Penicillin (cloxacillin)-tolerant Staphylococcus aureus from bovine mastitis: identification and lack of correlation between tolerance in vitro and response to therapy in vivo.
Twenty-four isolates of Staphylococcus aureus from naturally occurring cases of bovine mastitis were examined in vitro for resistance to cloxacillin. All strains produced penicillinase and none showed intrinsic resistance (methicillin resistance) to cloxacillin. The minimum inhibitory concentration of cloxacillin for all these strains was normal (low) but differences were found between them in their sensitivities to the bactericidal action. Three were considered to be tolerant to cloxacillin and a further five possibly so. In a mouse model of mastitis there was no difference in the response to intramammary therapy with cloxacillin between cloxacillin-sensitive or tolerant strains of S aureus and a known methicillin-resistant strain was similarly sensitive to cloxacillin therapy in vivo. It is concluded that cloxacillin tolerance may have little clinical significance in mastitis therapy.


[Asynchronous implantation of a penile prosthesis (AMS 700) in patients with an artificial urinary sphincter (AMS 800): what functional outcomes can we expect from the AMS 1500?].
To report the functional results and morbidity after metachronous implantation of an AMS 800 artificial urinary sphincter (AUS) and an AMS 700 inflatable penile prosthesis (IPP). From the 250 patients treated in our department between 2000 and 2011 for the insertion of an AUS, we retrospectively selected patients who also underwent implantation of an IPP. The following data were recorded: age, aetiology of urinary incontinence (UI) and erectile dysfunction (ED), treatment history of UI/ED, date of insertion of the AUS and the IPP and time gap between the two implants. We evaluated both the pad-test and the number of protective pads used per day, before and after AUS insertion. We also analysed the IIEF5 score before and after IPP. Patients were reviewed at 3, 6 and 12 months and annually thereafter. In total, five patients were included. The median age was 69 years. The median follow-up after IPP was 22.6 months and the time gap between the two implants was 50 months. The aetiology of UI and ED was prostate surgery in four cases. Complete continence without leakage was observed in three patients and the IIEF5 score increased from 6.6 preoperatively to 22.2 for four patients. One patient developed a urethral erosion of the AUS cuff 6 months after implantation of the IPP. The AUS cuff has been explanted but the patient remains continent with the IPP cylinders semi-inflated. From our small study, it appears that the combined use of an AMS 800 AUS and an AMS 700 IPP was a feasible and efficacious option in patients with concomitant refractory UI and ED.


Ethnomedical interactions: health and identity on Nicaragua's Atlantic coast.
This paper describes contemporary and historical interactions of medical belief and practice among the six ethnic groups of Nicaragua's Atlantic Coast--Mestizo, Creole, Miskitu, Sumu, Garifuna and Rama. The expansion of preventive medicine and primary care under the Sandanista-led government during the 1980s is presented, along with brief descriptions of counter-revolutionary attacks on the health care system. Traditional uses of medicinal plants and various forms of spiritual healing are then juxtaposed with the sporadic introduction of European and North American biomedicine throughout history. Next, the results of a health care survey carried out in 1990 are used to: (1) demonstrate the widespread use of the official health care system; and (2) show that traditional practices--use of herbal medicine, visits to spiritual healers, and home birth--are more prevalent among specific ethnic and socioeconomic strata of Nicaraguan Atlantic Coast society. Finally, I use these descriptions and survey results to argue for an understanding of health care behavior based on personal identity. I argue that a number of identities--ethnic, historical, political, socioeconomic and spatial (village, city, region or nation)--both situate and influence health care behavior, and thus mediate between the psychological and spiritual realms of illness and healing. Each individual chooses, variably and often subconsciously, to identify with any of a number these 'imagined communities' as he or she makes health care choices. These identity-influenced decisions are then manifested as specific health-related behaviors, forming the real-world data on which this argument is premised.


Influence of metabolic-linked early life factors on the eruption timing of the first primary tooth.
Early eruption of permanent teeth has been associated with childhood obesity and diabetes mellitus, suggesting links between tooth eruption and metabolic conditions. This longitudinal study aimed to identify pre-, peri- and postnatal factors with metabolic consequences during infancy that may affect the eruption timing of the first primary tooth (ETFT) in children from an ethnically heterogeneous population residing within the same community. Participants were recruited (n = 1033) through the GUSTO (Growing Up in Singapore Towards healthy Outcomes) birth cohort (n = 1237). Oral examinations were performed at 3-month intervals from 6 to 18 months of age. Crude and adjusted analyses, with generalized linear modelling, were conducted to link ETFT to potential determinants occurring during pregnancy, delivery/birth and early infancy. Overall mean eruption age of the first primary tooth was 8.5 (SD 2.6) months. Earlier tooth eruption was significantly associated with infant's rate of weight gain during the first 3 months of life and increased maternal childbearing age. Compared to their Chinese counterparts, Malay and Indian children experienced significantly delayed tooth eruption by 1.2 and 1.7 months, respectively. Infant weight gain from birth to 3 months, ethnicity and maternal childbearing age were significant determinants of first tooth eruption timing. Early life influences can affect primary tooth development, possibly via metabolic pathways. Timing of tooth eruption is linked to general growth and metabolic function. Therefore, it has potential in forecasting oral and systemic conditions such as caries and obesity.


Effects of substrate improvement on winter nitrogen removal in riparian reed (Phragmites australis) wetlands: rhizospheric crosstalk between plants and microbes.
With continued anthropogenic inputs of nitrogen (N) into the environment, non-point source N pollutants produced in winter cannot be ignored. As the water-soil interface zones, riparian wetlands play important roles in intercepting and buffering N pollutants. However, winter has the antagonistic effect on the N removal. Substrate improvement has been suggested as a strategy to optimize wetland performance and there remain many uncertainties about the inner mechanism. This study explores the effects of substrate improvement on N removal in winter and rhizospheric crosstalk between reed (Phragmites australis) and microbes in subtropical riparian reed wetlands. The rates of wetland N removal in winter, root metabolite profiles, and rhizosphere soil microbial community compositions were determined following the addition of different substrates (gravel, gravel + biochar, ceramsite + biochar, and modified ceramsite + biochar) to natural riparian soil. The results showed that the addition of different substrates to initial soil enhanced N removal from the microcosms in winter. Gravel addition increased NH4+-N removal by 8.3% (P < 0.05). Gravel + biochar addition increased both TN and NH4+-N removals by 8.9% (P < 0.05). The root metabolite characteristics and microbial community compositions showed some variations under different substrate additions compared to the initial soil. The three treatments involving biochar addition decreased lipid metabolites and enhanced the contents and variety of carbon sources in rhizosphere soil, while modified ceramsite + biochar addition treatment had a greater impact on the microbial community structure. There was evidence for a complex crosstalk between plants and microbes in the rhizosphere, and some rhizosphere metabolites were seen to be significantly correlated with the bacterial composition of the rhizospheric microbial community. These results highlighted the importance of rhizospheric crosstalk in regulating winter N removal in riparian reed wetland, provided a scientific reference for the protection and restoration of riparian reed areas and the prevention and control of non-point source pollution.


Mathematically modelling and controlling prostate cancer under intermittent hormone therapy.
In this review, we summarize our recently developed mathematical models that predict the effects of intermittent androgen suppression therapy on prostate cancer (PCa). Although hormone therapy for PCa shows remarkable results at the beginning of treatment, cancer cells frequently acquire the ability to grow without androgens during long-term therapy, resulting in an eventual relapse. To circumvent hormone resistance, intermittent androgen suppression was investigated as an alternative treatment option. However, at the present time, it is not possible to select an optimal schedule of on- and off-treatment cycles for any given patient. In addition, clinical trials have revealed that intermittent androgen suppression is effective for some patients but not for others. To resolve these two problems, we have developed mathematical models for PCa under intermittent androgen suppression. The mathematical models not only explain the mechanisms of intermittent androgen suppression but also provide an optimal treatment schedule for the on- and off-treatment periods.


Pro-apoptotic gene knockdown mediated by nanocomplexed siRNA reduces radiation damage in primary salivary gland cultures.
A critical issue in the management of head and neck tumors is radioprotection of the salivary glands. We have investigated whether siRNA-mediated gene knock down of pro-apoptotic mediators can reduce radiation-induced cellular apoptosis in salivary gland cells in vitro. We used novel, pH-responsive nanoparticles to deliver functionally active siRNAs into cultures of salivary gland cells. The nanoparticle molecules are comprised of cationic micelles that electrostatically interact with the siRNA, protecting it from nuclease attack, and also include pH-responsive endosomolytic constituents that promote release of the siRNA into the target cell cytoplasm. Transfection controls with Cy3-tagged siRNA/nanoparticle complexes showed efficiently internalized siRNAs in more than 70% of the submandibular gland cells. We found that introduction of siRNAs specifically targeting the Pkcδ or Bax genes significantly blocked the induction of these pro-apoptotic proteins that normally occurs after radiation in cultured salivary gland cells. Furthermore, the level of cell death from subsequent radiation, as measured by caspase-3, TUNEL, and mitochondrial disruption assays, was significantly decreased. Thus, we have successfully demonstrated that the siRNA/nanoparticle-mediated knock down of pro-apoptotic genes can prevent radiation-induced damage in submandibular gland primary cell cultures.


Return to Sport After Arthroscopic Autologous Matrix-Induced Chondrogenesis for Patients With Osteochondral Lesion of the Talus.
To determine the rate of return of patients to sport after arthroscopic autologous matrix-induced chondrogenesis (AT-AMIC) for outcomes 2 years after surgery. Retrospective observational cross-sectional study. C.A.S.C.O.-Foot and Ankle Unit, Istituto Ortopedico Galeazzi, Milan, Italy. Twenty-six consecutive patients, 65.4% male (mean ± SD age: 33.7 ± 11.0 years), that underwent AT-AMIC procedure between 2012 and 2015 were selected retrospectively. From this population, only sporting patients at amateur's level were included. Arthroscopic autologous matrix-induced chondrogenesis was proposed in patients with pain and persistent disability. All patients were assessed with the American Orthopaedic Foot and Ankle Score (AOFAS), physical component score of the 12-Item Short Form Health Survey (SF-12), Halasi ankle activity score, and University of California, Los Angeles (UCLA) activity scale preoperatively and at 24 months postoperatively. Overall, 80.8% of the patient group returned to the same preinjury sport. The mean follow-up was 42.6 ± 10.9 months (range from 25 to 62 months). Significant differences were observed with reference to AOFAS, SF-12, Halasi, and UCLA scores at the last follow-up in patients who had undergone AT-AMIC (all, P < 0.001). A high percentage of patients return to their preinjury sport after AT-AMIC surgery.


Validity of the alcohol purchase task: a meta-analysis.
Behavioral economists assess alcohol consumption as a function of unit price. This method allows construction of demand curves and demand indices, which are thought to provide precise numerical estimates of risk for alcohol problems. One of the more commonly used behavioral economic measures is the Alcohol Purchase Task (APT). Although the APT has shown promise as a measure of risk for alcohol problems, the construct validity and incremental utility of the APT remain unclear. This paper presents a meta-analysis of the APT literature. Sixteen studies were included in the meta-analysis. Studies were gathered via searches of the PsycInfo, PubMed, Web of Science and EconLit research databases. Random-effects meta-analyses with inverse variance weighting were used to calculate summary effect sizes for each demand index-drinking outcome relationship. Moderation of these effects by drinking status (regular versus heavy drinkers) was examined. Additionally, tests of the incremental utility of the APT indices in predicting drinking problems above and beyond measuring alcohol consumption were performed. The APT indices were correlated in the expected directions with drinking outcomes, although many effects were small in size. These effects were typically not moderated by the drinking status of the samples. Additionally, the intensity metric demonstrated incremental utility in predicting alcohol use disorder symptoms beyond measuring drinking. The Alcohol Purchase Task appears to have good construct validity, but limited incremental utility in estimating risk for alcohol problems.


Evidence of a disposition toward fearfulness and vulnerability to posttraumatic stress in dysfunctional pain patients.
Few investigations have addressed whether patient subgroups derived using the Multiaxial Assessment of Pain (MAP) [Turk, D. C., & Rudy, T. E. (1987). Towards a comprehensive assessment of chronic pain patients. Behaviour Research and Therapy, 25, 237-249; Turk, D. C., & Rudy, T. E. (1988). Toward an empirically derived taxonomy of chronic pain patients: integration of psychological assessment data. Journal of Consulting and Clinical Psychology, 56, 233-238.] differ with regard to fear and avoidance. It has, however, been reported that dysfunctional patients exhibit more pain-specific fear and avoidance than patients classified as interpersonally distressed or minimizers/adaptive copers [Asmundson, G. J. G., Norton, G. R., & Allerdings, M. D. (1997). Fear and avoidance in dysfunctional chronic back pain patients. Pain, 69, 231-236.]. We attempted to extend these findings by examining two fear constructs that are receiving increased attention in the chronic pain literature-anxiety sensitivity and PTSD. The sample comprised 115 patients with chronic pain. Of these, 14 (12.2%) were classified as dysfunctional, 21 (18.3%) as interpersonally distressed and 47 (40.8%) as minimizers/adaptive copers. Between-group differences were observed on the fear of cognitive and emotional dyscontrol dimension of anxiety sensitivity, total and symptom cluster scores on the PTSD measure, and depression. No differences were observed for the fear of somatic sensations dimension of anxiety sensitivity or agoraphobia, social phobia, and blood/injury fears. Dysfunctional patients generally exhibited elevated scores relative to one or both of the other MAP subgroups on fear of cognitive and emotional dyscontrol, depressed affect, PTSD symptom total score and PTSD symptom cluster scores. As well, a substantial proportion of dysfunctional and interpersonally distressed patients were classified as having PTSD (71.4 and 42.9%, respectively) when compared to minimizers/adaptive copers (21.3%). These results suggest that MAP subgroups differ with regard to their propensity to be(come) fearful and in their likelihood of having PTSD. Theoretical and clinical implications are discussed.


Percutaneous Peripheral Nerve Stimulation for Chronic Low Back Pain: Prospective Case Series With 1 Year of Sustained Relief Following Short-Term Implant.
Percutaneous peripheral nerve stimulation (PNS) provides an opportunity to relieve chronic low back pain and reduce opioid analgesic consumption as an alternative to radiofrequency ablation and permanently implanted neurostimulation systems. Traditionally, the use of neurostimulation earlier in the treatment continuum has been limited by its associated risk, invasiveness, and cost. Percutaneous PNS leads (SPRINT MicroLead) were placed bilaterally to target the medial branches of the dorsal rami nerves under image guidance. The percutaneous leads were connected to miniature wearable stimulators (SPRINT PNS System) for the 1-month therapy period, after which the leads were removed. Pain and disability were assessed long-term up to 12 months after lead removal. Substantial, clinically significant reductions in average pain intensity (≥50% reduction as measured by the Brief Pain Inventory Short Form) were experienced by a majority of subjects (67%) at end of treatment compared to baseline (average 80% reduction among responders; P < 0.05, analysis of variance; n = 9). Twelve months after the end of PNS treatment, a majority of subjects who completed the long-term follow-up visits experienced sustained, clinically significant reductions in pain and/or disability (67%, n = 6; average 63% reduction in pain intensity and 32-point reduction in disability among responders). No serious or unanticipated adverse events were reported. This study challenges the long-held notion that a positive trial of PNS should be followed by a permanent implant in responders. Percutaneous PNS may serve as an effective neurostimulation therapy for patients with chronic low back pain and should be considered earlier in the treatment continuum as a motor-sparing means of avoiding opioids, denervation, and permanently implanted neurostimulation systems.


Source dependent variation in phenolics, antioxidant and antimicrobial activity of Paeonia emodi in west Himalaya, India.
Paeonia emodi is one of the ethno therapeutically important Himalayan plants used to cure various diseases. However, a systematic investigation of the effect of altitude on phytochemical, antioxidant, and antimicrobial activity has not been reported so far. The present study assessed the variation in the bioactive compounds, antioxidant and antimicrobial activity of the leaf, and rhizome of P. emodi collected from different altitudes. Phytochemicals such as phenols, flavonoids, flavanol, tannins, emodin, and paeoniflorin were found in all the sampled populations, but the quantity varied significantly across the altitude. In leaf, phenolics, flavonoids, and tannins content positively correlated with altitude (p < 0.01), but flavanol did not show any connection. Similarly, in the rhizome, positive relation with altitude (p < 0.01) was observed in phenol, flavonoids, and paeoniflorin. Antioxidant activity measured by 1, 1-diphenyl- 2 picrylhydrazyl (DPPH) and nitric oxide assays showed a positive correlation (p < 0.05) with altitude. 2, 2-azinobis (3-ethylbenzothiazoline-6-sulphonic acid), ferric reducing antioxidant power, and hydroxyl ion assays did not show any relation with altitude. Antimicrobial activity was higher in the case of rhizome for the minimum inhibitory concentration and positively correlated with phenolics, flavonoids, and flavanol (p < 0.05). The present study further revealed that the secondary metabolites in the leaf and rhizome extracts of P. emodi are an excellent source of antioxidant and antimicrobial activity, thus validating the species' therapeutic potential. The online version contains supplementary material available at 10.1007/s12298-022-01242-z.


MicroRNAs in Cancer: challenges and opportunities in early detection, disease monitoring, and therapeutic agents.
The goals of this review are to examine the usefulness of miRNAs as diagnostic and prognostic biomarkers for cancer and to evaluate the applicability of miRNAs as cancer therapeutics. Examination of miRNA milieu from body fluids offers a new alternative for quick, affordable and easy analysis of disease status in patients. Blood-based exosomal miRNAs have increased stability and are an excellent choice for clinical cancer diagnostics and prognostics. Currently, there are many miRNA signatures associated with cancer and progression but there is no consensus among multiple sera and tumor sample studies. Off-target and immunological effects remains an obstacle for use of miRNAs as novel chemotherapeutics in the clinic. Recent developments in nanotechnology and drug delivery systems which target the tumor microenvironment may provide an alternative therapeutic approach with decreased toxicity. This review critically evaluates the literature investigating the use of miRNAs as biomarkers and their future as potential therapeutics.


Association of FOXP3 (rs3761548) promoter polymorphism with nondermatomal vitiligo: A study from India.
The rs3761548 polymorphism (-3279 C>A) of FOXP3 gene is associated with several autoimmune disorders. We sought to determine whether rs3761548 polymorphism is associated with nondermatomal vitiligo in Indian subjects. Genomic DNA was isolated from blood samples of 303 patients and 305 control subjects and genotyping was done by allele-specific primers. Data analysis was carried out for the entire cohort and separately for male and female participants as FOXP3 is an X-linked marker. Statistics were performed using software. The genotype frequencies differed significantly from patients to control subjects (P = .002). Further analysis demonstrated female participants with CC genotype were protected (CC vs CA+AA; odds ratio 0.38, 95% confidence interval 0.238-0.615) and those with CA genotype were at higher risk to develop vitiligo (CA vs CC+AA; odds ratio 2.634, 95% confidence interval 1.604-4.325). However, no such statistical difference was observed in male participants. Our study is, to our knowledge, the first report from India with respect to vitiligo and rs3761548; however, we lack adequate literature assistance. The rs3761548 of FOXP3 gene in our population may be associated with susceptibility to vitiligo because of altered expression. CC genotype appears to be protective and CA genotype seems to impart nearly 3-fold risk to develop vitiligo in women and girls.


Diagnosis of Chlamydia trachomatis genitourinary infections.
The lack of a widely available diagnostic test for genital infections with Chlamydia trachomatis, coupled with their often nonspecific clinical nature, have been important factors contributing to the increasing incidence of these infections. Recent studies have more clearly defined the clinical manifestations of C. trachomatis infections, especially mucopurulent cervicitis and pelvic inflammatory disease. In addition, methods for the direct detection of chlamydial antigen in genital secretions have been developed. Although less sensitive than traditional cultural methods, these noncultural methods are more widely available than cultures and can facilitate the earlier recognition and more specific diagnosis of chlamydial genital infections. This article reviews these recent developments and outlines specific applications of tests for diagnostic purposes and for screening of high-risk populations.


Experience wiht vasovasostomy: operative technique and results.
Between 1972 and 1977 vasovasostomy to reverse a previous vasectomy for contraception has been attempted in 27 cases. The procedure was abandoned as a technical impossiblity in only 1 case. The first 17 have been studied and in these there have been 11 pregnancies, 10 of which have already come to term with the birth of normal children, including one set of twins. Of the remainder, 2 are known to have oligozoospermia and 4 have been lost to follow-up although 2 of these were euspermic when last heard of. In spite of the encouraging results it is considered that there are no grounds for altering the present basis of vasectomy counselling in which the operation is described as likely to be irreversible.


Endovascular strategies for stroke management after subacute in-stent thrombosis.
Subacute in-stent thrombosis is a rare but potentially fatal condition that can occur after treatment for intracranial aneurysms or stenosis. While immediate and late thromboembolic post-stent complications are well-described, subacute (2-30 days post-intervention) thrombosis is unusual. The administration of peri-operative dual anti-platelet therapy (DAPT) has significantly reduced the risk for thrombosis, but questions remain as to the choice of agents and treatment of thromboembolic complications in this setting. We present our acute endovascular management strategies for three patients who suffered thromboembolic complications.


Suicide and alcohol poisoning in Belarus between 1970 and 2005.
The association between alcohol and suicide is well documented. The solid body of research and empirical evidence suggests that hazardous pattern of alcohol consumption (binge drinking) lead to quicker and deeper intoxication, increasing the propensity for alcohol-related suicide. To estimate the aggregate level effect of binge drinking on suicide rate. Trends in suicide and fatal alcohol poisoning rate (as a proxy for binge drinking) from 1970 to 2005 in Belarus were analyzed employing ARIMA analysis in order to assess bivariate relationship between two time series. The results of time series analysis suggests close relationship between suicide and fatal alcohol poisoning rate at aggregate level. This study supports the hypothesis that suicide and alcohol closely connected in culture with prevailing intoxication-oriented drinking patterns and adds to the growing body of evidence that a substantial proportion of suicide in Belarus is due to acute effect of binge drinking.


IL-33 receptor ST2 amplifies the expansion of NK cells and enhances host defense during mouse cytomegalovirus infection.
NK cells provide important host defense against viruses and can differentiate into self-renewing memory NK cells after infection, alloantigen stimulation, and cytokine stimulation. In this study, we investigated the role of the IL-33 receptor ST2 in the differentiation of NK cells during mouse CMV (MCMV) infection. Although ST2-deficient (Il1rl1 (-/-)) Ly49H(+) NK cells develop normally and differentiate into memory cells after MCMV infection, naive and memory Il1rl1 (-/-) Ly49H(+) NK cells exhibited profound defects in MCMV-specific expansion, resulting in impaired protection against MCMV challenge. Additionally, IL-33 enhanced m157 Ag-specific proliferation of Ly49H(+) NK cells in vitro. Thus, an IL-33/ST2 signaling axis in NK cells contributes to host defense against MCMV.


Blastomycosis of the esophagus presenting with gastrointestinal bleeding.
A patient with abdominal discomfort and hematemesis was found to have lower esophageal inflammation on endoscopy. A biopsy specimen from this area showed yeast forms of Blastomyces dermatitidis with a polymorphonuclear infiltrate and granuloma formation. Extensive evaluation showed no other bleeding site. Sputum samples obtained earlier also showed B. dermatitidis. Treatment with amphotericin B led to resolution of bleeding and eradication of the fungus on repeat biopsy and sputum samples. An esophageal stricture subsequently developed and required dilation. Seven previously reported cases of esophageal blastomycosis are reviewed.


Discriminative ability of conventional echocardiography and tissue Doppler imaging techniques for the detection of subclinical cardiotoxic effects of treatment with anthracyclines.
This study investigated improvement of diagnosing myocardial damage caused by anthracyclines using tissue Doppler imaging (TDI). The optimal set of conventional echocardiographic and/or TDI parameters, needed for the discrimination of survivors from healthy controls, was retrospectively assessed. A total of 60 patients and 99 controls, age range 8.5 to 17.6 years, were studied. The survivors received 50 to 400 mg/m(2) cumulative dose of anthracyclines, with a mean follow-up of 7.3 (+/-2.3) years. The parameters used in the discriminant score (S-score) were selected from a large set of 51 echocardiographic parameters, using logistic regression analysis (stepwise selection). The correct classification probability (C-index) and the generalized distance (d) between the distributions of S-scores were used to measure the overall discriminative performance of each echocardiographic technique separately and in combination. The overall discriminative performance of the conventional echo-Doppler parameters (C = 77.3%, d = 1.04) was lower than that of the TDI (C = 84.2%, d = 1.37); the highest C-index was obtained using both techniques (C = 89.2%, d = 1.66). The set of parameters includes: LV fractional shortening and MV early diastolic flow velocity, two long-axis and five apical 4-CV TDI wall velocities (systolic and diastolic). In the patient group, the S-score was positively associated with cumulative dose of anthracyclines (p = 0.05) and duration of treatment (p = 0.01). The diagnostic index S-score, based on a limited number of variables from both techniques simultaneously, could retrospectively discriminate asymptomatic children with anthracycline-induced cardiomyopathy from healthy controls. The potentials of the S-score for serial and prospective studies are further investigated.


A morphometric and X-ray energy dispersive approach to monitoring pH-altered cadmium toxicity in Anabaena flos-aquae.
Cadmium toxicity and uptake as influenced by different pH values have been studied in the freshwater cyanobacterium Anabaena flos-aquae, using the techniques of morphometric analysis, x-ray energy dispersive analysis and atomic absorption spectrophotometry. A general reduction in cell dimension, thylakoid surface area, number and volume of polyhedral bodies, polyphosphate bodies, cyanophycin granules, lipid bodies, membrane limited crystalline inclusions, volume and number of wall layers and mesosomes was observed. These reductions were more pronounced in both acidic and alkaline medium than at pH 7.2. At 0.12 microM Cd, the uptake increased with alkaline pH values, and uptake was greater at pH 7.2 than at either acid or alkaline pHs. Lysis of cell wall at 1.18 microM Cd showed the following decreasing trend: pH 4.0 greater than pH 5.5 greater than pH 10.0 greater than pH 9.0 greater than pH 7.2. There was a total loss of lipid bodies at 1.18 microM Cd at all pH values listed. It is suggested that these techniques can be successfully employed for bioassay studies of metal toxicity to algae. In particular, cell wall lysis and loss of lipids by algae are good indicators of pH effects and metal toxicity in the aquatic ecosystem.


STIM1 tyrosine-phosphorylation is required for STIM1-Orai1 association in human platelets.
Stromal interaction molecule 1 (STIM1) is a key element of the store-operated Ca(2+) entry mechanism (SOCE). Recently, regulation of STIM1 by glycosylation and phosphorylation on serine/threonine or proline residues has been described; however other modes of phosphorylation that are important for activating SOCE in platelets, such as tyrosine phosphorylation, have been poorly investigated. Here we investigate the latency of STIM1 phosphorylation on tyrosine residues during the first steps of SOCE activation. Human platelets were stimulated and fixed at desired times using rapid kinetic assays instruments, and immunoprecipitation and western blotting techniques were then used to investigate the pattern of STIM1 tyrosine phosphorylation during the first steps of SOCE activation. We have found that maximal STIM1 tyrosine phosphorylation occurred 2.5s after stimulation of human platelets with thapsigargin (Tg). STIM1 localized in the plasma membrane were also phosphorylated in platelets stimulated with Tg. By using chemical inhibitors that target different members of the Src family of tyrosine kinases (SKFs), two independent signaling pathways involved in STIM1 tyrosine phosphorylation during the first steps of SOCE activation were identified. We finally conclude that STIM1 tyrosine phosphorylation is a key event for the association of STIM1 with plasma membrane Ca(2+) channels such as Orai1, hence it is required for conducting SOCE activation.


Unexpected Pd-catalyzed hydrogenation of phenol to 2-cyclohexene-1-one: enhanced activity and selectivity assisted by molecular oxygen.
Addition of O(2) enables the liquid-phase hydrogenation of phenol using H(2) at low temperatures under atmospheric pressure with an unexpected selectivity towards 2-cyclohexene-1-one rather than cyclohexanone. As a catalyst, as-synthesized Pd/MCM-41 including the residual templates within the mesoporous channels exhibits a prominent positive effect on the catalytic performance.


SMART-PET: multimodality white matter imaging and display without loss of quantitative information.
To improve analysis of cerebral white matter (WM) in fluoro-deoxy-glucose positron emission tomography (PET) images. A multimodality analysis technique (segmented MRI and registered Talairach-transformed PET [SMART-PET]) was used for quantitative assessment of WM metabolism. Data processing included Talairach transformation of three-dimensional magnetic resonance imaging (MRI) and subsequent automated segmentation and coregistration to normalized PET images. Color model transformations were used for combined display: the hue saturation value color model was regarded as a three-dimensional data matrix, integrating quantitative voxel data of both modalities. The technique was applied in normal subjects and in patients suffering from different WM diseases. Regional analysis was performed to classify metabolic impairment on a five-point scale. Using SMART-PET, a considerable gain in image contrast for WM was achieved in all cases. In the normal subjects, WM metabolism was shown to be homogeneously unimpaired. Sum scores of regional analysis revealed metabolic WM changes in all patients. Extent of WM hypometabolism exceeded the extent of the lesions as delineated by MRI signal changes. The potential of the method for further elucidation of the role of WM diseases in brain dysfunction in patients is discussed.


The application of machine learning to air pollution research: A bibliometric analysis.
Machine learning (ML) is an advanced computer algorithm that simulates the human learning process to solve problems. With an explosion of monitoring data and the increasing demand for fast and accurate prediction, ML models have been rapidly developed and applied in air pollution research. In order to explore the status of ML applications in air pollution research, a bibliometric analysis was made based on 2962 articles published from 1990 to 2021. The number of publications increased sharply after 2017, comprising approximately 75% of the total. Institutions in China and United States contributed half of all publications with most research being conducted by individual groups rather than global collaborations. Cluster analysis revealed four main research topics for the application of ML: chemical characterization of pollutants, short-term forecasting, detection improvement and optimizing emission control. The rapid development of ML algorithms has increased the capability to explore the chemical characteristics of multiple pollutants, analyze chemical reactions and their driving factors, and simulate scenarios. Combined with multi-field data, ML models are a powerful tool for analyzing atmospheric chemical processes and evaluating the management of air quality and deserve greater attention in future.


Insulin promotes sodium transport but suppresses gluconeogenesis via distinct cellular pathways in human and rat renal proximal tubules.
Insulin is known to promote sodium transport and regulate gluconeogenesis in renal proximal tubules. Although protein kinase B (also known as Akt) and mammalian target of rapamycin complexes (mTORC) have been established as key regulators in the insulin signaling pathway, their roles in proximal tubules are poorly understood. To help define this, we examined the components of insulin signaling in sodium transport and gluconeogenesis in isolated human and rat proximal tubules, and also investigated the role of insulin in sodium handling and mTORC1 in insulin signaling in vivo. In isolated human and rat proximal tubules, Akt and mTORC1/2 inhibition suppressed insulin-stimulated sodium-bicarbonate co-transporter 1 (NBCe1) activity, whereas mTORC1 inhibition had no effect. Akt2 and mTORC2 gene silencing largely inhibited insulin-stimulated NBCe1 activity, whereas silencing of Akt1 and mTORC1 had no effect. Furthermore, insulin decreased sodium excretion, and this effect depended on phosphoinositide 3 kinase in vivo. Moreover, insulin reduced glucose production in rat proximal tubules and the expression of gluconeogenic genes in human and rat proximal tubules. Akt and mTORC1 inhibition largely abolished the observed insulin-mediated inhibitory effects. Gene silencing of insulin receptor substrate 1 (IRS1), Akt2, mTORC1, and mTORC2 also abolished insulin-mediated inhibition of gluconeogenesis. Additionally, in vivo, mTORC1 inhibition abolished insulin-mediated inhibitory effects in rat proximal tubules, although not in liver. These results indicate that insulin-stimulated proximal tubule sodium transport is mediated via the Akt2/mTORC2 pathway, whereas insulin-suppressed proximal tubule gluconeogenesis is mediated via the IRS1/Akt2/mTORC1/2 pathway. Thus, distinct pathways may play important roles in hypertension and hyperglycemia in metabolic syndrome and diabetes.


Current Management and Treatment of Extramammary Paget's Disease.
Extramammary Paget's disease (EMPD) is a rare neoplastic disease affecting areas rich in apocrine glands in the elderly. EMPD clinically resembles a benign inflammatory skin disease, and ill-defined tumor borders can lead to misdiagnosis and incomplete excision. Several prognostic factors have been reported, including nodule formation, tumor thickness, tumor invasion, lymphovascular invasion, and a perianal location, which are characteristic of primary tumors. EMPD typically presents as an in situ tumor spreading horizontally within the epidermis and then invading into the dermis as it transitions to a vertical growth phase. For this reason, tumor thickness, rather than tumor size, is correlated with patient prognosis. The best treatment for resectable EMPD is complete surgical removal of the tumor. EMPD sometimes has unclear tumor borders, and it can unexpectedly spread beyond its clinical boundaries. Surgical resection in such cases is often associated with tumor-positive margins, which can result in recurrence. However, surgical excision with wide margins may deteriorate patients' organ functions and quality of life. Mohs micrographic surgery may be ideal for controlling the surgical margins and minimizing the sacrifice of normal tissue, but this technique is not always feasible because of constraints associated with the medical environment. No standard treatment for unresectable or metastatic EMPD has been established. Although conventional chemotherapy has been used as the first-line treatment, it frequently causes adverse events, and consequently, targeted therapy will become more valuable in the near future.


Synthesis of PHAs from waster under various C:N ratios.
Polyhydroxyalkanoates (PHAs) production was carried out under various C:N ratios. A ratio of 100 resulted best polymer yield. C-source was an important factor in synthesis. For example, as the ratio of valeric acid (C5) to butyric acid (C4) in N-free medium was increased, the mole fraction of HV in the copolymer increased. When soy waste was used as a C-source a copolymer, a high HV mole fraction (HB:HV, 75:25) was produced while when malt waste was used, a much lower HV mole fraction (HB:HV, 90:10) was generated. It was concluded that activated sludge bacteria could be induced to produce PHAs using food wastes as C-sources and this could be the basis for production of biodegradable plastics.


Infantile or hypoplastic uterus? A proposal for a modification to the ESHRE/ESGE classification of female genital tract congenital abnormalities.
We argue that the graphical depiction of "infantile uterus" in the ESHRE/ESGE classification of Mullerian anomalies does not fall under class U1b, i.e. uterine corpus anomalies with a normal external contour. The verbal description of "infantile uterus" by the ESHRE/ESGE classification seems to better suit a hypoplastic uterus and as such, arguably, can be omitted from this classification. We also suggest the inclusion of a "Y shaped" uterus under Class U1.


The effect of chronic pulmonary hypertension on left ventricular size, function, and interventricular septal motion.
The effect of right ventricular pressure overload secondary to chronic pulmonary arterial hypertension on left ventricular size and function and on interventricular septal motion was studied in 13 patients in whom coronary artery disease, hypertension, and hypoxemia were excluded. Regional and global left ventricular function were assessed by computer-assisted analysis of two-dimensional directed M-mode echocardiograms obtained within 24 hours of a hemodynamic study. Septal position and motion were further analyzed by delineating seven points along the right and left sides of the septum during a single cardiac cycle. All echocardiographic data were compared to those of 10 normal subjects. Mean values for right ventricular systolic, mean pulmonary artery and pulmonary capillary wedge pressures were: 71 +/- 26 mm Hg, 46 +/- 16 mm Hg, and 7 +/- 1 mm Hg, respectively. Septal motion was interpreted from the M-mode echocardiograms as normal in seven patients (group I) and abnormal in the remaining six patients (group II). The only hemodynamic parameter which distinguished these two patterns was delta P, the transseptal systolic pressure gradient across the interventricular septum, which was significantly different (p less than 0.02) in group I (delta P = 65 +/- 16 mm Hg) from that of group II (delta P = 21 +/- 24 mm Hg). As a result of abnormal septal position, the septal-free wall dimensions of the left ventricle were reduced, but there was no evidence of depressed left ventricular performance in these patients. We conclude that resting left ventricular function is well preserved in patients with pulmonary hypertension, despite significant alterations in septal position and left ventricular size.(ABSTRACT TRUNCATED AT 250 WORDS)


Identification of psychologic impairment in patients with mild-moderate thermal injury: small burn, big problem.
Sixty-eight patients hospitalized at a tertiary care burn center for more than 1 week, aged 18-32 years, with a mild or moderate burn, adequate social and economic support, and the absence of preexisting psychopathology, substance abuse, or medical illness were studied. From this group 16 patients were identified who had been unable to resume social or occupational functioning even after several months and were impaired by psychologic symptoms related to the burn. Utilizing a psycho-social data base of 250 items, these "Small Burn, Big Problem" (SBBP) patients were compared to those who did not have this problem (control). There were no differences between the two groups with respect to age, sex, race, hospital length of stay, agent of injury, circumstances of the accident, extent of burn, or amount of disfigurement. The SBBP patients did develop significantly more sleep disturbances, which continued into the posthospitalization period. There were significant differences in the use of the defense mechanisms of regression and displacement, the extent of experiencing the injury as a narcisistic injury and in the indication of sexual dysfunction in the SBBP patients as compared to the control group. There were no differences in the amount of psychiatric treatment performed while the patients were in the hospital, although 68% of the SBBP group were referred for psychiatric treatment upon discharge as compared to 14% of the control group. Two case vignettes are presented to demonstrate some of the psychodynamics involved.


The association of circulating levels of complement-C1q TNF-related protein 5 (CTRP5) with nonalcoholic fatty liver disease and type 2 diabetes: a case-control study.
It is well-established that nonalcoholic fatty liver disease (NAFLD) is associated with type 2 diabetes mellitus (T2DM). Complement-C1q TNF-related protein 5 (CTRP5) is a novel adipokine involved in the regulation of lipid and glucose metabolism. We aimed to assess plasma levels of CTRP5 in patients with NAFLD (n = 22), T2DM (n = 22) and NAFLD with T2DM (NAFLD + T2DM) (n = 22) in comparison with healthy subjects (n = 21) and also to study the association between CTRP5 levels and NAFLD and diabetes-related parameters. All subjects underwent anthropometric assessment, biochemical evaluation and liver stiffness (LS) measurement. Insulin resistance (IR) was determined by the homeostasis model assessment (HOMA). Plasma CTRP5 levels were measured by enzyme-linked immunosorbent assay. We found significantly lower plasma levels of CTRP5 in patients with NAFLD + T2DM, NAFLD and T2DM (122.52 ± 1.92, 124.7 ± 1.82 and 118.31 ± 1.99 ng/ml, respectively) in comparison with controls (164.96 ± 2.95 ng/ml). In the whole study population, there was a significant negative correlations between CTRP5 and body mass index (r = -0.337; p = 0.002), fasting blood glucose (FBG) (r = -0.488; p < 0.001), triglyceride (TG) (r = -0.245; p = 0.031), HOMA-IR (r = -0.492; p < 0.001), insulin(r = -0.338; p = 0.002), LS (r = -0.544; p < 0.001), alanine aminotransferase (ALT) (r = -0.251; p = 0.027), waist-to-hip ratio (WHR) (r = -0.352; p = 0.002) and waist circumference (WC) (r = -0.357; p = 0.001). After adjustment for BMI, decrease in circulating levels of CTRP5 remained as a significant risk factor for NAFLD, T2DM and NAFLD + T2DM. The receiver operating characteristic (ROC) curves of circulating CTRP5 in predicting NAFLD and T2DM demonstrated an area under the curve (AUC) of 0.763 in T2DM, and 0.659 in NAFLD + T2DM. It appears that the decreased levels of CTRP5 contribute to the increased risk of T2DM and NAFLD.


The relativity of biological function.
Function is a central concept in biological theories and explanations. Yet discussions about function are often based on a narrow understanding of biological systems and processes, such as idealized molecular systems or simple evolutionary, i.e., selective, dynamics. Conflicting conceptions of function continue to be used in the scientific literature to support certain claims, for instance about the fraction of "functional DNA" in the human genome. Here we argue that all biologically meaningful interpretations of function are necessarily context dependent. This implies that they derive their meaning as well as their range of applicability only within a specific theoretical and measurement context. We use this framework to shed light on the current debate about functional DNA and argue that without considering explicitly the theoretical and measurement contexts all attempts to integrate biological theories are prone to fail.


Gallbladder visualization during technetium-99m-labeled red cell scintigraphy for gastrointestinal bleeding.
Localization of radionuclide activity in the gallbladder was seen on delayed views following injection of 99mTc-labeled red blood cells for gastrointestinal bleeding in five patients. The mechanism for this unusual finding probably relates to labeling of heme, the biochemical precursor of bilirubin. All patients had had prior transfusions. All but one had severe renal impairment, probably an important predisposing factor.


Olfaction and olfactory-mediated behaviour in psychiatric disease models.
Rats and mice are the most widely used species for modelling psychiatric disease. Assessment of these rodent models typically involves the analysis of aberrant behaviour with behavioural interactions often being manipulated to generate the model. Rodents rely heavily on their excellent sense of smell and almost all their social interactions have a strong olfactory component. Therefore, experimental paradigms that exploit these olfactory-mediated behaviours are among the most robust available and are highly prevalent in psychiatric disease research. These include tests of aggression and maternal instinct, foraging, olfactory memory and habituation and the establishment of social hierarchies. An appreciation of the way that rodents regulate these behaviours in an ethological context can assist experimenters to generate better data from their models and to avoid common pitfalls. We describe some of the more commonly used behavioural paradigms from a rodent olfactory perspective and discuss their application in existing models of psychiatric disease. We introduce the four olfactory subsystems that integrate to mediate the behavioural responses and the types of sensory cue that promote them and discuss their control and practical implementation to improve experimental outcomes. In addition, because smell is critical for normal behaviour in rodents and yet olfactory dysfunction is often associated with neuropsychiatric disease, we introduce some tests for olfactory function that can be applied to rodent models of psychiatric disorders as part of behavioural analysis.


The effects of prepulse inhibition timing on the startle reflex and reaction time.
A loud acoustic stimulus has been shown to provoke a reflexive startle response and accelerate simple reaction times. However, an auditory prepulse presented in advance of a startling stimulus can reduce the effect of the startling stimulus. The current study examined the effect of the timing of the prepulse on startle-induced reaction times and the startle reflex. The task was to perform a 30° arm extension movement in response to a visual "go" stimulus. On selected trials, an auditory prepulse (80dB) was presented either 100ms, 500ms or 1000ms prior to the "go" signal. In addition, an auditory startling stimulus (124dB) was presented in conjunction with the "go" signal on some trials. Our results indicated that an auditory prepulse presented 100ms, and to a lesser extent 500ms, significantly decreased the amplitude of the startle reflex; however, the reaction time acceleration associated with the startling acoustic stimulus (SAS) was unaffected. The differential effect of the prepulse on the startle reflex and reaction time acceleration confirm different neural pathways for these effects while the differential effect of the prepulse on the control and startle RTs suggest different mechanisms for movement initiation.


Right hemisphere advantage for topographical orientation in the domestic chick.
When male chicks have to choose whether to orient by distant or proximal cues, chicks using the left eye (and so the right hemisphere) orient far better and make more use of distant cues than do right-eyed chicks. When both eyes are in use, left eye systems are mainly responsible for orientation, whereas right eye systems may concentrate on identifying food. Brief bias towards control of behaviour by the right eye system on day 8 allows it temporarily to be used successfully by the chick for orientation; apparently interference from the left eye system is reduced at this time.


Intra- and intermolecular oxidation of oxymyoglobin and oxyhemoglobin induced by hydroxyl and carbonate radicals.
The mechanism of the reactions of myoglobin and hemoglobin with *OH and CO3*- in the presence of oxygen was studied using pulse and gamma-radiolysis. Unlike *NO2, which adds to the porphyrin iron, *OH and CO3*- form globin radicals. These secondary radicals oxidize the Fe(II) center through both intra- and intermolecular processes. The intermolecular pathway was further demonstrated when BSA radicals derived from *OH or CO3*- oxidized oxyhemoglobin and oxymyoglobin to their respective ferric states. The oxidation yields obtained by pulse radiolysis were lower compared to gamma-radiolysis, where the contribution of radical-radical reactions is negligible. Full oxidation yields by *OH-derived globin radicals could be achieved only at relatively high concentrations of the heme protein mainly via an intermolecular pathway. It is suggested that CO3*- reaction with the protein yields Tyr and/or Trp-derived phenoxyl radicals, which solely oxidize the porphyrin iron under gamma-radiolysis conditions. The *OH particularly adds to aromatic residues, which can undergo elimination of H2O forming the phenoxyl radical, and/or react rapidly with O2 yielding peroxyl radicals. The peroxyl radical can oxidize a neighboring porphyrin iron and/or give rise to superoxide, which neither oxidize nor reduce the porphyrin iron. The potential physiological implications of this chemistry are that hemoglobin and myoglobin, being present at relatively high concentrations, can detoxify highly oxidizing radicals yielding the respective ferric states, which are not toxic.


Single transition metal-decorated C4N/MoS2 heterostructure for boosting oxygen reduction, oxygen evolution, and hydrogen evolution.
Multifunctional electrocatalysts for oxygen reduction reaction (ORR), oxygen evolution reaction (OER), and hydrogen evolution (HER) are required preconditions for the development of a highly promising new green energy conversion and storage technology. Herein, a comprehensive computation of the ORR, OER and HER catalytic performance for the pristine and metal-decorated C4N/MoS2 (TM-C4N/MoS2) is researched using density functional theory. Remarkably, Pd-C4N/MoS2 exhibits distinguished bifunctional catalytic performance with lower ORR/OER overpotentials of 0.34/0.40 V. Rh-C4N/MoS2 is the prospective trifunctional catalyst with the low ORR/OER/HER overpotentials of 0.48/0.55/-0.16 V, but its electrochemical stability needs to be further improved. Furthermore, the strong correlation between intrinsic descriptor (φ) and adsorption free energy of *OH verifies that the catalytic activity of TM-C4N/MoS2 is affected by active metal and surrounding coordination environment. The heap map has summarized the correlations of d-band center, adsorption free energy of reaction species, and φ as the vital parameter for ORR/OER overpotentials of designing catalysts. The electronic structure analysis uncovers the activity enhancement is due to the adjustable adsorption behavior of reaction intermediates on TM-C4N/MoS2. This finding paves the way to develop high-activity and multifunctional catalysts, making them suitable for multifunctional applications in the forthcoming critically needed green energy conversion and storage technologies.


Development and validation of a life expectancy calculator for US patients with prostate cancer.
To develop and validate an accurate, usable prediction model for other-cause mortality (OCM) in patients with prostate cancer diagnosed in the United States. Model training was performed using the National Health and Nutrition Examination Survey 1999-2010 including men aged >40 years with follow-up to the year 2014. The model was validated in the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial prostate cancer cohort, which enrolled patients between 1993 and 2001 with follow-up to the year 2015. Time-dependent area under the curve (AUC) and calibration were assessed in the validation cohort. Analyses were performed to assess algorithmic bias. The 2420 patient training cohort had 459 deaths over a median follow-up of 8.8 years among survivors. The final model included eight predictors: age; education; marital status; diabetes; hypertension; stroke; body mass index; and smoking. It had an AUC of 0.75 at 10 years for predicting OCM in the validation cohort of 8220 patients. The final model significantly outperformed the Social Security Administration life tables and showed adequate predictive performance across race, educational attainment, and marital status subgroups. There is evidence of major variability in life expectancy that is not captured by age, with life expectancy predictions differing by 10 or more years among patients of the same age. Using two national cohorts, we have developed and validated a simple and useful prediction model for OCM for patients with prostate cancer treated in the United States, which will allow for more personalized treatment in accordance with guidelines.


An unusual cause of burning mouth sensation.
A case of burning mouth and disturbed taste following accidental exposure to pyrethroid in an insecticide is reported. The symptoms were more prolonged than have been previously reported following cutaneous exposure.


New approaches to therapy.
L-DOPA-induced dyskinesia (LID) is a major complication of the treatment of Parkinson's disease (PD). LID comprises two major components, the priming process responsible for its onset and the expression of involuntary movements that underlies its clinical manifestation. The mechanisms responsible for these components are partially understood and their biochemical basis is being unraveled but avoidance and treatment remain an issue. In this chapter, we review what is known about the involvement of dopaminergic systems in LID and the way in which dopaminergic therapy can be used to avoid the onset of LID or to reverse or suppress involuntary movements once these have been established. The involvement of specific dopamine receptor subtypes, continuous dopaminergic stimulation (CDS) and continuous drug delivery (CDD) is reviewed. However, a major role is emerging in the avoidance and suppression of LID through the use of nondopaminergic mechanisms and we consider the present and future use of glutamatergic drugs, serotoninergic agents, adenosine antagonists and others as a means of improving therapy. There is compelling basic science supporting a role for nondopaminergic approaches to LID but at the moment the translational benefit to PD is not being achieved as predicted. There needs to be further consideration of why this is the case and how in future, both experimental models of dyskinesia and clinical trial design can be optimized to ensure success.


Efficacy and safety of open-label caplacizumab in patients with exacerbations of acquired thrombotic thrombocytopenic purpura in the HERCULES study.
Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune thrombotic microangiopathy. Caplacizumab, an anti-von Willebrand Factor Nanobody® , is effective for treating aTTP episodes and is well tolerated. In the phase 3 HERCULES trial (NCT02553317), patients with aTTP received double-blind caplacizumab or placebo during daily therapeutic plasma exchange (TPE) and for ≥30 days thereafter. Patients who experienced an exacerbation while on blinded study drug treatment switched to receive open-label caplacizumab plus re-initiation of daily TPE. Exacerbations were defined as recurrence of disease occurring within 30 days after cessation of daily TPE. Thirty-one patients (placebo, n = 28; caplacizumab, n = 3) had an exacerbation during double-blind treatment. Twenty-eight patients switched to open-label caplacizumab (placebo, n = 26; caplacizumab, n = 2); the three others discontinued upon exacerbation. Median time to platelet count response (≥150 × 109 /L) was 3.49 days upon receiving caplacizumab. There were no deaths. During open-label treatment, further exacerbation or a major thromboembolic event (vena cava thrombosis) was experienced by one patient (3.6%) each. Consistent with the double-blind phase, the most frequent treatment-emergent adverse events were catheter site hemorrhage (28.6%), headache (21.4%), and epistaxis (17.9%). These results suggest that caplacizumab was efficacious and well tolerated in patients with aTTP who experienced a disease exacerbation during double-blind treatment in HERCULES.


Uneventful removal of an epidural catheter guided by impedance aggregometry in a patient with recent coronary stenting and treated with clopidogrel and acetylsalicylic acid.
This report suggests that impedance aggregometry can be helpful to assess optimum time for and minimize the risk of catheter removal during double antiplatelet therapy. A 52-year-old patient undergoing cystectomy during combined general and epidural anesthesia suffered an acute myocardial infarction, and required coronary artery stenting and dual antiplatelet function therapy. Balancing the risks of stent occlusion and epidural bleeding, bedside impedance aggregometry helped to identify the optimum time window for epidural catheter removal with the lowest bleeding risk in this patient.


Olive Pomace and Soybean-Sunflower Acid Oils as Alternative Fat Sources in European Seabass (Dicentrarchus labrax) Diets: Effects on Performance, Digestibility and Flesh Fatty Acid Composition and Quality Parameters.
The effects of dietary inclusion of soybean-sunflower and olive pomace acid oils on growth, digestibility and flesh composition were studied in European seabass. Eight diets were fed for 100 days (101.37 ± 0.33 g initial weight, mean ± SD), differing in the added fat source (25% fish oil, 75% experimental oil): S (crude soybean oil), SA (soybean-sunflower acid oil), O (crude olive pomace oil) or OA (olive pomace acid oil); 3 blends: S-O, S-OA, SA-OA at a 1:1 ratio; and a diet containing only fish oil (F) as a control. Animals fed OA showed the worst performance among dietary treatments, with the lowest weight, specific growth ratio, average daily gain and the highest feed conversion ratio (p < 0.01). In contrast, other diets including acid oils did not impair performance. Acid oil diets did not affect the apparent digestibility of dry matter, crude protein or total fatty acids (p > 0.05), but a lower digestibility of lipids and saturated fatty acids was observed (p < 0.001). Flesh composition and fatty acid profile were not affected by the high dietary free FA content (p > 0.05). Hence the results suggest that the studied acid oils may potentially be used in fish diets although further studies are needed.


High-efficiency biolistic co-transformation and regeneration of 'Chardonnay' (Vitis vinifera L.) containing npt-II and antimicrobial peptide genes.
A reliable and efficient system for transformation and regeneration of 'Chardonnay' (Vitis vinifera L.) plants via microprojectile bombardment was developed. Improvements over the previous biolistic transformation system included: (1) the use of gold particles for bombardment; (2) step-wise selection at 10 then 15 mg/l kanamycin; and (3) embryo induction at 27 degrees C. Embryogenic cell cultures were either bombarded with pBI426, which contains the reporter gene gus (uidA) coding for beta-glucuronidase (GUS), or were co-bombarded with pSAN237 carrying the npt-II (neomycin phosphotransferase II) selectable marker gene, and a second plasmid with an antimicrobial peptide gene. A large number of transient (7,883 +/- 1,928) and stable (46 +/- 32) blue spots per plate at 2 and 95 days after bombardment, respectively, were obtained according to GUS expression analyses. A total of 447 putative transgenic embryos was harvested from 84 bombarded plates. From these embryos, 242 (54%) were regenerated into plants within the first year of the experiment. Southern blot analyses confirmed integration of the transgenes into the grape genome. Co-transformation was tested with four separate antimicrobial constructs. The co-transformation frequency of unlinked genes was 48% as measured by polymerase chain reaction (PCR), and 56% as estimated by dot blot hybridization. Expression of the gus gene, and PCR and Southern blot analyses of npt-II and antimicrobial genes from regenerated plants document stable transformation of 'Chardonnay' and establish the parameters for highly-efficient biolistic transformation in V. vinifera.


Methods to increase muscle tonus of upper airway to treat snoring: systematic review.
Snoring is the noise caused by vibration during the in-breath; and which structure actually vibrates depends on many factors. The treatment of snoring with methods to increase muscle tonus of upper airway has been controversial, and poorly reported, thus a review of evidence is necessary to evaluate the effectiveness of these methods. A review of randomized or quasi-randomized, double blind trials on snoring treatment that have employed any method to increase muscle tonus of upper airway like phonotherapy or physical therapy among others. decrease or completely stop of snoring, sleep quality, quality of life, and adverse events. Three eligible trials were potentially analyzed, but none of them could provide good scientific evidence favoring the intervention. The objective analyses of one study showed improvement of snoring, although the objective sub-analyses and subjective analyses showed controversial results. The adverse events were not reported. There is no enough evidence to support the recommendation of methods to increase muscle tonus of upper airways in treatment of snoring. Well designed randomized clinical trials are needed to asses the efficacy of such methods, and a standard and worldwide accepted method for snoring assessment would be useful for future researches.


Can We Exploit β-Lactamases Intrinsic Dynamics for Designing More Effective Inhibitors?
β-lactamases (BLs) represent the most frequent cause of antimicrobial resistance in Gram-negative bacteria. Despite the continuous efforts in the development of BL inhibitors (BLIs), new BLs able to hydrolyze the last developed antibiotics rapidly emerge. Moreover, the insurgence rate of effective mutations is far higher than the release of BLIs able to counteract them. This results in a shortage of antibiotics that is menacing the effective treating of infectious diseases. The situation is made even worse by the co-expression in bacteria of BLs with different mechanisms and hydrolysis spectra, and by the lack of inhibitors able to hit them all. Differently from other targets, BL flexibility has not been deeply exploited for drug design, possibly because of the small protein size, for their apparent rigidity and their high fold conservation. In this mini-review, we discuss the evidence for BL binding site dynamics being crucial for catalytic efficiency, mutation effect, and for the design of new inhibitors. Then, we report on identified allosteric sites in BLs and on possible allosteric inhibitors, as a strategy to overcome the frequent occurrence of mutations in BLs and the difficulty of competing efficaciously with substrates. Nevertheless, allosteric inhibitors could work synergistically with traditional inhibitors, increasing the chances of restoring bacterial susceptibility towards available antibiotics.


[Coffin-Lowry syndrome. Description of 2 cases associated with cardiovascular anomalies].
In this work the authors describe two cases of Coffin-Lowry syndrome, diagnosed in two brothers of different age and with a different degree of evolution of the illness. The brothers present the mitral prolapse association. The clinic and instrumental examination have been executed. The various pathogenetic hypothesis have been discussed and the authors propose the most recent that considers the fibroblast incapable to produce the substances of connective matrix. This hypothesis explain also the evolution and the progression of the lesion at the interested organs (skin, joints, bones, heart). The illness is genetic, with a X-linked, semidominant transmission.


Can only one person be right? The development of objectivism and social preferences regarding widely shared and controversial moral beliefs.
Prior work has established that children and adults distinguish moral norms (e.g., hitting is wrong) from conventional norms (e.g., wearing pajamas to school is wrong). Specifically, moral norms are generally perceived as universal across time and space, similar to objective facts. We examined preschoolers' and adults' perceptions of moral beliefs alongside facts and opinions by asking whether only one person could be right in the case of disagreements. We also compared perceptions of widely shared moral beliefs (e.g., whether it is better to pull someone's hair or share with someone) and controversial moral beliefs (e.g., whether it is better to help someone with a project or make cookies for someone). In Studies 1 and 2, preschoolers and adults were more likely to judge that only one person could be right in the case of widely shared versus controversial moral beliefs, treating the former as more objective or fact-like. Children were also more likely than adults to say that only one person could be right in a moral disagreement. Study 2 additionally revealed that adults were more likely than children to report preferring individuals who shared their controversial moral beliefs. Study 3 replicated these patterns using a different sample of widely shared beliefs (e.g., whether it is okay to mock a poor classmate) and controversial moral beliefs (e.g., whether it is okay to tell small, prosocial lies). While some aspects of moral cognition may depend on abundant social learning and cognitive development, the perception that disagreements about widely shared moral beliefs have only one right answer while disagreements about controversial moral beliefs do not emerges relatively early. We discuss implications for moral learning and social preferences.


Educating adolescents about the influence of the media via the French program « Service sanitaire »
Gathered within the context of the French "Service Sanitaire des Etudiants en Santé" (SSES), the leaders of a local prevention project and the coordinators of the said device have joined forces to propose a course dedicated to media education. Sharing their target population: middle school students, the aim was to put health students in a position to disseminate prevention interventions integrating the potential influence of digital media, in the region's middle schools. The present study proposes to evaluate the integration of this media education module into the local SSES. Using the referentialization model developed by G. Figari, we study the relevance of the plan, by combining and comparing the context of the creation of the media education module (MEM) and the strategies of integration into the SESS. The integration mechanism analyzed in the light of the effects produced allows us to address the effectiveness of the tool. Finally, the usefulness and efficiency of the implementation of the module are evaluated by relating the final product to the initial objectives. This study results in a description of the reality of the newly established local system. The cooperation between the SSES team and professionals competent in prevention and health promotion is both a source of opportunities and difficulties&#8230.


The zinc finger proteins ZC3H20 and ZC3H21 stabilise mRNAs encoding membrane proteins and mitochondrial proteins in insect-form Trypanosoma brucei.
ZC3H20 and ZC3H21 are related trypanosome proteins with two C(x)8 C(x)5 C(x)3 H zinc finger motifs. ZC3H20 is present at a low level in replicating mammalian-infective bloodstream forms, but becomes more abundant when they undergo growth arrest at high density; ZC3H21 appears only in the procyclic form of the parasite, which infects Tsetse flies. Each protein binds to several hundred mRNAs, with overlapping but not identical specificities. Both increase expression of bound mRNAs, probably through recruitment of the MKT1-PBP1 complex. At least 28 of the bound mRNAs decrease after depletion of ZC3H20, or of ZC3H20 and ZC3H21 together; their products include procyclic-specific proteins of the plasma membrane and energy metabolism. Simultaneous depletion of ZC3H20 and ZC3H21 causes procyclic forms to shrink and stop growing; in addition to decreases in target mRNAs, there are other changes suggestive of loss of developmental regulation. The bloodstream-form-specific protein RBP10 controls ZC3H20 and ZC3H21 expression. Interestingly, some ZC3H20/21 target mRNAs also bind to and are repressed by RBP10, allowing for dynamic regulation as RBP10 decreases and ZC3H20 and ZC3H21 increase during differentiation.


Long-Term Impact of Additional Ablation After Pulmonary Vein Isolation: Results From EARNEST-PVI Trial.
Background An optimal strategy for left atrial ablation in addition to pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (AF) has not been determined. Methods and Results We conducted an extended follow-up of the multicenter randomized controlled EARNEST-PVI (Efficacy of Pulmonary Vein Isolation Alone in Patients With Persistent Atrial Fibrillation) trial, which compared 12-month rhythm outcomes in patients with persistent AF between patients randomized to a PVI-alone strategy (n=248) or PVI-plus strategy (n=248; PVI followed by left atrial additional ablation, including linear ablation or ablation targeting areas with complex fractionated electrograms). The present study extended the follow-up period to 3 years after enrollment. Outcomes were compared not only between randomly allocated groups but also between on-treatment groups categorized by actually created ablation lesions. Recurrence rate of AF or atrial tachycardia (AT) was lower in the randomly allocated to PVI-plus group than the PVI-alone group (29.0% versus 37.5%, P=0.036). On-treatment analysis revealed that patients with PVI+linear ablation (n=205) demonstrated a lower AF/AT recurrence rate than those with PVI only (26.3% versus 37.8%, P=0.007). In contrast, patients with PVI+complex fractionated electrograms ablation (n=37) had an AF/AT recurrence rate comparable to that of patients with PVI only (40.5% versus 37.8%, P=0.76). At second ablation in 126 patients with AF/AT recurrence, ATs excluding common atrial flutter were more frequent in patients with PVI+linear ablation than in those with PVI only (32.6% versus 5.7%, P<0.0001). Conclusions Left atrial ablation in addition to PVI was efficacious during 3-year follow-up. Linear ablation was superior to other ablation strategies but may increase iatrogenic ATs. Registration URL: http://www.umin.ac.jp/ctr/index-j.htm; Unique identifier: UMIN000019449.


Maintenance of arachidonic acid and evidence of Δ5 desaturation in cats fed γ-linolenic and linoleic acid enriched diets.
Cats have limited Δ6 desaturase activity. However, γ-linolenate (GLA) feeding may by-pass the Δ6 desaturase step allowing arachidonate (ARA) accumulation via Δ5-desaturation. Alternatively, high dietary linoleate (LNA) may induce limited Δ6 desaturase also resulting in ARA accumulation. Fatty acid profiles were determined after feeding high LNA, high GLA, or adequate LNA diets. Adult female cats (n = 29) were assigned to one of three groups and fed for 8 weeks. Plasma samples were collected at weeks 0, 2, 4 and 8 for plasma triacylglycerol (TAG), total cholesterol (TC), lipoprotein (LP), and plasma and red blood cell membrane phospholipid fatty acid determinations. Time, but no diet, effects were observed for TAG, TC, and LP fractions at weeks 2 and 4 with significant increases likely due to increased dietary fat. However, all values were within feline normal limits. The GLA diet resulted in increased dihomo-γ-linolenic acid (DGLA) and ARA as early as week 2, supporting a ∆5 desaturase. Further evidence of Δ5 desaturase was found at high dietary LNA with the appearance of a novel fatty acid, 20:3 ∆7, 11, 14, apparently formed via ∆5 desaturation and chain elongation of LNA. However, Δ6 desaturase induction at high dietary LNA concentration was not observed. Cats are able to maintain plasma and red blood cell ARA when fed a practical diet containing GLA using what appears to be an active Δ5 desaturase enzyme.


GluN3A subunit tunes NMDA receptor synaptic trafficking and content during postnatal brain development.
Signaling via N-methyl-d-aspartate receptors (NMDARs) is critical for the maturation of glutamatergic synapses, partly through a developmental switch from immature synapses expressing primarily GluN2B- and GluN3A-containing subtypes to GluN2A-rich mature ones. This subunit switch is thought to underlie the synaptic stabilization of NMDARs necessary for neural network consolidation. However, the cellular mechanisms controlling the NMDAR exchange remain unclear. Using a combination of single-molecule and confocal imaging and biochemical and electrophysiological approaches, we show that surface GluN3A-NMDARs form a highly diffusive receptor pool that is loosely anchored to synapses. Remarkably, changes in GluN3A subunit expression selectively alter the surface diffusion and synaptic anchoring of GluN2A- but not GluN2B-NMDARs, possibly through altered interactions with cell surface receptors. The effects of GluN3A on NMDAR surface diffusion are restricted to an early time window of postnatal development in rodents, allowing GluN3A subunits to control the timing of NMDAR signaling maturation and neuronal network refinements.


Pathological and incidental findings on brain MRI in a single-center study of 229 consecutive girls with early or precocious puberty.
Central precocious puberty may result from organic brain lesions, but is most frequently of idiopathic origin. Clinical or biochemical factors which could predict a pathological brain MRI in girls with CPP have been searched for. With the recent decline in age at pubertal onset among US and European girls, it has been suggested that only girls with CPP below 6 years of age should have brain MRI performed. To evaluate the outcome of brain MRI in girls referred with early signs of puberty in relation to age at presentation as well as clinical and biochemical parameters. A single-center study of 229 consecutive girls with early or precocious puberty who had brain imaging performed. We evaluated medical history, clinical and biochemical factors, and four groups were defined based on the outcome of their MRI. Thirteen out of 208 (6.3%) girls with precocious puberty, but no other sign of CNS symptoms, had a pathological brain MRI. Importantly, all 13 girls were above 6 years of age, and 6 girls were even 8-9 years old. Twenty girls (9.6%) had incidental findings on brain MRI. Furthermore, 21 girls had known CNS pathology at time of evaluation. Basal LH was significantly higher in girls with newly diagnosed CNS pathology compared to girls with a non-pathological MRI (p = 0.025); no cut of value was found as values overlapped. A high frequency of 6-8 year old girls with precocious puberty in our study had a pathological brain MRI, which could not be predicted from any clinical nor biochemical parameters. Thus, we believe that girls with precocious pubertal development of central origin before 8 years of age should continue to be examined by a brain MRI.


Excitability changes of dorsal inspiratory neurons during lung inflations as studied by measurement of antidromic invasion latencies.
(1) Glass microelectrodes were used to record extracellularly the activity of single dorsal (in the region of nucleus tractus solitarius (NTS)) inspiratory neurons in either chloralose- or pentobarbitone-anaesthetized, paralyzed cats. (2) In the lateral and ventral part of NTS, 89 cells were localized which responded antidromically to stimulation applied to the contralateral spinal cord (C3). Seventy were not excited by lung inflation and were classified as Ralpha, while 19 excited by that stimulus were classified as Rbeta. Usually Rbeta neurons fired both during each pump-induced lung inflation and during the central inspiratory excitation (CIE). (3) A technique similar to Merrill's recording small variations in the antidromic latency measured to the SD spike was used to ascertain excitability of Ralpha and Rbeta cells during the CIE time and during lung inflation in expiration. The technique was extended by averaging antidromic latency patterns within many respiratory cycles. (4) In the majority of Ralpha cells the averaging revealed a shortening of the antidromic latency during lung inflation in expiration, which indicated a subthreshold depolarization. Lengthening of the antidromic latency by this stimulus was never observed. These results are in disagreement with the concept of a direct inhibitory input from Rbeta to Ralpha neurons. (5) It is concluded that the dorsal Ralpha and Rbeta neurons differ less in their properties than was previously assumed on the basis of classical extracellular techniques. The inhibitory influence of pulmonary stretch receptor input on inspiratory discharge of Ralpha cells seems to be exerted through an indirect action on the source of the CIE.


Location of robotic surgical systems worldwide and in France.
The advent of robot-assisted surgery is a surgical revolution. However, the costs of installing and using a da Vinci system are impediments to the proliferation of this technology. This article reviews the locations of robotic surgical systems worldwide and in France, in 2010.


Where and when adolescents are physically active: Neighborhood environment and psychosocial correlates and their interactions.
Female adolescents are less active than male peers in certain contexts including the neighborhood. Adolescents' physical activity can be explained by interactions between environmental and psychosocial factors, but few studies have tested such interactions in relation to context-specific behaviors. This study tested interactions between neighborhood environmental and psychosocial factors in relation to adolescents' context-specific physical activity. Data were collected in 2009-11 from 910 adolescents and a parent/guardian residing in the Baltimore/Seattle regions. Measures included adolescent-reported neighborhood leisure-time physical activity (LTPA) and non-neighborhood LTPA, accelerometer-based non-school moderate-to vigorous-physical activity (MVPA), psychosocial factors, and objective and parent-perceived neighborhood environmental factors. Gender-stratified mixed effects linear models tested associations of 6 environmental and 4 psychosocial factors and their interactions in relation to each physical activity outcome. The psychosocial factors had consistent associations with the physical activity outcomes but the environmental correlates were context-specific. Decisional balance (weighing of pros and cons of physical activity) moderated the association between recreation facility density and neighborhood LTPA among females, with a negative association only among those with high decisional balance (pros outweighed cons). Decisional balance also moderated associations of neighborhood walkability with non-school MVPA among females and non-neighborhood LTPA among males, with positive associations only among those with high decisional balance. Results support context-specific ecological models of physical activity. Targeting environmental factors that may promote opportunities for physical activity in specific contexts as well as adolescent decision-making may help promote their physical activity in those contexts, potentially leading to increased overall physical activity.


[Epidemiological impact of the COVID-19 pandemic on enucleation cases in Germany].
To determine the rate of enucleation in Germany and the impact that the COVID-19 pandemic may have had on its characteristics. The rates of enucleation in Germany during 2019 and 2020 were extracted from the diagnosis-related groups (DRG) registry using the operation and procedure classification system codes 5‑163.0 through 5‑163.23 and 5‑163.x. The data were statistically analyzed. The number of enucleations showed a 16.6% reduction from 1295 cases in 2019 compared to 1080 cases in 2020 (p = 0.17). In both years men averaged 54.1% of cases. Patients older than 65 years represented 53% and 56% of cases in 2019 and 2020, respectively. The most common indication for enucleation in both years was phthisis bulbi (n = 373 and n = 307, respectively), accounting for 29.7% of the cases, followed by choroidal malignancies (24%). Enucleation with the simultaneous introduction of an alloplastic orbital implant into Tenon's capsule represented the most common procedure (38.7% combined 2‑year average), followed by a sheathed variant (26.6%) and a bulbar implant made of nonabsorbable microporous material (16.8%), without a significant change between years. Enucleations without the introduction of an implant increased from 7.8% in 2019 to 11.1% in 2020 (p = 0.006). The proportion of patients undergoing a reoperation slightly increased from 5.6% to 8% (p = 0.018). Most procedures (65.6%) were performed in large (> 1000 beds) public hospitals. Despite the decrease in the total number of procedures performed, the rate of enucleation in Germany was not significantly altered by the COVID-19 pandemic. The rate of enucleation without implants and reoperations significantly increased.


Primary isolated aortic valve replacement. Early and late results.
A total of 1689 consecutive patients underwent isolated aortic valve replacement at the Cleveland Clinic Foundation from 1972 through 1986. There were 57 (3.4%) in-hospital deaths. Multivariate analysis identified advanced age (p = 0.0014), preoperative blood urea nitrogen level greater than 25 mg/100 ml (p = 0.008), New York Heart Association function class (p = 0.015), and preoperative atrial fibrillation (p = 0.04) as independent variables associated with increased in-hospital mortality and the use of cardioplegia for myocardial protection (p = 0.006) as a factor decreasing mortality. Follow-up documented survival rates of 85% and 66% and event-free survival rates of 71% and 43% at 5 and 10 postoperative years, respectively. Advanced age, moderate or severe impairment of left ventricular function, coronary artery disease, and preoperative blood urea nitrogen level greater than 25 mg/100 ml were associated with decreased late survival and event-free survival (all p less than 0.05). Patients with bioprostheses had better survival (p = 0.003) and event-free survival (p = 0.0007) rates than patients with mechanical valves. Patients with bioprostheses had superior results only if not receiving warfarin, and they experienced more reoperations and endocarditis; those with mechanical prostheses had more strokes, myocardial infarctions, bleeding complications, and thromboembolic events. Analysis of patients grouped according to age at operation showed that bioprostheses were associated with improved survival and event-free survival for patients 40 years older or older. Younger patients experienced more reoperations and episodes of endocarditis, and older patients more thromboembolic complications. We conclude that 10-year results after isolated aortic valve replacement are influenced by both patient-related and management-related variables, and the impact of these factors is different for patients of different ages.


Finite element analysis of retroacetabular osteolytic defects following total hip replacement.
Periprosthetic osteolysis in the retroacetabular region with cancellous bone loss is a recognized phenomenon in the long-term follow-up of total hip replacement. The effects on load transfer in the presence of defects are less well known. A finite element model incorporating a retroacetabular defect behind a cementless component was validated against a 4th generation sawbone pelvis. Computational predictions of surface strain and von Mises stresses were closely correlated to experimental findings. The presence of a cancellous defect increased von Mises stress in the cortical bone of the medial wall of the pelvis. At a load of 600 N this was under the predicted failure stress for cortical bone. Increases in the cup size relative to the acetabulum caused increased stress in the cortical bone of the lateral wall of the pelvis, adjacent to the acetabulum. We are confident that our modeling approach can be applied to patient specific defects to predict pelvis stress with large loads and a range of activities.


Sleep apnoeas and neurobehavioral effects in solvent exposed workers.
Exposure to organic solvents may cause an increase of sleep apnoeas, which may explain the excess of fatigue, concentration and memory problems reported in exposed workers. Polysomnography was performed in 21 long-term exposed printers and 27 controls. In addition, a questionnaire regarding sleep related complaints, Q16 questionnaire and computerized neurobehavioral tests were administered. The groups matched well regarding age, weight, neck circumference and schooling level. A semi-quantitative cumulative exposure index was calculated. Excessive sleepiness while watching TV (p<0.01) and diminished sexual interest (p=0.03) was found in the organic solvent-workers. The sleep complaints score correlated positively with the exposure index and duration (both p=0.01). The polysomnography results showed an increase of central apnoeas in the exposed workers (67%) compared to the referents (30%). The presence of central apnoeas was positively correlated with the exposure index (p<0.05) in regression models. Of the neurobehavioral test only hand-eye coordination was dose-related impaired in the exposed workers. The co-existence of abnormal values on at least one neurobehavioral test and the presence of central apnoeas was observed in the exposed workers, but did not reach significance. Workers chronically exposed to low organic solvent levels may experience mild sleeping problems, however, our data do not support the hypothesis that the clinical picture of chronic toxic encephalopathy can be primarily caused by the induction of sleep apnoea syndrome. It seems thus that the risk to experience central apnoeas rather accompanies the risk of impaired neurobehavioral performance with increasing exposure in a working population.


A study of the combined effect of the CLDN5 locus and the genes for the phospholipid metabolism pathway in schizophrenia.
The present study attempts to test the combined effect of the CLDN5 gene and those for the phospholipid metabolism pathway, including PTGS1, PTGS2, PLA2G4A and PLA2G4C. We detected five single nucleotide polymorphisms (SNPs) present in these genes among 131 British family trios of schizophrenic patients. The transmission disequilibrium test (TDT) showed that BanI-SNP located in the 5'-flanking region of the PLA2G4A gene was associated with schizophrenia (chi(2) = 5.16, P = 0.023) although the others failed to show such allelic associations. The global P-value was 0.150 for 1000 permutations with the TDT analysis. The conditioning on genotype test, but not on allele test, revealed a strong association for the combination of the CLDN5 gene with the PLA2G4A gene (chi(2) = 10.17, df = 2, P = 0.006). The present results suggest that the PLA2G4A locus may be involved in schizophrenia and its combination with the CLDN5 gene may increase further the risk for the illness.


Application of optimized parallel processing digital computers and numerical approximation methods to the ultra high-speed three-dimensional reconstruction of the intact thorax.
In order to achieve the computational capability to carry out many thousands of cross-sectional reconstructions, necessary to support a prototype high temporal and spatial resolution cylindrical scanning multiaxial tomographic unit, a series of design, software simulation, and fabrication studies is underway to develop a special-purpose high-speed reconstruction computer. This processor will rely upon integrated circuit arithmetic components of advanced design, and highly parallel architecture to execute X-ray based transaxial reconstruction algorithms at the rate of hundreds of cross sections/sec.


Exposure to estrogenic mixtures results in tissue-specific alterations to the metabolome of oysters.
The current study investigated the effect of environmentally relevant mixtures of estrogens at levels representative of receiving waters on the metabolome of the Sydney rock oyster, Saccostrea glomerata. Oysters were exposed to a "low" and a "high" mixture of (xeno) estrogens (representative of Australian and global receiving waters respectively) for 7 days and digestive gland, gill, and gonad tissue were sampled for quantification of polar metabolites by 1H NMR spectroscopy. Exposure to both mixtures lowered body mass and altered the metabolite profile in the digestive glands. Comparatively, gills, and ovaries demonstrated lesser sensitivity to the mixtures, with significant metabolomic alterations observed only for the high mixture. The male gonad did not respond to either estrogenic exposure. In the responsive tissues, major metabolites including amino acids, carbohydrates, intermediates of the tricarboxylic acid cycle and ATP were all down-regulated and exhibited tissue-specific patterns of down-regulation with the greatest proportion of metabolites down-regulated due to estrogenic exposure in the digestive gland. Exposure to (xeno) estrogen mixtures representative of concentrations reported in receiving waters in Australia and globally can impact the metabolome and associated energy metabolism, especially in the digestive gland, translating to lower pools of available ATP energy for potential cellular homeostasis, somatic maintenance and growth, reproduction and fitness.


Flow over a membrane-covered, fluid-filled cavity.
The flow-induced response of a membrane covering a fluid-filled cavity located in a section of a rigid-walled channel was explored using finite element analysis. The membrane was initially aligned with the channel wall and separated the channel fluid from the cavity fluid. As fluid flowed over the membrane-covered cavity, a streamwise-dependent transmural pressure gradient caused membrane deformation. This model has application to synthetic models of the vocal fold cover layer used in voice production research. In this paper, the model is introduced and responses of the channel flow, the membrane, and the cavity flow are summarized for a range of flow and membrane parameters. It is shown that for high values of cavity fluid viscosity, the intracavity pressure and the beam deflection both reached steady values. For combinations of low cavity viscosity and sufficiently large upstream pressures, large-amplitude membrane vibrations resulted. Asymmetric conditions were introduced by creating cavities on opposing sides of the channel and assigning different stiffness values to the two membranes. The asymmetry resulted in reduction in or cessation of vibration amplitude, depending on the degree of asymmetry, and in significant skewing of the downstream flow field.


Methylglyoxal inhibits nuclear division through alterations in vacuolar morphology and accumulation of Atg18 on the vacuolar membrane in Saccharomyces cerevisiae.
Methylglyoxal (MG) is a natural metabolite derived from glycolysis, and it inhibits the growth of cells in all kinds of organisms. We recently reported that MG inhibits nuclear division in Saccharomyces cerevisiae. However, the mechanism by which MG blocks nuclear division remains unclear. Here, we show that increase in the levels of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) is crucial for the inhibitory effects of MG on nuclear division, and the deletion of PtdIns(3,5)P2-effector Atg18 alleviated the MG-mediated inhibitory effects. Previously, we reported that MG altered morphology of the vacuole to a single swelling form, where PtdIns(3,5)P2 accumulates. The changes in the vacuolar morphology were also needed by MG to exert its inhibitory effects on nuclear division. The known checkpoint machinery, including the spindle assembly checkpoint and morphological checkpoint, are not involved in the blockade of nuclear division by MG. Our results suggest that both the accumulation of Atg18 on the vacuolar membrane and alterations in vacuolar morphology are necessary for the MG-induced inhibition of nuclear division.


Clinical Observation of Uninterrupted Thrombolytic Therapy via Indwelling Catheter for Lower Limb Deep Vein Thrombosis.
Observe uninterrupted thrombolytic therapy via indwelling catheter for lower limb deep vein thrombosis. We retrospectively studied data from 32 patients with lower extremity deep vein thrombosis who received comprehensive treatment, consisting of general treatment, inferior vena cava filter implantation, interventional thrombolysis, angioplasty, stenting, and post-operative monitoring. The efficacy and safety of the comprehensive treatment were observed for a follow-up period of 6-12 months. The treatment was 100% effective; patient results indicated no serious bleeding, acute pulmonary embolism, or death after surgery. The combination of intravenous and healthy side femoral vein puncture and directed thrombolysis to treat acute lower limb deep vein thrombosis is safe, effective, and minimally invasive while still achieving a good therapeutic effect.


Purification and biophysical analysis of microtubule-severing enzymes in vitro.
Microtubule-severing enzymes are a novel class of microtubule regulators. They are enzymes from the ATPases associated with various cellular activities family (AAA+) that utilize ATP to cut microtubules into smaller filaments. Discovered over 20 years ago, there are still many open questions about severing enzymes. Both cellular and biochemical studies need to be pursued to fully understand how these enzymes function mechanistically in the cell. Here, we present methods to express, purify, and test the biophysical nature of these proteins in vitro to begin to address the biochemical and biophysical mechanisms of this important and novel group of microtubule destabilizers.