Bleeding and thrombosis in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) has evolved from being a deadly to a highly curable disease, due to targeted molecular therapy with all-trans retinoic acid (ATRA). As a result, the incidence of early hemorrhagic deaths for which APL is notorious has reduced to 5-10% as reported in clinical trials. These results are not replicated outside of clinical trials as is evident from recent population-based registries. High incidence of early hemorrhagic deaths remains the greatest contributor to treatment failure in this otherwise curable leukemia. Additionally, thrombosis is now being increasingly recognized in APL patients and may be associated with ATRA usage.     

Comparative Analysis of Osteosynthesis of Mandibular Anterior Fractures Following Open Reduction Using ‘Stainless Steel Lag Screws and Mini Plates’

Introduction

The purpose of this study was to compare the outcome of open treatment of mandibular fracture (symphysis or parasymphysis) using lag screw or mini plate clinically as well as radiologically in young (age range 12–45 years) and healthy individuals of poor socioeconomic status.

Method

This prospective study was conducted on 30 patients diagnosed as cases of displaced mandibular anterior fractures treated with open reduction and internal fixation. The patients were then randomly allocated to either of two groups––Group A: Two 2.5 mm stainless steel lag screws were placed in 15 patients. Group B: Two 2.5 mm stainless steel mini plates were placed in 15 patients for the fixation of fractures. Subsequent follow up was done on 2nd, 4th, 6th and 8th week postoperatively. During every follow up patient was assessed clinically for infection, malocclusion, loosening of plate/screw, sensory disturbance, plate fracture, malunion/non-union, devitalisation of associated dentoalveolar segment and masticatory efficiency. Radiographs were taken if necessary and patients were further assessed for any complaint. Pain was objectively measured using a visual analogue scale, bite force was measured using a bite force transducer at biweekly interval. The data collected was subjected to unpaired t test and paired t test for statistical analysis.

Results

During follow up period a significant improvement in bite force was present in both the groups, with more improvement seen in the lag screw group (p < 0.01). There was a significant pain reduction present in the lag screw group (p < 0.01) and also masticatory efficiency showed a steadier improvement in lag screw group while mini plate group patients showed a tendency to masticate only food items of medium hard consistency.

Conclusion

The sample size is small to conclude lag screws are better than mini plates but the result of our study provides a basis for further studies done to conclude that the application of LAG SCREW is an effective, inexpensive, quick treatment modality to accelerate healing of fresh, displaced mandibular anterior fracture.     

Thrombotic microangiopathy and acute kidney injury following vivax malaria

Background

Infection with Plasmodium vivax, a common human parasite, is occasionally recognized to cause severe organ dysfunction similar to P. falciparum infection. Acute kidney injury (AKI) in malaria is attributed to acute tubular necrosis; thrombotic microangiopathy is not described.

Methods

This observational study includes patients referred to a tertiary care center in North India during June to September 2011 with severe AKI, anemia, and thrombocytopenia following vivax malaria. Renal biopsies were processed by light, immunofluorescence, and electron microscopy.

Results

Nine patients (including 5 children) had persistent AKI with thrombocytopenia and variable anemia following the diagnosis of malaria. Based on peripheral smear, eight patients were diagnosed with vivax malaria and had received antimalarial therapy prior to referral; a laboratory diagnosis of P. vivax infection was made for one patient at this center. Renal histology in all cases showed features of thrombotic microangiopathy, including fibrin thrombi, subendothelial widening, and mesangiolysis, along with variable tubulointerstitial nephritis and acute tubular or cortical necrosis. Ultrastructural examination confirmed endothelial injury and subendothelial widening. All patients required hemodialysis, and six were dialysis dependent at four weeks. Delayed presentation to the hospital (P = 0.019), hemolysis on peripheral smear (P = 0.083), and prolonged oligoanuria (P = 0.036) were associated with dialysis dependence.

Conclusion

The association of anemia, thrombocytopenia, and renal histological evidence of thrombotic microangiopathy with vivax malaria is novel, and suggests the presence of severe endothelial injury. Further studies are necessary to confirm the association and examine the factors associated with its occurrence.     

Detection of New Delhi Metallo‐beta‐Lactamase and Extended‐Spectrum beta‐Lactamase Genes in Escherichia coli Isolated from Mastitic Milk Samples

In this study, eight Escherichia coli isolates were obtained from milk samples of dairy cattle suffering from clinical/subclinical mastitis. Isolates were characterized for antimicrobial resistance traits and virulence genes. Results revealed that one isolate was harbouring New Delhi metallo‐beta‐lactamase gene (bla_NDM). Cloning and sequencing of the PCR amplicon confirmed the identity of the gene (GenBank accession no. KC769583 ) having 100% homology with bla_NDM‐5 (GenBank accession no. JN104597.1 ), and this isolate was susceptible to colistin, chloramphenicol and tetracycline only. Moreover, another isolate carried extended‐spectrum beta‐lactamase (ESBL) gene – bla_CTX‐M, and all isolates possessed bla_TEM gene. Of the eight isolates, only one isolate was positive for shiga toxin gene (stx2), and none were harbouring stx1 gene. Occurrence of New Delhi metallo‐beta‐lactamase (bla_NDM) in one E. coli isolate and ESBL genes in other isolates poses a potential threat to human health following possible entry and spread through food chain.     

Loss of p53 cooperates with K‐ras activation to induce glioma formation in a region‐independent manner

Gliomas are recognized as a heterogeneous group of neoplasms differing in their location and morphological features. These differences, between and within varying grades of gliomas, have not been explained solely on the grounds of an oncogenic stimulus. Interactions with the tumor microenvironment as well as inherent characteristics of the cell of origin are likely a source of this heterogeneity. There is an ongoing debate over the cell of origin of gliomas, where some suggest a progenitor, while others argue for a stem cell origin. Thus, it is presumed that neurogenic regions of the brain such as the subventricular zone (SVZ) containing large numbers of neural stem and progenitor populations are more susceptible to transformation. Our studies demonstrate that K‐ras^G12D cooperates with the loss of p53 to induce gliomas from both the SVZ and cortical region, suggesting that cells in the SVZ are not uniquely gliomagenic. Using combinations of doxycycline‐inducible K‐ras^G12D and p53 loss, we show that tumors induced by the cooperative actions of these genes remain dependent on active K‐ras expression, as deinduction of K‐ras^G12D leads to complete tumor regression despite absence of p53. These results suggest that the interplay between specific combinations of genetic alterations and susceptible cell types, rather than the site of origin, are important determinates of gliomagenesis. Additionally, this model supports the view that, although several genetic events may be necessary to confer traits associated with oncogenic transformation, inactivation of a single oncogenic partner can undermine tumor maintenance, leading to regression and disease remission. GLIA 2013;61:1862–1872     

DOACs for stroke prevention in patients with AF and cancer

Stroke prophylaxis in atrial fibrillation is an important consideration in patients with cancer. However, there is little consensus on the choice of anticoagulation, due to the numerous difficulties associated with active cancer. Direct oral anticoagulants (DOACs) have been shown to be a promising option. Here, we conduct a simple cross-sectional analysis of 29 cancer patients receiving DOACs for stroke prophylaxis in atrial fibrillation at a tertiary-care institution in London. Our study demonstrates an encouraging efficacy and safety profile of DOACs used in this setting. We conclude by suggesting that, while DOACs may be useful, anticoagulation in cancer patients should continue to be individualised.     

Phenotype of dent disease in a cohort of Indian children

Objective

To describe the clinical and genotypic features of Dent disease in children diagnosed at our center over a period of 10 years.

Design

Case series.

Setting

Pediatric Nephrology Clinic at a referral center in Northern India.

Methods

The medical records of patients with Dent disease diagnosed and followed up at this hospital from June 2005 to April 2015 were reviewed. The diagnosis of Dent disease was based on presence of all three of the following: (i) low molecular weight proteinuria, (ii) hypercalciuria and (iii) one of the following: nephrolithiasis, hematuria, hypophosphatemia or renal insufficiency, with or without mutation in CLCN5 or OCRL1 genes.

Results

The phenotype in 18 patients diagnosed with Dent disease during this period was characterized by early age at onset (median 1.8 y), and polyuria, polydipsia, salt craving, hypophosphatemic rickets and night blindness. Rickets was associated with severe deformities, fractures or loss of ambulation in six patients. Nephrocalcinosis was present in three patients, while none had nephrolithiasis. Generalized aminoaciduria was seen in 13 patients, two had glucosuria alone, and one had features of Fanconi syndrome. Over a median follow up of 2.7 years, one patient developed renal failure. Genetic testing (n=15) revealed 5 missense mutations and 3 nonsense mutations in CLCN5 in 13 patients. Five of these variations (p.Met504Lys, p.Trp58Cys, p.Leu729X, p.Glu527Gln and p.Gly57Arg) have not been reported outside the Indian subcontinent.

Conclusion

Our findings suggest a severe phenotype in a cohort of Indian patients with Dent disease.

     

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r²=0.31, P<0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 μM [54.8–133.0 μM] for dialysis-dependent patients versus 3.3 μM [3.1–6.0 μM] for healthy controls; P<0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min–max] 71.2 μM [29.2–189.7 μM] pretransplant versus 11.4 μM [8.9–20.2 μM] post-transplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 μM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P<0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography.