Detection of latent tuberculosis infection among laboratory personnel at a University Hospital in Eastern Saudi Arabia using an interferon gamma release assay

SummaryBackground/aimsA few recent reports have demonstrated an elevated prevalence of latent tuberculosis infection (LTBI) among laboratory personnel. We sought to evaluate the prevalence of LTBI among laboratory personnel using the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and to assess the risk factors associated with positive test results.MethodsThe study population included laboratory personnel who were working in the routine diagnostic laboratories of different departments of a university hospital. Subjects were interviewed using a standardized questionnaire that assessed information related to risk factors for LTBI and underwent the QFT-GIT assay.ResultsPositive QFT-GIT tests results were detected in 19.4% (26/134) of the laboratory personnel. The following factors were significantly associated with positive QFT-GIT results: age≥30 years [odds ratio (OR): 4.741, 95% CI: 1.41–17.50, P=0.004]; duration of employment in the healthcare profession >10 years (P<0.0001); and non-Saudi nationality (OR: 21.67, 95% CI: 6.69–73.94, P<0.0001).ConclusionThese data highlight the need for effective institutional TB infection control plans. Additionally, our data reinforce the necessities of pre-employment and regular LTBI screening of laboratory personnel and the importance of offering preventive therapies to positive subjects to prevent the progression to active disease

Approved and experimental small-molecule oncology kinase inhibitor drugs: a mid-2016 overview

Kinase inhibitor research is a comparatively recent branch of medicinal chemistry and pharmacology and the first small-molecule kinase inhibitor, imatinib, was approved for clinical use only 15 years ago. Since then, 33 more kinase inhibitor drugs have received regulatory approval for the treatment of a variety of cancers and the volume of reports on the discovery and development of kinase inhibitors has increased to an extent where it is now difficult—even for those working in the field—easily to keep an overview of the compounds that are being developed, as currently there are 231 such compounds, targeting 38 different protein and lipid kinases (not counting isoforms), in clinical use or under clinical investigation. The purpose of this review is thus to provide an overview of the biomedical rationales for the kinases being targeted on the one hand, and the design principles, as well as chemical, pharmacological, pharmaceutical, and toxicological kinase inhibitor properties, on the other hand. Two issues that are especially important in kinase inhibitor research, target selectivity and drug resistance, as well as the underlying structural concepts, are discussed in general terms and in the context of relevant kinases and their inhibitors

Experimental bacterial meningitis: Studies on immunopathogenesis and immunoregulation

Bacterial meningitis is an inflammatory disease of the central nervous system (CNS) which occurs when bacteria gain entry to the subarachnoid space (SAS). Bacterial replication or Iysis leads to the exposure of cell componentsThese products elicit synthesis and release of IL-1ß, TNF-a, and / or other endogenous mediators into the cerobrospinal fluid (CSF) andintravascular space by endothelial cells. These mediators facilitate activation of polymorphonuclear leukocytes (PMNs ) as well as expression of and receptor affinity for adhesion and transendothelial passage of PMNs into the SAS. Within the SAS, PMNs are further activated by bacterial products or by cytokines to release molecules, including platelet activating factor, prostaglandins, nitric oxide and toxic oxygen metabolites that may contribute to the neulogic damage. Intraperitoneal (i.p.) inoculation of Haemophilus influenzae type b (Hib) to 3 weeks old rats resulted in nonlethal meningitis. Using in situ hybridization (ISH), levels of cytokine mRNA expressing cells were determined in the brain, CSF and spleen from Hib-inoculated and uninfected control rats. IFN-y, IL-lß, IL-4, IL-6, IL-10, IL-12 and TNF-a mRNA levels were elevated at 12 h post inoculation (p.i.) in spleen and CSF. At this time point, strong expression of IL-6 and TGF-ß was detected in the brain, and also of L-10 at 48 h. The expression of IFN-y and IL-12 was very low throughout the observaton time in the brain. Delayed cytokine induction occuned in CSF compared to spleen and brain. TGF-ß was high in CSF at 48 h, and some elevation of IL-lß, IL-6, IL-10, TNF-a, IFN-y and IL-12 was evident at 72 h p.i. This rnay suggest that measures promoting prcduction of TGF-ß and/or IL-10 should be evaluated in treatment of bacterial meningitis. Intracisternal inoculation of Hib or Streptococcus (S.) pneumoniae to 3 weeks old rats resulted in lethal meningitis. Levels of cytokine mRNA expression of IL-lß, IL4, IL-6, IL-10, IL-12, TNF-a, TNF-ß, IFN-y, and TGF-ß in the brain from Hib or S pneumoniae-inoculated and in uninfected control rats was evaluated. The production of IL-lß, IL-4, IL-6 and IFN-y was also evaluated by immunohistochemistry (IHC). In the brain of Hib inoculated rats, there was marked mRNA expression of IL-lß, IL-6, TNF-a, IL-12 and IFN-y. IL-lß, IL-6 and TNF-a were upregulated, with similar patterns of induction IFN-y and TNF-ß were up-regulated within 8 h p.i. IL-10 and TGF-ß were down-regulated at 18 h p.i., while IL-4 was not detected. In contrast, the brain of S. pneumoniae-inoculated rats showed lower levels of IL-lß, IL-6 and TNF-a, but higher levels of TNF-ß and detectable mRNA expression of IL- 4 when compared to the Hib-inoculated rats. IL-12, IFN-y, IL-10 and TGF-ß exhibited similar patterns of induction in the brains of Hib and S pneumoniae- inoculated rats. At 18 h p.i., IHC showed similar patterns of IL-lß, IL-4, IL-6 and IFN-y as mRNA expression The predominant cytokine messages in Hib-infected rats were associated with a pro-inflammtory response, while S. pneumoniae-infected rats responded with mixed pro- and anti-inflammatory responses. Brains of infant rats challenged with Hib i.p. resulted in the time-dependent mRNA of expression of MIP-2, MlP-la, MCP-I and RANTES, which was maximal 24-48 h p.i. IHC showed significant increases in neutrophils and macrphages infiltrating the mening, the ventricular system and the periventricular area. The kinetics of MIP-2, MlP-la, MCP-I and RANTES rnRNA expression paralleled those of the recuitment of inflammatory cells and disease severity. Blocking the fundion of MIP-2 and MlP-la resulted in significant reduction of neutrophils.Administration of anti-MCP-I Ab significartly decreased macrohage infiltration. Combined studies using ISH and IHC showed that MIP-2 and MlP-la positiveve cells were neutrophils and macrophages. MCP-I positive cells were neutrophils macrophages and astrocytes. Expression of RANTES was localized predominantly to resident astrocytes and microglia. Blocking of MIP-2 or MlP-la bioactivity in vivo results in decreased influx of neutrophils. An immunoregulatory mechanism involving release of neutralizing autoantibodies (Aabs) to self cytokines during bacterial infection is presented herein. High levels of cells expressing mRNA for IFN-y and TNF-a were detected 12 to 48 h p.i. in splenocytes, and large numbers of IFN-y-secreting cells were present in the spleen on day 3 p.i. These cytokines were undetectable at day 9 and 14 p.i. Increased titers of Aabs to both cytokines were observed, with a peak at day 7 p.i. and with very low levels at day 30. Similariy, the induction of five potentially important cytokines and their autoantibody responses in the CSF was examined. Protein levels of the cytokines IFN-y, TNF-a, TGF-ß, IL-4 and 10, were detected on day 3 p.i. with maximum induction at day 8. Thereafter, cytokine levels become undetectable. Increased Aab titers to these cytokines, except IL-4, were registered with peak levels between day 7 and 9. Upon reinoculation with Hib at day 30, regeneration of Aabs was recorded at day 37.These data suggest a role for autoimmunity in cytokine regulation and that a maintained balance of this mechanism may protect from sequelae

Comparative and molecular analysis of MRSA isolates from infection sites and carrier colonization sites

Abstract Background Methicillin resistant Staphylococcus aureus (MRSA) constitutes a major global health concern causing hospital and community acquired infections. A wide diversity of MRSA genotypes are circulating in geographically related regions. Therefore understanding the molecular epidemiology of MRSA is fundamental to design control and clearance measures. Methods A total of 106 MRSA isolates from infection (51) and carrier colonization sites (55) are characterized genetically based on SCCmec and MLST genotyping methods in addition to detection of PVL, TSST-1 and enterotoxins. Results Sccmec-IV was the most frequently detected genotype (77.3%) followed by genotype V (13.2%) and III (9.4%). SCCmec-IVa was more prevalent among the carrier group (p value 0.002). CC80 was the most commonly identified clonal complex (CC). CC6 and CC22 were significantly more prevalent among the carrier group (p value 0.02 and 0.01, respectively). PVL was highly prevalent among the isolates (58.5%). PVL was detected in 70.6% of isolates from infection sites and 47.3% of isolates from carriers. All strains were sensitive to vancomycin, however, MRSA strains isolated from infection sites had significantly higher MICs compared to strains isolated from carrier colonization sites (p value 0.021). Five new sequence types mainly from the carrier group were identified and described in the study. Conclusions MRSA population is genetically very diverse among carriers and infected individuals. With SCCmec type IV being most prevalent, this suggests a community origin of most MRSA strains. Therefore very well designed surveillance and clearance strategies should be prepared to prevent emergence and control spread of MRSA in the community

Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series

All clinical trials to date with encorafenib and binimetinib (US Food and Drug Administration–approved in June 2018 for BRAF ‐mutated metastatic melanoma) have excluded untreated melanoma brain metastases. This case series provides the first clinical evidence of intracranial activity of the combination of encorafenib plus binimetinib in patients with BRAF ‐mutant melanoma with active brain metastases. Intracranial clinical activity is observed for the first time in patients previously treated with BRAF/MEK inhibitors, a population that has not been previously investigated