with better survival among them.     

Sotatercept in patients with osteolytic lesions of multiple myeloma

This phase IIa study evaluated the safety and tolerability of sotatercept, and its effects on bone metabolism and haematopoiesis in newly diagnosed and relapsed multiple myeloma (MM) patients. Patients were randomized (4:1) to receive four 28‐d cycles of sotatercept (0·1, 0·3, or 0·5 mg/kg) or placebo. Patients also received six cycles of combination oral melphalan, prednisolone, and thalidomide (MPT). Thirty patients were enrolled; six received placebo and 24 received sotatercept. Overall, 25% of patients received all four sotatercept doses; 71% of sotatercept‐treated patients had ≥1 dose interruption mainly due to increases in haemoglobin levels. Grade ≥3 adverse events (AEs) were reported in 17% of patients receiving placebo and 58% receiving sotatercept. Grade 4 AEs in sotatercept‐treated patients were neutropenia, granulocytopenia, and atrial fibrillation (one patient each). In patients without bisphosphonate use, anabolic improvements in bone mineral density and in bone formation relative to placebo occurred, whereas bone resorption was minimally affected. Increases in haemoglobin levels, versus baseline, and the duration of the increases, were higher in the sotatercept‐treated patients, with a trend suggesting a dose‐related effect. Multiple doses of sotatercept plus MPT appear to be safe and generally well‐tolerated in MM patients.     

Transcatheter closure of a residual aortopulmonary window through internal jugular vein access

The use of Amplatzer septal occluder for closing a residual aortopulmonary defect has been described. This is usually performed by femoral access. We report closure of a residual aortopulmonary defect using right internal jugular vein access in a patient who had no femoral access as a result of previous cannulation for surgical repair. The 1 cm defect was closed successfully using a 10 mm Amplatzer septal occluder.Technical difficulty anticipated was unfounded although it was more cumbersome than femoral access. Left to right cardiac defects including PDA and AP window are amenable to transcatheter closure through internal jugular vein access.     

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Hypersecretion of cytokines by innate immune cells is thought to initiate multiple organ failure in murine models of sepsis. Whether human cytokine storm also plays a similar role is not clear. Here, we show that human hematopoietic cells are required to induce sepsis-induced mortality following cecal ligation and puncture (CLP) in the severely immunodeficient nonobese diabetic (NOD)/SCID/IL2Rγ^−/− mice, and siRNA treatment to inhibit HMGB1 release by human macrophages and dendritic cells dramatically reduces sepsis-induced mortality. Following CLP, compared with immunocompetent WT mice, NOD/SCID/IL2Rγ^−/− mice did not show high levels of serum HMGB1 or murine proinflammatory cytokines and were relatively resistant to sepsis-induced mortality. In contrast, NOD/SCID/IL2Rγ^−/− mice transplanted with human hematopoietic stem cells [humanized bone marrow liver thymic mice (BLT) mice] showed high serum levels of HMGB1, as well as multiple human but not murine proinflammatory cytokines, and died uniformly, suggesting human cytokines are sufficient to induce organ failure in this model. Moreover, targeted delivery of HMGB1 siRNA to human macrophages and dendritic cells using a short acetylcholine receptor (AchR)-binding peptide [rabies virus glycoprotein (RVG)-9R] effectively suppressed secretion of HMGB1, reduced the human cytokine storm, human lymphocyte apoptosis, and rescued humanized mice from CLP-induced mortality. siRNA treatment was also effective when started after the appearance of sepsis symptoms. These results show that CLP in humanized mice provides a model to study human sepsis, HMGB1 siRNA might provide a treatment strategy for human sepsis, and RVG-9R provides a tool to deliver siRNA to human macrophages and dendritic cells that could potentially be used to suppress a variety of human inflammatory diseases.Sepsis is an important cause of mortality in intensive-care units, with more than 750,000 individuals developing severe sepsis in North America annually and a mortality rate varying between 35 and 50% (1, 2). The pathogenesis of sepsis includes countless disturbances of the host immune system starting with a harmful, infection-triggered exaggerated inflammatory cascade that results in tissue injury and rapidly leads to massive apoptosis of immune cells (2, 3). This is followed by a secondary immune paralysis phase accompanied by uncontrolled growth of bacteria and tissue damage. Although therapy to suppress the immediate cytokine response, such as treatment with TNF and IL-1β antibodies, have failed in clinical trials (4–6), it has now come to be recognized that, at least in animal models, high-mobility group protein 1 (HMGB1), which is secreted from macrophages and dendritic cells (DCs) but not lymphocytes late in the disease, acts as a master regulator of late and sustained cytokine storm, up-regulating many cytokines including TNF-α, IL-6, IL-1β, and IL-8 (reviewed in refs. 7–11). In fact, injection of mice with HMGB1 is enough to induce the lethal organ damage seen in sepsis (12), whereas treatment with neutralizing HMGB1 antibody can rescue mice and rats from experimental sepsis (13, 14). However, although HMGB1 is also secreted in human sepsis (12), its role in sepsis pathogenesis or the impact of its neutralization on human cells remain unclear.RNA interference can be used to silence virtually any gene, including multiple genes, as long as a way can be found to introduce small interfering (si)RNAs into relevant cell types in vivo without toxicity. Several advances have been made in developing methods to deliver siRNA in vivo to different cell types, most successfully to the liver cells (reviewed in refs. 15–17). A lipid-like nanoparticle called C12-200, which had been developed for liver-specific delivery of siRNA, was recently also shown to deliver siRNA to murine monocytes, and silencing C-C chemokine receptor type 2 (CCR2) in monocytes using this reagent was effective in reducing atherosclerosis, islet transplantation and tumors (18). Whether this reagent also targets human DCs and monocytes/macrophages is unclear. We have reported previously that a short 29-aa peptide derived from the rabies virus glycoprotein (RVG), fused to 9R residues (RVG-9R), can deliver siRNA to murine macrophages and brain cells by specific binding to its ligand acetylcholine receptor (AchR) (19, 20). Because AchR is also expressed on human macrophages and DCs (21) and also because the acetylcholine-binding site on the α7 subunit is highly conserved, we reasoned that RVG-9R might also be used to target human macrophages and DCs. In this study, we validate this hypothesis in vitro, as well as in vivo, using human hematopoietic stem cell–engrafted nonobese diabetic NOD/SCID/IL2Rγ^−/− mice that lack mouse innate and adaptive immune systems (22). More importantly, we also show that silencing human HMGB1 using this delivery reagent in this mouse model substantially reduces human lymphocyte apoptosis and cytokine storm and protects mice from sepsis-induced mortality.     

Comparative Evaluation of Tensile Bond Strength between Silicon Soft Liners and Processed Denture Base Resin Conditioned by Three Modes of Surface Treatment: An Invitro Study

Soft denture liners act as a cushion for the denture bearing mucosa through even distribution of functional load, avoiding local stress concentrations and improving retention of dentures there by providing comfort to the patient. The objective of the present study was to compare and evaluate the tensile bond strengths of silicone-based soft lining materials (Ufi Gel P and GC Reline soft) with different surface pre treatments of heat cure PMMA denture base acrylic resin. Stainless steel dies measuring 40 mm in length; 10 mm in width and 10 mm in height (40 × 10 × 10) were machined to prepare standardized for the polymethyl methacrylate resin blocks. Stainless steel dies (spacer for resilient liner) measuring 3 mm thick; 10 mm long and 10 mm wide were prepared as spacers to ensure uniformity of the soft liner being tested. Two types of Addition silicone-based soft lining materials (room temperature polymerised soft lining materials (RTPSLM): Ufi Gel P and GC Reline soft) were selected. Ufi Gel P (VOCO, Germany), GC Reline soft (GC America) are resilient, chairside vinyl polysiloxane denture reliners of two different manufacturers. A total of 80 test samples were prepared of which 40 specimens were prepared for Group A (Ufi Gel P) and 40 specimens for Group B (GC Reline soft). In these groups, based on Pre-treatment of acrylic resin specimens each group was subdivided into four sub groups of 10 samples each. Sub-group I—without any surface treatment. Sub-group II—sand blasted Sub-group III—treated with Methyl Methacrylate monomer Sub-group IV-treated with chemical etchant Acetone. The results were statistically analysed by Kruscal Wallis test, Mann–Whitney U test, and Independent t test. The specimens treated with MMA monomer wetting showed superior and significant bond strength than those obtained by other surface treatments. The samples belonging to subgroups of GC Reline soft exhibit superior tensile bond strength than subgroups of Ufi Gel P. The modes of failure of all specimens were mostly adhesive in nature. Surface pre treatments by chemical means improved the bond strength between the silicone liners and denture base.     

Biosimilar DMARD in rheumatology: A general perspective with focus on India

Biologic disease modifying anti-rheumatic drugs (DMARD) have revolutionized the management of several rheumatic disorders, especially those with autoimmune inflammatory etiology. A decade of experience has further endorsed their efficacy and unraveled safety issues. Treat to target remission is the current mantra. Infections remain the single most important complication. However, the access to biologics has been severely restricted by their exorbitant cost. Several biologics will lose their patent in the imminent future. An exact replica of a protein molecule is difficult if not impossible. Molecules seemingly similar to biologics called biosimilars or ‘follow on biologics’ are likely to flood the markets world wide at a challenging and affordable price. However, the acceptability of biosimilars will be driven by several contentious issues connected with manufacture, standardization, extent of validation (compared to source innovator biologic), interchangeability (with biologic), regulatory issues, and other patient centric socioeconomic issues. India is likely to provide a fertile field for biosimilar drugs and patients stand to gain from an expanded access and newer treatment paradigms. The fierce competition between several pharmaceutical companies (Indian and multinationals) to gain supremacy will fuel better affordability, equity and access to medicine while upholding the science of quality drugs. The stage is now set for this next big revolution in therapeutics.