CB2-mediated attenuation of nucleus pulposus degeneration via the amelioration of inflammation and oxidative stress in vivo and in vitro.
Nucleus pulposus cell (NPC) degeneration is widely accepted as one of the major causes of intervertebral disc (IVD) degeneration (IVDD). The pathogenesis of IVDD is complex and consists of inflammation, oxidative stress, and the loss of extracellular matrix (ECM). Cannabinoid type 2 receptor (CB2) has been shown to be involved in the pathological mechanism of a variety of diseases due to its anti-inflammatory effects and antioxidative stress capacity. In Vitro, H2O2 was used to induce degeneration of nucleus pulposus cells, mRNA and protein expression level was determined by RT-PCR and Western Blot, and Immunocytochemical staining were used to detect expression of collagen II, aggrecan, MMP3/13, superoxide dismutase 2 (SOD2) and inducible nitric oxide synthase (iNOS). In vivo, the potential therapeutic effect of CB2 was detected in the rat acupuncture model. In vitro, we found that the CB2 agonist (JWH133) treatment reduced the oxidative stress level in NPCs induced by hydrogen peroxide (H2O2) treatment. Furthermore, the expression of inflammatory cytokines was also decreased by JWH133 treatment. We found that collagen II and aggrecan expression was preserved, whereas matrix metalloproteinase levels were reduced. In vivo, we established a rat model by needle puncture. Imaging assessment revealed that the disc height index (DHI) and morphology of IVD were significantly improved, and the disc degeneration process was delayed by treatment of JWH133. Furthermore, immunohistochemical (IHC) staining revealed that JWH133 could inhibit the degradation of collagen II and decrease the expression of MMP3. The experiment indicates the oxidative stress and inflammatory response of rat NPCs induced by H2O2 could be inhibited by activating CB2. This study reveals that CB2 activation can effectively delay the development of IVDD, providing an effective therapeutic target for IVDD.


Humans as geomorphic agents: Lidar detection of the past, present and future of the Teotihuacan Valley, Mexico.
As humans are the primary geomorphic agents on the landscape, it is essential to assess the magnitude, chronological span, and future effects of artificial ground that is expanding under modern urbanization at an alarming rate. We argue humans have been primary geomorphic agents of landscapes since the rise of early urbanism that continue to structure our everyday lives. Past and present anthropogenic actions mold a dynamic "taskscape" (not just a landscape) onto the physical environment. For example, one of the largest Pre-Columbian metropolitan centers of the New World, the UNESCO world heritage site of Teotihuacan, demonstrates how past anthropogenic actions continue to inform the modern taskscape, including modern street and land alignments. This paper applies a multi-scalar, long durée approach to urban landscapes utilizing the first lidar map of the Teotihuacan Valley to create a geospatial database that links modern and topographic features visible on the lidar map with ground survey, historic survey, and excavation data. Already, we have recorded not only new features previously unrecognized by historic surveys, but also the complete erasure of archaeological features due to modern (post-2015) mining operations. The lidar map database will continue to evolve with the dynamic landscape, able to assess continuity and changes on the Teotihuacan Valley, which can benefit decision makers contemplating the stewardship, transformation, or destruction of this heritage landscape.


Fast and exact Hessian computation for a class of nonlinear functions used in radiation therapy treatment planning.
In nonlinear optimisation, using exact Hessian computations (full-Newton) hold superior convergence properties over quasi-Newton methods or gradient-based methods. However, for medium-scale problems, computing the Hessian can be computationally expensive and thus time-consuming. For solvers dedicated to a specific problem type, it can be advantageous to hard-code optimised implementations to keep the computation time to a minimum. In this paper we derive a computationally efficient canonical form for a class of additively and multiplicatively separable functions. The major computational cost is reduced to a single multiplication of the data matrix with itself, allowing simple parallellisation on modern-day multi-core processors. We present the approach in the practical application of radiation therapy treatment planning, where this form appears for many common functions. In this case, the data matrices are the dose-influence matrices. The method is compared against automatic differentiation.


A strategy for controlling the marketing of tobacco products: a regulated market model.
To outline a novel strategy for controlling the tobacco market. More comprehensive controls over the tobacco market are essential and long overdue. Effective controls need to encourage the development of less harmful products; control commercial communication to ensure that potential harms are highlighted relative to any benefits; and provide mechanisms to move consumers away from tobacco use, or at least towards less harmful alternatives. Achieving this by regulating the existing industry is one strategy. This paper puts the case for an alternative: to have marketing controlled by an agency (called here the Tobacco Products Agency, or TPA) which tendered to manufacturers for product and which distributed to retailers in ways that reduce incentives to bend or break the law. The TPA would be backed by legislation that made tobacco a controlled substance with possession sale and use only allowed as permitted by the regulations, which in reality would be only as provided by the TPA. The overall effect of such a model, which we call a "regulated market model", would be to eliminate most of the incentives and remaining opportunities for commercial promotion of tobacco and to create incentives to encourage the development of less harmful tobacco products. Such a model preserves the competition inherent in a free market, but directs it towards the challenge of reducing the harm from tobacco use.


Effect of cerebral perfusion pressure on contusion volume following impact injury.
Although it is generally acknowledged that a sufficient cerebral perfusion pressure (CPP) is necessary for treatment of severe head injury, the optimum CPP is still a subject of debate. The purpose of this study was to investigate the effect of various levels of blood pressure and, thereby, CPP on posttraumatic contusion volume. The left hemispheres of 60 rats were subjected to controlled cortical impact injury (CCII). In one group of animals the mean arterial blood pressure (MABP) was lowered for 30 minutes to 80, 70, 60, 50, or 40 mm Hg 4 hours after contusion by using hypobaric hypotension. In another group of animals the MABP was elevated for 3 hours to 120 or 140 mm Hg 4 hours after contusion by administering dopamine. The MABP was not changed in respective control groups. Intracranial pressure (ICP) was monitored with an ICP microsensor. The rats were killed 28 hours after trauma occurred and contusion volume was assessed using hematoxylin and eosin-stained coronal slices. No significant change in contusion volume was caused by a decrease in MABP from 94 to 80 mm Hg (ICP 12+/-1 mm Hg), but a reduction of MABP to 70 mm Hg (ICP 9+/-1 mm Hg) significantly increased the contusion volume (p < 0.05). A further reduction of MABP led to an even more enlarged contusion volume. Although an elevation of MABP to 120 mm Hg (ICP 16+/-2 mm Hg) did not significantly affect contusion volume, there was a significant increase in the contusion volume at 140 mm Hg MABP (p < 0.05; ICP 18+/-1 mm Hg). Under these experimental conditions, CPP should be kept within 70 to 105 mm Hg to minimize posttraumatic contusion volume. A CPP of 60 mm Hg and lower as well as a CPP of 120 mm Hg and higher should be considered detrimental.


Components of the tumor immune microenvironment based on m-IHC correlate with prognosis and subtype of triple-negative breast cancer.
The spatial distribution and interactions of cells in the tumor immune microenvironment (TIME) might be related to the different responses of triple-negative breast cancer (TNBC) to immunomodulators. The potential of multiplex IHC (m-IHC) in evaluating the TIME has been reported, but the efficacy is insufficient. We aimed to research whether m-IHC results could be used to reflect the TIME, and thus to predict prognosis and complement the TNBC subtyping system. The clinical, imaging, and prognosis data for 86 TNBC patients were retrospectively reviewed. CD3, CD4, CD8, Foxp3, PD-L1, and Pan-CK markers were stained by m-IHC. Particular cell spatial distributions and interactions in the TIME were evaluated with the HALO multispectral analysis platform. Then, we calculated the prognostic value of components of the TIME and their correlations with TNBC transcriptomic subtypes and MRI radiomic features reflecting TNBC subtypes. The components of the TIME score were established by m-IHC and demonstrated positive prognostic value for TNBC (p = 0.0047, 0.039, <0.0001 for DMFS, RFS, and OS). The score was calculated from several indicators, including Treg% in the tumor core (TC) or stromal area (SA), PD-L1+ cell% in the SA, CD3 + cell% in the TC, and PD-L1+ /CD8+ cells in the invasive margin and SA. According to the TNBC subtyping system, a few TIME indicators were significantly different in different subtypes and significantly correlated with MRI radiomic features reflecting TNBC subtypes. We demonstrated that the m-IHC-based quantitative score and indicators related to the spatial distribution and interactions of cells in the TIME can aid in the accurate diagnosis of TNBC in terms of prognosis and classification.


Psychological distress, self-harm and suicide attempts in gender minority compared with cisgender adolescents in the UK.
Few population-based studies have compared the mental health of gender minority and cisgender adolescents. To compare reports of psychological distress, behavioural and emotional difficulties, self-harm and suicide attempts between gender minority and cisgender adolescents. Data came from the Millennium Cohort Study (n = 10 247), a large nationally representative birth cohort in the UK. At a 17-year follow-up, we assessed gender identity, psychological distress (Kessler K6 scale), behavioural and emotional difficulties (parent and child reports on the Strengths and Difficulties Questionnaire), self-harm in the previous year, suicide attempts, substance use, and victimisation including harassment and physical and sexual assaults. Multivariable modified Poisson and linear regression models were used. Attenuation after the inclusion of victimisation and substance use was used to explore mediation. Of the 10 247 participants, 113 (1.1%) reported that they were a gender minority. Gender minority participants reported more psychological distress (coefficient 5.81, 95% CI 4.87-6.74), behavioural and emotional difficulties (child report: coefficient 5.60; 95% CI 4.54-6.67; parent/carer report: coefficient 2.60; 95% CI 1.47-3.73), self-harm including cutting or stabbing (relative risk (RR) 4.38; 95% CI 3.55-5.40), burning (RR 3.81; 95% CI 2.49-5.82), taking an overdose (RR 5.25; 95% CI 3.35-8.23) and suicide attempts (RR 3.42; 95% CI 2.45-4.78) than cisgender youth. These associations were partially explained by differences in exposure to victimisation. Gender minority adolescents experience a disproportionate burden of mental health problems. Policies are needed to reduce victimisation and services should be adapted to better support the mental health of gender minority adolescents.


Bidirectional uncoating of the genomic RNA of a helical virus.
An essential step in the initiation of a virus infection is the release of the viral genome from the other constituents of the virus particle, a process referred to as uncoating. We have used reverse transcription and polymerase chain reaction amplification procedures to determine the rate and direction of in vivo uncoating of the rod-shaped tobacco mosaic virus. The virus particles contain a single 6.4-kb RNA molecule that lies between successive turns of a helical arrangement of coat protein subunits. When the particles are introduced into plant cells, the subunits are removed via a bidirectional uncoating mechanism. Within 2-3 min, the part of the viral RNA from the 5' end to a position >70% toward the 3' end has been freed of coat protein subunits. This is followed by removal of subunits from the 3' end of the RNA and sequential uncoating of the RNA in a 3'-to-5' direction. An internal region of the viral RNA is the final part to be uncoated. Progeny virus particles are detected in the cells 35-40 min after inoculation.


Naringin promotes osteogenesis and ameliorates osteoporosis development by targeting JAK2/STAT3 signalling.
Osteoporosis is a systemic bone metabolism disorder, which increases the risk of fractures, and in severe cases it may cause disability or even death. An important factor contributing to osteoporosis is the imbalance between bone formation and resorption. Naringin was reported to promote osteoblast differentiation, thus enhancing bone formation and alleviating osteoporosis development. However, the signalling pathways related to the regulatory mechanism of naringin in osteoporosis development are not clear. Proliferation of bone mesenchymal stem cells (BMSCs) treated with naringin in vitro was detected by CCK-8. An osteogenesis differentiation medium supplemented with naringin was applied to explore the effects of naringin on BMSC osteogenic differentiation, as detected by Alizarin red staining. Ovariectomy (OVX)-induced postmenopausal osteoporosis (PMOP) rats were orally administered with naringin. Dual-energy X-ray absorptiometry (DEXA) and micro-CT were applied to measure bone mineral density (BMD), bone volume/total volume (BV/TV), trabecula thickness (Tb.Th), trabecula number (Tb.N), trabecular separation (Tb.Sp) and bone surface/bone volume (BS/BV). H&E staining was performed to show pathological changes of the femur in PMOP rats after naringin treatment. Bone metabolism indicators were assessed by ELISA. We found that naringin suppressed the activation of the JAK2/STAT3 pathway. Naringin promoted BMSC proliferation and osteogenic differentiation. Furthermore, naringin alleviates bone loss and improves abnormal bone metabolism of PMOP rats. Collectively, naringin promotes BMSC osteogenic differentiation to ameliorate osteoporosis development by targeting JAK2/STAT3 signalling.


Advances in statistical methods for substance abuse prevention research.
The paper describes advances in statistical methods for prevention research with a particular focus on substance abuse prevention. Standard analysis methods are extended to the typical research designs and characteristics of the data collected in prevention research. Prevention research often includes longitudinal measurement, clustering of data in units such as schools or clinics, missing data, and categorical as well as continuous outcome variables. Statistical methods to handle these features of prevention data are outlined. Developments in mediation, moderation, and implementation analysis allow for the extraction of more detailed information from a prevention study. Advancements in the interpretation of prevention research results include more widespread calculation of effect size and statistical power, the use of confidence intervals as well as hypothesis testing, detailed causal analysis of research findings, and meta-analysis. The increased availability of statistical software has contributed greatly to the use of new methods in prevention research. It is likely that the Internet will continue to stimulate the development and application of new methods.


The role of TRPV6 in breast carcinogenesis.
TRPV6 is an endothelial calcium entry channel that is strongly expressed in breast adenocarcinoma tissue. In this study, we further confirmed this observation by analysis of breast cancer tissues, which indicated that TRPV6 mRNA expression was up-regulated between 2-fold and 15-fold compared with the average in normal breast tissue. Whereas TRPV6 is expressed in the cancer tissue, its role as a calcium channel in breast carcinogenesis is poorly understood. Therefore, we investigated how TRPV6 affects the viability, apoptosis, and calcium transport in the breast cancer cell line T47D. Hormones can also affect the tumor development; hence, we determined the effects of estradiol, progesterone, and 1,25-vitamin D on TRPV6 transcription. Interestingly, the estrogen receptor antagonist tamoxifen reduced expression of TRPV6 and is able to inhibit its calcium transport activity (IC(50), 7.5 micromol/L). The in vitro model showed that TRPV6 can be regulated by estrogen, progesterone, tamoxifen, and 1,25-vitamin D and has a large influence on breast cancer cell proliferation. Moreover, the effect of tamoxifen on cell viability was enhanced when TRPV6 expression was silenced with small interfering RNA. TRPV6 may be a novel target for the development of calcium channel inhibitors to treat breast adenocarcinoma expressing TRPV6.


[Analysis of mortality in perforated gastroduodenal ulcers].
Lethality from ruptured gastroduodenal ulcers in the Smolensk region in the period from 1976 till 1988 was analyzed. Operations were performed on 2222 patients, 76 of them died (3.42%). Reducing lethality should be based on timely planned operations for ulcer disease, prophylactics of ulcer formation, refuse of self-treatment, improvement of the professional level of workers of the first medical aid service and surgeons of primary links of public health, especially in questions of operative tactics, pre- and postoperative management of the patients.


The reaction pathway of membrane-bound rat liver mitochondrial monoamine oxidase.
1. A preparation of a partly purified mitochondrial outer-membrane fraction suitable for kinetic investigations of monoamine oxidase is described. 2. An apparatus suitable for varying the O(2) concentration in a spectrophotometer cuvette is described. 3. The reaction catalysed by the membrane-bound enzyme is shown to proceed by a double-displacement (Ping Pong) mechanism, and a formal mechanism is proposed. 4. KCN, NaN(3), benzyl cyanide and 4-cyanophenol are shown to be reversible inhibitors of the enzyme. 5. The non-linear reciprocal plot obtained with impure preparations of benzylamine, which is typical of high substrate inhibition, is shown to be due to aldehyde contamination of the substrate.


The Effectiveness of Stroke Riskometer™ in Improving Stroke Risk Awareness in Malaysia: A Study Protocol of a Cluster-Randomized Controlled Trial.
Stroke is considered the second leading cause of mortality and disability worldwide. The increasing burden of stroke is strong evidence that currently used primary prevention strategies are not sufficiently effective. The Stroke Riskometer™ application (app) represents a new stroke prevention strategy distinctly different from the conventional high-cardiovascular disease risk approach. This proposed study aims to evaluate the effectiveness of the Stroke Riskometer™ app in improving stroke awareness and stroke risk probability amongst the adult population in Malaysia. A non-blinded, parallel-group cluster-randomized controlled trial with a 1:1 allocation ratio will be implemented in Kelantan, Malaysia. Two groups with a sample size of 66 in each group will be recruited. The intervention group will be equipped with the Stroke Riskometer™ app and informational leaflets, while the control group will be provided with standard management, including information leaflets only. The Stroke Riskometer™ app was developed according to the self-management model of chronic diseases based on self-regulation and social cognitive theories. Data collection will be conducted at baseline and on the third week, sixth week, and sixth month follow-up via telephone interview or online questionnaire survey. The primary outcome measure is stroke risk awareness, including the domains of knowledge, perception, and intention to change. The secondary outcome measure is stroke risk probability within 5 and 10 years adjusted to each participant's socio-demographic and/or socio-economic status. An intention-to-treat approach will be used to evaluate these measures. Pearson's χ2 or independent t test will be used to examine differences between the intervention and control groups. The generalized estimating equation and the linear mixed-effects model will be employed to test the overall effectiveness of the intervention. This study will evaluate the effect of Stroke Riskometer™ app on stroke awareness and stroke probability and briefly evaluate participant engagement to a pre-specified trial protocol. The findings from this will inform physicians and public health professionals of the benefit of mobile technology intervention and encourage more active mobile phone-based disease prevention apps. ClinicalTrials.gov Identifier NCT04529681.


Gene characterization and promoter analysis of the human 5-lipoxygenase-activating protein (FLAP).
The human gene for the recently identified 5-lipoxy-genase-activating protein (FLAP) has been cloned. The gene was isolated from two different genomic libraries and is contained within four overlapping bacteriophage clones. The gene spans greater than 31 kilobases and consists of five small exons and four large introns. Southern blot analysis of human genomic DNA suggests the presence of a single FLAP gene per haploid genome. A restriction site polymorphism was identified in intron II of the gene. This restriction fragment length polymorphism appears to be present in the normal population at a fairly high frequency. The transcription initiation site was located, at an adenine residue, 74 base pairs upstream of the ATG initiation codon. Examination of the sequence of the gene 5' to the mRNA start site revealed the presence of a possible TATA box (TGTAAT) 22 base pairs upstream and potential AP-2 and glucocorticoid receptor binding sites. Functional analysis of the FLAP gene promoter was assayed by transient transfection of mouse P388D1 cells (macrophage) and human HepG2 cells (hepatoma) with 5'-flanking sequences of the FLAP gene fused upstream of the chloramphenicol acetyltransferase reporter gene. Expression in the mouse macrophage cell line of the various FLAP gene promoter constructs revealed both tissue specificity and enhancer-like activities whereas in the hepatoma cell line only a minimum level of activity was obtained.


Investigation of the Effect of Asthma on Mortality and Morbidity After Coronary Artery Bypass Surgery.
No studies have been specifically conducted on asthma patients undergoing cardiac surgery for assessing mortality and morbidity. Distinct effects of cardiac surgery lead to negative effects on respiratory functions, putting patients with existing lung diseases under an increased risk. We aimed to investigate whether asthma patients are under higher risk for mortality and possible complications after coronary artery bypass graft (CABG) surgery than patients without asthma. The study included patients who underwent elective CABG surgery at our hospital between November 2014 and November 2015. Patients with a history of asthma were verified with physical examination and spirometric measurements by a single. The asthma group was compared with the controls in terms of mortality and morbidities. Asthma patients were extubated later than control patients (p=0.028); however, prolonged intubation (longer than 24 h) frequency was not different (p>0.05). Asthma patients required longer stay in the intensive care unit (ICU) (p=0.003) than controls. The incidence of perioperative asthma exacerbations was significantly lower in patients in whom asthma was previously well-controlled. The incidence of postoperative sibilant rhonchi was lower in patients in whom asthma was under control than in those in whom asthma was partially controlled (p=0.020). Asthma is associated with longer ICU stay and asthma-related pulmonary complications after CABG surgery. Preoperative evaluation of asthma patients scheduled for CABG surgery requires consideration of the control status of asthma. Studies with more controls are needed to provide further evidence on the topic.


Activation of lipolysis by epinephrine and electrical stimulation in the perfused hindquarters of lean and obese-diabetic (db/db) mice.
The effects of epinephrine and electrical stimulation on lipolysis in the skeletal muscles of lean, and obese-diabetic (db/db) mice were studied using the perfused mouse hindquarter preparation. The rate of glycerol release from the obese mouse preparation was two times that of their lean littermates. Epinephrine sensitivity in the db/db mice was reduced only with respect to lipolytic activation, but was unaltered with respect to tissue cyclic AMP elevation and glycogen phosphorylase activation. Electrical stimulation caused a prompt increase in lactate production in both lean and obese mice and elevated glycerol release only in the obese mice. Glycerol release was also increased in the lean mice by stimulating at voltages exceeding 10 volts. Cyclic AMP levels were unaffected by electrical stimulation. Omission of calcium from the perfusion medium severely blunted lipolytic activation by electrical stimulation, which could be restored by calcium readdition. These results suggest that an impairment in lipolytic activation by epinephrine distal to activation of adenylate cyclase exists in the skeletal muscle of young db/db mice. Despite of this impairment, however, lipolysis in the obese mouse muscle was more sensitive to activation by electrical stimulation through a mechanism unrelated to changes in cyclic AMP, but is dependent on extracellular calcium.


Chlorella vulgaris modulates hydrogen peroxide-induced DNA damage and telomere shortening of human fibroblasts derived from different aged individuals.
The objective of this study was to investigate the modulatory effect of Chlorella vulgaris on cultured fibroblast cells derived from young and old aged individuals focusing on DNA damage, telomere length and telomerase activity. Dose-response test of the algal extract on cells in both age groups revealed that optimum viability was observed at a concentration of 50 microg/ml. Results obtained showed that Chlorella vulgaris exhibited protective effects against H(2)O(2)-induced oxidative stress as shown by the reduction in damaged DNA caused by H(2)O(2) treatment (p<0.05) in Chlorella vulgaris pre- and post-treated groups (p<0.05). Pre-treatment of Chlorella vulgaris resulted in a significant decrease in DNA damage suggesting a bioprotective effect against free radical attacks. A decline in DNA damage was observed in post-treated cells which proves Chlorella vulgaris to present bioremediative properties. In cells induced with oxidative stress, telomere length decreased significantly coupled with a concomitant decline of telomerase activity (p<0.05). However, these reductions were prevented with prior and post treatment of Chlorella vulgaris. Therefore, we concluded that Chlorella vulgaris exhibited bioprotective effects especially in cells obtained from young donor but were more bioremediative for cells obtained from old donor as indicated by DNA damage, telomere shortening and reduction in telomerase activity.


A 2D Photographic and 3D Digital Dental Model Analysis of Golden Percentage in Maxillary Anterior Teeth.
The objective of this paper was to evaluate the existence of golden percentage in natural maxillary anterior teeth with the aid of 3D digital dental models and 2D photographs. And to propose regional values of golden percentage for restoration of maxillary anterior teeth. For this purpose, one hundred and ninety dentate subjects with sound maxillary anterior teeth were selected. Standardized frontal images were captured with DSLR, and the apparent width of maxillary anterior teeth was measured utilizing a software on a personal laptop computer. Once the dimensions were recorded, the calculations were made according to the golden percentage theory (GPT). The data were analyzed by independent and paired T-test. The level of significance was set at p < 0.05. The golden percentage values were not found in this study. The values obtained were 16%, 15%, 20%, 20%, 15%, and 16% moving from the right canine to the left canine teeth. There was no significant gender difference in the golden percentage values. Thus, golden percentage should not be used solely for the correction of anterior teeth or for determining dental attractiveness. Emphasis should be given to a range of dental proportion on regional basis.


Correlations between COVID-19 cases and temperature, air humidity, and social isolating rate with cross wavelet transform and wavelet coherence: Case study of New York and São Paulo cities.
The COVID-19 pandemic originated in 2019 and has become an endemic disease that we must learn to live with, similar to other strains of influenza. The Organization (WHO) declared on May 5, 2023, in Geneva, Switzerland, the end of the Public Health Emergency of International Concern regarding COVID-19. As vaccines become more widely available and the pandemic appears to be improved, our focus shifts to the challenges we still face. Understanding how external factors like temperature, air humidity, and social isolation impact the spread of the SARS-CoV-2 virus remains a crucial challenge beyond our control. In this study, potential links between the number of COVID-19 cases in São Paulo City (SPC) and New York City (NWC) were explored. Our analysis was carried out utilizing the continuous wavelet transform, alongside other tools such as cross-wavelet transform and wavelet coherence. Based on our findings, there appears to be a correlation between the variables related to low frequencies, which aligns with previous research on the topic. Particularly, our research has revealed a connection between COVID-19 cases and factors such as temperature, air humidity, and social isolation rates. Regarding the latter, our findings indicate that implementing social distancing measures was a wise public policy decision, although the correlation with daily COVID-19 cases requires careful analysis. For this study, we analyzed data from February of 2020, when the first cases were reported in the cities under investigation, SPC and NWC, up until December 31, 2022, by which time the vaccination campaign was well under way.


"Betwixt Mine Eye and Heart a League Is Took": The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy.
The ultimate goal of precision disease modeling is to artificially recreate the disease of affected people in a highly controllable and adaptable external environment. This field has rapidly advanced which is evident from the application of patient-specific pluripotent stem-cell-derived precision therapies in numerous clinical trials aimed at a diverse set of diseases such as macular degeneration, heart disease, spinal cord injury, graft-versus-host disease, and muscular dystrophy. Despite the existence of semi-adequate treatments for tempering skeletal muscle degeneration in dystrophic patients, nonischemic cardiomyopathy remains one of the primary causes of death. Therefore, cardiovascular cells derived from muscular dystrophy patients' induced pluripotent stem cells are well suited to mimic dystrophin-associated cardiomyopathy and hold great promise for the development of future fully effective therapies. The purpose of this article is to convey the realities of employing precision disease models of dystrophin-associated cardiomyopathy. This is achieved by discussing, as suggested in the title echoing William Shakespeare's words, the settlements (or "leagues") made by researchers to manage the constraints ("betwixt mine eye and heart") distancing them from achieving a perfect precision disease model.


Relevant aspects of coronary artery disease in candidates for non-cardiac surgery.
Due to its prevalence, coronary artery disease (CAD) represents the main cause of morbidity and mortality in elective surgeries, which justifies this review, whose objective was to establish preoperative conducts based on rules and directive to minimize peri- and postoperative morbidity and mortality of patients with CAD. General characteristics of CAD, as well as its physiopathogenic mechanisms, the main variables related to preoperative care of patients with CAD, and the conducts for patients with greater surgical risk are presented. Patients with CAD who are candidates for non-cardiac surgeries should be evaluated judiciously. Those identified as being at high risk can benefit from preoperative myocardial ischemia-provoking tests, as well as from invasive coronary interventions preceding elective surgeries. In selected patients, one should consider the use of beta-blockers and statins.


Conditional disease-free survival after surgical resection of gastrointestinal stromal tumors: a multi-institutional analysis of 502 patients.
Gastrointestinal stromal tumors (GISTs) are the most commonly diagnosed mesenchymal tumors of the gastrointestinal tract. The risk of recurrence following surgical resection of GISTs is typically reported from the date of surgery. However, disease-free survival (DFS) over time is dynamic and changes based on disease-free time already accumulated following surgery. To assess the comparative performance of established GIST recurrence risk prognostic scoring systems and to characterize conditional DFS following surgical resection of GISTs. A retrospective cohort study of 502 patients who underwent surgery for a primary, nonmetastatic GIST between January 1, 1998, and December 31, 2012, at 7 major academic cancer centers in the United States and Canada. Disease-free survival of the patients was classified according to 5 prognostic scoring systems, including the National Institutes of Health criteria, modified National Institutes of Health criteria, Memorial Sloan Kettering Cancer Center GIST nomogram, and American Joint Committee on Cancer gastric and nongastric categories. The concordance index (also known as the C statistic or the area under the receiver operating curve) of established GIST recurrence risk prognostic scoring systems. Conditional DFS estimates were calculated. Overall 1-year, 3-year, and 5-year DFS following resection of GISTs was 95%, 83%, and 74%, respectively. All the prognostic scoring systems had fair prognostic ability. For all tumor sites, the American Joint Committee on Cancer gastric category demonstrated the best discrimination (C = 0.79). Using conditional DFS, the probability of remaining disease free for an additional 3 years given that a patient was disease free at 1 year, 3 years, and 5 years was 82%, 89%, and 92%, respectively. Patients with the highest initial recurrence risk demonstrated the greatest increase in conditional survival as time elapsed. Conditional DFS improves over time following resection of GISTs. This is valuable information about long-term prognosis to communicate to patients who are disease free after a period following surgery.


In vitro CNS tissue analogues formed by self-organisation of reaggregated post-natal brain tissue.
In this paper, we report the characterization of 'Hi-Spot' cultures formed by the re-aggregation of dissociated postnatal CNS tissue grown at an air-liquid interface. This produces a self-organised, dense, organotypic cellular network. Western blot, immunohistochemical, viral transfection and electron microscopy analyses reveal neuronal and glial populations, and the development of a synaptic network. Multi-electrode array recordings show synaptically driven network activity that develops through time from single unit spiking activity to global network bursting events. This activity is blocked by tetanus toxin and modified by antagonists of glutamatergic and GABAergic receptors suggesting tonic activity of excitatory and inhibitory synaptic signaling. The tissue-like properties of these cultures has been further demonstrated by their relative insensitivity to glutamate toxicity. Exposure to millimolar concentrations of glutamate for hours is necessary to produce significant excitotoxic neuronal death, as in vivo. We conclude that 'Hi-Spots' are biological analogues of CNS tissue at a level of complexity that allows for detailed functional analyses of emergent neuronal network properties.


Dynamics and energetics of solute permeation through the Plasmodium falciparum aquaglyceroporin.
The aquaglyceroporin from Plasmodium falciparum (PfAQP) is a potential drug target for the treatment of malaria. It efficiently conducts water and other small solutes, and is proposed to intervene in several crucial physiological processes during the parasitic life cycle. Despite the wealth of experimental data available, a dynamical and energetic description at the single-molecule level of the solute permeation through PfAQP has been lacking so far. Here we address this question by using equilibrium and umbrella sampling molecular dynamics simulations. We computed the water osmotic permeability coefficient, the pore geometry and the potential of mean force for the permeation of water, glycerol and urea. Our simulations show that the PfAQP, the human aquaporin 1 (hAQP1) and the Escherichia coli glycerol facilitator (GlpF) have nearly identical water permeabilities. The Arg196 residue at the ar/R region was found to play a crucial role regulating the permeation of water, glycerol and urea. The computed free energy barriers at the ar/R selectivity filter corroborate that PfAQP conducts glycerol at higher rates than urea, and suggest that PfAQP is a more efficient glycerol and urea channel than GlpF. Our results are consistent with a solute permeation mechanism for PfAQP which is similar to the one established for other members of the aquaglyceroporin family. In this mechanism, hydrophobic regions near the NPA motifs are the main water rate limiting barriers, and the replacement of water-arg196 interactions and solute-matching in the hydrophobic pocket at the ar/R region are the main determinants underlying selectivity for the permeation of solutes like glycerol and urea.


An evaluation of palliative care services for cancer patients in the Southern Health and Social Services Board of Northern Ireland.
An interview study of 55 lay carers of people who died from cancer in the Southern Board of Northern Ireland was undertaken using a combination of closed-format and open-ended questions. The aim of the study was to evaluate palliative care services delivered in the last six months of their lives to cancer patients who died either at home or in hospital. Two-thirds of the deaths (36) occurred in the domestic home, 45 of the deceased were admitted as hospital inpatients, and the great majority were in receipt of community nursing (53) and general practitioner (54) services. Open-ended questions were used to allow respondents to give their views about services in some detail and their views about good and bad aspects of services were sought. While they were generally satisfied with services specific areas of difficulty were identified in each aspect of care addressed by the study. The most favourable assessments were made of community nursing with the greatest number of negative comments being made about inpatient hospital care. Differing interests between some of those who were dying and their lay carers were found in two areas: the receipt of help from nonfamily members and the information that the deceased received about their terminal status.


Novel approaches to control of parasites—a workshop.
With the advent of helminth parasite populations that have developed resistance to anthelmintics over the last decade or so, especially in small ruminants, sustainable productivity has been threatened. This workshop on novel approaches to control was held at the 19th International Conference of the World Association for the Advancement of Veterinary Parasitology (WAAVP) at New Orleans,LA, USA, during 10–14 August 2003. The workshop was organized and chaired by J.E. Miller and P.J. Waller. Novel or alternative approaches to control have been the focus of research (basic and applied) in many parts of the world. The objective of the workshop was to discuss where we have been and what direction(s) appears to be viable for both the short and long term future. In the long term, all represented regions at the workshop have promulgated programs where breeding for resistance may be the best approach as genes for resistance can be fixed in host populations. However,it does take many years to achieve results and the question of tradeoff concerning alteration of production traits needs further evaluation. Vaccination, especially against Haemonchus contortus,has been a thrust of laboratories in Scotland and Australia where natural "hidden gut" antigens have shown promise, but recombinant products have yet to be developed. In Europe, North and South America, Australia, South Africa and Asia, biocontrol using the nematode-trapping fungus Duddingtonia flagrans has been shown to be effective under experimental conditions, but some field evaluations have been disappointing. Most recently, the FAMACHA system was developed in South Africa. This system is directly and immediately applicable to all regions where H. contortus is a problem. Although not a new or novel approach, copper-oxide wire particles have been revived as a means to control H. contortus.Work being done in Europe, North and South America,South Africa and Australia have shown very encouraging results and can probably be considered the best short term approach available. However, caution needs to be considered in sheep to avoid potential copper toxicity problems. Work in New Zealand, Scotland and the US with forages and feeds containing condensed tannins have shown some limited control. Many laboratories have demonstrated that adequate and balanced nutrition programs are also important to maintain mechanisms that combat infections. Overall, no one approach alone is the answer. Approaches that are integrated, including "smart" use of anthelmintics, are necessary.


Experimental evidence of momentum transport induced by an up-down asymmetric magnetic equilibrium in toroidal plasmas.
The first experimental evidence of parallel momentum transport generated by the up-down asymmetry of a toroidal plasma is reported. The experiments, conducted in the Tokamak à Configuration Variable, were motivated by the recent theoretical discovery of ion-scale turbulent momentum transport induced by an up-down asymmetry in the magnetic equilibrium. The toroidal rotation gradient is observed to depend on the asymmetry in the outer part of the plasma leading to a variation of the central rotation by a factor of 1.5-2. The direction of the effect and its magnitude are in agreement with theoretical predictions for the eight possible combinations of plasma asymmetry, current, and magnetic field.


Sex differences in mortality: results from a population-based study of 12 longitudinal cohorts.
Women generally have longer life expectancy than men but have higher levels of disability and morbidity. Few studies have identified factors that explain higher mortality in men. The aim of this study was to identify potential factors contributing to sex differences in mortality at older age and to investigate variation across countries. This study included participants age ≥ 50 yr from 28 countries in 12 cohort studies of the Ageing Trajectories of Health: Longitudinal Opportunities and Synergies (ATHLOS) consortium. Using a 2-step individual participant data meta-analysis framework, we applied Cox proportional hazards modelling to investigate the association between sex and mortality across different countries. We included socioeconomic (education, wealth), lifestyle (smoking, alcohol consumption), social (marital status, living alone) and health factors (cardiovascular disease, diabetes, mental disorders) as covariates or interaction terms with sex to test whether these factors contributed to the mortality gap between men and women. The study included 179 044 individuals. Men had 60% higher mortality risk than women after adjustment for age (pooled hazard ratio [HR] 1.6; 95% confidence interval 1.5-1.7), yet the effect sizes varied across countries (I 2 = 71.5%, HR range 1.1-2.4). Only smoking and cardiovascular diseases substantially attenuated the effect size (by about 22%). Lifestyle and health factors may partially account for excess mortality in men compared with women, but residual variation remains unaccounted for. Variation in the effect sizes across countries may indicate contextual factors contributing to gender inequality in specific settings.


Spatiotemporal links between meteorological and agricultural droughts impacted by tropical cyclones in China.
Both droughts and tropical cyclones (TCs) are among the world's most widespread natural disasters. This paper is concentrated on the effects of TCs on the links between meteorological droughts (MDs) and agricultural droughts (ADs). Specifically, changes in characteristics of drought events and variations in propagation features of matched MD and AD event pairs are quantified by using the renowned three-dimensional connected components algorithm; both alleviation and exacerbation effects of TCs are evaluated; and the Spearman's correlation is employed to identify potential contributors to exacerbated droughts after TCs. The results show that TCs exhibit more pronounced and widespread alleviation effects on MD events compared to AD events. >98 % of small-scale drought events are terminated by TCs, leading to 65 % reduction in the total area of MD events smaller than 50,000 km2 and 32 % reduction in AD events of the same scale. In the meantime, TCs can reshape the spatiotemporal links between MDs and ADs by reducing the overall propagation rate from 77 % to 40 % and ameliorating the characteristics of drought event pairs with higher propagation efficiency, by >40 %. After TCs, over 55 % of drought exacerbations in TC-affected regions occur first in the vicinity of the residual large-scale AD events. This occurrence is partially associated with the reduction in moisture exports from these residual droughts downwind to the interior of TC-affected regions, a process potentially facilitated by the TC-induced temperature lowering. The in-depth evaluation of this paper presents useful information for better drought preparation and mitigation under TCs.


Preterm and postterm birth in immigrant- and Swedish-born parents: a population register-based study.
Ethnic minorities/immigrant groups tend to have increased risk for preterm birth. Less is known about this risk in diverse immigrant groups, couples of mixed ethnic-origin and in relation to duration of residence. Data from the Swedish Medical Birth Register on 1,028,303 mothers who gave birth to 1,766,026 singleton live born infants (1982-2002), was linked to the Education and Total Population Registers. Immigrant parents were identified by country of birth. Risk of early preterm, late preterm and postterm birth was analyzed using multinomial logistic regression. Polish, Yugoslavian, Iranian, South Asian, East Asian and Sub-Saharan African parents, Swedish mothers who had children with non-Swedish fathers, and parents from two different immigrant groups had higher risk of early preterm birth [adjusted relative risk (RR) (95% CI) 1.76 (1.24-2.50), 1.57 (1.31-1.87), 1.67 (1.30-2.14), 1.52 (1.07-2.16), 1.51 (1.08-2.10), 2.03 (1.32-3.12), 1.56 (1.45-1.67), and 1.55 (1.35-1.77) respectively] compared to Swedish-born parents. South Asian, Sub-Saharan African, and East Asian immigrants had a higher risk of late preterm birth compared to Swedish-born parents. North African and Middle Eastern, Somali, and Ethiopian/Eritrean groups had increased risk of postterm birth [adjusted RR 1.31 (1.16-1.47), 2.57 (2.31-2.86), 1.85 (1.67-2.04) respectively]. Adjustment for covariates did not substantially change associations. Immigrant mothers resident <3 years had higher risk for early preterm and postterm birth compared to residents >10 years [adjusted RR 1.46 (1.24-1.71) and 1.16 (1.11-1.23) respectively]. In addition to higher risk of preterm birth in select immigrant groups, some immigrant groups are also at higher risk of postterm birth. Shorter duration of residence is associated with higher risk of non-term deliveries.


Aclacinomycin A stabilizes topoisomerase I covalent complexes.
Aclacinomycin A (aclarubicin) is an anthracycline anticancer agent with demonstrated activity against both leukemias and solid tumors. Previous results suggested that a major activity of aclacinomycin A is the inhibition of topoisomerase II catalytic activity. We have applied a yeast system to test whether aclacinomycin A is a topoisomerase II inhibitor in vivo and to test whether we could identify other important targets of this drug. We have found that overexpression of yeast topoisomerase II confers resistance to aclacinomycin A in yeast, consistent with the hypothesis that this drug is a catalytic inhibitor of topoisomerase II. Interestingly, we have also found that in yeast, aclacinomycin A, like camptothecin, stabilizes topoisomerase I cleavage. We carried out biochemical analysis with purified human topoisomerase I and demonstrated that this drug efficiently stabilizes topoisomerase I covalent complexes, indicating that aclacinomycin A represents a novel class of combined topoisomerase I/II inhibitor.


Conditional lethality of recA and recB derivatives of a strain of Escherichia coli K-12 with a temperature-sensitive deoxyribonucleic acid polymerase I.
We have isolated a strain of Escherichia coli K-12 carrying a mutation, polA12, that results in the synthesis of a temperature-sensitive deoxyribonucleic acid (DNA) polymerase I. The double mutants polA12 recA56 and polA12 recB21, constructed at 30 C, are inviable at 42 C. About 90% of the cells of both double mutants die after 2 hr of incubation at 42 C. Both double mutants filament at 42 C and show a dependence on high cell density for growth at 30 C. In polA12 recB21 cells at 42 C, DNA and protein synthesis gradually stop in parallel. In polA12 recA56 cells, DNA synthesis continues for at least 1 hr at 42 C, and there is extensive DNA degradation. The results suggest that the primary lesion in these double mutants is not in DNA replication per se.


Eye Can Hear Clearly Now: Inverse Effectiveness in Natural Audiovisual Speech Processing Relies on Long-Term Crossmodal Temporal Integration.
Speech comprehension is improved by viewing a speaker's face, especially in adverse hearing conditions, a principle known as inverse effectiveness. However, the neural mechanisms that help to optimize how we integrate auditory and visual speech in such suboptimal conversational environments are not yet fully understood. Using human EEG recordings, we examined how visual speech enhances the cortical representation of auditory speech at a signal-to-noise ratio that maximized the perceptual benefit conferred by multisensory processing relative to unisensory processing. We found that the influence of visual input on the neural tracking of the audio speech signal was significantly greater in noisy than in quiet listening conditions, consistent with the principle of inverse effectiveness. Although envelope tracking during audio-only speech was greatly reduced by background noise at an early processing stage, it was markedly restored by the addition of visual speech input. In background noise, multisensory integration occurred at much lower frequencies and was shown to predict the multisensory gain in behavioral performance at a time lag of ∼250 ms. Critically, we demonstrated that inverse effectiveness, in the context of natural audiovisual (AV) speech processing, relies on crossmodal integration over long temporal windows. Our findings suggest that disparate integration mechanisms contribute to the efficient processing of AV speech in background noise. The behavioral benefit of seeing a speaker's face during conversation is especially pronounced in challenging listening environments. However, the neural mechanisms underlying this phenomenon, known as inverse effectiveness, have not yet been established. Here, we examine this in the human brain using natural speech-in-noise stimuli that were designed specifically to maximize the behavioral benefit of audiovisual (AV) speech. We find that this benefit arises from our ability to integrate multimodal information over longer periods of time. Our data also suggest that the addition of visual speech restores early tracking of the acoustic speech signal during excessive background noise. These findings support and extend current mechanistic perspectives on AV speech perception.


[Determination of the eosinophil count in nasal mucus. Comparison of 2 techniques].
We compared swab and scraping (Rhino-probe) technics in the nasal cytology obtention for eosinophils count in 36 patients with a range of 2-46 years old (mean age 18.6 years) with diagnosis of Allergic Rhinitis. The eosinophil count with swab technic was between 0-79 cells with average of 6.5 cells and in the scraping (Rhino-probe) was in a rate of 0-100 cells with a average of 13.4 cells. Of the 36 patients with Rhinitis seen at our clinic, 13 (36%) of positive with swab and 19 (53%) with scraping technics (Rhino-probe) with percent differential of 17%. The comparison between the eosinophils count with both technics was p less than 0.05 for scraping (Rhino-probe) technic.


Modulation of N-methyl-D-aspartate receptors by donepezil in rat cortical neurons.
Nicotinic acetylcholine receptors and N-methyl-D-aspartate (NMDA) receptors are known to be down-regulated in the brain of patients with Alzheimer's disease. It was previously shown that the nootropic drugs nefiracetam and galantamine potentiate the activity of both nicotinic and NMDA receptors. We hypothesized that donepezil, a nootropic with a potent anticholinesterase activity, might also affect the NMDA system. NMDA-induced currents were recorded from rat cortical neurons in primary culture using the whole-cell patch-clamp technique at a holding potential of -70 mV in Mg2+-free solutions. In multipolar neurons, NMDA currents were decreased by bath and U-tube applications of 1 to 10 microM donepezil but were increased by 30 to 100 microM donepezil. Donepezil suppression occurred in a manner independent of NMDA concentrations ranging from 3 to 1000 microM. The donepezil suppression of NMDA currents was prevented by inhibition of protein kinase C (PKC) but unaffected by protein kinase A (PKA) and G proteins. In bipolar neurons, however, NMDA currents were potently augmented by bath and U-tube applications of 0.01 to 100 microM donepezil. Donepezil potentiation occurred at high NMDA concentrations that evoked the saturating responses and in a manner independent of NMDA concentrations ranging from 3 to 1000 microM. The potentiation of NMDA currents by donepezil was decreased by inhibition of PKC and abolished by modulation of G proteins but not by PKA inhibition. It was concluded that donepezil at low therapeutic concentrations (0.01-1 microM) potentiated the activity of the NMDA system and that this action together with cholinesterase inhibition would contribute to the improvement of learning, memory, and cognition in patients with Alzheimer's disease.


Key genetic elements, single and in clusters, underlying geographically dependent SARS-CoV-2 genetic adaptation and their impact on binding affinity for drugs and immune control.
To define key genetic elements, single or in clusters, underlying SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) evolutionary diversification across continents, and their impact on drug-binding affinity and viral antigenicity. A total of 12 150 SARS-CoV-2 sequences (publicly available) from 69 countries were analysed. Mutational clusters were assessed by hierarchical clustering. Structure-based virtual screening (SBVS) was used to select the best inhibitors of 3-chymotrypsin-like protease (3CL-Pr) and RNA-dependent RNA polymerase (RdRp) among the FDA-approved drugs and to evaluate the impact of mutations on binding affinity of these drugs. The impact of mutations on epitope recognition was predicted following Grifoni et al. (Cell Host Microbe 2020. 671-80.). Thirty-five key mutations were identified (prevalence: ≥0.5%), residing in different viral proteins. Sixteen out of 35 formed tight clusters involving multiple SARS-CoV-2 proteins, highlighting intergenic co-evolution. Some clusters (including D614GSpike + P323LRdRp + R203KN + G204RN) occurred in all continents, while others showed a geographically restricted circulation (T1198KPL-Pr + P13LN + A97VRdRp in Asia, L84SORF-8 + S197LN in Europe, Y541CHel + H504CHel + L84SORF-8 in America and Oceania). SBVS identified 20 best RdRp inhibitors and 21 best 3CL-Pr inhibitors belonging to different drug classes. Notably, mutations in RdRp or 3CL-Pr modulate, positively or negatively, the binding affinity of these drugs. Among them, P323LRdRp (prevalence: 61.9%) reduced the binding affinity of specific compounds including remdesivir while it increased the binding affinity of the purine analogues penciclovir and tenofovir, suggesting potential hypersusceptibility. Finally, specific mutations (including Y541CHel + H504CHel) strongly hampered recognition of Class I/II epitopes, while D614GSpike profoundly altered the structural stability of a recently identified B cell epitope target of neutralizing antibodies (amino acids 592-620). Key genetic elements reflect geographically dependent SARS-CoV-2 genetic adaptation, and may play a potential role in modulating drug susceptibility and hampering viral antigenicity. Thus, a close monitoring of SARS-CoV-2 mutational patterns is crucial to ensure the effectiveness of treatments and vaccines worldwide.


The Social Brain and Emotional Contagion: COVID-19 Effects.
Coronavirus disease 2019 (COVID-19) is a highly contagious infectious disease, responsible for a global pandemic that began in January 2020. Human/COVID-19 interactions cause different outcomes ranging from minor health consequences to death. Since social interaction is the default mode by which individuals communicate with their surroundings, different modes of contagion can play a role in determining the long-term consequences for mental health and emotional well-being. We examined some basic aspects of human social interaction, emphasizing some particular features of the emotional contagion. Moreover, we analyzed the main report that described brain damage related to the COVID-19 infection. Indeed, the goal of this review is to suggest a possible explanation for the relationships among emotionally impaired people, brain damage, and COVID-19 infection. COVID-19 can cause several significant neurological disorders and the pandemic has been linked to a rise in people reporting mental health problems, such as depression and anxiety. Neurocognitive symptoms associated with COVID-19 include delirium, both acute and chronic attention and memory impairment related to hippocampal and cortical damage, as well as learning deficits in both adults and children. Although our knowledge on the biology and long-term clinical outcomes of the COVID-19 infection is largely limited, approaching the pandemic based on lessons learnt from previous outbreaks of infectious diseases and the biology of other coronaviruses will provide a suitable pathway for developing public mental health strategies, which could be positively translated into therapeutic approaches, attempting to improve stress coping responses, thus contributing to alleviate the burden driven by the pandemic.


Carpal tunnel syndrome with thenar atrophy: evaluation of the pinch and grip strength in patients undergoing surgical treatment.
This aim of this study was to evaluate the progression of grip, tip pinch, key (lateral) pinch, and tripod pinch strengths in patients suffering from carpal tunnel syndrome with thenar atrophy following surgery. Between October 2008 and May 2010, 46 patients (49 hands) with carpal tunnel syndrome associated with thenar atrophy underwent surgery. Thenar atrophy was assessed by clinical inspection. Evaluations for grip strength and for tip, key, and tripod pinch strengths were made using a hydraulic hand dynamometer grip and a hydraulic pinch gauge, respectively. These measurements were taken before surgery and at 3 and 6 months after the procedure. When we compared the averages of all forces measured in the affected hand before the surgery with all forces measured at 3 months postoperative, we found no significant differences. However, after 6 months, we found significant differences for all four strength tests as compared with those measurements taken preoperatively and at the 3 month time point. Our results suggest that patients with thenar atrophy show increased grip strength and pinch strength by the sixth month after surgical treatment.


Genetic variants in the PIWI-piRNA pathway gene DCP1A predict melanoma disease-specific survival.
The Piwi-piRNA pathway is important for germ cell maintenance, genome integrity, DNA methylation and retrotransposon control and thus may be involved in cancer development. In this study, we comprehensively analyzed prognostic roles of 3,116 common SNPs in PIWI-piRNA pathway genes in melanoma disease-specific survival. A published genome-wide association study (GWAS) by The University of Texas M.D. Anderson Cancer Center was used to identify associated SNPs, which were later validated by another GWAS from the Harvard Nurses' Health Study and Health Professionals Follow-up Study. After multiple testing correction, we found that there were 27 common SNPs in two genes (PIWIL4 and DCP1A) with false discovery rate < 0.2 in the discovery dataset. Three tagSNPs (i.e., rs7933369 and rs508485 in PIWIL4; rs11551405 in DCP1A) were replicated. The rs11551405 A allele, located at the 3' UTR microRNA binding site of DCP1A, was associated with an increased risk of melanoma disease-specific death in both discovery dataset [adjusted Hazards ratio (HR) = 1.66, 95% confidence interval (CI) = 1.21-2.27, p =1.50 × 10-3 ] and validation dataset (HR = 1.55, 95% CI = 1.03-2.34, p = 0.038), compared with the C allele, and their meta-analysis showed an HR of 1.62 (95% CI, 1.26-2.08, p =1.55 × 10-4 ). Using RNA-seq data from the 1000 Genomes Project, we found that DCP1A mRNA expression levels increased significantly with the A allele number of rs11551405. Additional large, prospective studies are needed to validate these findings.


Low incidence of X-chromatin in congenital hypothyroidism.
Buccal smears of 5 female patients with hypothyroidism (3 with congenital hypothyroidism or cretinism and 2 with acquired type) were studied for X-chromatin. Very low incidence of X-chromatin positive cells (1.33%, 1.59% and 2.06%) was found in all the three cases with cretinism while the incidence was the same (15.0% and 15.61%) as in the control females (15.5%), in 2 cases with acquired hypothyroidism. Chromosome studies were carried out in two cases of cretinism. They had a normal karyotype, 46 XX.


Signatures of evanescent transport in ballistic suspended graphene-superconductor junctions.
In Dirac materials, the low energy excitations behave like ultra-relativistic massless particles with linear energy dispersion. A particularly intriguing phenomenon arises with the intrinsic charge transport behavior at the Dirac point where the charge density approaches zero. In graphene, a 2-D Dirac fermion gas system, it was predicted that charge transport near the Dirac point is carried by evanescent modes, resulting in unconventional "pseudo-diffusive" charge transport even in the absence of disorder. In the past decade, experimental observation of this phenomenon remained challenging due to the presence of strong disorder in graphene devices which limits the accessibility of the low carrier density regime close enough to the Dirac point. Here we report transport measurements on ballistic suspended graphene-Niobium Josephson weak links that demonstrate a transition from ballistic to pseudo-diffusive like evanescent transport below a carrier density of ~10(10) cm(-2). Approaching the Dirac point, the sub-harmonic gap structures due to multiple Andreev reflections display a strong Fermi energy-dependence and become increasingly pronounced, while the normalized excess current through the superconductor-graphene interface decreases sharply. Our observations are in qualitative agreement with the long standing theoretical prediction for the emergence of evanescent transport mediated pseudo-diffusive transport in graphene.


The Microbial Tryptophan Metabolite Contributes to the Remission of Salmonella typhimurium Infection in Mice.
Salmonella enterica serovar Typhimurium (S. Tm) causes severe foodborne diseases. Interestingly, gut microbial tryptophan (Trp) metabolism plays a pivotal role in such infections by a yet unknown mechanism. This study aimed to explore the impact of Trp metabolism on S. Tm infection and the possible mechanisms involved. S. Tm-infected C57BL6/J mice were used to demonstrate the therapeutic benefits of the Bacillus velezensis JT3-1 (B. velezensis/JT3-1) strain or its cell-free supernatant in enhancing Trp metabolism. Targeted Trp metabolomic analyses indicated the predominance of indole-3-lactic acid (ILA), an indole derivative and ligand for aryl hydrocarbon receptor (AHR). Based on the 16S amplicon sequencing and correlation analysis of metabolites, we found that B. velezensis supported the relative abundance of Lactobacillus and Ligilactobacillus in mouse gut and showed positive correlations with ILA levels. Moreover, AHR and its downstream genes (especially IL-22) significantly increased in mouse colons after B. velezensis or cell-free supernatant treatment, suggesting the importance of AHR pathway activation. In addition, ILA was found to stimulate primary mouse macrophages to secrete IL-22, which was antagonized by CH-223191. Furthermore, ILA could protect mice from S. Tm infection by increasing IL-22 in Ahr+/- mice, but not in Ahr-/- mice. Finally, Trp-rich feeding showed amelioration of S. Tm infection in mice, and the effect depended on gut microbiota. Taken together, these results suggest that B. velezensis-associated ILA contributes to protecting mice against S. Tm infection by activating the AHR/IL-22 pathway. This study provides insights into the involvement of microbiota-derived Trp catabolites in protecting against Salmonella infection.


[Adenocarcinoma of prostate in men younger than 50--rectal palpation mandatory with micturition problems].
In three men, aged 44, 47, and 48 years, prostatic carcinoma was diagnosed after a long delay, more than eight months after the onset of symptoms (obstructive and irritative micturition problems, erectile dysfunction, and haemospermia). The cancer was suspected on eventually performed rectal palpation and confirmed in biopsies. The serum prostate-specific antigen (PSA) levels were moderately increased. All were treated with goserelin and flutamide and radiotherapy on the emerging metastases (two patients). Two patients died, the third one, who had received antibiotic treatment for three months because at first prostatitis was suspected, was still in remission at the last follow up. Prostate cancer in young men is rare and may demonstrate aggressive biological behaviour. The age group less than 50 years of age accounts for 0.8% to 1.1% of all patients with prostate cancer. This form of the disease responds poorly to radiation or hormonal therapy and is often already too advanced for surgery. The symptoms at presentation of prostate cancer in young men are quite similar to those in prostate cancer patients beyond the fifth decade. When carcinoma grows beyond the margins of the prostate the prognosis is poor. In all men with micturition problems, rectal palpation of the prostate should be carried out as a routine.


Sulfuretin protects hepatic cells through regulation of ROS levels and autophagic flux.
Palmitate (PA) exposure induces stress conditions featuring ROS accumulation and upregulation of p62 expression, resulting in autophagic flux blockage and cell apoptosis. Sulfuretin (Sul) is a natural product isolated from Rhus verniciflua Stokes; the cytoprotective effect of Sul on human hepatic L02 cells and mouse primary hepatocytes under PA-induced stress conditions was investigated in this study. Sul induced mitophagy by activation of p-TBK1 and LC3 and produced a concomitant decline in p62 expression. Autophagosome formation and mitophagy were assessed by the sensitive dual fluorescence reporter mCherry-EGFP-LC3B, and mitochondrial fragmentation was analyzed using MitoTracker Deep Red FM. A preliminary structure-activity relationship (SAR) for Sul was also investigated, and the phenolic hydroxyl group was found to be pivotal for maintaining the cytoprotective bioactivity of Sul. Furthermore, experiments using flow cytometry and western blots revealed that Sul reversed the cytotoxic effect stimulated by the autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ), and its cytoprotective effect was almost eliminated when the autophagy-related 5 (Atg5) gene was knocked down. These studies suggest that, in addition to its antioxidative effects, Sul stimulates mitophagy and restores impaired autophagic flux, thus protecting hepatic cells from apoptosis, and that Sul has potential future medical applications for hepatoprotection.


Immunogenicity of pneumococcal vaccination in renal transplant recipients and hemodialysis patients: a comparative controlled trial.
The objectives of this study were: to assess and compare the antibody responses of renal allograft recipients and dialysis patients to pneumococcal vaccination. 14 stable dialysis patients as well as 37 kidney transplant recipients were eligible for inclusion in this trial. Participated patients receive a single 0.5-mL of 23-valent vaccine Pneumovax administered intramuscularly in the upper extremities. The efficacy of vaccination was evaluated by measuring the antibody response to the whole vaccine. Sera were obtained prior to vaccination and 4 weeks, 6 months and 1 year after the vaccination. Prior to vaccination, mean IgG and IgG2 titers were equivalent in Dx and KTx patients (p>0.1 in both). Four weeks after vaccination, 49 out of 51 participated patients (96%) represented an increase in their anti pneumococcal IgG levels (mean 99+/-66) compared to 48 out of 51 (94%) for month 6 (mean 90+/-59), and 38 out of 45 (85%) for the first year after vaccination (mean 73+/-69). KTx patients kept significantly more serum IgG2 levels at months 6 and 12 after vaccination (p=0.001, p=0.03, respectively; Table 1). Mean IgG values for month 6 was 9+/-41 units lesser than month 1 post vaccination serum IgG levels. We found that patients with renal failure on hemodialysis and kidney transplantation well respond to immunization by anti pneumococcal vaccination. But, they rapidly loss their serum antibody levels during the one year after vaccination. Specifying protective levels for serum IgG and IgG2 levels in these patients would help us to more precisely follow these patients and to consider a revaccination when they failed to save the protective serum antibody level.


Clonidine ameliorates Gilles de la Tourette syndrome.
Gilles de la Tourette syndrome (TS) is a severe, familial neuropsychiatric disorder of childhood onset that is characterized by multiform motor, phonic, behavioral, and psychological symptoms. Clonidine hydrochloride, a centrally active alpha-adrenergic agonist, was observed to ameliorate the disorder in the majority of 25 patients who could not tolerate or did not benefit from treatment with haloperidol. Clonidine had a gradual onset of action. Compulsive behavior, frustration intolerance, speech difficulties, behavioral blocking, attentional problems, and tics were responsive to treatment. The noradrenergic system may be involved, primarily or secondarily, in the expression of the genetic predisposition to TS. These observations will require testing by suitably controlled efficacy studies.


Influence of periodontal health on probing depth and bleeding tendency.
This study investigates the effect of initial treatment on 1) probing force related to probing depth, 2) the attachment level, 3) the position of the gingival margin and 4) the clinical signs of color and change of contour of the gingiva in relation to the bleeding tendency of a pocket. It also addresses the question of whether, in deep inflamed periodontal pockets, the tip of the probe is located at the attachment level when a probing force of 0.75N is used, as has already been shown in pockets related to noninflamed gingival margins. Four different probing forces are used: 0.15N, 0.25N, 0.50N and 0.75N and results show an increasing probing depth with an increasing probing force, both before and after treatment. Initial treatment results in a decrease of mean probing depth but the change is dependent on the applied probing force. The mean probing depth reduction decreased from 1.71 mm (assessed with 0.15N) to 1.24 mm (assessed with 0.75N). Since results from this and a previous study indicate that both before and after treatment the tip of the probe is located at the attachment level when a probing force of 0.75N is used, it may be postulated that the reduction of mean probe-tip level measurements (= probing depth measurement from a fixed point) reflects a degree of connective tissue reattachment. Patients in the initial treatment study were selected on the basis of obvious redness and swelling of the gingiva. After treatment, both of these symptoms almost disappear, whereas the Periodontal Pocket Bleeding Index (P.P.B.I.) decreases only from 0.87 before treatment, to 0.45 after treatment.


Loss-of-function mutations in the human ortholog of Chlamydomonas reinhardtii ODA7 disrupt dynein arm assembly and cause primary ciliary dyskinesia.
Cilia and flagella are evolutionarily conserved structures that play various physiological roles in diverse cell types. Defects in motile cilia result in primary ciliary dyskinesia (PCD), the most prominent ciliopathy, characterized by the association of respiratory symptoms, male infertility, and, in nearly 50% of cases, situs inversus. So far, most identified disease-causing mutations involve genes encoding various ciliary components, such those belonging to the dynein arms that are essential for ciliary motion. Following a candidate-gene approach based on data from a mutant strain of the biflagellated alga Chlamydomonas reinhardtii carrying an ODA7 defect, we identified four families with a PCD phenotype characterized by the absence of both dynein arms and loss-of-function mutations in the human orthologous gene called LRRC50. Functional analyses performed in Chlamydomonas reinhardtii and in another flagellated protist, Trypanosoma brucei, support a key role for LRRC50, a member of the leucine-rich-repeat superfamily, in cytoplasmic preassembly of dynein arms.


The effects of alcohol on rat placenta.
In this study, daily food and water consumption and body weights, histopathology of placenta, tenascin (TN), type IV collagen and EGF and its receptor immunolocalization in the placenta of albino rats treated with two doses of alcohol (1 and 5 g kg(-1) day(-1)) were determined. Alcohol was administered in three different periods i.e. the whole 4 weeks before the pregnancy, during the pregnancy, and during the 4 weeks before the pregnancy plus pregnancy itself. The samples of placenta obtained from control and treated rats on days 10, 12, 14, 16, 18, 20 and 21 of gestation were evaluated morphologically and fixed for histology and immunohistochemistry. Some differences in food and water consumption between the groups were determined. The placental weight, especially in the groups receiving 1 and 5 g kg(-1) day(-1) alcohol during the pregnancy, showed increases. The changes in placental histology such as increases in the number and the size of trophoblastic giant cells, cytoplasmic dissolution and nuclear polymorphism, degenerations in spongiotrophoblasts, hyperemia at the basal zone and labyrinth, hyperplasia at the labyrinth and irregular vascularization were seen particularly in the groups receiving alcohol during the pregnancy, and during the 4 weeks before the pregnancy plus pregnancy itself. Increases in the immunolocalization of TN and type IV collagen and decreases in the immunolocalization of EGF and EGFR in the placentas of alcohol-receiving rats were found. In conclusion, ethanol treatment during pregnancy in rats affected placentation and the immunolocalization of TN, type IV collagen, EGF and EGFR in the placentas.


Estimating the effect size of surgery to improve walking in children with cerebral palsy from retrospective observational clinical data.
Single-event multilevel surgery (SEMLS) is a standard treatment approach aimed at improving gait for patients with cerebral palsy, but the effect of this approach compared to natural progression without surgical intervention is unclear. In this study, we used retrospective patient history, physical exam, and three-dimensional gait analysis data from 2,333 limbs to build regression models estimating the effect of SEMLS on gait, while controlling for expected natural progression. Post-hoc classifications using the regression model results identified which limbs would exhibit gait within two standard deviations of typical gait at the follow-up visit with or without a SEMLS with 73% and 77% accuracy, respectively. Using these models, we found that, while surgery was expected to have a positive effect on 93% of limbs compared to natural progression, in only 37% of limbs was this expected effect a clinically meaningful improvement. We identified 26% of the non-surgically treated limbs that may have shown a clinically meaningful improvement in gait had they received surgery. Our models suggest that pre-operative physical therapy focused on improving biomechanical characteristics, such as walking speed and strength, may improve likelihood of positive surgical outcomes. These models are shared with the community to use as an evaluation tool when considering whether or not a patient should undergo a SEMLS.


Fractional flow reserve in acute coronary syndromes and in stable ischemic heart disease: clinical implications.
Fractional Flow Reserve (FFR) in Stable Ischemic Heart Disease (SIHD) is universally accepted, while in Acute Coronary Syndromes (ACS) is less established. Aims of this retrospective study were: to compare in patients undergoing FFR assessment the prognostic impact of ACS vs SIHD, to evaluate the clinical relevance of the modality of utilization and timing of FFR assessment and to assess the different outcomes associated with an FFR> or ≤0.80. Major cardiac adverse events were assessed at a follow up of 16.4 ± 10.5 months in 543 patients with SIHD and 231 with ACS needing functional evaluation. FFR was used for lesions of ambiguous significance in the absence of a clear culprit vessel (first intention, FI) and for incidental lesions in the presence of a clear culprit vessel (second intention, SI). The decision to perform FFR and the identification of the stenosis needing functional assessment were left to the operator's discretion. Revascularization was performed when FFR was ≤0.80. SIHD and ACS patients were not significantly different for principal clinical characteristics. ACS patients had significantly more events than SIHD, due to an excess of death and myocardial infarction. This was confirmed when FFR was used as FI, in particular if FFR was >0.80. On the contrary, when FFR was used as SI, event rates were similar between ACS and SIHD patients, regardless of FFR value. Our study shows that using FFR the risk of recurrent events in ACS is significantly higher than in SIHD. This different outcome is confined to those patients in whom FFR is utilized for lesions of ambiguous significance in the absence of a clear culprit vessel.


Exploring the impact of a transdiagnostic cognitive behavioural therapy-based intervention on a group of Malaysian adolescents with problematic drug use and emotional problems.
Adolescents with problematic substance use frequently have anxiety and depression and tend to have "unhealthy" lifestyle such as having poor dietary patterns and physical inactivity. The overall aim of the present study was to explore the impact of a Transdiagnostic Cognitive Behavioral Therapy-based Intervention ("Super Skills for Life" - adolescent version; SSL-A) on emotional problems among adolescents with problematic substance use and to identify demographic factors which influence the intervention outcomes. A total of 108 adolescents (M = 16.30 years, SD = 1.6) with problematic substance use who showed high levels of anxiety and depression participated in this study. They completed a set of questionnaires to measure substance use, mental health problems, cognitive emotion regulation strategies, loneliness, and lifestyle and habits at pre- and post-intervention. The adolescents reported less emotional symptoms and more prosocial behavior after the intervention. These adolescents were also consumed less substance and used less maladaptive emotion regulation strategies after participating in SSL-A. Females compared to males showed more treatment gains (i.e., reduction in loneliness and improvement in psychological health and self-esteem) after the intervention. This study provides empirical evidence for the utility of the SSL-A in reducing emotional problems and substance use among adolescents with problematic substance use.


Distribution of heavy metals in agricultural soils near a petrochemical complex in Guangzhou, China.
The aim of the study was to investigate influence of an industrialized environment on the accumulation of heavy metals in agricultural soils. Seventy soil samples collected from surface layers (0-20 cm) and horizons of five selected pedons in the vicinity area of petrochemical complex in Guangzhou, China were analyzed for Zn, Cu, Pb, Cd, Hg and As concentrations, the horizontal and vertical variation of these metals were studied and geographic information system (GIS)-based mapping techniques were applied to generate spatial distribution maps. The mean concentrations of these heavy metals in the topsoils did not exceed the maximum allowable concentrations in agricultural soil of China with the exception of Hg. Significant differences between land-use types showed that Cu, Pb, Cd, Hg and As concentrations in topsoils were strongly influenced by agricultural practices and soil management. Within a radius of 1,300 m there were no marked decreasing trends for these element concentrations (except for Zn) with the increase of distance from the complex boundary, which reflected little influence of petroleum air emission on soil heavy metal accumulation. Concentrations of Zn, Cu, Pb, Cd, Hg and As in the five pedons, particularly in cultivated vegetable field and orchard, decreased with soil depth, indicating these elements mainly originated from anthropogenic sources. GIS mapping was a useful tool for evaluating spatial variability of heavy metals in the affected soil. The spatial distribution maps allowed the identification of hot-spot areas with high metal concentration. Effective measures should be taken to avoid or minimize heavy metal further contamination of soils and to remediate the contaminated areas in order to prevent pollutants affecting human health through agricultural products.


Genotoxic Stress-Induced Senescence.
A cell's genomic integrity is at risk when DNA-damaging stress, evoked by mitogenic oncogenes or genotoxic treatment modalities such as radiation or chemotherapy, apply. If the DNA repair machinery fails to fix the damaged site during a temporary cell-cycle arrest, or if massive genotoxic stress overwhelmed the repair capacity, cellular failsafe programs such as apoptosis or senescence will be triggered to limit aberrant propagation of these damaged and potentially harmful cells. After decades of scientific focusing on apoptosis, cellular senescence is increasingly recognized as an equally important but biologically and fundamentally different type of ultimate cell-cycle exit program, because of its lastingly persistent nature and cell-intrinsic and extrinsic roles within the tissue and tumor microenvironment. We established primary apoptosis-compromised, Bcl2-expressing Eμ-myc transgenic mouse lymphomas as a versatile and clinically relevant model system to study therapy-induced senescence (TIS). Given the lack of a single specific senescence-defining marker, we previously exploited co-staining of senescence-associated β-galactosidase (SA-β-gal) activity with immunohistochemical detection of trimethylated histone H3 lysine 9 (H3K9me3), an established S-phase gene expression-controlling, repressive chromatin mark, and the proliferation marker Ki67. This biomarker panel is instrumental to characterize cells as senescent via their high SA-β-gal activity, strong nuclear H3K9me3 expression and Ki67-negative profile. In this chapter, we demonstrate the detection of viable senescent cells by novel methods based on a fluorescent version of the SA-β-gal (fSA-β-gal) assay, combined with immuno-fluoroscence staining of H3K9me3 or Ki67, or analysis of the DNA replication status by incorporating 5-ethynyl-2'-deoxyuridine (EdU) detection into the protocol. Notably, while most senescence markers, irrespective of their specificity and sensitivity, may only be assessed in endpoint assays, we would like to emphasize here the strength of viable fSA-β-gal to track single-cell fate in senescent populations over time.


Perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: clinicopathologic and immunohistochemical characterization of 16 cases.
Perivascular epithelioid cell tumor (PEComa) belongs to a family of tumors characterized by coexpression of melanocytic and muscle markers. Recent studies have shown that sporadic and tuberous sclerosis complex-associated PEComa may respond to mTOR inhibitors underscoring the importance of recognizing this tumor. However, its occurrence in the gynecologic tract continues to be disputed owing to its common misclassification as other types of uterine sarcoma and its controversial relationship with epithelioid smooth muscle tumors. To more fully characterize PEComa of the female genital tract, 16 cases of gynecologic PEComa were identified (1990 to 2012) and formed the basis of this study. Each case was analyzed for conventional morphologic and immunohistochemical characteristics established for PEComa of extrauterine sites; clinical outcome data were obtained for all cases. The 16 patients were aged 28 to 60 (mean 49; median 50) years, and 1 had a history of tuberous sclerosis complex. Thirteen cases were primary of the uterus, 2 of the adnexa, and 1 of the vagina. Tumor size ranged from 0.3 to 25.0 (mean 8.7) cm. Three patients died of disease, 6 were alive with disease, and 7 were alive without evidence of disease at last follow-up (1 mo to 13 y follow-up; mean 26 mo). All patients with an adverse outcome met established criteria for malignancy as proposed for extrauterine sites (ie, 2 or more features present: size ≥5 cm, high-grade nuclear features, infiltration, necrosis, lymphovascular invasion, or a mitotic rate ≥1/50 high-power fields). Of the melanocytic markers, HMB45 was most commonly expressed (16/16 positive, 100%), followed by microphthalmia transcription factor (11/12 positive, 92%), MelanA (14/16 positive, 88%), and S100 protein (2/10 positive, 20%). Of the smooth muscle markers, desmin was most commonly expressed (15/15 cases, 100%), followed by SMA (14/15 cases, 93%) and h-caldesmon (11/12 cases, 92%). TFE3 immunopositivity was identified in 5 of 13 cases; however, 3 tested cases were negative for a TFE3 rearrangement by fluorescence in situ hybridization. Current criteria for malignancy appear to be valid in the female genital tract, although modified criteria, as described herein, may be more specific. Awareness of the characteristic features of PEComa is important to help distinguish it from epithelioid smooth muscle tumors and other mimics as PEComa may respond to unique chemotherapeutic regimens.


Renal Function Assessment During Peptide Receptor Radionuclide Therapy.
Theranostics labeled with Y-90 or Lu-177 are highly efficient therapeutic approaches for the systemic treatment of various cancers including neuroendocrine tumors and prostate cancer. Peptide receptor radionuclide therapy (PRRT) has been used for many years for metastatic or inoperable neuroendocrine tumors. However, renal and hematopoietic toxicities are the major limitations for this therapeutic approach. Kidneys have been considered as the "critical organ" because of the predominant glomerular filtration, tubular reabsorption by the proximal tubules, and interstitial retention of the tracers. Severe nephrotoxity, which has been classified as grade 4-5 based on the "Common Terminology Criteria on Adverse Events," was reported in the range from 0%-14%. There are several risk factors for renal toxicity; patient-related risk factors include older age, preexisting renal disease, hypertension, diabetes mellitus, previous nephrotoxic chemotherapy, metastatic lesions close to renal parenchyma, and single kidney. There are also treatment-related issues, such as choice of radionuclide, cumulative radiation dose to kidneys, renal radiation dose per cycle, activity administered, number of cycles, and time interval between cycles. In the literature, nephrotoxicity caused by PRRT was documented using different criteria and renal function tests, from serum creatinine level to more accurate and sophisticated methods. Generally, serum creatinine level was used as a measure of kidney function. Glomerular filtration rate (GFR) estimation based on serum creatinine was preferred by several authors. Most commonly used formulas for estimation of GFR are "Modifications of Diet in Renal Disease" (MDRD) equation and "Cockcroft-Gault" formulas. However, more precise methods than creatinine or creatinine clearance are recommended to assess renal function, such as GFR measurements using Tc-99m-diethylenetriaminepentaacetic acid (DTPA), Cr-51-ethylenediaminetetraacetic acid (EDTA), or measurement of Tc-99m-MAG3 clearance, particularly in patients with preexisting risk factors for long-term nephrotoxicity. Proximal tubular reabsorption and interstitial retention of tracers result in excessive renal irradiation. Coinfusion of positively charged amino acids, such as l-lysine and l-arginine, is recommended to decrease the renal retention of the tracers by inhibiting the proximal tubular reabsorption. Furthermore, nephrotoxicity may be reduced by dose fractionation. Patient-specific dosimetric studies showed that renal biological effective dose of <0Gy was safe for patients without any risk factors. A renal threshold value <28Gy was recommended for patients with risk factors. Despite kidney protection, renal function impairment can occur after PRRT, especially in patients with risk factors and high single or cumulative renal absorbed dose. Therefore, patient-specific dosimetry may be helpful in minimizing the renal absorbed dose while maximizing the tumor dose. In addition, close and accurate renal function monitoring using more precise methods, rather than plasma creatinine levels, is essential to diagnose the early renal functional changes and to follow-up the renal function during the treatment.


Design, Implementation and Evaluation of an Indoor Navigation System for Visually Impaired People.
Indoor navigation is a challenging task for visually impaired people. Although there are guidance systems available for such purposes, they have some drawbacks that hamper their direct application in real-life situations. These systems are either too complex, inaccurate, or require very special conditions (i.e., rare in everyday life) to operate. In this regard, Ultra-Wideband (UWB) technology has been shown to be effective for indoor positioning, providing a high level of accuracy and low installation complexity. This paper presents SUGAR, an indoor navigation system for visually impaired people which uses UWB for positioning, a spatial database of the environment for pathfinding through the application of the A* algorithm, and a guidance module. The interaction with the user takes place using acoustic signals and voice commands played through headphones. The suitability of the system for indoor navigation has been verified by means of a functional and usable prototype through a field test with a blind person. In addition, other tests have been conducted in order to show the accuracy of different relevant parts of the system.


Beta-adrenergic activity and conformation of the antihypertensive specific alpha 2-agonist drug, guanabenz.
In recent research a new series of specific drugs, one of which is guanabenz (GBZ, 2,6(dichlorobenzyliden)-aminoguanidine) has been introduced into the clinical treatment of centrally mediated hypertension. Guanabenz (GBZ) is considered to be among the most specific alpha 2-adrenergic agonists, acting similarly to clonidine by decreasing the sympathetic outflow from the brain to the peripheral circulatory system. In the present report we show that GBZ displays a significant affinity for beta-adrenoceptors. In displacement studies of the iodinated beta-antagonist [125I]cyanopindolol (CYP) from turkey erythrocyte membranes, the dissociation constant of GBZ was 3.8 microM. Inhibition of the (-) epinephrine induced adenylate cyclase activity by GBZ is competitive, with an apparent dissociation constant of 30 microM. A similar value was obtained by studies of GBZ's effect on the (-) epinephrine-induced [3H]cAMP accumulation in intact turkey erythrocytes. In view of its unexpected affinity for beta-adrenoceptors, we examined the three-dimensional structure of crystalline GBZ. In these studies substantial differences between clonidine and GBZ were observed, despite their strong structural resemblance. These dissimilarities (angle of rotation phi = 39.7 degrees as compared to 76 degrees in clonidine, and the rotational restriction of clonidine as compared to the greater mobility in rotation of GBZ) could explain the difference of specificity between these two compounds.


Canine Neutrophil Extracellular Traps Enhance Clot Formation and Delay Lysis.
Autoimmune diseases increase the risk of thrombosis. Neutrophil extracellular traps (NETs) are webs of DNA and protein that may mediate thrombosis in autoimmune diseases. Human and murine studies show NET-releasing neutrophils within a thrombus promote its growth, but it is unclear to what extent NET fragments released into circulation during inflammation are prothrombotic. This study hypothesized that canine NETs promote clot formation and impair lysis even in the absence of neutrophils. NETs were prepared from PMA-stimulated neutrophils and added to fibrinogen and thrombin or to recalcified pooled canine platelet-poor plasma, tissue factor, and tissue plasminogen activator. Clot formation and lysis were measured spectrophotometrically. NETs did not alter fibrin clot formation, but NETs increased maximum clot formation velocity ( P = .001) and delayed lysis ( P = .009) of plasma clots compared with supernatants from nonstimulated neutrophils. DNase digestion of NETs reduced their effect on clot lysis but not maximum clot formation velocity. This suggested impaired lysis was principally mediated by DNA within NETs but that NET proteins were principally responsible for increased speed of clot formation. Previous reports suggested elastase or histones might be responsible for the effect of NETs on clot formation. Elastase activity was greatly reduced by plasma, and addition of histones to plasma did not increase formation velocity, suggesting these proteins were not responsible for increasing maximum formation velocity. This study showed that NETs enhanced clot formation and impaired clot lysis in canine platelet-poor plasma. These in vitro findings suggest both NET proteins and DNA may contribute to thrombosis in inflammatory disease.


Orthodontic treatment for the adult periodontal patient.
The purpose of this article is to outline a method of orthodontic treatment for adult patients, particularly those with periodontal disease. The rationale for recommending orthodontics to these patients is discussed, with an emphasis on periodontal and occlusal management during treatment. Methods of using orthodontics to improve the periodontal status of adult patients are also demonstrated. Finally, there is a brief discussion on retention, and age considerations, as well as the obligations of both dentists and patients.


Is country of birth a risk factor for acute hospitalization for cardiovascular disease in Victoria, Australia?
International mortality studies show that some subgroups of migrants have a higher risk of Cardiovascular Disease (CVD) than the native-born. To investigate whether country of birth increases the risk for acute myocardial infarction (AMI) and cerebral infarction (stroke) hospitalization in Victoria, Australia. A retrospective analysis of Victorian AMI (ICD-10-AM codes I21 and I22) and stroke (ICD-10-AM I63 and I64) discharges from routinely collected hospital data in 2001-2002 was conducted. The outcome measures were directly age standardized rate ratios (RRs) of AMI and stroke hospitalization, calculated using 2001 Australian census data, with the Australian-born as the reference group. Males from 4 ethnic groups--USSR/Baltic; Southern Asia; Middle East; and Eastern Europe, displayed higher risk for AMI hospitalization than Australian-born men, whereas males and females from Southeast Asia and Northeast Asia were at lower risk. Furthermore, males from Western Europe and females from the Pacific were also at lower risk. Females from the Middle East, Southern Asia, and Southern Europe were at higher risk of stroke hospitalization than Australian-born women; in contrast, males from Eastern Europe, NorthAsia, Southern Asia, Southern Europe, and the United Kingdom and Ireland were at lower risk. Risk for AMI and stroke hospitalization varies by country of birth in comparison with the Australian-born population. It will be import to identify the factors associated with these varying risks in order to target preventive strategies aimed at reducing risk of AMI and stroke.