Genetic Diversity of the Plasmodium falciparum Glutamate-Rich Protein R2 Region Before and Twelve Years after Introduction of Artemisinin Combination Therapies among Febrile Children in Nigeria.
The genetic diversity of glutamate-rich protein (GLURP) R2 region in Plasmodium falciparum isolates collected before and 12 years after the introduction of artemisinin combination treatment of malaria in Osogbo, Osun State, Nigeria, was compared in this study. Blood samples were collected on filter paper in 2004 and 2015 from febrile children from ages 1-12 years. The R2 region of the GLURP gene was genotyped using nested polymerase chain reaction and by nucleotide sequencing. In all, 12 GLURP alleles were observed in a total of 199 samples collected in the two study years. The multiplicity of infection (MOI) marginally increased over the two study years; however, the differences were statistically insignificant (2004 samples MOI = 1.23 versus 2015 samples MOI = 1.47). Some alleles were stable in their prevalence, whereas two GLURP alleles, VIII and XI, showed considerable variability between both years. This variability was replicated when GLURP sequences from other regions were compared with ours. The expected heterozygosity (He) values (He = 0.87) were identical for the two groups. High variability in the rearrangement of the amino acid repeat units in the R2 region were observed, with the amino acid repeat sequence DKNEKGQHEIVEVEEILPE more prevalent in both years, compared with the two other repeat sequences observed in the study. The parasite population characterized in this study displayed extensive genetic diversity. The detailed genetic profile of the GLURP R2 region has the potential to help guide further epidemiological studies aimed toward the rational design of novel chemotherapies that are antagonistic toward malaria.


Dose-dependent and cell type-specific cell death and proliferation following in vitro exposure to radial extracorporeal shock waves.
Radial extracorporeal shock wave (rESW) therapy is widely used in musculoskeletal disorders and wound repair. However, the mechanisms of action are still largely unknown. The current study compared the effects of rESWs on two cell types. Human fetal foreskin fibroblasts (HFFF2) and human placental choriocarcinoma cell line JEG-3 were exposed to 0, 100, 200, 500 or 5000 rESWs generated with a Swiss DolorClast device (2.5 bar, 1 Hz). FACS analysis immediately after rESW exposure showed that initially, rESWs rather induced mechanical cell destruction than regulated or programmed cell death. Cell damage was nearly negated by reducing cavitation. Furthermore, cell viability decreased progressively with higher numbers of rESWs. Exposure to rESWs had no impact on growth potential of JEG-3 cells, but dose-dependently increased growth potential of HFFF2 cells. Cultivation of cells that were initially exposed to sham-rESWs in conditioned media increased the growth potential of HFFF2 cells, nevertheless, an even stronger effect was achieved by direct exposure to rESWs. Additionally, cell cycle distribution analysis demonstrated a shift in proportion from G0/G1 to G2/M phase in HFFF2 cells, but not in JEG-3 cells. These data demonstrate that rESWs leads to initial and subsequent dose-dependent and cell type-specific effects in vitro.


Correlation between VDR expression and antiproliferative activity of vitamin D3 compounds in combination with cytostatics.
Calcitriol is a potent antiproliferative agent against various tumour cells in vitro. Its biological activity is mediated by the vitamin D receptors (VDRs). Here, we present the results of a study on vitamin D3 compounds (calcitriol and its analogue PRI-2191) as potential agents in combined antitumour therapy in vitro. Applying antiproliferative SRB and MTT assays, we measured the growth inhibitory effects of vitamin D compounds applied alone or in combination with either cisplatin or doxorubicin. Next, we examined the correlation of this effect with the presence of nVDR (nuclear VDR). The following cancer cell lines were applied: HL-60 (human leukaemia), SW707 (human colon cancer), A549 (human lung cancer), WEHI-3 (mouse leukaemia). The treatment of tumour cells with the combination of vitamin D compounds and cytostatics decreased the inhibitory concentration 50% (IC50) values compared with the effects of cytostatics applied alone. The synergistic effect was positively correlated with nVDR expression.


Preparation of 3-acetoacetylaminobenzo[b]furan derivatives with cysteinyl leukotriene receptor 2 antagonistic activity.
Novel 3-acetoacetylaminobenzo[b]furan derivatives with a modified triene system at the 3-position were prepared through acylation of the 3-aminobenzo[b]furans with 5-methylisoxazole-4-carboxylic acid chloride followed by basic cleavage of the isoxazole ring and several of these compounds showed moderate cysteinyl leukotriene receptor 2 antagonistic activity.


Longitudinal Tracking of Autoantibody Levels in a Pemphigus Vulgaris Patient: Support for a Role of Anti-Desmoglein 1 Autoantibodies as Predictors of Disease Progression.
Anti-desmoglein (Dsg) 1 and -Dsg3 antibody titers have an established role in the diagnosis of the autoimmune blistering skin disease pemphigus vulgaris (PV). However, their usefulness for disease monitoring has been controversial. A recent large-scale immunoprofiling study by our group indicated that anti-Dsg1 levels may be a better predictor of disease activity than anti-Dsg3 levels, with declining levels predicting progression from active phase of disease to early remission, irrespective of lesional subtypes. Here, we report an illustrative case of a PV patient with mucocutaneous disease that was followed longitudinally for >2.5 years clinically and by serum serology. Autoantibody levels directed against both Dsg1 and -3 showed a moderate correlation with PDAI scores, supporting a correlation of Dsg1 and 3 levels with disease severity. However, while both anti-Dsg3 and -Dsg1 antibody levels demonstrated a steady parallel decline after initiation of rituximab therapy, only anti-Dsg1 antibodies fell to levels below detectability with the progression to remission, while anti-Dsg3 levels remained elevated. This case illustrates the potential key role and clinical benefit of tracking anti-Dsg1 levels to monitor and conceivably predict disease activity in patients with PV. J Drugs Dermatol. 2017;16(2):135-139..


Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment .
To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 - 109%, respectively. The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups. .


Spontaneous ocular prolapse as an unusual late presentation of acrocephalosyndactyly.
A 38-year-old man presented with an unusual complaint of spontaneous left ocular prolapse, which had occurred while scratching his lower eyelid. He was noted to have an atypical facial appearance with frontal bossing and maxillary hypoplasia. Examination of the hands revealed bilateral syndactyly, suggesting a diagnosis of acrocephalosyndactyly. While it is common for eyes to prolapse in childhood in Crouzon or Apert syndrome, it is unusual for them to present in this way in middle age. It may be that age-related loss of tissue elasticity and consequent lower eyelid laxity decreased the inferior support of the globe, explaining the late presentation.


Modeling monthly variation of Culex tarsalis (Diptera: Culicidae) abundance and West Nile Virus infection rate in the Canadian Prairies.
The Canadian prairie provinces of Alberta, Saskatchewan, and Manitoba have generally reported the highest human incidence of West Nile virus (WNV) in Canada. In this study, environmental and biotic factors were used to predict numbers of Culex tarsalis Coquillett, which is the primary mosquito vector of WNV in this region, and prevalence of WNV infection in Cx. tarsalis in the Canadian prairies. The results showed that higher mean temperature and elevated time lagged mean temperature were associated with increased numbers of Cx. tarsalis and higher WNV infection rates. However, increasing precipitation was associated with higher abundance of Cx. tarsalis and lower WNV infection rate. In addition, this study found that increased temperature fluctuation and wetland land cover were associated with decreased infection rate in the Cx. tarsalis population. The resulting monthly models can be used to inform public health interventions by improving the predictions of population abundance of Cx. tarsalis and the transmission intensity of WNV in the Canadian prairies. Furthermore, these models can also be used to examine the potential effects of climate change on the vector population abundance and the distribution of WNV.


Endocrine secretions under abnormal light-dark cycles and in the blind.
Both endogenous and exogenous factors are involved in regulation of endocrine secretions. Among the exogenous ones, light plays an important role both in animals and in humans. Pineal gland mediates light action on the endocrine system, by means of variations of melatonin (MT) secretion. Here we discuss about the influence of abnormal light-dark cycles and in particular of blindness on pineal and pituitary secretions and on those of correlated glands. MT secretion is usually inhibited by light: thus it reaches the highest levels at night. Exposure to short or long photoperiod causes variations in circadian or infradian MT rhythmicity. Blind patients can show higher daytime levels with a phase-advanced or phase-delayed circadian rhythm. Lack of light stimulus affects cortisol rhythm shifting the zenith of secretion and inducing a free-running rhythm. Blindness can abolish nocturnal growth hormone (GH) peak and impair the GH response to some stimuli; moreover it impairs the growth of affected patients. Light stimulus influences favorably gonadal function both in animals and in man. In animals, sexual activity and gonadal function decline during the seasons with reduced luminosity. A similar finding has been described in women living in a region with a strong seasonal contrast in luminosity. Blindness can impair luteinizing hormone, follicle-stimulating hormone, prolactin and testosterone secretion in prepubertal boys causing pubertal delay or more severe hypogonadism; it can affect pubertal development and fertility in women. Light can influence thyroid function in animals. Lack of light stimulus in blind man seems to cause different effects on thyroid function before and after puberty. Increase of free thyroid hormone levels has been found in prepubertal but not in adult blind patients, probably due to a resetting of the threshold for thyrotropin feedback suppression after puberty in these patients.


Confrontation naming of familiar sounds and pictures by individuals with Down syndrome.
We investigated whether adolescents and young adults with Down syndrome experience difficulty in finding words to name familiar objects. In Experiment 1, IQ- and MA-matched individuals with Down syndrome and with mental retardation due to other causes orally identified familiar pictures and sounds. Results showed no evidence of syndrome-specific word-finding difficulty in accuracy or speed. Although both groups identified auditory stimuli less accurately and more slowly than visual stimuli, results of Experiments 2 and 3 confirmed that young children without mental retardation and college students showed the same pattern. Although previous researchers have shown expressive speech deficits among people with Down syndrome, these results suggest that adolescents and young adults with Down syndrome show no syndrome-specific difficulty in finding words to label familiar nonverbal sounds or pictures.


Colonialism and genetics of comparative development.
This study argues that European colonial policies and former colonies' genetic variation (genetic distance to Europeans and genetic diversity) were interlinked. Over a prolonged period of time, populations that were genetically far from Europeans and had extreme levels of genetic diversity (e.g. in Sub-Saharan Africa and the Americas) adapted to environments that were significantly different from the climatic conditions of continental Europe. This resulted in a divergence in populations' resistance to infectious diseases and positive relationships between European settler mortality at the time of colonization, genetic distance to the technological frontier, and genetic diversity. I evaluate the consequences of the aforementioned relationships first, for the role of genetic distance and diversity in development (e.g. Spolaore and Wacziarg, 2009; Ashraf and Galor, 2013), and second, for studies that use European settler mortality as an instrument for institutions (e.g. Acemoglu et al., 2001). The results highlight a potential bias in the estimates of the effect of genetic distance and diversity on contemporary development in a sample of former colonies and suggest that the effect of these measures on current economic and institutional outcomes is indirect and works through Europeans' colonial policies.


Essential Oils and Pure Volatile Compounds as Potential Drugs in Alzheimer's Disease Therapy: An Updated Review of the Literature.
The use of aromatic plants to relief different illness is not a new therapy. Actually aromatic plants have been used for many centuries by different cultures around the world. Pharmacological studies provide scientific support to the traditional use of aromatic medicinal plants and aromatherapy; nevertheless, more clinical trials are required regarding to their effectiveness in order to establish a guidance for their use in routine healthcare. Moreover, modern medicine in studies about olfactory function has attained great achievements and got Nobel Prize in 2004. These new searches have obviously fueled interest in the essential oils and volatile compounds of natural origin. Several reviews on the newly discovered AChEi obtained from plants, fungus and marine organisms have also been published over the last years. The majority of these AChEi belong to the alkaloid group, including indole, isoquinoline, quinolizidine, piperidine and steroidal alkaloids. Probably the interest in the essential oils and volatile compounds will be fueled from the new available scientific data about receptor on olfactory mucosa of nasal cavity. It can receive and distinguish different odor molecules, which produce nerve impulse and transmit into olfactory bulb via olfactory nerves. The nerve cells in the olfactory bulb transmit the signals into hippocampus. Because hippocampus is closely related with learning and memory functions, the volatile compounds can be potential drugs in AD therapies.


Dilemmas in management: the controversial role of chemotherapy in PS 2 advanced NSCLC and the potential role of CT-2103 (Xyotax).
Platinum-based chemotherapy improves long-term survival in patients with advanced non-small cell lung cancer (NSCLC). Meta-analyses have demonstrated an improvement in median and 1-year survival times as well as quality of life. However, these benefits are largely confined to patients with a good performance status (PS), one of the most critical determinants influencing outcome. Several clinical trials that initially included PS 2 patients ultimately discontinued their enrollment due to a high propensity of adverse reactions to treatment. The advent of more active, less toxic agents has revitalized investigator interest in treating PS 2 patients. CT-2103 is a novel paclitaxel conjugate undergoing investigation in the treatment of advanced NSCLC. The median survival for PS 2 patients treated with single-agent CT-2103 in one small trial proved similar to that reported for paclitaxel/carboplatin in NSCLC patients and was associated with an improved safety profile compared with conventional taxanes. Phase III studies comparing CT-2103 as a single agent and in combination with carboplatin to current standards of care are in progress. Unlike a well-defined population with good PS, the therapeutic index in PS 2 patients is narrower and not as clearly defined. These and other efforts will determine the optimal mode of therapy in PS 2 individuals with NSCLC.


[HIV-2 in The Netherlands].
By comparing data from the HIV confirmation laboratories it could be established that in the period prior to February 1991 a HIV-2 infection was demonstrated in at least 18 persons in the Netherlands. Consequently, use of combined HIV-1/2 tests is urgently recommended for screening in diagnostic and blood bank laboratories in the Netherlands. A suspicion of presence of HIV-2 antibodies may arise in the interpretation of a combined HIV-1/2-ELISA, a specific HIV-1-ELISA and the pattern of HIV-1 western immunoblot. Confirmation of the presence of HIV-2 antibodies should be obtained by means of western blots of viral lysates of both HIV-1 and HIV-2 and peptide tests from the transmembranous region. Most persons with a HIV-2 infection originated from Africa south of the Sahara or the Cape Verdean Islands or had had a sexual relationship with a person from these areas. The vast majority was heterosexual and 13 of the 18 infected persons were women. This differs greatly from the epidemiological pattern of HIV-1 infections in the Netherlands. The possibility of further spread of HIV-2 in the Netherlands via heterosexual contacts should be seriously taken into account.


[Antidotes and medicines used to treat poisoning in Brazil: needs, availability and opportunities].
Antidotes and certain other drugs are essential for treating some types of poisoning. Failures in their supply can jeopardize the population's health and safety. The current study aimed to assess the availability of antidotes and other drugs used in the treatment of poisonings in Brazil. International guidelines were used as the basis for selecting 41 antidotes for analysis, none of which currently protected by patents. Of these, 27 are registered in Brazil, but 11 of these are available in inadequate forms for treating poisoning, leaving 16 commercially available antidotes. Only one-third of the drugs needed for treating poisoning are included in the country's list of essential drugs. The article also presents a proposal for supplying the demand for one of the antidotes, anti-digoxin antibody, considering Brazil's domestic capacity for manufacturing immunobiologicals. The study's results show the limitations to adequate treatment for poison victims in Brazil and reinforce the urgent need to strengthen public policies in this area.


Tandem C-O and C-N Bonds Formation Through O-Arylation and [3,3]-Rearrangement by Diaryliodonium Salts: Synthesis of N-Aryl Benzo[1,2,3]triazin-4(1H)-one Derivatives.
Metal-free O-arylation and [3, 3]-rearrangement have been shown as an efficient strategy to construct new C-O and C-N bonds in one-pot reactions. The method was used to prepare N-aryl benzo[1,2,3]triazin-4(1H)-one derivatives in good yields from N-hydroxy benzo[1,2,3]triazin-4(3H)-one and diaryliodonium salts. The reaction was tolerated a variety of sensitive functional groups such as iodine, nitro, ester, and aldehyde groups. A rational mechanism was proposed based on the experimental results, and the reaction was easily up to gram scale.


A Nordic model for learning compassionate care in clinical education.
Preceptorship is one model of supporting student nurses' learning and development during their clinical education. However, little is known about what there is in preceptorship that promotes or hinders learning. Earlier studies found that there were ethical dimensions to students' encounters with preceptors. The overall purpose of this Nordic follow-up study was to develop a model for learning compassionate care among student nurses during their clinical education - first, to deeper understand the learning of student nurses, and second, to investigate the phenomenon of preceptorship from the preceptors´ point of view. This study used a mixed methods design. Undergraduate student nurses (n = 139) from three universities in Finland and Sweden were shadowed for a period of three years. Quantitative data were collected through a questionnaire and were analysed using statistical methods. To better understand the learning acquired by the student nurses, focus group interviews (n = 70) were conducted. The phenomenological-hermeneutical approach was adopted. To capture the preceptors' point of view, narrative interviews were held with them (n = 88) in western Finland and northern Sweden. A hermeneutical approach was used when analysing the data. According to both student nurses and preceptors, a caring student-preceptor relationship, imbued with commitment, reverence and responsibility, is fundamental and serves as the basis for students' learning and development more than pedagogical methods used. Three main themes emerged: a caring student-preceptor relationship; a caring manner of being-the conduct; and a caring culture-the tone of the learning space. This study shows the importance of preceptorship on student nurses in their quest of becoming compassionate and caring nurses. Therefore, based on earlier findings and the findings in this study, there is a need to facilitate and support the students' transformation, that is, the process of becoming, from student to a professional nurse.


The Association Between HLA Genetic Susceptibility Markers and Sonographic Enthesitis in Psoriatic Arthritis.
Enthesitis is an important pathophysiologic component of psoriatic arthritis (PsA). HLA genes are implicated in the pathogenesis of PsA. Little is known about the relationship between HLA genetic susceptibility markers and enthesitis in PsA patients. Our aim was to examine the association between HLA genetic susceptibility markers and sonographic enthesitis in PsA. A cross-sectional analysis was conducted in patients with PsA. Sonographic enthesitis was assessed according to the Madrid Sonography Enthesitis Index scoring system. HLA genotyping was performed using sequence-specific oligonucleotide probes. The association between 6 HLA susceptibility markers of PsA and the severity of sonographic enthesitis was assessed using multivariate regression models adjusted for age, sex, body mass index, and disease duration. Two hundred twenty-five patients were included, 57.8% of whom were men. The mean ± SD age was 56.1 ± 12.7 years, and the mean ± SD PsA duration was 16.9 ± 12.3 years. In the multivariate regression model, HLA-B*27 was associated with a higher enthesitis score (β = 4.24 [95% confidence interval {95% CI} 0.02, 8.46]), and the interaction between HLA-B*27 and PsA duration was statistically significant, showing an increasing effect of HLA-B*27 with longer PsA duration (β = 4.62 [95% CI 1.38, 7.86]). HLA-B*27 is associated with more severe sonographic enthesitis in PsA, particularly in patients with longer disease duration. This finding highlights the possible role of genetic variants in predisposing to PsA subphenotypes.


Improving the Efficiency of Configurational-Bias Monte Carlo: A Jacobian-Gaussian Scheme for Generating Bending Angle Trials for Linear and Branched Molecules.
A new method, called Jacobian-Gaussian scheme, has been developed to overcome the challenge of bending angle generation for linear and branched molecules in configurational-bias Monte Carlo. This method is simple, general, fast, and robust which can yield high acceptance rates. Since there are several bending angles in a branched point and their energies are coupled to each other, generating one trial that is acceptable for all energetic terms is a difficult problem. In order to reach reasonable acceptance rates, traditional methods either generate many trials uniformly or use prepared tables to generate trials according to the expected distribution. While the former consumes a considerable amount of simulation time, the later needs a modest amount of memory to store the tabulated distribution information. In contrast, this Jacobian-Gaussian scheme decouples the energetic terms through simple variable transformations and then generates each bending angle according to its Boltzmann distribution. Thus, high acceptance rates can be obtained using only a few trials without requirement for generation and storage of distribution data. This method has been shown to be efficient for various molecular types including propane, 2-methylpropane, 2,2-dimethylpropane, and acetone.


Simulation using novel equipment designed to explain spirometric abnormalities in respiratory disease enhances learning in higher cognitive domains.
Simulation of disorders of respiratory mechanics shown by spirometry provides insight into the pathophysiology of disease but some clinically important disorders have not been simulated and none have been formally evaluated for education. We have designed simple mechanical devices which, along with existing simulators, enable all the main dysfunctions which have diagnostic value in spirometry to be simulated and clearly explained with visual and haptic feedback. We modelled the airways as Starling resistors by a clearly visible mechanical action to simulate intra- and extra-thoracic obstruction. A narrow tube was used to simulate fixed large airway obstruction and inelastic bands to simulate restriction. We hypothesized that using simulators whose action explains disease promotes learning especially in higher domain educational objectives. The main features of obstruction and restriction were correctly simulated. Simulation of variable extra-thoracic obstruction caused blunting and plateauing of inspiratory flow, and simulation of intra-thoracic obstruction caused limitation of expiratory flow with marked dynamic compression. Multiple choice tests were created with questions allocated to lower (remember and understand) or higher cognitive domains (apply, analyse and evaluate). In a cross-over design, overall mean scores increased after 1½ h simulation spirometry (43-68 %, effect size 1.06, P < 0.0001). In higher cognitive domains the mean score was lower before and increased further than lower domains (Δ 30 vs 20 %, higher vs lower effect size 0.22, P < 0.05). In conclusion, the devices successfully simulate various patterns of obstruction and restriction. Using these devices medical students achieved marked enhancement of learning especially in higher cognitive domains.


Gasless video-assisted bilateral thyroidectomy by the anterior chest wall approach: 4 years of experience.
Thyroidectomy can be performed in a variety of ways, and gasless video-assisted approaches have recently become more popular. We performed a study of thyroidectomy on 77 patients with bilateral thyroid lesions carried out using a gasless video-assisted unilateral anterior chest wall approach. Seventy-seven patients underwent bilateral thyroidectomy by the gasless video-assisted unilateral anterior chest wall approach, whereas 64 patients underwent conventional surgery during the same time frame and were considered to be the control group. The eligibility criteria for thyroid surgery by gasless video-assisted unilateral anterior chest wall approach were: no previous neck surgical history, no radiotherapy history, a diagnosis of benign thyroid tumor according to preoperative computed tomographic scan, no inflammation-related diseases or thyroid hyperfunction, no lymphadenectasis, and bilateral tumors ≤ 4 cm in diameter (1 side ≤ 2 cm, located in the lower part of the thyroid and near the surface of the thyroid). The 2 groups were compared by surgical style, complications, operative time, cosmetic result, and postoperative pain. The 2 groups were matched in terms of age and sex; the scoring for operative procedure (P=0.443), postoperative drainage (P=0.686), and postoperative pain (P=0.294) were not significantly different. The gasless video-assisted group had less bleeding during surgery than the conventional group and had better cosmetic results (P<0.001), but also had longer surgical durations (P=0.003) and higher costs of hospitalization (P<0.001). Neither group had any permanent recurrent laryngeal nerve paralysis or hypocalcemia, nor were there recurrences duration followed up for 21 ± 10 months. The gasless video-assisted group had 1 case of ecchymoma and 1 case of temporary recurrent laryngeal nerve paralysis, but both recovered within a month. The complication rates in the 2 groups were not significantly different (χ=1.423, P=0.292). The gasless video-assisted thyroidectomy by the unilateral anterior chest wall approach is a safe and feasible way to treat patients with benign bilateral thyroid lesion with good cosmetic results. The gasless video-assisted thyroidectomy is a valid surgical option for selected patients and that its application will grow in the future.


Long-term hardware-related complications of deep brain stimulation.
To determine the incidence of long-term hardware-related complications of deep brain stimulation (DBS). The study design is a retrospective chart review of a single-surgeon, single-institution experience with DBS in 84 consecutive cases from 1993 to 1999. Only patients with a minimum follow-up of 1 year were considered. Five patients were excluded because trial stimulation failed to achieve pain relief (n = 4) or because the procedure was aborted owing to hemorrhage (n = 1). Seventy-nine patients received 124 permanent DBS electrode implants. The mean follow-up period was 33 months, and the cumulative follow-up time was 217 patient-years or 310 electrode-years. Overall, 20 patients (25.3%) had 26 hardware-related complications involving 23 (18.5%) of the electrodes. There were 4 lead fractures, 4 lead migrations, 3 short or open circuits, 12 erosions and/or infections, 2 foreign body reactions, and one cerebrospinal fluid leak. The hardware-related complication rate per electrode-year was 8.4%. The most common complications were related to the electrode connectors. A significant finding was a high number of complications involving erosions or infections, which occurred in 7 of 12 instances as a late complication (beyond 12 mo). Long-term follow-up reveals that hardware-related complications occur in a significant number of patients. Factors that lead to such complications must be identified and addressed to maximize the important benefits of DBS therapy.


Healthy for My Baby Research Protocol- a Randomized Controlled Trial Assessing a Preconception Intervention to Improve the Lifestyle of Overweight Women and Their Partners.
Background: Preconception lifestyle interventions appear promising to reduce pregnancy complications, prevent adult cardiometabolic diseases, and prevent childhood obesity. These interventions have almost exclusively been studied in populations of obese infertile women. The development of preconception lifestyle interventions targeting a broader population of overweight and obese women without a history infertility and their partners is needed. Methods: This study is a multicenter open label parallel group randomized controlled trial. Sixty-eight non-infertile women with overweight or obesity in the preconception period and their partners will be recruited from the Sherbrooke and Quebec City regions. The couples will be randomized in a 1:1 ratio to receive the Healthy for my Baby intervention or standard care in the preconception period and pregnancy. Women and their partners will be invited to take part in this lifestyle intervention which includes motivational interviews and daily self-monitoring of lifestyle goals through a mobile phone application. The primary endpoint of this study is the diet quality of women during the preconception period, which will be evaluated using the C-HEI 2007 score at baseline, 2, 4- and 6-months following study enrolment. Women's dietary quality will also be evaluated through the measure of urinary biomarkers of habitual dietary intake at baseline and 2 months in preconception, and 24-26 weeks in pregnancy. Additional indicators of women's lifestyle as well as anthropometric measures will be documented in preconception and pregnancy. For the pregnancy period, the main secondary endpoint is the pattern of gestational weight gain. Pregnancy and neonatal complications will also be evaluated. For partners, diet quality, other lifestyle habits, and anthropometric measures will be documented in the preconception and pregnancy periods. Discussion: This study will evaluate the effectiveness of a low-cost intervention designed to improve diet and other lifestyle characteristics of women in the preconception period who are overweight or obese. If the Healthy for my Baby intervention is efficacious regarding dietary measures, larger trials will be needed to evaluate the impact of this intervention on the rates of pregnancy complications, childhood obesity, and adult cardiometabolic disease. Clinical Trial Registration:clinicaltrials.gov (NCT04242069).


Charge migration following ionization in systems with chromophore-donor and amine-acceptor sites.
The ultrafast charge migration following outer-valence ionization in three different but related molecules, namely, 2-phenylethyl-N,N-dimethylamine (PENNA), and its butadiene (MePeNNA) and ethylene (BUNNA) derivates, is studied in detail. The molecules have different chromophore-donor sites, but nearly identical amine-acceptor sites. The results show that the charge migration process depends strongly on the particular donor site, varying from ultrafast migration of the charge from the donor to the acceptor site (4 fs for MePeNNA) to no migration at all (for BUNNA). The influence of the geometrical structure of the molecule on the charge migration is also investigated. It is shown that energetically closely lying conformers may exhibit dramatically different charge migration behaviors. The basic mechanism of the charge migration process in the studied molecules is analyzed in detail and is demonstrated to be due to electron correlation and relaxation effects.


Multisystem disorder in late-onset chronic progressive external ophthalmoplegia.
Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial syndrome on a disease spectrum with Kearns-Sayre syndrome (KSS). Clinical presentation is variable and our experience suggested that phenotypic differences exist in CPEO with onset after age 20. This descriptive study is a retrospective chart review of 40 patients with late-onset CPEO. Clinical features, laboratory and neurophysiology results were reviewed. Multisystem dysfunction was very common in this series. Gastrointestinal dysfunction was more common than expected (60%) as was migraine headache (40%). Clinical characteristics on the KSS disease spectrum were uncommon in this series with only 2.5% having pigmentary retinopathy, 5% with cardiac conduction abnormality, and 22.5% having endocrinopathy (most often thyroid dysfunction rather than diabetes). Neurophysiology abnormalities included length-dependent axonal polyneuropathy in 44% (sometimes subclinical) and myopathic EMG changes in 26%. Exposure to sources of acquired mitochondrial toxicity including cigarette use and hepatitis C infection were more common than expected in this series. Phenotype was different in this late-onset series compared with previous reports in CPEO patients. In this series of late-onset patients, multi-organ dysfunction was more common than previously reported in CPEO, and some classical mitochondrial manifestations, such as pigmentary retinopathy were rare. We suggest that acquired mitochondrial toxicity may have a role in the pathogenesis of adult-onset CPEO.


People with Disabilities and COVID-19 in the state of Espírito Santo, Brazil: between invisibility and lack of Public Policies.
This article aims to analyze the profile of people with disabilities among the cases notified by the COVID-19 panel of Espírito Santo and the possible associations with the positive result of the COVID-19 test. Descriptive cross-sectional study among people with disabilities with positive and negative tests for the diagnosis of COVID-19. Associations of epidemiological and clinical variables were performed using the chi-square test and logistic regression models to estimate the odds ratio. Lethality rate of COVID-19 was 4.9% (175 cases) in the group of people with disabilities, and 3% (3,016) in the group without disabilities. People with disabilities, male (OR=1.34; 95%CI 1.22-1.47), race/black color (OR=1.55; 95%CI 1.09-2.20), and those who were hospitalized (OR=2.27; 95%CI 1.71-3.02) were associated with positive tests for COVID-19. The pandemic emphasizes the need to create specific legal care mechanisms and targeted public policies for this population.


Dental pulp stem cells and the management of neurological diseases: An update.
Medical research in regenerative medicine has brought promising perspectives for the use of stem cells in clinical trials. Stem cells are undifferentiated cells capable of multilineage differentiation and available in numerous sources in the human body. Dental pulp constitutes an attractive source of these cells since collecting mesenchymal stem cells from this site is a noninvasive practice that can be performed after a common surgical extraction of supernumerary or wisdom teeth. Thus, tissue sacrifice is very low and several cytotypes can be obtained owing to these cells' multipotency, in addition to the fact that they can be cryopreserved and stored for long periods. Mesenchymal stem cells have high proliferation rates, making them favorable for clinical application. These multipotent cells, present in biological waste, constitute an appropriate resource in the treatment of many neurological diseases.


Direct quantification of loop interaction and π-π stacking for G-quadruplex stability at the submolecular level.
The well-demonstrated biological functions of DNA G-quadruplex inside cells call for small molecules that can modulate these activities by interacting with G-quadruplexes. However, the paucity of the understanding of the G-quadruplex stability contributed from submolecular elements, such as loops and tetraguanine (G) planes (or G-quartets), has hindered the development of small-molecule binders. Assisted by click chemistry, herein, we attached pulling handles via two modified guanines in each of the three G-quartets in human telomeric G-quadruplex. Mechanical unfolding using these handles revealed that the loop interaction contributed more to the G-quadruplex stability than the stacking of G-quartets. This result was further confirmed by the binding of stacking ligands, such as telomestatin derivatives, which led to similar mechanical stability for all three G-quartets by significant reduction of loop interactions for the top and bottom G-quartets. The direct comparison of loop interaction and G-quartet stacking in G-quadruplex provides unprecedented insights for the design of more efficient G-quadruplex-interacting molecules. Compared to traditional experiments, in which mutations are employed to elucidate the roles of specific residues in a biological molecule, our submolecular dissection offers a complementary approach to evaluate individual domains inside a molecule with fewer disturbances to the native structure.


Murine macrophage precursor cell lines are unable to differentiate into osteoclasts: a possible implication for osteoclast ontogeny.
Six murine macrophage precursor cell lines, thought to be arrested around the CFU-GM stage of the myeloid differentiation and shown to be negative for acid phosphatase, F4/80 antigen expression and phagocytosis capacity, were tested for their ability to differentiate into osteoclasts. Their differentiation potential was compared with that of the haemopoietic stem cell line FDCP-mix C2GM. None of the macrophage precursor cell lines could be induced to differentiate into osteoclasts when the cells were cocultured with either periosteum-free metatarsal bones of fetal mice, or monolayers of osteoblast-like cells. In contrast, when the haemopoietic stem cell line FDCP-mix C2GM, murine fetal liver cells or murine spleen cells were used as a source of haemopoietic precursor cells, numerous osteoclasts were formed in both culture systems. During cell culture a small percentage of the macrophage precursor cells attached to the bottom of the culture well. These firmly attached cells acquired acid phosphatase activity, F4/80 antigen expression and phagocytosis capacity. Furthermore, when the cell lines were cultured for 2 or 4 days with 1% DMSO, up to 30% of the precursor cells differentiated into metamyelocytes. These results suggest that the macrophage precursor cell lines are able to acquire macrophage and granulocyte characteristics, but are unable to differentiate into osteoclasts. In contrast, the haemopoietic stem cell line FDCP-mix C2GM is able to differentiate into both macrophages and osteoclasts. We therefore suggest that the osteoclast lineage branches off at an early stage of the myeloid differentiation pathway.


Predictive value of a positive fecal occult blood test increases as the severity of CKD worsens.
Because chronic kidney disease (CKD) may be associated with gastrointestinal bleeding from trivial mucosal lesions, we hypothesized that the predictive value of a positive fecal occult blood test (FOBT) result for clinically important colonic lesions would decrease as the stage of CKD worsened. We prospectively identified 1,225 consecutive asymptomatic average-risk patients who were referred for colonoscopy to evaluate a positive FOBT result. Using the Modification of Diet in Renal Disease equation, we estimated glomerular filtration rate (GFR) and staged the severity of CKD by using standard criteria as follows: normal/stage 1 (GFR > or = 90 mL/min/1.73 m2 [> or = 1.50 mL/s]), stage 2/3 (GFR 30 to 89 mL/min/1.73 m2 [0.50 to 1.48 mL/s]), and stage 4/5 (GFR < 30 mL/min/1.73 m2 [< 0.50 mL/s] or dialysis). Clinically important lesions were identified in 23.9% of 531 individuals with none/stage 1 CKD, 32.8% of 497 subjects with stage 2/3 CKD, and 42.6% of 197 patients with stage 4/5 CKD (P < 0.001). Compared with patients with none/stage 1 CKD, adjusted odds of identifying a clinically important lesion were 1.61 (95% confidence interval, 1.21 to 2.15) in subjects with stage 2/3 CKD and 2.33 (95% confidence interval, 1.62 to 3.36) in patients with stage 4/5 CKD. Prevalences of adenomas of 1 cm or greater (15.1% versus 20.1% versus 22.8%; P = 0.007), carcinomas (5.1% versus 10.1% versus 13.2%; P < 0.001), and vascular ectasias (1.7% versus 2.4% versus 6.1%; P = 0.003) increased with the severity of CKD. Contrary to our initial hypothesis, we found that the predictive value of a positive FOBT result for clinically important colonic lesions increased as the severity of CKD worsened.


ATPase may play a critical role in disturbance of energy metabolism in congestive heart failure rats.
This study aims to explore the expression and significance of ATPase in myocardium of congestive heart failure induced by pressure overload in rats. Male SD rats were divided into 3 groups randomly: Control group (C group), coarctation of abdominal aorta 15 weeks group (A group) and sham operation group (SH group). The hemodynamics parameters were measured. The size of adenine acid pool (ATP, ADP) in myocardium was measured by high performance liquid chromatography (HPLC). The mRNA copies of ATPase-α subunit, ATPase-6 subunit in ventricular myocardium were determined by RT-PCR. The protein content of F1-ATPase in mitochondria was detected by Western blot analysis. The ±dp/dtmax and contents of ATP and ADP decreased significantly in myocardium were decreased in A group. Compared with C and SH group, the mRNA copies of ATPase-α subunit, ATPase-6 subunit and the protein content of F1-ATPase were decreased in A group. The expression of F1-ATPase decreased parallel with abnormal of the adenine nucleotide in myocardium of congestive heart failure. It may play a critical role in disturbance of energy metabolism in disfunction of heart.


Post-transplant diabetes mellitus and HCV seropositive status after renal transplantation: meta-analysis of clinical studies.
Hepatitis C virus (HCV) infection has a detrimental role on patient and graft survival after renal transplantation (RT). Some studies have also implicated HCV in the development of post-transplant diabetes mellitus (PTDM). We conducted a systematic review of the published medical literature of the relationship between anti-HCV seropositive status and DM after RT. The risk of DM occurrence in anti-HCV-positive and -negative patients after RT was regarded as the most reliable outcome end-point. We used the random effects model of DerSimonian and Laird to generate a summary estimate of the Odds Ratio (OD) of new onset DM in HCV-positive and -negative patients after kidney transplantation. Ten studies involving 2502 unique RT recipients were identified. The incidence of PTDM after RT ranged between 7.9% and 50%. The summary estimate for adjusted OR was 3.97 with a 95% confidence interval (CI) of 1.83-8.61 (p-value for homogeneity <0.0473). Thus, pooling of study results demonstrated the presence of a significant link between anti-HCV seropositive status and DM after RT. This relationship provides one potential explanation for the adverse effects of HCV on patient and graft survival after RT.


The effects of selective cholinergic basal forebrain lesions and aging upon expectancy in the rat.
The effects of selective cholinergic cell loss within the basal forebrain (BF) were determined using a task that requires shifting of attention between two visual stimuli. Discriminability between two stimuli and response bias were determined in young and old F-344 rats given BF injections of IgG-192 saporin (100 ng). The lesion reduced ChAT activity in the frontal and parietal cortices, hippocampus, and olfactory bulbs. The lesion did not significantly alter Na+/K(+)-ATPase activity in cortex, hippocampus, or olfactory bulbs, or endogenous levels of neuropeptide Y and neurokinin B within the BF. The BF lesions impaired both stimulus discriminability and response bias in young and old rats. The BF lesions had a significantly greater effect upon stimulus discriminability and response bias in aged rats, compared to young rats, only when the stimulus duration was very brief, i.e., when the task was most difficult to solve. At longer stimulus durations, aging and lesions showed no interaction. The results suggest that the selective loss of cholinergic cells in the BF, but not normal aging, impairs the ability to discriminate between independent sensory stimuli. The loss of these cells confers a response bias in simple operant tasks involving motor responses to reward-related visual stimuli.


Psychosocial challenges of young people affected by HIV: experiences from Hamilton County, Chattanooga, Tennessee.
The number of young people affected by HIV and AIDS in Tennessee has steadily grown over the last few years. As a response to this situation, several organizations are working hard to address the needs of families impacted by HIV and AIDS. However, a close examination of some of the services provided suggests that young people within these families are ignored. Most of the services are geared toward HIV and AIDS-infected adult members of these families. Young people within these household are not targeted, and little is known about psychosocial challenges they experience in living with HIV-positive parents or guardians. In an attempt to address this gap, this small-scale qualitative study investigated the psychosocial challenges of young people affected by HIV and AIDS as a result of living with HIV-positive parents or guardians. Perceived sense of depression, experiencing stigma, self-blame, and lack of communication and loneliness were challenges that young people faced regularly.


Au Nanoparticles Decorated CoP Nanowire Array: A Highly Sensitive, Anticorrosive, and Recyclable Surface-Enhanced Raman Scattering Substrate.
Metal-semiconductor composites are promising candidates for surface-enhanced Raman scattering (SERS) substrates, but their inert basal plane, poor active sites, and limited stability hamper their commercial prospects. Herein, we report a three-dimensional CoP nanowire array decorated with Au nanoparticles on carbon cloth (Au@CoP/CC) as a self-supporting flexible SERS substrate. The Au nanoparticles spontaneously grew on the surface of the CoP nanowire array to form efficient SERS hot spots by a redox reaction with HAuCl4 without any additional reducing agents. Such Au@CoP/CC substrate exhibited a limit of detection of 10-11 M using rhodamine 6G as a model dye with outstanding corrosion resistance ability even under extreme acid and alkali conditions, which is better than many recently reported Au-based SERS substrates. Finite-difference time-domain simulation results demonstrated that Au@CoP/CC can provide a high density of regions with intense local electric field enhancement. Moreover, Au@CoP/CC can degrade target organic dyes for the self-cleaning and reproduction of SERS-active substrates under visible light irradiation. This work provides a novel means of using the plasmonic metal-transition metal phosphide composites for high-performance SERS sensing and photodegradation.


Proteinous amino acids in muscle cytosol of rats' heart after exercise and hypoxia.
Levels of 19 proteinous amino acids and of total free amino acids were assayed by gas-liquid chromatography in cytosols of rat atrial and ventricular heart muscle cardiomyocytes. These amino acids were assayed after the rats had been exposed to either exercise (swimming) or hypoxia (hypobaric pressure of 686 hectoPascals). Out of the total free amino acids levels of arginine, glutamine and cysteine in atrial and ventricular cardiac muscle cytosols of control rats were the highest of all amino acids assayed. The control levels of all other amino acids assayed in atrial or ventricular cardiac muscles ranged from 0.1% to 10.6% of the total free amino acids in the control rats. Physical stress (exercise and hypoxia) significantly reduced the total amount of cytosolic free amino acids in both heart muscles. While hypoxia decreased the levels of arginine in both heart muscles, exercise abolished the level of cysteine in the atrial heart muscle. Decrease in arginine levels, and elimination of cysteine from the heart's atrial muscle after physical stress, may be attributed to its utilization of nitric oxide and to its synthesis of atriopeptin and/or endothelin during stress. No change was recorded in either experimental group in the level of glutamine in heart muscle cytosol. Exercise and hypoxia affect, in different modes, the levels of all other amino acids assayed, except for tryptophan, tyrosine, and histidine, which are precursors of endogenous neurotransmitters. The impact of proteinous amino acids on some bodily functions is discussed.


Segmental rigidity and spinal myoclonus as a paraneoplastic syndrome.
A 68 year old woman is described with persisting muscular rigidity of the left lower leg together with transient myoclonic jerking in the left quadriceps muscle. Six weeks after onset a small cell carcinoma of the lung became manifest. With radiotherapy and chemotherapy complete remission was achieved. Segmental muscular spasm improved at the same time. Necropsy revealed loss and degeneration of alpha-motor neuron cells at one side of the anterior horn of the lumbar enlargement. This case may represent another manifestation of paraneoplastic subacute motor neuronopathy.


Effects of grazing cow diet on volatile compounds as well as physicochemical and sensory characteristics of 12-month-ripened Montasio cheese.
The aim of this study was to evaluate the effects of pasture type and cow feeding supplementation level on a 12-mo-ripened Montasio protected designation of origin (PDO) cheese, which is one of the most important PDO cheeses produced in northeast Italy. Cheeses were characterized for volatile compounds, color, mechanical variables, and sensory descriptors. Pasture type significantly affected most of the instrumental variables considered and, as a consequence, sensory properties were affected as well. Cheeses from the pasture characterized by a nutrient-rich vegetation type were higher in protein and lower in fat content. Furthermore, such cheeses, evaluated by a sensory panel, were more intense in color with a more pungent and less cow-like odor, in agreement with what found through instrumental analyses. Supplementation level resulted in less pronounced effects, limited to volatile compounds and texture properties, which were not detected by sensory analysis. The characterization of the 12-mo ripened Montasio cheese reported here is an important step for the valorization of this PDO product.


Anomalous scaling in kinematic magnetohydrodynamic turbulence: Two-loop anomalous dimensions of leading composite operators.
Using the field theoretic formulation of the kinematic magnetohydrodynamic turbulence, the explicit expressions for the anomalous dimensions of leading composite operators, which govern the inertial-range scaling properties of correlation functions of the weak magnetic field passively advected by the electrically conductive turbulent environment driven by the Navier-Stokes velocity field, are derived and analyzed in the second order of the corresponding perturbation expansion (in the two-loop approximation). Their properties are compared to the properties of the same anomalous dimensions obtained in the framework of the Kazantsev-Kraichnan model of the kinematic magnetohydrodynamics with the Gaussian statistics of the turbulent velocity field as well as to the analogous anomalous dimensions of the leading composite operators in the problem of the passive scalar advection by the Gaussian (the Kraichnan model) and non-Gaussian (driven by the Navier-Stokes equation) turbulent velocity field. It is shown that, regardless of the Gaussian or non-Gaussian statistics of the turbulent velocity field, the two-loop corrections to the leading anomalous dimensions are much more important in the case of the problem of the passive advection of the vector (magnetic) field than in the case of the problem of the passive advection of scalar fields. At the same time, it is also shown that, in phenomenologically the most interesting case with three spatial dimensions, higher velocity correlations of the turbulent environment given by the Navier-Stokes velocity field play a rather limited role in the anomalous scaling of passive scalar as well as passive vector quantities, i.e., that the two-loop corrections to the corresponding leading anomalous dimensions are rather close to those obtained in the framework of the Gaussian models, especially as for the problem of scalar field advection. On the other hand, the role of the non-Gaussian statistics of the turbulent velocity field becomes dominant for higher spatial dimensions in the case of the kinematic magnetohydrodynamic turbulence but remains negligible in the problem of the passive scalar advection.


Inflammatory response after transanal total mesorectal excision.
The advantages of transanal total mesorectal excision (taTME) would be a reduction of the hernia rate and surgical trauma. The present study reports data for patients undergoing taTME and compares the post-operative immune response in taTME with those of conven-tional laparoscopic surgery (CLS) and single-port laparo-scopic surgery (SPLS). A comparative cohort study in patients with rectal cancer undergoing taTME. C-reactive protein (CRP) and white blood cell count (WBC) were measured pre-operatively and on post-operative days one, two, three and four. A total of 40 patients were included in taTME, 20 patients in CLS and 20 in SPLS. Patients' demographics (except for clinical staging), R0 resection and post-operative complication rates were comparable. The length of abdom-inal incisio-n was significantly lower by taTME than by both SPLS and CLS (p < 0.001). Distant resection margin was shorter in the taTME group (p < 0.01), and the quality of specimen differed between groups (p < 0.01). CRP and WBC increased significantly in each group (p < 0.05), but there was no difference between the groups. There is no difference in the inflammatory response in patients with rectal cancer undergoing taTME surgery compared with CLS and SPLS. We therefore conclude that the length/presence of abdominal incision does not further reduce the post-operative inflammatory stress response in minimally invasive procedures. The surgical trauma extends beyond the abdominal incision and depends on the intra-abdominal handling of the tissue. none. ID NCT00157972, ethical approval ID H-1-2011-007, H-15000540.


Simultaneous assay of cortisol and dexamethasone improved diagnostic accuracy of the dexamethasone suppression test.
The overnight dexamethasone (DXM) suppression test (DST) has high sensitivity, but moderate specificity, for diagnosing hypercortisolism. We have evaluated if simultaneous measurement of S-DXM may correct for variable DXM bioavailability and increase the diagnostic performance of DST, and if saliva (sa) is a feasible adjunct or alternative to serum. Prospective study of DST was carried out in patients with suspected Cushing's syndrome (CS) (n = 49), incidentaloma (n = 152) and healthy controls (n = 101). Cortisol, cortisone and DXM were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Three hundred and two subjects underwent DST; S-cortisol was ≥50 nmol/L in 83 patients, of whom 11 had CS and 27 had autonomous cortisol secretion. The lower 2.5 percentile of S-DXM in subjects with negative DST (n = 208) was 3.3 nmol/L, which was selected as the DXM cut-off level. Nine patients had the combination of low S-DXM and positive DST. Of these, three had been misdiagnosed as having autonomous cortisol secretion. DST results were highly reproducible and confirmed in a replication cohort (n = 58). Patients with overt CS had significantly elevated post-DST sa-cortisol and sa-cortisone levels compared with controls; 23 of 25 with autonomous cortisol secretion had elevated sa-cortisone and 14 had elevated sa-cortisol. Simultaneous measurement of serum DXM and cortisol reduced false-positive DSTs by 20% and improved the specificity. S-DXM >3.3 nmol/L is sufficient for the suppression of cortisol <50 nmol/L. Measurement of glucocorticoids in saliva is a non-invasive and easy procedure and post-DST sa-cortisone was found particularly useful in the diagnosis of CS.


Microtubule release from the centrosome.
Although microtubules (MTs) are generally thought to originate at the centrosome, a number of cell types have significant populations of MTs with no apparent centrosomal connection. The origin of these noncentrosomal MTs has been unclear. We applied kinetic analysis of MT formation in vivo to establish their mode of origin. Time-lapse fluorescence microscopy demonstrated that noncentrosomal MTs in cultured epithelial cells arise primarily by constitutive nucleation at, and release from, the centrosome. After release, MTs moved away from the centrosome and tended to depolymerize. Laser-marking experiments demonstrated that released MTs moved individually with their plus ends leading, suggesting that they were transported by minus end-directed motors. Released MTs were dynamic. The laser marking experiments demonstrated that plus ends of released MTs grew, paused, or shortened while the minus ends were stable or shortened. Microtubule release may serve two kinds of cellular function. Release and transport could generate the noncentrosomal MT arrays observed in epithelial cells, neurons, and other asymmetric, differentiated cells. Release would also contribute to polymer turnover by exposing MT minus ends, thereby providing additional sites for loss of subunits. The noncentrosomal population of MTs may reflect a steady-state of centrosomal nucleation, release, and dynamics.


Effect of mast cell chymase inhibitor on the development of scleroderma in tight-skin mice.
1 Although the pathogenesis of scleroderma is not fully understood, activation of connective-tissue-type mast cells (CTMCs) has been implicated in various fibrotic diseases. 2 Our previous study showed that the number of CTMCs was markedly increased during fibrous proliferation in the skin of a scleroderma model, namely tight-skin (Tsk) mice. Because mast cells express numerous bioactive factors, such as cytokines, growth factors, proteases, and others, it is crucial to identify the primary factors that may be involved in the pathogenesis of scleroderma. Our previous study also showed that a CTMC-specific protease, chymase-4, was selectively upregulated in accordance with the development of skin fibrosis in Tsk mice. 3 To further elucidate the role of chymase secreted from CTMCs, we evaluated the therapeutic effects of a synthetic chymase-specific inhibitor, SUN-C8257, on the development of skin fibrosis in Tsk mice. SUN-C8257 (50 mg kg-1 day-1) was administered via intraperitoneal injection in 13-week-old Tsk mice for a period of 2 weeks. 4 Treatment with SUN-C8257 significantly reduced chymase activity by 43% and the chymase-4 mRNA level by 47%, and also decreased the thickness of the subcutaneous fibrous layer of Tsk mice by 42% compared with that of Tsk mice injected with vehicle. 5 Furthermore, immunohistochemical analysis revealed that transforming growth factor (TGF)-beta1 staining in the fibrous layer of Tsk skin was markedly reduced by the treatment with SUN-C8257. This chymase inhibitor may prevent the chymase-dependent pathway that activates the latent TGF-beta1 in fibrous tissue, and may exhibit beneficial effects that inhibit the development of fibrosis. 6 In conclusion, our results strongly support the assumption that CTMC-derived chymase may play a key role in the pathogenesis of scleroderma.


Paramagnetic {[Fe(CO)2]2-μ2-η2:η2-η2:η2-(C60)2}2- Dimer Bridged by Iron Atoms and C-C Bonds: Effect of Starting Iron Carbonyls on Structures and Properties of Negatively Charged Iron-Bridged Fullerene Dimers.
The reaction between an excess of Fe(CO)5 with {Cryptand(K+)}(C60•-) produced the salt {Cryptand(K+)}2{[Fe(CO)2]2-μ2-η2:η2-η2:η2-(C60)2}2-·4C6H4Cl2 (1) containing negatively charged iron-bridged fullerene dimers. In these dimers, the C60 cages are linked via two Fe(CO)2 fragments, forming short Fe-C(C60) bonds with a length of 2.070(3) Å and via two intercage C-C bonds with a length of 1.566(3) Å. Interfullerene center-to-center distance is short, being 9.02 Å. Thus, the coordination-induced dimerization of fullerenes is observed in 1. The dimer is negatively charged, with additional negative electron density mainly localized on iron atoms and, to a lesser extent, on the C60 cages, as revealed by optical and electron paramagnetic resonance spectra. These dimers have a diamagnetic singlet ground state with a small singlet-triplet gap of 25 K; consequently, they transfer to a paramagnetic state with two S = 1/2 spins per dimer above 50 K. Previously, different dimers with isomeric structures were obtained starting from {Cryptand(K+)}(C60•-) and Fe3(CO)12. However, these dimers exhibit diamagnetic properties, owing to the formation of a Fe-Fe bond. In contrast, in dimer 1, the Fe atoms are positioned too far apart to form such a bond, preserving the spin on Fe. We assume that both dimers are formed through the same [Fe(CO)3](C60•-) intermediate, but the subsequent interaction of this intermediate with Fe3(CO)12 or its dimerization yields different dimers. Therefore, the starting carbonyls can control the structures and properties of the resulting dimers.


Harnessing epithelial homeostatic mechanisms to fight cancer.
Cancer treatments have, in general, targeted the cancer cell itself. This approach has often been unsuccessful in the long term, especially for solid tumors. Even targeted therapies based on sequencing cancer genomes can be thwarted by genetic heterogeneity within tumors. Furthermore, genomic instability in cancer cells accelerates the generation of variants that are resistant to the treatment. Immunotherapies and anti-angiogenic treatments, which target the tumor-interacting and tumor-adjacent cells, have overcome some of these challenges, suggesting that other methods that target wild-type cells could be valuable in arresting tumor progression. Studies in Drosophila have uncovered mechanisms by which cells within an epithelium can react to neighboring cells that have genetic differences, resulting in the elimination of one population at the expense of another. Some of these mechanisms are now known to be conserved in mammals. The possibility of harnessing such mechanisms to empower normal epithelial cells to eliminate their precancerous neighbors before they develop into fully fledged cancers is an area of research that merits more attention.


The Regular Interaction Pattern among Odorants of the Same Type and Its Application in Odor Intensity Assessment.
The olfactory evaluation function (e.g., odor intensity rating) of e-nose is always one of the most challenging issues in researches about odor pollution monitoring. But odor is normally produced by a set of stimuli, and odor interactions among constituents significantly influenced their mixture's odor intensity. This study investigated the odor interaction principle in odor mixtures of aldehydes and esters, respectively. Then, a modified vector model (MVM) was proposed and it successfully demonstrated the similarity of the odor interaction pattern among odorants of the same type. Based on the regular interaction pattern, unlike a determined empirical model only fit for a specific odor mixture in conventional approaches, the MVM distinctly simplified the odor intensity prediction of odor mixtures. Furthermore, the MVM also provided a way of directly converting constituents' chemical concentrations to their mixture's odor intensity. By combining the MVM with usual data-processing algorithm of e-nose, a new e-nose system was established for an odor intensity rating. Compared with instrumental analysis and human assessor, it exhibited accuracy well in both quantitative analysis (Pearson correlation coefficient was 0.999 for individual aldehydes (n = 12), 0.996 for their binary mixtures (n = 36) and 0.990 for their ternary mixtures (n = 60)) and odor intensity assessment (Pearson correlation coefficient was 0.980 for individual aldehydes (n = 15), 0.973 for their binary mixtures (n = 24), and 0.888 for their ternary mixtures (n = 25)). Thus, the observed regular interaction pattern is considered an important foundation for accelerating extensive application of olfactory evaluation in odor pollution monitoring.


Evaluation of Gibbilimbol B, Isolated from Piper malacophyllum (Piperaceae), as an Antischistosomal Agent.
Infections caused by parasitic worms impose a considerable worldwide health burden. One of the most impactful is schistosomiasis, a disease caused by blood-dwelling of the genus Schistosoma that affects more than 230 million people worldwide. Since praziquantel has also been extensively used to treat schistosomiasis and other parasitic flatworm infections, there is an urgent need to identify novel anthelmintic compounds, mainly from natural sources. In this study, the hexane extract from roots of Piper malacophyllum (Piperaceae) showed to be mainly composed for gibbilimbol B by HPLC/ESI-HRMS. Based on this result, this compound was isolated by chromatographic steps and its structure was confirmed by NMR. In vitro bioassays showed that gibbilimbol B was more active than praziquantel against larval stage of S. mansoni, with effective concentrations of 50 % (EC50 ) and 90 % (EC90 ) values of 2.6 and 3.4 μM, respectively. Importantly, gibbilimbol B showed no cytotoxicity to mammalian cells at a concentration 190 times greater than the antiparasitic effect, giving support for the anthelmintic potential of gibbilimbol B as lead compound for novel antischistosomal agents.


Enzyme-linked immunosorbent assay detection of melamine in infant formula and wheat food products.
The adulteration of food products with melamine to inflate the nitrogen content necessitates the establishment of analytical methods that can distinguish between proteinaceous ingredients and such adulterants. The specificity and ability to detect melamine by two commercial enzyme-linked immunosorbent assay (ELISA) kits were evaluated along with three protocols for sample preparation. Both ELISAs displayed cross-reactivity with ammeline, but neither was able to detect ammelide or cyanuric acid, indicating either a requirement for the 4,6-diamino-1,3,5-triazine structure or inability to bind 1,3,5-triazine-4,6-diones. The limits of detection for melamine in powder infant formula ranged from 0.2 to 3 microg/g depending on the ELISA kit and the method used to prepare the sample. The limits of detection for melamine in liquid infant formula and wheat products were <1 microg/ml and <2.5 microg/g, respectively. The ELISA kits provide an effective alternative for the analysis of samples suspected of containing melamine without relying on extensive sample preparation or expensive instrumentation.


Advances in Exercise Therapy in Hemodialysis: A Systematic Review.
The main and common treatment of renal replacement therapy (RRT) for chronic kidney disease (CKD), especially in end-stage kidney disease (ESKD) patients, is hemodialysis (HD). Many reports have shown that exercise therapy is good for HD patients. This review aims to describe recent advances in exercise therapy in HD patients. Our key opinions have focused on varied types of exercise therapy and identified barriers to exercise therapy among HD patients. Exercise implementation includes aerobic exercise training, resistance exercise training, combined exercise training, and novel exercise interventions. Barriers include internal and external distress, such as HD patients' restrictions and environmental problems. This review is based on the novel/ most findings in PubMed, Web of Science, Google Scholar, and MEDLINE from the inception of every database until August 2022. The systematic search strategy identified 6 articles that met the inclusion criteria. Four were specific to exercise therapy in HD, and three were to exercise barriers in HD. Massive evidence has demonstrated exercise therapy for HD has specific benefits and neglectful causes of exercise barriers. In this review, we aimed to summarize recent advances in individual exercise therapy recommendations (type, intensity, time, and frequency) and exercise barriers in HD patients. In conclusion, Low/moderate-intensity exercise trained for at least thirty minutes five times per week, including aerobic exercise (Walking, Jogging, Swimming, and Health Exercises), resistance training (Dumbbells, Band training, and Knee extension), and combination exercise (both) during the first 2 hours of dialysis treatment or non-dialysis days is advisable treatment recommendation.


Manipulating the Ordered Nanostructure of Self-Assembled Monoolein and Phytantriol Nanoparticles with Unsaturated Fatty Acids.
Mesophase structures of self-assembled lyotropic liquid crystalline nanoparticles are important factors that directly influence their ability to encapsulate and release drugs and their biological activities. However, it is difficult to predict and precisely control the mesophase behavior of these materials, especially in complex systems with several components. In this study, we report the controlled manipulation of mesophase structures of monoolein (MO) and phytantriol (PHYT) nanoparticles by adding unsaturated fatty acids (FAs). By using high throughput formulation and small-angle X-ray scattering characterization methods, the effects of FAs chain length, cis-trans isomerism, double bond location, and level of chain unsaturation on self-assembled systems are determined. Additionally, the influence of temperature on the phase behavior of these nanoparticles is analyzed. We found that in general, the addition of unsaturated FAs to MO and PHYT induces the formation of mesophases with higher Gaussian surface curvatures. As a result, a rich variety of lipid polymorphs are found to correspond with the increasing amounts of FAs. These phases include inverse bicontinuous cubic, inverse hexagonal, and discrete micellar cubic phases and microemulsion. However, there are substantial differences between the phase behavior of nanoparticles with trans FA, cis FAs with one double bond, and cis FAs with multiple double bonds. Therefore, the material library produced in this study will assist the selection and development of nanoparticle-based drug delivery systems with desired mesophase.


Clastogenic effects of biosynthetic human growth hormone in Snell dwarf mice and CHO cells in vitro.
Treatment of Snell dwarf mice with high concentrations of human growth hormone from pituitaries as well as of bacterial origin, significantly increased the frequencies of chromosomal aberrations in bone-marrow cells, as measured by the micronucleus test. In vitro treatment of Chinese hamster ovary (CHO) cells with the two types of hormone likewise induced structural chromosomal aberrations.


Bone mineral density measurement and treatment for osteoporosis in older individuals with fractures: a gap in evidence-based practice guideline implementation.
Osteoporosis evaluation and treatment guidelines state that, because of the high risk for future fractures, a fracture in an older individual warrants initiation of pharmacological treatment or bone mineral density (BMD) measurement followed by treatment according to BMD. We compared current practice with these guidelines. We used the electronic data systems of a health maintenance organization to collect fracture, BMD measurement, and pharmacy data for women aged 50 to 89 years and men aged 65 to 89 years who sustained a study-defined fracture during 1998 or 1999. We determined those who had BMD measurement or pharmacological treatment for osteoporosis (bisphosphonate or estrogen) during the 2 years. We compared the evaluation and treatment data with evidence-based clinical guidelines (for women) or expert consensus (for men). Of 70 513 members in the eligible age groups, 2804 persons sustained study-defined fractures. Overall, only 4.6% of those with fractures had treatment initiated after the fracture. Women sustained 80.7% of the study-defined fractures; 8.4% had BMD measurement and 42.4% received any treatment during the 2 years. Bone mineral density measurement and treatment frequency decrease significantly with age in women. In men, 1.5% had BMD measurement and 2.8% received any treatment. Approximately 51% (51.2%) of women and 95.5% of men in our study population were not evaluated or treated in accord with guideline or expert recommendations. Evaluation and treatment rates for osteoporosis in older individuals with fractures fall far below national recommendations, especially for men. Intervention strategies should be developed and evaluated to prevent refracture in older individuals with fractures.


Modulation of Ca2+ transients and contractile properties by beta-adrenoceptor stimulation in ferret ventricular muscles.
1. The mechanism of modulation of Ca2+ transients and contraction by beta-adrenoceptor stimulation was studied in ferret ventricular muscles using aequorin to measure intracellular Ca2+. 2. Peaks of tension and light transients were increased by isoprenaline (10(-9) - 5 x 10(-7) M) which also abbreviated their time courses. 3. Time-to-peak tension was significantly shortened by 5 x 10(-9) M-isoprenaline and time-to-peak light was abbreviated by 10(-9) M-isoprenaline. 4. The time for the light to decay was shortened at 10(-9) M-isoprenaline. However, a higher concentration of isoprenaline (10(-8) M) was required for significant shortening of the half-relaxation time (TR50). 5. When isoprenaline was removed and beta-blocker (bupranolol, 1 microM) was applied, the time course of the light transients recovered but the time course of relaxation did not recover. 6. The relationship between [Ca2+]i and tension in tetanic contraction produced in the presence of ryanodine (5 microM) was shifted to the right by isoprenaline (10(-8) M). This was recovered by the replacement of isoprenaline with bupranolol (1 microM). 7. Isoprenaline (10(-7) M) added to the solution containing 20 mM [Ca2+]O and Bay K 8644 (1 microM), which produced maximal tension, caused a large light signal and enhancement of the initial phasic tension in tetanic contraction. However, the replacement of isoprenaline with bupranolol after immersing the preparation in 20 mM [Ca2+]O solution with Bay K 8644 and isoprenaline, did not significantly change the tension level, although the light signal decreased. Similar results were obtained in the ventricular muscle of young rats. 8. These results suggest that the dose dependence of modulation of the contractile element and sarcoplasmic reticulum (SR) by beta-adrenoceptor stimulation differs, and that additional factors, other than the faster Ca2+ uptake by SR and the decrease in Ca2+ sensitivity of the contractile element, might be involved in the shortening of the half-relaxation time by beta-adrenoceptor stimulation. In addition, beta-adrenoceptor stimulation does not produce a marked change in the maximal tension level.


Comparison of effect between simulated patient clinical skill training and student role play on objective structured clinical examination performance outcomes for medical students in Australia.
Optimal methods for communication skills training (CST) is an active area for research but the effect on communication performance in objective structured clinical examinations (OSCE) has not been so closely studied. Student role play (RP) for CST is common whilst volunteer simulated patient (SP) CST is cost-effective and provides authentic interactions. We assessed whether our volunteer SP CST improved OSCE performance compared to our previous RP strategy. We performed a retrospective, quasi-experimental study of two second year medical student cohorts' OSCE data in Australia. The 2014 cohort received RP-only CST (N=182) while the 2016 cohort received SP-only CST (N=148). T-test and ANOVA were used to compare the total scores for three assessment domains: generic communication, clinical communication and physical examination/procedural skills. Baseline characteristics for groups (scores for Australian Tertiary Admission Rank (ATAR), Undergraduate Medicine and Health Sciences Admission Test (UMAT) and medicine program interview) showed no significantt difference between groups. For each domain, the SP-only CST group demonstrated superior outcomes in the OSCE and the difference between cohorts was significant (P < 0.01). Volunteer SP CST was superior to student RP CST when considering OSCE performance outcome., which was found across generic and clinical communication skills, and physical examination/procedural skills. Better performance of the SP cohort in physical examination/procedural skills might be explained by the requirement for patient compliance and cooperation, facilitated by good generic communication skills. We recommend a volunteer SP Program as an effective and efficient way to improve CST for junior medical students.


Ghrelin attenuates intestinal ischemia/reperfusion injury in mice by activating the mTOR signaling pathway.
Intestinal ischemia/reperfusion (I/R) injury is a serious condition in intensive care patients, resulting in severe inflammation and remote organ damage. The activation of the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) signaling pathway exerts protective effect against ischemia/reperfusion injury. Ghrelin, an orexigenic hormone, inhibits the release of pro-inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor-α and IL-6. In this study, we investigated the effects of ghrelin on gut I/R injury and the regulation of the mTOR/p70S6K signaling pathway following gut I/R injury in mice. C57BL/6 mice underwent superior mesenteric artery occlusion for 45 min, followed by reperfusion for 4 h. Ghrelin was administered at the onset of reperfusion. We assessed survival, organ injury variables, pro-inflammatory cytokine expression and observed the histological changes of the small intestine and lungs. Our results revealed that the administration of ghrelin inhibited the release of certain pro-inflammatory cytokines, reduced neutrophil infiltration, attenuated organ injury and improved survival following gut I/R injury. The administration of D-Lys-GHRP6, a specific ghrelin receptor antagonist, to a certain extent, counteracted the protective effects of ghrelin in gut I/R-induced organ injury and mortality. To determine whether the beneficial effects of ghrelin following gut I/R injury are associated with the mTOR/p70S6K signaling pathway, the phosphorylation levels of mTOR and p70S6K were detected by western blot analysis. Our results revealed that mTOR and p70S6K phosphorylation increased in the tissue from the small intestine and pulmonary tissue in the animals treated with ghrelin. These findings suggest that ghrelin attenuates organ injury following gut I/R by promoting the activation of the mTOR/p70S6K signaling pathway.


Cheating to benefit others? On the relation between Honesty-Humility and prosocial lies.
Among basic personality traits, Honesty-Humility yields the most consistent, negative link with dishonest behavior. The theoretical conceptualization of Honesty-Humility, however, suggests a potential boundary condition of this relation, namely, when lying is prosocial. We therefore tested the hypothesis that the association between Honesty-Humility and dishonesty weakens once lying benefits someone else, particularly so if this other is needy. In two online studies (Study 1: N = 775 in Germany; Study 2: N = 737 in the UK, preregistered), we measured self-reported Honesty-Humility and dishonest behavior in incentivized cheating paradigms in which the beneficiary of participants' dishonesty was either the participants themselves, a "non-needy" other (e.g., another participant), or a "needy" other (e.g., a charity). We found support for the robustness of the negative association between Honesty-Humility and dishonesty, even if lying was prosocial. Individuals high in Honesty-Humility largely prioritize honesty, even if there is a strong moral imperative to lie; those low in Honesty-Humility, by contrast, tend to lie habitually and thus even if they themselves do not directly profit monetarily. This suggests that (un)truthfulness may be an absolute rather than a relative aspect of Honesty-Humility, although further systematic tests of this proposition are needed.


Transparent Layer Derived from Layered Europium Hydroxide Sensitized with 2-Thenoyltrifluoroacetone.
In this study, we present a novel layered material (LEuH-TTA) consisting of layered europium hydroxide (LEuH) and organic sensitizer 2-thenoyltrifluoroacetone (TTA) in a simple and environmental benign way and it was characterized by FT-IR and XRD. The luminescence intensity of LEuH-TTA increased significantly after modified with TTA, almost 8 times that of LEuH at 612 nm. The luminescence behavior of LEuH-TTA was investigated by luminescence analysis, the results showed that red emission is caused by energy transfer from the TTA ligand to the coordinated Eu3+ ions. Furthermore, the thickness of luminescence film was measured and the SEM showed that it is about 1 μm.


[The first French guide for the use of pharmacy students].
The author analyzes the Nouveau guide de l'étudiant en médecine et en pharmacie published in 1825, in which the section on pharmacy is due to J.-B.-A. Chevallier. In particular he stresses the importance of this work in understanding the history of pharmacy instruction.


Sex difference in the effects of alcohol on gastric emptying in healthy volunteers: a study using the (13)C breath test.
Several studies on alcohol and gastric emptying using the (13)C breath test showed that alcohol consumption delayed gastric emptying of meals in healthy male subjects. However, they did not employ female subjects, and the retention time of alcoholic beverages in the stomach has not been examined, yet. We examined the retention time (= gastric emptying rate) of alcoholic beverages in the stomach in healthy male and female subjects. We also examined whether the congeners (nonalcoholic components) of red wine have any effect on gastric emptying. The retention time of 60 mL of red wine, vodka, congeners of red wine, or mineral water, was measured using a (13)C labeled acetic acid breath test. In male subjects, the retention time of wine and vodka was significantly longer than that of congeners and mineral water. In female subjects, although the (13)C content in the breath was slightly but significantly decreased by wine and congeners, but not by vodka, and the parameters for gastric emptying did not differ significantly among the 4 drinks. That is, alcohol hardly influenced the retention time in female subjects. In conclusion, there are sex differences in the gastric emptying rate of alcohol.


Imaging the mucosa of the human vocal fold with optical coherence tomography.
Discerning the layered microstructure of the vocal folds is critical for effective phonomicrosurgery. Optical coherence tomography (OCT), a noncontact, noninvasive technology that provides cross-sectional images by means of backscattered light, offers the potential for delineating these layers in vivo. The glottal mucosa of 3 human cadaver larynges was imaged with conventional OCT and polarization-sensitive OCT (PS-OCT). Images were obtained through the epithelium and lamina propria. Although the superficial layer of the lamina propria appeared quite homogeneous, the outer surface of the superficial lamina propria was correlated with an increase in backscatter with OCT. The superficial lamina propria and vocal ligament were correlated with a marked increase in tissue birefringence with PS-OCT. This preliminary study demonstrates the capacity of OCT and PS-OCT for visualizing the layered microstructure of the vocal fold mucosa. We believe that these imaging techniques will have applications in the exploration of solutions to vocal fold scarring and in imaging vocal fold disorders in the clinic and operating room.


Mutations within the decoding site of Escherichia coli 16S rRNA: growth rate impairment, lethality and intragenic suppression.
Several C----U transitions and small deletions were introduced into the conserved region centered on base C1400 in Escherichia coli 16S rRNA by in vitro mutagenesis. The mutations were placed within rrnB operons on multicopy plasmids under the transcriptional regulation of either the normal rrnB P1P2 promoters or the temperature-inducible PL promoter from bacteriophage lambda and introduced into E. coli hosts. When expressed from the P1P2 promoters, several of the mutant 16S rRNAs impaired cell growth while others, including one in which U replaced C at position 1400 within the ribosomal decoding site, had little or no effect on cell doubling time. However, C----U transitions at positions 1395 and 1407, as well as the deletion of C1400, appeared to render their hosts inviable. Cells in which these mutations were expressed from the lambdaPL promoter died within four generations after induction. Unexpectedly, the lethal phenotype was suppressed intragenically by replacement of G1505 with A, C or U. Suppression may alleviate a functional defect in 30S subunits containing the U1395, U1407 or deltaC1400 mutations.


Some examples of anomalous radiosensitizing behaviour of electron-affinic compounds in vitro.
Studies using V79 379A cells on about 50 nitroaromatic and nitroheterocyclic radisosensitizers have confirmed the relationship between sensitizing efficiency and electron affinity. Almost all the compounds studied behaved similarly by sensitizing hypoxic cells to X-irradiation in a dose-modifying manner whilst having no sensitizing effect on oxygenated cells. However, a small number of the radiosensitizers studied exhibited additional or atypical properties. A 4-nitroimidazole ring substituted with chlorine sensitized hypoxic cells much more efficiently than predicted from its redox potential. A 2-nitroimidazole substituted with a carboxylic acid side chain showed a low but constant level of sensitization over 5 decades of concentration. A 5-nitrofuran, in addition to sensitizing hypoxic cells by dose modification, sensitized oxygenated cells by a reduction in extrapolation number.


Short shrift for the sane? The hospital management of self-harm patients with and without mental illness.
In recent years the British government has sought to target service provision both on people with severe enduring mental illness and on those considered to be at risk of suicide. The study reported here suggests these policies may have had unforeseen repercussions on services for people who self-harm but have no identifiable mental illness. This paper compares the hospital management of self-harm patients with and without mental illness. Over the years 1996-2000, a total of 4,329 self-harm patient attendances were recorded at the accident and emergency department of a British hospital. Whilst patients in 63.7% of attendances could reasonably have been considered to have some form of mental illness, we found that in the remaining 36.3% of attendances (where patients had no indicator of mental illness) a particularly poor standard of service was given. We suggest that if government targets for a reduction in the suicide rate are to be met, it is crucial that there should be marked improvements in services for all self-harm patients presenting at accident and emergency departments. However, in improving services we must be vigilant to the danger that targeting those with a mental illness may mean we fail to provide even basic levels of care for others.


Rational approaches to combating resistance.
Traditional treatment paradigms based on national guidelines and administrative policies, such as restricted formularies, that are intended to guide antibiotic selection for empirical therapy of community- and hospital-acquired infections have been largely unsuccessful in curbing the spread of antimicrobial resistance. Evidence suggests that restricting antibiotic availability may lead to potential misuse of unrestricted agents as well as to increased adverse drug reactions, costs and, potentially, increased antibiotic resistance. New treatment paradigms, such as that embodied in the LDS Hospital computer-based "automated antibiotic assistant", that address antibiotic use from a process-of-care approach, using local clinician-derived solutions implemented at the patient's bedside, may offer strategic advantages over traditional approaches based on restricting antibiotic use. By using patient- and institution-specific data to tailor therapy to individual patient circumstances, such systems can help reduce the dosage, duration, frequency of adverse events and cost of antibiotic therapy as well as improving clinical outcomes and potentially avoiding drug resistance.


7-Epiclusianone, a tetraprenylated benzophenone, relaxes airway smooth muscle through activation of the nitric oxide-cGMP pathway.
This study was undertaken to investigate the putative mechanism(s) underlying the antispasmodic effect of 7-epiclusianone, a naturally occurring compound isolated from the plant Garcinia brasiliensis. Guinea pig tracheal rings were mounted in tissue baths filled with Krebs' solution, and the contractile response to distinct stimuli was measured in the presence or absence of 7-epiclusianone. We also tested the effect of 7-epiclusianone on methacholine-evoked airways obstruction in BALB/c mice using barometric plethysmography. 7-Epiclusianone (10 microM) inhibited epithelium-intact tracheal ring contraction induced by allergen, histamine, 5-hydroxytryptamine, or carbachol challenge. The relaxation effect was abrogated by epithelium removal, the presence of nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (100 microM), or soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 microM). 7-Epiclusianone (1-100 microM) induced a dose-dependent increase in the intracellular cGMP levels of cultured tracheal rings. The relaxation effect of 7-epiclusianone was also inhibited by K(+) channel blockers tetraethylammonium (10 microM), glibenclamide (1 microM), or apamin (1 microM), but not by 9-(tetrahydro-2'-furyl)adenine (SQ22,536) (100 microM), an adenylate cyclase inhibitor. In epithelium-intact tracheal rings, 7-epiclusianone also inhibited Ca(2+)-induced contractions in K(+) (60 mM)-depolarized preparations, but it seemed ineffective in assays in which epithelium-denuded tracheal ring preparations were used. Oral administration of 7-epiclusinone (25-100 mg/kg) dose-dependently inhibited airway obstruction triggered by aerosolized methacholine (6-25 mg/ml), in a mechanism sensitive to L-NAME (20 mg/kg). In conclusion, the relaxation effect of 7-epiclusinone seems to be mediated by epithelium-, nitric oxide-, and cGMP-dependent mechanisms. Furthermore, oral administration of 7-epiclusianone reduces episodes of bronchial obstruction, warranting further research on this compound regarding a putative application in asthma therapy.


Cardiac compression due to gastric volvulus: an unusual cause of chest pain.
A 42-year-old man was admitted to coronary care for assessment with severe retrosternal chest pain. Echocardiography showed significant external compression of the left atrium. A subsequent CT scan revealed him to have a large hiatus hernia, with most of his stomach herniating into his thorax causing left atrial compression and gastric volvulus. He subsequently underwent successful emergency decompression of the gastric volvulus and repair of his hiatus hernia.


Connective tissue activation. XXXVI. The origin, variety, distribution, and biologic fate of connective tissue activating peptide-III isoforms: characteristics in patients with rheumatic, renal, and arterial disease.
To determine the origin, distribution, and biologic fate of platelet-derived connective tissue activating peptide-III (CTAP-III), to define the relative amounts of the antigen forms (CTAP-III, beta-thromboglobulin [beta-TG], neutrophil activating peptide-2 [NAP-2]) in plasma of normal persons and those with rheumatic or end-stage renal disease, and to define the isoforms of CTAP-III in platelets, plasma, transudates, and tissue deposits. CTAP-III in plasma was measured by enzyme-linked immunosorbent assay, and growth promoting activity of CTAP-III isoforms was tested in synovial and peritoneal cell cultures by measuring increased synthesis of 14C-glycosaminoglycan (14C-GAG) and 3H-DNA. Isolated CTAP-III was characterized by Western blotting, microsequencing, and mass spectrometry. CTAP-III was the primary isoform of this antigen family in normal platelets and platelet-rich plasma; beta-TG and NAP-2 accounted for < 1% of CTAP-III isoforms. Previously undescribed isoforms, i.e., CTAP-III des 1, des 1-2, des 1-3, and a phosphate adduct of CTAP-III, were observed in varying amounts. Elevated plasma levels of CTAP-III antigen were found in a substantial fraction of rheumatic disease patients: 24% of those with rheumatoid arthritis, 36% of those with systemic sclerosis, and 15% of those with systemic lupus erythematosus. All 10 patients with end-stage kidney disease had marked elevations of plasma CTAP-III levels, which stimulated DNA and GAG synthesis by peritoneal cells in culture. Only large isoforms (such as CTAP-III) were detected in venous plasma of normal subjects, rheumatic disease patients, and patients receiving long-term dialysis. Normal human spleen and kidney contained substantial (micrograms/gm) amounts of CTAP-III and traces of an isoform with the electrophoretic mobility of CTAP-III des 1-15/NAP-2. Liver, lung, and urine contained lesser (ng/gm) amounts of CTAP-III. These data show that, among the 10 known isoforms, intact CTAP-III itself was the major circulating isoform (> 90%), and beta-TG was the most rare (0-1%). Deposition of CTAP-III in tissues, such as synovium, spleen, and kidney, is associated with partial processing to NAP-2-like isoforms and the potential to induce neutrophil and fibroblast activation in patients with rheumatic or end-stage renal disease.


Prevalence of traumatic brain injury in psychiatric and non-psychiatric subjects.
Traumatic brain injury (TBI) and its sequelae may impact the expression and treatment of psychiatric disorders. The prevalence of TBI in psychiatric patients is unknown and investigations in the general population are limited. This study examined the prevalence of TBI with loss of consciousness in mental health setting patients (n = 231), general hospital and university staff and students (n = 534) and non-psychiatric medical clinical patients (n = 59). The Traumatic Brain Injury Questionnaire was used to assess TBI. A greater percentage of psychiatric patients reported TBI than medical patients or staff and students. Traumatic brain injuries were typically mild--moderate, medical assistance was frequently sought and use of alcohol and drugs was reported in a minority of TBI incidents. Multiple injuries were most common in psychiatric patients. The percentage of medical patients and staff and students reporting TBI was similar to previous research. The greater percentage of psychiatric patients reporting TBI indicates the need to assess TBI in this population. The role of TBI in the emergence, expression and treatment outcome of psychiatric disorders and the risk factors that leave psychiatric patients vulnerable to TBI should be further examined.