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(131)I-metaiodobenzylguanidine ((131)I-mIBG) is a targeted radiation therapy developed for the treatment of advanced neuroblastoma. We have previously shown that this patient cohort can be used to predict absorbed dose associated with early (131)I exposure, 72 h after treatment. We now expand these studies to identify gene expression differences associated with (131)I-mIBG exposure 15 days after treatment. Total RNA from peripheral blood lymphocytes was isolated from 288 whole blood samples representing 59 relapsed or refractory neuroblastoma patients before and after (131)I-mIBG treatment. We found that several transcripts predictive of early exposure returned to baseline levels by day 15, however, selected transcripts did not return to baseline. At 72 h, all 17 selected pathway-specific transcripts were differentially expressed. Transcripts CDKN1A (P < 0.000001), FDXR (P < 0.000001), DDB2 (P < 0.000001), and BBC3 (P < 0.000001) showed the highest up-regulation at 72 h after (131)I-mIBG exposure, with mean log(2) fold changes of 2.55, 2.93, 1.86 and 1.85, respectively. At day 15 after (131)I-mIBG, 11 of the 17 selected transcripts were differentially expressed, with XPC, STAT5B, PRKDC, MDM2, POLH, IGF1R, and SGK1 displaying significant up-regulation at 72 h and significant down-regulation at day 15. Interestingly, transcripts FDXR (P = 0.01), DDB2 (P = 0.03), BCL2 (P = 0.003), and SESN1 (P < 0.0003) maintained differential expression 15 days after (131)I-mIBG treatment. These results suggest that transcript levels for DNA repair, apoptosis, and ionizing radiation-induced cellular stress are still changing by 15 days after (131)I-mIBG treatment. Our studies showcase the use of biodosimetry gene expression panels as predictive biomarkers following early (72 h) and late (15 days) internal (131)I exposure. Our findings also demonstrate the utility of our transcript panel to differentiate exposed from non-exposed individuals up to 15 days after exposure from internal (131)I.

Significant opportunities remain for pharmacologically enhancing the clinical effectiveness of proton and carbon ion-based radiotherapies to achieve both tumor cell radiosensitization and normal tissue radioprotection. We investigated whether pretreatment with the hydroxamate-based histone deacetylase inhibitors (HDACi) SAHA (vorinostat), M344, and PTACH impacts radiation-induced DNA double-strand break (DSB) induction and repair, cell killing, and transformation (acquisition of anchorage-independent growth in soft agar) in human normal and tumor cell lines following gamma ray and light ion irradiation. Treatment of normal NFF28 primary fibroblasts and U2OS osteosarcoma, A549 lung carcinoma, and U87MG glioma cells with 5–10 µM HDACi concentrations 18 h prior to cesium-137 gamma irradiation resulted in radiosensitization measured by clonogenic survival assays and increased levels of colocalized gamma-H2AX/53BP1 foci induction. We similarly tested these HDACi following irradiation with 200 MeV protons, 290 MeV/n carbon ions, and 350 MeV/n oxygen ions delivered in the Bragg plateau region. Unlike uniform gamma ray radiosensitization, effects of HDACi pretreatment were unexpectedly cell type and ion species-dependent with C-12 and O-16 ion irradiations showing enhanced G0/G1-phase fibroblast survival (radioprotection) and in some cases reduced or absent tumor cell radiosensitization. DSB-associated foci levels were similar for proton-irradiated DMSO control and SAHA-treated fibroblast cultures, while lower levels of induced foci were observed in SAHA-pretreated C-12 ion-irradiated fibroblasts. Fibroblast transformation frequencies measured for all radiation types were generally LET-dependent and lowest following proton irradiation; however, both gamma and proton exposures showed hyperlinear transformation induction at low doses (≤25 cGy). HDACi pretreatments led to overall lower transformation frequencies at low doses for all radiation types except O-16 ions but generally led to higher transformation frequencies at higher doses (>50 cGy). The results of these in vitro studies cast doubt on the clinical efficacy of using HDACi as radiosensitizers for light ion-based hadron radiotherapy given the mixed results on their radiosensitization effectiveness and related possibility of increased second cancer induction.

Implant rehabilitation is a successful treatment modality for the replacement of missing teeth, but careful treatment planning, restoratively-driven implant placement and individualized maintenance are prerequisites for success in order to control and minimize technical and biologic complications. The first part of the series focused on new patient assessment and pre-operative planning. The second part of the series will discuss the surgical and prosthodontic considerations and maintenance of implant-supported restorations. CPD/Clinical Relevance: To provide the dental practitioner with an evidence-based overview regarding treatment planning, surgical and prosthodontic considerations and maintenance of implant-supported restorations.

Background: There is need to understand biological markers and mechanisms in Gulf War illness (GWI).Goal: To examine whether and how eicosanoids – prostaglandins and leukotrienes – are alte...

RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the treatment of several autoimmune diseases. Human genetic studies indicate a significant contributory role for RORC in several human disease conditions. Furthermore, genome-wide association studies (GWAS) report a significant association between inflammatory bowel disease (IBD) and the RORC regulatory variant rs4845604. To investigate if the rs4845604 variant may affect CD4+ T cell differentiation events, naïve CD4+ T cells were isolated from eighteen healthy subjects homozygous for the rs4845604 minor (A) or major (G) allele). Isolated cells from each subject were differentiated into distinct T cell lineages by culturing in either T cell maintenance medium or Th17 driving medium conditions for six days in the presence of an RORC inverse agonist (to prevent constitutive receptor activity) or an inactive diastereomer (control). Our proof of concept study indicated that genotype had no significant effect on the mean number of naïve CD4 T cells isolated, nor the frequency of Th1-like and Th17-like cells following six days of culture in any of the four culture conditions. Analysis of the derived RNA-seq count data identified genotype-driven transcriptional effects in each of the four culture conditions. Subsequent pathway enrichment analysis of these profiles reported perturbation of metabolic signalling networks, with the potential to affect the cellular detoxification response. This investigation reveals that rs4845604 genotype is associated with transcriptional effects in CD4+ T cells that may perturb immune and metabolic pathways. Most significantly, the rs4845604 GG, IBD risk associated, genotype may be associated with a differential detoxification response. This observation justifies further investigation in a larger cohort of both healthy and IBD-affected individuals.

Background An apparent increase in the incidence of severe community-acquired pneumonia (CAP) caused by Streptococcus pyogenes (group A Streptococcus – GAS) was observed during 2017 in the Newcastle area. The study was undertaken to establish whether there was a true increase in severe S. pyogenes pneumonia and to explore its epidemiology and clinical features. Methods The study was a retrospective descriptive study of S. pyogenes pneumonia set in two tertiary referral hospitals in Newcastle, a large regional city, during the period 2007 to 2018. Subjects were adults identified as having S. pyogenes pneumonia by searching a database of severe CAP (defined as requiring intensive care unit [ICU] admission) for the period 2007–2018. Laboratory records were also searched for sterile site isolates of S. pyogenes to identify patients not requiring ICU admission. Results There were 13 cases of S. pyogenes CAP identified during the study period, of whom 12 (92%) required ICU admission. S. pyogenes accounted for 12/728 (1.6%) cases of severe CAP during the study period. The severity of S. pyogenes pneumonia was high despite a mean patient age of 48 years and 7/13 (54%) having no significant past medical history. The mortality rate was 2/13 (15%). Viral co-infection was found in 6/12 (50%) of patients tested. Overall 7/12 (58%) of the patients with severe S. pyogenes CAP during the study period presented in the winter or spring of 2017. Conclusions Streptococcus pyogenes is a rare cause of severe CAP in the Newcastle area, but there was a marked increase in frequency observed during the 2017 influenza season. Further study of the epidemiology of invasive GAS (iGAS) disease in Newcastle is warranted to identify emerging trends in this severe infection.

The focus of the present chapter is on the role and function of the presence of a native or non-native teacher in an English L2 class and its effect on students’ emotions and learning outcomes. It specifically assesses the effects associated with shame, fear, anxiety, anger, hopelessness and pride in this respect, emotions not often discussed in the available literature on L2 learning. The students’ self-reports concerning these questions revealed that native language teachers appear to elicit more negative emotions in their students compared with their non-native teacher counterparts. Further results suggested that the specific emotion elicited in L2 students by native teachers vis-a-vis non-native teachers is anxiety.

The stem cell compartment of the hematopoietic system constitutes one of the most radiosensitive tissues of the body and leukemias represent one of the most frequent radiogenic cancers with short latency periods. As such, leukemias may pose a particular threat to astronauts during prolonged space missions. Control of hematopoiesis is tightly governed by a specialized bone marrow (BM) microenvironment/niche. As such, any environmental insult that damages cells of this niche would be expected to produce pronounced effects on the types and functionality of hematopoietic/immune cells generated. We recently reported that direct exposure of human hematopoietic stem cells (HSC) to simulated solar energetic particle (SEP) and galactic cosmic ray (GCR) radiation dramatically altered the differentiative potential of these cells, and that simulated GCR exposures can directly induce DNA damage and mutations within human HSC, which led to leukemic transformation when these cells repopulated murine recipients. In this study, we performed the first in-depth examination to define changes that occur in mesenchymal stem cells present in the human BM niche following exposure to accelerated protons and iron ions and assess the impact these changes have upon human hematopoiesis. Our data provide compelling evidence that simulated SEP/GCR exposures can also contribute to defective hematopoiesis/immunity through so-called "biological bystander effects" by damaging the stromal cells that comprise the human marrow microenvironment, thereby altering their ability to support normal hematopoiesis.

A 61-year-old man with chronic lymphocytic leukemia (CLL) developed disseminated cryptococcal infection, diagnosed 7 months after commencement of acalabrutinib, a Bruton's tyrosine kinase inhibitor. To our knowledge, this is the first reported case of cryptococcal infection occurring in a pa

Climate change is predicted to affect the reproductive ecology of wildlife; however, we have yet to understand if and how species can adapt to the rapid pace of change. Clock genes are functional genes likely critical for adaptation to shifting seasonal conditions through shifts in timing cues. Many of these genes contain coding trinucleotide repeats, which offer the potential for higher rates of change than single nucleotide polymorphisms (SNPs) at coding sites, and, thus, may translate to faster rates of adaptation in changing environments. We characterized repeats in 22 clock genes across all annotated mammal species and evaluated the potential for selection on repeat motifs in three clock genes (NR1D1, CLOCK, and PER1) in three congeneric species pairs with different latitudinal range limits: Canada lynx and bobcat (Lynx canadensis and L. rufus), northern and southern flying squirrels (Glaucomys sabrinus and G. volans), and white‐footed and deer mouse (Peromyscus leucopus and P. maniculatus). Signatures of positive selection were found in both the interspecific comparison of Canada lynx and bobcat, and intraspecific analyses in Canada lynx. Northern and southern flying squirrels showed differing frequencies at common CLOCK alleles and a signature of balancing selection. Regional excess homozygosity was found in the deer mouse at PER1 suggesting disruptive selection, and further analyses suggested balancing selection in the white‐footed mouse. These preliminary signatures of selection and the presence of trinucleotide repeats within many clock genes warrant further consideration of the importance of candidate gene motifs for adaptation to climate change.

This first truly global conference on the use of zygomatic implants for the oral reconstruction of patients with compromised or deficient maxillae was held at the Museum of London from 1 to 2 March 2019. It attracted over 200 clinicians and academics from 24 nations and reviewed over 25 years' experience and research in this field. This conference presented concepts heralding new opportunities for the oro-facial rehabilitation of doctor-induced osteonecrosis of the jaw (ONJ), both osteonecrosis radiation-induced (ORN) and medication-induced ONJ (MRONJ) in oncology patients.

Two studies are reported that assess the moderation of shame and related emotions in Polish university students in different English L2 learning scenarios. In the first study, students on speaking and writing courses completed a questionnaire in which they rated the likelihood of their emotional responses to hypothetical situations in learning scenarios that they experienced. In both courses the main reduction in shame was shown in scenarios that provided more private as opposed to public evaluation. The corresponding decreases for fear, anxiety, anger and hopelessness were less pronounced and were dependent on the emotion and scenario. In the second study, results of regular email peer co-operation between students of English at Polish and US universities are reported. In both studies the reduction of the level of shame/embarrassment, conditioned by the presence of less formal communication scenarios, is observed, along with the development of the students’ more positive linguistic self-evaluation.

Background GSK2586184 is a selective oral Janus kinase (JAK)1 inhibitor being evaluated as a treatment for moderate-to-severe plaque-type psoriasis. Objectives To assess the relationship between dose of GSK2586184 and clinical response, primarily by the Psoriasis Area Severity Index (PASI). Methods Sixty patients with moderate-to-severe plaque psoriasis were randomized to cohort A: 100 mg, 200 mg or 400 mg GSK2586184 twice daily or placebo; and eight were randomized to open-label cohort B, a small exploratory cohort treated with 400 mg GSK2586184 twice daily, to explore differential gene expression. Results At week 12, a 75% reduction in PASI (PASI 75) response rates in the intent-to-treat population were 0% in the placebo group compared with 13%, 25% and 57% in the 100 mg, 200 mg and 400 mg GSK2586184 twice-daily groups, respectively. Increases in the proportion of PASI 75 responses were seen across all dose levels by week 4. Improvement in itch and quality of life were observed at all doses relative to placebo with the greatest improvement seen in the 400-mg dose group. Overall, the incidence of adverse events (AEs) was similar across treatment groups, and no relationship between frequency of AE and GSK2586184 dose was identified. Differential gene expression was observed in involved and uninvolved skin at baseline and in involved skin after 2 weeks of treatment with GSK2586184. Conclusions Our study demonstrates that 12 weeks of treatment with GSK2586184 resulted in clinical improvement and was generally well tolerated in patients with moderate-to-severe plaque-type psoriasis.

To investigate Toll-like receptor activation in human skin using tape stripping and imiquimod cream challenges in healthy volunteers.Seventeen male Caucasian subjects underwent a baseline biopsy on their lower back prior to two tape stripping procedures 7 days apart. Subjects were then treated with 5% imiquimod for 2 and 4 days on separate sites in the same area. Further biopsies were taken 22-24 h after each challenge and mRNA and microRNA extracted and expression values analysed using robust statistical and pathway analysis methods.Fifteen of the 17 subjects completed the study according to protocol. No adverse events were associated with the procedures. A significant change (p0.05, fold change1.5 or-1.5) in mRNA expression of 7,996 genes was evident in biopsies taken at both time points post tape stripping, compared to baseline biopsy expression values. The induction of mRNAs involved in various pathways including adhesion and migration was evident. mRNA markers representing inflammatory cells [e.g., CD14, CD3E (p0.0001)] and mRNAs encoding genes regulated by type 1 interferon (IFN) [e.g., MX1, OAS1and CXCL10 (p0.0001)] were significantly up-regulated. IFNα and CXCL10 proteins were detectable in exudates released 1 and 4 h post tape stripping. A putative signalling network associating these transcripts and six microRNAs (hsa-miR, -31, -132, -155, 548c, 548n and 574) was identified using a meta-regulation network model. microRNAs not previously associated with IFN signalling have been identified. In contrast, only 223 known transcripts were significantly changed after imiquimod treatment, including CXCL10, and OAS1.Results suggest that IFN signalling is important in these translational models and novel miRNA may be new targets in the treatment of IFN associated skin disease.

Biological responses of human cells and tissues to ionizing radiation (IR) are strongly influenced by dose and dose-rate. Unlike the robust activation of cellular DNA damage responses (DDR) seen after high IR doses, the efficiency of activation of DNA damage repair and signaling pathways after much lower doses and dose-rates varies appreciably among different individuals. Genomic and functional assays measuring low dose and dose-rate IR responses repeatedly show increased inter-individual variability when cells and tissues experience DNA damage levels comparable to those experienced endogenously (due to aerobic metabolism, diet, lifestyle, etc). Complicating matters for risk assessment are recent observations of dose-response non-linearity (hyper-linearity) in the low dose range. With both physical and biological factors strongly influencing individual responses to IR at low doses and dose-rates, further radiobiological research is required to assist regulatory agencies in determining appropriate radiological protection standards for such exposures.

Successful demonstrations of novel short-cut taking by animals, including humans, are open to interpretation in terms of learning that is not necessarily spatial. A classic example is that of Tolman, Ritchie, and Kalish (1946) who allowed rats to repeat a sequence of turns through the corridors of a maze to locate a food reward. When the entrance to the corridors was subsequently blocked and alternative corridors were made available, rats successfully selected the corridor leading most directly to the food location. However, the presence of a distinctive light above the goal, in both the training and testing phases, means that approach to the light as a beacon could have been the source of successful short-cutting. We report a replication of the experimental design of Tolman et al. with human participants who explored geometrically equivalent virtual environments. An experimental group, who followed the original procedure in the absence of any distinctive cues proximal to the goal, did not select the corridor which led most directly to the goal. A control group, who experienced a light above the goal during training and testing, were more likely to select a corridor which led in the direction of the goal. A second control group experienced the light above the goal during training, but in the test the location of this cue was shifted by 90° with respect to the start point of exploration. This latter group responded unsystematically in the test, neither selecting a corridor leading to the original goal location, nor one leading directly to the relocated light cue. The results do not support the hypothesis that travelling a multi-path route automatically leads to an integrated cognitive representation of that route. The data offer support for the importance of local cues which can serve as beacons to indicate the location of a goal.

Early detection and prevention is an important goal in acute respiratory distress syndrome research. We determined the concentration of the anti-inflammatory 15-deoxy-Δ(12,14)-prostaglandin-J2 (15d-PGJ2) and other components of the cyclopentenone prostaglandin cascade in relation to lung inflammation in cytokine (IL-1/LPS)-insufflated rats. We found that 15d-PGJ2 levels increase in the bronchoalveolar lavage (BAL) fluid of rats insufflated with cytokines 2 h before. BAL 15d-PGJ2 increases preceded neutrophil recruitment, lung injury, and oxidative stress in the lungs of cytokine-insufflated rats. 15d-PGJ2 was localized in alveolar macrophages that decreased following cytokine insufflation. 15d-PGJ2 may constitute an early biomarker of lung inflammation and may reflect an endogenous attempt to regulate ongoing inflammation in macrophages and elsewhere after cytokine insufflation.

Future deep space missions to Mars and near-Earth asteroids will expose astronauts to chronic solar energetic particles (SEP) and galactic cosmic ray (GCR) radiation, and likely one or more solar particle events (SPEs). Given the inherent radiosensitivity of hematopoietic cells and short latency period of leukemias, space radiation-induced hematopoietic damage poses a particular threat to astronauts on extended missions. We show that exposing human hematopoietic stem/progenitor cells (HSC) to extended mission-relevant doses of accelerated high-energy protons and iron ions leads to the following: (1) introduces mutations that are frequently located within genes involved in hematopoiesis and are distinct from those induced by γ-radiation; (2) markedly reduces in vitro colony formation; (3) markedly alters engraftment and lineage commitment in vivo; and (4) leads to the development, in vivo, of what appears to be T-ALL. Sequential exposure to protons and iron ions (as typically occurs in deep space) proved far more deleterious to HSC genome integrity and function than either particle species alone. Our results represent a critical step for more accurately estimating risks to the human hematopoietic system from space radiation, identifying and better defining molecular mechanisms by which space radiation impairs hematopoiesis and induces leukemogenesis, as well as for developing appropriately targeted countermeasures.

Aleutian mink disease (AMD) is a prominent infectious disease in mink farms. The AMD virus (AMDV) has been well characterized in Europe where American mink (Neovison vison) are an introduced species; however, in North America, where American mink are native and the disease is thought to have originated, the virus’ molecular epidemiology is unknown. As such, we characterized viral isolates from Ontario free-ranging mink of domestic, hybrid, and wild origin at two proteins: NS1, a nonstructural protein, and VP2, a capsid protein. AMDV DNA was detected in 25% of free-ranging mink (45 of 183), indicating prevalent active infection. Median-joining networks showed that Ontario AMDV isolates formed two subgroups in the NS1 region and three in the VP2 region, which were somewhat separate from, but closely related to, AMDVs circulating in domestic mink worldwide. Molecular analyses showed evidence of AMDV crossing from domestic to wild mink. Our results suggest that AMDV isolate grouping is linked to both wild endogenous reservoirs and the long-term global trade in domestic mink, and that AMD spills back and forth between domestic and wild mink. As such, biosecurity on mink farms is warranted to prevent transmission of the disease between mink farms and the wild.

Pseudomonas putida is a Gram-negative bacillus which is widely distributed in soil and water habitats. It is not a common human pathogen and infrequently causes bacteraemia, which is most often intravenous catheter-associated. There are only 2 reports of bacteremia occurring due to soft tiss

Systemic infectious complications following adenotonsillectomy are exceedingly rare. We describe an otherwise healthy 2-year-old patient who developed group A beta-hemolytic Streptococcus sepsis and presumptive scarlet fever 3 days after an uncomplicated adenotonsillectomy. After resolution of fever, rash, and discharge home on antibiotics, the patient returned on postoperative day 10 with an abdominal wall abscess. This is the first reported case of an abdominal wall abscess as a complication of adenotonsillectomy. This case demonstrates that an awareness of unexpected infectious complications of adenotonsillectomy should be a part of postsurgical management. Laryngoscope, 125:1230-1232, 2015.

Frontier techniques, including data envelopment analysis (DEA) and stochastic frontier analysis (SFA), have been used to measure health care provider efficiency in hundreds of published studies. Although these methods have the potential to be useful to decision makers, their utility is limited by both methodological questions concerning their application, as well as some disconnect between the information they provide and the insight sought by decision makers. The articles in this special issue focus on the application of DEA and SFA to hospitals with the hope of making these techniques more accurate and accessible to end users. This introduction to the special issue highlights the importance of measuring the efficiency of health care providers, provides a background on frontier techniques, contains an overview of the articles in the special issue, and suggests a research agenda for DEA and SFA.

Chronic kidney disease and associated co-morbidities (diabetes, cardiovascular diseases) manifest with an accelerated ageing phenotype, leading ultimately to organ failure and renal replacement therapy. This process can be modulated by epigenetic and environmental factors and promote loss of physiological function and resilience to stress earlier, linking biological age with adverse outcomes post-transplantation including Delayed Graft Function (DGF). \ud The molecular features underpinning this have yet to be fully elucidated. We have determined a molecular signature for loss of resilience and impaired physiological function, via a synchronous genome, transcriptome and proteome snapshot, using human renal allografts as a source of healthy tissue for in vivo model of ageing in humans. \ud This comprises 42 specific transcripts, related through IFNγ signalling, which in allografts displaying clinically impaired physiological function (DGF) exhibited a greater magnitude of change in transcriptional amplitude and elevated expression of non-coding RNAs and pseudogenes, consistent with increased allostatic load. This was accompanied by increased DNA methylation within the promoter and intragenic regions of the DGF panel in pre-perfusion allografts with Immediate Graft Function (IGF) \ud Pathway analysis indicated that an inability to sufficiently resolve inflammatory responses was enabled by decreased resilience to stress and resulted in impaired physiological function in biologically older allografts. Cross-comparison with publically available data sets for renal pathologies identified significant transcriptional commonality for over 20 DGF transcripts. Our data are clinically relevant and important, as they provide a clear molecular signature for the burden of ‘wear and tear’ within the kidney and thus age related physiological capability and resilience.

This article is written from the perspective of a forensic psychologist and criminologist who observed the recent trial of Duch, the commandant of S-21, the prison where up to 14,000 men, women and children were systematically interrogated, tortured and then murdered during the reign of Pol Pot's Khmer Rouge regime. It focuses on what the trial revealed about Duch's personality and notes the absence of any form of psychopathology or mental illness in his psychological profile. Duch, however, like many other middle-ranking officials involved in major human rights abuses, may well have distinct personality characteristics. This finding lends weight to the view that an individual's involvement in genocide and other related crimes is best understood as a complex interaction between the situation in which people find themselves during times of war or civil conflict and their personality characteristics.

DNA double-strand breaks (DSB) are generally considered the most critical lesion induced by ionizing radiation (IR) and may initiate carcinogenesis and other disease. Using an immunofluorescence assay to simultaneously detect nuclear foci of the phosphorylated forms of histone H2AX and ATM kinase at sites of DSBs, we examined the response of 25 apparently normal and 10 DNA repair-deficient (ATM, ATR, NBN, LIG1, LIG4, and FANCG) primary fibroblast strains irradiated with low doses of (137)Cs gamma-rays. Quiescent G(0)/G(1)-phase cultures were exposed to 5, 10, and 25 cGy and allowed to repair for 24h. The maximum level of IR-induced foci (0.15 foci per cGy, at 10 or 30 min) in the normal strains showed much less inter-individual variation (CV approximately 0.2) than the level of spontaneous foci, which ranged from 0.2-2.6 foci/cell (CV approximately 0.6; mean+/-SD of 1.00+/-0.57). Significantly slower focus formation post-irradiation was observed in seven normal strains, similar to most mutant strains examined. There was variation in repair efficiency measured by the fraction of IR-induced foci remaining 24h post-irradiation, curiously with the strains having slower focus formation showing more efficient repair after 25 cGy. Interestingly, the ranges of spontaneous and residual induced foci levels at 24h in the normal strains were as least as large as those observed for the repair-defective mutant strains. The inter-individual variation in DSB foci parameters observed in cells exposed to low doses of ionizing radiation in this small survey of apparently normal people suggests that hypomorphic genetic variants in genomic maintenance and/or DNA damage signaling and repair genes may contribute to differential susceptibility to cancer induced by environmental mutagens.

The implications of the NSW Court of Criminal Appeal's ruling in Commonwealth of Australia v Griffiths and Anor, to the effect that an expert who gives incorrect evidence against a party is protected from civil suit by the ‘witness immunity’ rule are reviewed. It is argued that there is an urgent need to reconsider the sanctions that may be imposed on those whose forensic evidence falls short of the high standard expected in this increasingly important area of justice.

Objective Chronic subdural haematoma is a disease of the elderly and surgery in these patients carries a much higher risk. The common surgical procedures for chronic subdural haematoma include twist drill craniostomy, burr hole evacuation or craniotomy. The aim of this study was to analyse the results of twist drill craniostomy with drainage in elderly patients with chronic subdural haematoma. Methods Forty-two elderly patients (>65 years) with radiologically proven chronic subdural haematoma were analysed. All the patients underwent twist drill craniostomy and continuous drainage of the haematoma under local anaesthesia and total intravenous anaesthesia (TIVA). Results There were 24 males and 18 females. Headache and cognitive decline was seen in 50% and weakness of limbs in 60% of patients. CT scan was done in all cases. All patients underwent twist drill 2–3 cm in front of the parietal eminence under local anaesthesia. The drain was left for 24–72 h depending on the drainage. At 1 week, 88% of patients had a good outcome. Conclusion Twist drill craniostomy with drainage under local anaesthesia is a safe and effective procedure for chronic subdural haematoma in the elderly and could be used as the first and only option in these people.

The purpose of this case study was to review the 10-year outcome of a patient with a history of diabetes, pedal osteomyelitis, and peripheral vascular disease, who underwent a Chopart's amputation of the right foot. Key evaluative elements to consider for long-term success of any amputation include the vascular status of the foot, control of infection, adequate soft tissue coverage, biomechanics associated with amputation, the metabolic challenge of amputation, and the psychosocial consequences linked to loss of a limb. The results of the case study show that Chopart's amputation is an excellent limb salvage surgical option that can achieve beneficial long-term outcomes in properly selected patients.

Evidence indicates that workshop training, personalized feedback, and individual consultation can increase competence in motivational interviewing (MI) among highly motivated and skilled substance abuse counselors. Little is known, however, about the translational value of these training strategies for counselors with fewer counseling skills and less stated motivation to learn MI. This study presents evidence from a randomized, controlled trial of 129 behavioral health providers assigned to receive workshop training and enrichments to learn MI. A diverse group of Air Force behavioral health providers working in substance abuse treatment programs were trained in MI and subsequently observed in clinical sessions at 4, 8 and 12 months after training. Results indicate that training was effective in increasing the skill level of these clinicians; however, these gains had decreased by the 4-month follow-up point. Training enrichments in the form of personalized feedback and consultation phone calls did not have an expected, additive effect on clinician skill level. The results of this study lend support to the hypothesis that a greater investment of resources and incentives may be necessary to achieve gains in MI skills for counselors with relatively lower baseline skills than those commonly participating in research studies.

Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene “mountains” and a much larger number of gene “hills” that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.

In a prospective study of 660 HIV-positive Malawian adults, we diagnosed Pneumocystis jirovecii pneumonia (PcP) using clinical features, induced sputum for immunofluorescent staining, real-time PCR, and posttreatment follow-up. PcP incidence was highest in patients with the lowest CD4 counts, but PcP is uncommon compared with incidences of pulmonary tuberculosis and bacterial pneumonia.

Background: There is some evidence that surgical plume may pose a risk to health professionals, but the risks posed by volatile organic compounds have not been thoroughly investigated. Methods: The composition of volatile organic compounds in diathermy plume produced during surgery was analysed by selected ion flow tube mass spectrometry. Results: Hydrogen cyanide (3–51 parts per million), acetylene (2–8 parts per million), and 1,3-butadiene (0.15–0.69 parts per million) were identified in the plume. Conclusion: Although there is no evidence of adverse health effects from the volatile organic compound in diathermy plume, the evidence that it is safe to breathe this plume is lacking. Therefore, we would recommend the use of smoke evacuators where practical.

Aleutian mink disease virus (AMDV) causes a parvovirus infection, initially characterized in American mink (Neovison vison), that may have harmful effects on wild populations of susceptible animals. In North America, where American mink are native, the origin, host range, and prevalence of AMDV in wild species is not clear. We studied striped skunks (Mephitis mephitis) and raccoons (Procyon lotor) to determine whether species sympatric with mink are potential reservoirs in the transmission of AMDV to wild mink and mink farms. Antibodies to AMDV were detected in 41% of skunk serum samples (143/347) and AMDV nucleic acids were detected in 32% (14/40) of skunk spleen samples by PCR, indicating that AMDV exposure and infection were frequent in skunks. We detected no AMDV antibodies in 144 raccoon blood samples. Phylogenetic analysis revealed a newly identified AMDV haplogroup consisting of isolates from Ontario skunks and a free-ranging domestic mink from Ontario. Our findings of frequent AMDV infection in skunks, close genetic similarity between skunk and mink AMDV isolates, and evidence of AMDV transmission from skunks to mink support the hypothesis that skunks may be acting as alternative hosts and reservoirs of AMDV to wild mink through cross-species virus spillover.

In the Funding section, the grant number from the funder National Aeronautic and Space Administration has been updated by the funder. The updated grant number is: NNX11AD22G.

The sound pressure levels (SPLs) of common infant humidifiers were determined to identify the likely sound exposure to infants and young children. This primary investigative research study was completed at a tertiary-level academic medical center otolaryngology and audiology laboratory. Five commercially available humidifiers were obtained from brick-and-mortar infant supply stores. Sound levels were measured at 20-, 100-, and 150-cm distances at all available humidifier settings. Two of 5 (40%) humidifiers tested had SPL readings greater than the recommended hospital infant nursery levels (50 dB) at distances up to 100 cm. In this preliminary study, it was demonstrated that humidifiers marketed for infant nurseries may produce appreciably high decibel levels. Further characterization of the effect of humidifier design on SPLs and further elucidation of ambient sound levels associated with hearing risk are necessary before definitive conclusions and recommendations can be made.

Drug-resistant Plasmodium falciparum is a challenge to malaria control programs. Policy makers currently depend on in vivo (and, sometimes, in vitro ) resistance testing to set treatment guidelines. Molecular markers such as mutations in dhfr , dhps , pfcrt and pfmdr1 represent potential surveillance tools. In this article, we describe newer high-throughput methods for detecting these molecular markers. One method, 5′ nuclease real-time polymerase chain reaction, is discussed in detail.

Using field, molecular and histological methods, an epizootic, systemic disease causing death within wood frog Rana sylvatica tadpoles and leopard frog Rana pipiens metamorphs at 3 different locations within Southern Ontario, Canada, has been investigated. Our results demonstrated that the probable cause of this disease was a ranavirus. Affected amphibians were found to exhibit necrosis within the hematopoietic cells. Liver tissue samples were found positive for the virus by PCR amplification of the ranavirus (Family: Iridoviridae) major capsid protein (MCP). Positive samples were confirmed by sequence analysis. Clinically normal, laboratory-raised wood frog egg broods were also found to test weakly positive for ranavirus. The population effects of disease on these amphibian communities have not yet been conclusively associated with population declines, but warrant more focused consideration.

Nucleotides (NTPs and dNTPs) have been measured in patient-derived chronic lymphocytic leukaemia (CLL) cells stimulated with TPA plus ionomycin and then exposed to cladribine, fludarabine or deoxycoformycin (1 microM, 16 h). dNTPs were not measurable in 10(8) unstimulated CLL cells which are quiescent. Time-dependent changes in nucleotides in CLL cells showed that the mechanism of action changed as the drug triphosphate accumulated. dCf induced substantial accumulation of dATP in CLL cells in culture, and similar levels of dATP in the same patient during subsequent treatment with dCf. Determination of "metabolic response patterns" of nucleotides in CLL cells treated with drugs might distinguish patients with susceptible and refractory CLL prior to chemotherapy.

Automatism is a defence in criminal violence that raises some critical issues about the role of the expert witness in the determination of guilt and innocence. The recent Australian case of R V Leonboyer illustrates some of these issues including psychiatrists and psychologists going beyond their area of expertise, establishing reasonable doubt on the basis of possibilities rather than probabilities and failing to differentiate between automatic behaviour and its causes. Though there may be a necessity to utilise the experience of psychologists and psychiatrists to explain the complex issues arising from the defence of automatism, there are particular problems in using such expert witnesses in this under-researched and complex area.