Treatment Outcomes of Multidrug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis

Background

Treatment outcomes for multidrug-resistant Mycobacterium Tuberculosis (MDRTB) are generally poor compared to drug sensitive disease. We sought to estimate treatment outcomes and identify risk factors associated with poor outcomes in patients with MDRTB.

Methodology/Principal Findings

We performed a systematic search (to December 2008) to identify trials describing outcomes of patients treated for MDRTB. We pooled appropriate data to estimate WHO-defined outcomes at the end of treatment and follow-up. Where appropriate, pooled covariates were analyzed to identify factors associated with worse outcomes. Among articles identified, 36 met our inclusion criteria, representing 31 treatment programmes from 21 countries. In a pooled analysis, 62% [95% CI 57–67] of patients had successful outcomes, while 13% [9]–[17] defaulted, 11% [9]–[13] died, and 2% [1]–[4] were transferred out. Factors associated with worse outcome included male gender 0.61 (OR for successful outcome) [0.46–0.82], alcohol abuse 0.49 [0.39–0.63], low BMI 0.41[0.23–0.72], smear positivity at diagnosis 0.53 [0.31–0.91], fluoroquinolone resistance 0.45 [0.22–0.91] and the presence of an XDR resistance pattern 0.57 [0.41–0.80]. Factors associated with successful outcome were surgical intervention 1.91 [1.44–2.53], no previous treatment 1.42 [1.05–1.94], and fluoroquinolone use 2.20 [1.19–4.09].

Conclusions/Significance

We have identified several factors associated with poor outcomes where interventions may be targeted. In addition, we have identified high rates of default, which likely contributes to the development and spread of MDRTB.     

Evaluation of functional RAGE gene polymorphisms in childhood acute lymphoblastic leukemia—A case-control study from Iran

We examined the possible relationship between three RAGE polymorphisms, ?429C/T, ?374 T/A, and 63-bp deletion, and susceptibility to childhood acute lymphoblastic leukemia (ALL) in an Iranian population. This study included 75 ALL patients and 115 healthy subjects. Genotyping was performed using HEXA-ARMS-polymerase chain reaction. We found no significant association among RAGE gene polymorphisms and the risk for ALL at genotype, allelic and haplotype levels (P > 0.05). The hemoglobin levels were higher in patients with RAGE ?374 TT than in the TA carriers (P = 0.019). Our results demonstrated that the RAGE gene variations were not associated with risk of pediatrics ALL.     

Identification of methionine synthase (Sal k 3), as a novel allergen of <Emphasis Type="Italic">Salsola kali</Emphasis> pollen

Salsola kali pollen is a common cause of pollinosis during summer and early fall in desert and semi-desert regions. The aim of this study was the identification and characterization of Sal k 3, a new allergen from S. kali pollen. S. kali pollen extract was fractionated by SDS-PAGE and the allergenic profile was determined by IgE-immunoblotting using twelve S. kali allergic patients. Protein identification was carried out by the means of mass spectrometry. Using degenerated primers, two DNA fragments encoding N- and C-terminal domain of Sal k 3 were amplified by PCR, then cloned into the PTZ57R/T vector and sequenced. The open reading frame of Sal k 3 fragments were subcloned in the pET-32b(+) vector, expressed in E. coli, and purified by Ni²⁺ affinity chromatography. The IgE-binding capacity of rSal k 3 fragments was then studied by IgE-immunoblotting, inhibition assays, and skin prick tests. A 45-kDa allergen was identified as a fragment of the cobalamin-independent methionine synthase (MetE) by mass spectrometry and was detected in the sera of 8/12 (66.6%) of S. kali allergic patients. Moreover, inhibition assays demonstrated that the purified rSal k 3 fragments were similar to their counterparts in the crude extract. Sal k 3 represents a new allergen of S. kali pollen and seems to be an important allergenic compound in S. kali pollen.     

An analysis of temperature adaptation in cold active, mesophilic and thermophilic Bacillus α-amylases

A comparative biochemical and structural study was performed on a cold active α-amylase from Bacillus cereus (BCA) and two well-known homologous mesophilic and thermophilic α-amylases from Bacillus amyloliquefaciens (BAA) and Bacillus licheniformis (BLA). In spite of a high degree of sequence and structural similarity, drastic variations were found for T_opt as 50, 70 and 90 °C for BCA, BAA and BLA, respectively. The half-lives of thermoinactivation were 1 and 9 min for BCA and BAA at 80 °C respectively, whilst there was no inactivation for BLA at this temperature. Thermodynamic studies on inactivation process suggested that lower thermostability of BCA is due to lower inactivation slope of the Arrhenius plots and subsequently, lower E_a and ΔH^#. Increased K_m and accessible surface area for catalytic residues along with a decreased number of internal interactions in this region in BCA compared to BLA suggest that BCA substrate-binding site might be temperature sensitive and is probably more flexible. On the other hand, fewer ion pairs, destructive substitutions and disruption of aromatic interaction networks in structurally critical regions of Bacillus α-amylases result in a severe decrease in BCA thermostability compared to its mesophilic and thermophilic homologues.     

Intraperitoneal Aminoguanidine Improves Sciatic Nerve Ischemia–Reperfusion Injury in Male Sprague-Dawley Rats

The present work was designed to investigate the potential protective effects of post-ischemic treatment with aminoguanidine (AG) on sciatic nerve ischemia/reperfusion (I/R) injury in rat. Seventy-two rats were divided into 12 groups (n = 6). We used ischemia model in these groups by occluding the right common iliac and femoral arteries for 3 h with a silk suture 6-0 using slipknot technique. Treatment groups (2, 4, 6, 8, 10, and 12) received 150 mg/kg AG intraperitoneally 24 h after induction of ischemia. After certain time intervals of reperfusion (2, 4, 7, 14, and 28 days), the function of the hind limb was assessed using behavioral scores based on gait, racing reflex, toe spread, pinch sensitivity, paw position, and grasp. After euthanasia, sciatic nerves were removed at the end of reperfusion times and sections were cut at 5 μm, then were stained for light microscopy studies and graded for ischemic fiber degeneration (IFD), edema, and apoptosis. Maximal behavioral deficit occurred at 7 days of reperfusion. The comparison of behavioral score pertaining to the control and AG groups revealed significant differences and showed also a better time course in recovery (P < 0.05). Other than 3 and 4 groups, the amount of edema in AG treatment groups showed significant differences compared with control groups (P < 0.05). IFD was also significantly decreased in the AG treatment groups than controls. Most importantly, I/R-induced apoptosis were improved significantly on the 4th, 7^th, and 14th days of reperfusion in AG-treated groups compared to controls. In conclusion, our findings suggest that post-ischemic administration of AG exhibits protective effect against sciatic nerve I/R injury.     

Aminoguanidine Changes Hippocampal Expression of Apoptosis-Related Genes,Improves Passive Avoidance Learning and Memory in Streptozotocin-Induced Diabetic Rats

Cognitive dysfunction occurs in patients with diabetes mellitus. The objective of this study was to examine whether bilateral intrahippocampal CA1 (intra-CA1) injection of aminoguanidine (AG) can either affect the Bcl-2 family gene expression or reduce the diabetic imposing abnormalities of passive avoidance learning (PAL) and memory. Rats were divided into five groups: control (C), control treated with normal saline (CS), control treated with AG (S-AG), diabetics (D), and diabetics treated with AG (D-AG). Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg). AG (30 μg/rat) or vehicle was administered intra-CA1 bilaterally at the onset of hyperglycemia. PAL was assessed 7 weeks later. Animals were killed, and hippocampus was dissected following the behavioral test. The expressions of Bax, Bcl-2, and Bcl-xl mRNAs were measured using semiquantitative RT-PCR technique. The result of passive avoidance task showed that AG significantly improved the cognitive performance in diabetic rats. Moreover, AG treatment decreased the levels of Bcl-2 and Bcl-x_L expressions in diabetic group. The ratio of Bax/Bcl-2 and Bax/Bcl-x_L decreased significantly in AG-treated diabetic animals. In conclusion, initial treatment with AG by intra-CA1 micro-injection improves the impaired passive avoidance task in STZ-induced diabetic rats which may be related to the decreased Bax/Bcl-2 and Bax/Bcl-x_L ratios.