MRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy

Early detection of progressive multifocal leucoencephalopathy (PML) in the setting of natalizumab therapy currently is performed by rapid evaluation of new symptoms occurring in treated patients. The role of MR scanning has not been investigated but holds promise since MR detection is highly sensitive for PML lesions. The authors report a case of presymptomatic PML of the posterior fossa detected by MR scans. Immediate suspension of natalizumab and plasma exchanges resulted in a rapid decline of natalizumab serum concentration. Intravenous steroids started together with plasma exchanges followed by an oral tapering course were used to minimise the immune reconstitution inflammatory syndrome. No symptoms (beyond mild headache) developed, and the repeat PCR for JC Virus (JCV) DNA detection performed 10 weeks later was negative. This case suggests that: (1) periodic brain MR scans may detect signs of presymptomatic PML in MS patients treated with natalizumab, (2) corticosteroid management of inflammatory reaction may contribute to optimal control of the immune reconstitution inflammatory syndrome routinely seen with natalizumab-associated PML and (3) early radiological detection of PML can have an excellent outcome even in a clinically critical region and despite prior immunosuppressant exposure. The potential benefit of regular MR scanning just using the T2/FLAIR modalities could be further investigated in order to detect early natalizumab-associated PML, leading to benign outcomes.     

Phase II Study of Topotecan and Bevacizumab in Advanced,Refractory Non–Small-Cell Lung Cancer

BackgroundThis clinical trial evaluated whether topotecan in combination with bevacizumab improved progression-free survival (PFS) in patients with advanced, refractory non–small-cell lung cancer in a second-line setting.Patient and MethodsPatients aged 18 years old and older received topotecan (4.0 mg/m²) on days 1, 8, and 15, and bevacizumab (10 mg/kg) on days 1 and 15 as intravenous infusions on a 28-day treatment cycle. Available tumor specimens were analyzed for ISG15 gene expression as a biomarker of response to topotecan.ResultsForty-two patients were enrolled in the study, with a median age of 62.5 years and a median of 3 (range, 1-7) prior treatment regimens. Almost half (n = 18, 42.9%) of the patients received prior bevacizumab therapy. PFS was 5.1 months (95% CI, 3.7-7.8 months), and overall survival was 11.5 months (95% CI, 6.8-15.5 months). Response rates were as follows: 14.3% partial response, 54.8% stable disease, and 28.6% progressive disease. Hematologic toxicities included grade 3 thrombocytopenia (n = 7, 16.7%), neutropenia (n = 4, 9.5%), and anemia (n = 2, 4.8%). One toxic death occurred due to pulmonary hemorrhage, and one patient experienced a grade 4 pulmonary embolism. Grade 3 nonhematologic adverse events were uncommon (< 8%). There was a trend for improved median PFS, 3.5 months vs. 1.8 months (P = .26), in patients with high ISG15 expression.ConclusionBevacizumab in combination with topotecan as a salvage therapy for metastatic non–small-cell lung cancer is well tolerated and is worthy of further investigation.     

Seroprevalence of human immunodeficiency virus among blood donors in Northwest Ethiopia, 1995-2002

Data on age, sex, occupation, HIV serostatus and year of donation were collected from the blood donors log book of Gondar College of Medical Sciences Hospital, Northwest Ethiopia, for the period between January 1995 and December 2002 and analysed. The crude HIV seroprevalence was 9.9% (1109/11,204). A declining trend in the prevalence was observed from as high as 15.7% (207/1321) in 1995 to 9.3% (123/1327) in 1999 and down to 4.3% (68/1576) in 2002. The declining trend observed in recent years is encouraging and should further be strengthened by making use of the blood bank as an entry point for HIV testing and counselling services.     

Prevalence and risk factors analysis of bovine tuberculosis in cattle raised in mixed crop‐livestock farming system in Tigray region,Ethiopia

Bovine tuberculosis (BTB) is a disease of animal and public health importance in developing countries. In rural Ethiopia, there is potential for a shift in the epidemiologic of this disease driven by transformation of dairy industry. This includes gradual change from the traditional mixed crop‐livestock husbandry practice to a semi‐intensification system. It is therefore, essential to document the prevalence and risk factors of BTB to continuously update the designing and implementation of control and prevention strategies. Here, we present findings of a cross‐sectional study on the prevalence and associated risk factors of BTB among cattle reared under mixed crop‐livestock farming system in Tigray region, Ethiopia. A multistage purposive sampling approach was used to select districts, villages, herds and individual cattle. A total of 1,357 cattle from 310 herds were examined for BTB infection using a comparative intradermal tuberculin skin test (CIDT). Questionnaires were used to gather data on herd structure and herd management practices. A multilevel logistic mixed effect model was used to determine risk factors after accounting for clustering effect at three levels (village, herd and individual animal). Overall prevalence of BTB was 4.3% (95% CI = 3.4–5.6), with the highest prevalence recorded in Alamata district (5.6%) and lowest in Korem (1.6%). Multilevel logistic mixed effect model analysis identified exotic breed (OR = 3, p = 0.014), closed barn (OR = 2.6, p = 0.018), large herd size (OR = 2.6, p = 0.05) and purchase of cattle (OR = 2.1, p = 0.027) as important risk factors for BTB. Taken together, these findings suggest that the current dairy development program centred on the introduction of exotic and or crossed animals could have contributed to changing epidemiological situations of BTB in the study area.     

Magnitude of Gene Mutations Conferring Drug Resistance in Mycobacterium Tuberculosis Isolates from Lymph Node Aspirates in Ethiopia

Objective: Resistance to drugs is due to particular genomic mutations in the specific genes of Mycobacterium tuberculosis. Timely genetic characterization will allow identification of resistance mutations that will optimize an effective antibiotic treatment regimen. We determine the magnitude of gene mutations conferring resistance to isoniazid (INH), rifampicin (RMP) and ethambutol (EMB) among tuberculosis (TB) lymphadenitis patients.Methods: A cross sectional prospective study was conducted among 226 M.tuberculosis isolates from culture positive lymph node aspirates collected from TB lymphadenitis patients between April 2012 and May 2012. Detection of mutations conferring resistance to drugs was carried out using GenoType^® MTBDRplus and GenoType® MTBDRsl assay.Results: Out of the 226 strains, mutations conferring resistance to INH, RMP, multidrug resistance tuberculosis (MDR-TB) and EMB were 8, 3, 2 and 2 isolates, respectively. There was no isolated strain that showed mutation in the inhA promoter region gene. All INH resistant strains had mutations in the katG gene at codon 315 with amino acid change of S315T1. Among rifampicin resistant strains, two isolates displayed mutations at codon 531 in the rpoB gene with amino acid change of S531L and one isolate was by omission of wild type probes at Q513L. According to mutations associated with ethambutol resistance, all of the isolates had mutations in the embB gene with aminoacid change of M306I. All isolates resistant to INH, RMP and MDR using BacT/AlerT 3D system were correctly identified by GenoType® MTBDRplus assay.Conclusion: We observed mutations conferring resistance to INH at S315T1 of the katG gene, RMP at S531L and Q513L in the rpoB genes and EMB at M306I of the embB gene. In the absence of conventional drug susceptibility testing, the effort to develop easy, rapid and cost effective molecular assays for drug resistance TB monitoring is definitely desirable and the GenoType® MTBDRplus assay was found to be a useful method for diagnosis of resistance to INH, RMP and MDR from lymph node aspirates. Further molecular cluster analysis to determine transmission dynamics of mutated strain is required.     

Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis.

Nitric oxide (NO) is involved in the host defence against tuberculosis (TB). Patients with TB exhibit increased catabolism and reduced energy intake. Thus the hypothesis for this study was that restoring a relative deficiency in the amino acid arginine, the substrate for mycobactericidal NO production, would improve the clinical outcome of TB by increasing NO production. In a randomised double-blind study, patients with smear-positive TB (n = 120) were given arginine or placebo for 4 weeks in addition to conventional chemotherapy. Primary outcomes were sputum conversion, weight gain, and clinical symptoms after week 8. Secondary outcomes were sedimentation rate and levels of NO metabolites, arginine, citrulline, and tumour necrosis factor-a. Compared with the human immunodeficiency virus (HIV)-/TB+ placebo group, the HIV-/TB+ patients in the arginine group showed significant improvement, defined as increased weight gain, higher sputum conversion rate and faster reduction of symptoms, such as cough. The arginine level increased after week 2 in the HIV-/TB+ arginine group (100.2 microM (range 90.5-109.9) versus 142.1 microM (range 114.1-170.1)) compared with the HIV-/TB+ placebo group (105.5 microM (range 93.7-117.3) versus 95.7 microM (range 82.4-108.9)). HIV seroprevalence was 52.5%. No clinical improvement or increase in serum arginine was detected in arginine supplemented HIV+/TB+ patients compared with placebo. Arginine is beneficial as an adjuvant treatment in human immunodeficiency virus-negative patients with active tuberculosis, most likely mediated by increased production of nitric oxide.     

Peripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression

Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising chemotherapeutic candidates. However, conflicting results were reported regarding the actual effect of these drugs on cellular survival ranging from protection to toxicity. Moreover, the concentrations needed to observe such a toxicity were usually high, far above the affinity range for their receptor, hence questioning its specificity. In the present study, we have shown that micromolar concentrations of FGIN-1-27 and Ro 5-4864, two chemically unrelated PBR ligands are toxic for both PBR-expressing SK-N-BE neuroblastoma cells and PBR-deficient Jurkat lymphoma cells. We have thereby demonstrated that the cytotoxicity of these drugs is unrelated to their PBR-binding activity. Moreover, Ro 5-4864-induced cell death differed strikingly between both cell types, being apoptotic in Jurkat cells while necrotic in SK-N-BE cells. Again, this did not seem to be related to PBR expression since Ro 5-4864-induced death of PBR-transfected Jurkat cells remained apoptotic. Taken together, our results show that PBR is unlikely to mediate all the effects of these PBR ligands. They however confirm that some of these ligands are very effective cytotoxic drugs towards various cancer cells, even for reputed chemoresistant tumors such as neuroblastoma, and, surprisingly, also for PBR-lacking tumor cells.     

Perforated peptic ulcer in Tikur Anbessa Hospital: a review of 74 cases

Little is known on the pattern of perforated peptic ulcer in Ethiopia. To evaluate the early, outcome of management, a five-year retrospective analysis of 74 operated cases of perforated peptic ulcer was undertaken. Perforated peptic ulcer accounted for 3.4% of the adult emergency surgical procedures. The mean age was 32.6 years, with a male to female ratio of 7.2 to 1.0. Fifty-six percent of the cases were unmarried. In nearly 22.0% of the patients, no previous history of peptic ulcer disease was documented. Delay in diagnosis was noted in 95% of the cases. Most patients had duodenal ulcer perforation, and about 78% had purulent peritonitis at laparotomy. Fourteen died in hospital. Early presentation of patients to surgical care facilities may reduce morbidity and mortality in cases of peptic ulcer perforation.