Basal cell carcinoma in skin of color.
Non-melanoma skin cancer most commonly affects Caucasians, and only rarely affects darker-skinned individuals. However, skin cancer in these groups is associated with greater morbidity and mortality. Ultraviolet radiation is the major etiologic factor in basal cell carcinoma (BCC) and likely plays a pivotal role in the development of other forms of skin cancer. Yet it is commonly thought among patients as well as physicians that darker pigmentation inherently affords complete protection from skin cancer development. This low index of suspicion results in delayed diagnoses and poorer outcomes. This review follows a detailed computer search that cross-matched the diagnosis of BCC with skin color type in a large commercial dermatopathology facility. The reported skin types, all Fitzpatrick skin types IV, V, and VI, and histories were confirmed. A predominance of pigmented BCCs was found in sun-exposed areas of these older individuals. Although less common in darker-skinned ethnic groups, BCC does occur and can pose significant morbidity. Thus, it is essential that dermatologists are familiar with the epidemiology and clinical presentation of all cutaneous malignancies in darker skin so that these patients are fully aware of risks as well as prevention of the disease.


Analytical modeling of uniaxial strain effects on the performance of double-gate graphene nanoribbon field-effect transistors.
: The effects of uniaxial tensile strain on the ultimate performance of a dual-gated graphene nanoribbon field-effect transistor (GNR-FET) are studied using a fully analytical model based on effective mass approximation and semiclassical ballistic transport. The model incorporates the effects of edge bond relaxation and third nearest neighbor (3NN) interaction. To calculate the performance metrics of GNR-FETs, analytical expressions are used for the charge density, quantum capacitance, and drain current as functions of both gate and drain voltages. It is found that the current under a fixed bias can change several times with applied uniaxial strain and these changes are strongly related to strain-induced changes in both band gap and effective mass of the GNR. Intrinsic switching delay time, cutoff frequency, and Ion/Ioff ratio are also calculated for various uniaxial strain values. The results indicate that the variation in both cutoff frequency and Ion/Ioff ratio versus applied tensile strain inversely corresponds to that of the band gap and effective mass. Although a significant high frequency and switching performance can be achieved by uniaxial strain engineering, tradeoff issues should be carefully considered.


The tumor supressor function of STGC3 and its reduced expression in nasopharyngeal carcinoma.
STGC3 is a novel candidate tumor suppressor gene that was found to be associated with nasopharyngeal carcinoma (NPC) via the cDNA cloning and RACE processes. The biological function of the STGC3 protein and its expression level in nasopharyngeal carcinoma remain unknown. This study aimed to evaluate the STGC3 protein expression level in NPC and to investigate the inhibitory function of STGC3 as a candidate tumor suppressor gene. We assessed the expression of the STGC3 protein in NPC biopsies and normal control specimens via Western blot and immunohistochemical analysis. The expression of STGC3 as induced by doxycycline (Dox) via a tetracycline (Tet)-regulated system in human nasopharyngeal carcinoma cell line CNE2 was also established, and the effect of STGC3 restoration on the biological behavior of CNE2 was observed. A reduced level of STGC3 expression (0.978 +/- 0.213 versus 0.324 +/- 0.185, P < 0.05) was detected in NPC versus normal nasopharyngeal tissue by Western blot assay. Immunohistochemical assays for STGC3 detected positive staining in the nuclei and cytoplasm of epithelial cells, and the positive expression rate in NPC, 8 of 21 (38%), was lower than that in normal nasopharynx samples, 16 of 22 (72%). After STGC3 expression was restored, the growth capacity and clone formation potential of CNE2 cells in soft agar were significantly suppressed, and the cell percentage in G(0)/G(1) phase increased, while the percentage of cells entering the S and G(2) phases decreased. This indicates that an abnormality in STGC3 expression is associated with nasopharyngeal carcinogenesis and that it may play an important role in controlling cell growth and regulating the cell cycle.


Interaction of human adipose tissue-derived mesenchymal stromal cells with breast cancer cells.
Human adipose tissue was shown to be a very attractive source of mesenchymal stromal cells that have a wide scale of potential applications in reconstructive plastic surgery and regenerative medicine. However, these cells were described to have profound effects on biological behaviour of tumour cells. The aim of this study was to analyze the influence of adipose tissue-derived human mesenchymal stromal cells (AT-MSC) on the proliferation of breast cancer cells. We have tested proliferation of three different human breast cancer cell lines under the influence of AT-MSC derived soluble factors as well as in the direct cocultures. These data were supplemented with the expression analysis of cytokines and their cognate receptors on the target cells. We have observed stimulation of proliferation in breast cancer cells MDA-MB-361, T47D and EGFP-MCF7. AT-MSC were found to secrete wide scale of cytokines, chemokines and growth factors, thus we concluded that this pro-proliferative effect was a result of their synergistic action. These data bring out a need to evaluate whether primary breast tumour derived human cells would respond to these type of stimuli in a similar manner in order to exclude any potential clinical risk related to the application of human mesenchymal stromal cells under the context of patient with history of breast cancer malignancy.


A novel interface for hybrid mock circulations to evaluate ventricular assist devices.
This paper presents a novel mock circulation for the evaluation of ventricular assist devices (VADs), which is based on a hardware-in-the-loop concept. A numerical model of the human blood circulation runs in real time and computes instantaneous pressure, volume, and flow rate values. The VAD to be tested is connected to a numerical-hydraulic interface, which allows the interaction between the VAD and the numerical model of the circulation. The numerical-hydraulic interface consists of two pressure-controlled reservoirs, which apply the computed pressure values from the model to the VAD, and a flow probe to feed the resulting VAD flow rate back to the model. Experimental results are provided to show the proper interaction between a numerical model of the circulation and a mixed-flow blood pump.


Self-handicapping and burnout.
Self-handicapping is a process containing strategies of externalization in which an individual can excuse failure and internalize success. This study investigated the relationship of self-handicapping with measures of burnout. The Self-handicapping Scale and the Maslach Burnout Inventory were administered to 309 university students. Self-handicapping was positively correlated to emotional exhaustion, lowered personal accomplishment, and depersonalization. A structural equation model fit the data well and accounted for 20% of the variance in emotional exhaustion, 14% in lowered personal accomplishment, and 10% in depersonalization.


Regulation of hrp genes and type III protein secretion in Erwinia amylovora by HrpX/HrpY, a novel two-component system, and HrpS.
Two novel regulatory components, hrpX and hrpY, of the hrp system of Erwinia amylovora were identified. The hrpXY operon is expressed in rich media, but its transcription is increased threefold by low pH, nutrient, and temperature levels--conditions that mimic the plant apoplast. hrpXY is autoregulated and directs the expression of hrpL; hrpL, in turn, activates transcription of other loci in the hrp gene cluster (Z.-M. Wei and S. V. Beer, J. Bacteriol. 177:6201-6210, 1995). The deduced amino -acid sequences of hrpX and hrpY are similar to bacterial two-component regulators including VsrA/VsrD of Pseudomonas (Ralstonia) solanacearum, DegS/DegU of Bacillus subtilis, and UhpB/UhpA and NarX/NarP, NarL of Escherichia coli. The N-terminal signal-input domain of HrpX contains PAS domain repeats. hrpS, located downstream of hrpXY, encodes a protein with homology to WtsA (HrpS) of Erwinia (Pantoea) stewartii, HrpR and HrpS of Pseudomonas syringae, and other delta54-dependent, enhancer-binding proteins. Transcription of hrpS also is induced under conditions that mimic the plant apoplast. However, hrpS is not autoregulated, and its expression is not affected by hrpXY. When hrpS or hrpL were provided on multicopy plasmids, both hrpX and hrpY mutants recovered the ability to elicit the hypersensitive reaction in tobacco. This confirms that hrpS and hrpL are not epistatic to hrpXY. A model of the regulatory cascades leading to the induction of the E. amylovora type III system is proposed.


Genetic variation and adaptation in Africa: implications for human evolution and disease.
Because modern humans originated in Africa and have adapted to diverse environments, African populations have high levels of genetic and phenotypic diversity. Thus, genomic studies of diverse African ethnic groups are essential for understanding human evolutionary history and how this leads to differential disease risk in all humans. Comparative studies of genetic diversity within and between African ethnic groups creates an opportunity to reconstruct some of the earliest events in human population history and are useful for identifying patterns of genetic variation that have been influenced by recent natural selection. Here we describe what is currently known about genetic variation and evolutionary history of diverse African ethnic groups. We also describe examples of recent natural selection in African genomes and how these data are informative for understanding the frequency of many genetic traits, including those that cause disease susceptibility in African populations and populations of recent African descent.


Identifying New Sources of Resistance to Eyespot of Wheat in Aegilops longissima.
Eyespot, caused by Oculimacula yallundae and O. acuformis, is an economically important disease of wheat. Currently, two eyespot resistance genes, Pch1 and Pch2, are used in wheat breeding programs but neither provides complete control or prevents yield loss. Aegilops longissima is a distant relative of wheat and proven donor of genes useful for wheat improvement, including disease resistance. Forty A. longissima accessions and 83 A. longissima chromosome addition or substitution lines were evaluated for resistance to eyespot. Among the 40 accessions tested, 43% were resistant to O. yallundae, 48% were resistant to O. acuformis, and 33% were resistant to both. Addition or substitution lines containing chromosomes 1S1, 2S1, 5S1, and 7S1, and a 4S17S1 translocation were resistant to O. yallundae. Chromosomes 1S1, 2S1, 4S1, and 5S1 contributed to resistance to O. acuformis more than others. Chromosomes 1S1, 2S1, 5S1, and 7S1 provided resistance to both pathogens. This is the first report of eyespot resistance in A. longissima. These results provide evidence that genetic control of eyespot resistance is present on multiple chromosomes of the S1 genome. This research demonstrates that A. longissima is a potential new source of eyespot resistance genes that could broaden the genetic diversity for wheat improvement.


Purification of xyloglucan endotransglycosylases (XETs): a generally applicable and simple method based on reversible formation of an enzyme-substrate complex.
We describe a novel and general, mechanism-based, method for purification of xyloglucan endotransglycosylases (XETs) from crude plant extracts. Putative isoforms, obtained by step-wise precipitation with (NH4)2SO4, were incubated with tamarind xyloglucan (approximately 1 MDa) to form stable xyloglucan-XET complexes with apparent molecular masses >500 kDa on gel-permeation chromatography (GPC). Subsequent addition of xyloglucan-derived oligosaccharides (a mixture of XET acceptor substrates) caused a shift in the GPC elution volume of the activity back to that expected of a approximately 32 kDa protein, presumably by completing the transglycosylation reaction and so freeing the enzyme from the xyloglucan (donor substrate). This simple two-step method enabled the isolation of each XET activity attempted [various (NH4)2SO4 cuts from extracts of cauliflower florets and mung bean seedlings], in pure form as judged by SDS/PAGE.


Neurological Manifestations of Coronavirus Disease 2019: A Comprehensive Review and Meta-Analysis of the First 6 Months of Pandemic Reporting.
Background: There is growing evidence that SARS-Cov-2 infection is associated with severe neurological complications. Understanding the nature and prevalence of these neurologic manifestations is essential for identifying higher-risk patients and projecting demand for ongoing resource utilisation. This review and meta-analysis report the neurologic manifestations identified in hospitalised COVID-19 patients and provide a preliminary estimate of disease prevalence. Methods: MEDLINE, Embase and Scopus were searched for studies reporting the occurrence of neurological complications in hospitalised COVID-19 patients. Results: A total of 2,207 unique entries were identified and screened, among which 14 cohort studies and 53 case reports were included, reporting on a total of 8,577 patients. Central nervous system manifestations included ischemic stroke (n = 226), delirium (n = 79), intracranial haemorrhage (ICH, n = 57), meningoencephalitis (n = 13), seizures (n = 3), and acute demyelinating encephalitis (n = 2). Peripheral nervous system manifestations included Guillain-Barrè Syndrome (n = 21) and other peripheral neuropathies (n = 3). The pooled period prevalence of ischemic stroke from identified studies was 1.3% [95%CI: 0.9-1.8%, 102/7,715] in all hospitalised COVID-19 patients, and 2.8% [95%CI: 1.0-4.6%, 9/318] among COVID-19 patients admitted to ICU. The pooled prevalence of ICH was estimated at 0.4% [95%CI: 0-0.8%, 6/1,006]. Conclusions: The COVID-19 pandemic exerts a substantial neurologic burden which may have residual effects on patients and healthcare systems for years. Low quality evidence impedes the ability to accurately predict the magnitude of this burden. Robust studies with standardised screening and case definitions are required to improve understanding of this disease and optimise treatment of individuals at higher risk for neurologic sequelae.


Current Concepts of Phenylpiperidine Derivatives Use in the Treatment of Acute and Chronic Pain.
Phenylpiperidines are a chemical class of drugs with a phenyl moiety directly attached to piperidine. These agents have an important role in many aspects of medicine including anesthesia and pain medicine. After the development of meperidine, fentanyl, which is a second generation synthetic phenylpiperidine series opioid, was synthesized and introduced into clinical anesthesia practice as fentanyl citrate in 1968. Fentanyl-mediated or modulated responses involve action at the mu-opioid receptor as an agonist at the dorsal horn inhibiting ascending pain pathways in the rostral ventral medulla, increasing pain threshold, and producing both analgesic and sedative effects. Clinicians should appreciate that since fentanyl is metabolized mainly via CYP3A4, potential adverse effects can occur with concomitant use of any drug which affects CYP3A4 activity. Discontinuation of CYP3A4 inducers can also result in an increase in fentanyl plasma concentration. We describe the role of remifentanil, a short-acting, organ independent analgesic and sufentanil, including newer formulations of sufentanil currently being evaluated sublingually for pain management. We examine the routes of administration and clinical considerations, including the role of opioids such as fentanyl as a natural killer cell suppressive agent. Fentanyl and other opioids have been shown to potentiate propagation of infection or cancer. In recent years, fentanyl and other phenylpiperidine formulations have been developed and successfully marketed for chronic pain patients. Because all opioids have complex physiological responses and potential drug-drug interactions, the clinician should appreciate all aspects of this drug class and consider all available options in appropriate clinical settings. Key words: Fentanyl; Remifentanil, Sufentanil, opioids, analgesics, pain, perioperative, management.


Perceptual video coding based on SSIM-inspired divisive normalization.
We propose a perceptual video coding framework based on the divisive normalization scheme, which is found to be an effective approach to model the perceptual sensitivity of biological vision, but has not been fully exploited in the context of video coding. At the macroblock (MB) level, we derive the normalization factors based on the structural similarity (SSIM) index as an attempt to transform the discrete cosine transform domain frame residuals to a perceptually uniform space. We further develop an MB level perceptual mode selection scheme and a frame level global quantization matrix optimization method. Extensive simulations and subjective tests verify that, compared with the H.264/AVC video coding standard, the proposed method can achieve significant gain in terms of rate-SSIM performance and provide better visual quality.


Geographical variation in allometry in the guppy (Poecilia reticulata).
Variation in static allometry, the power relationship between character size and body size among individuals at similar developmental stages, remains poorly understood. We tested whether predation or other ecological factors could affect static allometry by comparing the allometry between the caudal fin length and the body length in adult male guppies (Poecilia reticulata) among populations from different geographical areas, exposed to different predation pressures. Neither the allometric slopes nor the allometric elevations (intercept at constant slope) changed with predation pressure. However, populations from the Northern Range in Trinidad showed allometry with similar slopes but lower intercepts than populations from the Caroni and the Oropouche drainages. Because most of these populations are exposed to predation by the prawn Macrobrachium crenulatum, we speculated that the specific selection pressures exerted by this predator generated this change in relative caudal fin size, although effects of other environmental factors could not be ruled out. This study further suggests that the allometric elevation is more variable than the allometric slope.


Self-reported pain and utilization of pain treatment between minorities and nonminorities in the United States.
To investigate differences in reported pain and pain treatment utilization (use of over-the-counter and prescription pain medications, seeing a pain specialist, and use of complementary and alternative medicine) among minorities and nonminorities in the general population. Secondary analysis of a national probability survey conducted by the CBS News/New York Times in January 2003. Adult population in the United States, 18 years or older, having a telephone line at home. The survey asked respondents a series of questions about demographics, pain characteristics, and utilization of pain treatment; logistic regression was used to identify variables predicting reported utilization of pain treatment. Of the 902 respondents completing the survey, 676 (75%) reported experiencing "any type of pain." Of these, 17% reported being diagnosed with chronic pain. Minorities reported a higher average daily pain than Whites (4.75 vs. 3.72; p<.001). However, race/ethnicity did not explain utilization of pain treatment; income, education, age, gender, and pain levels explained more variability in different pain treatment utilization variables than race/ethnicity. Although minorities report higher pain levels than Whites, race/ethnicity does not explain utilization of treatment for pain. Future studies should consider more nuanced examination of interactions among race/ethnicity, pain, and socioeconomic variables.


Fine mapping and association studies in a candidate region for autism on chromosome 2q31-q32.
Autism (OMIM %209850) is a neurodevelopmental disorder with a strong genetic component. We previously reported a de novo rearrangement of chromosome 2q31 in a patient with autism [Gallagher et al. (2003); J Autism Dev Disord 33(1):105-108]. Further cytogenetic analysis revealed this to be a 46,XY, t(9;2)(q31.1;q32.2q31.3) translocation. Association mapping with microsatellite and SNP markers of this translocated region on 2q revealed association with markers in Integrin alpha-4 (ITGA4; GeneID 3676). ITGA4 was tested for association in a sample of 179 trio-based families. SNP markers in exons 16 and 17 showed evidence of association. Mutation screening revealed a G to A synonymous variation in the last nucleotide of exon 16 (rs12690517), significantly associated with autism in the Irish sample (OR = 1.6; P = 0.04). The location of this SNP at a putative splice donor site may affect the splicing of the ITGA4 protein. Haplotype analysis showed significant overtransmission of haplotypes surrounding this marker. These markers were investigated in two additional samples, 102 families from Vanderbilt University (VT) (n = 102), and AGRE (n = 267). A non-significant trend towards overtransmission of the associated allele of rs12690517 in the Irish sample (OR = 1.2; P = 0.067) and haplotypes at the 3' end of ITGA4 was observed in the AGRE sample. The VT sample showed association with markers and haplotypes across the gene, but no association with the rs12690517 marker or its surrounding haplotypes. The combined sample showed evidence of association with rs12690517 (OR = 1.3; P = 0.008) and surrounding haplotypes. The findings indicate some evidence for the role of ITGA4 as candidate gene for autism.


Radiological and clinical outcomes of 3-level cervical disc arthroplasty.
One- and two-level cervical disc arthroplasty (CDA) has been compared to anterior cervical discectomy and fusion (ACDF) in several large-scale, prospective, randomized trials that have demonstrated similar clinical outcomes. However, whether these results would be similar when treating 3-level disc herniation and/or spondylosis has remained unanswered. This study aimed to investigate the differences between 3-level CDA and ACDF. A series of 50 patients who underwent 3-level CDA at C3-7 was retrospectively reviewed and compared with another series of 50 patients (age- and sex-matched controls) who underwent ACDF at C3-7. Clinical outcomes were measured using the visual analog scale (VAS) for neck and arm pain, the modified Japanese Orthopaedic Association (mJOA) scale, and the Neck Disability Index (NDI). Radiological outcomes included range of motion (ROM) at the index levels. Every patient was evaluated by CT for the presence of fusion in the ACDF group. Also, complication profiles were investigated. The demographics and levels of distribution in both groups were very similar. During the follow-up period of 24 months, clinical outcomes improved (overall and respectively in each group) for both the CDA and ACDF patients when compared with the patients' preoperative condition. There were essentially few differences between the two groups in terms of neck and arm pain VAS scores, mJOA scores, and NDI scores preoperatively and at 3, 6, 12, and 24 months postoperatively. After the 3-level surgery, the CDA group had an increased mean ROM of approximately 3.4°, at 25.2° ± 8.84°, compared to their preoperative ROM (21.8° ± 7.20°) (p = 0.001), whereas the ACDF group had little mobility (22.8° ± 5.90° before and 1.0° ± 1.28° after surgery; p < 0.001). The mean operative time, estimated blood loss, and complication profiles were similar for both groups. In this selectively matched retrospective study, clinical outcomes after 3-level CDA and ACDF were similar during the 2-year follow-up period. CDA not only successfully preserved but slightly increased the mobility at the 3 index levels. However, the safety and efficacy of 3-level CDA requires more long-term data for validatation.


Impact of smoke from prescribed burning: Is it a public health concern?
Given the increase in wildfire intensity and frequency worldwide, prescribed burning is becoming a more common and widespread practice. Prescribed burning is a fire management tool used to reduce fuel loads for wildfire suppression purposes and occurs on an annual basis in many parts of the world. Smoke from prescribed burning can have a substantial impact on air quality and the environment. Prescribed burning is a significant source of fine particulate matter (PM2.5 aerodynamic diameter<2.5µm) and these particulates are found to be consistently elevated during smoke events. Due to their fine nature PM2.5 are particularly harmful to human health. Here we discuss the impact of prescribed burning on air quality particularly focussing on PM2.5. We have summarised available case studies from Australia including a recent study we conducted in regional Victoria, Australia during the prescribed burning season in 2013. The studies reported very high short-term (hourly) concentrations of PM2.5 during prescribed burning. Given the increase in PM2.5 concentrations during smoke events, there is a need to understand the influence of prescribed burning smoke exposure on human health. This is important especially since adverse health impacts have been observed during wildfire events when PM2.5 concentrations were similar to those observed during prescribed burning events. Robust research is required to quantify and determine health impacts from prescribed burning smoke exposure and derive evidence based interventions for managing the risk. Given the increase in PM2.5 concentrations during PB smoke events and its impact on the local air quality, the need to understand the influence of PB smoke exposure on human health is important. This knowledge will be important to inform policy and practice of the integrated, consistent, and adaptive approach to the appropriate planning and implementation of public health strategies during PB events. This will also have important implications for land management and public health organizations in developing evidence based objectives to minimize the risk of PB smoke exposure.


Long-Term Retrospective Assessment of Clinical Efficacy of Radiofrequency Ablation of the Knee Using a Cooled Radiofrequency System.
Cooled radiofrequency ablation (CRFA) in a randomized, prospective study demonstrated significantly greater improvements in pain, functional, and global outcome measures. This large, real-life, retrospective study evaluated the long-term effectiveness of CRFA in the general chronic knee pain population. Retrospective electronic chart review. Outpatient private practice. After institutional review board approval, we reviewed data of 275 consecutive patients who had undergone a geniculate nerve block at a single-site pain practice between July 1, 2014 and July 1, 2017. A total of 44 patients had a negative response to the geniculate block, and 11 patients had long-term pain relief from the block and declined CRFA. Eight patients underwent knee surgery after the block, and 7 never followed up for further treatment. Finally, 205 patients had undergone CRFA, and 183 (89%) of them returned to provide data. The average age of the 183 patients was 61 (28-95) years, body mass index 34 (18.5-57), and there were 105 women and 78 men. A total of 137 patients had unilateral knee pain, whereas 46 patients had bilateral knee pain. Eighty percent (146/183) reported at least one or more additional sources of chronic pain (back, shoulder, and others). The average opioid use at baseline was 50 mg morphine sulfate equivalents (median 30 mg). The average baseline pain scores were 8.5, which decreased to 2.2 after the geniculate local anesthetic block, and to 4.2 after CRFA. A total of 65% of the patients claimed > 50% pain relief, whereas 77% had 2 or more Visual Analog Scale points decrease, and 26 (14%) patients reported no pain at all after CRFA. The mean duration of > 50% pain relief after CRFA was 12.5 months (range 0-35 months). There was no significant decrease of opioid use. Patients who underwent a repeated procedure (n = 43) achieved a similar pain relief (P = 0.402). We could not find a statistical difference in geniculate CRFA outcomes between the group who had total knee arthroplasty (TKA; n = 21) and maintained chronic knee pain and patients who had no prior surgery (P = 0.542). Retrospective nature of the study. This study demonstrates the clinical effectiveness of CRFA in the treatment of chronic knee pain from osteoarthritis, and even in those patients who maintained chronic knee pain after TKA. Our real-life data seems to agree with data previously published in a randomized controlled trial, despite the fact that this was quite a heterogenous patient population with various sources of chronic pain. Radiofrequency ablation, chronic knee pain, knee osteoarthritis.


Characteristics of magnetic resonance images of granulomatous meningoencephalomyelitis in 11 dogs.
The characteristics of magnetic resonance imaging (mri) of the brains and spinal cords of 11 dogs with histologically confirmed granulomatous meningoencephalomyelitis (gme) were determined. The lesions were in the brain of eight of the dogs, in the brain and spinal cord of two, and in the spinal cord alone in one dog. A single lesion was present in four of the dogs and multiple lesions were found in six. In one dog with intracranial signs, no visible lesions could be detected on mri. No meningeal enhancement was detected in T1-weighted images post-contrast, or in fluid attenuation inversion recovery (flair) images, but there were histological lesions in the meninges in nine of the dogs. The T2-weighted images and flair sequences were characterised in all cases by hyperintensity, whereas the signal intensity of the lesions on T1-weighted images was variable. After the administration of paramagnetic contrast, some of the lesions showed no enhancement, but others showed marked patterns of enhancement. The lesions in 10 of the dogs were easily identifiable by mri and the images had several unifying characteristics, but they could not be considered disease-specific.


Genetic mouse models of depression.
This chapter focuses on the use of genetically modified mice in investigating the neurobiology of depressive behaviour. First, the behavioural tests commonly used as a model of depressive-like behaviour in rodents are described. These tests include those sensitive to antidepressant treatment such as the forced swim test and the tail suspension test, as well as other tests that encompass the wider symptomatology of a depressive episode. A selection of example mutant mouse lines is then presented to illustrate the use of these tests. As our understanding of depression increases, an expanding list of candidate genes is being investigated using mutant mice. Here, mice relevant to the monoamine and corticotrophin-releasing factor hypotheses of depression are covered as well as those relating to the more recent candidate, brain-derived neurotrophic factor. This selection provides interesting examples of the use of complimentary lines, such as those that have genetic removal or overexpression, and also opposing behavioural changes seen following manipulation of closely related genes. Finally, factors such as the issue of background strain and influence of environmental factors are reflected upon, before considering what can realistically be expected of a mouse model of this complex psychiatric disorder.


Sphingosine-1-phosphate receptor-1 controls venous endothelial barrier integrity in zebrafish.
Endothelial sphingosine-1-phosphate (S1P) receptor-1 (S1P(1)) affects different vascular functions, including blood vessel maturation and permeability. Here, we characterized the role of the zS1P(1) ortholog in vascular development in zebrafish. zS1P(1) is expressed in dorsal aorta and posterior cardinal vein of zebrafish embryos at 24 to 30 hours postfertilization. zS1P(1) downregulation by antisense morpholino oligonucleotide injection causes early pericardial edema, lack of blood circulation, alterations of posterior cardinal vein structure, and late generalized edema. Also, zS1P(1) morphants are characterized by downregulation of vascular endothelial cadherin (VE-cadherin) and Eph receptor EphB4a expression and by disorganization of zonula occludens 1 junctions in posterior cardinal vein endothelium, with no alterations of dorsal aorta endothelium. VE-cadherin knockdown results in similar vascular alterations, whereas VE-cadherin overexpression is sufficient to rescue venous vascular integrity defects and EphB4a downregulation in zS1P(1) morphants. Finally, S1P(1) small interfering RNA transfection and the S1P(1) antagonist (R)-3-amino-(3-hexylphenylamino)-4-oxobutylphosphonic acid (W146) cause EPHB4 receptor down-modulation in human umbilical vein endothelial cells and the assembly of zonula occludens 1 intercellular contacts is prevented by the EPHB4 antagonist TNYL-RAW peptide in these cells. The data demonstrate a nonredundant role of zS1P(1) in the regulation of venous endothelial barrier in zebrafish and identify a S1P(1)/VE-cadherin/EphB4a genetic pathway that controls venous vascular integrity.


IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation.
AKT activation requires phosphorylation of the activation loop (T308) by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and the hydrophobic motif (S473) by the mammalian target of rapamycin complex 2 (mTORC2). We recently observed that phosphorylation of the AKT hydrophobic motif was dramatically elevated, rather than decreased, in mTOR knockout heart tissues, indicating the existence of other kinase(s) contributing to AKT phosphorylation. Here we show that the atypical IκB kinase ε and TANK-binding kinase 1 (IKKε/TBK1) phosphorylate AKT on both the hydrophobic motif and the activation loop in a manner dependent on PI3K signaling. This dual phosphorylation results in a robust AKT activation in vitro. Consistently, we found that growth factors can induce AKT (S473) phosphorylation in Rictor(-/-) cells, and this effect is insensitive to mTOR inhibitor Torin1. In IKKε/TBK1 double-knockout cells, AKT activation by growth factors is compromised. We also observed that TBK1 expression is elevated in the mTOR knockout heart tissues, and that TBK1 is required for Ras-induced mouse embryonic fibroblast transformation. Our observations suggest a physiological function of IKKε/TBK1 in AKT regulation and a possible mechanism of IKKε/TBK1 in oncogenesis by activating AKT.


Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review.
To conduct a systematic review to determine clearance rates and adverse effects of topical imiquimod or fluorouracil therapy in the treatment of nonmelanoma skin cancers such as basal (BCC) and squamous cell carcinoma (SCC), and to develop recommendations for the use of topical imiquimod or fluorouracil to treat BCC and SCC. MEDLINE, CANCERLIT, and Cochrane databases. Prospective, retrospective, and case studies in English containing a minimum of 4 subjects and a 6-month follow-up or posttreatment histologic evaluation. We calculated the rate of clearance and adverse effects for BCC subtypes and invasive and in situ SCC treated with topical imiquimod or fluorouracil. Clearance rates varied by drug regimen, and most of the studies lacked long-term follow-up. Imiquimod use produced the following clearance rates: 43% to 100% for superficial BCC, 42% to 100% for nodular BCC, 56% to 63% for infiltrative BCC, 73% to 88% for SCC in situ, and 71% for invasive SCC. Fluorouracil use produced the following clearance rates: 90% for superficial BCC and 27% to 85% for SCC in situ. Up to 100% and 97% of patients applying imiquimod and fluorouracil, respectively, experienced at least 1 adverse event. Adverse event intensity ranged from mild to severe; erythema, pruritus, and pain were common. Evidence supports the use of topical imiquimod as monotherapy for superficial BCC and topical fluorouracil as monotherapy for superficial BCC and SCC in situ. Based on the available evidence, the strength of any recommendations for the use of these 2 agents in the primary treatment of these tumors is weak. We recommend that their use be limited to patients with small tumors in low-risk locations who will not or cannot undergo treatment with better-established therapies for which long-term clearance rates have been determined. Long-term clinical follow-up is essential for patients treated with topical imiquimod or fluorouracil. Limitations of therapy include high rates of adverse effects, lower clearance rates than other treatment modalities, dependence on patient adherence to treatment, and higher costs than other therapies.


Whole Mitochondrial Genome Sequencing and Re-Examination of a Cytoplasmic Male Sterility-Associated Gene in Boro-Taichung-Type Cytoplasmic Male Sterile Rice.
Nuclear genome substitutions between subspecies can lead to cytoplasmic male sterility (CMS) through incompatibility between nuclear and mitochondrial genomes. Boro-Taichung (BT)-type CMS rice was obtained by substituting the nuclear genome of Oryza sativa subsp. indica cultivar Chinsurah Boro II with that of Oryza sativa subsp. japonica cultivar Taichung 65. In BT-type CMS rice, the mitochondrial gene orf79 is associated with male sterility. A complete sequence of the Boro-type mitochondrial genome responsible for BT-type CMS has not been determined to date. Here, we used pyrosequencing to construct the Boro-type mitochondrial genome. The contiguous sequences were assembled into five circular DNA molecules, four of which could be connected into a single circle. The two resulting subgenomic circles were unable to form a reliable master circle, as recombination between them was scarcely detected. We also found an unequal abundance of DNA molecules for the two loci of atp6. These results indicate the presence of multi-partite DNA molecules in the Boro-type mitochondrial genome. Expression patterns were investigated for Boro-type mitochondria-specific orfs, which were not found in the mitochondria from the standard japonica cultivar Nipponbare. Restorer of fertility 1 (RF1)-dependent RNA processing has been observed in orf79-containing RNA but was not detected in other Boro-type mitochondria-specific orfs, supporting the conclusion that orf79 is a unique CMS-associated gene in Boro-type mitochondria.


Cessation of Cryptosporidium-associated diarrhea in an acquired immunodeficiency syndrome patient after treatment with hyperimmune bovine colostrum.
Cryptosporidium is a parasite of the human gastrointestinal tract that can cause life-threatening diarrhea in immunodeficient patients. Although more than 80 agents have been tried with occasional anecdotal success, treatment remains primarily limited to hydration. A 38-yr-old homosexual man with antibody to human immunodeficiency virus and Cryptosporidium-related diarrhea is described. The patient excreted 6-12 L of stool per day for at least 3 mo, 2 of them spent in the hospital. Trials with more than 6 antidiarrheal medications were ineffective. The patient received bovine colostrum hyperimmune to Cryptosporidium by direct duodenal infusion. During infusion, the patient's fecal output decreased to less than 2 L per day, and 48 h after treatment, stools were formed and oocysts to Cryptosporidium were absent. The patient remained asymptomatic for 3 mo. Hyperimmune bovine colostrum offers an exciting new therapy for cryptosporidiosis; controlled trials to establish efficacy should be undertaken and the active factor(s) characterized.


What makes Ras an efficient molecular switch: a computational, biophysical, and structural study of Ras-GDP interactions with mutants of Raf.
Ras is a small GTP-binding protein that is an essential molecular switch for a wide variety of signaling pathways including the control of cell proliferation, cell cycle progression and apoptosis. In the GTP-bound state, Ras can interact with its effectors, triggering various signaling cascades in the cell. In the GDP-bound state, Ras looses its ability to bind to known effectors. The interaction of the GTP-bound Ras (Ras(GTP)) with its effectors has been studied intensively. However, very little is known about the much weaker interaction between the GDP-bound Ras (Ras(GDP)) and Ras effectors. We investigated the factors underlying the nucleotide-dependent differences in Ras interactions with one of its effectors, Raf kinase. Using computational protein design, we generated mutants of the Ras-binding domain of Raf kinase (Raf) that stabilize the complex with Ras(GDP). Most of our designed mutations narrow the gap between the affinity of Raf for Ras(GTP) and Ras(GDP), producing the desired shift in binding specificity towards Ras(GDP). A combination of our best designed mutation, N71R, with another mutation, A85K, yielded a Raf mutant with a 100-fold improvement in affinity towards Ras(GDP). The Raf A85K and Raf N71R/A85K mutants were used to obtain the first high-resolution structures of Ras(GDP) bound to its effector. Surprisingly, these structures reveal that the loop on Ras previously termed the switch I region in the Ras(GDP).Raf mutant complex is found in a conformation similar to that of Ras(GTP) and not Ras(GDP). Moreover, the structures indicate an increased mobility of the switch I region. This greater flexibility compared to the same loop in Ras(GTP) is likely to explain the natural low affinity of Raf and other Ras effectors to Ras(GDP). Our findings demonstrate that an accurate balance between a rigid, high-affinity conformation and conformational flexibility is required to create an efficient and stringent molecular switch.


Long-Term Results of Patellar Bone-Grafting for Severe Patellar Bone Loss During Revision Total Knee Arthroplasty.
There is no consensus on managing severe patellar bone loss after total knee arthroplasty. We previously described an initial series involving a novel technique of patellar bone-grafting with a short follow-up. The purpose of this study was to determine long-term survivorship and the radiographic and clinical results of patellar bone-grafting during revision total knee arthroplasty in a larger series with an extended follow-up. We identified 90 patients from a single institution who underwent 93 patellar bone-grafting procedures for severe patellar bone loss from 1997 to 2014. The mean age of the patients was 70 years, and 46% of patients were female. Forty-five knees (48%) underwent first-time revisions, and 19 knees (20%) had undergone a failed attempt at patellar resurfacings. Intraoperative patellar caliper thickness increased from a mean of 7 to 25 mm after patellar bone-grafting (p < 0.01). Radiographic review determined changes in patellar height, tracking, and remodeling. Knee Society scores (KSSs) were calculated. The mean follow-up was 8 years (range, 2 to 18 years). Kaplan-Meier methods determined survivorship free of any revision and any reoperation. Cox proportional hazards analysis determined predictive factors for failure. Survivorship free of patellar revision was 96% at 10 years. Survivorship free of any revision was 84% at 10 years. Survivorship free of any reoperation was 78% at 10 years. Increasing patient age was the only protective factor against further patellar revision (hazard ratio, 0.95; p < 0.01). When comparing initial radiographs with final radiographs, patellar height decreased from 22 to 19 mm (p < 0.01), 80% compared with 59% of patellae articulated centrally in the trochlea (p = 0.01), and 32% compared with 77% had remodeling over the lateral femoral condyle (p < 0.01). Anterior knee pain decreased from 51% to 27% postoperatively (p = 0.01). The mean knee flexion improved from 101° to 108° (p = 0.03). The mean KSS improved from 50 to 85 points (p < 0.01). Reliable long-term clinical results can be expected with patellar bone-grafting for severe patellar bone loss during revision total knee arthroplasty. Pain, range of motion, and other reported outcomes improve despite radiographic changes to patellar height, tracking, and remodeling. This technique is a durable and reliable option when standard patellar resurfacing is not possible. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Needle exchange programs for the prevention of hepatitis C virus infection in people who inject drugs: a systematic review with meta-analysis.
Previous research on the effectiveness of needle exchange programs (NEP) in preventing hepatitis C virus (HCV) in people who inject drugs (PWID) has shown mixed findings. The purpose of this study was to use the meta-analytic approach to examine the association between NEP use and HCV prevention in PWIDs. Study inclusion criteria were (1) observational studies, (2) PWIDs, (3) NEP use, (4) HCV status ascertained by serological testing, (5) studies published in any language since January 1, 1989, and (6) data available for measures of association. Studies were located by searching four electronic databases and cross-referencing. Study quality was assessed using the Newcastle Ottawa (NOS) scale. A ratio measure of association was calculated for each result from cohort or case-control studies and pooled using a random effects model. Odds ratio (OR) and hazard ratio (HR) models were analyzed separately. Results were considered statistically significant if the 95% confidence interval (CI) did not cross 1. Heterogeneity was estimated using Q and I 2 with alpha values for Q ≤ 0.10 considered statistically significant. Of the 555 citations reviewed, 6 studies containing 2437 participants were included. Studies had an average NOS score of 7 out of 9 (77.8%) stars. Concerns over participant representativeness, unclear adjustments for confounders, and bias from participant nonresponse and loss to follow-up were noted. Results were mixed with the odds ratio model indicating no consistent association (OR, 0.51, 95% CI, 0.05-5.15), and the hazard ratio model indicating a harmful effect (HR, 2.05, 95% CI, 1.39-3.03). Substantial heterogeneity (p ≤ 0.10) and moderate to large inconsistency (I 2 ≥ 66%) were observed for both models. The impact of NEPs on HCV prevention in PWIDs remains unclear. There is a need for well-designed research studies employing standardized criteria and measurements to clarify this issue. PROSPERO CRD42016035315.


Endoscopic transsphenoidal treatment of hormonally active pituitary adenomas.
The paper presents endoscopic surgical technique used in the treatment of hormonally active pituitary adenomas and assessment of the method in terms of its effectiveness and safety. In 217 cases the surgery was performed due to pituitary adenomas applying the technique developed by Jho and Carrau, with our own modifications. 70 patients were treated for hormonally active adenomas. The group consisted of 36 somatotrophic adenomas, 21 prolactinomas and 13 corticotrophic adenomas. There were 51 females and 19 males with mean age of 42.6 years (range 11-77 years). The follow-up period was between 7 and 56 months (mean - 34 months). The effectiveness and occurrence of complications were confirmed on the basis of neurosurgical, laryngological, endocrinological, ophthalmological examinations and neuroimaging. Biochemical and neurosurgical criteria for complete resection were obtained in 21 (58.3%) of 36 patients with all somatotrophic adenomas. In the group of prolactinomas complete resection was achieved in 17 (80.9%) of 21 patients. Of the 13 patients with Cushing's disease 11 (84.6%) were cured. In the studied group there were no deaths. In the postoperative course only 2 (2.8%) patients suffered liquorrhoeas and new anterior lobe pituitary insufficiency was noted in 8 (11.4%) cases. Meningitis was noted in 1 (1.4%) case and another 1 (1.4%) patient had epistaxis which required repeated endoscopic surgery. Endoscopic technique is an effective method of treatment of hormonally active pituitary adenomas. It is characterised as being minimal invasive and has a low severe complication rate.


Use of image registration and fusion algorithms and techniques in radiotherapy: Report of the AAPM Radiation Therapy Committee Task Group No. 132.
Image registration and fusion algorithms exist in almost every software system that creates or uses images in radiotherapy. Most treatment planning systems support some form of image registration and fusion to allow the use of multimodality and time-series image data and even anatomical atlases to assist in target volume and normal tissue delineation. Treatment delivery systems perform registration and fusion between the planning images and the in-room images acquired during the treatment to assist patient positioning. Advanced applications are beginning to support daily dose assessment and enable adaptive radiotherapy using image registration and fusion to propagate contours and accumulate dose between image data taken over the course of therapy to provide up-to-date estimates of anatomical changes and delivered dose. This information aids in the detection of anatomical and functional changes that might elicit changes in the treatment plan or prescription. As the output of the image registration process is always used as the input of another process for planning or delivery, it is important to understand and communicate the uncertainty associated with the software in general and the result of a specific registration. Unfortunately, there is no standard mathematical formalism to perform this for real-world situations where noise, distortion, and complex anatomical variations can occur. Validation of the software systems performance is also complicated by the lack of documentation available from commercial systems leading to use of these systems in undesirable 'black-box' fashion. In view of this situation and the central role that image registration and fusion play in treatment planning and delivery, the Therapy Physics Committee of the American Association of Physicists in Medicine commissioned Task Group 132 to review current approaches and solutions for image registration (both rigid and deformable) in radiotherapy and to provide recommendations for quality assurance and quality control of these clinical processes.


Overexpression of CD64 on CD14++CD16- and CD14++CD16+ monocytes of rheumatoid arthritis patients correlates with disease activity.
It is well-known that monocytes are a heterogeneous cell population and different monocyte subsets play important roles in rheumatoid arthritis (RA). Cluster of differentiation (CD)64 is one of Fc receptor, which initiates immunological and inflammatory reactions. However, the roles in RA remain to be elucidated. In the present study, the expression of CD64, CD40, CD163, CD206, HLA-DR, CD80 and CD86 on monocytes and the expression of CD64 on monocyte subsets were determined by flow cytometry. The expression of CD64 on monocyte subsets in patients with RA was further analyzed for their correlation with markers of autoimmune response, inflammation, disease activity of RA and serum cytokines. Compared to the health volunteers, the expression of CD64 on monocytes and each monocyte subset were significantly elevated in RA patients. The expression of CD64 on CD14++CD16- and CD14++CD16+ monocytes were positively correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) and disease activity score 28 (DAS28). Furthermore, the expression of CD64 on CD14++CD16+ monocytes was found to be associated with the serum level of IL-6. In conclusions, these data demonstrated the expression of CD64 on CD14++CD16- and CD14++CD16+ monocytes are elevated and associated with the disease activity in RA.


Influence of stimulus parameters on human postural responses.
1. The role of sensory information in shaping muscle activation patterns to postural perturbations in humans was investigated by varying velocity, amplitude, or duration of the perturbing stimulus. Ten normal subjects were exposed to 120 backward translations of the support surface under conditions of varying velocities (10-35 cm/s, constant amplitude), varying amplitudes (1.2-12 cm, constant velocity), or varying durations (40-800 ms). The effects of perturbation parameters on movement kinematics and EMG latencies, patterns, and integrated areas in six trunk and leg muscles were examined. Integrated EMG activity was normalized across subjects and the early (first 75 ms), middle (second 75 ms), and late (last 350 ms) components were analyzed separately. 2. Ankle, knee, and hip angle trajectories and surface reactive forces suggest that a relatively consistent movement strategy was scaled to the perturbation velocities and amplitudes applied. 3. Short-duration perturbations (75 ms) evoked a single burst of muscle activity (75-100 ms duration) in gastrocnemius, hamstrings, paraspinal, and rectus abdominis muscles at latencies too long to be explained by simple stretch reflexes. EMG latencies, patterns, and integrated areas were independent of the velocity and amplitude of the short-duration perturbations, suggesting a minimal time to incorporate peripheral velocity information into the triggered response. 4. For translations lasting longer than 75 ms, the integrated areas of the early agonist EMG bursts were positively correlated with stimulus velocity. The integrated area of later, more tonic EMG components were best correlated with stimulus amplitude. These relationships were found in both distal (stretched) muscles and in proximal muscles. Absolute latencies (94-145 ms), intersegmental latencies (18-29 ms), and burst durations (75-100 ms) were not influenced by the velocity or amplitude of the stimulus. 5. These results suggest that the spatial and temporal organization of automatic postural responses may be organized independently of response intensity. Within a particular spatial-temporal pattern, the amount of muscle activation appears to be adjusted by sensory information, which specifies velocity and amplitude of the perturbation.


Longitudinal analysis is more powerful than cross-sectional analysis in detecting genetic association with neuroimaging phenotypes.
Most existing genome-wide association analyses are cross-sectional, utilizing only phenotypic data at a single time point, e.g. baseline. On the other hand, longitudinal studies, such as Alzheimer's Disease Neuroimaging Initiative (ADNI), collect phenotypic information at multiple time points. In this article, as a case study, we conducted both longitudinal and cross-sectional analyses of the ADNI data with several brain imaging (not clinical diagnosis) phenotypes, demonstrating the power gains of longitudinal analysis over cross-sectional analysis. Specifically, we scanned genome-wide single nucleotide polymorphisms (SNPs) with 56 brain-wide imaging phenotypes processed by FreeSurfer on 638 subjects. At the genome-wide significance level P < 1.8 x 10(9)) or a less stringent level (e.g. P < 10(7)), longitudinal analysis of the phenotypic data from the baseline to month 48 identified more SNP-phenotype associations than cross-sectional analysis of only the baseline data. In particular, at the genome-wide significance level, both SNP rs429358 in gene APOE and SNP rs2075650 in gene TOMM40 were confirmed to be associated with various imaging phenotypes in multiple regions of interests (ROIs) by both analyses, though longitudinal analysis detected more regional phenotypes associated with the two SNPs and indicated another significant SNP rs439401 in gene APOE. In light of the power advantage of longitudinal analysis, we advocate its use in current and future longitudinal neuroimaging studies.


Tumor dormancy and cell signaling. V. Regrowth of the BCL1 tumor after dormancy is established.
The majority of BALB/c mice immunized with the BCL1 lymphoma-derived idiotype (Id+) IgM and subsequently challenged with BCL1 tumor cells develop a state of tumor dormancy. The vast majority of dormant lymphoma cells are in cell cycle arrest, but there are also residual replicating cells. In the present studies, we attempted to define features of both the dormant lymphoma cells and the host that lead to escape from dormancy. Escape from dormancy occurs at a steady rate over a 2-year period, suggesting that it is a stochastic process. We found that, in the majority of mice, escape was due to the emergence of genetic variants that were no longer susceptible to the anti-Id-mediated induction of dormancy. Ten percent of these variants were Id-; the remainder were Id+ but could grow in the presence of anti-Id antibodies, suggesting that there were mutations in molecules involved in one or more mIg-mediated negative-signaling pathways. In two of five such escapees, alterations in either Syk, HS1, and/or Lyn were observed. In a small percentage of mice, a low titer of circulating anti-Id antibody before tumor challenge correlated with a subsequent, more rapid loss of dormancy.


Promoting self-change with alcohol abusers: a community-level mail intervention based on natural recovery studies.
By using a public health approach to the treatment of alcohol problems, this study analyzed the efficacy and cost analysis of two versions of a community-level mail intervention to promote self-change among alcohol abusers who had never sought help or treatment. A total of 825 participants who responded to media solicitations were randomly assigned to one of two interventions: (a) for bibliotherapy/drinking guidelines (n = 411), they were given two pamphlets with information about the effects of alcohol and guidelines for low-risk drinking and self-monitoring, and (b) for motivational enhancement/personalized feedback (n = 414), personalized advice/feedback was provided on the basis of the participants' assessment of their drinking and related behaviors. Although both groups exhibited significant reductions in drinking from 1 year before to 1 year after intervention, there were no significant differences between the two interventions for any variable. This suggests that the materials, irrespective of whether they were personalized, facilitated the reduction of drinking. Cost analysis revealed that a brief mail intervention could reduce drinking at a very low cost per participant (US$46 to US$97). A brief community-level mail intervention for problem drinkers who had never sought treatment resulted in sizable reductions in alcohol use over the year after the intervention compared with the year before. Furthermore, many of those with poorer outcomes engaged in a natural stepped-care process by seeking help. These results, coupled with the low cost to deliver the intervention, suggest that public health campaigns could have a substantial effect on reducing alcohol problems and associated costs as well as getting some individuals into treatment. Such an approach would represent a shift from the alcohol field's long-standing clinical focus to a broader public health perspective.


Role of nonfeminizing estrogens in brain protection from cerebral ischemia: an animal model of Alzheimer's disease neuropathology.
Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in in vitro assays using a library of more than 70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large, bulky group at the C2 and/or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C, or D rings either reduced or did not markedly change neuroprotection. For this library of compounds, there was a negative correlation between ER binding and neuroprotection, as the more potent compounds showed weaker or no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. Finally, estradiol protected brains from insult-induced Alzheimer's disease (AD) neuropathology, including activation of apoptosis, stimulation of Abeta production, hyperphosphorylation of tau, activation of cyclin-dependent kinases, and activation of catastrophic attempts at neuronal mitosis. Collectively, these results demonstrate that nonfeminizing estrogens are neuroprotective and protect the brain from the induction of AD-like neuropathology in an animal model. These features of nonfeminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, because they are not expected to show the side effects of chronic estrogen therapy that are ER mediated in the liver, uterus, and breast.


A quantitative electrophysiological study of uraemic neuropathy. Diabetic and renal neuropathies compared.
The numbers of functioning motor units and the parameters of the electrically evoked motor unit potentials in the extensor digitorum brevis muscles of 30 patients on chronic haemodialysis for renal failure were obtained using recently introduced quantitative electrophysiological techniques. Measurements of the distal motor latencies and motor nerve conduction velocities in the lateral popliteal nerves of the same patients are also presented. The results support the presence of a "dying back" type of neuropathy in uraemia, with a preferential involvement of the fastest conducting motor axons. Collateral reinnervation and compensatory increase in size of surviving motor units is relatively impaired in uraemic neuropathy in comparison with a similar study on diabetic neuropathy. The significance of paranodal and segmental demyelination in producing abnormalities of conduction velocity in these neuropathies is discussed.


Living into the imagined body: how the diagnostic image confronts the lived body.
In this paper I will show how the medical image, presented to the patient by the physician, participates in medicine's cold culture of abstraction, objectification and mandated normativity. I begin by giving a brief account of the use of anatomical imaging since the Renaissance to show how images have historically functioned in contrast to how they are currently used in medical practice. Next, I examine how contemporary medical imaging techniques participate in a kind of knowledge production that objectifies the human body. Finally, I elucidate how physicians ought to place the medical image within the context of the lived body so as to create a healing relationship with the patient. In all this I hope to show that the medical image, far from a piece of objective data, testifies to the interplay of particular beliefs, practices and doctrines contemporary medicine holds dear. To best treat her patient, the physician must appreciate the influence of these images and appropriately place them within the context of the patient's lived experience.


Soluble invasion plasmid antigen C (IpaC) from Shigella flexneri elicits epithelial cell responses related to pathogen invasion.
Shigella flexneri invades colonic epithelial cells by pathogen-induced phagocytosis. The three proposed effectors of S. flexneri internalization are invasion plasmid antigens B (IpaB), IpaC, and IpaD, which are encoded on the pathogen's 230-kb virulence plasmid and translocated to the extracellular milieu via the Mxi-Spa translocon. To date, there are no definitive functional data for any purified Ipa protein. Here, we describe the first characterization of highly purified recombinant IpaC, which elicits numerous epithelial cell responses related to events that take place during pathogen invasion. 125I-labeled IpaC binds cultured Henle 407 intestinal cells with an apparent dissociation constant in the low micromolar range. Moreover, incubation of epithelial cells with IpaC results in general changes in cellular phosphoprotein content, demonstrating this protein's ability to influence cellular protein kinase activities. These results contrast dramatically with those seen for recombinant IpaD, which does not bind to or induce detectable changes in the normal activities of cultured epithelial cells. In addition to influencing host cell activities, preincubation of epithelial cells with purified IpaC enhances uptake of S. flexneri by host cells. A similar result is seen when the cells are preincubated with a highly concentrated water extract of virulent S. flexneri 2a (strain 2457T). Interestingly, soluble IpaC also appears to promote uptake of the noninvasive S. flexneri 2a strain BS103. Purified IpaD failed to enhance the uptake of virulent S. flexneri and did not facilitate uptake of BS103. Taken together, the data suggest that IpaC is a potential effector of the host cell biological activities and may be responsible for entry of S. flexneri into target cells.


Metformin reduces systemic methylglyoxal levels in type 2 diabetes.
Methylglyoxal (MG) is a reactive alpha-dicarbonyl that is thought to contribute to diabetic complications either as a direct toxin or as a precursor for advanced glycation end products. It is produced primarily from triose phosphates and is detoxified to D-lactate (DL) by the glyoxalase pathway. Because guanidino compounds can block dicarbonyl groups, we have investigated the effects of the diamino biguanide compound metformin and of hyperglycemia on MG and its detoxification products in type 2 diabetes. MG and DL were measured by high-performance liquid chromatography in plasma from 57 subjects with type 2 diabetes. Of these subjects, 27 were treated with diet, sulfonylureas, or insulin (nonmetformin), and 30 were treated with metformin; 28 normal control subjects were also studied. Glycemic control was determined by HbA1c. MG was significantly elevated in diabetic subjects versus the normal control subjects (189.3 +/- 38.7 vs. 123.0 +/- 37 nmol/l, P = 0.0001). MG levels were significantly reduced by high-dosage (1,500-2,500 mg/day) metformin (158.4 +/- 44.2 nmol/l) compared with nonmetformin (189.3 +/- 38.7 nmol/l, P = 0.03) or low-dosage (< or = 1,000 mg/day) metformin (210.98 +/- 51.0 nmol/l, P = 0.001), even though the groups had similar glycemic control. Conversely, DL levels were significantly elevated in both the low- and high-dosage metformin groups relative to the nonmetformin group (13.8 +/- 7.7 and 13.4 +/- 4.6 vs. 10.4 +/- 3.9 micromol/l, P = 0.03 and 0.06, respectively). MG correlated with rising HbA1c levels (R = 0.4, P = 0.03, slope = 13.2) in the nonmetformin subjects but showed no increase with worsening glycemic control in the high-dosage metformin group (R = 0.0004, P = 0.99, slope = 0.02). In conclusion, MG is elevated in diabetes and relates to glycemic control. Metformin reduces MG in a dose-dependent fashion and minimizes the effect of worsening glycemic control on MG levels. To the extent that elevated MG levels lead to their development, metformin treatment may protect against diabetic complications by mechanisms independent of its antihyperglycemic effect.


Progesterone synthesis and myelin formation by Schwann cells.
Progesterone is shown here to be produced from pregnenolone by Schwann cells in peripheral nerves. After cryolesion of the sciatic nerve in male mice, axons regenerate and become myelinated. Blocking either the local synthesis or the receptor-mediated action of progesterone impaired remyelination. Administration of progesterone or its precursor, pregnenolone, to the lesion site increased the extent of myelin sheath formation. Myelination of axons was also increased when progesterone was added to cultures of rat dorsal root ganglia. These observations indicate a role for locally produced progesterone in myelination, demonstrate that progesterone is not simply a sex steroid, and suggest a new therapeutic approach to promote myelin repair.


Raman spectroscopy of oxidized and reduced nicotinamide adenine dinucleotides.
We have measured the Raman spectra of oxidized nicotinamide adenine dinucleotide, NAD+, and its reduced form, NADH, as well as a series of fragments and analogues of NAD+ and NADH. In addition, we have studied the effects of pH as well as deuteration of the exchangeable protons on the Raman spectra of these molecules. In comparing the positions and intensities of the peaks in the fragment and analogue spectra with those of NADH and NAD+, we find that it is useful to consider these large molecules as consisting of component parts, namely, adenine, two ribose groups, two phosphate groups, and nicotinamide, for the purpose of assigning their spectral features. The Raman bands of NADH and NAD+ are found generally to arise from molecular motions in one or another of these molecular moieties, although some peaks are not quite so easily identified in this way. This type of assignment is the first step in a detailed understanding of the Raman spectra of NAD+ and NADH. This is needed to understand the binding properties of NADH and NAD+ acting as coenzymes with the NAD-linked dehydrogenases as deduced recently by using Raman spectroscopy.


Utilization of triacylglycerol-rich lipoproteins by the working rat heart: routes of uptake and metabolic fates.
Very-low-density lipoprotein (VLDL) and chylomicrons (CMs) transport triacylglycerol (TAG) to peripheral tissues. Lipoprotein-TAG may gain access to target cells by lipoprotein lipase (LPL) hydrolysis or via receptor-mediated uptake; the principal routes of entry of VLDL and CM into heart are unknown, and different routes of entry may result in different metabolic fates. To examine this, isolated working rat hearts were perfused with rat VLDL and CMs, dual-labelled with [3H]TAG and [14C]cholesterol. Uptake and utilization of CM-TAG were significantly greater than VLDL-TAG, but both were decreased significantly (more than halved) by tetrahydrolipstatin (THL, an inhibitor of lipoprotein lipase). By contrast, uptake of VLDL-cholesterol was much higher than CM-cholesterol (P < 0.01), and suramin (a lipoprotein receptor antagonist) decreased cholesterol uptake of both forms. CM-TAG oxidation rate was more than 4-fold higher than VLDL-TAG oxidation. However, suramin decreased TAG oxidation from both VLDL and CM without affecting TAG uptake or total utilization, suggesting that the TAG gaining access through receptor-mediated pathways is preferentially 'channelled' towards oxidation. Most (79%) CM-TAG was oxidized whilst the proportion of VLDL-TAG oxidized was only about half (49%). In the presence of suramin, there was a significant increase in esterification (incorporation of assimilated [3H]TAG into myocardial tissue [3H]lipids, mainly TAG) of assimilated TAG from both VLDL and CMs, again suggesting that receptor-mediated TAG uptake is directed towards oxidation rather than esterification. The importance of this relatively small pool of TAG is indicated by the fact that cardiac mechanical function declined markedly when lipoprotein receptors were inhibited. These results suggest that CMs, most fatty acids of which gain access into cardiomyocytes through LPL-mediated hydrolysis, are the major supplier of TAG for hearts to oxidize; however, the metabolic fate of VLDL was split evenly between oxidation and deposition as myocardial tissue lipid. Most importantly, VLDL may play a regulatory role in heart lipid metabolism through a lipoprotein receptor-mediated mechanism.


Saprochaete capitata as an emerging fungus among patients with haematological malignencies.
Saprochaete capitata is a very rare pathogen that causes invasive disease particularly in patients with haematological malignancies. We recognised a clustering of S. capitata fungaemia in recent years. So, we report our 6-year surveillance study of fungaemia among patients with haematological malignancies and haematopoietic stem cell transplant. We performed a retrospective and observational study. Hospitalised patients aged >18 years with haematological malignancies were included in the study. A total of 51 fungaemia episodes of 47 patients were analysed. The characteristics of fungaemia in patients with S. capitata compared to patients with candidemia. Median duration of neutropenia was 21.5 days in patients with S. capitata fungaemia, whereas this duration was significantly shorter in patients with candidemia (8 days). Interval between first and last positive culture was significantly longer in patients with S. capitata fungaemia (P < 0.05). Previous use of caspofungin was significantly more common in patients with S. capitata fungaemia. Thirty-day mortality was found 40% for patients with candidemia, whereas it was 39% for patients with S. capitata. In conclusion, despite its limitations this study showed that a novel and more resistant yeast-like pathogen become prevalent due to use of caspofungin in patients with long-lasting neutropenia which was the most noteworthy finding of this 6-year surveillance study.


Sequencing detects human papillomavirus in some apparently HPV-negative invasive cervical cancers.
Introduction. Cervical cancer is caused by human papillomavirus (HPV), but some cases may test HPV-negative. We previously tested 2850 Swedish cases and found that 394/2850 (13.8 %) cases tested HPV DNA-negative by PCR. Sequencing is the most thorough method to assess HPV status.Aim. We wished to assess whether deep sequencing might detect HPV sequences among these HPV-negative cervical cancer specimens, and to increase the likelihood of detecting transcriptionally active infections.Methodology. Out of the 2850 cancer cases, we sequenced a random sample of 92 HPV PCR-negative cervical cancers and 34 HPV PCR-positive cervical cancers. Four pools of blank blocks were sequenced as negative controls. To enrich for mRNA - a hallmark of active viral infection - the samples were extracted, reverse-transcribed, rRNA-depleted and then sequenced using the NovaSeq 6000 system (Illumina, USA). High-quality reads were aligned to the human genome and non-human reads were queried against HPV proteins.Results. We obtained a median of 23 million paired reads per sample. HPV was detected in 31/34 HPV PCR-positive cases. Among cases negative for HPV by PCR, 48/92 (52.2 %) contained HPV sequences, with HPV33 being the most commonly detected type among these (14/48 cases, 29.2 %). Comparison of the ratio of exon and intron sequences found that the sequenced material contained both DNA and RNA. Splice junctions were detected in 12 cases.Conclusion. Apparently, some cervical cancers contain HPV that is difficult to detect by PCR. Sequencing may be a helpful tool for additional quality assurance for HPV testing methods.


Comparison of native anatomy with recommended safe component orientation in total hip arthroplasty for primary osteoarthritis.
The adverse consequences of impingement, dislocation, and implant wear have stimulated increasing interest in accurate component orientation in total hip arthroplasty and hip resurfacing. The aims of the present study were to define femoral and acetabular orientation in a cohort of patients with primary hip osteoarthritis and to determine whether the orientation of their native hip joints corresponded with established recommendations for implantation of prosthetic components. We retrospectively evaluated a consecutive series of 131 preoperative computed tomography (CT) scans of patients with primary end-stage hip osteoarthritis (fifty-seven male and seventy-four female patients; mean age, sixty years). Patients were positioned according to a standardized protocol. Accounting for pelvic tilt, three-dimensional acetabular orientation was determined in the anatomical reference frame. Moreover, three-dimensional femoral version was measured. Differences in native anatomy between male and female patients were assessed with use of nonparametric tests. Native anatomy was evaluated with reference to the "safe zone" as described by Lewinnek et al. and to a "safe" combined anteversion of 20° to 40°. In the entire cohort, the mean femoral anteversion was 13° and the mean acetabular anteversion was 19°. No significant differences in femoral, acetabular, or combined (femoral and acetabular) anteversion were observed between male and female patients. The mean acetabular inclination was 62°. There was no significant difference in acetabular inclination between female and male patients. We did not observe a correlation among acetabular inclination, acetabular anteversion, and femoral anteversion. Ninety-five percent (125) of the native acetabula were classified as being within the safe anteversion zone, whereas only 15% (nineteen) were classified as being within the safe inclination zone. Combined anteversion was within the safe limits in 63% (eighty-three) of the patients. However, only 8% (ten) of the cases in the present cohort met the criteria of both "safe zone" definitions (that of Lewinnek et al. and combined anteversion). Acetabular anteversion of the osteoarthritic hip as defined by the native acetabular rim typically matches the recommended component "targets" for cup insertion. There was no specific relationship among native acetabular inclination, acetabular anteversion, and femoral anteversion. Neither native acetabular inclination nor native combined anteversion appears to be related to current implant insertion targets. The present findings of native acetabular and femoral orientation in patients with primary hip osteoarthritis support intraoperative component positioning for total hip arthroplasty.


Consequences of captivity: health effects of far East imprisonment in World War II.
Though medical consequences of war attract attention, the health consequences of the prisoner-of-war (POW) experience are poorly researched and appreciated. The imprisonment of Allied military personnel by the Japanese during the World War II provides an especially dramatic POW scenario in terms of deprivation, malnutrition and exposure to tropical diseases. Though predominantly British, these POWs also included troops from Australia, Holland and North America. Imprisonment took place in various locations in Southeast Asia and the Far East for a 3.5-year period between 1942 and 1945. Nutritional deficiency syndromes, dysentery, malaria, tropical ulcers and cholera were major health problems; and supplies of drugs and medical equipment were scarce. There have been limited mortality studies on ex-Far East prisoners (FEPOWs) since repatriation, but these suggest an early (up to 10 years post-release) excess mortality due to tuberculosis, suicides and cirrhosis (probably related to hepatitis B exposure during imprisonment). In terms of morbidity, the commonest has been a psychiatric syndrome which would now be recognized as post-traumatic stress disorder--present in at least one-third of FEPOWs and frequently presenting decades later. Peptic ulceration, osteoarthritis and hearing impairment also appear to occur more frequently. In addition, certain tropical diseases have persisted in these survivors--notably infections with the nematode worm Strongyloides stercoralis. Studies 30 years or more after release have shown overall infection rates of 15%. Chronic strongyloidiasis of this type frequently causes a linear urticarial 'larva currens' rash, but can potentially lead to fatal hyperinfection if immunity is suppressed. Finally, about 5% of FEPOW survivors have chronic nutritional neuropathic syndromes--usually optic atrophy or sensory peripheral neuropathy (often painful). The World War II FEPOW experience was a unique, though often tragic, accidental experiment into the longer term effects of under nutrition and untreated exotic disease. Investigation of the survivors has provided unique insights into the medical outcome of deprivation in tropical environments.


Effect of socioeconomic risk factors on the difference in prevalence of diabetes between rural and urban populations in Bangladesh.
To compare the prevalence of diabetes between the poor and rich of rural and urban populations in Bangladesh. A total of 1,052 subjects from urban and 1,319 from rural communities (age > or = 20 years) of different socioeconomic classes were investigated. Capillary blood glucose levels, fasting and 2 h after a 75-g glucose drink (2-h blood glucose [BG]), were measured. Height, weight, waist, hips, and blood pressure were also measured. Age-adjusted (30-64 years) prevalence of NIDDM was higher in urban (7.97% with 95% CI 6.17-9.77) than in rural subjects (3.84%, CI 2.61-5.07), whereas impaired glucose tolerance (IGT) prevalence was higher in rural subjects. In either urban or rural areas, the highest prevalence of NIDDM was observed among the rich, and the lowest prevalence was observed among the poor socioeconomic classes. The rural rich had much higher prevalence of IGT than their urban counterpart (16.5 vs. 4.4%, CI 6.8-17.4). Increased age was an important risk factor for IGT and NIDDM in both rural and urban subjects, whereas the risk related to higher BMI and waist-to-hip ratio (WHR) was less significant in rural than urban subjects. Using logistic regression and adjusting for age, sex, and social class, the urban subjects had no excess risk for NIDDM. In contrast, an excess risk for glucose intolerance (2-h BG > or = 7.8 mmol/l) was observed in the rural subjects. Adjusting for age, sex, and social class, the prevalence of NIDDM among urban subjects did not differ significantly from that among rural subjects. Increased age, higher socioeconomic class, and higher WHR were proven to be independent risk factors for glucose intolerance in either area.


An investigation to assess the potential of CD25highCD4+ T cells to regulate responses to donor alloantigens in clinically stable renal transplant recipients.
Regulatory T cells are enriched within CD25(high)CD4(+) leukocytes, however their role in renal transplant recipients with stable function vs. recipients with biopsy-proven chronic allograft dysfunction remains unclear. We therefore studied the number, phenotype, and function of CD25(high)CD4(+) cells in the peripheral blood of 30 renal transplant recipients of living-related grafts, comprising 15 rejection-free recipients with stable graft function (Group A) and 15 with biopsy-proven chronic graft dysfunction (Group B). A higher absolute number of CD25(high)CD4(+) cells were present in the peripheral blood of rejection-free recipients (Group A) vs. those recipients with chronic graft dysfunction (Group B) (P = 0.019); but there was no significant difference with healthy volunteers (P = 0.084). In carboxyfluorescein diacetate succinimidyl ester-mixed leukocyte culture assays, depletion of CD25(high)CD4(+) revealed active regulation in 11 (74%) of 15 rejection-free recipient samples (Group A) in response to donor- but not third party-leukocytes, whereas no regulatory activity was observed in any samples from recipients with chronic graft dysfunction (Group B). In conclusion, these data provide evidence for the presence of an increased number of CD25(high)CD4(+) T cells with donor-specific regulatory activity in the peripheral blood of renal transplant recipients with stable graft function compared with recipients with chronic graft dysfunction.


D2 dopamine receptor expression and trafficking is regulated through direct interactions with ZIP.
We have used the yeast two-hybrid system to identify protein kinase C-zeta interacting protein (ZIP) as a novel interacting protein for the D(2) dopamine receptor (DAR). This interaction was identified by screening a rat brain cDNA library using the third intracellular loop of the D(2) DAR as bait. A partial-length cDNA encoding ZIP was isolated and characterized as specifically interacting with the third intracellular loop of the D(2) DAR, but not with the third intracellular loops of other DAR subtypes. Biochemical confirmation of the ZIP-D(2) DAR interaction was obtained by expressing the full-length ZIP and D(2) DAR proteins in mammalian cells and demonstrating that they could be co-immunoprecipitated. We further showed that ZIP and the D(2) DAR could be co-immunoprecipitated from endogenous brain tissues. Immunohistochemical analyses further revealed that ZIP and the D(2) DAR were extensively co-localized within numerous neurons in various brain regions. ZIP exists as three protein isoforms of varying length, which are derived from alternative RNA splicing. All three isoforms were found to interact with the D(2) DAR, which allowed for the delineation of the receptor interacting domain to within 38 residues of ZIP. Functionally, over-expression of ZIP was found to result in decreased expression of the D(2) DAR with a corresponding decrease in receptor modulation of cAMP accumulation. Confocal microscopy revealed that ZIP over-expression also lead to an intracellular accumulation of D(2) DAR protein in lysosome compartments. These results suggest that ZIP can physically interact with the D(2) DAR leading to increased intracellular trafficking to lysosomes with subsequent down-regulation of receptor expression and function.


Structure and activity of a bacterial defense-associated 3'-5' exonuclease.
The widespread CBASS (cyclic oligonucleotide-based anti-phage signaling system) immune systems in bacteria protect their hosts from bacteriophage infection by triggering programmed cell death. CBASS systems all encode a cyclic oligonucleotide synthase related to eukaryotic cGAS but use diverse regulators and effector proteins including nucleases, phospholipases, and membrane-disrupting proteins to effect cell death. Cap18 is a predicted 3'-5' exonuclease associated with hundreds of CBASS systems, whose structure, biochemical activities, and biological roles remain unknown. Here we show that Cap18 is a DEDDh-family exonuclease related to the bacterial exonucleases RNase T and Orn and has nonspecific 3'-5' DNA exonuclease activity. Cap18 is commonly found in CBASS systems with associated CapW or CapH+CapP transcription factors, suggesting that it may coordinate with these proteins to regulate CBASS transcription in response to DNA damage. These data expand the repertoire of enzymatic activities associated with bacterial CBASS systems and provide new insights into the regulation of these important bacterial immune systems.


Laser beam scanning by rotary mirrors. II. Conic-section scan patterns.
Part II of this study is an application of the general theory of Part I to the following scanners: the galvanometer-based scanner, the paddle scanner, and the regular polygon. The scan field produced by these scanners is (or approximates) a circular cone. Therefore the scan pattern on the plane of observation can be one of the following curves, circle, ellipse, parabola, or hyperbola, depending on the position and orientation of the plane. Special topics to be addressed are (1) the effect of input offset, (2) the locus of the instantaneous scan center and the waist of the scan field, (3) the scanning on curved surfaces, and (4) the generalization of the scan-field expression. In Part III, X-Y scanning will be studied.


Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.
HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.


Relationship of anthropometric and training characteristics with race performance in endurance and ultra-endurance athletes.
A variety of anthropometric and training characteristics have been identified as predictor variables for race performance in endurance and ultra-endurance athletes. Anthropometric characteristics such as skin-fold thicknesses, body fat, circumferences and length of limbs, body mass, body height, and body mass index were bi-variately related to race performance in endurance athletes such as swimmers in pools and in open water, in road and mountain bike cyclists, and in runners and triathletes over different distances. Additionally, training variables such as volume and speed were also bi-variately associated with race performance. Multi-variate regression analyses including anthropometric and training characteristics reduced the predictor variables mainly to body fat and speed during training units. Further multi-variate regression analyses including additionally the aspects of previous experience such as personal best times showed that mainly previous best time in shorter races were the most important predictors for ultra-endurance race times. Ultra-endurance athletes seemed to prepare differently for their races compared to endurance athletes where ultra-endurance athletes invested more time in training and completed more training kilometers at lower speed compared to endurance athletes. In conclusion, the most important predictor variables for ultra-endurance athletes were a fast personal best time in shorter races, a low body fat and a high speed during training units.


A Locally Optimal Algorithm for Estimating a Generating Partition from an Observed Time Series and Its Application to Anomaly Detection.
Estimation of a generating partition is critical for symbolization of measurements from discrete-time dynamical systems, where a sequence of symbols from a (finite-cardinality) alphabet may uniquely specify the underlying time series. Such symbolization is useful for computing measures (e.g., Kolmogorov-Sinai entropy) to identify or characterize the (possibly unknown) dynamical system. It is also useful for time series classification and anomaly detection. The seminal work of Hirata, Judd, and Kilminster ( 2004 ) derives a novel objective function, akin to a clustering objective, that measures the discrepancy between a set of reconstruction values and the points from the time series. They cast estimation of a generating partition via the minimization of their objective function. Unfortunately, their proposed algorithm is nonconvergent, with no guarantee of finding even locally optimal solutions with respect to their objective. The difficulty is a heuristic nearest neighbor symbol assignment step. Alternatively, we develop a novel, locally optimal algorithm for their objective. We apply iterative nearest-neighbor symbol assignments with guaranteed discrepancy descent, by which joint, locally optimal symbolization of the entire time series is achieved. While most previous approaches frame generating partition estimation as a state-space partitioning problem, we recognize that minimizing the Hirata et al. ( 2004 ) objective function does not induce an explicit partitioning of the state space, but rather the space consisting of the entire time series (effectively, clustering in a (countably) infinite-dimensional space). Our approach also amounts to a novel type of sliding block lossy source coding. Improvement, with respect to several measures, is demonstrated over popular methods for symbolizing chaotic maps. We also apply our approach to time-series anomaly detection, considering both chaotic maps and failure application in a polycrystalline alloy material.


Identification of two tRNA thiolation genes required for cell growth at extremely high temperatures.
Thermostability of tRNA in thermophilic bacteria is effected by post-transcriptional modifications, such as 2-thioribothymidine (s2T) at position 54. Using a proteomics approach, we identified two genes (ttuA and ttuB; tRNA-two-thiouridine) that are essential for the synthesis of s2T in Thermus thermophilus. Mutation of either gene completely abolishes thio-modification of s2T, and these mutants exhibit a temperature-sensitive phenotype. These results suggest that bacterial growth at higher temperatures is achieved through the thermal stabilization of tRNA by a 2-thiolation modification. TtuA (TTC0106) is possibly an ATPase possessing a P-loop motif. TtuB (TTC0105) is a putative thio-carrier protein that exhibits significant sequence homology with ThiS of the thiamine synthesis pathway. Both TtuA and TtuB are required for in vitro s2T formation in the presence of cysteine and ATP. The addition of cysteine desulfurases such as IscS (TTC0087) or SufS (TTC1373) enhances the sulfur transfer reaction in vitro.


Protocol for a cluster randomised controlled trial evaluating a parenting with home visitation programme to prevent physical and emotional abuse of children in Indonesia: the Families First Programme.
Every year, up to 1 billion children are victims of violence worldwide. Most child abuse takes place in the context of punishment. The Families First Programme, an adaptation of the Positive Discipline in Everyday Parenting Programme to the West Java context, is a parenting support programme anchored on children's rights that gives parents guidance on child development, parenting and positive discipline practices. This trial will evaluate the effectiveness of the Families First Programme compared with a waitlist control group. This is a pragmatic, parallel-group, stratified, cluster-randomised controlled trial. Twenty rural and urban villages in the Cianjur District, Indonesia, involving 720 caregivers of children up to 7 years of age, will be randomised. Villages will receive either a parenting programme consisting of 10 group sessions and four home visits over 3 months and standard community health and social services or just the latter. After completion of the trial period, the programme will be offered to those in the delayed group. Outcome data will be collected before randomisation (baseline), immediately postintervention (3 months postrandomisation) and 6 months later (9 months postrandomisation). The primary outcome will be frequency of physical and emotional punishment as measured by a weighted sum from three self-report items. Primary outcome analysis will use Poisson regression with generalised estimating equations and assess the interaction between intervention and time over baseline and 3 and 9 months postrandomisation assessments. Concurrent process evaluation will be conducted to assess programme satisfaction and facilitators and barriers to the implementation of the programme generalisable to other settings. Ethics approval was obtained from McGill University and Universitas Katolik Indonesia Atma Jaya. Results will be published in peer-reviewed journals and presented at scientific conferences and events for decision-makers, including in the participating communities. NCT03374761.


Temporomandibular joint injury potential imposed by the low-velocity extension-flexion maneuver.
It has been proposed that significant temporomandibular joint injury can occur as a result of rapid extension-flexion motion of the neck (whip-lash). This motion, which is experienced by passengers in vehicles that undergo rear-end collisions, has been described as causing rapid protrusion and opening of the mandible. It has been speculated that this relative motion between the mandible and the cranium produces forces at the temporomandibular joint (TMJ) that injure the articular elements. The objective of this study was to measure these forces by an experimental method. Accelerometer sensor and high-speed cinematographic data were obtained from the kinematic responses of live human test subjects positioned as occupants in motor vehicles that underwent staged low-velocity rear-end collisions. Linear and moment forces generated at the TMJs were obtained from the resultant acceleration pulse at the craniomandibular complex, estimation of the mass properties of the mandible and its appended soft tissues, and the application of Newton's Second Law of motion. The maximum linear forces generated at the TMJ in a rear-end collision resulting in a velocity change of the test subject of 8 km/h (5 mph) were in the 7 to 10 N (1.6 to 2.2 lb) range. Moment forces at the joint peaked briefly at 0.55 N.m (4.81 lb-in). These force magnitudes generated at the TMJ constitute a minor fraction of the forces experienced at the joint during normal physiologic function. It is a conclusion of this study that injuries to the TMJ attributed to low-velocity "whiplash" cannot be accounted for by the joint forces produced by this maneuver.