Amphetamine-type stimulant use and self-harm: protocol for a systematic review of observational studies.
Amphetamine type stimulant (ATS) use and self-harm are both major public health concerns globally. Use of ATS is associated with a range of health and social problems, and has been increasing internationally in the last decade. Self-harm and ATS use share a number of underlying risk factors and occur at elevated rates in marginalised groups with high rates of exposure to trauma. The relationship between self-harm and ATS use is likely complex, and the causal pathway may run in either direction. A comprehensive review, synthesis and analysis of the evidence are warranted to investigate this relationship and inform policy and practice. We will search the Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO and Scopus databases for relevant observational studies published in peer-reviewed journals. The initial search was conducted on 5 February 2021, with a final search expected on 1 February 2022. All studies will be independently screened by two reviewers, first on title and abstract, and then on full-text to determine inclusion in the review. We place no restriction on the population that studies investigate, our exposure of interest is both prescription and illicit ATS use, comparators will be those not currently using ATS, and our primary outcome of interest is the prevalence of self-harm. Data will be extracted using a predesigned template, and pooled prevalence and pooled measures of effect for the association between ATS use and self-harm. If sufficient data are available, we will perform multiple meta-analyses to produce pooled measures of effect for each measure of ATS exposure, as well as different population sub-groups. The Methodological Standard for Epidemiological Research scale will be used to assess study quality, and Egger's test and I2 values will be used to assess publication bias and heterogeneity, respectively. No ethical approval is required for this review. We will only synthesise information from published studies that were conducted with ethical approval, so no individual participant data will be used. We will disseminate our findings via publication in a peer-reviewed journal, national and international conference presentations, and presentations to stakeholders in the community. This study has been registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021226562).


Antibiotic susceptibilities of 96 isolates of Bacillus anthracis isolated in France between 1994 and 2000.
Ninety-six isolates of Bacillus anthracis recovered in France between 1994 and 2000 were tested for their susceptibilities to 25 different antibiotics. Resistance to penicillin G and amoxicillin was 11.5%. All of the isolates were resistant to cotrimoxazole and susceptible to doxycycline, ciprofloxacin, pefloxacin, levofloxacin, teicoplanin, vancomycin, clindamycin, imipenem, and rifampin.


Acid phosphatase response in murine rhabdomyosarcoma for various tumour volumes and after different doses of neutron irradiation, alone or combined with exogenous ATP.
Acid phosphatase activity measured in a methylocholanthrene-induced murine rhabdomyosarcoma showed a monotonically increasing relation between enzyme activity and tumour volume. This could be related to the lytic activity of the enzyme in large tumours which become more hypoxic and necrotic, and hence enhance degradation and turnover of damaged tumour cells. The tumours were also subjected to irradiation using doses of 2.0, 3.8 and 6.0 Gy from a neutron therapy facility p(66MeV)/Be. The correlation between different doses and response of acid phosphatase activity could reflect the relation of magnitude of damage from metabolic disturbances, with dose. Furthermore exogenous ATP was shown to provide radioprotective action against neutron irradiation in two different experiments. The ATP reduced the activity of this lytic enzyme in irradiated tumours and also decreased tumour growth delay. This radioprotective role of exogenous ATP in a murine tumour could be related to physiological regulatory processes during defence mechanisms to maintain self-organisation in response to the radiation damage.


Double-blind dose reduction study of vigabatrin in complex partial epilepsy.
Seventy-five epilepsy patients with at least two complex partial seizures/month were treated with gamma-vinyl GABA (GVG) 3 g/day for 3 months. Forty-one patients (54%) showed a reduction of greater than or equal to 50% in seizures. The median monthly seizure frequency decreased from 11.5 to 4 seizures/month. Twenty percent of patients had an improvement in general performance without a significant reduction in seizures. The responders entered the second phase of the study, in which 28 patients were randomly allocated to 3 g/day and 25 patients to 1.5 g/day GVG under double-blind conditions. The dosage of 3 g/day appeared to be clearly more effective than 1.5 g/day. However, even with 1.5 g/day GVG the seizure frequency was significantly reduced as compared to baseline. Drowsiness was the most commonly observed side effect, and it diminished with continued treatment. In three cases side effects led to the withdrawal of GVG therapy.


Development and Feasibility Assessment of a Rotational Orthosis for Walking with Arm Swing.
Interlimb neural coupling might underlie human bipedal locomotion, which is reflected in the fact that people swing their arms synchronously with leg movement in normal gait. Therefore, arm swing should be included in gait training to provide coordinated interlimb performance. The present study aimed to develop a Rotational Orthosis for Walking with Arm Swing (ROWAS), and evaluate its feasibility from the perspectives of implementation, acceptability and responsiveness. We developed the mechanical structures of the ROWAS system in SolidWorks, and implemented the concept in a prototype. Normal gait data were used as the reference performance of the shoulder, hip, knee and ankle joints of the prototype. The ROWAS prototype was tested for function assessment and further evaluated using five able-bodied subjects for user feedback. The ROWAS prototype produced coordinated performance in the upper and lower limbs, with joint profiles similar to those occurring in normal gait. The subjects reported a stronger feeling of walking with arm swing than without. The ROWAS system was deemed feasible according to the formal assessment criteria.


Stem cell stimulation in vitro by the dekapeptide (pEEDCK)2: a single-factor alternative for multifactor cocktails.
Insertion of foreign genes into cellular DNA requires (at least one round of) DNA replication. Since hemopoietic stem cells do not divide rapidly, numerous semi-empirically designed multifactor cocktails have been used to stimulate them. In an attempt to find an alternative to this approach we have investigated the effects of the stem cell stimulatory peptide (pGlu-Glu-Asp-Glys-Lys)2, (pEEDCK)2, on progenitor output in murine long-term bone marrow cultures (LTBMC). (pEEDCK)2 may act by inducing growth factor production in stromal cells. Addition of (pEEDCK)2 to LTBMCs resulted in a three-fold increase in CFU-GM production. For showing an effect of (pEEDCK)2 on primitive hemopoietic cells (long-term-culture initiating cells, (LTC-IC)) LTBMCs were depleted of rapidly dividing progenitors by 5-Fluoro-Uracil (5-FU). LTC-IC survive and repopulate the culture with new CFU-GM. (pEEDCK)2 greatly enhanced this process (eight-fold in the second week after 5-FU). Enhanced progenitor production was observed for several weeks even after discontinuation of (pEEDCK)2 additions to the cultures (100-fold, five weeks after 5-FU, three weeks after end of peptide additions). This increase in progenitor production resulted in increased numbers of total nucleated cells. Our results suggest that (pEEDCK)2 may be a useful alternative for multifactor cocktails when proliferation of primitive stem-cell-like cells is required, as in gene therapy and transplantation. Our experiments also indicate that the redox equilibrium between (stem cell inhibitory) monomeric pEEDCK and (stem cell stimulatory) dimeric (pEEDCK)2, which are both endogenous constituents of LTBMCs may play a role in physiological stem cell regulation.


Ultrasound and magnetic resonance imaging in prenatal diagnosis of sacrococcygeal teratoma--case report.
Fetal tumors are relatively rare and the early prenatal diagnosis enables the prediction of possible complications and decision for appropriate treatment. This paper deals with the role of ultrasonography and magnetic resonance imaging in the early prenatal diagnosis of sacrococcygeal teratoma. A 21-year-old primigravida was found to have a large sacrococcygeal tumor measuring 25 x 30mm, presented mainly as a solid mass, when she underwent the initial ultrasound examination on the first day of 19th week of gestation. There were no other associated anomalies. The second ultrasound examination was obtained after 6 days and revealed that the tumor had doubled its size. The prominent enlargement raised suspicion of immature sacrococcygeal teratoma and thus, fetal magnetic resonance imaging was performed in the 20th gestation week. The examination showed a crococcygeal teratoma presented as a large solid mass with small microcystic areas, the largest diameter being 60mm, completely externally positioned with no intra-pelvic extension. Rapid tumor growth posed a threat to the fetal circulation and it was the main reason when opting for the termination of pregnancy at 20 weeks of gestation. Pathohystological examination confirmed the diagnosis of immature sacrococcygeal teratoma. In the prenatal period the magnetic resonance imaging of a fetal tumor initially diagnosed by ultrasound examination is an additional part of diagnostic procedure, and it is not contraindicated during pregnancy. Magnetic resonance imaging improves the delineation of the tumor. The prompt prenatal diagnosis of sacrococcygeal teratoma, as well as the detection of possible associated anomalies, is important for the pregnancy management, prediction of possible complications and choice of appropriate treatment. Ultrasonography and magnetic resonance imaging are noninvasive, compatible and complementary diagnostic modalities in evaluation of sacrococcygeal teratoma in prenatal period.


A prospective study on knee pain and its risk factors.
To evaluate the effects of work-related and individual factors as well as physical activity and sports on the incidence and persistence of knee pain among a working population. Employees of a large Finnish forestry company replied to a questionnaire (a modified version of the Nordic Questionnaire) on musculoskeletal pain and its possible risk factors at the baseline of this study. A cohort of 2122 workers free of knee pain and another cohort of 333 workers with severe knee pain were followed up for one year. The effects of the risk factors on the incidence and persistence of knee pain were studied using multivariable logistic regression models. A total of 214 (10%) workers developed knee pain during the follow-up. Significant predictors of incident knee pain in the multivariable model were higher age, overweight, smoking, and previous knee injuries. Also, working with the trunk forward flexed in kneeling or standing position and physically strenuous work were non-significant predictors of incident knee pain. Of those 333 workers with severe knee pain at baseline, 220 (66%) still reported severe knee pain after one year. Higher age and job dissatisfaction increased the risk of persistent symptoms. General physical exercise and different sports activities did not predict the incidence or persistence of knee pain. In this large prospective study, the risk factors for self-reported knee pain seemed to be highly similar to the risk factors for knee osteoarthritis (OA) reported in other papers. Age, previous knee injuries, overweight, and knee-straining work were those risk factors, which contributed to the incidence of knee pain. Psychosocial elements of work were more involved in the persistence of the symptoms in the knee.


Residency programs for new nurse graduates: how widespread are they and what are the primary obstacles to further adoption?
The objective of this study was to determine the prevalence of hospital RN residencies and the associated factors. The 2010 Institute of Medicine/Robert Wood Johnson Foundation report, The Future of Nursing: Leading Change, Advancing Health, recommends the adoption of nurse residency programs. Members of the American Organization of Nurse Executives were surveyed, and covariates were identified. We found approximately 36.9% of all hospitals in our study offered a nurse residency in 2011. Associated covariates included not-for-profit status, midsize, and location in the South. Hospitals that offer residency programs were more likely to have other training programs. Findings suggest that residencies have been widely supported even in times of economic recession. It is important to track the expansion of these programs and to initiate research to examine the long-term impacts of residencies on nurse retention and clinical outcomes.


Complementary and alternative medicine use amongst Malaysian orthopaedic oncology patients.
Although studies have shown that a large proportion of cancer patients use CAM, no study on CAM use amongst orthopaedic oncology patients has been published. Therefore, this study aims to determine the prevalence, characteristics and factors associated with CAM use amongst orthopaedic oncology patients. All consecutive consenting patients/parents who presented at the Orthopaedic Oncology Clinic, University Malaya Medical Centre (1st January to 31st December 2013) were interviewed using a structured questionnaire. Overall, one hundred sixty-eight of the 274 patients recruited (61.3%) had used CAM at some time during their current illness. The prevalence of CAM used was 68% (123/181) for patients with malignant tumours and 48.4% (45/93) for patients with benign tumours. The most popular CAMs were biological-based therapies (90.5%), followed by mind-body techniques (40.5%). The most frequently used biological therapies were mega/multivitamins (31%), snakehead (Chana striatus) (28%) and sea cucumber (Stichopus horrens) (18%); whereas prayers (31%) and holy water (13%) dominated the mind-body category. Common reasons for CAM use were to improve physical well-being (60.1%), try out everything that would help (59.5%) and to enhance wound-healing (39.3%). Independent predictors for CAM use in multivariate analysis were paediatric patients [OR 2.46; 95% CI 0.99-6.06; p = 0.05], malignant tumours [OR 1.90; 95% CI 1.12-3.25; p = 0.018] and patients who underwent surgery [OR 2.06; 95% CI 1.15-3.69; p = 0.015]. Majority patients started taking CAMs following suggestions from family members (53%) and friends (49%). Sixty-six percent of patients felt they actually benefitted from CAM and 83.3% were satisfied/very satisfied. Only 5 patients reported side-effects. Majority of CAM users planned to continue CAM use or recommend it to others. However, only 31.5% of patients disclosed their CAM usage to their doctors. This survey revealed a high prevalence of CAM usage amongst orthopaedic oncology patients, with majority patients expressing satisfaction towards CAM. Oncologists should proactively ask patients about CAM to prevent potential adverse effects, as most patients do not share this information with them.


Histone acetyltransferase Hbo1: catalytic activity, cellular abundance, and links to primary cancers.
In addition to the well-characterized proteins that comprise the pre-replicative complex, recent studies suggest that chromatin structure plays an important role in DNA replication initiation. One of these chromatin factors is the histone acetyltransferase (HAT) Hbo1 which is unique among HAT enzymes in that it serves as a positive regulator of DNA replication. However, several of the basic properties of Hbo1 have not been previously examined, including its intrinsic catalytic activity, its molecular abundance in cells, and its pattern of expression in primary cancer cells. Here we show that recombinant Hbo1 can acetylate nucleosomal histone H4 in vitro, with a preference for lysines 5 and 12. Using semi-quantitative western blot analysis, we find that Hbo1 is approximately equimolar with the number of active replication origins in normal human fibroblasts but is an order of magnitude more abundant in both MCF7 and Saos-2 established cancer cell lines. Immunohistochemistry for Hbo1 in 11 primary human tumor types revealed strong Hbo1 protein expression in carcinomas of the testis, ovary, breast, stomach/esophagus, and bladder.


Spectroscopic studies on the interaction of colloidal capped CdS nanoparticles with bovine serum albumin.
Colloidal uncapped and starch capped CdS (SCdS) nanoparticles were prepared and interaction with bovine serum albumin (BSA) have been studied by UV-visible, FT-IR, steady state, time resolved and synchronous fluorescence spectroscopic measurements. BSA molecules adsorbed on the surface of colloidal CdS through the capping agent. The apparent association constant (K(app)=2.54x10(2) M(-1)) and degree of association has been calculated (alpha=1.12) from absorption studies. The binding constant from fluorescence quenching method (6.6x10(2) M(-1)) matches well with that determined from the absorption spectral changes. Static quenching mechanism and conformational changes on BSA molecules were confirmed by time resolved and synchronous fluorescence measurements respectively. The effect of starch capped CdS on the conformation of BSA has been analyzed by means of UV-visible absorption and synchronous fluorescence spectra.


Transnuclear retrotransposition of the Tad element of Neurospora.
Tad is a LINE-like DNA element found in Neutrospora crassa. A Neurospora artificial intron based on the first intron of the am (glutamate dehydrogenase) gene was constructed and introduced, in the correct orientation, into a unique Nru I site in open reading frame 1 of an active Tad element, Tad1-1. Transformants containing the Tad element with the artificial intron were placed in forced heterokaryons with strains lacking Tad elements. Tad was shown to transpose between nuclei in these heterokaryons. Examination of the transposed Tad elements showed that the intron had been precisely removed in all cases. This confirms that Tad is a retrotransposon and that there is a cytoplasmic phase in these retrotransposition events.


Self-Limiting Opto-Electrochemical Thinning of Transition-Metal Dichalcogenides.
Two-dimensional monolayer and few-layer transition-metal dichalcogenides (TMDs) are promising for advanced electronic and photonic applications due to their extraordinary optoelectronic and mechanical properties. However, it has remained challenging to produce high-quality TMD thin films with controlled thickness and desired micropatterns, which are essential for their practical implementation in functional devices. In this work, a self-limiting opto-electrochemical thinning (sOET) technique is developed for on-demand thinning and patterning of TMD flakes at high efficiency. Benefiting from optically enhanced electrochemical reactions, sOET features a low operational optical power density of down to 70 μW μm-2 to avoid photodamage and thermal damage to the thinned TMD flakes. Through selective optical excitation with different laser wavelengths based on the thickness-dependent band gaps of TMD materials, sOET enables precise control over the final thickness of TMD flakes. With the capability of thickness control and site-specific patterning, our sOET offers an effective route to fabricating high-quality TMD materials for a broad range of applications in nanoelectronics, nanomechanics, and nanophotonics.


Central nervous system toxicity of cancer therapy in children.
Cancer treatment of the central nervous system has contributed positively to long-term disease-free survival from childhood cancers such as acute leukemia and medulloblastoma. However, intrathecal chemotherapy and whole brain radiation are associated with acute, subacute, and delayed toxicities. The purpose of this review article is to summarize what is known about critical events in prenatal and postnatal brain development; the pathophysiology of radiation and chemotherapy neurotoxicity and clinical manifestations and risk factors for acute, subacute, and delayed toxicities. The importance of long-term follow-up and for multidisciplinary interventions that focus on prevention as well as management of identified problems are addressed.


Short-chain fatty acids reduce expression of specific protein kinase C isoforms in human colonic epithelial cells.
LIM1215 colon cancer cells were used as a model of human colonic epithelium to examine the effects of butyrate on protein kinase C (PKC) activity and isoform expression. On Western blot analysis, LIM1215 cells express the PKC isoforms alpha, beta, epsilon, zeta, and lambda, but not gamma, straight theta, or micro. Treatment with 2 mM butyrate for 48 h reduced cellular PKC activity up to 50% and specifically reduced the expression of PKC alpha and PKC epsilon. Similar results were obtained using Caco-2 colon cancer cells. These effects were neither a consequence of the induction of differentiation itself nor the result of direct or indirect activation of PKC. Although dependent on gene transcription and protein synthesis, the effect was not due to a reduction in the synthesis of PKC protein. Butyrate's effect was independent of its beta-oxidation but was mimicked, at least in part, by trichostatin A, an inhibitor of histone deacetylase.


Attitudes towards homosexuality in American health care literature 1983-1987.
The purpose of this paper was to content analyze a purposive sample of American health care literature from 1983-1987 to ascertain what impact if any, the AIDS epidemic has had on the images of gay men and lesbian women in health sciences literature. Empirical studies, letters to the editor, policy statements and opinion papers expressing attitudes towards homosexuality and psychosocial aspects of AIDS in nursing, general medicine, and psychiatric literature were content analyzed. Findings indicate that although positive, neutral and negative images were found in the 59 articles which were examined, the largest proportion (61%) were negative. This reflects a change in the literature from previously neutral positions. Implications for patient care and further research are addressed.


A causal and fractional all-frequency wave equation for lossy media.
This work presents a lossy partial differential acoustic wave equation including fractional derivative terms. It is derived from first principles of physics (mass and momentum conservation) and an equation of state given by the fractional Zener stress-strain constitutive relation. For a derivative order α in the fractional Zener relation, the resulting absorption α(k) obeys frequency power-laws as α(k) ∝ ω(1+α) in a low-frequency regime, α(k) ∝ ω(1-α/2) in an intermediate-frequency regime, and α(k) ∝ ω(1-α) in a high-frequency regime. The value α=1 corresponds to the case of a single relaxation process. The wave equation is causal for all frequencies. In addition the sound speed does not diverge as the frequency approaches infinity. This is an improvement over a previously published wave equation building on the fractional Kelvin-Voigt constitutive relation.


Conformational preferences of the potent dopamine reuptake blocker BTCP and its analogs and their incorporation into a pharmacophore model.
Molecular mechanics calculations using MM3-92 and ab initio quantum mechanical calculations using SPARTAN 5.0 were performed on the structurally similar PCP and BTCP, in which only the latter has a cocaine-like pharmacological profile as a dopamine reuptake blocker. Calculations were also performed on BTCP analogs with a methyl group in various positions of the cyclohexane ring. The results for the cis-2-methyl compound, which retains good pharmacological activity, allowed us to determine that an aryl-axial conformer is the biologically active form for at least some of the compounds in this series. However, an aryl-equatorial conformer presents the identical pharmacophore, as shown by superposition of the two conformers. X-ray crystallographic structures were also obtained for BTCP and related compounds with a 2-methyl group on the cyclohexane ring, with reasonable agreement between the computational and experimental results. Superposition studies were performed with two rigid analogs of cocaine which illustrate the optimal orientations of the ammonium hydrogen for monoamine transporters. There is excellent agreement between a 'back-bridged' cocaine analog that is optimal as a dopamine reuptake blocker and the previously proposed biologically active conformer of methylphenidate. However, BTCP is found to be a better fit to the 'front-bridged' cocaine analog that is optimal for a serotonin reuptake blocker.


Communication Among Photoreceptors and the Central Clock Affects Sleep Profile.
Light is one of the most important factors regulating rhythmical behavior of Drosophila melanogaster. It is received by different photoreceptors and entrains the circadian clock, which controls sleep. The retina is known to be essential for light perception, as it is composed of specialized light-sensitive cells which transmit signal to deeper parts of the brain. In this study we examined the role of specific photoreceptor types and peripheral oscillators located in these cells in the regulation of sleep pattern. We showed that sleep is controlled by the visual system in a very complex way. Photoreceptors expressing Rh1, Rh3 are involved in night-time sleep regulation, while cells expressing Rh5 and Rh6 affect sleep both during the day and night. Moreover, Hofbauer-Buchner (HB) eyelets which can directly contact with s-LN v s and l-LN v s play a wake-promoting function during the day. In addition, we showed that L2 interneurons, which receive signal from R1-6, form direct synaptic contacts with l-LN v s, which provides new light input to the clock network.


Alcohol misuse and associations with childhood maltreatment and out-of-home placement among urban two-spirit American Indian and Alaska Native people.
This study examined associations between alcohol misuse and childhood maltreatment and out-of-home placement among urban lesbian, gay, and bisexual (referred to as two-spirit) American Indian and Alaska Native adults. In a multi-site study, data were obtained from 294 individuals who consumed alcohol during the past year. The results indicated that 72.3% of men and 62.4% of women engaged in hazardous and harmful alcohol use and 50.8% of men and 48.7% of women met criteria for past-year alcohol dependence. The most common types of childhood maltreatment were physical abuse among male drinkers (62.7%) and emotional abuse (71.8%) among female drinkers. Men and women reported high percentages of out-of-home placement (39% and 47%, respectively). Logistic multiple regressions found that for male drinkers boarding school attendance and foster care placement were significant predictors of past-year alcohol dependence. For female drinkers, being adopted was significantly associated with a decreased risk of past-year drinking binge or spree. Dose-response relationships, using number of childhood exposures as a predictor, were not significant. The results highlight the need for alcohol and violence prevention and intervention strategies among urban two-spirit individuals.


Comparison of Minimally Invasive Versus Abdominal Radical Hysterectomy for Early-Stage Cervical Cancer: An Updated Meta-Analysis.
Although minimally invasive surgery (MIS) was commonly used to treat patients with early-stage cervical cancer, its efficacy remained controversial. We systematically searched PubMed, Web of Science, and Cochrane Library databases until March 2021 to compare the prognosis of early-stage cervical cancer patients who underwent MIS (laparoscopic or robot-assisted radical hysterectomy) or ARH. The primary outcomes included rates of 3- and 5-year disease-free survival (DFS) and overall survival (OS). The study protocol was registered in PROSPERO: CRD42021258116. This meta-analysis included 48 studies involving 23346 patients (11220, MIS group; 12126, ARH group). The MIS group had a poorer medium-term (3-year) DFS (HR=1.08, 95% CI: 1.01-1.16, p=0.031) than the ARH group, without significant difference in medium-term OS as well as long-term (5-year) DFS and OS. Subgroup analysis of 3-year prognosis revealed that although patients in Western countries who underwent MIS had shorter DFS than those who underwent ARH (HR=1.10, p=0.024), no difference was observed in DFS among those in Asian countries. Moreover, MIS was linked to poorer 3-year DFS in patients with stage I cervical cancer (HR=1.07, p=0.020). Notably, subgroup analysis of 5-year prognosis revealed that patients with tumor size ≥2 cm undergoing MIS exhibited a shorter DFS than those who underwent ARH (HR=1.65, p=0.041). Patients with early-stage cervical cancer undergoing MIS may have a poorer prognosis than those undergoing ARH. Therefore, applying MIS in early-stage cervical cancer patients should be conducted with caution. The study protocol was registered in PROSPERO: CRD42021258116.


Mutational analysis of the PITX2 and NKX2-5 genes in patients with idiopathic atrial fibrillation.
Atrial fibrillation (AF) is the most frequently encountered arrhythmia in clinical practice. In a subgroup of patients, AF is regarded as idiopathic when no signs of structural heart disease or other causes of the arrhythmia can be identified during conventional clinical work-up. Recent studies have demonstrated that AF has a substantial genetic basis in a number of cases. The entire coding sequences, including intron-exon boundaries, of the genes PITX2 and NKX2-5 were screened for genetic variants by means of initial polymerase chain reaction followed by DNA sequencing in 96 patients with idiopathic AF. Although we detected a number of variants, our candidate gene approach did not result in identification of mutations associated with AF in the coding regions of PITX2 or NKX2-5 in our well characterized AF cohort.


Cancer-preventive selenocompounds induce a specific redox modification of cysteine-rich regions in Ca(2+)-dependent isoenzymes of protein kinase C.
Since protein kinase C (PKC) serves as a receptor for phorbol ester type tumor promoters and oxidants and has unique redox-active cysteine-rich regions, we have determined whether various chemopreventive selenocompounds could affect this enzyme. At lower concentrations, selenite decreased the kinase activity (IC50 = 0.5 microM), while at higher concentrations it decreased phorbol ester binding. However, when the catalytic and regulatory domains of PKC were separated by proteolysis, the catalytic domain retained its sensitivity to selenite, while the regulatory domain lost its sensitivity. Cysteine residues were quantitated in PKC modified with selenite by using 5,5'-dithiobis(2-nitrobenzoic acid) and also by using 2-nitro-5-thiosulfobenzoic acid after sulfitolysis. At lower concentrations, selenite induced a modification of four cysteine residues resulting in the formation of two disulfides, while at higher concentrations it induced a modification of seven to eight cysteine residues resulting in the formation of three to four disulfides. Contrary to selenite, selenocystine and selenodiglutathione (GSSeSG) readily inactivated the kinase activity, but not the phorbol ester binding. These two agents induced a two-stage modification of PKC; a limited modification at low concentrations leads to a loss of affinity for ATP, while an excessive modification at high concentrations leads to a loss of Vmax. Selenocystine and GSSeSG were 100,000-fold more potent than GSSG in inactivating PKC. The isoenzymes alpha, beta, and gamma exhibited an identical susceptibility to these selenocompounds. These results suggested that the cysteine residues present within the catalytic domain of these isoenzymes, although apart in the sequence, may be clustered in the tertiary structure to react with selenite, as well as may be in close proximity to some of the cysteines in the regulatory domain. Selenite did not affect protein kinase A, whereas GSSeSG and selenocystine inactivated the catalytic subunit after dissociation from the regulatory subunit at concentrations 100- and 800-fold, respectively, higher than that required for PKC inactivation. All three selenocompounds did not affect the activities of phosphorylase kinase and protein phosphatase 2A. Taken together, these results suggest that the accessible redox-active cysteine residues present in the PKC catalytic domain can react with certain specificity with redox-active selenocompounds such as selenite, selenocystine, and GSSeSG relative to other protein kinases tested.


[Acute retinal necrosis. Silicon oil tamponade in retinal detachment].
Because retinal necrosis syndrome seldom occurs, we present our results of silicone oil tamponade for associated retinal detachment. Thirteen eyes from 13 patients undergoing retinal reattachment surgery for retinal detachment associated with acute retinal necrosis in a consecutive series between January 1988 and June 1995 were followed up. Patients were 25 to 56 years of age. Four patients had acquired immune deficiency syndrome (AIDS). Five eyes that were operated on with cryopexy and scleral buckling received vitrectomy, membrane peeling, silicone oil tamponade and endolaser treatment in a second operation. Eight eyes were primarily operated on with cryopexy, encircling buckle, vitrectomy with membrane peeling, silicone oil tamponade and endolaser treatment. All patients were treated with acyclovir. Postoperative complete reattachment was observed in 12 eyes and persistence of a peripheral detachment in one eye. Vision improved in eight eyes, but only five eyes achieved 20/200 or better vision. Limited functional results in our series were caused by retinal ischemia, optic atrophy and macula scars. After a median of 9.3 months silicone oil was removed in nine eyes. No retinal redetachment or recurrent retinitis was observed during a follow-up time of at least 6 months. Vitrectomy and silicone oil tamponade allowed all cases of retinal detachment associated with acute retinal necrosis to be successfully repaired. Further studies must be conducted to find out how we can improve the visual outcome-perhaps by earlier therapy with acyclovir or earlier vitrectomy.


Seleno-auranofin (Et3PAuSe-tagl): synthesis, spectroscopic (EXAFS, 197Au Mössbauer, 31P, 1H, 13C, and 77Se NMR, ESI-MS) characterization, biological activity, and rapid serum albumin-induced triethylphosphine oxide generation.
Seleno-auranofin (SeAF), an analogue of auranofin (AF), the orally active antiarthritic gold drug in clinical use, was synthesized and has been characterized by an array of physical techniques and biological assays. The Mössbauer and extended X-ray absorption fine structure (EXAFS) parameters of the solid compound demonstrate a linear P-Au-Se coordination environment at a gold(I) center, analogous to the structure of auranofin. The (31)P, (13)C, and (1)H NMR spectra of SeAF in chloroform solution closely resemble those of auranofin. The (77)Se spectrum consists of a singlet at 481 ppm, consistent with a metal-bound selenolate ligand. The absence of (2)J(PSe) coupling in the (31)P and (77)Se spectra may arise from dynamic processes occurring in solution or because the (2)J(PSe) coupling constants are smaller than the observed bandwidths. Electrospray ionization mass spectrometry (ESI-MS) spectra of SeAF in 50:50 methanol-water exhibited strong signals for [(Et(3)P)(2)Au](+), [(Et(3)PAu)(2)-mu-Se-tagl](+), and [Au(Se-tagl)(2)](-), which arise from ligand scrambling reactions. Three assays of the anti-inflammatory activity of SeAF allowed comparison to AF. SeAF exhibited comparable activity in the topically administered murine arachadonic acid-induced and phorbol ester-induced anti-inflammatory assays but was inactive in the orally administered carrageenan-induced assay in rats. However, in vivo serum gold levels were comparable in the rat, suggesting that differences between the in vivo metabolism of the two compounds, leading to differences in transport to the inflamed site, may account for the differential activity in the carrageenan-induced assay. Reactions of serum albumin, the principal transport protein of gold in the serum, demonstrated formation of AlbSAuPEt(3) at cysteine 34 and provided evidence for facile reduction of disulfide bonds at cysteine 34 and very rapid formation of Et(3)P=O, a known metabolite of auranofin.


Scaling property of the diffusion equation for light in a turbid medium with varying refractive index.
A spatially varying refractive index leads to the bending of photon paths in a medium, which complicates the Monte Carlo modeling of a photon random walk. We show that the process of photon diffusion in a turbid medium with varying refractive index and curved photon paths can be mapped to the diffusion process in a medium with straight photon paths and modified optical properties. Specifically, the diffusion coefficient, the absorption, and the refractive index of the second medium should differ from the corresponding properties of the first medium by the factor of the squared refractive index of the first medium. The specific intensity of light in the second medium will then be equal to the specific intensity in the first medium divided by the same factor, which also means that the photon density distributions in the two media will be identical. In a Monte Carlo simulation the scaling property suggests that two different algorithms can be used to obtain the photon density distribution, namely, the algorithm with curved photon paths and given optical properties and the algorithm with straight photon paths and modified optical properties.


[Studies on the mechanism of embryo implantation].
Implantation is a complex process accomplished by synchronization and interactions between embryo and endometrium by local exchange of signals including a number of cytokines and growth factors and direct cell-cell and cell-matrix contact. However, the research in early events of human implantation is still in its infancy. This presentation comprises the results of our attempts to investigate the mechanisms of human implantation process in its early stage by cell-biological method, including establishment of experimental implantation model in vitro. 1. Human trophoblast of early stage of gestation showed active cell locomotion, active endocytosis, and invasion of endometrial cell monolayer in mixed cultures. Trophoblast invasion was later arrested by transformed endometrial cells similar to decidual cells in vivo. These results appeared to indicate the interactions between trophoblast and endometrial cells in implantation. 2. Coculture system of rabbit preimplantation blastocyst and endometrial epithelium reformed from isolated endometrial epithelial cells on basement membrane matrix (Matrigel) simulated the in vivo rabbit implantation processes. This coculture system may provide a useful experimental implantation model. 3. A human trophoblast cell line was established from chorionic tissues of normal early pregnancy. These cells were cytotrophoblast-like morphology and endocrine functions. They formed the villous structures similar to those in vivo in culture on Matrigel and invasion of Matrigel was observed. These indicated the extracellular matrix may affect the morphology and function of invading trophoblast in implantation site. 4. Human endometrial epithelial single cells were cultured on Matrigel. Reconstruction of gland followed by epithelium formation quite similar to in vivo structures by migration and proliferation of isolated cells was demonstrated. Height of gland was promoted by estrogen and initiation of epithelization was upregulated by platelet-derived growth factors. This system revealed the extracellular matrix regulated morphogenesis of endometrial epithelium in vivo and is an essential substrate in experimental implantation model of endometrial epithelium. 5. Parallel cultures of endometrial epithelial cells on Matrigel were carried out with the IVF. ET patients to evaluate the endometrial morphology at time of ET. Endometrial cultures were initiated in previous cycles on Matrigel and the sera of patients were added to her own cultures from 1st day of IVF treatment cycle. Evaluation of reformed epithelium revealed the apparently unsuitable morphology for implantation in group of patients who eventually failed in pregnancy. This system may provide a useful measures in evaluation of endometrial receptivity and modality of treatment for endometrial aberrations. 6. Cyclic changes of extracellular matrix components in endometrium were investigated. Collagen I, III, IV, V were immunohistochemically estimated. Relative levels of all types of collagen except for collagen V declined at early secretory phase. In rodents, not only collagen but also laminin and fibronectin levels declined at early secretory phase. These changes may facilitate trophoblast invasion of endometrium. Collagen V distributed in myometrial surface was found to consist of subunit (alpha 1)2 alpha 2 and trophoblast growth was inhibited on substrate of alpha 1 subunit. Collagen V in myometrial surface may have a role in blocking trophoblast invasion. 7. HGF (hepatocyte growth factor) mRNA was demonstrated to be expressed during menstruation and secretory phase in endometrium distinctly and its receptor in endometrial epithelial cells and decidual cells. Positive correlation between plasma HGF levels and ultrasonographic thickness of endometrium was observed at late secretory phase. Recombinant HGF promoted proliferation of endometrial epithelial cells and decidual cells and upregulated initiation of endometrial epithelization of Matrigel.


An ultraviolet spectrophotometric assay for measuring lipase activity using long-chain triacyglycerols from Aleurites fordii seeds.
In this study, we designed a specific, continuous, and sensitive UV spectrophotometric lipase assay using natural triacylglycerols (TAGs) from the Aleurites fordii seed oil (tung oil). alpha-Eleostearic acid (9,11,13-cis, trans,trans-octadecatrienoic acid) is the main fatty acid component (it accounts for up to 70%) of the TAGs from tung oil. The conjugated triene present in alpha-eleostearic acid constitutes an intrinsic chromophore, which confers strong UV absorption properties on both the free fatty acid and the TAGs from tung oil. The lipase assay is based on the difference between the apparent molar extinction coefficients of the two types of alpha-eleostearic acid present, that which is esterified into TAGs and that which is released into the reaction medium. This difference is responsible for the variations in the UV absorption spectrum of the reaction medium occurring upon enzymatic TAGs hydrolysis. Using the purified lipase from Thermomyces lanuginosa (TLL) and the detergent sodium taurodeoxycholate (NaTDC, 4 mM), it was established that the most suitable method of measuring lipolysis consisted of monitoring the decrease in the OD at 292 nm, which was linear with time and proportional to the amount of lipase added. In order to be able to estimate the specific activity of TLL, we determined an apparent molar extinction coefficient of alpha-eleostearic acid (epsilon = 13,900 M(-1) cm(-1)) under the assay conditions. Amounts of pure TLL as small as 1 ng can be easily detected in the presence of 4 mM NaTDC. Interestingly, the NaTDC concentration can be decreased as far as 0.05 mM. In comparison with other well-known methods of lipase assay, the detection limit of this new method is 100-fold lower than with the pH-stat method and similar to that of a fluorescent assay recently developed at our laboratory.


Prognostic indicators for malignant tumours of the parotid gland.
The best treatment of malignant parotid tumours still remains to be defined, and a better knowledge about the tumour features that predict the treatment result is needed. The histological classification of parotid tumours may present difficulties on account of their great morphological diversity. In a series of 152 patients with a malignant tumour of the parotid gland, the prognostic factors and treatment results were investigated over a 25-year period. Treatment consisted of surgery, radiation therapy or a combination (49%, 13% and 38% respectively). Crude 5-year survival was 50% with significant differences related to stage (stage I, 65%; stage II, 50%; stage III, 21%; and stage IV, 9%). With respect to histopathology, the adenoid cystic carcinomas and the acinic cell carcinomas had the best prognosis (76% and 67% 5-year crude survival and 53% and 67% 10-year crude survival respectively). There was a significant difference in crude survival between well/intermediate and poorly differentiated tumours (P = 0.007). In a Cox hazard regression analysis including 136 patients and using death from cancer as the end-point, the following parameters were independent prognostic predictors: T-classification (P = 0.002), M-classification (P < 0.0001), N-classification (N+versus N0) (P = 0.005), local invasion (P = 0.003) and histological differentiation of the tumour (P = 0.03). The TNM system is a good predictor of treatment outcome for malignant parotid tumours. The use of a combination of clinical and histological factors will assist the design of treatment strategies for parotid gland tumours.


[Analysis of perfluorinated compounds in sludge by liquid extraction and high performance liquid chromatography-tandem mass spectrometry].
Perfluorinated compounds are emerging persistent organic pollutants. Wastewater treatment plants are reported to be one of their primary sources. However, a standard analytical method for sludge samples has not been set up. A novel and rapid analytical method based on the liquid extraction, followed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was set up for 7 perfluorocarboxylic acids (PFCAs) and their precursors, 6:2 and 8:2 unsaturated flourotelomer carboxylic acids (FTUCAs), and 2 perfluoroalkyl sulfonates (PFASs) and their precursors, 5 derivates of sulfonamide in sludge. The parameters of methanol extraction, including pH, sonication temperature and time, and eluent volume were optimized. The extraction method was optimized as neutral extraction under sonication at 40 degrees C for 10 min, and it was successfully used for the analysis of perfluorinated compounds in the sludge samples. The linear calibration curves were obtained in the ranges of 0.1-20 microg/L for PFCAs and 6: 2/8: 2 FTUCA and 0.25-50 microg/L for PFASs and their precusors with linear correlation coefficients larger than 0.99. The recoveries of the target compounds ranged from 74% to 141% (except for FTUCAs) and the limits of quantification ranged from 0.6 to 30 microg/kg (dry weight). The use of internal standards can well correct the ion suppression (or enhancement) induced by co-eluting components present in the sample extracts, and improve the quantitative accuracy.


Female common lizards (Lacerta vivipara) do not adjust their sex-biased investment in relation to the adult sex ratio.
Sex allocation theory predicts that facultative maternal investment in the rare sex should be favoured by natural selection when breeders experience predictable variation in adult sex ratios (ASRs). We found significant spatial and predictable interannual changes in local ASRs within a natural population of the common lizard where the mean ASR is female-biased, thus validating the key assumptions of adaptive sex ratio models. We tested for facultative maternal investment in the rare sex during and after an experimental perturbation of the ASR by creating populations with female-biased or male-biased ASR. Mothers did not adjust their clutch sex ratio during or after the ASR perturbation, but produced sons with a higher body condition in male-biased populations. However, this differential sex allocation did not result in growth or survival differences in offspring. Our results thus contradict the predictions of adaptive models and challenge the idea that facultative investment in the rare sex might be a mechanism regulating the population sex ratio.


Prevalence of refractive error in the United States, 1999-2004.
To describe the prevalence of refractive error in the United States. The 1999-2004 National Health and Nutrition Examination Survey (NHANES) used an autorefractor to obtain refractive error data on a nationally representative sample of the US noninstitutionalized, civilian population 12 years and older. Using data from the eye with a greater absolute spherical equivalent (SphEq) value, we defined clinically important refractive error as follows: hyperopia, SphEq value of 3.0 diopters (D) or greater; myopia, SphEq value of -1.0 D or less; and astigmatism, cylinder of 1.0 D or greater in either eye. Of 14,213 participants 20 years or older who completed the NHANES, refractive error data were obtained for 12,010 (84.5%). The age-standardized prevalences of hyperopia, myopia, and astigmatism were 3.6% (95% confidence interval [CI], 3.2%-4.0%), 33.1% (95% CI, 31.5%-34.7%), and 36.2% (95% CI, 34.9%-37.5%), respectively. Myopia was more prevalent in women (39.9%) than in men (32.6%) (P < .001) among 20- to 39-year-old participants. Persons 60 years or older were less likely to have myopia and more likely to have hyperopia and/or astigmatism than younger persons. Myopia was more common in non-Hispanic whites (35.2%) than in non-Hispanic blacks (28.6%) or Mexican Americans (25.1%) (P < .001 for both). Estimates based on the 1999-2004 NHANES vision examination data indicate that clinically important refractive error affects half of the US population 20 years or older.


Helical extension of the neuronal SNARE complex into the membrane.
Neurotransmission relies on synaptic vesicles fusing with the membrane of nerve cells to release their neurotransmitter content into the synaptic cleft, a process requiring the assembly of several members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) family. SNAREs represent an evolutionarily conserved protein family that mediates membrane fusion in the secretory and endocytic pathways of eukaryotic cells. On membrane contact, these proteins assemble in trans between the membranes as a bundle of four alpha-helices, with the energy released during assembly being thought to drive fusion. However, it is unclear how the energy is transferred to the membranes and whether assembly is conformationally linked to fusion. Here, we report the X-ray structure of the neuronal SNARE complex, consisting of rat syntaxin 1A, SNAP-25 and synaptobrevin 2, with the carboxy-terminal linkers and transmembrane regions at 3.4 A resolution. The structure shows that assembly proceeds beyond the already known core SNARE complex, resulting in a continuous helical bundle that is further stabilized by side-chain interactions in the linker region. Our results suggest that the final phase of SNARE assembly is directly coupled to membrane merger.


Antibodies to pneumococcal proteins PhtD, CbpA, and LytC in Filipino pregnant women and their infants in relation to pneumococcal carriage.
This study focuses on the immunogenicity of the following three pneumococcal vaccine candidate proteins in Filipino infants, all inducing protection in animal models: pneumococcal histidine triad protein D (PhtD), choline binding protein A (CbpA), and the lysozyme LytC. The immunoglobulin G antibody concentrations to PhtD, its putative, protective, and exposed C-terminal fragment (PhtD C), CbpA, and LytC were measured by enzyme immunoassay in 52 serum samples from pregnant women, 39 cord blood samples, and consecutive serum samples (n = 263) from 52 newborns between 6 weeks and 10 months of age scheduled to be taken at six time points. A nasopharyngeal swab to detect pneumococcal carriage was taken parallel to the serum samples. The antibody concentrations in the cord blood samples were similar to those in the samples from the mothers. In infant sera, the geometric mean antibody concentrations (GMCs) for all three proteins decreased until the age of 18 weeks and started to increase after that age, suggesting that the infants' own antibody production started close to the age of 4 to 5 months. The increase in GMCs by age, most clear-cut for CbpA, was associated with pneumococcal carriage. Anti-PhtD concentrations were higher than anti-PhtD C concentrations but correlated well (r of 0.89 at 10.5 months), suggesting that antibodies are directed to the supposedly exposed and protective C-terminal part of PhtD. Our results show that young children are able to develop an antibody response to PhtD, CbpA, and LytC and encourage the development of pneumococcal protein vaccines for this age group.


Carbon nanotubes selective destabilization of duplex and triplex DNA and inducing B-A transition in solution.
Single-walled carbon nanotubes (SWNTs) have been considered as the leading candidate for nanodevice applications ranging from gene therapy and novel drug delivery to membrane separations. The miniaturization of DNA-nanotube devices for biological applications requires fully understanding DNA-nanotube interaction mechanism. We report here, for the first time, that DNA destabilization and conformational transition induced by SWNTs are sequence-dependent. Contrasting changes for SWNTs binding to poly[dGdC]:poly[dGdC] and poly[dAdT]:poly[dAdT] were observed. For GC homopolymer, DNA melting temperature was decreased 40 degrees C by SWNTs but no change for AT-DNA. SWNTs can induce B-A transition for GC-DNA but AT-DNA resisted the transition. Our circular dichroism, competitive binding assay and triplex destabilization studies provide direct evidence that SWNTs induce DNA B-A transition in solution and they bind to the DNA major groove with GC preference.


Matrix metalloproteinase-9 inhibition ameliorates pathogenesis and improves skeletal muscle regeneration in muscular dystrophy.
Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disorder of skeletal muscle caused by mutation in dystrophin gene. Although the degradation of skeletal muscle extracellular matrix, inflammation and fibrosis are the common pathological features in DMD, the underlying mechanisms remain poorly understood. In this study, we have investigated the role and the mechanisms by which increased levels of matrix metalloproteinase-9 (MMP-9) protein causes myopathy in dystrophin-deficient mdx mice. The levels of MMP-9 but not tissue inhibitor of MMPs were drastically increased in skeletal muscle of mdx mice. Besides skeletal muscle, infiltrating macrophages were found to contribute significantly to the elevated levels of MMP-9 in dystrophic muscle. In vivo administration of a nuclear factor-kappa B inhibitory peptide, NBD, blocked the expression of MMP-9 in dystrophic muscle of mdx mice. Deletion of Mmp9 gene in mdx mice improved skeletal muscle structure and functions and reduced muscle injury, inflammation and fiber necrosis. Inhibition of MMP-9 increased the levels of cytoskeletal protein beta-dystroglycan and neural nitric oxide synthase and reduced the amounts of caveolin-3 and transforming growth factor-beta in myofibers of mdx mice. Genetic ablation of MMP-9 significantly augmented the skeletal muscle regeneration in mdx mice. Finally, pharmacological inhibition of MMP-9 activity also ameliorated skeletal muscle pathogenesis and enhanced myofiber regeneration in mdx mice. Collectively, our study suggests that the increased production of MMP-9 exacerbates dystrophinopathy and MMP-9 represents as one of the most promising therapeutic targets for the prevention of disease progression in DMD.


A three-week intervention emphasized diagonal eccentric contraction on balance and joint position sense and ankle strength in subjects with ankle instability: A randomized controlled trial.
Problems related to ankle instability, decreased proprioceptive sensation, altered static and dynamic balance abilities are suggested as major representative factors that contribute to the recurrence of ankle sprains. To assess the effect of a three-week intervention (intervention emphasizing diagonal eccentric contraction (IEDEC) and intervention of general exercise (IGE)) on static and dynamic balance abilities, ankle strength and joint position sense at pre- and post-intervention, and at two- and three-week post-intervention. Twenty-five participants with ankle instability, including a history of ankle sprain and recurrent episodes of giving way, were enrolled in the study. They were randomly classified into the IEDEC group (n= 12) and the IGE group (n= 13). Dynamic balance was examined using the Y Balance Test, four-way ankle strength was measured, and the static balance was evaluated using the total displacement of the center of pressure (COP). To identify the joint position error, eversion and inversion of the ankle angle were measured. The results revealed significant increases in ankle dynamic stability and strength at two and three weeks post-intervention (p< 0.05). Similarly, the total displacement of the COP differed significantly over time, with a higher COP during the initial measurement than at two and three weeks intervention (p< 0.05) General balance training with IEDEC can improve position sense during ankle inversion (p< 0.05). General balance training with IEDEC improved the position sense of the inversion. Combined therapeutic intervention, such as with the manual technique, could be a beneficial approach to maximize the treatment effects.


The relationship between aerobic fitness and recovery from high-intensity exercise in infantry soldiers.
The relationship between aerobic fitness and recovery from high-intensity exercise was examined in 197 infantry soldiers. Aerobic fitness was determined by a maximal-effort, 2,000-m run (RUN). High-intensity exercise consisted of three bouts of a continuous 140-m sprint with several changes of direction. A 2-minute passive rest separated each sprint. A fatigue index was developed by dividing the mean time of the three sprints by the fastest time. Times for the RUN were converted into standardized T scores and separated into five groups (group 1 had the slowest run time and group 5 had the fastest run time). Significant differences in the fatigue index were seen between group 1 (4.9 +/- 2.4%) and groups 3 (2.6 +/- 1.7%), 4 (2.3 +/- 1.6%), and 5 (2.3 +/- 1.3%). It appears that recovery from high-intensity exercise is improved at higher levels of aerobic fitness (faster time for the RUN). However, as the level of aerobic fitness improves above the population mean, no further benefit in the recovery rate from high-intensity exercise is apparent.


The immunology of coeliac disease.
Coeliac disease is defined as that disorder in which there is an abnormality of the small intestinal mucosa manifested by contact with the gluten of wheat and certain other cereal grains. In the immunological theory of the pathogenesis of coeliac disease, gluten, or a component, is viewed as the antigen responsible for the immune response. The search for the gluten component responsible for 'toxicity' and, by implication, antigenicity, is described. The antigen may be presented differently to the immune system by an abnormal cell membrane, either of the enterocyte, lymphocyte or macrophage. Alternatively, increased amounts of antigen may be absorbed due to increased membrane binding or permeability, either of which could be genetically determined. As a further possibility, coeliac disease may occur because the patients are immunologically hyperresponsive and this too appears to be genetically determined. The perturbations which occur in the mucosal immune system and the systemic immune system are described. It is conceivable that the major complications described (intestinal ulceration, malignancy and splenic atrophy) result from immunological disturbances. The incidence of childhood coeliac disease is declining, which may be due to altered exposure to, or increased protection from, the antigen in infancy, or to changes in environmental factors. The immunological mystery of coeliac disease continues to excite interest and fascination, and has certainly been a stimulus to our deeper understanding of gastrointestinal immunology.


The ATAC ('Arimidex', Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: baseline endometrial sub-protocol data on the effectiveness of transvaginal ultrasonography and diagnostic hysteroscopy.
The 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial is a randomized, double-blind trial comparing anastrozole ('Arimidex'), alone or in combination with tamoxifen, relative to tamoxifen alone as 5 year adjuvant treatment for post-menopausal women with early breast cancer. Since tamoxifen is associated with endometrial pathology, the ATAC endometrial sub-protocol was initiated to establish the background prevalence of intrauterine pathology, and to assess prospectively the incidence and nature of intrauterine changes following endocrine therapy. Another aim was to provide data from which advice could be generated on the best endometrium screening method for patients receiving tamoxifen. Patients underwent endometrial assessments at entry to the sub-protocol. The baseline investigations comprised transvaginal ultrasound scanning (TVUS), a hysteroscopy and an endometrial biopsy. A total of 285 gynaecologically asymptomatic women from 31 centres in 10 countries entered the endometrial sub-protocol. The mean uterine volume was 47.7 cm3. The median endometrial thickness overall was 3 mm. Twenty-four histologically confirmed, pathological changes were observed. Twenty-three pathologies were confirmed by TVUS, and 21 were identified by hysteroscopy and confirmed by histopathology. Women with or without intrauterine pathology had median endometrial thickness of 5 and 3 mm respectively. The presence of pathology was associated with increased endometrial thickness. The relative sensitivity and specificity of hysteroscopy and endometrial thickness for the diagnosis of endometrial pathology was comparable to other studies. If screening of the endometrium prior to treatment is appropriate, this study supports the use of an endometrial thickness of 3 mm, as assessed by TVUS, as a threshold for needing further investigation. This study demonstrates that if the endometrial thickness is >3 mm, hysteroscopy and biopsy is the optimal method of detecting intrauterine pathology in women with breast cancer who are about to commence endocrine treatment.


Short hydrogen bond between redox-active tyrosine Y(Z) and D1-His190 in the photosystem II crystal structure.
The crystal structure of photosystem II (PSII) analyzed at a resolution of 1.9 Å revealed a remarkably short H-bond between redox-active tyrosine Y(Z) and D1-His190 (2.46 Å donor-acceptor distance). Using large-scale quantum mechanical/molecular mechanical (QM/MM) calculations with the explicit PSII protein environment, we were able to reproduce this remarkably short H-bond in the original geometry of the crystal structure in the neutral [Y(Z)O···H···N(ε)-His-N(δ)H···O═Asn] state, but not in the oxidized states, indicating that the neutral state was the one observed in the crystal structure. In addition to the appropriate redox/protonation state of Y(Z) and D1-His190, we found that the presence of a cluster of water molecules played a key role in shortening the distance between Y(Z) and D1-His190. The orientations of the water molecules in the cluster were energetically stabilized by the highly polarized PSII protein environment, where the Ca ion of the oxygen-evolving complex (OEC) and the OEC ligand D1-Glu189 were also involved.


VMP1-related autophagy induced by a fructose-rich diet in β-cells: its prevention by incretins.
The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.


Hepatocyte growth factor ameliorates progression of interstitial injuries in tubular epithelial cells.
Hepatocyte growth factor (HGF) and its c-met receptor comprise a signalling system that has been reported to prevent injury in several models of renal disease; however, whether HGF can also retard progression of chronic kidney disease is not known. The aim of the present study was to examine the effects of HGF on progression of chronic kidney disease in tubular epithelial cells. Studies were performed in human tubular epithelial cells that underwent different glucose concentrations, and then receive HGF or vehicle. The cell apoptosis was tested by DAPI and TUNEL staining. The level of activity of HGF was examined at multiple time-points. The expression of HGF, transforming growth factor-beta(1) (TGF-beta(1)), plasminogen activator inhibitor-1 (PAI-1) and collagen IV were examined by reverse transcription-polymerase chain reaction, Western blot and enzyme-linked immunosorbent assay. HGF administration was associated with a reduction in TGF-beta(1). The beneficial effects of HGF were associated with reductions in the expression of TGF-beta(1), and in the extent of epithelial cell apoptosis. HGF appeared to induce fibrinolytic pathways by reducing the expression of collagen IV and decreasing levels of PAI-1. These findings suggest that HGF can retard progression of diabetic nephropathy, primarily by promoting matrix degradation, and that HGF is a potent antifibrogenic factor.


Milk thistle impedes the development of carbontetrachloride-induced liver damage in rats through suppression of bcl-2 and regulating caspase pathway.
The objective of this study was to examine whether MT plays a protective role against the damage in the liver by administering carbontetrachloride (CCl4) to rats. 28 male Wistar albino (n=28, 8weeks old) rats have been used in the study. The rats were distributed into 4 groups according to their live weights. The groups were: (i) negative control (NC): normal water consuming group to which no CCl4 and milk thistle (MT) is administered; (ii) positive control (PC): normal water consuming group to which no CCl4 is administered but MT is administered; (iii) CCl4 group: normal water consuming and group to which CCl4 is administered (2ml/kg live weight, ip); and (iv) CCl4+MT group: CCl4 and MT administered group (2ml/kg live weight, ip). Caspase-3, caspase-9, bax, and bcl-2 protein syntheses were examined via western blotting. MDA determination in liver tissue was made using spectrophotometer. MDA amount has decreased in the CCl4+MT group in comparison to CCl4 group whereas caspase-3 and caspase-9 has increased and bax and bcl-2 has decreased. These results show that MT protects the liver against oxidative damage.


Circular RNA_0033596 aggravates endothelial cell injury induced by oxidized low-density lipoprotein via microRNA-217-5p /chloride intracellular channel 4 axis.
In recent years, the modulatory functions of some circular RNAs (circRNAs) in the pathogenesis of atherosclerosis (AS) have been reported. Nonetheless, the role of circular RNA_0033596 (circ_0033596) in AS and its mechanism remains unclarified. In this study, oxidized low-density lipoprotein (ox-LDL) was applied to treat human umbilical vein endothelial cells (HUVECs) to establish a cell model of endothelial cell injury. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to detect the expression of circ_0033596, microRNA-217-5p (miR-217-5p), and chloride intracellular channel 4 (CLIC4) in HUVECs. The binding sites between circ_0033596 and miR-217-5p, as well as between miR-217-5p and CLIC4 mRNA 3'UTR were determined through a dual-luciferase reporter gene assay. It was found that circ_0033596 expression was increased in ox-LDL-induced HUVECs. After ox-LDL stimulation, HUVEC viability and cell cycle progression were inhibited, and the apoptosis was promoted, while circ_0033596 overexpression aggravated these effects. MiR-217-5p was identified as a downstream target of circ_0033596, and circ_0033596 negatively regulated miR-217-5p expression. CLIC4 was identified as miR-217-5p's downstream target gene and could be positively modulated by circ_0033596. All in all circ_0033596 aggravates ox-LDL-induced HUVEC apoptosis by regulating the miR-217-5p/CLIC4 axis, by which circ_0033596 participates in the pathogenesis of AS.


Driven by Vision: Learning Navigation by Visual Localization and Trajectory Prediction.
When driving, people make decisions based on current traffic as well as their desired route. They have a mental map of known routes and are often able to navigate without needing directions. Current published self-driving models improve their performances when using additional GPS information. Here we aim to push forward self-driving research and perform route planning even in the complete absence of GPS at inference time. Our system learns to predict in real-time vehicle's current location and future trajectory, on a known map, given only the raw video stream and the final destination. Trajectories consist of instant steering commands that depend on present traffic, as well as longer-term navigation decisions towards a specific destination. Along with our novel proposed approach to localization and navigation from visual data, we also introduce a novel large dataset in an urban environment, which consists of video and GPS streams collected with a smartphone while driving. The GPS is automatically processed to obtain supervision labels and to create an analytical representation of the traversed map. In tests, our solution outperforms published state of the art methods on visual localization and steering and provides reliable navigation assistance between any two known locations. We also show that our system can adapt to short and long-term changes in weather conditions or the structure of the urban environment. We make the entire dataset and the code publicly available.


Ethyl Acetate Fraction of Amomum xanthioides Exerts Antihepatofibrotic Actions via the Regulation of Fibrogenic Cytokines in a Dimethylnitrosamine-Induced Rat Model.
Amomum xanthioides has been traditionally used to treat diverse digestive system disorders in the Asian countries. We investigated antihepatofibrotic effects of ethyl acetate fraction of Amomum xanthioides (EFAX). Liver fibrosis is induced by dimethylnitrosamine (DMN) injection (intraperitoneally, 10 mg/kg of DMN for 4 weeks to Sprague-Dawley rats). EFAX (25 or 50 mg/kg), silymarin (50 mg/kg), or distilled water was orally administered every day. The DMN injection drastically altered body and organ mass, serum biochemistry, and platelet count, while EFAX treatment significantly attenuated this alteration. Severe liver fibrosis is determined by trichrome staining and measurement of hydroxyproline contents. EFAX treatment significantly attenuated these symptoms as well as the increase in oxidative by-products of lipid and protein metabolism in liver tissues. DMN induced a dramatic activation of hepatic stellate cells and increases in the levels of protein and gene expression of transforming growth factor-beta (TGF-β), platelet derived growth factor-beta (PDGF-β), and connective tissue growth factor (CTGF). Immunohistochemical analyses revealed increases in the levels of protein and gene expression of α-smooth muscle actin. These alterations were significantly normalized by EFAX treatment. Our findings demonstrate the potent antihepatofibrotic properties of EFAX via modulation of fibrogenic cytokines, especially TGF-β in the liver fibrosis rat model.


Upregulation of aldolase B and overproduction of methylglyoxal in vascular tissues from rats with metabolic syndrome.
Methylglyoxal (MG) overproduction has been reported in metabolic syndrome with hyperglycaemia (diabetes) or without hyperglycaemia (hypertension), and the underlying mechanism was investigated. Contributions of different pathways or enzymes to MG formation were evaluated in aorta or cultured vascular smooth muscle cells (VSMCs). In all four animal models of metabolic syndrome, i.e. chronically fructose-fed hypertensive Sprague-Dawley rats, spontaneously hypertensive rats, obese non-diabetic Zucker rats, and diabetic Zucker rats, serum and aortic MG and fructose levels were increased, and the expression of GLUT5 (transporting fructose) and aldolase B (converting fructose to MG) in aorta were up-regulated. Aortic expressions of aldolase A, semicarbazide-sensitive amine oxidase (SSAO), and cytochrome P450 2E1 (CYP 2E1), accounting for MG formation during glycolysis, protein, and lipid metabolism, respectively, was unchanged/reduced. Fructose (25 mM) treatment of VSMCs up-regulated the expression of GLUT5 and aldolase B and accelerated MG formation. Insulin (100 nM) increased GLUT5 expression and augmented fructose-increased cellular fructose accumulation and MG formation. Glucose (25 mM) treatment activated the polyol pathway and enhanced fructose formation, leading to aldolase B upregulation and MG overproduction. Inhibition of the polyol pathway reduced the glucose-increased aldolase B expression and MG generation. The excess formation of MG in under these conditions was eliminated by knock-down of aldolase B, but not by knock-down of aldolase A or inhibition of SSAO or CYP 2E1. Upregulation of aldolase B by accumulated fructose is a common mechanism for MG overproduction in VSMCs and aorta in different models of metabolic syndrome.


Tracer diffusion in granular shear flows.
Tracer diffusion in a granular gas in simple shear flow is analyzed. The analysis is made from a perturbation solution of the Boltzmann kinetic equation through first order in the gradient of the mole fraction of tracer particles. The reference state (zeroth-order approximation) corresponds to a Sonine solution of the Boltzmann equation, which holds for arbitrary values of the restitution coefficients. Due to the anisotropy induced in the system by the shear flow, the mass flux defines a diffusion tensor D(ij) instead of a scalar diffusion coefficient. The elements of this tensor are given in terms of the restitution coefficients and mass and size ratios. The dependence of the diffusion tensor on the parameters of the problem is illustrated in the three-dimensional case. The results show that the influence of dissipation on the elements D(ij) is in general quite important, even for moderate values of the restitution coefficients. In the case of self-diffusion (mechanically equivalent particles), the trends observed in recent molecular-dynamics simulations are similar to those obtained here from the Boltzmann kinetic theory.


Anthropogenic and natural barriers affect genetic connectivity in an Alpine butterfly.
Dispersal is a key biological process serving several functions including connectivity among populations. Habitat fragmentation caused by natural or anthropogenic structures may hamper dispersal, thereby disrupting genetic connectivity. Investigating factors affecting dispersal and gene flow is important in the current era of anthropogenic global change, as dispersal comprises a vital part of a species' resilience to environmental change. Using finescale landscape genomics, we investigated gene flow and genetic structure of the Sooty Copper butterfly (Lycaena tityrus) in the Alpine Ötz valley system in Austria. We found surprisingly high levels of gene flow in L. tityrus across the region. Nevertheless, ravines, forests, and roads had effects on genetic structure, while rivers did not. The latter is surprising as roads and rivers have a similar width and run largely in parallel in our study area, pointing towards a higher impact of anthropogenic compared with natural linear structures. Additionally, we detected eleven loci potentially under thermal selection, including ones related to membranes, metabolism, and immune function. This study demonstrates the usefulness of molecular approaches in obtaining estimates of dispersal and population processes in the wild. Our results suggest that, despite high gene flow in the Alpine valley system investigated, L. tityrus nevertheless seems to be vulnerable to anthropogenically-driven habitat fragmentation. With anthropogenic rather than natural linear structures affecting gene flow, this may have important consequences for the persistence of species such as the butterfly studied here in altered landscapes.


Leading From Darkness to Light: Understanding Chronic Disease and Coronavirus: An Integrative Perspective.
Disease is defined as complex interaction of 3 things: disease-causing agent, host and environment. The government, CDC and hospital administrations have had reasonable success with the effects of social distancing and coronavirus testing; kudos to them. That addresses 1 of the 3 main factors of a disease; i.e. disease -causing agent. However, there are 2 other ingredients in the complex of a disease; i.e. the host of the disease and finally the environment of the disease. We are the hosts and it is time we take ownership of this ourselves and join the effort with the government towards understanding the dysregulated immune response seen in severe covid-19 and enable the public in strengthening the inner environment and the host immune response. Social distancing can be complete only when the host is prepared to fight the war in the coming fall and winter seasons. The outer environment seems to spontaneously recharging itself as a consequence of social distancing.


Digital informed consent on radical prostatectomy surgery - A turning point on patient communication means.
To the Editor, Radical Prostatectomy (RP) is one of the preferred treatments for localized prostatic cancer and although surgical complications have been reduced over the years, urinary incontinence and erectile dysfunction are still common and significantly impact the patient's life. Therefore, adequate patient education and counselling before RP is essential. Informed Consent (IC) is a crucial element of doctor-patient interaction, and it must ensure that patients receive and understand all the information regarding their diseases and treatments. Implicit in providing IC is assessing the patient's understanding, since accessible communication enables them to make informed decisions consciously and autonomously about their health status [...].


Genetic Architecture of Natural Variation in Rice Nonphotochemical Quenching Capacity Revealed by Genome-Wide Association Study.
The photoprotective processes conferred by nonphotochemical quenching (NPQ) serve fundamental roles in maintaining plant fitness and sustainable yield. So far, few loci have been reported to be involved in natural variation of NPQ capacity in rice (Oryza sativa), and the extents of variation explored are very limited. Here we conducted a genome-wide association study (GWAS) for NPQ capacity using a diverse worldwide collection of 529 O. sativa accessions. A total of 33 significant association loci were identified. To check the validity of the GWAS signals, three F2 mapping populations with parents selected from the association panel were constructed and assayed. All QTLs detected in mapping populations could correspond to at least one GWAS signal, indicating the GWAS results were quite reliable. OsPsbS1 was repeatedly detected and explained more than 40% of the variation in the whole association population in two years, and demonstrated to be a common major QTL in all three mapping populations derived from inter-group crosses. We revealed 43 single nucleotide polymorphisms (SNPs) and 7 insertions and deletions (InDels) within a 6,997-bp DNA fragment of OsPsbS1, but found no non-synonymous SNPs or InDels in the coding region, indicating the PsbS1 protein sequence is highly conserved. Haplotypes with the 2,674-bp insertion in the promoter region exhibited significantly higher NPQ values and higher expression levels of OsPsbS1. The OsPsbS1 RNAi plants and CRISPR/Cas9 mutants exhibited drastically decreased NPQ values. OsPsbS1 had specific and high-level expression in green tissues of rice. However, we didn't find significant function for OsPsbS2, the other rice PsbS homologue. Manipulation of the significant loci or candidate genes identified may enhance photoprotection and improve photosynthesis and yield in rice.


Molecular modeling of mutations in the DNA-binding domain of the oncoprotein Qin.
The retroviral oncogene qin, homologue of mammalian brain factor 1 (FOXG1 B), belongs to the family of winged helix transcription factors. Oncogenic transformation by Qin requires sequence-specific DNA binding. Missense mutations in the forkhead domain of Qin modulate its oncogenic transforming ability in chicken embryonic fibroblasts. We used homology model building (threading) techniques to generate atomic structures of wild-type c-Qin and c-Qin mutants, using the solution structure of the forkhead domain of the adipocyte transcription factor as a template (M. J. van Dongen et al., J. Mol. Biol., 296: 351-359, 2000). Energy calculations indicate that the Qin forkhead structure is stabilized primarily by hydrophobic interactions between residues at the helical interface. None of the missense mutations analyzed here were responsible for maintaining the most critical pairwise interactions holding the forkhead domain together. The mutated proteins form the overall structure of the forkhead domain, but the mutations do interfere with DNA binding.


Inequities and psychiatry disability in transition among the elderly population from 1987 to 2006 in China: Data based on national surveys.
The world will be facing huge population aged 65 and older, accounting for 13% of the total population in the future. Significant disabilities rates reflect an accumulation of health risks. Psychiatry disability is one of the most significant disabilities, because it manifests in cognitive, affective, and behavior disorders that limit one's daily life and restrict their participations. Very few studies have explored the 20 years associations between demographic factors and psychiatry disability among older people in China.In this study, we investigated psychiatry disability transitional association behind China rapid development from 1987 to 2006 among the 60 and older population. Data used 2 nationally represented, population-based data from the China National Sample Surveys on Disability, conducted in 1987 and 2006. The sample size of the current study was 140,008 in 1987 and 354,859 in 2006, respectively. Associations between socioeconomic factors and psychiatry disability were determined by using a logistic regression model.The prevalence of psychiatric disabilities increased from 1987 to 2006. In both surveys, the most common psychiatric disabilities were schizophrenia, schizotypal, and delusional disorders, and they presented the same associations with age increase. Socioeconomic inequities, such as current employment status and marital status, were associated with psychiatry disability in both surveys. These associations remained even after these 2 surveys were combined.The rapidly rising prevalence of psychiatric disorders expected warrants strategies to reduce the burden of these disabilities among females and rural residents.


Gastrointestinal tract cancer in association with hepatitis and HIV infection.
One hundred and fifty patients with histologically proven gastrointestinal tract (GIT) cancer, 150 patients with a variety of other malignancies and 150 normal subjects were screened for human immunodeficiency virus (HIV) and hepatitis B sero-markers. Only one patient with nasopharyngeal carcinoma proved to be HIV seropositive. Hepatitis B surface antigen (HBsAg) was detected in 18% (n = 26) of the GIT cancer patients, in 16% (n = 24) of the other cancers group and in 12% (n = 20) of the control. There was no significant difference between the three groups (P > 0.1). The HBsAg was detected mainly in patients with primary hepatocellular (25%), gastric (12%), rectal (10%) and colonic carcinoma (8%). Hepatitis B core antibody (HBc AB) was detected in 12% of the GIT cancer patients, in 11% of the other cancers patients and in 13% of the control. In this study, there was no association between HIV, hepatitis B infections and GIT cancer.


Incidentally detected focal fundal gallbladder wall thickening: Differentiation contrast enhanced ultrasound features with high-resolution linear transducers.
To investigate the value of contrast enhanced ultrasound with high resolution linear transducers (HF-CEUS) for differential diagnosis of focal fundal gallbladder (GB) wall thickening. A total of 32 patients with incidentally detected focal fundal GB wall thickening were included. After conventional B mode ultrasound (BMUS) examinations, HF-CEUS were performed with a 7.5-12 MHz 9L4 linear transducer (S2000 HELX OXANA unit, Siemens). Two radiologists independently reviewed the HF-CEUS enhancement patterns to determine the differential features between malignancy and benignity with a five-point confidence scale. The diagnostic accuracy of BMUS and HF-CEUS for GB wall thickening was compared. The final gold standard was surgery with histological examination. Final diagnoses included GB adenocarcinoma (n = 16), adenomyomatosis (n = 12), Xanthogranulomatous (n = 2) and cholecystitis (n = 2). HF-CEUS features associated with GB adenocarcinoma including arterial phase inhomogeneous hyperenhancement, venous phase hypoenhancement and disruption of GB wall layer structure (P < 0.05). Two small (5 mm) liver metastasis were confirmed by HF-CEUS during the late phase liver sweep as hypoenhanced lesions. Nonenhanced Rokitansky-Aschoff sinuses were clearly observed in 83.3% focal adenomyomatosis. Overall sensitivity, specificity and accuracy for differentiation between malignant and benign focal fundal GB wall thickening of HF-CEUS and BMUS were 84.3% vs 53.1%, 90.6% vs 59.3% and 87.5% vs 56.2% (P < 0.005). CEUS performed with high frequency linear transducers could be a useful alternative in the differential diagnosis of focal fundal GB wall thickening on conventional ultrasound.


Alcohol consumption does not affect melatonin circadian synchronization in healthy men.
Alcohol intake alters melatonin secretion both in healthy volunteers and in alcoholics in a variety of different situations (while drinking, during or after withdrawal, and with neurological complications). This alteration may reduce secretion or affect its circadian rhythm, thus causing daytime secretion in some alcoholics. We sought to determine if daytime melatonin secretion is caused directly by acute alcohol consumption or if it instead indicates a change in circadian synchronization. Because alcohol consumption as it occurs in alcoholics (continuous consumption of large amounts) has never been examined in healthy volunteers, we exposed 11 healthy volunteers to 256 g of alcohol over 24 h to study the circadian profiles of melatonin secretion. Our results demonstrate a lack of daytime secretion in our subjects. This suggests that the disordered circadian melatonin secretion seen in alcoholics indicates a shift in melatonin secretion rather than an acute effect of alcohol on this secretion, or alternatively, that it is a direct effect of chronic rather than acute exposure to high blood alcohol levels.


[Gastric cancer with multiple liver metastases, which responded significantly to oral administration of TS-1 following intravenous FMP therapy under hospitalization].
TS-1, a novel oral formation of 5-fluorouracil that consists of 1 M tegafur (FT), 0.4 M gimeracil and 1 M otacil potassium, was reported to achieve a relatively high response rate of 49% in patients with advanced gastric cancer in a late phase II study. We report a case of inoperable gastric cancer with multiple liver metastases, which responded significantly to the short-term administration of TS-1 following intravenous FMP therapy. A 79-year-old man, who had nothing of note in his past or family history, presented with multiple liver tumors and type 3 gastric tumor. His diagnosis was inoperable gastric cancer with liver metastases, and he underwent outpatient treatment of oral administration of TS-1, following FMP therapy under hospitalization. The main and metastatic lesions shrunk dramatically with the two courses of the chemotherapy. There were no noticeable adverse effects. QOL has been maintained and the patient remains in good condition. TS-1 can be considered well-tolerable and quite effective for inoperable gastric cancer, especially if preceding therapy with 5-FU shows significant efficacy. TS-1 may therefore be a new candidate as a first line drug in outpatient cancer treatment.


Cloning, molecular characterization, and functional activity of Schistosoma japonicum glyceraldehyde-3-phosphate dehydrogenase, a putative vaccine candidate against schistosomiasis japonica.
We report the cloning, molecular characterization, and purification of functionally active recombinant glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the human bloodfluke Schistosoma japonicum. The GAPDH homolog from the related species Schistosoma mansoni has shown correlation of antibody titer to resistance to reinfection. A 1,164-bp cDNA (C1) was isolated from an S. japonicum lambda ZapII cDNA expression library immunoscreened with hyperimmune rabbit serum raised against soluble adult S. japonicum proteins. The open reading frame of C1 encodes a protein of 338 amino acids exhibiting 90% identity to the amino acid sequence of S. mansoni GAPDH. The inferred molecular mass of the protein is 36,589 daltons, and in vitro translation of the cDNA with [35S]methionine produced a radiolabelled band of the predicted size. Antibodies to C1 selected from hyperimmune rabbit serum by affinity purification recognized an S. japonicum protein doublet of 37 kDa but did not cross-react with a corresponding protein in S. mansoni extracts. The S. japonicum GADPH appears to be translated from a single mRNA encoded by a single-copy gene. After subcloning in the QIAexpress vector pQE-10 and subsequent expression, the recombinant protein was purified under nondenaturing conditions and shown to exhibit functional GAPDH enzymatic activity.


Emotion (Dys)regulation and Links to Depressive Disorders.
Clinical depression is a significant mental health problem that is associated with personal suffering and impaired functioning. These effects underscore the continuing need for new approaches that can inform researchers and clinicians when designing interventions. We propose that individual differences in the self-regulation of sadness and distress provide an important link between stress, depressed mood, and the onset of depressive disorder, and that if we have a better understanding of the ways children successfully manage negative emotions, we can better prevent and treat pediatric depression. In this article, we therefore examine the normative development of responses that children use to attenuate sadness, and aspects of the neurobiological infrastructure that both enable and constrain such self-regulatory efforts. We also address the emerging literature on affect regulation among children at familial risk for depressive disorders. We conclude that problems with adaptively self-regulating sadness and distress represent one pathway that can lead to juvenile-onset depression. And we need integrated, developmental studies of the psychosocial and neurobiological aspects of self-regulatory responses to sadness and distress in order to better understand this process, and to design age-sensitive intervention strategies for pediatric depression.


Management of renal dysfunction in the liver transplant recipient.
Acute and chronic kidney injury following orthotopic liver transplantation (OLT) is associated with increased morbidity and mortality. With the increasing longevity of liver transplant recipients, chronic kidney disease (CKD) has become an increasingly prevalent complication among long-term survivors. This article provides an overview of the literature on suggested risk factors for acute and CKD following OLT and a discussion of an approach to their medical management. In OLT candidates with pretransplant renal dysfunction, the use of interleukin-2 receptor blockers or antithymocyte globulin induction therapy in conjunction with delayed introduction of calcineurin inhibitors may preserve early renal function. In long-term stable OLT recipients with established calcineurin inhibitor nephrotoxicity, calcineurin inhibitor minimization or withdrawal protocols may halt or ameliorate renal dysfunction without compromising patient and graft survival. However, large-scale, multicenter, randomized controlled trials are still needed. The occurrence of acute kidney injury is common immediately after OLT, whereas the incidence of CKD and end-stage renal disease increases with time. Identifying patients at risk for acute kidney injury and CKD following OLT and early implementation of measures to preserve, halt, or ameliorate the progression of renal dysfunction should be an integral part in the management of OLT recipients.


The phase model of burnout: conceptual, theoretical, and practical issues.
This essay highlights major challenges and opportunities that highlight the products of over a decade of research and applications relying on the phase model. Nine points are developed, which rest upon progress with the phase model and also will further test the adequacy of the foundation it provides for more comprehensive work. To illustrate, the first of these points summarizes what we know with reasonable certainty, and what needs investigation, concerning cross-cultural replications; and a second point deals with the group locus of burnout. The relevance of this essay is substantial in the context of available research. Thus, the phase model isolates quite similar patterns of covariation in worldwide populations; and the phase operations also permit estimating what proportion of respondents have which degree of burnout, a capability beyond that of alternative operational definitions. Hence, the centrality of this effort to highlight sectors for further assessing the reliability and validity of the phase model.


Potential significance of CX3CR1 dynamics in stress resilience against neuronal disorders.
Recent findings have implicated inflammatory responses in the central nervous system in a variety of neuropsychiatric and neurodegenerative diseases, and the understanding and control of immunological responses could be a major factor of future therapeutic strategies for neurological disorders. Microglia, derived from myelogenous cells, respond to a number of stimuli and make immune responses, resulting in a prominent role as cells that act on inflammation in the central nervous system. Fractalkine (FKN or CX3CL1) signaling is an important factor that influences the inflammatory response of microglia. The receptor for FKN, CX3CR1, is usually expressed in microglia in the brain, and therefore the inflammatory response of microglia is modified by FKN. Reportedly, FKN often suppresses inflammatory responses in microglia and activation of its receptor may be effective in the treatment of inflammatory neurological disorders. However, it has also been suggested that inflammatory responses facilitated by FKN signaling aggravate neurological disorders. Thus, further studies are still required to resolve the conflicting interpretation of the protective or deleterious contribution of microglial FKN signaling. Yet notably, regulation of FKN signaling has recently been shown to be beneficial in the treatment of human diseases, although not neurological diseases. In addition, a CX3CR1 inhibitor has been developed and successfully tested in animal models, and it is expected to be in human clinical trials in the future. In this review, I describe the potential therapeutic consideration of microglial CX3CR1 dynamics through altered FKN signaling.


Lever holding under free-operant avoidance.
Rate of response under a free-operant avoidance procedure decreases as the response-shock interval increases. The present experiment demonstrated an inverse relation between rate of response and lever-holding time. An invariance was found in the total time per session that a subject was in contact with the lever. It is suggested that lever-holding behavior may be as sensitive as response rate to changes in the response-shock interval.