Drug resistance pattern of Mycobacterium tuberculosis isolates from patients of five provinces of Iran

Objective:To determine the patterns of resistance to first line anti-tuberculosis(TB)drugs among a collection of Mycobacterium tuberculosis(MTB)isolates from 5 provinces of Iran.Methods:A total of the 6 426 clinical specimens from patients suspected of active TB were collected from March 2010 to June 2012.All specimens were subjected for microscopy and culture tests in the TB centers of studies provinces.Drug susceptibility testing to the first line anti-TB drugs for culture positive MTB was performed on Lwenstein-Jensen(LJ)medium using proportion method.Results:Of 6 426 clinical specimens,261 were culture positive for mycobacteria,of which 252 were MTB and 9 were MOTT(mycobacteria other than tuberculosis).Of 252 MTB isolates.211(83.7%)were pan-susceptible and 41(16.3%)were resistant to at least one drug.Resistance was most common to streptomycin.30 isolates(12.0%),followed by isoniuzid,20isolates(8.0%),rifampin,15 isolates(6.0%)and ethambutol,14 isolates(5.5%).Sixteen(6.3%)MTB isolates were MDR.A clear evidence of heterogeneity amongst the 5 provinces in the proportions with resistance to one or more drugs was observed[χ~2=12.209(4 degrees of freedom),P values=0.015 9].Conclusions:The prevalence of drug resistance in this study area underscoring the need for further enforcement of TB control strategies in the Iran.Drug susceptibility testing for all TB cases to provide optimal treatment,establishing advanced diagnostic facilities for rapid detection of MDR-TB and continuous monitoring of drug resistance are recommended for prevention and control of drug-resistant TB.     

T helper 17 cells play a critical pathogenic role in lung cancer

Lung cancer development is associated with extensive pulmonary inflammation. In addition, the linkage between chronic obstructive pulmonary disease (COPD) and lung cancer has been demonstrated in population-based studies. IL-17–producing CD4 helper T cells (Th17 cells) play a critical role in promoting chronic tissue inflammation. Although Th17 cells are found in human COPD and lung cancer, their role is not understood. We have thus used a mouse model of lung cancer, in which an oncogenic form of K-ras (K-ras^G12D), frequently found in human lung cancer, is restrictedly expressed in lung epithelial cells [via Clara cell secretory protein (CCSP^cre)]. In this model, Th17 and Treg but not Th1 cells were found enriched at the tumor tissues. When CCSP^cre/K-ras^G12D mice were weekly challenged with a lysate of nontypeable Haemophilus influenza (NTHi), which induces COPD-type inflammation and accelerates the tumor growth, they showed greatly enhanced Th17 cell infiltration in the lung tissues. Lack of IL-17, but not IL-17F, resulted in a significant reduction in lung tumor numbers in CCSP^cre/K-ras^G12D mice and also those treated with NTHi. Absence of IL-17 not only resulted in reduction of tumor cell proliferation and angiogenesis, but also decreased the expression of proinflammatory mediators and reduced recruitment of myeloid cells. Depletion of Gr-1⁺CD11b⁺ myeloid cells in CCSP^cre/K-ras^G12D mice suppressed tumor growth in lung, indicating Gr-1⁺CD11b⁺ myeloid cells recruited by IL-17 play a protumor role. Taken together, our data demonstrate a critical role for Th17 cell-mediated inflammation in lung tumorigenesis and suggest a novel way for prevention and treatment of this disease.Inflammation plays an important role in tumor development (1, 2). Although targeting inflammation and tumor microenvironment has been considered as a new direction of cancer therapy, the mechanisms underlying cancer-associated inflammation have not been well understood. Lung cancer is a leading cause of death in the world. Accumulating evidence has shown that inflammation is associated with pathogenesis of lung cancer, especially those induced by cigarette smoke (3). The primary risk factor among smokers to develop lung cancer is the presence of chronic obstructive pulmonary disease (COPD) (4), which is characterized by chronic pulmonary inflammation, airway remodeling and destruction of lung parenchyma. Human lung cancers are inflicted with alterations in various subsets of lymphocytes and myeloid cells (5, 6), reminiscent of immune activation during chronic inflammation. Several studies have shown NFκB signaling as a mechanistic link between inflammation and lung cancer using a mouse model of lung adenocarcinoma (7, 8). However, the specific inflammatory cell types or molecules potentiating lung cancer are not understood clearly.We and others have identified a novel subset of CD4 helper T cells that produce IL-17 and are referred as Th17 cells (9, 10). Th17 cells have been associated with inflammatory diseases such as rheumatoid arthritis, asthma, lupus, and allograft rejection. An important function of IL-17 is to promote tissue inflammation through the up-regulation of proinflammatory cytokines and chemokines (11). Consistently, we have shown that transgenic overexpression of IL-17 in the lungs resulted in chemokine up-regulation and tissue infiltration by leukocytes, although mice treated with neutralizing IL-17–specific antibody were also found to be resistant to the induction of experimental autoimmune encephalomyelitis (9). These and other studies collectively demonstrated that IL-17 and Th17 cells play nonredundant function in promoting inflammation.Increased frequencies of IL-17 and Th17 cells have been reported in patients with different types of tumors (12), including lung adenocarcinoma (13). The density of intratumoral IL-17–positive cells in primary human nonsmall cell lung cancer was inversely correlated with patient outcome and correlated with smoking status of the patients (14). Th17 cells specific for a common tumor antigen were found in lung cancer patients as part of their spontaneous immune response to the autologous tumor (15). However, the function of Th17 cells and IL-17 in the development of lung cancer remains to be shown. Animal model studies have revealed contrasting roles of IL-17 in various tumors (16). Tumor-promoting effect of IL-17 was shown in some models such as colon cancer (17–20), whereas in others, IL-17 supported anti-tumor immunity, including in B16 melanoma model (21–24). Thus, the role of IL-17 could be complex and tumor-specific.To properly evaluate the role of IL-17 in inflammation-associated lung cancer, we used a model of oncogenic K-ras mutation expressed only in the lung. Mice expressing K-ras mutation in Clara cells (CCSP^cre/K-ras^G12D mice) spontaneously develop lung adenocarcinoma (25). In addition, we induced COPD-type lung inflammation by challenging mice with lysates of nontypeable Haemophilus influenza (NTHi). Inflammation driven by NTHi can promote tumor growth in CCSP^cre/K-ras^G12D mice (25). These experiments collectively indicate a tumorigenic role of IL-17–mediated inflammation in the development of lung cancer.     

Effect of different frequencies of repetitive transcranial magnetic stimulation on acquisition of chemical kindled seizures in rats

In the current study we investigated the effect of repetitive transcranial magnetic stimulation (rTMS) at different frequencies on chemical kindling in rats. Chemical kindling was induced by injection of pentylenetetrazol (PTZ; 45 mg/kg) at the intervals of 48 h between the injections. In the first experiment, effect of 0.25, 1 and 5 Hz rTMS (four trains of 4 s at motor threshold intensity) on kindling acquisition was investigated. In the second experiment, the stability of rTMS effects was checked in animals of the first experiment during a follow-up period of 2 weeks. Animals received a single dose of PTZ at 7th and 14th day after the last PTZ injection (12th injection) and their seizure parameters were recorded. Obtained results showed that application of rTMS at the frequencies of 0.25 and 1 Hz had anticonvulsant effect and decreased the PTZ kindling acquisition. However, when applied at the frequency of 5 Hz, it had an increasing effect on PTZ kindling rate. During the follow-up study, the seizure severity increased in animals treated with 0.25 Hz rTMS (and somehow in animals treated with 1 Hz rTMS), but did not change in animals treated with 5 Hz rTMS compared to the 12th PTZ injection. Our results showed that rTMS application may have an anticonvulsant effect during chemical kindling acquisition at very low frequency (0.25 Hz) and can increase the seizure severity at high frequency (5 Hz). However, during follow-up, the anticonvulsant effects of rTMS may be converted to proconvulsive effects.     

Electrical Low Frequency Stimulation of the Kindling Site Preserves the Electrophysiological Properties of the Rat Hippocampal CA1 Pyramidal Neurons From the Destructive Effects of Amygdala Kindling: The Basis for a Possible Promising Epilepsy Therapy

BackgroundDeep brain stimulation (DBS) has emerged as a potential therapeutic strategy in the treatment of neurological disorders including epilepsy. However, the cellular mechanism responsible for the effects of DBS remains largely undefined. Therefore, using electrophysiological approach, we aimed to determine the antiepileptic effects and restorative potential of low frequency stimulation (LFS) on amygdala kindling-induced changes in electrophysiological properties of rat hippocampal CA1 pyramidal neurons.MethodsAnimals were kindled by electrical stimulation of amygdala in a rapid kindling manner (12 times per day). In one group of animals, immediately after termination of daily 12 rapid kindling stimulations, the kindling site was subjected to 4 packages of LFS at intervals of 5 min (each package contained 200 monophasic square-wave pulses, 0.1 ms pulse duration at 1 Hz). Whole cell patch clamp recording under current clamp conditions was performed on visually identified pyramidal neurons in hippocampal slice preparations obtained from amygdala-kindled rats and the rats receiving LFS.ResultsKindling of the right basolateral amygdala profoundly affected spontaneous firing behavior and repetitive discharge characteristics of pyramidal neuronal electrophysiological properties. Application of LFS at the kindling site almost completely prevented the development of epilepsy and the disruptive effects of kindling on neuronal electrical activity through restoration of the normal electrophysiological characteristics.ConclusionsThe results of this study implied that application of LFS during kindling acquisition prevents the kindling induced changes in functional electrical properties of CA1 pyramidal neurons, suggesting that this action may be involved in the antiepileptogenic mechanism of LFS.     

Effect of Weight Reduction Following Bariatric Surgery on Serum Visfatin and Adiponectin Levels in Morbidly Obese Subjects

ObjectiveAdipokines are signaling and mediator proteins secreted from adipose tissue. A novel adipokine, visfatin, was reported as a protein which was mainly expressed in visceral adipose tissue. Controversial results have been shown regarding the changes of adipokines following weight reduction. So we investigated the effects of weight reduction on serum concentrations of adiponectin and visfatin in morbidly obese subjects.Methods35 severely obese patients (26 females and 9 males), aged 15-58 years, were studied. Anthropometric parameters and biochemical parameters as well as adiponectin and visfatin were analyzed before and 6 weeks after weight reduction.ResultsAnthropometric indices decreased significantly. Blood levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride were reduced significantly. The reduction of visfatin and the elevation of adiponectin were significant as well. However, other parameters like fasting glucose and insulin did not change. Moreover, we could not find any significant correlation between the change of serum visfatin and that of adiponectin. Conclusions: 6-week weight reduction after bariatric surgery resulted in decreased serum visfatin and increased adiponectin levels. However, we cannot find any significant correlation between changes of adiponectin, visfatin, BMI, waist circumference, and insulin resistance. Further studies with different design are suggested to clarify these associations.Key Words: Adiponectin, Visfatin, Morbid obesity, Bariatric surgery, Weight loss