Whole body vibration exercise training for fibromyalgia.
Exercise training is commonly recommended for adults with fibromyalgia. We defined whole body vibration (WBV) exercise as use of a vertical or rotary oscillating platform as an exercise stimulus while the individual engages in sustained static positioning or dynamic movements. The individual stands on the platform, and oscillations result in vibrations transmitted to the subject through the legs. This review is one of a series of reviews that replaces the first review published in 2002. To evaluate benefits and harms of WBV exercise training in adults with fibromyalgia. We searched the Cochrane Library, MEDLINE, Embase, CINAHL, PEDro, Thesis and Dissertation Abstracts, AMED, WHO ICTRP, and ClinicalTrials.gov up to December 2016, unrestricted by language, to identify potentially relevant trials. We included randomized controlled trials (RCTs) in adults with the diagnosis of fibromyalgia based on published criteria including a WBV intervention versus control or another intervention. Major outcomes were health-related quality of life (HRQL), pain intensity, stiffness, fatigue, physical function, withdrawals, and adverse events. Two review authors independently selected trials for inclusion, extracted data, performed risk of bias assessments, and assessed the quality of evidence for major outcomes using the GRADE approach. We used a 15% threshold for calculation of clinically relevant differences. We included four studies involving 150 middle-aged female participants from one country. Two studies had two treatment arms (71 participants) that compared WBV plus mixed exercise plus relaxation versus mixed exercise plus relaxation and placebo WBV versus control, and WBV plus mixed exercise versus mixed exercise and control; two studies had three treatment arms (79 participants) that compared WBV plus mixed exercise versus control and mixed relaxation placebo WBV. We judged the overall risk of bias as low for selection (random sequence generation), detection (objectively measured outcomes), attrition, and other biases; as unclear for selection bias (allocation concealment); and as high for performance, detection (self-report outcomes), and selective reporting biases.The WBV versus control comparison reported on three major outcomes assessed at 12 weeks post intervention based on the Fibromyalgia Impact Questionnaire (FIQ) (0 to 100 scale, lower score is better). Results for HRQL in the control group at end of treatment (59.13) showed a mean difference (MD) of -3.73 (95% confidence interval [CI] -10.81 to 3.35) for absolute HRQL, or improvement of 4% (11% better to 3% worse) and relative improvement of 6.7% (19.6% better to 6.1% worse). Results for withdrawals indicate that 14 per 100 and 10 per 100 in the intervention and control groups, respectively, withdrew from the intervention (RR 1.43, 95% CI 0.27 to 7.67; absolute change 4%, 95% CI 16% fewer to 24% more; relative change 43% more, 95% CI 73% fewer to 667% more). The only adverse event reported was acute pain in the legs, for which one participant dropped out of the program. We judged the quality of evidence for all outcomes as very low. This study did not measure pain intensity, fatigue, stiffness, or physical function. No outcomes in this comparison met the 15% threshold for clinical relevance.The WBV plus mixed exercise (aerobic, strength, flexibility, and relaxation) versus control study (N = 21) evaluated symptoms at six weeks post intervention using the FIQ. Results for HRQL at end of treatment (59.64) showed an MD of -16.02 (95% CI -31.57 to -0.47) for absolute HRQL, with improvement of 16% (0.5% to 32%) and relative change in HRQL of 24% (0.7% to 47%). Data showed a pain intensity MD of -28.22 (95% CI -43.26 to -13.18) for an absolute difference of 28% (13% to 43%) and a relative change of 39% improvement (18% to 60%); as well as a fatigue MD of -33 (95% CI -49 to -16) for an absolute difference of 33% (16% to 49%) and relative difference of 47% (95% CI 23% to 60%); and a stiffness MD of -26.27 (95% CI -42.96 to -9.58) for an absolute difference of 26% (10% to 43%) and a relative difference of 36.5% (23% to 60%). All-cause withdrawals occurred in 8 per 100 and 33 per 100 withdrawals in the intervention and control groups, respectively (two studies, N = 46; RR 0.25, 95% CI 0.06 to 1.12) for an absolute risk difference of 24% (3% to 51%). One participant exhibited a mild anxiety attack at the first session of WBV. No studies in this comparison reported on physical function. Several outcomes (based on the findings of one study) in this comparison met the 15% threshold for clinical relevance: HRQL, pain intensity, fatigue, and stiffness, which improved by 16%, 39%, 46%, and 36%, respectively. We found evidence of very low quality for all outcomes.The WBV plus mixed exercise versus other exercise provided very low quality evidence for all outcomes. Investigators evaluated outcomes on a 0 to 100 scale (lower score is better) for pain intensity (one study, N = 23; MD -16.36, 95% CI -29.49 to -3.23), HRQL (two studies, N = 49; MD -6.67, 95% CI -14.65 to 1.31), fatigue (one study, N = 23; MD -14.41, 95% CI -29.47 to 0.65), stiffness (one study, N = 23; MD -12.72, 95% CI -26.90 to 1.46), and all-cause withdrawal (three studies, N = 77; RR 0.72, 95% CI -0.17 to 3.11). Adverse events reported for the three studies included one anxiety attack at the first session of WBV and one dropout from the comparison group ("other exercise group") due to an injury that was not related to the program. No studies reported on physical function. Whether WBV or WBV in addition to mixed exercise is superior to control or another intervention for women with fibromyalgia remains uncertain. The quality of evidence is very low owing to imprecision (few study participants and wide confidence intervals) and issues related to risk of bias. These trials did not measure major outcomes such as pain intensity, stiffness, fatigue, and physical function. Overall, studies were few and were very small, which prevented meaningful estimates of harms and definitive conclusions about WBV safety.


[Mesothelioma: the aetiological role of ultrathin fibres and repercussions on prevention and medical legal evaluation].
Mesothelioma has until now been considered to be a manifestation, occurring in the pleura and/or peritoneum, of the carcinogenic action of the total burden of inhaled asbestos fibres, in the same way as lung cancer. Because of the pathogenic potential of very low exposure levels, the fact that the onset of the neoplasm always occurs in the parietal pleura, and the absence of any synergism with smoking, which is typical in the case of carcinoma, it was suspected that aetiopathogenetic differences existed but the reasons for such differences still could not be explained. In the past experimental results indicated the oncogenicity of very thin fibres but mesothelioma in practice was not exclusively linked to this specific dimensional size class. The paper proposes to take full advantage of the significant knowledge that must emerged from research carried out in recent years and use this knowledge to reconstruct the mosaic of the aetiopathogenesis of mesothelioma. Due consideration will also be given to the consequent new approach required in the field of medical-legal evaluation of cases and in the field of prevention. The most important knowledge that must today be taken as certain is the fact that mesothelioma is not caused, as is the case for asbestosis, by all the fibres that are inhaled but only by the ultrathin fraction of these fibres, having diameter of 0.2 microm and length of only a few microm. Only fibres of this class of size can cross the pulmonary-pleural barrier and are, therefore, the causal agent of mesothelioma and other benign pleural manifestations (plaques). Moreover the ultrathin fibres that translocate from the lung to the pleura are not distributed casually on the parietal and visceral surfaces but move over the surfaces, to concentrate around the lymphatic reabsorption stomata situated on the parietal pleura. Due to their shape, the fibres cannot easily be absorbed into the stoma via the lymphatic flow and so remain clustered for an indefinite period of time among the mesothelial cells that surround the stoma. The concentration of ultrathin fibres in punctiform areas of the parietal pleura and the extremely long biopersistence of the amphiboles now finally explain how very low exposures can cause mesothelioma in susceptible subjects and why the neoplasm always occurs on the parietal pleura. In medical-legal assessments of cases of mesothelioma the etiological importance of the ultrathin fraction of fibres means that any assumption of the disease being avoidable must be discarded, at least up to the second half of the 1980s because until then this class of fibres, which today must be considered as the true causal agent of the neoplasm, was not visible under the optical microscope, nor could such fibres be measured or eliminated from the atmosphere of working environments. The filter materials available both for fixed ventilation systems and for individual protective masks were not able to block the ultrathin fibres and were therefore only efficacious for the prevention of asbestosis and probably pulmonary carcinoma. It was only with the use of highly efficient HEPA filters and "absolute" filters towards the end of the 1980s that efficacious protection against all size classes of respirable fibres became possible in industrial plants. Preventive measures in the public hygiene area must also take account of the aetiological role of ultrathin fibres by making full use of electron microscope investigations and by using "absolute" filters for domestic purposes, in ventilation systems and above all in the filter systems of the mechanical devices used in town street cleaning operations.


The hypoxic ventilatory response and TRPA1 antagonism in conscious mice.
Recently, TRPA1 channels, richly expressed in both peripheral and central neural systems, have been proposed as novel sensors of changes in oxygen concentration along the hypoxic-hyperoxic continuum. In this study, we investigated the hypothesis that TRPA1 channels blockade should profoundly affect the hypoxic ventilatory response (HVR). We examined the chemosensory ventilatory responses in conscious mice before and after intraperitoneal administration of the specific TRPA1 antagonist HC-030031 in two doses of 50 and 200 (cumulative dose 250) mg kg(-1) . Ventilation and its responses to mild 13% and severe 7% hypoxia, pure O2 , and 5% CO2 in O2 were recorded in a whole-body plethysmograph. TRPA1 antagonism caused a dose-dependent attenuation of the HVR. Ventilatory stimulation was virtually abrogated in response to the mild, but it remained viable, albeit slashed, at severe hypoxia after the bigger dose of HC-030031. The TRPA1 function seemed specific for the hypoxic chemoreflex as neither the response to pure O2 nor hypercapnia was appreciably influenced by the TRPA1 antagonist. The study unravelled the role of TRPA1 in shaping the ventilatory response to low-intensity hypoxia, liable to be mediated by vagally innervated respiratory chemosensors of lower functional rank, but contradicted the TRPA1 being indispensable for the powerful carotid body chemoreflex in face of a severe hypoxic threat.


A Placebo-Controlled Double-Blind Randomized Trial with Individualized Homeopathic Treatment Using a Symptom Cluster Approach in Women with Premenstrual Syndrome.
In a double-blind placebo-controlled randomized trial with parallel groups, the efficacy of individually prescribed homeopathic medicines was evaluated in women with premenstrual syndrome (PMS). In an outpatient department of a university clinic in Jerusalem, Israel (1996-1999), women with PMS, aged 18 to 50 years, entered a 2-month screening phase with prospective daily recording of premenstrual symptoms by the Menstrual Distress Questionnaire (MDQ). They were included after being diagnosed with PMS. A reproducible treatment protocol was used: women received a homeopathic prescription based on symptom clusters identified in a questionnaire. The symptoms were verified during a complementary, structured, interview. Only women whose symptoms matched the symptom profile of one of 14 pre-selected homeopathic medicines were included. Each participant was administered active medicine or placebo via random allocation. Primary outcome measures were differences in changes in mean daily premenstrual symptom (PM) scores by the MDQ. Analysis was by intention-to-treat. A total of 105 women were included: 49 were randomized to active medicine and 56 to placebo. Forty-three women in the active medicine group and 53 in the placebo group received the allocated intervention with at least one follow-up measurement and their data were analyzed. Significantly greater improvement of mean PM scores was measured in the active medicine group (0.443 [standard deviation, SD, 0.32] to 0.287 [SD, 0.20]) compared to placebo (0.426 [SD, 0.34] to 0.340 [SD, 0.39]); p = 0.043. Individually prescribed homeopathic medicines were associated with significantly greater improvement of PM scores in women with PMS, compared to placebo. Replication, with larger sample size and other refinements, is recommended to confirm the efficacy of this treatment in other settings.


CD18/ICAM-1-dependent nitric oxide production of Kupffer cells as a cause of mitochondrial dysfunction in hepatoma cells: influence of chronic alcohol feeding.
The present study was designed to monitor the process for hepatoma cell injury induced by Kupffer cells. The non-activated Kupffer cells isolated from male Wistar rats reduced the mitochondrial membrane potential in the cocultured AH70 cells, which was indicated by the decreased rhodamine 123 (Rh123) fluorescence. Increased level of nitrite and nitrate in the medium and induction of iNOS in Kupffer cells were observed after coculture with AH70 cells. Incubation with either NG-monomethyl-L-arginine or aminoguanidine attenuated the increased nitric oxide (NO) production of Kupffer cells and the decreased Rh123 fluorescence of AH70 cells. Fluo-3, a calcium-sensitive probe, fluorescence in Kupffer cells increased after coculture with AH70 cells. Addition of TMB-8, a calcium inhibitor, or monoclonal antibody directed against ICAM-1 or CD18 prevented the increases in fluo-3 fluorescence and NO production of Kupffer cells and Kupffer cell-induced mitochondrial dysfunction in AH70 cells, suggesting the involvement of calcium mobilization and CD18/ICAM-1. It is therefore suggested that the Kupffer cell-mediated mitochondrial dysfunction of hepatoma cells largely depends on NO production by iNOS, and that the NO production by Kupffer cells is triggered by CD18/ICAM-1-dependent interaction with hepatoma cells and subsequent calcium mobilization. In other series of experiments, male Wistar rats fed ethanol for 4 weeks were used. The NO production and calcium mobilization of Kupffer cells and reduction of the mitochondrial membrane potential in cocultured hepatoma cells were diminished in the case of Kupffer cells isolated from chronically ethanol-fed rats, while CD18 and ICAM-1 expression was still observed. Thus, the present study further suggests that NO-dependent anti-hepatoma cell activity of Kupffer cells is suppressed in chronically ethanol-fed animals.


Hypnotherapy or medications: a randomized noninferiority trial in urgency urinary incontinent women.
Urgency urinary incontinence afflicts many adults, and most commonly affects women. Medications, a standard treatment, may be poorly tolerated, with poor adherence. This warrants investigation of alternative interventions. Mind-body therapies such as hypnotherapy may offer additional treatment options for individuals with urgency urinary incontinence. To evaluate hypnotherapy's efficacy compared to medications in treating women with urgency urinary incontinence. This investigator-masked, noninferiority trial compared hypnotherapy to medications at an academic center in the southwestern United States, and randomized women with non-neurogenic urgency urinary incontinence to weekly hypnotherapy sessions for 2 months (and continued self-hypnosis thereafter) or to medication and weekly counseling for 2 months (and medication alone thereafter). The primary outcome was the between-group comparison of percent change in urgency incontinence on a 3-day bladder diary at 2 months. Important secondary outcomes were between-group comparisons of percent change in urgency incontinence at 6 and 12 months. Outcomes were analyzed based on noninferiority margins of 5% for between group differences (P < 0.025) (that is, for between group difference in percentage change in urgency incontinence, if the lower bound of the 95% confidence interval was greater than -5%, noninferiority would be proved). A total of 152 women were randomized to treatment between April 2013 and October 2016. Of these women, 142 (70 hypnotherapy, 72 medications) had 3-day diary information at 2 months and were included in the primary outcome analysis. Secondary outcomes were analyzed for women with diary data at the 6-month and then 12-month time points (138 women [67 hypnotherapy, 71 medications] at 6 months, 140 women [69 hypnotherapy, 71 medications] at 12 months. There were no differences between groups' urgency incontinence episodes at baseline: median (quartile 1, quartile 3) for hypnotherapy was 8 (4, 14) and medication was 7 (4, 11) (P = .165). For the primary outcome, although both interventions showed improvement, hypnotherapy did not prove noninferior to medication at 2 months. Hypnotherapy's median percent improvement was 73.0% (95% confidence interval, 60.0-88˖9%), whereas medication's improvement was 88.6% (95% confidence interval, 78.6-100.0%). The median difference in percent change between groups was 0% (95% confidence interval, -16.7% to 0.0%); because the lower margin of the confidence interval did not meet the predetermined noninferiority margin of greater than -5%, hypnotherapy did not prove noninferior to medication. In contrast, hypnotherapy was noninferior to medication for the secondary outcomes at 6 months (hypnotherapy, 85.7% improvement, 95% confidence interval, 75.0-100%; medications, 83.3% improvement, 95% confidence interval, 64.7-100%; median difference in percent change between groups of 0%, 95% confidence interval, 0.0-6.7%) and 12 months (hypnotherapy, 85.7% improvement, 95% confidence interval, 66.7-94.4%; medications, 80% improvement, 95% confidence interval, 54.5-100%; median difference in percent change between groups of 0%, 95% confidence interval, -4.2% to -9.5%). Both hypnotherapy and medications were associated with substantially improved urgency urinary incontinence at all follow-up. The study did not prove the noninferiority of hypnotherapy compared to medications at 2 months, the study's primary outcome. Hypnotherapy proved noninferior to medications at longer-term follow-up of 6 and 12 months. Hypnotherapy is a promising, alternative treatment for women with UUI.


[Apoptosis--universal mechanisms of cell death and survival in ischemia and reperfusion: ways to pharmacological control].
Cell death is the main element of ischemic-reperfusive states. The balance of main cell death forms (necrosis and apoptosis) in impaired tissues determines the extent of cellular loss and the rate of pathological process spreading, as well as the possibility of functional recovery. The review describes triggering mechanisms of apoptosis under the ischemia-reperfusion conditions, considers the role of inflammation in limiting the cell loss and its dependence on the balance of necrotic and apoptotic forms of cell death at the site of ischemia-reperfusion, and suggests potential methods for pharmacological correction of protective potency of the cell and the balance of cell death forms.


The Impact of Late-Life Parental Death on Adult Sibling Relationships: Do Parents' Advance Directives Help or Hurt?
The authors examined whether the effect of parental death on adults siblings' relationship quality varies on the basis of the presence and perceived effectiveness of a deceased parent's formal preparations for end-of-life care. The authors used data from the Wisconsin Longitudinal Study and focused on the relationship quality of a bereaved adult child and his or her randomly selected sibling. Parental death was associated with a decrease in sibling closeness. The parent's use of advance directives (living will and durable power of attorney for health care) did not have uniformly positive effects on adult siblings' relationship quality. Sibling relationships suffered when the living will was believed to "cause problems," but relationships improved when the deceased parent named someone other than his or her spouse or a child as durable power of attorney for health care. The authors discuss the implications for developing effective end-of-life preparations that benefit both the decedent and surviving kin.


Elution of antitransglutaminase antibodies from duodenal biopsies: a novel approach in the diagnosis of celiac disease.
Celiac disease (CeD) is a disease more prevalent and multisymptomatic than was earlier recognized. Whereas prompt initiation of gluten-free diet (GFD) is beneficial in relieving the symptoms, an accurate CeD diagnosis is necessary also to avoid years of restricted diet on uncertain grounds. We propose a new diagnostic method, based on elution of deposited antibodies against transglutaminase (anti-tTG) from duodenal biopsies in patients with symptoms and screening serology analyses suggestive of CeD. The eluates were analyzed in a Phadia 250 fluoroimmunoassay, demonstrating elevated concentrations of anti-tTG in CeD patients, corresponding to serology and histopathology findings. In one case histology was inconclusive, displaying only unspecific inflammation, but eluted anti-tTG was positive. This patient has clinically improved following GFD. We conclude that our novel method represents a new tool in the diagnostic work up in CeD. The detection of deposited anti-tTG at the site of inflammation appears to provide a high sensitivity and specificity using a technique that is quick, simple and reliable. Further studies are needed for optimization and elucidation of suitable applications for this elution method.


Small-molecule inhibitors of the human epidermal receptor family.
Small molecule inhibitors of human epidermal receptors (HER) have become an integral part of the armamentarium available to the medical oncologist in the treatment of solid tumor malignancies. At present, there are two small-molecule inhibitors (erlotinib and lapatinib) approved by the FDA in the USA, and a third inhibitor, gefitinib, is approved in other countries. To summarize the current standards of care for these new agents in solid tumors, and to discuss ongoing clinical trials; to review the known mechanisms of action of these inhibitors as well as to discuss both the known predictive markers for response and likely mechanisms of resistance. We reviewed key presentations and recent publications on small-molecule inhibitors targeting the HER family in solid tumors. Recent data have highlighted the importance of mutations and amplifications of receptors within the HER family. Amplification of HER2 often translates into responses in anti-HER2 therapy. Mutations either enhance sensitivity or confer resistance to small-molecule inhibitors. Other mechanisms of resistance are being elucidated which should lead to the ability to predict both responses and resistance to HER family inhibitors and should translate into improvements in patient care.


Xylem and Leaf Functional Adjustments to Drought in Pinus sylvestris and Quercus pyrenaica at Their Elevational Boundary.
Climatic scenarios for the Mediterranean region forecast increasing frequency and intensity of drought events. Consequently, a reduction in Pinus sylvestris L. distribution range is projected within the region, with this species being outcompeted at lower elevations by more drought-tolerant taxa such as Quercus pyrenaica Willd. The functional response of these species to the projected shifts in water availability will partially determine their performance and, thus, their competitive success under these changing climatic conditions. We studied how the cambial and leaf phenology and xylem anatomy of these two species responded to a 3-year rainfall exclusion experiment set at their elevational boundary in Central Spain. Additionally, P. sylvestris leaf gas exchange, water potential and carbon isotope content response to the treatment were measured. Likewise, we assessed inter-annual variability in the studied functional traits under control and rainfall exclusion conditions. Prolonged exposure to drier conditions did not affect the onset of xylogenesis in either of the studied species, whereas xylem formation ceased 1-3 weeks earlier in P. sylvestris. The rainfall exclusion had, however, no effect on leaf phenology on either species, which suggests that cambial phenology is more sensitive to drought than leaf phenology. P. sylvestris formed fewer, but larger tracheids under dry conditions and reduced the proportion of latewood in the tree ring. On the other hand, Q. pyrenaica did not suffer earlywood hydraulic diameter changes under rainfall exclusion, but experienced a cumulative reduction in latewood width, which could ultimately challenge its hydraulic performance. The phenological and anatomical response of the studied species to drought is consistent with a shift in resource allocation under drought stress from xylem to other sinks. Additionally, the tighter stomatal control and higher intrinsic water use efficiency observed in drought-stressed P. sylvestris may eventually limit carbon uptake in this species. Our results suggest that both species are potentially vulnerable to the forecasted increase in drought stress, although P. sylvestris might experience a higher risk of drought-induced decline at its low elevational limit.


Nicotinamide Improves Cognitive Function in Mice With Chronic Cerebral Hypoperfusion.
Normal brain function requires steady blood supply to maintain stable energy state. When blood supply to the brain becomes suboptimal for a long period of time, chronic cerebral hypoperfusion (CCH) and a variety of brain changes may occur. CCH causes white matter injury and cognitive impairment. The present study investigated the effect of nicotinamide (NAM) on CCH-induced cognitive impairment and white matter damage in mice. Male C57Bl/6J mice aged 10-12 weeks (mean age = 11 ± 1 weeks) and weighing 24 - 29 g (mean weight = 26.5 ± 2.5 g) were randomly assigned to three groups (eight mice/group): sham group, CCH group and NAM group. Chronic cerebral hypoperfusion (CCH) was induced using standard methods. The treatment group mice received intraperitoneal injection of NAM at a dose of 200 mg/kg body weight (bwt) daily for 30 days. Learning, memory, anxiety, and depression-like behaviors were measured using Morris water maze test (MWMT), open field test (OFT), sucrose preference test (SPT), and forced swim test (FST), respectively. White matter damage and remodeling were determined via histological/ immunohistochemical analyses, and western blotting, respectively. The results showed that the time spent in target quadrant, number of crossings and escape latency were significantly lower in CCH group than in sham group, but they were significantly increased by NAM (p < 0.05). Mice in NAM group moved significantly faster and covered longer distances, when compared with those in CCH group (p < 0.05). The percentage of time spent in open arms and the number of entries to the open arms were significantly lower in CCH group than in NAM group (p < 0.05). Moreover, anhedonia and histologic scores (index of myelin injury) were significantly higher in CCH group than in sham group, but they were significantly reduced by NAM (p < 0.05). The results of immunohistochemical staining and Western blotting showed that the protein expressions of 2', 3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) and synaptophysin were significantly downregulated in CCH group, relative to sham group, but they were significantly upregulated by NAM (p < 0.05). These results indicate that NAM improves cognitive function in mice with CCH.


Artificial neural network--based analysis of high-throughput screening data for improved prediction of active compounds.
Artificial neural networks (ANNs) are trained using high-throughput screening (HTS) data to recover active compounds from a large data set. Improved classification performance was obtained on combining predictions made by multiple ANNs. The HTS data, acquired from a methionine aminopeptidases inhibition study, consisted of a library of 43,347 compounds, and the ratio of active to nonactive compounds, R(A/N), was 0.0321. Back-propagation ANNs were trained and validated using principal components derived from the physicochemical features of the compounds. On selecting the training parameters carefully, an ANN recovers one-third of all active compounds from the validation set with a 3-fold gain in R(A/N) value. Further gains in R(A/N) values were obtained upon combining the predictions made by a number of ANNs. The generalization property of the back-propagation ANNs was used to train those ANNs with the same training samples, after being initialized with different sets of random weights. As a result, only 10% of all available compounds were needed for training and validation, and the rest of the data set was screened with more than a 10-fold gain of the original R(A/N) value. Thus, ANNs trained with limited HTS data might become useful in recovering active compounds from large data sets.


Quirks of dye nomenclature. 3. Trypan blue.
Trypan blue is colorant from the 19(th) century that has an association with Africa as a chemotherapeutic agent against protozoan (Trypanosomal) infections, which cause sleeping sickness. The dye still is used for staining biopsies, living cells and organisms, and it also has been used as a colorant for textiles.


Comparative genomics of the niche-specific plant pathogen Streptomyces ipomoeae reveal novel genome content and organization.
While most plant-pathogenic Streptomyces species cause scab disease on a variety of plant hosts, Streptomyces ipomoeae is the sole causative agent of soil rot disease of sweet potato and closely related plant species. Here, genome sequencing of virulent and avirulent S. ipomoeae strains coupled with comparative genomic analyses has identified genome content and organization features unique to this streptomycete plant pathogen. The results here will enable future research into the mechanisms used by S. ipomoeae to cause disease and to persist in its niche environment.


Mammalian tyrosinase. A comparison of tyrosine hydroxylation and melanin formation.
1. Melanosomal tyrosinase was isolated from normal C57B1 mice, and a comparison of the tyrosine-hydroxylation and dopa (3,4-dihydroxyphenylalanine)-oxidation activities of this enzyme was made. 2. The results indicate that in the absence of dopa cofactor, this enzyme is capable of tyrosine hydroxylation, but with very little subsequent dopa oxidation and melanin formation. 3. This mechanism of enzyme action may play an important role in the intracellular regulation of melanin formation. 4. Further, dopa appears to act as a positive allosteric effector for tyrosine hydroxylation by tyrosinase, in addition to its known activity as a hydrogen donor for the reaction.


Pharmacological treatment of diabetes in older people.
The pharmacological management of diabetes in older people is complex and challenging. It requires a comprehensive understanding of the individual beyond the diabetes itself. Through the ageing years, the older individual presents with diabetes-related and non-related comorbidities and complications, develops functional limitations and psychological issues, and may lack social support and access to care. A disturbance in these categories, known as the four geriatric domains, will negatively affect diabetes self-management and self-efficacy, leading to poor outcomes and complications. Furthermore, older people with diabetes may be more interested in the management of other chronic conditions such as pain or impaired mobility, and diabetes may be lower in their list of priorities. Proper education must be provided to the older individual and caregivers, with continuous monitoring and counselling, especially when pharmacological interventions offer risks of side effects, adverse reactions and interactions with other medications. Informed shared medical decisions will help to improve adherence to the regimen; however, such discussions ought to be based on the best evidence available, which is unfortunately limited in this age group. We performed a review focused on pharmacological agents and summarize current evidence on their use for the treatment of diabetes in older people. We encourage clinicians to investigate and incorporate the four geriatrics domains in the selection and monitoring of these agents.


Early proinflammatory activation of renal tubular cells by normal and pathologic IgG.
To verify whether human IgG induces proinflammatory activation of human proximal tubular epithelial cells (PTEC) independent of the metabolic overload of protein reabsorption. Cultured PTEC were incubated with normal IgG, IgG from systemic lupus erythematosus (SLE) patients, albumin or transferrin. IL-6 secretion and extracellular regulated kinase (ERK) activation (dual-phosphorylated ERK) were measured by ELISA and by Western blotting of PTEC extracts, respectively; renal biopsy specimens from patients with IgG and non-IgG proteinuria were analyzed by immunohistochemistry and in situ hybridization to detect ERK-P and IL-6. Normal and SLE IgG, but not albumin or transferrin, induced an early significant increase in IL-6 secretion by PTECs. Also ERK activation was found after 1-hour incubation of PTEC with IgG, but not with control medium and albumin-treated PTEC. Activated ERK and IL-6 were found to colocalize in tubular cells in the kidney specimens of patients with IgG proteinuria only. IgG-dependent early activation of ERK and increased IL-6 secretion in PTEC suggest that IgG filtered during nonselective proteinuria may play a specific role in tubulointerstitial disease. Such a role could be particularly relevant in diseases associated with abnormal IgG pool compositions, such as SLE. Preliminary results on human renal biopsy specimens suggest that our in vitro observations may also be relevant in vivo.


[Lesions of the radial nerve in fractures of the humeral diaphysis. Apropos of 62 cases].
Evaluate outcome of different techniques used for radial nerve repair after humeral shaft fractures. Identify situations where nerve exploration is required or inversely unneeded. Evaluate the risk of more systematic nerve exploration in case of radial nerve palsy. Over a 10 year period, we cared for 62 patients with humeral fractures associated with radial nerve palsy who were addressed directly to our unit or referred after prior care. There were 54 men (mean age 30 years, 17 - 66) and 8 women (mean age 40 years, 19 - 80). There were 40 fractures of the mid-third and 22 fractures of the distal third of the humerus. Anatomic severity varied although most fractures were displaced or subsequent to high-energy trauma. Orthopedic treatment was used alone in 14 cases. There were 6 plate fixations and 42 intramedullary nailings. Twenty-four of the 62 cases of radial nerve palsy resulted from nerve tears but a continuous nerve was found in 38 cases. Tears were treated by primary suture (n =4), secondary graft (n =17, 5 with 2 torons and 12 with 3 or 4 torons), or primary muscle transfer (n =3). Neurolysis was used in 6 of the 38 cases with continuous nerve. Motor outcome was assessed using composite criteria taking into account the physiological role of each muscle group. All primary sutures gave excellent results. Excellent or good outcome was achieved in 12 of the 17 secondary grafts although a complementary transfer was required in 2 cases. Conversely, outcome was average in 2 cases and a failure in 3. Outcome depended on the length of the graft and the number of torons used. The importance of a proximal resection in healthy tissue sometimes required a complementary medial access and a graft between the biceps and the brachialis. Recovery was achieved in 37 of the 38 lesions with continuous nerve including 31 cases which did not require a second procedure. In case of nerve rupture, the outcome of primary suture appears to be better than that of secondary grafts. The success of the graft depends on the length of the tissue loss after sectioning in healthy tissue and on the number of torons used. This difference in prognosis points out the usefulness of systematic exploration in order to use primary or early direct suture in cases of high-energy displaced fractures. Minimally displaced fractures often are accompanied by a simple contusion with spontaneous recovery. However, in intermediary cases, the decision to make a systematic nerve exploration during the osteosynthesis procedure (aimed at early mobilization) is based on the fact that recovery was achieved in 23 cases in which initial exploration of a continuous nerve has been performed. Indirectly, the favorable outcome of postoperative paralyses reported by several authors, also supports this policy.


Perceived barriers and effective strategies to diabetes self-management.
This paper reports the perceived barriers to and effective strategies for self-management of adults with type 2 diabetes in a rural setting. Worldwide, diabetes is a major public health concern and financial burden. Research shows that, for people with diabetes, adhering to programs of self-care is often problematic. Despite the potential for improved metabolic control and quality of life, little is published on the barriers and effective strategies that people with diabetes successfully use to incorporate plans of care into their lifestyles. Twenty-four adults diagnosed with type 2 diabetes were recruited from a rural primary care practice to participate in one of three audiotaped focus groups. Content analysis was conducted on the focus group transcripts and validity was strengthened through independent rankings of barriers and strategies by an expert panel and by the nurse researchers. The data were collected 2002. The most frequently reported barriers were lack of knowledge of a specific diet plan, lack of understanding of the plan of care and helplessness and frustration from lack of glycaemic control and continued disease progression despite adherence. Effective strategies identified were developing a collaborative relationship with a provider, maintaining a positive attitude that prompts proactive learning and having a support person who provides encouragement and promotes accountability. These data highlight the importance of barrier and strategy identification in developing and implementing realistic self-management plans and the significance of collaborative alliances between patients and practitioners. Awareness of barriers, identification of strategies to overcome obstacles and the opportunity to problem solve with practitioners assists patients in managing a chronic illness that requires numerous daily decisions.


Alteration of the large-scale white-matter functional networks in autism spectrum disorder.
Autism spectrum disorder is a neurodevelopmental disorder whose core deficit is social dysfunction. Previous studies have indicated that structural changes in white matter are associated with autism spectrum disorder. However, few studies have explored the alteration of the large-scale white-matter functional networks in autism spectrum disorder. Here, we identified ten white-matter functional networks on resting-state functional magnetic resonance imaging data using the K-means clustering algorithm. Compared with the white matter and white-matter functional network connectivity of the healthy controls group, we found significantly decreased white matter and white-matter functional network connectivity mainly located within the Occipital network, Middle temporo-frontal network, and Deep network in autism spectrum disorder. Compared with healthy controls, findings from white-matter gray-matter functional network connectivity showed the decreased white-matter gray-matter functional network connectivity mainly distributing in the Occipital network and Deep network. Moreover, we compared the spontaneous activity of white-matter functional networks between the two groups. We found that the spontaneous activity of Middle temporo-frontal and Deep network was significantly decreased in autism spectrum disorder. Finally, the correlation analysis showed that the white matter and white-matter functional network connectivity between the Middle temporo-frontal network and others networks and the spontaneous activity of the Deep network were significantly correlated with the Social Responsiveness Scale scores of autism spectrum disorder. Together, our findings indicate that changes in the white-matter functional networks are associated behavioral deficits in autism spectrum disorder.


[Preliminary study on differentiation-inducing associated genes of human brain glioma cells in vitro].
Glioma cells can be induced in vitro from low differentiation state to high differentiation state with differentiation-inducing agents, as our previous studies have showed. However, the relevant molecular mechanisms remained unclear. This paper was to establish differentiation-inducing gene expression pedigree of glioma cells and clone new relevant genes, for the purpose of offering genomic information on the molecular mechanisms of differentiation-inducing effects of tumor cells. A low differentiated human brain glioma cell line (SHG-44-9) was treated with differentiation-inducing agents. The differentiation-inducing effects on glioma cells were determined using MTT assay, colony-forming efficiency in double-layer soft agar, cell morphological changes, flow cytometry, and fluoroimmunoassay of glial fibrillary acidic protein expression. Gene expression differences of tumor cells before and after inducing were assayed with cDNA microarray techniques. The relevant genes were cloned with differential display polymerase chain reaction (DD-PCR), and verified with Northern blot analysis, then the genomic information about these genes were analyzed with bioinformatics technologies. At dose of 1.75 mmol x L(-1), sodium butyrate caused a marked proliferation inhibitory effect on the SHG-44-9 cells, and drove them to a more mature phenotype. The expression of 98 genes changed obviously when were screened with gene chips immobilized with 18,000 human cDNAs, which were further proved by Northern blot analysis. Twelve differentiation-associated genes were cloned, including MIBP1 gene, which can regulate the c-myc gene expression and may be relevant with glioma cell differentiation. Ninety-eight genes associated with differentiation and 12 genes were cloned. These data may help to further study the molecular mechanisms of glioma cells differentiation, and to find new targets for gene therapy against glioma.


Diagnostic assessment, therapeutic care and education pathways in persons with autism spectrum disorder in transition from childhood to adulthood: the Italian National Ev.A Longitudinal Project.
The transition from childhood to adulthood is one of the main critical points in the network of services for taking care of people with autism spectrum disorder (ASD). Within the framework of the national research programs on autism, an exploratory longitudinal multicentre study was conducted. This research program, called "Ev.A Project (Developmental and Adult Age)", was proposed by the Italian National Institute of Health (Istituto Superiore di Sanità, ISS) and the aim was the development and testing of a diagnostic, therapeutic, assistance and educational pathway (PDTAE) for autism. The present study aimed to evaluate two impact outcomes of the care protocol: the response obtained by the ASD person, and the perception of the change in the family context. Participants underwent an initial clinical evaluation and then after one year. Over the course of the year, participants undertook a program of intervention. The measures of adaptive functioning, need for support, psychiatric symptomatology and family quality of life were used for the outcome assessment. Linear mixed models were constructed for each measure to estimate the explanatory/predictive behavior of the intensity of the interventions, adjusted for the participant's level of symptom severity. The results estimate a main effect of Intervention Group (b=-27.22, p<0.001) and severity level (b=-41.87, p<0.001) on the adaptive functioning of the ASD person, but no effect on performance on the dimension of Family Quality of Life (b=0.523, p=0.455). The most significant predictor of the impact on the ASD person is the activation of the service network, which must take into account the level of severity of the presented symptoms.


Identification and Characterization of a Neutral Locus for Knock-in Purposes in C. parapsilosis.
Invasive fungal infections caused by Candida species affect approximately 700,000 people worldwide resulting in 300,000 deaths annually. Besides Candida albicans, other members of the genus have gained relevance in the last two decades, including C. parapsilosis whose incidence is particularly high amongst low birth weight neonates. To investigate the virulence properties of this pathogen several techniques have been developed for generating knock-out mutants, however, no target locus for knock-in approaches have been published so far. Here we report CpNEUT5L (N5L), an intergenic locus in C. parapsilosis, and introduce an integrative GatewayTM and a classical ligation based replacement plasmid to target it with. As a proof of principle, we fluorescently tagged laboratory and prototroph strains and established that this locus is also suitable for reintegration purposes. We concluded that GFP-expressing constructs integrated into this region provide strong, homogenous fluorescent signals while alteration of this locus affects neither the growth of the mutants in liquid or on solid media, even in the presence of different stressors, nor their basic virulence properties. Hence, our findings demonstrate that N5L is a highly effective neutral locus for knock-in approaches in C. parapsilosis.


In-TOX-icating neurogenesis.
Early development of the mammalian cerebral cortex proceeds via a sequence of proliferative and differentiative steps from neural stem cells toward neurons and glia. However, how these steps are molecularly orchestrated is still only partially understood. In this issue of The EMBO Journal, Artegiani and colleagues implicate Tox, a HMG-box transcription factor previously known only for its role in lymphocyte development, in early cortical development.


Initiation-promotion versus complete skin carcinogenesis in mice: importance of dark basal keratinocytes (stem cells).
Tumor promotion research has accelerated at an explosive level during the past decade and continues to do so because of its importance to the understanding of the induction of human cancer. Furthermore, the promotion process, being mostly reversible allows one to find very effective ways to prevent cancer. The extensive data available as well as the multistage nature of tumor promotion suggests that this process, which is thought to occur in most tissues where cancer can be induced or occurs spontaneously, may involve the interaction of a number of environmental factors such as chemical, radiation, viruses and diet and nutrition, thus unifying all of the current areas of cancer research. In terms of human cancer, smoking, asbestos, radiation, alcohol and diet, and nutrition just to mention a few, are not thought to have more than a promotional influence in the carcinogenesis process. Here and in later papers we will discuss some important aspects of promotion as well as discuss the possible controversial nature of this process. In this review we present data which suggest that carcinogenesis can be operatively and mechanistically divided into various stages.


Loss of somatic heterozygosity in hepatocellular carcinoma.
Loss of tumor suppressor genes is involved in the mechanism of tumorigenesis of many solid tumors. We tested 9 hepatitis B virus (HBV)-positive and 10 HBV-negative hepatocellular carcinomas for loss of somatic heterozygosity using 14 polymorphic probes mapping to chromosomes 4, 11, 13, and 17. Losses were found on all chromosome arms tested. The highest frequency of loss was observed at the D13S1 locus (67%) at band 13q12. Losses were also observed at three other loci on 13q. Twenty-one % of informative cases showed loss on 17p using the probe pYNZ22 which maps near the p53 locus. Losses on 4q were infrequent with 17% found at one locus and no loss at two others. The retinoblastoma gene and the locus on 17p were only inactivated in our HBV-negative tumors, although the numbers were too small for statistical significance. For all loci tested, we found no significant differences in the frequency of losses with HBV status, ethnic background, cirrhosis, grade of tumor, or presence of hemochromatosis.


[Role of laparoscopic biopsy in the management of intra-abdominal lymphadenopathy].
Intra- or retroperitoneal lymphadenopathy is often a diagnostic challenge Surgical radiology techniques, such as fine needle aspiration and core needle biopsy, are useful but frequently inadequate and sometimes difficult and dangerous to perform. Deep abdominal lymph node sampling can be done laparoscopically, avoiding the risks of a large laparotomy. The objective of this study was to assess the safety, efficacy and diagnostic accuracy of laparoscopic biopsy, when compared with historic needle biopsy studies reported in the literature. From January 1999 to June 2001, 19 laparoscopic biopsies were performed for 18 patients with intra- or retroperitoneal lymphadenopathy. Clinical and technical characteristics and histopathological findings for each laparoscopic biopsy performed were analysed retrospectively. In 15 patients the biopsy was performed in order to achieve the diagnosis. In the other 4 cases laparoscopic biopsy was required to confirm a relapse or the evolution of a lymphoma during treatment or follow-up. The conversion rate was nil. There were no major complications. None of the patients died postoperatively. The average hospital stay was 2.4 days (range: 1-6 days). In 94% of the cases, the laparoscopic biopsy supplied the necessary information for the correct diagnosis and consequent therapeutic decisions. These results confirm that laparoscopic biopsy is safe and effective. This procedure has a higher diagnostic yield than the percutaneous techniques and should be proposed as the gold standard biopsy approach in all cases of deep abdominal lymphadenopathy.


Seroreactivity against MAGE-A and LAGE-1 proteins in melanoma patients.
Cancer-testis antigens exemplify a growing number of tumour antigens which are expressed in a variety of malignancies, but not in normal tissues other than germ cells, primarily those of the testis. To investigate the humoral response to known cancer-testis antigens in melanoma patients. We used phage clones coding for seven different melanoma antigens MAGE-A or LAGE-1A proteins. These clones were isolated using the newly developed DNA hybridization analysis of recombinantly expressed cDNA libraries (HYREX) approach. HYREX combines the advantage of a nonradioactive library screening method with the possibility of subsequently analysing the serological response to the recombinant proteins. We isolated clones coding for MAGE-A1, -A3, -A4b, -A6, -A9 and -A12, as well as LAGE-1A. Additionally, we correlated gene expression and seroreactivity. Between 13% and 27% of sera (n = 15) were reactive against individual tumour antigens. We found the presence of specific antibodies was, with only two exceptions, generally correlated with mRNA expression of the antigen within cell lines derived from the same patient. While cross-reactivity of patients' IgG might play a role in these cases, antibodies from patients' sera were able to distinguish even the closely related MAGE-A3 and -A6. In general, the mRNA expression frequency was higher than the detected IgG responses. Antibody recognition of specific tumour antigens by patients' sera may be used for evaluating the possible immunogenicity of new antigens; serological tests could be used for tumour monitoring purposes.


Attitudes of Gay, Bisexual, and Other Men Who Have Sex with Men (GBM) toward Their Use of Amphetamine-Type Stimulants and Relation to Reducing Use in Three Canadian Cities.
We explored attitudes of gay, bisexual, and other men who have sex with men (GBM) toward their amphetamine-use and associations with reduced use over time. We recruited sexually-active GBM aged 16+ years in Montreal, Toronto, and Vancouver, Canada, from 02-2017 to 08-2019, with follow-up visits every 6-12 months until November 2020. Among participants who reported past-six-month (P6M) amphetamine-use at enrollment, we used logistic regression to identify demographic, psychological, social, mental health, other substance-use, and behavioral factors associated with reporting needing help reducing their substance-use. We used mixed-effects logistic regression to model reduced P6M amphetamine-use with perceived problematic-use as our primary explanatory variable. We enrolled 2,449 GBM across sites. 15.5-24.7% reported P6M amphetamine-use at enrollment and 82.6 - 85.7% reported needing no help or only a little help in reducing their substance use. Reporting needing a lot/of help or completely needing help in reducing substance-use was associated with group sex participation (AOR = 2.35, 95%CI:1.25-4.44), greater anxiety symptomatology (AOR = 2.11, 95%CI:1.16-3.83), greater financial strain (AOR = 1.35, 95%CI:1.21-1.50), and greater Escape Motive scores (AOR = 1.07, 95%CI:1.03-1.10). Reductions in P6M amphetamine-use were less likely among GBM who perceived their amphetamine-use as problematic (AOR = 0.17 95% CI 0.10 - 0.29). Most amphetamine-using GBM did not feel they needed help reducing their substance use, and many reported reduced amphetamine-use at subsequent visits. Those who perceived their use as problematic were less likely to reduce their use. Further interventions to assist GBM in reducing their use are needed to assist those who perceive their use as problematic.


Interactions of hyperthermia and drugs: treatments and probes.
At temperatures above 37 degrees C, the abilities of many, but not of all, anticancer drugs to kill cells increases substantially. The increased cytotoxic rate can vary smoothly with temperature (e.g., nitrosoureas or cis-platinum(II) diamminedichloride) or show a marked threshold near 43 degrees C (e.g., adriamycin or bleomycin). Clinically, the increased cell killing rate can be used in the combination of localized hyperthermia and systemic chemotherapy. Drugs can also be useful in the study of cell killing by heat. Aliphatic alcohols which mimic and interact with heat, tend to be localized in lipid-rich regions of the cell, i.e., membranes. Heat modifies the rate at which plant lectins agglutinate cells and also modifies capping rates; most likely, these changes reflected membrane alterations. Because other data strongly imply that proteins are involved in cell death, we think that the first step in hyperthermic killing of cells involves damage to specific membrane-associated proteins.


Learning with Weak Annotations for Robust Maritime Obstacle Detection.
Robust maritime obstacle detection is critical for safe navigation of autonomous boats and timely collision avoidance. The current state-of-the-art is based on deep segmentation networks trained on large datasets. However, per-pixel ground truth labeling of such datasets is labor-intensive and expensive. We propose a new scaffolding learning regime (SLR) that leverages weak annotations consisting of water edges, the horizon location, and obstacle bounding boxes to train segmentation-based obstacle detection networks, thereby reducing the required ground truth labeling effort by a factor of twenty. SLR trains an initial model from weak annotations and then alternates between re-estimating the segmentation pseudo-labels and improving the network parameters. Experiments show that maritime obstacle segmentation networks trained using SLR on weak annotations not only match but outperform the same networks trained with dense ground truth labels, which is a remarkable result. In addition to the increased accuracy, SLR also increases domain generalization and can be used for domain adaptation with a low manual annotation load. The SLR code and pre-trained models are freely available online.


[CBO-guideline 'Bacterial meningitis'].
Neisseria meningitidis and Streptococcus pneumoniae are the most frequent causes of bacterial meningitis. The incidence of Haemophilus meningitis in the Netherlands is low due to successful Haemophilus influenzae type b vaccination. This implies that there is no need to take account into this microorganism in using initial empiric antimicrobial therapy for bacterial meningitis. Vomiting (especially children), headache, fever, and a stiff neck characterize acute bacterial meningitis. However, even without these signs a patient may still have acute bacterial meningitis. The characteristics in neonates are less specific. An emergency lumbar puncture should be performed in all patients with meningeal irritation or other signs of bacterial meningitis. Examination of the CSF is not indicated for convulsive children (between the ages of 6 months and 6 years) who do not exhibit other clinical signs. In patients who respond adequately to the treatment, it is not necessary to examine the CSF again. Papilloedema or focal neurological symptoms contraindicate a lumbar puncture in patients with bacterial meningitis, until CT results justify that it can be performed safely. Antibiotic treatment should not be delayed until after the CT. General practitioners should treat their patients with suspected meningococcus infection by admitting them to the hospital without first injecting antibiotics. In the Netherlands, patients with suspected pneumococcus meningitis may still be treated with benzylpenicillin. Patients with bacterial meningitis have no fluid restrictions; only in case of the syndrome of inadequate secretion of antidiuretic hormone is fluid reduction indicated. The physician is responsible for prescribing prophylaxis to family members. The Regional Health Services organize chemoprophylaxis for classmates. The latter is only indicated if at least 2 related cases occur in one month.


An empirical study of schema-associated mnemonic method for classical Chinese poetry in primary and secondary education based on cognitive schema migration theory.
Classical Chinese poetry, as an indispensable part of China's national culture, provides valuable resources for improving literary literacy and fostering patriotism among primary and secondary school students. This study, based on cognitive schema migration theory, investigated the effect of a "schema-associated mnemonic method" on the memory efficiency and retention of classical Chinese poetry memorization among the students. Through a controlled experiment, the results revealed that the experimental group (n = 63) outperformed the control one in memorizing classical poetry with higher memory efficiency and retention, which indicates the sustainable application prospects of the method in primary and secondary education. The findings of this research can provide beneficial insights for the effective integration of classical Chinese poetry teaching and educational technologies.


Acquisition dynamics of Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis at the host-vector interface.
The population dynamics of two cotransmitted tick-borne pathogens, Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis (aoHGE), were assessed at the skin-vector interface at intervals after tick attachment on infected mice. Quantitative real-time polymerase chain reaction targeting the B. burgdorferi flagellin gene revealed consistent decreases in spirochete numbers in skin at the sites of tick attachment compared with non-tick attachment sites. This phenomenon was found during early (2 weeks) and late (8 weeks) infection and at 24, 48, and 72 h after tick attachment. A nonspecific inflammatory stimulus, implantation of suture material, did not have this effect. In contrast to B. burgdorferi, copy numbers of an aoHGE p44 target gene target were significantly increased at the sites of tick attachment, compared with non-tick sites. The non-specific stimulus of suture material had the same effect on aoHGE recruitment as tick attachment in aoHGE infected mice. These results reinforce the concept that B. burgdorferi interfaces with its vector by virtue of its non-systemic dermatotropism, and not via systemic hematogenous acquisition. In contrast, results indicate that the aoHGE relies upon hematogenous acquisition. Thus, these two cotransmitted tick-borne pathogens utilize distinctly different means of vector acquisition.


Prostatism: how useful is routine imaging of the urinary tract?
The clinical effects of routinely imaging the renal tract (by intravenous urography and ultrasonography) were evaluated prospectively in 128 consecutive patients with prostatism. Patients with haematuria, previous renal disease, or infection were excluded. Urologists completed a standard questionnaire in the patient's notes stating the diagnosis and the intended management. The patient then had intravenous urography and abdominal ultrasonography, urine was analysed, and plasma urea and serum creatinine concentrations and acid phosphatase activity were determined. From six months to a year later the eventual management was compared with the intended management to see the effect of these routine investigations on the outcome. For four out of 28 patients whose management was intended to be conservative the decision was changed; for only three of them was this because of the results of urography, ultrasonography, and biochemical determinations. For 31 patients the management was to be decided by cystoscopic findings, and for none of these was the final decision altered by the results from the investigations after the initial consultation. Similarly for five patients who were assessed urodynamically the final management was not changed by the results of these investigations. The planned management was changed in three of the remaining 64 patients but not because of the results of the initial investigations. Thus no indication was found for either routine urography or ultrasonography, but the total abandonment of imaging of the renal tract would be unwise. Patients scheduled for conservative management (about a quarter of the patients in this study) should have ultrasonography to detect unsuspected hydronephrosis, but in all other patients urography or ultrasonography, or both, is an unhelpful ritual. Moreover, urography is becoming more expensive, and has a recognised (albeit small) mortality.


Genetics of phototaxis in a model eukaryote, Dictyostelium discoideum.
The life cycle of Dictyostelium discoideum offers a unique opportunity to study signal transduction in eukaryotic cells at both the unicellular and multicellular levels of organization. Adding to the already extensive knowledge of the unicellular stages, classical and molecular genetics have begun to unravel transduction of signals controlling morphogenesis and behaviour (phototaxis and thermotaxis) in the multicellular 'slug' stage of the life cycle. Distributed over all seven genetic linkage groups are probably about 20, but possibly as many as 55, genes of importance for slug behaviour. The encoded proteins appear from pharmacological studies and mutant phenotypes to govern transduction pathways involving the intracellular second messengers cyclic AMP, cyclic GMP, IP3 and Ca2+. Pathways from the photo- and thermoreceptors converge first with each other and thence, at the level of the second messengers, with those from extracellular tip activation (cyclic AMP) and inhibition (Slug Turning Factor and/or ammonia and/or adenosine) signals that control slug movement and morphogenesis.


mGluR5 in cortical excitatory neurons exerts both cell-autonomous and -nonautonomous influences on cortical somatosensory circuit formation.
Glutamatergic neurotransmission plays important roles in sensory map formation. The absence of the group I metabotropic glutamate receptor 5 (mGluR5) leads to abnormal sensory map formation throughout the mouse somatosensory pathway. To examine the role of cortical mGluR5 expression on barrel map formation, we generated cortex-specific mGluR5 knock-out (KO) mice. Eliminating mGluR5 function solely in cortical excitatory neurons affects, not only the whisker-related organization of cortical neurons (barrels), but also the patterning of their presynaptic partners, the thalamocortical axons (TCAs). In contrast, subcortical whisker maps develop normally in cortical-mGluR5 KO mice. In the S1 cortex of cortical-mGluR5 KO, layer IV neurons are homogenously distributed and have no clear relationship to the location of TCA clusters. The altered dendritic morphology of cortical layer IV spiny stellate neurons in cortical-mGluR5 KO mice argues for a cell-autonomous role of mGluR5 in dendritic patterning. Furthermore, morphometric analysis of single TCAs in both cortical- and global-mGluR5 KO mice demonstrated that in these mice, the complexity of axonal arbors is reduced, while the area covered by TCA arbors is enlarged. Using voltage-clamp whole-cell recordings in acute thalamocortical brain slices, we found that KO of mGluR5 from cortical excitatory neurons reduced inhibitory but not excitatory inputs onto layer IV neurons. This suggests that mGluR5 signaling in cortical excitatory neurons nonautonomously modulates the functional development of GABAergic circuits. Together, our data provide strong evidence that mGluR5 signaling in cortical principal neurons exerts both cell-autonomous and -nonautonomous influences to modulate the formation of cortical sensory circuits.


Hepatic autophagy mediates endoplasmic reticulum stress-induced degradation of misfolded apolipoprotein B.
Induction of endoplasmic reticulum (ER) stress was previously shown to impair hepatic apolipoprotein B100 (apoB) production by enhancing cotranslational and posttranslational degradation of newly synthesized apoB. Here, we report the involvement of autophagy in ER stress-induced degradation of apoB and provide evidence for a significant role of autophagy in regulating apoB biogenesis in primary hepatocyte systems. Induction of ER stress following short-term glucosamine treatment of McA-RH7777 cells resulted in significantly increased colocalization of apoB with green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3), referred to as apoB-GFP-LC3 puncta, in a dose-dependent manner. Colocalization with this autophagic marker correlated positively with the reduction in newly synthesized apoB100. Treatment of McA-RH7777 cells with 4-phenyl butyric acid, a chemical ER stress inhibitor, prevented glucosamine- and tunicamycin-induced increases in GRP78 and phosphorylated eIF2α, rescued newly synthesized [(35) S]-labeled apoB100, and substantially blocked the colocalization of apoB with GFP-LC3. Autophagic apoB degradation was also observed in primary rat and hamster hepatocytes at basal conditions as well as upon the induction of ER stress. In contrast, this pathway was inactive in HepG2 cells under ER stress conditions, unless proteasomal degradation was blocked with N-acetyl-leucinyl-leucinyl-norleucinal and the medium was supplemented with oleate. Transient transfection of McA-RH7777 cells with a wild-type protein kinase R-like ER kinase (PERK) complementary DNA resulted in dramatic induction of apoB autophagy. In contrast, transfection with a kinase inactive mutant PERK gave rise to reduced apoB autophagy, suggesting that apoB autophagy may occur via a PERK signaling-dependent mechanism. Taken together, these data suggest that induction of ER stress leads to markedly enhanced apoB autophagy in a PERK-dependent pathway, which can be blocked with the chemical chaperone 4-phenyl butyric acid. ApoB autophagy rather than proteasomal degradation may be a more pertinent physiological mechanism regulating hepatic lipoprotein production in primary hepatocytes.


Unlocking repression of the human luteinizing hormone receptor gene by trichostatin A-induced cell-specific phosphatase release.
Our previous studies demonstrated that the histone deacetylase inhibitor, trichostatin A (TSA), induces derepression of the human luteinizing hormone receptor (LHR) gene by de-recruitment of the pRB homologue p107 repressor from the promoter in JAR and MCF-7 cancer cells. TSA initiates a mechanism whereby the phosphatidylinositol 3-kinase/protein kinase zeta (PKCzeta) cascade phosphorylates Sp1 at Ser-641, which is essential for the release of the repression of LHR transcription. The present studies have revealed that dissociation of serine/threonine protein phosphatases PP2A and PP1 from the LHR promoter mediates TSA-induced activation of LHR gene transcription in a cell-specific manner. Changes in chromatin structure induced by TSA cause the release of PP2A in JAR cells or of PP1 in MCF-7 cells, which is associated with Sp1 directly or through histone deacetylase 1/2, respectively, at the promoter. This favors the phosphorylation of Sp1 mediated by the phosphatidylinositol 3-kinase/PKCzeta pathway, which in turn causes the release of the p107 inhibitor from Sp1 and marked transcriptional activation of the LHR. These findings reveal the importance of phosphatases in the control of LHR transcription, where the balance between phosphatidylinositol 3-kinase/PKCzeta and phosphatases could be critical for up- and down-regulation of LHR gene expression in physiological and pathological settings.


Measuring health status in chronic airflow limitation.
A health status instrument for use in clinical trials must be valid (measuring what it is supposed to measure) and responsive (able to detect clinically important change). Approaches to measuring health status in clinical trials include using a battery of instruments, a general instrument which provides a profile of the patient's health, an instrument that generates a health utility, or an instrument that focuses on the problems associated with a particular disease. Disease-specific instruments have been used in clinical trials in chronic airflow limitation (CAL). The Oxygen Cost Diagram is simple and easy to administer, but responsiveness and validity are unproven. The Transition Dyspnoea Index is valid and responsive, but is difficult to use in trials in which multiple measurements are desired. The Chronic Respiratory Disease Questionnaire has proved valid and responsive in controlled trials in CAL patients. Health status measures should be included in all clinical trials in CAL.


[The incidence of clinical cases in a peri-urban farm animal practice].
The incidence of clinical cases in farm animals encountered in the ambulatory practice at the Faculty of Veterinary Science, University of Pretoria, is discussed. In a 3 year period 4 013 clinical cases were seen; these did not include cases seen during herd examinations. The diagnoses made are grouped under infectious diseases (19,6%), nonspecific inflammatory conditions (17,3%), gastro-intestinal conditions (9,7%), gynaecological conditions and procedures (14,5%), surgical conditions and procedures (26%), toxicological conditions (3,7%), metabolic diseases (1,5%), nutritional abnormalities (2,4%) and miscellaneous conditions.


Krüppel-like factors compete for promoters and enhancers to fine-tune transcription.
Krüppel-like factors (KLFs) are a family of 17 transcription factors characterized by a conserved DNA-binding domain of three zinc fingers and a variable N-terminal domain responsible for recruiting cofactors. KLFs have diverse functions in stem cell biology, embryo patterning, and tissue homoeostasis. KLF1 and related family members function as transcriptional activators via recruitment of co-activators such as EP300, whereas KLF3 and related members act as transcriptional repressors via recruitment of C-terminal Binding Proteins. KLF1 directly activates the Klf3 gene via an erythroid-specific promoter. Herein, we show KLF1 and KLF3 bind common as well as unique sites within the erythroid cell genome by ChIP-seq. We show KLF3 can displace KLF1 from key erythroid gene promoters and enhancers in vivo. Using 4sU RNA labelling and RNA-seq, we show this competition results in reciprocal transcriptional outputs for >50 important genes. Furthermore, Klf3-/- mice displayed exaggerated recovery from anemic stress and persistent cell cycling consistent with a role for KLF3 in dampening KLF1-driven proliferation. We suggest this study provides a paradigm for how KLFs work in incoherent feed-forward loops or networks to fine-tune transcription and thereby control diverse biological processes such as cell proliferation.


Vocalization Rate and Consonant Production in Toddlers at High and Low Risk for Autism.
Previous work has documented lower vocalization rate and consonant acquisition delays in toddlers with autism spectrum disorder (ASD). We investigated differences in these variables at 12, 18, and 24 months in toddlers at high and low risk for ASD. Vocalization rate and number of different consonants were obtained from speech samples from a prospective study of infant siblings of children with ASD. Three groups were compared: 18 toddlers at low risk for ASD (low-risk control), 18 high-risk siblings without ASD (HRA-), and 10 high-risk siblings with ASD (HRA+). All groups' mean language scores were within the normal range. HRA+ toddlers showed consistently lower vocalization rate; vocalization rate did not predict number of different consonants at 12 months for HRA+. HRA-, not HRA+, toddlers had the smallest number of different consonants and produced significantly fewer different consonants than predicted by their vocalization rate at 12 months. Consonant-acquisition trajectories differed between groups, with HRA- showing the greatest increase from 12 to 18 months. Lower vocalization rate was not associated with reduced number of different consonants in these toddlers. Between-groups differences in developmental trajectories are discussed in the context of the social feedback loop and differential ability to benefit from adult feedback between groups.


Extracellular cysteine protease produced by Streptococcus pyogenes participates in the pathogenesis of invasive skin infection and dissemination in mice.
The role of an extracellular cysteine protease encoded by the speB gene in group A Streptococcus (GAS) skin infection was studied with a mouse model. Mice were injected subcutaneously with a wild-type GAS serotype M3 strain or a cysteine protease-inactivated isogenic derivative grown to stationary phase. The mortality rate of mice injected with the M3 speB mutant strain was significantly decreased (P < 0.0008) compared to that of animals injected with the wild-type parental organism. The abscesses formed in animals infected with the cysteine protease mutant strain were significantly smaller (P < 0.0001) than those caused by the wild-type organism and slowly regressed over 3 to 4 weeks. In striking contrast, infection with the wild-type GAS isolate generated necrotic lesions, and in some animals the GAS disseminated widely from the injection site and produced extensive cutaneous damage. All of these animals developed bacteremia and died. GAS dissemination was accompanied by severe tissue and blood vessel necrosis. Cysteine protease expression in the infected tissue was identified by immunogold electron microscopy. These data demonstrate that cysteine protease expression contributes to soft tissue pathology, including necrosis, and is required for efficient systemic dissemination of the organism from the initial site of skin inoculation.


Intelligent controllers as hierarchical stochastic automata.
This paper introduces a design methodology for intelligent controllers, based on a hierarchical linguistic model of command translation by tasks-primitive tasks-primitive actions, and on a two-stage hierarchical learning stochastic automaton that models the translation interfaces of a three-level hierarchical intelligent controller. The methodology relies on the designer's a priori knowledge on how to implement by primitive actions the different primitive tasks which define the intelligent controller. A cost function applicable to any primitive task is introduced and used to learn on-line the optimal choices from the corresponding predesigned sets of primitive actions. The same concept applies to the optimal tasks for each command, whose choice is based on conflict sets of stochastic grammar productions. Optional designs can be compared using this performance measure. A particular design evolves towards the command translation (by tasks-primitive tasks-primitive actions) that minimizes the cost function.


Novel Compound Heterozygous Mutations of TGM1 Gene Identified in a Turkish Collodion Baby Diagnosed with Non-Bullous Congenital Ichthyosiform Erythroderma.
Autosomal recessive congenital ichthyosis (ARCI) is a group of diseases presenting as collodion baby at birth. ARCI is categorized as Harlequin ichthyosis, lamellar ichthyosis, and non-bullous congenital ichthyosiform erythroderma (NBCIE), bathing suit icthyosis (BSI) and others. We describe the case of a male newborn with NBCIE whose whole exome sequencing revealed two variants of TGM1 gene (NM_000359.3) in a compound heterozygous state: c.790C>T (p.Arg264Trp) in exon 5 and c.2060G>A (p.Arg687His) in exon 13. In the literature, the Arg264Trp variant has been reported as homozygous or compound heterozygous with other variants in patients with BSI. In contrast, the Arg687His variant has been reported only as homozygous in patients with BSI. To the best of our knowledge, this is the first case whose two compound heterozygous variants, exhibiting the NBCIE phenotype, instead of the BSI.


Indirect genetic effects and housing conditions in relation to aggressive behaviour in pigs.
Indirect Genetic Effects (IGEs), also known as associative effects, are the heritable effects that an individual has on the phenotype of its social partners. Selection for IGEs has been proposed as a method to reduce harmful behaviours, in particular aggression, in livestock and aquaculture. The mechanisms behind IGEs, however, have rarely been studied. The objective was therefore to assess aggression in pigs which were divergently selected for IGEs on growth (IGEg). In a one generation selection experiment, we studied 480 offspring of pigs (Sus scrofa) that were selected for relatively high or low IGEg and housed in homogeneous IGEg groups in either barren or enriched environments. Skin lesion scores, a proxy measure of aggression, and aggressive behaviours were recorded. The two distinct IGEg groups did not differ in number of skin lesions, or in amount of reciprocal fighting, both under stable social conditions and in confrontation with unfamiliar pigs in a 24 h regrouping test. Pigs selected for a positive effect on the growth of their group members, however, performed less non-reciprocal biting and showed considerably less aggression at reunion with familiar group members after they had been separated during a 24 h regrouping test. The enriched environment was associated with more skin lesions but less non-reciprocal biting under stable social conditions. Changes in aggression between pigs selected for IGEg were not influenced by G×E interactions with regard to the level of environmental enrichment. It is likely that selection on IGEg targets a behavioural strategy, rather than a single behavioural trait such as aggressiveness.


Management of chemical dependence in pregnancy.
Although the percentage of pregnant patients who use illicit drugs is relatively low, the effects can be devastating on both mother and fetus-loss of custody, growth restriction, placental abruption, and death. The practicing obstetrician may be unfamiliar with the various presentations of chemical dependency in pregnancy, including intoxication and withdrawal, and difficulty in making the diagnosis. The obstetrician is in the unique situation of being responsible for the safety of both mother and fetus, which may involve engaging the unwilling patient in treatment.


Developmental changes in multivariate neuroanatomical patterns that predict risk for psychosis in 22q11.2 deletion syndrome.
The primary objective of the current prospective study was to examine developmental patterns of voxel-by-voxel gray and white matter volumes (GMV, WMV, respectively) that would predict psychosis in adolescents with 22q11.2 deletion syndrome (22q11.2DS), the most common known genetic risk factor for schizophrenia. We performed a longitudinal voxel-based morphometry analysis using structural T1 MRI scans from 19 individuals with 22q11.2DS and 18 typically developing individuals. In 22q11.2DS, univariate analysis showed that greater reduction in left dorsal prefrontal cortical (dPFC) GMV over time predicted greater psychotic symptoms at Time2. This dPFC region also showed significantly reduced volumes in 22q11.2DS compared to typically developing individuals at Time1 and 2, greater reduction over time in 22q11.2DS COMT(Met) compared to COMT(Val), and greater reduction in those with greater decline in verbal IQ over time. Leave-one-out Multivariate pattern analysis results (MVPA) on the other hand, showed that patterns of GM and WM morphometric changes over time in regions including but not limited to the dPFC predicted risk for psychotic symptoms (94.7-100% accuracy) significantly better than using univariate analysis (63.1%). Additional predictive brain regions included medial PFC and dorsal cingulum. This longitudinal prospective study shows novel evidence of morphometric spatial patterns predicting the development of psychotic symptoms in 22q11.2DS, and further elucidates the abnormal maturational processes in 22q11.2DS. The use of neuroimaging using MVPA may hold promise to predict outcome in a variety of neuropsychiatric disorders.


Efficacy and safety of probiotics in preterm infants.
Probiotics are live microbial feed supplements that beneficially affect the recipient by improving intestinal balance. In an updated systematic review, nineteen trials randomizing more than 2800 infants were included. In a meta-analysis of trial data, enteral probiotic supplementation significantly reduced the incidence of severe necrotizing enterocolitis (typical RR 0.35, 95% CI 0.24 to 0.52) and mortality (typical RR 0.55, 95% CI 0.40 to 0.74). There was no evidence of significant reduction of nosocomial sepsis (typical RR 0.89, 95% CI 0.77 to 1.03). The included trials reported no systemic infection with - supplemented probiotics. Recent data in addition to a report by the European Society for Pediatric Gastroenterology (ESPGAN) concluded probiotics could be generally considered safe.


Novel bleeding prediction model in atrial fibrillation patients on new oral anticoagulants.
Clinical models such as the HAS-BLED (standing for Hypertension, Abnormal liver/renal function, Stroke history, Bleeding history or predisposition, Labile INR, Elderly, Drug/alcohol usage) were developed to predict risk of major bleeding on vitamin K antagonists/antiplatelet therapy. We aimed to develop a model that will improve the ability to predict major bleeding events in patients with non-valvular atrial fibrillation (AF) treated with new oral anticoagulants (NOACs). Clalit Health Services is the largest of four integrated healthcare organisations in Israel, which insures 4.7 million patients (53% of the population). We identified in Clalit Health Services all patients with AF, new users of an NOAC (2013-2017), and followed them until first occurrence of a major bleeding event, death, switch to another oral anticoagulant, 30 days after discontinuation of NOAC or end of follow-up (31 December 2019). Importance of the candidate model variables was estimated by inclusion frequencies across forward selection algorithm applied to 50 bootstrap samples. Then, backward selection algorithm using the modified Bayesian Information Criterion for competing risks was applied to select predictors for the final model. 47 623 patients with AF prescribed NOAC were studied. 28 055 patients with AF, initiators of apixaban (mean age 78.7, SD 9.0), were included in the first phase and had 662 major bleeding events. Nine variables were selected for inclusion in a final points-based risk-scoring system: male sex, anaemia, thrombocytopaenia (<99×103/µL), concurrent antiplatelet therapy, hypertension, prior major bleeding, risk factors for a fall, low cholesterol level and low estimated glomerular filtration rate, with apparent area-under-curve (AUC) of 0.6546. Applicability of the model was then shown for 14 118 and 5450 patients with AF, initiators of dabigatran and rivaroxaban, where the score achieved c indices of 0.62 and 0.61, respectively. We present a novel and simple risk score for prediction of major bleeding in patients with non-valvular AF treated with NOACs. Validation in additional cohorts is warranted.


Upper-arm elevation during office work.
The present aim was to measure and quantify upper-arm elevation and to find how changed work organization and work tasks influence arm movement during a working day. Sixteen female office workers participated in the study. Their main work was statistical data entry. Upper-arm elevation was measured on two occasions separated by 18 months, i.e., before and after a change of work organization. The measurements were performed during the whole of one ordinary working day. The differences between the two measurements were mostly non-significant. Arm elevation remained essentially below 30 degrees during the main time of the working day, and the subjects worked with limited arm movements. Despite new alternative office tasks, they did not achieve a change in their habitual arm postures, or in their neck-and-shoulder disorders.


[Chronic non-communicable diseases: a global epidemic of the 21st century].
Chronic non-communicable diseases (NCDs) are the cause of 86% of all deaths in the EU and 65% of deaths worldwide. A third of these deaths occur before the age of sixty years. The NCDs affect 40% of the adult population of the EU and two thirds of the population reaching retirement age suffers from two or more NCDs. The NCDs are a global epidemic challenging economic growth in most countries. According to the WHO, NCDs are one of the major threats to worldwide social and economic development in the 21st century. The problem is of great concern to the international community and was discussed at a High level meeting at the UN General Assembly in September 2011. In this paper we review the epidemic of NCDs both from a national and international perspective. We discuss the causes and consequences. In a second review paper we reflect on the political health policy issues raised by the international community in order to respond to the problem. These issues will become a major challenge for social and economic development in most countries of the world in the coming decades.


The association between transformation ability and antimicrobial resistant potential in Haemophilus influenzae.
The prevalence of quinolone low-susceptible H. influenzae has increased in Japan. Low quinolone susceptibility is caused by point mutations in target genes; however, it can also be caused by horizontal gene transfer via natural transformation. In this study, we examined whether this horizontal gene transfer could be associated with resistance to not only quinolones but also other antimicrobial agents. Horizontal transfer ability was quantified using the experimental transfer assay method for low quinolone susceptibility. Further, the association between horizontal transfer ability and resistance to β-lactams, the first-choice drugs for H. influenzae infection, was investigated. The transformation efficiency of 50 clinical isolates varied widely, ranging from 102 to 106 CFU of the colonies obtained by horizontal transfer assay. Efficiency was associated with β-lactam resistance caused by ftsI mutations, indicating that strains with high horizontal transfer ability acquired quinolone low-susceptibility as well as β-lactam resistance more easily. Strains with high transformation efficiency increased the transcript level of comA, suggesting that enhanced com operon was associated with a high DNA uptake ability. Overall, this study revealed that the transformation ability of H. influenzae was associated with multiple antimicrobial resistance. Increase in the number of strains with high horizontal transformation ability has raised concerns regarding the rapid spread of antimicrobial-resistant H. influenzae.


Radioisotope section scanning.
Radioisotope section scanning, a relatively new imaging technique, can be regarded as "in vivo autoradiography." It permits, via computer utilization, reconstruction of a three-dimensional image of the distribution of a radioactive tracer within the body. Rapid progress in the design of instrumentation has allowed for initial clinical trials to be carried out. Worldwide, some 30 centers are currently engaged in research in this field, simultaneously ascertaining the physical performance characteristics and figures of merit of the different apparatuses and clarifying the most promising areas of clinical application. This paper is concerned only with radioisotope section scanning via standard radionuclides and radiopharmaceuticals. It does not address itself to work involving positron-emitting radionuclides. Data are given on the physical parameters and areas of clinical application of several types of available equipment.


Soft-Tissue Myoepithelioma of the Retroperitoneal Space Mimicking a Pancreatic Tumor: A Case Report and Literature Review.
Soft-tissue myoepithelioma (STM) is an extremely rare benign tumor with predominant occurrence in head, neck, pelvic girdle and limbs. These tumors lack specific clinical and morphological features and can easily be confused with more common neoplasms. It may lead to incorrect diagnosis and management. Here, we present a clinical case of a young man with retroperitoneal STM which simulated a pancreatic tumor and required a distal pancreatectomy. Performed literature review highlights current data about clinical, morphologic, immunohistochemical and genetic evaluation, treatment and prognosis of STM.


Assessing Soybean Genotypes for Resistance to Helicoverpa armigera (Lepidoptera: Noctuidae).
Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) is an important pest capable of colonizing several species of cultivated plants, including soybean [Glycine max (L.) Merrill]. The primary management strategy for this insect is chemical control and adoption of Bt plants. However, alternative environmentally friendly strategies should be investigated and adopted as available for sustainable management of this insect pest. One potential underutilized method for insect control is plant resistance. The objective of this study was to categorize resistance (antixenosis and antibiosis) of 22 soybean genotypes on H. armigera in a laboratory setting. A preliminary experiment was conducted using soybean leaves and pods to determine the most promising genotypes for resistance. For each selected genotype, we collected biological parameters, leaf intake, and performed confinement tests. The genotypes PI 227687, PI 274453, PI 274454, PI 229358, PI 171451, 'IAC 17', and 'IAC 19' expressed resistance against H. armigera. Each genotype lowered larval survivorship. The genotypes PI 229358, PI 227687, PI 274453, and PI 274454 expressed resistance by prolonging larval development and reducing fifth-instar larvae weight. 'IAC 19' reduced leaf consumption and lowered the weight of fifth-instar larvae. Antixenosis was found in genotypes PI 227687, PI 274454, and 'IAC 19'. These genotypes might be used in breeding programs focusing on soybean resistance to lepidopterans.


Recognising Kawasaki disease in UK primary care: a descriptive study using the Clinical Practice Research Datalink.
Kawasaki disease is a rare childhood illness that can present non-specifically, making it a diagnostic challenge. The clinical presentation of Kawasaki disease has not been previously described in primary care. To describe how children with an eventual diagnosis of Kawasaki disease initially present to primary care in the UK. The Clinical Practice Research Datalink was used to find cases coded as Kawasaki disease. Hospital Episode Statistics, hospital admissions, and hospital outpatient attendances were used to identify the children with a convincing diagnosis of Kawasaki disease. Questionnaires and a request for copies of relevant hospital summaries, discharge letters, and reports were sent to GPs of the 104 children with a diagnosis of Kawasaki disease between 2007 and 2011. Most children presented with few clinical features typical of Kawasaki disease. Of those with just one feature, a fever or a polymorphous rash were the most common. By the time that most children were admitted to hospital they had a more recognisable syndrome, with three or more clinical features diagnostic of Kawasaki disease. Most GPs did not consider Kawasaki disease among their differential diagnoses, but some GPs did suspect that the child's illness was unusual. The study highlighted the difficulty of early diagnosis, with most children having a non-specific presentation to primary care. GPs are encouraged to implement good safety netting, and to keep Kawasaki disease in mind when children present with fever and rashes.


The hyper IgM syndromes.
The hyper IgM syndromes are a group of rare inherited immune deficiency disorders characterized by impairment of immunoglobulin isotype switching resulting from defects in the CD40 ligand/CD40 signaling pathway. X-linked forms of hyper IgM are caused by defects in the CD40 ligand gene or NF-κB essential modulator, while autosomal recessive forms of hyper IgM are caused by defects in CD40 or downstream signaling molecules including activation-induced cytidine deaminase, uracil N glycosylase or postmeiotic segregation increased 2. The loss of interaction between CD40 and its ligand results in an impairment of T cell function, of B cell differentiation and of monocyte function while only B cell differentiation appears to be affected in defects of sinaling molecules downstream of CD40 with the exception of defects of the NF-κB complex, which mediates signaling via multiple receptor pathways. With many genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitively, to perform genetic screening, and to delineate the clinical manifestations of the different diseases in this syndrome. Stem cell transplantation is an available therapeutic option for defects that result in a combined immunodeficiency while antibody replacement appears sufficient for the strictly humoral immunodeficiencies.


Peripheral signaling pathways contributing to non-histaminergic itch in humans.
Chronic itch (chronic pruritus) is a major therapeutic challenge that remains poorly understood despite the extensive recent analysis of human pruriceptors. It is unclear how the peripheral nervous system differentiates the signaling of non-histaminergic itch and pain. Here we used psychophysical analysis and microneurography (single nerve fiber recordings) in healthy human volunteers to explore the distinct signaling mechanisms of itch, using the pruritogens β-alanine, BAM 8-22 and cowhage extract. The mode of application (injection or focal application using inactivated cowhage spicules) influenced the itch/pain ratio in sensations induced by BAM 8-22 and cowhage but not β-alanine. We found that sensitizing pre-injections of prostaglandin E2 increased the pain component of BAM 8-22 but not the other pruritogens. A-fibers contributed only to itch induced by β-alanine. TRPV1 and TRPA1 were necessary for itch signaling induced by all three pruritogens. In single-fiber recordings, we found that BAM 8-22 and β-alanine injection activated nearly all CM-fibers (to different extents) but not CMi-fibers, whereas cowhage extract injection activated only 56% of CM-fibers but also 25% of CMi-fibers. A "slow bursting discharge pattern" was evoked in 25% of CM-fibers by β-alanine, in 35% by BAM 8-22, but in only 10% by cowhage extract. Our results indicate that no labeled line exists for these pruritogens in humans. A combination of different mechanisms, specific for each pruritogen, leads to itching sensations rather than pain. Notably, non-receptor-based mechanisms such as spatial contrast or discharge pattern coding seem to be important processes. These findings will facilitate the discovery of therapeutic targets for chronic pruritus, which are unlikely to be treated effectively by single receptor blockade.


Bone-added osteotome technique versus lateral approach for sinus floor elevation: a comparative radiographic study.
The aim of this study was to evaluate and compare the radiographic results of bone-added osteotome sinus floor elevation (BAOSFE) and lateral approach sinus floor elevation techniques. The 43 patients who had undergone implant procedure with either BAOSFE or lateral approach method on their maxillary molar edentulous area were included. Their dental records were confirmative and the radiographic-changes using orthopantomographs were consistently checked up during 2 years after the procedure (immediately after procedure and 6 months, 12 months, and 24 months after implant placement). The radiographic evaluation after 2 years of implantation with sinus elevation showed the significant amount of bone formation (6.75 mm for BAOSFE and 11.36 mm for lateral approach method). Largest amount of grafted height loss occurred during the first 6 months (62.8% of total amount of bone loss), but the resorption was minimal (1.35 mm for BAOSFE and 1.36 mm for lateral approach method) for overall 24 months. Long-term stability of graft height was achieved using both BAOSFE and lateral approach sinus floor elevation. Overall, graft height decreased gradually during 2 years after procedures, but the changes were minimal.