Cutaneous leukocytoclastic vasculitis due to anti-tuberculosis medications, rifampin and pyrazinamide

Anti-tuberculosis drugs frequently result in cutaneous adverse reactions, including pruritus, maculopapular exanthems, and urticaria. However, anti-tuberculosis drug-associated cutaneous leukocytoclastic vasculitis (CLV) has been rarely reported. We describe a case of CLV induced by rifampin and pyrazinamide. A 38-year-old male had been diagnosed with pulmonary tuberculosis two months ago and then he started standard anti-tuberculosis therapy with isoniazid, rifampin, ethambutol, and pyrazinamide. Purpuric lesions developed in the extremities after 1.5 months of anti-tuberculosis medication; the lesions progressively spread over the entire body. Histopathology of the purpuric skin lesion was consistent with leukocytoclastic vasculitis. The skin lesion improved after cessation of anti-tuberculosis medications and treatment with oral corticosteroids and antihistamines. Anti-tuberculosis drugs were rechallenged one at a time over 3 days. Purpura recurred on the right forearm and forehead after taking 300 mg of rifampin. The skin lesion disappeared after taking oral prednisolone. Finally, 1,500 mg of pyrazinamide was readministrated, and then purpuric lesions recurred on both forearms. This report describes a case of leukocytoclastic vasculitis secondary to rifampin and pyrazinamide therapy

Chedoke Arm and Hand Activity Inventory-9 (CAHAI-9): Perceived clinical utility within 14 days of stroke

Purpose: The Chedoke Arm and Hand Activity Inventory-9 (CAHAI-9) is an activity-based assessment developed to include relevant functional tasks and to be sensitive to clinically important changes in upper limb function. The aim of this study was to explore both therapists' and clients' views on the clinical utility of CAHAI-9 within 14 days of stroke. Method: Twenty-one occupational therapists actively working in stroke settings were recruited by convenience sampling from 8 hospitals and participated in semistructured focus groups. Five clients within 14 days of stroke were recruited by consecutive sampling from 1 metropolitan hospital and participated in structured individual interviews. The transcripts were analyzed thematically. Results: Six themes emerged from the focus groups and interviews: collecting information, decisions regarding client suitability, administration and scoring, organizational demands, raising awareness, and clients' perceptions of CAHAI-9 utility. All therapists agreed CAHAI-9 was suited for the stroke population and assisted identification of client abilities or difficulties within functional contexts. Opinions varied as to whether CAHAI-9 should be routinely administered with clients who had mild and severe upper limb deficits, but therapists agreed it was appropriate for clients with moderate deficits. Therapists made suggestions regarding refinement of the scoring and training to increase utility. All clients with stroke felt that the assessment provided reassurance regarding their recovery. Conclusion: The findings indicate that CAHAI-9 shows promise as an upper limb ability assessment for clients within 14 days of stroke

Understanding emotionally relevant situations in primary dental practice. 3. Emerging narratives

Background and aims. Dentists experience considerable occupational stress. Stressful clinical situations can provoke high levels of negative emotions, and situations which are associated with positive emotions tend to be overlooked by practitioners. Reflection regarding difficult situations is encouraged to facilitate learning. Cognitive behavioural therapy (CBT) formulations may be applied to situations appraised both positively and negatively. Analysis and interpretation of the dentist's coping behaviour and the consequent outcomes facilitate learning and reflection upon individual interactions with patients. Method. Twenty primary care dental practitioners in the greater Lincoln area participated in a semi-structured interview which explored their stressful and positive clinical experiences. Some of the episodes were analysed to create CBT formulations. Results and discussion. CBT formulations are presented and the learning points highlighted by this structured presentation are discussed. In particular, it is suggested that this structured reconstruction of events, which highlights dentists' emotions, responses and the transactional effects of coping responses, might well facilitate objective reflective learning either individually or as part of peer to peer support. It should facilitate dentists' emotional processing of events and may thus contribute to stress reduction. Conclusion. CBT formulations of positive and negative dental scenarios may be constructed. It is proposed that this is a useful technique to foster reflection and learning in clinical situations and should lead to improved communication skills and shared decision-making, resulting in fewer complaints and thereby reduced stress. It should also improve dentists' emotional processing

The pharmacokinetics of the interstitial space in humans

BACKGROUND: The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes. METHODS: The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphine-6-glucuronide, morphine-3-glucuronide, inulin and β-lactam antibiotics with a range of protein binding (amoxicillin, piperacillin, cefatrizine, ceforanide, flucloxacillin, dicloxacillin). A PBPK data set was developed for extracellular solutes based on the literature for interstitial organ volumes. The program PKQuest was used to generate the PBPK model predictions. The pharmacokinetics of the protein (albumin) bound β-lactam antibiotics were characterized by two parameters: 1) the free fraction of the solute in plasma; 2) the interstitial albumin concentration. A new approach to estimating the capillary permeability is described, based on the pharmacokinetics of the highly protein bound antibiotics. RESULTS: About 42% of the total body water is extracellular. There is a large variation in the organ distribution of this water – varying from about 13% of total tissue water for skeletal muscle, up to 70% for skin and connective tissue. The weakly bound antibiotics have flow limited capillary-tissue exchange kinetics. The highly protein bound antibiotics have a significant capillary permeability limitation. The experimental pharmacokinetics of the 11 solutes is well described using the new PBPK data set and PKQuest. CONCLUSIONS: Only one adjustable parameter (systemic clearance) is required to completely characterize the PBPK for these extracellular solutes. Knowledge of just this systemic clearance allows one to predict the complete time course of the absolute drug concentrations in the major organs. PKQuest is freely available

A bacterial genome in transition - an exceptional enrichment of IS elements but lack of evidence for recent transposition in the symbiont Amoebophilus asiaticus

<p>Abstract</p> <p>Background</p> <p>Insertion sequence (IS) elements are important mediators of genome plasticity and are widespread among bacterial and archaeal genomes. The 1.88 Mbp genome of the obligate intracellular amoeba symbiont <it>Amoebophilus asiaticus </it>contains an unusually large number of transposase genes (n = 354; 23% of all genes).</p> <p>Results</p> <p>The transposase genes in the <it>A. asiaticus </it>genome can be assigned to 16 different IS elements termed ISCaa1 to ISCaa16, which are represented by 2 to 24 full-length copies, respectively. Despite this high IS element load, the <it>A. asiaticus </it>genome displays a GC skew pattern typical for most bacterial genomes, indicating that no major rearrangements have occurred recently. Additionally, the high sequence divergence of some IS elements, the high number of truncated IS element copies (n = 143), as well as the absence of direct repeats in most IS elements suggest that the IS elements of <it>A. asiaticus </it>are transpositionally inactive. Although we could show transcription of 13 IS elements, we did not find experimental evidence for transpositional activity, corroborating our results from sequence analyses. However, we detected contiguous transcripts between IS elements and their downstream genes at nine loci in the <it>A. asiaticus </it>genome, indicating that some IS elements influence the transcription of downstream genes, some of which might be important for host cell interaction.</p> <p>Conclusions</p> <p>Taken together, the IS elements in the <it>A. asiaticus </it>genome are currently in the process of degradation and largely represent reflections of the evolutionary past of <it>A. asiaticus </it>in which its genome was shaped by their activity.</p

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR=1.33, p=4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR=1.07, p=0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR=0.90, p=0.00033; rs927062, OR =0.94, p=0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations