Pulmonary tuberculosis diagnostic delays in Chad: a multicenter, hospital-based survey in Ndjamena and Moundou

ABSTRACT: BACKGROUND: Tuberculosis remains one of the leading causes of morbidity and mortality in low-resource countries. One contagious patient can infect 10 to 20 contacts in these settings. Delays in diagnosing TB therefore contribute to the spread of the disease and sustain the epidemic. Objectives The aim of this study was to assess delays in diagnosing tuberculosis and the factors associated with these delays in the public hospitals in Moundou and Ndjamena, Chad. METHODS: A structured questionnaire was administered to 286 new tuberculosis patients to evaluate patient delay (time from the onset of symptoms to the first formal or informal care), health-care system delay (time from the first health care to tuberculosis treatment) and total delay (sum of the patient and system delays). Logistic regression was used to identify risk factors associated with long diagnostic delays (defined as greater than the median). RESULTS AND DISCUSSION: The median [interquartile range] patient delay, system delay and total delay were 15 [7-30], 36 [19-65] and 57.5 [33-95] days, respectively. Low economic status (aOR [adjusted odds ratio] =2.38 [1.08-5.25]), not being referred to a health service (aOR=1.75 [1.02- 3.02]) and a secondary level education (aOR=0.33 [0.12-0.92]) were associated with a long patient delay. Risk factors for a long system delay were a low level of education (aOR=4.71 [1.34-16.51]) and the belief that traditional medicine and informal care can cure TB (aOR=5.46 [2.37-12.60]). CONCLUSION: Targeted strengthening of the health-care system, including improving patient access, addressing deficiencies in health-related human resources, and improving laboratory networks and linkages as well as community mobilization will make for better outcomes in tuberculosis diagnosis.     

Selection of fusion levels in adults with spinal deformity: an update

Background contextAdult spinal deformity (ASD) is commonly associated with disability and represents a challenging condition for physicians. Although surgical management has been reported as superior to conservative care, the choice of patient-specific optimal strategy has been poorly defined. A key question remains selection of fusion levels as this implies careful balance of risks and benefits.PurposeThe aim of this review is to propose an update on current knowledge related to optimal fusion levels in the surgical treatment of ASD.Study designLiterature review.MethodsBased on a comprehensive literature search, recent studies focusing on the management of ASD were reviewed to establish current concepts on fusion levels in the management of symptomatic ASD.ResultsDespite numerous published studies, the management of ASD and specifically optimal fusion levels is incompletely defined. Described approaches carry benefits and risks. However, the need for detailed analysis and preoperative planning is confirmed as a prerequisite to obtaining realignment objectives and good outcomes.ConclusionsThe treatment of ASD is emerging as an important health-care issue of the 21st century because of prevalence and cost. Despite technical advances related to ASD surgery, complication rates remain elevated, particularly in the older population. Recent research, mostly driven by outcome measures, has improved our understanding of optimal treatment approaches to ASD. The development of a widely accepted classification system will help to share knowledge and improve our ability to treat these complex patients.     

Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5

Kinesin motor proteins exert essential cellular functions in all eukaryotes. They control mitosis, migration and intracellular transport through interaction with microtubules. Small molecule inhibitors of the mitotic kinesin KiF11/Eg5 are a promising new class of anti-neoplastic agents currently evaluated in clinical cancer trials for solid tumors and hematological malignancies. Here we report induction of Eg5 and four other mitotic kinesins including KIF20A/Mklp2 upon stimulation of in vivo angiogenesis with vascular endothelial growth factor-A (VEGF-A). Expression analyses indicate up-regulation of several kinesin-encoding genes predominantly in lymphoblasts and endothelial cells. Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro. Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition. In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models. Besides blocking tumor cell proliferation, impairing endothelial function is a novel mechanism of action of kinesin inhibitors.     

In vivo short TE localized 1H MR spectroscopy of mouse cervical spinal cord at very high magnetic field (11.75 T)

MR spectroscopy allows a noninvasive assessment of metabolic information in healthy and pathological central nervous system. Whereas MR spectroscopy has been extensively applied in the brain, only few spectroscopic studies of the spinal cord (SC) have been performed so far. For mice, due to additional technical challenges, in vivo ¹H SC MRS has not yet been reported. In this work, the feasibility of short echo time localized proton magnetic resonance spectroscopy using Point RESolved Spectroscopy sequence for the examination of mouse cervical SC at 11.75 T is presented. Several optimizations were performed to improve the static field homogeneity, to reduce physiological motion effects and lipid contaminations arising from SC surrounding tissues, and to provide a careful metabolic quantification. Satisfactory spectrum quality was obtained. The described protocol allowed reliable quantification of five metabolites in the cervical SC. The mean reproducibility regarding the quantification of tNAA, tCr and tCho was ≥ 80%, > 70% for mI and > 55% for Glu, whereas the intersubject variabilities were ≤ 21%. The application of this protocol to transgenic mouse models in pathological conditions such as SC injury or neurodegenerative diseases may thus provide complementary information to MRI and increase our understanding of such pathologies. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.     

BMP inhibition initiates neural induction via FGF signaling and Zic genes

Neural induction is the process that initiates nervous system development in vertebrates. Two distinct models have been put forward to describe this phenomenon in molecular terms. The default model states that ectoderm cells are fated to become neural in absence of instruction, and do so when bone morphogenetic protein (BMP) signals are abolished. A more recent view implicates a conserved role for FGF signaling that collaborates with BMP inhibition to allow neural fate specification. Using the Xenopus embryo, we obtained evidence that may unite the 2 views. We show that a dominant-negative R-Smad, Smad5-somitabun—unlike the other BMP inhibitors used previously—can trigger conversion of Xenopus epidermis into neural tissue in vivo. However, it does so only if FGF activity is uncompromised. We report that this activity may be encoded by FGF4, as its expression is activated upon BMP inhibition, and its knockdown suppresses endogenous, as well as ectopic, neural induction by Smad5-somitabun. Supporting the importance of FGF instructive activity, we report the isolation of 2 immediate early neural targets, zic3 and foxD5a. Conversely, we found that zic1 can be activated by BMP inhibition in the absence of translation. Finally, Zic1 and Zic3 are required together for definitive neural fate acquisition, both in ectopic and endogenous situations. We propose to merge the previous models into a unique one whereby neural induction is controlled by BMP inhibition, which activates directly, and, via FGF instructive activity, early neural regulators such as Zic genes.     

Determination of vitamin D3 and 25-hydroxyvitamin D3 in foodstuffs by HPLC UV-DAD and LC–MS/MS

In order to generate new data for vitamin D content for the Canadian Nutrient File, a method for the quantification of vitamin D₃ and 25(OH)D₃ in foodstuffs has been modified and improved. Vitamin D₃ was quantified using reverse phase liquid chromatography (LC) with UV-diode array detector (UV-DAD), while 25(OH)D₃ was measured by triple quadrupole mass spectrometry (APCI MS/MS). Quantification was by internal standards (IS) using vitamin D₂ and 25(OH)D₂. A Certified Reference Material (CRM-421 containing vitamin D₃) and a control sample (internally generated reference material of ground pork containing both vitamin D₃ and 25(OH)D₃) were used as validation and quality control tools. Limit of detection for both compounds was 0.04 μg/100 g. Accuracy for vitamin D in the CRM-421 was 99% (0.142 mg/kg for a target of 0.143, n = 10). Recovery of vitamin D₃ in ground pork was 97% (88% absolute recovery). For 25(OH)D₃, a recovery of 94% (73% absolute recovery) was obtained. Using this method, data for vitamin D₃ and 25(OH)D₃ content in a variety of foods (pork, beef, eggs, poultry, fish, and dinners) have been generated.     

Neutrophils promote aerogenous spread of lung adenocarcinoma with bronchioloalveolar carcinoma features.

PURPOSE: Adenocarcinoma with bronchioloalveolar carcinoma (BAC) features is a subtype of non-small cell lung cancers characterized by an intense inflammatory reaction composed of macrophages and neutrophils and by a distinct natural history with intrapulmonary spread leading to death due to respiratory failure. We hypothesized that neutrophils could promote aerogenous spread of lung adenocarcinoma with BAC features. EXPERIMENTAL DESIGN: We examined the effect of neutrophils on A549 cell line detachment in vitro and we quantified desquamation of tumor cells on tumor tissue (n = 25) and on matched bronchioloalveolar lavage (n = 17) in vivo in a series of patients with adenocarcinoma with BAC features. RESULTS: Neutrophils induced A549 detachment mediated by signals through cell-to-cell contact. Detached A549 cells were still viable and able to proliferate in vitro. Neutralization studies identified several membrane-bound molecules involved in detachment (i.e., intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, tumor necrosis factor alpha/tumor necrosis factor alpha receptor inhibitor, interleukin-1alpha /interleukin-1alpha receptor, and neutrophil elastase). In tumor tissue, shedding was detected in all samples, with a median shedding score of 42% (range, 4-95%). Micropapillary clusters were detected in 23 of the 25 tumor tissue samples, with a median micropapillary score of 1.40 (range, 0-2.1), and tumor cells were detected in 7 of 17 lavages. The micropapillary score was associated with a high neutrophil count in bronchioloalveolar lavage (P = 0.051). The shedding cell percentage was a significant factor in shorter survival (P = 0.034, univariate Cox analysis). CONCLUSIONS: Tumor shedding is induced by neutrophils. It is a significant factor of shorter survival and may be an important event in adenocarcinoma progression.     

Neutrophils do not contribute to infarction,oxidative stress,and NO synthase activity in severe brain ischemia

Polymorphonuclear leukocytes (PMNs) were reported to contribute to ischemia-reperfusion-induced brain damage. The present work examined whether PMN infiltration is deleterious in a severe model of transient focal cerebral ischemia and in which part PMNs contribute to oxidative stress and nitric oxide (NO) production. A 20-min occlusion of the left middle cerebral artery and both common carotid arteries was performed in rats. Infarction was maximal 24 h after reperfusion, while accumulation of PMNs in infarcted tissue was not significant before 48 h. Moreover, neutropenia induced by vinblastine (0.5 mg/kg iv) significantly decreased by 60-80% PMN infiltration 48 h after reperfusion but did not reduce the infarct volume. Thus PMNs do not contribute to cerebral injury in our model. Furthermore, decreased PMN infiltration modified neither oxidative stress evaluated by glutathione concentrations nor NO synthase activities 48 h after reperfusion. In conclusion, our results suggest that PMNs are not involved in severe cerebral ischemia and that anti-PMN strategies may be inefficient in some pathological conditions.