Hypoxia due to unusual right to left shunt after arterial switch surgery.

Hypoxia can occur after repair of transposition of great arteries. The most common cause of right to left shunt after arterial switch surgery is related to increased right ventricular pressures and persistent neonatal pulmonary arterial hypertension. We report a case of TGA repair causing right to left shunt with normal right ventricular pressures. Persistence of Eustachian valve with patent foramen ovale (PFO) is the unusual cause of hypoxia and desaturation. The patient was successfully managed by excision of Eustachian valve and closure of PFO.

Traumatic Arterio-Enteric Fistula-A Report of 2 Cases With Review of Literature.

BACKGROUND: Traumatic arterio-enteric fistula is predominantly seen after penetrating trauma with only 21 reported cases documented in the past 25 years. They may present in an acute or delayed manner with upper or lower gastrointestinal bleed. A detailed clinical examination with requisite imaging can help in detecting such injuries. CASE DESCRIPTION: Case 1: A 20-year-old gentleman, presented with penetrating stab injury to the gluteal region with bleeding per rectum. Imaging revealed evidence of injury to the inferior rectal artery which was found to be communicating with the extraperitoneal portion of the rectum. He was managed with a combination of endovascular and open surgery with a successful outcome. Case 2: A 29-year-old gentleman, presented in a delayed manner 2 weeks after a gunshot wound to the gluteal region, which was managed operatively in another hospital. He developed a massive lower gastrointestinal bleed 2 weeks after presentation. Imaging revealed evidence of a pseudoaneurysm of the inferior gluteal artery which had a fistulous communication with the gastrointestinal tract leading to bleeding. It was managed by endovascular techniques successfully. CONCLUSION: Arterio-enteric fistulas following trauma are rare phenomena and they need a high index of suspicion for diagnosis. Once diagnosed, they can be managed based on their location and patient physiology by interventional techniques, surgery, or a combination of the two.

A review on RNAi therapy for NSCLC: Opportunities and challenges.

Non-small cell lung cancer (NSCLC) is the primary cause of cancer death worldwide. Despite developments in chemotherapy and targeted therapies, the 5-year survival rate has remained at approximately 16% for the last four decades. NSCLC is a heterogeneous group of tumors that, through mutations and drivers, also demonstrate intra-tumor heterogeneity. Thus, current treatment approaches revolve around targeting these oncogenes, often using small molecule inhibitors and chemotherapeutics. However, the efficacy of these therapies has been crippled by acquired and inherent drug-resistance in the tumor, accompanied by increased therapeutic dosages and subsequent devastating off-target effects for patients. Evidently, there is a critical need for developing treatment methodologies more effective than the current standard of care. Fortunately, RNA interference, particularly small interfering RNA (siRNA), presents an alternative of silencing specific oncogenes to control tumor growth. Although siRNA therapy is subject to rapid degradation and poor internalization in vivo, nanoparticles can serve as nontoxic and efficient delivery vehicles, even introducing combinational delivery of multiple therapeutic agents. Indeed, siRNA-nanoconstructs possess extraordinary potential as an innovative modality to address clinical needs. This state-of-the-art review summarizes the recent advancements in the development of novel nanosystems for delivering siRNA to NSCLC tumors and analyzes the efficacy of representative examples. By illuminating the most promising biomarkers for silencing, we hope to streamline current therapeutic efforts and highlight powerful translational opportunities to combat NSCLC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Lipid-Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Osteogenesis imperfecta: Novel genetic variants and clinical observations from a clinical exome study of 54 Indian patients.

Osteogenesis imperfecta (OI) is a group of inherited disorders with increased bone fragility and wide genetic heterogeneity. We report the outcome of clinical exome sequencing validated by Sanger sequencing in clinically diagnosed 54 OI patients in Indian population. In 52 patients, we report 20 new variants involving both dominant and recessive OI-specific genes and correlate these with phenotypes. COL1A1 and COL1A2 gene variants were identified in 44.23%, of which 28.84% were glycine substitution abnormalities. Two novel compound heterozygous variants in the FKBP10 gene were seen in two unrelated probands. A novel heterogeneous duplication of chromosomal region chr17: 48268168-48278884 from exons 1-33 of the COL1A1 gene was found in one proband. In five probands, there were additional variants in association with OI. These were ANO5 in association with CRTAP in two probands of the same family causing gnathodiaphyseal dysplasia, COL5A2 with LEPRE1 causing Ehlers Danlos syndrome, COL11A1 in addition to COL1A1 causing Stickler syndrome, and a previously unreported combination of SLC34A1 gene variant with FKBP10 leading to Fanconi renal tubular syndrome type II. Our findings demonstrate the efficacy of clinical exome sequencing in screening OI patients, classifying its subtypes, and identifying associated disorders in consanguineous populations.

Interdomain communication suppressing high intrinsic ATPase activity of Sse1 is essential for its co-disaggregase activity with Ssa1.

In eukaryotes, Hsp110s are unambiguous cognates of the Hsp70 chaperones, in primary sequence, domain organization, and structure. Hsp110s function as nucleotide exchange factors (NEFs) for the Hsp70s although their apparent loss of Hsp70-like chaperone activity, nature of interdomain communication, and breadth of domain functions are still puzzling. Here, by combining single-molecule FRET, small angle X-ray scattering measurements (SAXS), and MD simulation, we show that yeast Hsp110, Sse1 lacks canonical Hsp70-like interdomain allostery. However, the protein exhibits unique noncanonical conformational changes within its domains. Sse1 maintains an open-lid substrate-binding domain (SBD) in close contact with its nucleotide-binding domain (NBD), irrespective of its ATP hydrolysis status. To further appreciate such ATP-hydrolysis-independent exhaustive interaction between two domains of Hsp110s, NBD-SBD chimera was constructed between Hsp110 (Sse1) and Hsp70 (Ssa1). In Sse1/Ssa1 chimera, we observed undocking of two domains leading to complete loss of NEF activity of Sse1. Interestingly, chimeric proteins exhibited significantly enhanced ATPase rate of Sse1-NBD compared to wild-type protein, implying that intrinsic ATPase activity of the protein remains mostly repressed. Apart from repressing the high ATPase activity of its NBD, interactions between two domains confer thermal stability to Sse1 and play critical role in the (co)chaperoning function of Sse1 in Ssa1-mediated disaggregation activity. Altogether, Sse1 exhibits a unique interdomain interaction, which is essential for its NEF activity, suppression of high intrinsic ATPase activity, co-chaperoning activity in disaggregase machinery, and stability of the protein.

Transanal high pressure barotrauma causing colorectal injuries: a case series.

BACKGROUND: Rectal perforation by foreign bodies is known; however, high-pressure injury leading to rectal blowout has been confined to battlefields and is less often encountered in general medical practice. Apart from iatrogenic injuries during colonoscopy, barotrauma from compressed air is encountered very less frequently. Owing to the infrequent nature of these injuries, the mechanism is still not well understood. We present our experience with treating high-pressure transanal barotrauma to the rectum and colon in three similar cases. CASE PRESENTATION: The mode of injury was accidental or a cruel, perverted joke played by acquaintances. The high-pressure air jet column overcomes the anal sphincter barrier, pushing enormous amounts of air through the anus into the bowel, which ruptures when the burst pressure is reached. A huge amount of free gas was noted in the peritoneal cavity on x-rays, and a big gush was noted during surgery. All these cases had rectosigmoid junction blowout with multiple colonic injuries. The patients underwent exploratory laparotomy with resection of severely injured segments and proximal ileostomy. They underwent restoration of bowel continuity after 2-3 months and were doing well in follow-up. CONCLUSIONS: Colorectal injuries by pneumatic insufflation through the anus depends on the air pressure, air flow velocity, anal resting pressure, and the distance between the source and anus. The relative fixity of the rectum and the bends of the sigmoid make the rectosigmoid junction more prone to rupture by high-pressure air jet. Education regarding such machines and their safe use must be encouraged because most of these cases are accidental and due to ignorance.

Increased expression of platelet-derived growth factor associated protein-1 is associated with PDGF-B mediated glioma progression.

The current treatment therapies available for malignant gliomas are inadequate. There is an urgent need to develop more effective therapies by characterizing the molecular pathogenesis of the disease. Over expression of platelet-derived growth factor (PDGF) ligands and receptors have been reported in malignant gliomas. Platelet-derived growth factor associated protein-1 (PDAP-1) is reported to modulate the mitogenic activity of PDGF ligands, but to date, there is no information concerning its role in PDGF-mediated glioma cell proliferation. This study aimed to characterize the role of PDAP-1 in PDGF-mediated glioma proliferation. The expression of PDAP-1 was observed to be significantly increased (p<0.05) in grade IV glioma tissue and cell lines compared to grade III. siRNA-mediated knockdown of PDAP-1 reduced the expression of PDGF-B and its downstream genes (Akt1/Protein kinase B (PKB) and phosphoinositide-dependent kinase-1 (PDK1) by up to 50%. In PDAP-1 knockdown glioma cells, more than a twofold reduction was also observed in the level of phosphorylated Akt. Interestingly, knockdown of PDAP-1 in combination with PDGF-B antibody inhibited glioma cell proliferation through activation of Caspase 3/7 and 9. We also demonstrate that PDAP-1 co-localizes with PDGF-B in the cytoplasm of glioma cells, and an interaction between both of the proteins was established. Collectively, these findings suggest that the expression of PDAP-1 is associated with disease malignancy, and its inhibition reduced the proliferation of malignant glioma cells through down-regulation of PDGF-B/Akt/PDK1 signaling. Thus, this study establishes PDAP-1 as an effecter of PDGF signaling in glioma cells and suggests that it could also be a promising therapeutic target.

Monitoring conformational heterogeneity of the lid of DnaK substrate-binding domain during its chaperone cycle.

DnaK or Hsp70 of Escherichia coli is a master regulator of the bacterial proteostasis network. Allosteric communication between the two functional domains of DnaK, the N-terminal nucleotide-binding domain (NBD) and the C-terminal substrate- or peptide-binding domain (SBD) regulate its activity. X-ray crystallography and NMR studies have provided snapshots of distinct conformations of Hsp70 proteins in various physiological states; however, the conformational heterogeneity and dynamics of allostery-driven Hsp70 activity remains underexplored. In this work, we employed single-molecule Förster resonance energy transfer (sm-FRET) measurements to capture distinct intradomain conformational states of a region within the DnaK-SBD known as the lid. Our data conclusively demonstrate prominent conformational heterogeneity of the DnaK lid in ADP-bound states; in contrast, the ATP-bound open conformations are homogeneous. Interestingly, a nonhydrolysable ATP analogue, AMP-PNP, imparts heterogeneity to the lid conformations mimicking the ADP-bound state. The cochaperone DnaJ confers ADP-like heterogeneous lid conformations to DnaK, although the presence of the cochaperone accelerates the substrate-binding rate by a hitherto unknown mechanism. Irrespective of the presence of DnaJ, binding of a peptide substrate to the DnaK-SBD leads to prominent lid closure. Lid closure is only partial upon binding to molten globule-like authentic cellular substrates, probably to accommodate non-native substrate proteins of varied structures.

ABVE-PC and modified BEACOPP regimen in Indian children with Hodgkin lymphoma: Feasibility and efficacy.

AIMS: To study the toxicity of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide) and modified-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in intermediate-risk and high-risk Hodgkin lymphoma patients. METHODS: High-risk patients received 4 cycles of modified-BEACOPP (m-BEACOPP) plus 4 cycles of ABVD. Intermediate-risk patients received 4 cycles of ABVE-PC plus 2 cycles of ABVD. RESULTS: From 2010 to 2014, 17 patients received 66 cycles of m-BEACOPP and 9 patients received 40 cycles of ABVE-PC. In the m-BEACOPP and ABVE-PC courses, respectively, significant thrombocytopenia (<50,000/mm(3)) occurred in 10.6% vs 0% of courses; anemia (Hb. <8 gm/dl) in 27.3% vs 15%; neutropenia (ANC<500/mm(3)) in 46.9% vs 32.5%; and febrile neutropenia in 33.3% vs. 22.5%. Only episode of documented infection (hepatic abscess) occurred in ABVE-PC. There were no episodes of sepsis, typhlitis or pneumonia in either group. All 26 patients are in remission with a median follow-up of 35 months (range, 17-61); and there have been no relapses. Two of 26 (7.7%) patients failed to achieve rapid early response after 2 cycles and complete remission after 4 cycles of chemotherapy; both achieved remission with more intensive regimens followed by radiation. The remaining 24 patients did not receive radiation therapy. CONCLUSIONS: Both m-BEACOPP and ABVE-PC regimens have acceptable toxicity; and thus can be used in most centres with optimum supportive care facilities. They offer promising response rate and relapse free survival without the need for radiation therapy in most patients; and thus may be considered for children with high-risk and intermediate-risk Hodgkin lymphoma.

Low-dose rasburicase in hematologic malignancies.

OBJECTIVE: To define the efficacy and safety of low-dose rasburicase in children from south India with hematologic malignancies. METHODS: This study is a retrospective analysis of data on 41 children with hematologic malignacies with laboratory evidence of tumor lysis syndrome (TLS) or clinical features indicating high risk for developing TLS. Patients were treated with rasburicase in doses of 0.1-0.15 mg/kg dose, repeated when necessary. RESULTS: Male : Female ratio was 32:9. Thirty-six children had laboratory evidence of TLS and 5 were at risk for TLS. Diagnoses were T-cell acute lymphoblastic leukemia (ALL), 19; Pre-B ALL, 17; B-non-Hodgkin lymphoma (NHL), 2; T-NHL, 2; and acute myeloid leukemia (AML), 1. Initial plasma uric acid (PUA): median, 8.5 mg/dl (range, 4.3 to 45.5). Six had creatinine levels of >2 mg/dl on admission; and 10 had peak PO4 levels of >10 mg/dl. Dose of rasburicase used: median, 0.12 mg/kg (range, 0.08-0.24). Median reduction of PUA at 6 h: 80 % (range 40 to 98 %). Twenty-seven needed only one dose; 12 needed 2 or 3 doses; and two needed 5 doses each. One child required dialysis. None of the children developed anaphylaxis or hemolysis and there were no deaths from TLS. CONCLUSIONS: Low-dose rasburicase (0.1-0.15 mg/kg) is safe and effective in reducing PUA in Indian children with lymphoid malignancies, and thus it may reduce the risk of renal failure from TLS.