Doxycycline Reduces Scar Thickness and Improves Collagen Architecture.
To investigate the effects of local doxycycline administration on skin scarring. Skin scarring represents a major source of morbidity for surgical patients. Doxycycline, a tetracycline antibiotic with off-target effects on the extracellular matrix, has demonstrated antifibrotic effects in multiple organs. However, doxycycline's potential effects on skin scarring have not been explored in vivo. Female C57BL/6J mice underwent dorsal wounding following an established splinted excisional skin wounding model. Doxycycline was administered by local injection into the wound base following injury. Wounds were harvested upon complete wound closure (postoperative day 15) for histological examination and biomechanical testing of scar tissue. A one-time dose of 3.90 mM doxycycline (2 mg/mL) within 12 hours of injury was found to significantly reduce scar thickness by 24.8% (P < 0.0001) without compromising tensile strength. The same effect could not be achieved by oral dosing. In doxycycline-treated scar matrices, collagen I content was significantly reduced (P = 0.0317) and fibers were favorably arranged with significantly increased fiber randomness (P = 0.0115). Common culprits of altered wound healing mechanics, including angiogenesis and inflammation, were not impacted by doxycycline treatment. However, engrailed1 profibrotic fibroblasts, responsible for scar extracellular matrix deposition, were significantly reduced with doxycycline treatment (P = 0.0005). Due to the substantial improvement in skin scarring and well-established clinical safety profile, locally administered doxycycline represents a promising vulnerary agent. As such, we favor rapid translation to human patients as an antiscarring therapy.


End-monomer Dynamics in Semiflexible Polymers.
Spurred by an experimental controversy in the literature, we investigate the end-monomer dynamics of semiflexible polymers through Brownian hydrodynamic simulations and dynamic mean-field theory. Precise experimental observations over the last few years of end-monomer dynamics in the diffusion of double-stranded DNA have given conflicting results: one study indicated an unexpected Rouse-like scaling of the mean squared displacement (MSD) 〈r(2)(t)〉 ~ t(1/2) at intermediate times, corresponding to fluctuations at length scales larger than the persistence length but smaller than the coil size; another study claimed the more conventional Zimm scaling 〈r(2)(t)〉 ~ t(2/3) in the same time range. Using hydrodynamic simulations, analytical and scaling theories, we find a novel intermediate dynamical regime where the effective local exponent of the end-monomer MSD, α(t) = d log〈r(2)(t)〉/d log t, drops below the Zimm value of 2/3 for sufficiently long chains. The deviation from the Zimm prediction increases with chain length, though it does not reach the Rouse limit of 1/2. The qualitative features of this intermediate regime, found in simulations and in an improved mean-field theory for semiflexible polymers, in particular the variation of α(t) with chain and persistence lengths, can be reproduced through a heuristic scaling argument. Anomalously low values of the effective exponent α are explained by hydrodynamic effects related to the slow crossover from dynamics on length scales smaller than the persistence length to dynamics on larger length scales.


Humectant permeability influences growth and compatible solute uptake by Staphylococcus aureus subjected to osmotic stress.
The effects of different humectants (sodium chloride, sucrose, and glycerol) on the growth of and compatible solute (glycine betaine, proline, and carnitine) uptake by the osmotolerant foodborne pathogen Staphylococcus aureus were investigated. While growth in the presence of the impermeant humectants sodium chloride and sucrose induced the accumulation of proline and glycine betaine by cells, growth in the presence of the permeant humectant glycerol did not. When compatible solutes were omitted from low-water-activity media, growth was very poor in the presence of impermeant humectants. In contrast, the addition of compatible solutes had essentially no effect on growth when cells were grown in low-water-activity media containing glycerol as the humectant. Carnitine was found to accumulate to high intracellular levels in osmotically stressed cells when proline and glycine betaine were absent, making it a potentially important compatible solute for this organism.


Internal AU-rich elements modulate activity of two competing 3' splice sites in plant nuclei.
In vivo analyses using an autonomously replicating Agrobacterium/geminivirus vector have enabled identification of AU-rich intronic elements critical for 5' and 3' splice site selection in dicot plant nuclei and development of a model for pre-mRNA intron recognition in plant nuclei. To determine the minimal length, spacing and nucleotide compositions constraining recognition of the 3' boundary of an intron, two or four nucleotide substitutions have been introduced into the two AU-rich elements located between 50 and 66 nucleotides upstream from the 3' splice site of maize Adh1 intron 3. In each case tested, substitutions in the distal left element (-62 to -66) inactivate the downstream 3' splice site at -1 more effectively than substitutions in the proximal right element (-50 to -55). Guanosine or cytosine substitutions in either element reduce recognition of the -1 site significantly; adenosine substitutions have a less severe effect. Mutations in both of these AU elements additively block recognition of the downstream 3' splice site. The strong additive effect of these mutations supports a model in which short sets of AU islands bind interactive factors and cooperatively modulate usage of the downstream splice site. In contrast to the uridine requirements documented for the 3' terminus of plant introns, adenosines are partially interchangeable with uridines within this internal region of the intron.


A theory for learning based on rigid bodies dynamics.
A new learning theory derived from the study of the dynamics of an abstract system of masses, moving in a multidimensional space under an external force field, is presented. The set of equations describing system's dynamics may be directly interpreted as a learning algorithm for neural layers. Relevant properties of the proposed learning theory are discussed within the paper, along with results of computer simulations performed in order to assess its effectiveness in applied fields.


The predictive value of microbiological findings on teeth, internal and external implant portions in clinical decision making.
The primary aim of this study was to evaluate 23 pathogens associated with peri-implantitis at inner part of implant connections, in peri-implant and periodontal pockets between patients suffering peri-implantitis and participants with healthy peri-implant tissues; the secondary aim was to estimate the predictive value of microbiological profile in patients wearing dental implants using data mining methods. Fifty participants included in the present case─control study were scheduled for collection of plaque samples from the peri-implant pockets, internal connection, and periodontal pocket. Real-time polymerase chain reaction was performed to quantify 23 pathogens. Three predictive models were developed using C4.5 decision trees to estimate the predictive value of microbiological profile between three experimental sites. The final sample included 47 patients (22 healthy controls and 25 diseased cases), 90 implants (43 with healthy peri-implant tissues and 47 affected by peri-implantitis). Total and mean pathogen counts at inner portions of the implant connection, in peri-implant and periodontal pockets were generally increased in peri-implantitis patients when compared to healthy controls. The inner portion of the implant connection, the periodontal pocket and peri-implant pocket, respectively, presented a predictive value of microbiologic profile of 82.78%, 94.31%, and 97.5% of accuracy. This study showed that microbiological profile at all three experimental sites is differently characterized between patients suffering peri-implantitis and healthy controls. Data mining analysis identified Parvimonas micra as a highly accurate predictor of peri-implantitis when present in peri-implant pocket while this method generally seems to be promising for diagnosis of such complex infections.


Are elderly people with co-morbidities involved adequately in medical decision making when hospitalised? A cross-sectional survey.
Medical decision making has long been in focus, but little is known of the preferences and conditions for elderly people with co-morbidities to participate in medical decision making. The main objective of the present study was to investigate the preferred and the actual degree of control, i.e. the role elderly people with co-morbidities wish to assume and actually had with regard to information and participation in medical decision making during their last stay in hospital.This study was a cross-sectional survey including three Swedish hospitals with acute admittance. The participants were patients aged 75 years and above with three or more diagnoses according to the International Classification of Diseases (ICD-10) and three or more hospitalisations during the last year. We used a questionnaire combined with a telephone interview, using the Control Preference Scale to measure each participant's preferred and actual role in medical decision making during their last stay in hospital. Additional questions were asked about barriers to participation in decision making and preferred information seeking role. The results are presented with descriptive statistics with kappa weights. Of the 297 elderly patients identified, 52.5% responded (n = 156, 46.5% male). Mean age was 83.1 years. Of the respondents, 42 of 153 patients said that they were not asked for their opinion (i.e. no shared decision making). Among the other 111 patients, 49 had their exact preferred level of participation, 37 had less participation than they would have preferred, and 23 had more responsibility than they would have preferred. Kappa statistics showed a moderate agreement between preferred and actual role (κw = 0.57; 95% CI: 0.45-0.69). Most patients wanted to be given more information without having to ask. There was no correlation between age, gender, or education and preferred role. 35% of the patients agreed that they experienced some of the various barriers to decision making that they were asked about: 1) the severity of their illness, 2) doctors with different treatment strategies, 3) difficulty understanding the medical information, and 4) difficulty understanding doctors who did not speak the patient's own language. Physicians are not fully responsive to patient preferences regarding either the degree of communication or the patient's participation in decision making. Barriers to participation can be a problem, and should be taken into account more often when dealing with hospitalised elderly people.


Proximity-Based Emergency Response Communities for Patients With Allergies Who Are at Risk of Anaphylaxis: Clustering Analysis and Scenario-Based Survey Study.
Anaphylaxis is a potentially fatal allergic reaction. However, many patients at risk of anaphylaxis who should permanently carry a life-saving epinephrine auto injector (EAI) do not carry one at the moment of allergen exposure. The proximity-based emergency response communities (ERC) strategy suggests speeding EAI delivery by alerting patient-peers carrying EAI to respond and give their EAI to a nearby patient in need. This study had two objectives: (1) to analyze 10,000 anaphylactic events from the European Anaphylaxis Registry (EAR) by elicitor and location in order to determine typical anaphylactic scenarios and (2) to identify patients' behavioral and spatial factors influencing their response to ERC emergency requests through a scenario-based survey. Data were collected and analyzed in two phases: (1) clustering 10,000 EAR records by elicitor and incident location and (2) conducting a two-center scenario-based survey of adults and parents of minors with severe allergy who were prescribed EAI, in Israel and Germany. Each group received a four-part survey that examined the effect of two behavioral constructs-shared identity and diffusion of responsibility-and two spatial factors-emergency time and emergency location-in addition to sociodemographic data. We performed descriptive, linear correlation, analysis of variance, and t tests to identify patients' decision factors in responding to ERC alerts. A total of 53.1% of EAR cases were triggered by food at patients' home, and 46.9% of them were triggered by venom at parks. Further, 126 Israeli and 121 German participants completed the survey and met the inclusion criteria. Of the Israeli participants, 80% were parents of minor patients with a risk of anaphylaxis due to food allergy; their mean age was 32 years, and 67% were women. In addition, 20% were adult patients with a mean age of 21 years, and 48% were female. Among the German patients, 121 were adults, with an average age of 47 years, and 63% were women. In addition, 21% were allergic to food, 75% were allergic to venom, and 2% had drug allergies. The overall willingness to respond to ERC events was high. Shared identity and the willingness to respond were positively correlated (r=0.51, P<.001) in the parent group. Parents had a stronger sense of shared identity than adult patients (t243= -9.077, P<.001). The bystander effect decreased the willingness of all patients, except the parent group, to respond (F1,269=28.27, P<.001). An interaction between location and time of emergency (F1,473=77.304, P<.001) revealed lower levels of willingness to respond in strange locations during nighttime. An ERC allergy app has the potential to improve outcomes in case of anaphylactic events, but this is dependent on patient-peers' willingness to respond. Through a two-stage process, our study identified the behavioral and spatial factors that could influence the willingness to respond, providing a basis for future research of proximity-based mental health communities.


Condom use among male migrant workers in dry zone, Myanmar.
To study the factors associated with condom use among male Myanmar migrant workers in Pakokku, Myanmar This cross-sectional study used two stages cluster sampling with probability proportional to size (PPS) method to collect samples. During 1-14 February 2010, 324 male Myanmar migrant workers between 18 and 60 years of age were asked to complete face-to-face structured interview on knowledge, perception, cues to action, peer influence and sexual behaviors. Data were analyzed by descriptive statistics, Chi-square test and Fishers exact test. Results revealed that 71.0 percent of respondents were under young and middle adult age and 66.7 percent were married. It showed that 11.1 percent of the respondents used condom regularly with spouse or girlfriends or sex workers during the past year There were associations between age (p = 0.006), marital status (p < 0.001), educational level (p = 0.014), monthly income (p = 0.015), level of knowledge on HIV/AIDS (p = 0.017), perceived susceptibility of getting HIV/ AIDS (p = 0.024) and condom use. No associations were noted between occupation, duration of career; duration of each trip, perceived severity, perceived benefit, perceived barrier, cues to action, peer influence and condom use. With low proportion of regular condom use among study group, behavior change, communication interventions and strengthening of the 100.0% Targeted Condom Promotion Project are recommended to promote perception and knowledge about HIV/AIDS and condom use among male migrant workers.


Loss of olfactory cell adhesion molecule reduces the synchrony of mitral cell activity in olfactory glomeruli.
Odours generate activity in olfactory receptor neurons, whose axons contact the dendritic tufts of mitral cells within olfactory bulb glomeruli. These axodendritic synapses are anatomically separated from dendrodendritic synapses within each glomerulus. Mitral cells within a glomerulus show highly synchronized activity as assessed with whole-cell recording from pairs of mitral cells. We examined glomerular activity in mice lacking the olfactory cell adhesion molecule (OCAM). Glomeruli in mice lacking OCAM show a redistribution of synaptic subcompartments, but the total area occupied by axonal inputs was similar to wild-type mice. Stimulation of olfactory nerve bundles showed that excitatory synaptic input to mitral cells as well as dendrodendritic inhibition was unaffected in the knockout. However, correlated spiking in mitral cells was significantly reduced, as was electrical coupling between apical dendrites. To analyse slow network dynamics we induced slow oscillations with a glutamate uptake blocker. Evoked and spontaneous slow oscillations in mitral cells and external tufted cells were broader and had multiple peaks in OCAM knockout mice, indicating that synchrony of slow glomerular activity was also reduced. To assess the degree of shared activity between mitral cells under physiological conditions, we analysed spontaneous sub-threshold voltage oscillations using coherence analysis. Coherent activity was markedly reduced in cells from OCAM knockout mice across a broad range of frequencies consistent with a decrease in tightly time-locked activity. We suggest that synchronous activity within each glomerulus is dependent on segregation of synaptic subcompartments.


Plasma prostaglandin F2 alpha and plasma 13,14-dihydro-15-keto-prostaglandin F2 alpha levels in women during induction of labor with i.v. infusion of prostaglandin F2 alpha in relation to uterine contractions.
The concentrations of plasma PGF2 alpha and its main metabolite, 13,14-dihydro-15-keto-PGF2 alpha (PGFM) were measured in serial samples of blood collected in 10 pregnant women at term who were given iv infusions of low doses of PGF2 alpha for induction of labor. Six other women served as controls and were given saline infusions. Uterine contractions began with a mean latency of 62 min in the PGF2 alpha infused women, in controls uterine activity remained unchanged. Plasma PGFM levels had increased significantly 30 min after PGF2 alpha infusion began, rising thereafter in a dose dependent manner. Plasma PGF2 alpha also rose reaching a steady state at 2 hours. No significant changes were observed in the controls. The 6-h infusion resulted in delivery in 5 of the 10 women, in the 5 others the cervical scores increased only by 1.25 points on the average and further treatment was needed to achieve delivery, although prostanoid levels rose to similar levels in all. The data show that when uterine contractions are induced by systemic PGF2 alpha, the levels of PGFM are significantly raised. In spontaneous labor uterine contractions begin long before plasma PGFM rises. Thus, if endogenous PGF2 alpha generation is involved in the initiation of uterine contractions during spontaneous labor, it must be synthetized in the myometrium at quantities too low to raise the levels of circulating PGFM.


TREM2 mitigates NLRP3-mediated neuroinflammation through the NF-κB and PI3k/Akt signaling pathways in juvenile rats exposed to ambient particulate matter.
Ambient particulate matter (PM) is a global public and environmental problem. PM is closely associated with several neurological disorders that typically involve neuroinflammation. There have been few studies on the effect of PM on neuroinflammation to date. In this study, we used a juvenile rat model (PM exposure was conducted at a dose of 10 mg/kg body weight per day for 4 weeks) and a BV-2 cell model (PM exposure was conducted at concentrations of 50, 100, 150, and 200 μg/ml for 24 h) to investigate PM-induced neuroinflammation mediated by NLRP3 inflammasome activation and the role of TREM2 in this process. Our findings revealed that PM exposure reduced TREM2 protein and mRNA levels in the rat hippocampus and BV-2 cells. TREM2 overexpression attenuated PM-induced spatial learning and memory deficits in rats. Moreover, we observed that TREM2 overexpression in vivo and in vitro effectively mitigated the increase in NLRP3 and pro-Caspase1 protein expression, as well as the secretion of IL-1β and IL-18. Exposure to PM increased the expression of NF-κB and decreased the phosphorylation of PI3k/Akt in vivo and in vitro, and this process was effectively reversed by overexpressing TREM2. Our results indicated that PM exposure could reduce TREM2 expression and induce NLRP3 inflammasome-mediated neuroinflammation and that TREM2 could mitigate NLRP3 inflammasome-mediated neuroinflammation by regulating the NF-κB and PI3k/Akt signaling pathways. These findings shed light on PM-induced neuroinflammation mechanisms and potential intervention targets.


Ellen Berscheid, Elaine Hatfield, and the Emergence of Relationship Science.
In the past 25 years, relationship science has grown from a nascent research area to a thriving subdiscipline of psychological science. In no small measure, this development reflects the pioneering contributions of Ellen Berscheid and Elaine Hatfield. Beginning at a time when relationships did not appear on the map of psychological science, these two scholars identified relationships as a crucial subject for scientific psychology and began to chart its theoretical and empirical territory. In this article, we review several of their most influential contributions, describing the innovative foundation they built as well as the manner in which this foundation helped set the stage for contemporary advances in knowledge about relationships. We conclude by discussing the broader relevance of this work for psychological science.


Post-traumatic stress disorder after car accidents.
Survivors of car crashes often suffer from a post-traumatic fear of driving, generalized anxiety and depression. Unremitting pains are also common. As part of a pilot study 30 referred subjects were exposed to imagery of driving and accidents. Seventy-seven percent were phobic of driving. Fifty-three percent responded with increased anxiety to the imagery. Twelve treatment referrals received exposure therapy and six improved markedly. An additional four improved when a Benzodiazepine was added temporarily. Four out of eight subjects lost their unremitting pains along with their fears. When guided imagery evoked intense anxiety this seemed to predict a favourable outcome. A resumption of pleasure trips was a reliable criterion of recovery. The frequency of phobic symptomatology and it's importance to the understanding and management of post-traumatic anxiety states is discussed.


Effectiveness of acute geriatric unit care on functional decline, clinical and process outcomes among hospitalised older adults with acute medical complaints: a systematic review and meta-analysis.
the aim of this systematic review and meta-analysis was to update and synthesise the totality of research evidence on the effectiveness of acute geriatric unit (AGU) care for older adults admitted to hospital with acute medical complaints. MEDLINE, CINAHL, CENTRAL and Embase databases were systematically searched from 2008 to February 2022. Screening, data extraction and quality grading were undertaken by two reviewers. Only trials with a randomised design comparing AGU care and conventional care units were included. Meta-analyses were performed in Review Manager 5.4 and the Grading of Recommendations, Assessment, Development and Evaluations framework was used to assess the certainty of evidence. The primary outcome was incidence of functional decline between baseline 2-week prehospital admission status and discharge and at follow-up. 11 trials recruiting 7,496 participants across three countries were included. AGU care resulted in a reduction in functional decline at 6-month follow-up (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.66-0.93; moderate certainty evidence) and an increased probability of living at home at 3-month follow-up (RR 1.06, 95% CI 0.99-1.13; high certainty evidence). AGU care resulted in little or no difference in functional decline at hospital discharge or at 3-month follow-up, length of hospital stay, costs, the probability of living at home at discharge, mortality, hospital readmission, cognitive function or patient satisfaction. AGU care improves clinical and process outcomes for hospitalised older adults with acute medical complaints. Future research should focus on greater inclusion of clinical and patient reported outcome measures.


Individual, socio-cultural and environmental predictors of uptake and maintenance of active commuting in children: longitudinal results from the SPEEDY study.
Active commuting is prospectively associated with physical activity in children. Few longitudinal studies have assessed predictors of change in commuting mode. To investigate the individual, socio-cultural and environmental predictors of uptake and maintenance of active commuting in 10-year-old children. Children were recruited in 2007 and followed-up 12 months later. Children self-reported usual travel mode to school. 31 child, parent, socio-cultural and physical environment characteristics were assessed via self-reported and objective methods. Associations with uptake and maintenance of active travel were studied using multi-level multiple logistic regression models in 2012. Of the 912 children (59.1% girls, mean ± SD baseline age 10.2 ± 0.3 yrs) with complete data, 15% changed their travel mode. Those children who lived less than 1 km from school were more likely to take up (OR: 4.73, 95% CI: 1.97, 11.32, p = 0.001) and maintain active commuting (OR: 2.80 95% CI: 0.98, 7.96, p = 0.02). Children whose parents reported it was inconvenient to use the car for school travel were also more likely to take up (OR: 2.04, 95% CI: 1.08, 3.85, p = 0.027) and maintain their active commuting (OR: 5.43 95% CI: 1.95, 15.13, p = 0.001). Lower socio-economic status and higher road safety were also associated with uptake. Findings from this longitudinal study suggest that reducing the convenience of the car and improving the convenience of active modes as well as improving the safety of routes to school may promote uptake and maintenance of active commuting and the effectiveness of these interventions should be evaluated.


Evolution of the SNF2 family of proteins: subfamilies with distinct sequences and functions.
The SNF2 family of proteins includes representatives from a variety of species with roles in cellular processes such as transcriptional regulation (e.g. MOT1, SNF2 and BRM), maintenance of chromosome stability during mitosis (e.g. lodestar) and various aspects of processing of DNA damage, including nucleotide excision repair (e.g. RAD16 and ERCC6), recombinational pathways (e.g. RAD54) and post-replication daughter strand gap repair (e.g. RAD5). This family also includes many proteins with no known function. To better characterize this family of proteins we have used molecular phylogenetic techniques to infer evolutionary relationships among the family members. We have divided the SNF2 family into multiple subfamilies, each of which represents what we propose to be a functionally and evolutionarily distinct group. We have then used the subfamily structure to predict the functions of some of the uncharacterized proteins in the SNF2 family. We discuss possible implications of this evolutionary analysis on the general properties and evolution of the SNF2 family.


Staudinger ligation of alpha-azido acids retains stereochemistry.
The Staudinger ligation of peptides with a C-terminal phosphinothioester and N-terminal azide is an emerging method in protein chemistry. Here, the first Staudinger ligations of nonglycyl azides are reported and shown to proceed both in nearly quantitative yield and with no detectable effect on the stereochemistry at the alpha-carbon of the azide. These results demonstrate further the potential of the Staudinger ligation as a general method for the total synthesis of proteins from peptide fragments.


Early phosphorylation events following the treatment of Swiss 3T3 cells with bombesin and the mammalian bombesin-related peptide, gastrin-releasing peptide.
Bombesin and the related mammalian peptides, such as gastrin-releasing peptide (GRP), are potent mitogens for some fibroblast cell lines. Here we have examined the bombesin- and GRP-mediated changes in the phosphorylation of proteins in Swiss 3T3 cells and compared these to the events observed after platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and tumor promoter treatment. In agreement with previous reports, bombesin, GRP and PDGF, but not EGF, increased the activity of protein kinase C. This was assayed by an inhibition of [125I]EGF binding, stimulation in phosphorylation of pp60c-src on serine 12 and stimulation in phosphorylation of a group of 80 kd proteins. The different phosphorylated forms of the 80 kd proteins were examined by tryptic peptide mapping and shown to contain multiple phosphorylation sites. An investigation of the tyrosine phosphorylation events following mitogen treatment revealed a significant difference between PDGF and the bombesin peptides. PDGF treatment caused a marked increase in total cellular phosphotyrosine levels, and tyrosine phosphorylation both of known substrates and its own receptor. In contrast, bombesin and GRP treatments resulted in only a weak or undetectable increase in tyrosine phosphorylation of total cellular protein or known substrates. In this respect bombesin and GRP were more similar to EGF. The fact that the bombesin peptides do not induce a phosphorylation response identical with either PDGF or EGF suggests that there is not a single common signal pathway which is activated by all these mitogens.


The role of counselling in tuberculosis diagnostic evaluation and contact tracing: scoping review and stakeholder consultation of knowledge and research gaps.
Tuberculosis (TB) care cascade analyses show large gaps at early stages, including care-seeking and diagnostic evaluation, where promising interventions to decrease attrition are urgently needed. Person-centered care is prioritized in the World Health Organization's End TB strategy; yet little is known about how it is delivered and can be optimized. Recommendations for counselling, a core component of person-centered care, are largely limited to its role in improving TB treatment adherence. The role of counselling to close key diagnostic gaps in the care cascade is poorly understood. We conducted a scoping review to identify evidence on the use of counselling at TB diagnosis, for both people with presumptive TB and index patients to promote patient retention and contact tracing. Using search terms for TB, diagnosis and counselling, we systematically searched PubMed, EMBASE and Web of Science. Two independent reviewers screened all abstracts, full-texts, extracted data and conducted a quality assessment. We used thematic analysis to identify key themes. After screening 1785 articles, we extracted data from 15 studies and determined that the major themes best corresponded to the following gaps in the TB care cascade: care-seeking, pre-diagnosis, and pre-treatment. Studies were conducted across varied settings including pharmacies, primary health centres, and clinics, primarily in high TB incidence countries. No study directly evaluated the impact of counselling on outcomes such as treatment initiation or retention in care. Included studies suggested counselling may play an important role in improving the uptake of diagnostic testing and contact tracing. Barriers to counselling included time and personnel requirements. Stakeholder consultation emphasized the importance of high-quality counselling as a core tenet of TB care. Data on the impact of counselling to improve TB case detection are absent from the literature. The shift towards person-centred care for TB presents an opportunity to incorporate counselling during earlier stages of the TB care cascade; however, evidence-based approaches are needed. Implementation research is needed to operationalize and evaluate counselling to strengthen high-quality TB care delivery.


Stereospecificity of reactions catalyzed by HIV-1 integrase.
The retroviral integrase catalyzes two successive chemical reactions essential for integration of the retroviral genome into a host chromosome: 3' end processing, in which a dinucleotide is cleaved from each 3' end of the viral DNA; and the integration reaction itself, in which the resulting recessed 3' ends of the viral DNA are joined to the host DNA. We have examined the stereospecificity of human immunodeficiency virus type 1 integrase for phosphorothioate substrates in these reactions and in a third reaction, disintegration, which is macroscopically the reverse of integration. Integrase preferentially catalyzed end processing and integration of a substrate with the (R(p))-phosphorothioate stereoisomer at the reaction center and disintegration of a substrate with an (S(p))-phosphorothiate at the reaction center. These results suggest a model for the architecture of the active site of integrase, and its interactions with key features of the viral and target DNA.


Novel Strategy To Protect against Influenza Virus-Induced Pneumococcal Disease without Interfering with Commensal Colonization.
Streptococcus pneumoniae commonly inhabits the nasopharynx as a member of the commensal biofilm. Infection with respiratory viruses, such as influenza A virus, induces commensal S. pneumoniae to disseminate beyond the nasopharynx and to elicit severe infections of the middle ears, lungs, and blood that are associated with high rates of morbidity and mortality. Current preventive strategies, including the polysaccharide conjugate vaccines, aim to eliminate asymptomatic carriage with vaccine-type pneumococci. However, this has resulted in serotype replacement with, so far, less fit pneumococcal strains, which has changed the nasopharyngeal flora, opening the niche for entry of other virulent pathogens (e.g., Streptococcus pyogenes, Staphylococcus aureus, and potentially Haemophilus influenzae). The long-term effects of these changes are unknown. Here, we present an attractive, alternative preventive approach where we subvert virus-induced pneumococcal disease without interfering with commensal colonization, thus specifically targeting disease-causing organisms. In that regard, pneumococcal surface protein A (PspA), a major surface protein of pneumococci, is a promising vaccine target. Intradermal (i.d.) immunization of mice with recombinant PspA in combination with LT-IIb(T13I), a novel i.d. adjuvant of the type II heat-labile enterotoxin family, elicited strong systemic PspA-specific IgG responses without inducing mucosal anti-PspA IgA responses. This response protected mice from otitis media, pneumonia, and septicemia and averted the cytokine storm associated with septic infection but had no effect on asymptomatic colonization. Our results firmly demonstrated that this immunization strategy against virally induced pneumococcal disease can be conferred without disturbing the desirable preexisting commensal colonization of the nasopharynx.


[Arthrocentesis in rheumatology practice].
This study of Norwegian rheumatologists' use of intraarticular steroid injections is based on a survey among members of the Norwegian Society for Rheumatology. 79% of the members responded, i.e. 108 rheumatologists. 69 reported having used intraarticular steroid injections in any joint during the last week, a total of 637 times. There have been no previous studies on this subject in Norway. The results show that Norwegian rheumatologists consider intraarticular steroid injections a very effective treatment. Only 9% reported that they had seen side effects over the last 12 months (a total of 51 side effects), of which post-injection pain and subcutaneous atrophy were the most common. There were no reports of septic arthritis. Almost all side effects were considered not serious.


Eighteen-Month Outcomes of Titanium Frameworks Using Computer-Aided Design and Computer-Aided Manufacturing Method.
The aim of the report is to introduce a new software and a new scanner with a noncontact laser probe and to present outcomes of computer-aided design and computer-aided manufacturing titanium frameworks using this new software and scanner with a laser probe. Seven patients received 40 implants placed using a 1-stage protocol. After all implants were planned using an implant planning software (NobelClinician), either 5 or 6 implants were placed in each edentulous arch. Each edentulous arch was treated with a fixed dental prosthesis using implant-supported complete-arch milled-titanium framework using the software (NobelProcera) and the scanner. All patients were followed up for 18 ± 3 months. Implant survival, prosthesis survival, framework fit, marginal bone levels, and maintenance requirements were evaluated. One implant was lost during the follow-up period, giving the implant survival rate of 97.5%; 0.4 ± 0.2 mm marginal bone loss was noted for all implants after 18 ± 3 months. None of the prostheses needed a replacement, indicating the prosthesis success rate of 100%. The results of this clinical study suggest that titanium frameworks fabricated using the software and scanner presented in this study fit accurately and may be a viable option to restore edentulous arches.


Optimization of Nutrition And Medication (OptiNAM) for acutely admitted older patients: protocol for a randomized single-blinded controlled trial.
Internationally, older patients (≥65 years) account for more than 40% of acute admissions. Older patients admitted to the emergency department (ED) are frequently malnourished and exposed to inappropriate medication prescribing, due in part to the inaccuracy of creatinine-based equations for estimated glomerular filtration rate (eGFR). The overall aims of this trial are to investigate: (1) the efficacy of a medication review (MED intervention) independent of nutritional status, (2) the accuracy of eGFR equations based on various biomarkers compared to measured GFR (mGFR) based on 99mTechnetium-diethylenetriaminepentaacetic acid plasma clearance, and (3) the efficacy of an individualized multimodal and transitional nutritional intervention (MULTI-NUT-MED intervention) in older patients with or at risk of malnutrition in the ED. The trial is a single-center block randomized, controlled, observer-blinded, superiority and explorative trial with two parallel groups. The population consists of 200 older patients admitted to the ED: 70 patients without malnutrition or risk of malnutrition and 130 patients with or at risk of malnutrition defined as a Mini Nutritional Assessment-Short Form score ≤11. All patients without the risk of malnutrition receive the MED intervention, which consists of a medication review by a pharmacist and geriatrician in the ED. Patients with or at risk of malnutrition receive the MULTI-NUT-MED intervention, which consists of the MED intervention in addition to, dietary counseling and individualized interventions based on the results of screening tests for dysphagia, problems with activities of daily living, low muscle strength in the lower extremities, depression, and problems with oral health. Baseline data are collected upon study inclusion, and follow-up data are collected at 8 and 16 weeks after discharge. The primary outcomes are (1) change in medication appropriateness index (MAI) score from baseline to 8 weeks after discharge, (2) accuracy of different eGFR equations compared to mGFR, and (3) change in health-related quality of life (measured with EuroQol-5D-5L) from baseline to 16 weeks after discharge. The trial will provide new information on strategies to optimize the treatment of malnutrition and inappropriate medication prescribing among older patients admitted to the ED. ClinicalTrials.gov NTC03741283 . Retrospectively registered on 14 November 2018.


Incidence of resensitization after tolerating penicillin treatment in penicillin-allergic patients.
The incidence of resensitization to penicillin in patients with a history of penicillin allergy appears to be low but the approach to patients is controversial. We sought to determine the incidence of penicillin resensitization in patients with a history of penicillin allergy who had negative skin tests to penicillin determinants and received an initial uneventful course of beta-lactam antibiotics. We identified 254 patients who had negative penicillin skin testing to the major and minor penicillin determinants from January 1, 1994 to October 1999 and then reviewed their hospital and/or clinic records to determine if the patient had received subsequent treatment with beta-lactams or cephalosporins after the initial course of antibiotics. Of 254 patients, we were able to review 33/35 (94.3%) patients' charts to evaluate adverse reactions to the antibiotics. These 33 patients received a total of 77 subsequent courses of beta-lactam antibiotics and 19 subsequent courses of cephalosporins. Thirty of the 33 patients (90.9%) received at least one course of a parenterally administered cephalosporin or beta-lactam antibiotic. Seven of the 33 patients received only cephalosporin antibiotics. None of the identified patients had evidence of an immunoglobulin E-mediated reaction. Three of the 33 patients (9.1%) developed cutaneous skin eruptions during subsequent antibiotic treatment. Two of these three patients had subsequent uneventful treatment with beta-lactam antibiotics. The third patient who developed a nonblistering eruption underwent repeat penicillin skin testing, which remained negative. These data suggest that penicillin resensitization in previously allergic patients is very low and do not support the notion that penicillin skin testing should be performed before each subsequent course of beta-lactam antibiotics.


[Phylogeny of neurohypophyseal hormones in birds: microidentification of mesotocin and vasotocin in the ostrich (Struthio camelus)].
Ostrich (Struthio camelus) neurohypophysial hormones have been isolated from 5 freeze-dried posterior pituitary glands. Purification has involved three steps: a first molecular sieving on Sephadex G-75 for eliminating proteins, a second molecular sieving on Bio-Gel P4 for separating the two active principles and a high pressure reverse-phase liquid chromatography (HPLC) on Nova-Pak C 18 with an 10 mM acetate-acetonitrile gradient for isolating each hormone. The active peptides have been identified by their retention time in HPLC and their amino acid composition. Mesotocin and vasotocin have thus been characterized. Although the phylogeny of Ratites is disputed, in particular their possible common origin with Carinates, which include most of the living birds, species of the first sub-class seem to have the same neurohypophysial hormones as those of the second.


Non-linear analysis using continuous chaotic modeling.
Recent research in nanotechnology is opening exciting new avenues not only for understanding the human body but also for creating devices that can effectively interact with it to alleviate the effects of disease. These new developments present both challenges and opportunities for adaptation of existing methodologies to create new approaches for analysis and modeling of nanotechnology-based systems. The concept of continuous chaotic modeling presents an avenue for a paradigm shift away from traditional digital computing to take advantage of analog models that are more compatible with biological systems. The theoretical basis of continuous chaotic modeling is summarized, followed by illustrations of applications of this methodology.


[Ophthalmologic and roentgenologic findings in a rare case of mucopolysaccharidosis 4 B].
A rare case of mucopolysaccharidosis, i.e., Morquio's disease with spondyloepiphyseal dysplasia, corneal clouding, normal intelligence, and deficiency of beta-galactosidase activity is described.


Health-related quality of life of Iranian children with attention deficit/hyperactivity disorder.
The present study aimed to examine the psychometric properties of the Persian version of the 23-item PedsQL™ 4.0 Generic Core Scales in Iranian children with attention deficit hyperactivity disorder (ADHD). A clinical sample of seventy-two children aged 8-17 years with ADHD and their parents completed the questionnaire. The control group consisted of 140 children matched for age and gender selected from schools by cluster sampling method. The English language version of the PedsQL™ 4.0 was translated into Persian. Factor analysis was conducted. Reliability analysis for the total scale score was 0.85 for the child report and it was 0.80 for parent report version. Factor loading for items of the questionnaire was very similar to its original version. The quality of life of children with ADHD was statistically lower than that of the control group. The Persian version of the scales has adequate reliability and validity. The HRQOL of children with ADHD is lower than that of the control group. It is lower than that of the community sample of ADHD children from USA or children with cancer.


Ancient Oyster Shells on the Atlantic Continental Shelf.
Shells of long-dead Crassostrea virginica are reported at 71 stations in depths of 14 to 82 meters. The depths exceed those of the estuaries where the species flourishes. Radiocarbon measurements indicate that the oysters were alive 8000 to 11,000 years ago. It is concluded that the oysters lived in lagoons or estuaries which became submerged when the sea level rose at the end of the latest glacial epoch.


A protein methylesterase involved in bacterial sensing.
A protein methylesterase has been identified in soluble extracts of Salmonella typhimurium and Escherichia coli. This enzyme catalyzes the hydrolysis of gamma-glutamyl methyl ester residues from membrane-bound 60,000-molecular weight proteins that are essential for chemotaxis. Analyses of methylesterase activity in a variety of chemotactically defective strains suggest that the methylesterase is a product of the cheX gene in Salmonella and the cheB gene in E. coli. In addition, the cheT gene product in S. typhimurium seems to play a role in expression of methylesterase activity. Mutant strains lacking the protein methylesterase tumble incessantly in the absence of attractant gradients. This behavior is the converse of that shown by mutant strains defective in methyltransferase activity, which swim smoothly in the absence of repellent gradients. This finding indicates that reversible methylation acts as a control mechanism and that both a methyltransferase and a protein methylesterase are instrumental in bacterial sensing.


Protein nanoparticles as drug delivery carriers for cancer therapy.
Nanoparticles have increasingly been used for a variety of applications, most notably for the delivery of therapeutic and diagnostic agents. A large number of nanoparticle drug delivery systems have been developed for cancer treatment and various materials have been explored as drug delivery agents to improve the therapeutic efficacy and safety of anticancer drugs. Natural biomolecules such as proteins are an attractive alternative to synthetic polymers which are commonly used in drug formulations because of their safety. In general, protein nanoparticles offer a number of advantages including biocompatibility and biodegradability. They can be prepared under mild conditions without the use of toxic chemicals or organic solvents. Moreover, due to their defined primary structure, protein-based nanoparticles offer various possibilities for surface modifications including covalent attachment of drugs and targeting ligands. In this paper, we review the most significant advancements in protein nanoparticle technology and their use in drug delivery arena. We then examine the various sources of protein materials that have been used successfully for the construction of protein nanoparticles as well as their methods of preparation. Finally, we discuss the applications of protein nanoparticles in cancer therapy.


Surveillance and simulation of bovine spongiform encephalopathy and scrapie in small ruminants in Switzerland.
After bovine spongiform encephalopathy (BSE) emerged in European cattle livestock in 1986 a fundamental question was whether the agent established also in the small ruminants' population. In Switzerland transmissible spongiform encephalopathies (TSEs) in small ruminants have been monitored since 1990. While in the most recent TSE cases a BSE infection could be excluded, for historical cases techniques to discriminate scrapie from BSE had not been available at the time of diagnosis and thus their status remained unclear. We herein applied state-of-the-art techniques to retrospectively classify these animals and to re-analyze the affected flocks for secondary cases. These results were the basis for models, simulating the course of TSEs over a period of 70 years. The aim was to come to a statistically based overall assessment of the TSE situation in the domestic small ruminant population in Switzerland. In sum 16 TSE cases were identified in small ruminants in Switzerland since 1981, of which eight were atypical and six were classical scrapie. In two animals retrospective analysis did not allow any further classification due to the lack of appropriate tissue samples. We found no evidence for an infection with the BSE agent in the cases under investigation. In none of the affected flocks, secondary cases were identified. A Bayesian prevalence calculation resulted in most likely estimates of one case of BSE, five cases of classical scrapie and 21 cases of atypical scrapie per 100'000 small ruminants. According to our models none of the TSEs is considered to cause a broader epidemic in Switzerland. In a closed population, they are rather expected to fade out in the next decades or, in case of a sporadic origin, may remain at a very low level. In summary, these data indicate that despite a significant epidemic of BSE in cattle, there is no evidence that BSE established in the small ruminant population in Switzerland. Classical and atypical scrapie both occur at a very low level and are not expected to escalate into an epidemic. In this situation the extent of TSE surveillance in small ruminants requires reevaluation based on cost-benefit analysis.


Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties.
Mesenchymal stem cells (MSCs) protect tissues against cell death induced by ischemia/reperfusion insults. This therapeutic effect seems to be controlled by physiological cues released by the local microenvironment following injury. Recent lines of evidence indicate that MSC can communicate with their microenvironment through bidirectional exchanges of mitochondria. In particular, in vitro and in vivo studies report that MSCs rescue injured cells through delivery of their own mitochondria. However, the role of mitochondria conveyed from somatic cells to MSC remains unknown. By using a co-culture system consisting of MSC and distressed somatic cells such as cardiomyocytes or endothelial cells, we showed that mitochondria from suffering cells acted as danger-signaling organelles that triggered the anti-apoptotic function of MSC. We demonstrated that foreign somatic-derived mitochondria were engulfed and degraded by MSC, leading to induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As a result, the capacity of MSC to donate their mitochondria to injured cells to combat oxidative stress injury was enhanced. We found that similar mechanisms - activation of autophagy, HO-1 and mitochondrial biogenesis - occurred after exposure of MSC to exogenous mitochondria isolated from somatic cells, strengthening the idea that somatic mitochondria alert MSC of a danger situation and subsequently promote an adaptive reparative response. In addition, the cascade of events triggered by the transfer of somatic mitochondria into MSC was recapitulated in a model of myocardial infarction in vivo. Specifically, MSC engrafted into infarcted hearts of mice reduced damage, upregulated HO-1 and increased mitochondrial biogenesis, while inhibition of mitophagy or HO-1 failed to protect against cardiac apoptosis. In conclusion, our study reveals a new facet about the role of mitochondria released from dying cells as a key environmental cue that controls the cytoprotective function of MSC and opens novel avenues to improve the effectiveness of MSC-based therapies.


Telomere dynamics in wild brown trout: effects of compensatory growth and early growth investment.
After a period of food deprivation, animals often respond with a period of faster than normal growth. Such responses have been suggested to result in decreased chromosomal maintenance, which in turn may affect the future fitness of an individual. Here, we present a field experiment in which a food deprivation period of 24 days was enforced on fish from a natural population of juvenile brown trout (Salmo trutta) at the start of the high-growth season in spring. The growth of the food-deprived fish and a non-deprived control group was then monitored in the wild during 1 year. Fin tissue samples were taken at the start of the experiment and 1 year after food deprivation to monitor the telomere dynamics, using reduced telomere length as an indicator of maintenance cost. The food-deprived fish showed partial compensatory growth in both mass and length relative to the control group. However, we found no treatment effects on telomere dynamics, suggesting that growth-compensating brown trout juveniles are able to maintain their telomeres during their second year in the stream. However, body size at the start of the experiment, reflecting growth rate during their first year of life, was negatively correlated with change in telomere length over the following year. This result raises the possibility that rapid growth early in life induces delayed costs in cellular maintenance.


Associations of birth size and duration of breast feeding with cardiorespiratory fitness in childhood: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC).
To explore the developmental origins of cardiorespiratory fitness. We examined the associations of birth size and duration of breast feeding with cardiorespiratory fitness assessed at the 9 year follow-up examination in 3612 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC). We used physical work capacity at a heart rate of 170 beats per minute (PWC(170)) as our assessment of cardiorespiratory fitness. This was estimated using standard regression methods from parameters measured using an electronically braked cycle ergometer. Birth weight, length and ponderal index were all positively associated with cardiorespiratory fitness in both sexes, with no strong evidence of a difference in effect between girls and boys. Work capacity increased by 1.12 W (95% CI: 0.83, 1.40) on average per 1 standard deviation (SD) greater birth weight. This association was not affected by adjustment for socioeconomic position and maternal smoking during pregnancy; there was some attenuation with adjustment for both maternal and paternal height and body mass index and more marked attenuation with adjustment for the child's height and body mass index. In the fully adjusted model work capacity increased by 0.51 W (95% CI: 0.21, 0.81) per SD birth weight. Whether an individual had been breastfed and duration of breastfeeding were not associated with cardiorespiratory fitness in any models. Our results provide some support for a role of intrauterine factors in determining cardiorespiratory fitness in childhood.


Male pattern baldness and clinical prostate cancer in the epidemiologic follow-up of the first National Health and Nutrition Examination Survey.
Male pattern baldness (MPB) and prostate cancer are common in American males; however, MPB is clinically observable decades earlier. Aging, androgens, and heritability are risk factors for both conditions. We prospectively studied the association between MPB and clinical prostate cancer in a cohort representative of the United States male population. A total of 4,421 men 25-75 years old without a history of prostate cancer were examined for baldness in the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey. Participants were followed from baseline (1971-1974) through 1992. Incident cases of prostate cancer were identified by interviews, medical records, and death certificates. Age-standardized incidence rates and proportional hazards models were used to examine the association between MPB and clinical prostate cancer. Prostate cancer was diagnosed in 214 subjects over 17-21 years of follow-up. The age-standardized incidence of prostate cancer was greater among men with baldness at baseline (17.5 versus 12.5 per 10,000 person-years). The adjusted relative risk for prostate cancer among men with baldness was 1.50 (95% confidence interval, 1.12-2.00) and was similar regardless of the severity of baldness at baseline and was independent of other risk factors, including race and age. MPB seems to be a risk factor for clinical prostate cancer.


Air pollution and homocysteine: more evidence that oxidative stress-related genes modify effects of particulate air pollution.
Ambient particles are associated with cardiovascular events and recently with total plasma homocysteine. High total plasma homocysteine is a risk for human health. However, the biologic mechanisms are not fully understood. One of the putative pathways is through oxidative stress. We aimed to examine whether associations of PM2.5 and black carbon with homocysteine were modified by genotypes including HFE H63D, C282Y, CAT (rs480575, rs1001179, rs2284367, and rs2300181), NQO1 (rs1800566), GSTP1 I105V, GSTM1, GSTT1 (deletion vs. nondeletion), and HMOX-1 (any short vs. both long). We attempted to replicate identified genes in an analysis of heart rate variability and in other outcomes reported in the literature. Study subjects were 1000 white non-Hispanic men in the Boston area, participating in a cohort study of aging. PM2.5, black carbon, total plasma homocysteine, and other covariates were measured at several points in time between 1995 and 2006. We fit mixed models to examine effect modification of genes on associations of pollution with total plasma homocysteine. Interquartile range increases in PM2.5 and black carbon (7-day moving averages) were associated with 1.5% (95% confidence interval = 0.2% to 2.8%) and 2.2% (0.6% to 3.9%) increases in total plasma homocysteine, respectively. GSTT1 and HFE C282Y modified effects of black carbon on total plasma homocysteine, and HFE C282Y and CAT (rs2300181) modified effects of PM2.5 on homocysteine. Several genotypes marginally modified effects of PM2.5 and black carbon on various endpoints. All genes with significant interactions with particulate air pollution had modest main effects on total plasma homocysteine. : Effects of PM2.5 and black carbon on various endpoints appeared to be mediated by genes related to oxidative stress pathways.


Metabolic and circulatory studies of fetal lamb at midgestation.
Uterine and umbilical blood flows, the placental clearance of 3H2O, uterine and umbilical uptakes of oxygen, glucose, and lactate were measured in conscious, pregnant sheep at 71-81 days gestation. Fetal weight was 210 +/- 20 g and less than half placental weight. In relation to fetal weight, umbilical flow was 468 +/- 57 ml X min-1 X kg-1, more than double normal values for the mature fetus. Clearance of 3H2O was approximately 12% of the late pregnancy value but high in relation to fetal weight (280 +/- 23 ml X min-1 X kg-1). Fetal oxygen uptake was 10.9 +/- 0.6 ml X min-1 X kg-1, approximately 40% greater than in late gestation. Umbilical uptake of glucose was also relatively high, whereas lactate uptake was low. Uteroplacental tissues consumed more than 80% of the oxygen and glucose taken up by the pregnant uterus. However, uteroplacental utilization rates of oxygen and glucose as well as net lactate production were lower (approximately 50, 30, and 25%, respectively) than in late pregnancy, despite a larger placental mass (486 +/- 22 vs. 302 +/- 12 g).


Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin.
Antibodies directed to the Sa antigen are highly specific for rheumatoid arthritis (RA) and can be detected in approximately 40% of RA sera. The antigen, a doublet of protein bands of about 50 kDa, is present in placenta and in RA synovial tissue. Although it has been stated that the Sa antigen is citrullinated vimentin, experimental proof for this claim has never been published. In this study, we investigated the precise nature of the antigen. Peptide sequences that were obtained from highly purified Sa antigen were unique to vimentin. Recombinant vimentin, however, was not recognized by anti-Sa reference sera. In vivo, vimentin is subjected to various post-translational modifications, including citrullination. Since antibodies to citrullinated proteins are known to be highly specific for RA, we investigated whether Sa is citrullinated and found that Sa indeed is citrullinated vimentin. Anti-Sa antibodies thus belong to the family of anticitrullinated protein/peptide antibodies. The presence of the Sa antigen in RA synovial tissue, and the recent observation that vimentin is citrullinated in dying human macrophages, make citrullinated vimentin an interesting candidate autoantigen in RA and may provide new insights into the potential role of citrullinated synovial antigens and the antibodies directed to them in the pathophysiology of RA.


Structure determination and biochemical studies on Bacillus stearothermophilus E53Q serine hydroxymethyltransferase and its complexes provide insights on function and enzyme memory.
Serine hydroxymethyltransferase (SHMT) belongs to the alpha-family of pyridoxal 5'-phosphate-dependent enzymes and catalyzes the reversible conversion of L-Ser and tetrahydrofolate to Gly and 5,10-methylene tetrahydrofolate. 5,10-Methylene tetrahydrofolate serves as a source of one-carbon fragment in many biological processes. SHMT also catalyzes the tetrahydrofolate-independent conversion of L-allo-Thr to Gly and acetaldehyde. The crystal structure of Bacillus stearothermophilus SHMT (bsSHMT) suggested that E53 interacts with the substrate, L-Ser and tetrahydrofolate. To elucidate the role of E53, it was mutated to Q and structural and biochemical studies were carried out with the mutant enzyme. The internal aldimine structure of E53QbsSHMT was similar to that of the wild-type enzyme, except for significant changes at Q53, Y60 and Y61. The carboxyl of Gly and side chain of L-Ser were in two conformations in the respective external aldimine structures. The mutant enzyme was completely inactive for tetrahydrofolate-dependent cleavage of L-Ser, whereas there was a 1.5-fold increase in the rate of tetrahydrofolate-independent reaction with L-allo-Thr. The results obtained from these studies suggest that E53 plays an essential role in tetrahydrofolate/5-formyl tetrahydrofolate binding and in the proper positioning of Cbeta of L-Ser for direct attack by N5 of tetrahydrofolate. Most interestingly, the structure of the complex obtained by cocrystallization of E53QbsSHMT with Gly and 5-formyl tetrahydrofolate revealed the gem-diamine form of pyridoxal 5'-phosphate bound to Gly and active site Lys. However, density for 5-formyl tetrahydrofolate was not observed. Gly carboxylate was in a single conformation, whereas pyridoxal 5'-phosphate had two distinct conformations. The differences between the structures of this complex and Gly external aldimine suggest that the changes induced by initial binding of 5-formyl tetrahydrofolate are retained even though 5-formyl tetrahydrofolate is absent in the final structure. Spectral studies carried out with this mutant enzyme also suggest that 5-formyl tetrahydrofolate binds to the E53QbsSHMT-Gly complex forming a quinonoid intermediate and falls off within 4 h of dialysis, leaving behind the mutant enzyme in the gem-diamine form. This is the first report to provide direct evidence for enzyme memory based on the crystal structure of enzyme complexes.


The intrinsic circadian clock within the cardiomyocyte.
Circadian clocks are intracellular molecular mechanisms that allow the cell to anticipate the time of day. We have previously reported that the intact rat heart expresses the major components of the circadian clock, of which its rhythmic expression in vivo is consistent with the operation of a fully functional clock mechanism. The present study exposes oscillations of circadian clock genes [brain and arylhydrocarbon receptor nuclear translocator-like protein 1 (bmal1), reverse strand of the c-erbaalpha gene (rev-erbaalpha), period 2 (per2), albumin D-element binding protein (dbp)] for isolated adult rat cardiomyocytes in culture. Acute (2 h) and/or chronic (continuous) treatment of cardiomyocytes with FCS (50% and 2.5%, respectively) results in rhythmic expression of circadian clock genes with periodicities of 20-24 h. In contrast, cardiomyocytes cultured in the absence of serum exhibit dramatically dampened oscillations in bmal1 and dbp only. Zeitgebers (timekeepers) are factors that influence the timing of the circadian clock. Glucose, which has been previously shown to reactivate circadian clock gene oscillations in fibroblasts, has no effect on the expression of circadian clock genes in adult rat cardiomyocytes, either in the absence or presence of serum. Exposure of adult rat cardiomyocytes to the sympathetic neurotransmitter norephinephrine (10 microM) for 2 h reinitiates rhythmic expression of circadian clock genes in a serum-independent manner. Oscillations in circadian clock genes were associated with 24-h oscillations in the metabolic genes pyruvate dehydrogenase kinase 4 (pdk4) and uncoupling protein 3 (ucp3). In conclusion, these data suggest that the circadian clock operates within the myocytes of the heart and that this molecular mechanism persists under standard cell culture conditions (i.e., 2.5% serum). Furthermore, our data suggest that norepinephrine, unlike glucose, influences the timing of the circadian clock within the heart and that the circadian clock may be a novel mechanism regulating myocardial metabolism.


Bovine colostrum or milk as a serum substitute for the cultivation of a mouse hybridoma.
A mouse-mouse hybridoma was grown in serum-free medium supplemented with bovine milk or colostrum. Bovine colostrum supported growth of the hybridoma whereas bovine milk alone did not support cellular proliferation. For growth in medium supplemented with colostrum, the maximum cell concentration achieved was 1.4 x 10(6) cells/mL in 2.2% colostrum, which is 44% of that obtained in 9% serum. When cells were grown in media containing milk and low amounts of serum (<1%) the maximum cell concentration in 2.2% milk with 0.4% serum was 2 x 10(6) cells/ml, whereas it was only 0.2 x 10(6) cells/ml and 1.3 x 10(6) cells/ml in 2.2% milk alone and 0.4% serum alone, respectively. Similar behavior was observed for growth in media containing colostrum and low amounts of serum. The monoclonal antibody production in media containing combinations of serum and milk or colostrum was comparable to that obtained in media with higher serum concentrations. Experiments performed with conditioned media suggest that the rapid decrease in viability, after the maximum cell concentration has been reached, is partially due to the presence of some inhibitory components generated during the cell culture rather than due to depletion of some serum components.


Hypercholesterolemia increases mitochondrial oxidative stress and enhances the MPT response in the porcine myocardium: beneficial effects of chronic exercise.
Hypercholesterolemia has been suggested to have direct negative effects on myocardial function due to increased reactive oxygen species (ROS) generation and increased myocyte death. Mitochondrial permeability transition (MPT) is a significant mediator of cell death, which is enhanced by ROS generation and attenuated by exercise training. The purpose of this study was to investigate the effect of hypercholesterolemia on the MPT response of cardiac mitochondria. We tested the hypothesis that familial hypercholesterolemic (FH) pigs would have an enhanced MPT response and that exercise training could reverse this phenotype. MPT was assessed by mitochondrial swelling in response to 10-100 μM Ca(2+). FH pigs did show an increased MPT response to Ca(2+) that was associated with decreases in the expression of the putative MPT pore components mitochondrial phosphate carrier (PiC) and cyclophilin-D (CypD). FH also caused increased oxidative stress, depicted by increased protein nitrotyrosylation, as well as decreased levels of reduced GSH in cardiac mitochondria. Expression of the mitochondrial antioxidant enzymes manganese superoxide dismutase (MnSOD), thioredoxin-2 (Trx2), and peroxiredoxin-3 (Prx3) was greatly reduced in the FH pigs. In contrast, cytosolic catalase expression and activity were increased. However, chronic exercise training was able to normalize the MPT response in FH pigs, reduce mitochondrial oxidative stress, and return MnSOD, Trx2, Prx3, and catalase expression/activities to normal. We conclude that FH reduces mitochondrial antioxidants, increases mitochondrial oxidative stress, and enhances the MPT response in the porcine myocardium, and that exercise training can reverse these detrimental alterations.


Effect of ischaemic limb injury on the rates of metabolism of ketone bodies in starved rats.
1. Rats starved for 30h were injected with trace amounts of [3-14C]acetoacetate and beta-hydroxy[3-14C]butyrate 1h after ischaemic limb injury in a 20 degrees C environment, and the concentrations and radioactivities of blood ketone bodies were determined at intervals. 2. Starvation alone raised the rates of production and utilization of beta-hydroxybutyrate plus acetoacetate about 3.7-fold, but lowered their metabolic clearance rates by about 50%. In the starved rat ketone-body oxidation could account for up to 30% of whole body O2 consumption. 3. Injury in starved rats lowered the rates of production and utilization of both beta-hydroxybutyrate and acetoacetate, the combined fall of about 37% slightly exceeding the concomitant fall in whole-body O2 consumption. The concentration of beta-hydroxybutyrate decreased after injury, but its metabolic clearance rate was unaltered; the concentration of acetoacetate rose slightly and its metabolic clearance rate fell.


Lysophosphatidic acid activates lipogenic pathways and de novo lipid synthesis in ovarian cancer cells.
One of the most common molecular changes in cancer is the increased endogenous lipid synthesis, mediated primarily by overexpression and/or hyperactivity of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). The changes in these key lipogenic enzymes are critical for the development and maintenance of the malignant phenotype. Previous efforts to control oncogenic lipogenesis have been focused on pharmacological inhibitors of FAS and ACC. Although they show anti-tumor effects in culture and in mouse models, these inhibitors are nonselective blockers of lipid synthesis in both normal and cancer cells. To target lipid anabolism in tumor cells specifically, it is important to identify the mechanism governing hyperactive lipogenesis in malignant cells. In this study, we demonstrate that lysophosphatidic acid (LPA), a growth factor-like mediator present at high levels in ascites of ovarian cancer patients, regulates the sterol regulatory element binding protein-FAS and AMP-activated protein kinase-ACC pathways in ovarian cancer cells but not in normal or immortalized ovarian epithelial cells. Activation of these lipogenic pathways is linked to increased de novo lipid synthesis. The pro-lipogenic action of LPA is mediated through LPA(2), an LPA receptor subtype overexpressed in ovarian cancer and other malignancies. Downstream of LPA(2), the G(12/13) and G(q) signaling cascades mediate LPA-dependent sterol regulatory element-binding protein activation and AMP-activated protein kinase inhibition, respectively. Moreover, inhibition of de novo lipid synthesis dramatically attenuated LPA-induced cell proliferation. These results demonstrate that LPA signaling is causally linked to the hyperactive lipogenesis in ovarian cancer cells, which can be exploited for development of new anti-cancer therapies.


A Tale of Two Viruses: Coinfections of Monkeypox and Varicella Zoster Virus in the Democratic Republic of Congo.
Recent enhanced monkeypox (MPX) surveillance in the Democratic Republic of Congo, where MPX is endemic, has uncovered multiple cases of MPX and varicella zoster virus (VZV) coinfections. The purpose of this study was to verify if coinfections occur and to characterize the clinical nature of these cases. Clinical, epidemiological, and laboratory results were used to investigate MPX/VZV coinfections. A coinfection was defined as a patient with at least one Orthopoxvirus/MPX-positive sample and at least one VZV-positive sample within the same disease event. Between September 2009 and April 2014, 134 of the 1,107 (12.1%) suspected MPX cases were confirmed as MPX/VZV coinfections. Coinfections were more likely to report symptoms than VZV-alone cases and less likely than MPX-alone cases. Significantly higher lesion counts were observed for coinfection cases than for VZV-alone but less than MPX-alone cases. Discernible differences in symptom and rash severity were detected for coinfection cases compared with those with MPX or VZV alone. Findings indicate infection with both MPX and VZV could modulate infection severity. Collection of multiple lesion samples allows for the opportunity to detect coinfections. As this program continues, it will be important to continue these procedures to assess variations in the proportion of coinfected cases over time.


Suprachoroidal devices in glaucoma surgery.
While conventional glaucoma filtration surgery provides excellent intraocular pressure (IOP) lowering effect, this comes at the expense of significant risks. As the physiology of the suprachoroidal space has become better understood, its potential as a source for aqueous drainage has generated significant interest. This has resulted in the creation of several suprachoroidal glaucoma devices with excellent IOP lowering ability and a much more favorable side effect profile.


Minimally Invasive Approach for Dorsal Arachnoid Web: 2-Dimensional Operative Video.
A 67-yr-old patient presented with severe paraparesis and lower limb spasticity. The spinal cord magnetic resonance imaging (MRI) revealed the "scalpel sign" 1,2 at the T7 level, suggesting a diagnosis of a dorsal arachnoid web. This video demonstrates a microsurgical technique for the excision of a dorsal arachnoid web with a minimally invasive approach. A paramedian skin incision, understanding the muscular aponeurosis, was performed from T7 to T8. Then, we inserted the tubular dilators until the lamina, to perform a muscle-sparing approach. An expandable tubular retractor of adequate length was passed over the widest dilator and docked into place along the subperiosteal plane. The T7 lamina was drilled, and the resection of the superior and inferior adjacent spine levels was completed with a rongeur. Additional contralateral bone resection was performed after tubular retractor tilt to the midline.3 After dura mater opening, it was carefully suspended and the dorsal arachnoid leaflet was cut to drain the dorsolateral and lateral spinal cisterns.4 The dorsal arachnoid web was, first, disconnected from its lateral anchorages. It was then gently removed with microsurgical forceps, to help its microdissection from the spinal cord surface. At this step, peculiar attention was paid to limit the traction or displacements of the spinal cord and surrounding vessels. Once the dorsal arachnoid web was removed, the quality of the spinal cord decompression was confirmed by its re-expansion. In conclusion, the minimally invasive approach is a safe and appropriate technique for dorsal arachnoid web excision.2,5,6-7 The patient gave her informed and signed consent for the writing and publication of this article. Image at 1:00 reused with permission from Castelnovo G et al, Spontaneous transdural spinal cord herniation, Neurology, 2014;82(14):1290.


Congenital malignant melanoma of the scalp in a 25-day-old neonate.
We present a case of congenital malignant melanoma of the scalp in a neonate. The child was born through caesarean section with a swelling, the size of a tennis ball, on the posterior scalp. At presentation to the clinic at 25 days after birth, the swelling had significantly increased in size and ulcerated. An excision was carried out but, because of extensive haemorrhage and haemodynamic instability, the procedure was limited to subtotal resection. Later on, completion of the excision and flap coverage of the wound were performed. After an initial stable course of a few months, the child came back with local recurrence. A re-excision was planned but the child developed pneumonia resulting in sepsis leading to the demise of the child. The report adds to the literature by describing a rare entity and challenges of managing large vascular scalp lesions with complete excision and defect coverage.


Magnetic Resonance Imaging with Active Implantable Hearing Devices: Reports from the Daily Radiological Routine in an Outpatient MR Center.
For people with hearing implants (HI), magnetic resonance imaging (MRI) still presents some difficulties due to the built-in magnet. Radiologists often have concerns regarding complications associated with HIs. The aim of this study was to record the experiences of HI users during and after MRI examinations. A survey including 15 questions regarding MRI specifics, namely changes in hearing ability, hearing/sound impressions, pain, uncomfortable feelings, etc., were mailed to our patients. Overall, 79 patients with HI had a total of 159 MR examinations in our institute. A total of 45 HI recipients reported back: 35% stated that they had been rejected by an MRI Institute because of their HI. Their feelings/impression ratings during the measurements were not present and therefore were not rated for the majority (49%), 42% of the HI users rated the pain with 0 (no pain), 2% with 1 (very light pain), 4% with 5 (acceptable pain), and 2% rated the pain with 7, which is between acceptable and strong pain. One examination resulted in a dislocation of the magnet of a cochlear implant (CI 512 Cochlear Limited). No adverse events were reported for MED-EL HI users in the survey (none of the contacted AB users answered the questionnaire). The reported mean daily wearing time was 11.6 ± 4.6 h per day for 6.3 ± 1.7 days per week. Based on these results and our experience we conclude that MRI examinations with HI are safe given that the measurements are performed according to the safety policies and procedures released by the manufacturers.


Climatic modulation of surface acidification rates through summertime wind forcing in the Southern Ocean.
While the effects of the Southern Annular Mode (SAM), a dominant climate variability mode in the Southern Ocean, on ocean acidification have been examined using models, no consensus has been reached. Using observational data from south of Tasmania, we show that during a period with positive SAM trends, surface water pH and aragonite saturation state at 60°-55° S (Antarctic Zone) decrease in austral summer at rates faster than those predicted from atmospheric CO2 increase alone, whereas an opposite pattern is observed at 50°-45° S (Subantarctic Zone). Together with other processes, the enhanced acidification at 60°-55° S may be attributed to increased westerly winds that bring in more "acidified" waters from the higher latitudes via enhanced meridional Ekman transport and from the subsurface via increased vertical mixing. Our observations support climatic modulation of ocean acidification superimposed on the effect of increasing atmospheric CO2.


Relationship between treatments with insulin and oral hypoglycemic agents versus the presence of vertebral fractures in type 2 diabetes mellitus.
Although previous studies indicated that hypoglycemic agents could affect bone metabolism, little is known about whether these agents are associated with the risks of osteoporotic fracture in Japanese patents with type 2 diabetes. We examined whether treatments of diabetes, such as insulin administration, sulfonylurea, thiazolidinedione, and metformin, were associated with the presence of vertebral fractures in 494 men and 344 postmenopausal women with type 2 diabetes. We analyzed the relationships between each treatment versus bone turnover markers, bone mineral density (BMD), and the presence of prevalent vertebral fractures. Multiple logistic regression analysis adjusted for age, duration of diabetes, body mass index, serum creatinine, serum C-peptide, and HbA(1c) showed that, in postmenopausal women, treatments with insulin administration or thiazolidinedione were significantly and positively associated with the presence of vertebral fractures [odds ratio (OR) = 2.27, P = 0.012 and OR = 3.38, P = 0.038, respectively], whereas treatment with sulfonylurea was significantly and inversely associated with vertebral fractures (OR = 0.48, P = 0.018). These relationships were still significant after additional adjustment for lumbar BMD. In contrast, no significant relationships between treatments with any agent and the presence of vertebral fractures were found in men. These findings suggest that postmenopausal women treated with insulin or thiazolidinedione have a high risk of vertebral fractures independent of age, body stature, blood glucose level, insulin secretion, or BMD whereas treatment with sulfonylurea is associated with a decreased risk.


Non-operative management of fingertip injuries with an intravenous dressing.
The optimal management of fingertip injuries is a much debated topic. Surgical and nonsurgical options, including treatment with dressings alone, have comparable results. IV3000 is a semi-occlusive dressing with a high reactive moisture vapour transmission rate (MVTR) compared to its alternatives. As the fingertip is crucial to hand function, determining the optimal dressing to treat these injuries is of clinical importance. The aim of this study is to collect preliminary data on the IV dressing when used to treat fingertip injuries. Patients were recruited from the department of orthopaedic surgery outpatient clinic. Inclusion criteria were a fingertip injury with skin loss and emergency department treatment consistent with the study protocol, including washing the fingertip, simple debridement as required, administration of antibiotics, tetanus prophylaxis, and fingertip dressed with the IV dressing. Fingertip injuries (15) from 13 male patients were identified. With the exception of one, all injuries were treated with the IV dressing and were included in the analysis. The treatment outcome of 13 injuries was rated as 'satisfactory' by the patients, while one was rated 'indifferent'. The latter was on one of two patients with injuries to two digits. No patient reported their outcome as 'unsatisfactory'. At the 18-24 months' follow-up, seven of the 14 affected digits had some degree of hypersensitivity, eight regained normal pulp thicknesses, one had thickened padding, and five had reduced pulp volume. All but one patient reported some degree of numbness. Nail involvement was seen in 11 injuries, all of which continued to have some degree of nail deformity. The IV dressing provides satisfactory outcomes when used to treat fingertip injuries. As the dressing possesses properties that suggest it would result in a superior healing environment compared to other semi-occlusive dressings, a prospective, randomised control trial should be conducted to determine whether these properties translate into superior outcomes when used to treat fingertip injuries.


Population history of southern Italy during Greek colonization inferred from dental remains.
We are testing competing scenarios regarding the population history of the ancient Greek colonization of southern Italy using dental phenotypic evidence. We collected dental metric and nonmetric trait data for 481 human skeletons from six archaeological sites along the Gulf of Taranto, dating to pre-colonial (900-700 BC) and post-colonial periods (700-200 BC). We are evaluating scenarios through an individual-level biodistance analysis using a three-pronged approach: (a) by analyzing levels of mobility in pre- and post-colonial periods under a model of isolation-by-distance; (b) by quantifying differences in group means and variances in pre- and post-colonial periods utilizing permutational multivariate analysis of variance and Betadisper analyses; and (c) by identifying ancestries of post-colonial individuals using naïve Bayes classification. Southern Italy during pre-colonial times was characterized by low levels of mobility and marked differences in group means and variances. During post-colonial times, mobility increased and there were no differences in group means and variances. About 18% of the people in post-colonial times were of Greek ancestry and lived equally distributed across Greek colonies and indigenous villages. Nevertheless, the overall biological composition and variability of southern Italy remained relatively unchanged across pre- and post-colonial periods. Our results support a scenario in which only few Greek colonists migrated to southern Italy and lived in smaller numbers alongside indigenous people in Greek colonies as well as in indigenous villages. Our results contradict a scenario in which large numbers of Greek invaders founded biologically isolated and substantially homogeneous colonial enclaves within conquered territories.


IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis.
Chronic rhinosinusitis (CRS) with nasal polyps (NPs) in Western populations is associated with TH2 cytokine polarization. IL-25, an IL-17 family cytokine, was recently reported to induce TH2-type immune responses and to contribute to several allergic diseases, such as atopic dermatitis and asthma. However, the role of IL-25 in Asian patients with nasal polyposis remains unclear. We sought to determine the role of IL-25 in Asian patients with nasal polyposis and CRS. We investigated IL-25 expression and its cellular origins in NPs of human subjects using immunohistochemistry (IHC), quantitative RT-PCR, and ELISA of NP tissues. Correlations between IL-25 expression and expression of other inflammatory markers in NP tissues were also explored. Anti-IL-25 neutralizing antibody was administered in an ovalbumin- and staphylococcal enterotoxin B-induced murine NP model to confirm the function of IL-25 during nasal polypogenesis. IL-25 expression was upregulated in NP mucosa from patients with CRS with NPs compared with uncinate process tissue from control subjects and those with CRS without NPs. Overexpression of epithelial IL-25 was confirmed by using IHC, and double IHC staining showed that tryptase-positive cells were one of the main sources of IL-25 among immune cells. Furthermore, IL-17 receptor B levels were also increased in immune cells of patients with NPs compared with those in control subjects. In NPs IL-25 mRNA expression positively correlated with the expression of several inflammatory markers, including T-box transcription factor, RAR-related orphan receptor C, GATA3, eosinophil cationic protein, TGF-β1, and TGF-β2. IL-25 was more abundant in the murine NP model compared with control mice, and similar correlations between IL-25 and inflammatory markers were observed in murine models. Anti-IL-25 treatment reduced the number of polyps, mucosal edema thickness, collagen deposition, and infiltration of inflammatory cells, such as eosinophils and neutrophils. This treatment also inhibited expression of local inflammatory cytokines, such as IL-4 and IFN-γ. Furthermore, expression of CCL11, CXCL2, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in the nasal mucosa was suppressed in the anti-IL-25-treated group. Our results suggest that IL-25 secreted from the sinonasal epithelia and infiltrating mast cells plays a crucial role in the pathogenesis of CRS with NPs in Asian patients. In addition, our results suggest the novel possibility of treating nasal polyposis with anti-IL-25 therapy.


The application of ceramsite ecological floating bed in aquaculture: its effects on water quality, phytoplankton, bacteria and fish production.
In recent years, biological floating bed technology has been applied increasingly in aquaculture ponds. In this study we developed a novel floating bed made from ceramsite and studied its effect on water quality, phytoplankton, bacteria and fish growth. Water quality was effectively regulated and controlled in ceramsite floating bed (CFB) ponds with an average transparency of 23.18 cm, ammonia nitrogen (NH4+-N) of 2.30 mg L-1, total nitrogen (TN) of 5.09 mg L-1 and total phosphate (TP) of 1.32 mg L-1 which are lower than in control ponds without CFB. Increased phytoplankton species diversity, bacterial number, metabolic activity and microbial diversity was observed with CFB. At the end of growth stage, feed conversion ratio (FCR) was reduced with a total fish yield of 14,838 kg ha-1 at a survival rate of 77.2% in CFB ponds, which is significantly higher than control (P < 0.05). These results emphasize the potential of ecological floating bed to improve water quality, microalgal diversity, reduce the risk of harmful algal blooms and increase the number, activity and diversity of microorganisms as well as fish yield.


[Unexpected admission to the intensive care unit following ambulatory surgical procedures].
Unexpected admission (UA) to the intensive care unit (ICU) among the ambulatory patient could be considered as an indicator of quality of attention on ambulatory services. However, the determinants associated with this rare complication are unknown. Objective. To identify the factors associated with UA to the ICU among the patients following ambulatory surgical procedures (ASP). Twenty one cases and 105 controls were selected from among 4,705 patients admitted for an ASP at a teaching hospital between January 2004 and May 2006. A case was that one with an UA to the ICU for monitoring and/or treatment after its ambulatory surgical procedure. Each case was paired with five controls according to type of procedure and date of accomplishment. Conditional logistic regression analyses were used to determine the potential factors associated with an UA to the ICU. Cases represented 0.4% of admitted ones for an ASP. Mean age of controls were 46.9 years and 52.4% were women. There were no statistically significant differences between cases and controls in relation to several clinical, biochemical and physical status variables (comorbidity, vital signs, biochemistry, surgical procedure, anesthetic, technical anesthetic, time of surgery, surgical bleeding). Fourteen patients were less than 48 hours at the ICU and there were no deaths. Most of UA to the ICU seem to be based on decisions non-related to general health status of patients and these are usually preventive. This decision is not based on scientific evidence. Admission to the ICU must be based on a multidisciplinary evaluation.


Figuring algorithm for high-gradient mirrors with axis-symmetrical removal function.
Figuring technologies based on intracone and intercone stitching for high-gradient mirrors are discussed. Based on the conventional computer-controlled optics shaping principle, a process model for a single cone with intracone stitching is constructed. With the circular stitching property of the model, a modified Bayesian-based Richardson-Lucy (RL) algorithm is deduced to deconvolute dwell time for single cone. Building on this algorithm, with the introduction of intercone stitching, a process model for a complex cone is built. Then another modified Bayesian-based RL algorithm is deduced to deconvolute the dwell time for a complex cone from the properties of intracone stitching and intercone stitching. With a velocity realization method for dwell time on a spiral path of the cone and the determination criterion of the path parameter, figuring technologies for single and complex cones are presented. Simulation and experiment demonstrate that theories and methods discussed can solve key problems of figuring high-gradient mirrors; the figuring technologies are novel methods for high-gradient mirrors and can be used to figure mirrors finely.


Friedreich's ataxia in northern Italy: I. Clinical, neurophysiological and in vivo biochemical studies.
Eighteen patients with the presumptive diagnosis of Friedreich's ataxia were studied. Clinical, neurophysiological and biochemical data were concordant in 14 patients and led to the diagnosis of typical Friedreich's ataxia in this group of patients. The remaining 4 patients differed from the typical patients in several respects, but mainly in the cardiological findings. It is concluded that no single clinical or laboratory finding is typical of F.A. Multidisciplinary approaches are essential to the diagnosis of Friedreich's ataxia.


Neuroprotective Effect of Tauroursodeoxycholic Acid (TUDCA) on In Vitro and In Vivo Models of Retinal Disorders: A Systematic Review.
Tauroursodeoxycholic acid (TUDCA) is a naturally produced hydrophilic bile acid that has been used for centuries in Chinese medicine. Numerous recent in vitro and in vivo studies have shown that TUDCA has neuroprotective action in various models of retinal disorders. To systematically review the scientific literature and provide a comprehensive summary on the neuroprotective action and the mechanisms involved in the cytoprotective effects of TUDCA. A systematic review was conducted in accordance with the PRISMA (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Systematic literature search of United States National Library of Medicine (PubMed), Web of Science, Embase, Scopus and Cochrane Library was performed, which covered all original articles published up to July 2022. The terms, "TUDCA" in combination with "retina", "retinal protection", "neuroprotection" were searched. Possible biases were identified with the adopted SYRCLE's tool. Of the 423 initially gathered studies, 24 articles met inclusion/exclusion criteria for full-text review. Six of them were in vitro experiments, 17 studies reported in vivo data and one study described both in vitro and in vivo data. The results revealed the effect of TUDCA on different retinal diseases, such as retinitis pigmentosa (RP), diabetic retinopathy (DR), retinal degeneration (RD), retinal gangli on cell (RGC) damage, Leber's hereditary optic neuropathy (LHON), choroidal neovascularization (CNV), and retinal detachment (RDT). The quality scores of the in vivo studies were ranged from 5 to 7 points (total 10 points), according to SYRCLE's risk of bias tool. Both in vitro and in vivo data suggested that TUDCA could effectively delay degeneration and apoptosis of retinal neurons, preserve retinal structure and function, and its mechanism of actions might be related with inhibiting apoptosis, decreasing inflammation, attenuating oxidative stress, suppressing endoplasmic reticulum(ES) stress, and reducing angiogenesis. This systematic review demonstrated that TUDCA has neuroprotective effect on in vivo and in vitro models of retinal disorders, reinforcing the currently available evidence that TUDCA could be a promising therapeutic agent in retinal diseases treatment. However, well designed clinical trials are necessary to appraise the efficacy of TUDCA in clinical setting.


Crystal and cryoEM structural studies of a cell wall degrading enzyme in the bacteriophage phi29 tail.
The small bacteriophage phi29 must penetrate the approximately 250-A thick external peptidoglycan cell wall and cell membrane of the Gram-positive Bacillus subtilis, before ejecting its dsDNA genome through its tail into the bacterial cytoplasm. The tail of bacteriophage phi29 is noncontractile and approximately 380 A long. A 1.8-A resolution crystal structure of gene product 13 (gp13) shows that this tail protein has spatially well separated N- and C-terminal domains, whose structures resemble lysozyme-like enzymes and metallo-endopeptidases, respectively. CryoEM reconstructions of the WT bacteriophage and mutant bacteriophages missing some or most of gp13 shows that this enzyme is located at the distal end of the phi29 tail knob. This finding suggests that gp13 functions as a tail-associated, peptidoglycan-degrading enzyme able to cleave both the polysaccharide backbone and peptide cross-links of the peptidoglycan cell wall. Comparisons of the gp13(-) mutants with the phi29 mature and emptied phage structures suggest the sequence of events that occur during the penetration of the tail through the peptidoglycan layer.