Parental longevity and diabetes risk in the Diabetes Prevention Program.
Longevity clusters in families, and parental longevity may be associated with lower risk of chronic diseases in their children. It is unknown if diabetes risk is associated with parental longevity. We evaluated participants in the Diabetes Prevention Program with a parental history questionnaire at study entry. We classified them into five groups: premature death (parental death at age < 50 years), parental longevity (living to at least 80 years), and three intermediate groups (alive by age 49 but dying at age 50-59, 60-69, or 70-79). Those with alive parents and younger than 80 years were excluded. We analyzed separately effects of paternal (n = 2,165) and maternal (n = 1,739) longevity on diabetes incidence and risk after an average follow-up of 3.2 years. At baseline, more diabetes risk factors (parental history of diabetes, coronary heart disease, higher body mass index, homeostasis model assessment for insulin resistance, and corrected insulin response) were found in participants whose parents died prematurely. Diabetes incidence was 9.5 cases/100 person-years in the 229 whose fathers died prematurely. In the 618 with paternal longevity, the rate was 6.6 cases/100 person-years (hazard ratio [95% confidence interval] = 0.68 [0.49-0.94]). The rates were 10.7 cases/100 person-years (n = 156) and 7.3 cases/100 person-years (n = 699, hazard ratio = 0.67 [95% confidence interval 0.47-0.95]) for those with maternal premature death or longevity, respectively. Associations with demographic and diabetes risk factors had minimal influence on the reduced risk found in those with paternal (adjusted hazard ratio = 0.78, 95% confidence interval 0.52-1.16) and maternal (adjusted hazard ratio = 0.64, 95% confidence interval 0.41-1.01) longevity. Parental longevity is associated with lower diabetes incidence in adults at high risk of type 2 diabetes.


Air pollution and age-dependent changes in emotional behavior across early adolescence in the U.S.
Recent studies have linked air pollution to increased risk for behavioral problems during development, albeit with inconsistent findings. Additional longitudinal studies are needed that consider how emotional behaviors may be affected when exposure coincides with the transition to adolescence - a vulnerable time for developing mental health difficulties. This study investigates if annual average PM2.5 and NO2 exposure at ages 9-10 years moderates age-related changes in internalizing and externalizing behaviors over a 2-year follow-up period in a large, nationwide U.S. sample of participants from the Adolescent Brain Cognitive Development (ABCD) Study®. Air pollution exposure was estimated based on the residential address of each participant using an ensemble-based modeling approach. Caregivers answered questions from the Child Behavior Checklist (CBCL) at the baseline, 1-year follow-up, and 2-year follow-up visits, for a total of 3 waves of data; from the CBCL we obtained scores on internalizing and externalizing problems plus 5 syndrome scales (anxious/depressed, withdrawn/depressed, rule-breaking behavior, aggressive behavior, and attention problems). Zero-inflated negative binomial models were used to examine both the main effect of age as well as the interaction of age with each pollutant on behavior while adjusting for various socioeconomic and demographic characteristics. Against our hypothesis, there was no evidence that greater air pollution exposure was related to more behavioral problems with age over time.


Ovarian remnant syndrome.
Ovarian remnant syndrome (ORS) refers to a condition occurring in women who have had a bilateral salpingo-oophorectomy (BSO), with or without a hysterectomy, that leaves behind ovarian tissue. This residual ovarian tissue then results in pelvic pain or a pelvic mass. Risk factors associated with incomplete removal of an ovary and subsequent development of ORS include a history of endometriosis, pelvic inflammatory disease, multiple previous surgeries, and pelvic adhesive disease. Patients most frequently present with chronic pelvic pain, pelvic pain associated with a pelvic mass, or an asymptomatic pelvic mass. Definitive criteria for diagnosis of ORS include a history of BSO with histologic documentation of ovarian tissue obtained during subsequent surgical excision. The recommended treatment for ORS is surgical excision by laparotomy or, more recently, laparoscopy. We present the presentation and management of patients with ORS and a review of the published literature.


An optomotor control system with automatic compensation for contrast and texture.
When an animal's surroundings move, the animal normally follows that movement by turning its eyes (that is, by an optomotor reaction). As a result, the retinal image is partly stabilized. The efficacy of this stabilization necessarily depends on the gain of the optomotor control circuit. So far no biological detectors of retinal image movements have been discovered in either vertebrates or invertebrates that is, elements capable of generating a signal proportional to the movement velocity, which could serve as sensors in this control system (Borst & Egelhaaf 1989). The reason is that many other parameters, such as the light intensity and the 'texture' of the pattern, also affect the neuronal output. If movement detection is texture dependent, for instance, the gain and hence the quality of stabilization must also be texture dependent. But in humans, at least, with large-field stimulation the quality of retinal image stabilization has been found to be largely independent of texture (de Graaf et al. 1990). Here I describe a control system with gain control that permits automatic compensation, under closed-loop conditions, of the dependence of movement detection on parameters such as texture, brightness and so on. Comparison with data from experiments on arthropods shows that, in these animals at least, a control circuit with nonlinear properties like those suggested here has in fact been realized.


Influence of comorbidity on self-assessment instrument scores of patients with idiopathic adhesive capsulitis.
The purpose of this study was to determine whether comorbid factors influence the results of self-assessment instruments completed by patients with idiopathic adhesive capsulitis of the shoulder. We hypothesized that an increased number of comorbidities would be correlated with greater pain and worse function as measured by general and shoulder-specific outcome tools. One hundred consecutive patients with phase-II adhesive capsulitis were prospectively evaluated with use of a general health questionnaire, a visual analog pain scale, the Simple Shoulder Test, the Disabilities of the Arm, Shoulder and Hand questionnaire, and the Short Form-36. There were seventy-one women and twenty-nine men, with a mean age of fifty-two years (range, thirty-six to eighty-two years). Comorbidities included medical factors (e.g., diabetes and heart disease) and social factors (e.g., tobacco use and pending litigation). Linear regression analysis was performed to determine correlations between the number of comorbidities and the results of the questionnaires. Patients with more comorbidities had significantly lower scores on the Disabilities of the Arm, Shoulder and Hand Questionnaire (p = 0.0005) and the Short Form-36 subscale of physical function (p = 0.0009) as well as poorer scores on the Simple Shoulder Test and the Short Form-36 subscales of physical role, social function, emotional role, and mental health. Although there was no correlation between increased comorbidity and pain as measured on the visual analog scale, the comfort/pain subscale of the Short Form-36 showed a significant correlation with increased comorbidity (p = 0.004). Idiopathic adhesive capsulitis is a debilitating condition. Comorbid factors have a significant effect on the pain and dysfunction (as measured on shoulder-specific and general health instruments) experienced by patients with this disorder. These findings can be applied to the evaluation of these patients and may help to identify patients who potentially require a longer treatment course or those whose outcome will be less satisfactory.


Modulation of enediyne-induced DNA damage by chromatin structures in transcriptionally active genes.
To better understand how the cellular environment of DNA affects it as a target for genotoxins, we have used ligation-mediated PCR to map DNA damage produced by two DNA-cleaving enediyne antibiotics, esperamicins A1 and C, in the transcriptionally active human p53 and phosphoglycerate kinase (pgk1) genes in vivo. Esperamicin A1, which is limited to damaging the linker region between nucleosome cores due to intercalation of an anthranilate moiety, did not detect the presence of a nucleosome proposed to reside between exons 5 and 6 of p53. This may be due to the absence of a nucleosome at this site in the p53 gene or to the altered structure of nucleosomes in transcriptionally active genes. In studies of the upstream region of the active pgk1 gene, we found that DNA damage produced by both enediynes was enhanced in sequences located between several transcription factor binding sites, while patterns of DNA damage within the binding sites were consistent with known drug binding modes and structures of the protein-DNA complexes. For both drugs, the DNA sequence appeared to be the major determinant of the location of DNA damage, with chromatin structures modulating the quantity of DNA damage.


Enhancement of the Upper Critical Field in Disordered Transition Metal Dichalcogenide Monolayers.
We calculate the effect of impurities on the superconducting phase diagram of transition metal dichalcogenide monolayers in the presence of an in-plane magnetic field. Because of strong intrinsic spin-orbit coupling, the upper critical field greatly surpasses the Pauli limit at low temperatures. We find that it is insensitive to intravalley scattering and, ultimately, limited by intervalley scattering.


Population momentum expresses population aging.
Population momentum and population aging occur when an initially growing population experiences a reduction in fertility to replacement level. Conceptually and empirically, momentum and aging express the same change, albeit on different scales. Fundamentally, they are two manifestations of the underlying process of demographic transformation. We consider three measures of aging over the transition to stationarity: the increase in mean population age, the decrease in the proportion under age 30, and the increase in the proportion over age 65. The three measures of aging are highly correlated, though the relationship to momentum is weakest for the increase in the proportion over age 65. We find that momentum is linearly related to aging. In both model and actual populations, a one-year increase in mean age translates into about 4.5% more population growth. The population below age 30 does not grow over the transition to stationarity and the ratio of initial to ultimate proportions under age 30 is virtually identical to momentum.


Chemopreventive effect and angiogenic activity of punicalagin isolated from leaves of Lafoensia pacari A. St.-Hil.
Punicalagin is the major ellagitannin constituent from leaves of Lafoensia pacari, a Brazilian medicinal plant widely used for the treatment of peptic ulcer and wound healing. Genotoxic, cytotoxic, antigenotoxic, and anticytotoxic effects of punicalagin were assessed using micronucleus (MN) test and comet assay in mice. Due to the extensive use of L. pacari in the wound healing process, we also assessed the angiogenic activity of punicalagin using the chick chorioallantoic membrane (CAM) angiogenic assay. The highest dose of punicalagin (50mg/kg) showed significant cytotoxic effect by MN test and in the co-treatment with cyclophosphamide (CPA), this cytotoxicity was enhanced. Co-treatment, pre-treatment and post-treatment of punicalagin with CPA led to a significant reduction in the number of DNA breaks and in the frequency of CPA-induced MN, indicating antigenotoxic effect. Using the CAM model, punicalagin exhibited angiogenic activity in all doses mainly at the lowest concentration (12.5μg/μL). Therefore, these findings indicate an effective chemopreventive role of punicalagin and a high capacity to induce DNA repair. Also, the angiogenic activity presented by punicalagin in this study could contribute for the processes of tissue repairing and wound healing.


Contribution of catechol O-methyltransferase to the removal of accumulated interstitial catecholamines evoked by myocardial ischemia.
Catechol O-methyltransferase (COMT) plays an important role for clearance of high catecholamine levels. Although myocardial ischemia evokes similar excessive catecholamine accumulation, it is uncertain whether COMT activity is involved in the removal of accumulated catecholamines evoked by myocardial ischemia. We examined how COMT activity affects myocardial catecholamine levels during myocardial ischemia and reperfusion. We implanted a dialysis probe into the left ventricular myocardial free wall and measured dialysate catecholamines levels in anesthetized rabbits. Dialysate catecholamine levels served as an index of myocardial interstitial catecholamine levels. We introduced myocardial ischemia by 60 min occlusion of the main coronary artery. The ischemia-induced dialysate catecholamines levels were compared with and without the pretreatment with entacapone (COMT inhibitor, 10 mg/kg, i.p.). Acute myocardial ischemia progressively increased dialysate catecholamine levels. Acute myocardial ischemia increased dialysate norepinephrine (NE) levels (20,453+/-7186 pg/ml), epinephrine (EPI) levels (1724+/-706 pg/ml), and dopamine (DA) levels (1807+/-800 pg/ml) at the last 15 min of coronary occlusion. Inhibition of COMT activity by entacapone augmented the ischemia-induced NE levels (54,306+/-6618 pg/ml), EPI levels (2681+/-567 pg/ml), and DA (3551+/-710 pg/ml) levels at the last 15 min of coronary occlusion. Myocardial ischemia evoked NE, EPI, and DA accumulation in the myocardial interstitial space. The inhibition of COMT activity augmented these increments in NE, EPI, and DA. These data suggest that cardiac COMT activity influences on the removal of accumulated catecholamine during myocardial ischemia.


Structure alignment via Delaunay tetrahedralization.
A novel protein structure alignment technique has been developed reducing much of the secondary and tertiary structure to a sequential representation greatly accelerating many structural computations, including alignment. Constructed from incidence relations in the Delaunay tetrahedralization, alignments of the sequential representation describe structural similarities that cannot be expressed with rigid-body superposition and complement existing techniques minimizing root-mean-squared distance through superposition. Restricting to the largest substructure superimposable by a single rigid-body transformation determines an alignment suitable for root-mean-squared distance comparisons and visualization. Restricted alignments of a test set of histones and histone-like proteins determined superpositions nearly identical to those produced by the established structure alignment routines of DaliLite and ProSup. Alignment of three, increasingly complex proteins: ferredoxin, cytidine deaminase, and carbamoyl phosphate synthetase, to themselves, demonstrated previously identified regions of self-similarity. All-against-all similarity index comparisons performed on a test set of 45 class I and class II aminoacyl-tRNA synthetases closely reproduced the results of established distance matrix methods while requiring 1/16 the time. Principal component analysis of pairwise tetrahedral decomposition similarity of 2300 molecular dynamics snapshots of tryptophanyl-tRNA synthetase revealed discrete microstates within the trajectory consistent with experimental results. The method produces results with sufficient efficiency for large-scale multiple structure alignment and is well suited to genomic and evolutionary investigations where no geometric model of similarity is known a priori.


Patients with coronary artery disease unsuitable for revascularization: definition, general principles, and a classification.
In the present report, we review the phenotypes of coronary artery disease (CAD) patients unsuitable for revascularization procedures. We then analyze these phenotypes and propose a simple angiographic-based classification for patients with CAD unsuitable for revascularization. Under this classification, the following four distinct angiographic phenotypes are proposed: (1) suspected cardiac syndrome X; (2) limited territory at risk; (3) diffuse thread-like coronary atherosclerosis; and (4) end-stage CAD. It is hoped that such a classification system, as well as the general principles described in this report, will help to standardize the collection of epidemiological data on patients with refractory angina (RFA) and advanced CAD. It is also hoped that this system will be useful to extend the principles of clinical equipoise to the development of clinical trials of innovative therapies or devices for the treatment of RFA. Finally, we anticipate that the elaboration of this system, the first of its type in the literature, will stimulate discussion of what we feel to be a subject that has received insufficient attention in the literature, and ultimately to improved management of a challenging patient population.


Charged residues next to transmembrane regions revisited: "Positive-inside rule" is complemented by the "negative inside depletion/outside enrichment rule".
Transmembrane helices (TMHs) frequently occur amongst protein architectures as means for proteins to attach to or embed into biological membranes. Physical constraints such as the membrane's hydrophobicity and electrostatic potential apply uniform requirements to TMHs and their flanking regions; consequently, they are mirrored in their sequence patterns (in addition to TMHs being a span of generally hydrophobic residues) on top of variations enforced by the specific protein's biological functions. With statistics derived from a large body of protein sequences, we demonstrate that, in addition to the positive charge preference at the cytoplasmic inside (positive-inside rule), negatively charged residues preferentially occur or are even enriched at the non-cytoplasmic flank or, at least, they are suppressed at the cytoplasmic flank (negative-not-inside/negative-outside (NNI/NO) rule). As negative residues are generally rare within or near TMHs, the statistical significance is sensitive with regard to details of TMH alignment and residue frequency normalisation and also to dataset size; therefore, this trend was obscured in previous work. We observe variations amongst taxa as well as for organelles along the secretory pathway. The effect is most pronounced for TMHs from single-pass transmembrane (bitopic) proteins compared to those with multiple TMHs (polytopic proteins) and especially for the class of simple TMHs that evolved for the sole role as membrane anchors. The charged-residue flank bias is only one of the TMH sequence features with a role in the anchorage mechanisms, others apparently being the leucine intra-helix propensity skew towards the cytoplasmic side, tryptophan flanking as well as the cysteine and tyrosine inside preference. These observations will stimulate new prediction methods for TMHs and protein topology from a sequence as well as new engineering designs for artificial membrane proteins.


[Metastatic breast cancer: what are the objectives?].
The medical approach to the treatment of metastatic breast cancer has changed in the last decade since the introduction of new drugs that demonstrate high activity and better tolerability profiles. The hormonal treatment, usually considered the first choice therapy for ER-positive metastatic breast cancer patients, has seen several improvements with the discovery of new selective aromatase-inhibitor agents and pure antiestrogens. New aromatase-inhibitors have shown higher activity and fewer side effects compared to megestrol acetate in second line treatment. The first line treatment has unchanged so far, but in the next future is possible that different agents, with lower toxicity, will replace tamoxifen since studies comparing this agent with pure antiestrogens or selective aromatase-inhibitors are ongoing. These new drugs would provide a better palliation of metastatic breast cancer in terms of higher clinical benefit, tolerability and quality of life. Chemotherapy is often used in ER-negative patients or in aggressive hormone refractory disease. Randomized trials have demonstrated that anthracyclin-containing regimens were more effective than combinations without anthracyclines. New cytotoxic drugs with high activity, such as taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine and capecitabine, have been introduced. Compared with older therapies, improved objective response rates and/or improved duration of response have been reported with these newer agents alone or in combination with other drugs. However, no clear improvement of overall survival has been shown so far. Taxanos alone or in combination are today considered the second line treatment of choice and studies are assessing the value of a taxane-anthracycline containing regimen in first line treatment. Some new agents (vinorelbine) showed, alone or in combination, an interesting cost-effectiveness ratio with similar or higher "quality adjusted progression free survival" if compared to taxanes. Promising are also the results of agents that own low toxicity with comparable efficacy such as liposomal anthracycline. Attempts to improve overall survival with increased dose intensity or with high dose chemotherapy are disappointing. Since the goal of treatment of metastatic breast cancer is disease control rather than disease skill i.e. palliation of patients with complications of progressive cancer, the new agents have brought significant improvements (higher response rates, median time to progression, cost benefit and better tolerability). Future progresses for this disease, hopefully even in overall survival, will depend on the introduction of new therapies such as immunotherapy, inhibition of intracellular signaling, interference with tumor angiogenesis, gene-therapy and the development of vaccines.


Quantification of subsurface hydrologic connectivity in four headwater catchments using graph theory.
Hillslope-stream connectivity significantly affects streamflow and water quality responses during rainfall and snowmelt events, but is difficult to quantify. One approach to quantify subsurface hillslope-stream connectivity is graph theory, which considers linear connections between groundwater measurement sites. We quantified subsurface connectivity based on surface topography and shallow groundwater data from four small (<14 ha) headwater catchments in the Italian Dolomites and the Swiss pre-Alps, determined the relation between rainfall, antecedent wetness conditions and subsurface connectivity and assessed the sensitivity of the results to changes in the measurement network. Event total stormflow was correlated to maximum subsurface connectivity. Subsurface connectivity increased during rainfall events but maximum connectivity occurred later than peak streamflow, resulting in anti-clockwise hysteretic relations between the two. Subsurface connectivity was positively correlated to rainfall amount. Maximum subsurface connectivity was related to the sum of total rainfall plus antecedent rainfall for the Dolomitic catchments, but these relations were less clear for the pre-alpine catchments. For the pre-alpine catchments, the fractions of time that the groundwater monitoring sites were connected to the stream were significantly correlated to the upslope site characteristics, such as the Topographic Wetness Index. For the Dolomitic catchments, the fractions of time that the monitoring sites were connected to the stream were correlated to the topographic characteristics of the upslope contributing area for the catchment with the small riparian zone, and with the distance to the nearest stream for the catchment with the large riparian zone. The leave-one-out sensitivity analysis showed that small changes in the structure of the groundwater monitoring networks had a limited influence on the results, suggesting that graph-theory approaches can be used to describe subsurface hydrologic connectivity. However, the proposed graph-theory approach should be verified in other catchments with different groundwater monitoring networks.


The case for orthopaedic medicine in Israel.
Musculoskeletal complaints are probably the most frequent reasons for visiting a doctor. They comprise more than a quarter of the complaints to primary practitioners and are also the most common reason for referral to secondary or tertiary medicine. The clinicians most frequently consulted on musculoskeletal problems, and probably perceived to know most on the topic are orthopaedic surgeons. But in Israel, there is significant ambivalence with various aspects of the consultations provided by orthopaedic surgeons, both among the public and among various groups of clinicians, particularly family practitioners and physiotherapists. In order to understand this problem we integrate new data we have collected with previously published data. New data include the rates of visits to orthopaedic surgeons per annum in one of Israel's large non-profit HMO's, and the domains of the visits to an orthopaedic surgeon. Orthopaedic surgeons are the third most frequently contracted secondary specialists in one of the Israeli HMO's. Between 2009 and 2012 there was a 1.7% increase in visits to orthopaedists per annum (P < 0.0001, after correction for population growth). Almost 80% of the domains of the problems presented to an orthopaedic surgeon were in fields orthopaedic surgeons have limited formal training. While orthopaedic surgeons are clearly the authority on surgical problems of the musculoskeletal system, most musculoskeletal problems are not surgical, and the orthopaedic surgeon often lacks training in these areas which might be termed orthopaedic medicine. Furthermore, in Israel and in many other developed countries there is no accessible medical specialty that studies these problems, trains medical students in the subject and focuses on treating these problems. The neglect of this area which can be called the "Orthopaedic Medicine Lacuna" is responsible for inadequate treatment of non-surgical problems of the musculoskeletal system with immense financial implications. We present a preliminary probe into possible solutions which could be relevant to many developed countries.


Child maltreatment online education for healthcare and social service providers: Implications for the COVID-19 context and beyond.
Evidence indicates that healthcare and social service providers (HSSPs) receive inadequate education related to recognizing and responding to child maltreatment. This is despite the fact HSSPs are identified as an important factor in the primary, secondary, and tertiary prevention of this childhood exposure. The need for online education for HSSPs' is highlighted during the COVID-19 pandemic restrictions and will continue to be relevant afterward. The objective of this commentary is to provide an overview of: (a) educational interventions for HSSPs' related to recognizing and responding to child maltreatment; (b) the development of VEGA (Violence, Evidence, Guidance, Action), which is an online platform of educational resources to support HSSPs to recognize and respond to child maltreatment; and (c) the RISE (Researching the Impact of Service provider Education) project, which is an ongoing multi-province evaluation of VEGA in Canada. It is important to consider ongoing ways that HSSPs can receive education related to recognizing and responding to child maltreatment. The virtual implementation of VEGA and the RISE Project provide a necessary opportunity to continue to increase the capacity of Canada's HSSPs to adequately and safely recognize and respond to child maltreatment, while simultaneously advancing education scholarship for the field of child maltreatment and which will have relevance for the COVID-19 context and beyond.


Neonatal dexamethasone induces premature microvascular maturation of the alveolar capillary network.
Postnatal glucocorticoid treatment of preterm infants was mimicked by treating newborn rats with dexamethasone (0.1-0.01 microg/g, days 1-4). This regimen has been shown to cause delayed alveolarization. Knowing that microvascular maturation (transformation of double- to single-layered capillary networks in alveolar septa) and septal thinning prevent further alveolarization, we measured septal maturation on electron photomicrographs in treated and control animals. In treated rats and before day 10, we observed a premature nonreversing microvascular maturation and a transient septal thinning, which both appeared focally. In vascular casts of both groups, we observed contacts between the two capillary layers of immature alveolar septa, which were predictive for capillary fusions. Studying serial electron microscopic sections of human lungs, we were able to confirm the postulated fusion process for the first time. We conclude that alveolar microvascular maturation indeed occurs by capillary fusion and that the dexamethasone-induced impairment of alveolarization is associated with focal premature capillary fusion.


[Effect of thermal treatments on the chemical characteristics of mora crab meat (Homalaspis plana)].
Marine species muscles present non-proteins nitrogenated compounds, used as quality index. They are total volatile basis (NBVT), trimethylamine oxide (TMAO) and trimethylamine (TMA). pH is considered too as a quality index. The aim of this work was to evaluate these parameters in a fresh and canned marine product from the V region, corresponding to mora crab (Homalaspis plana). Fresh pincer meat from mora crab was extracted and kept in ice until theits analysis and thermal process of the canned product. A 3(2) statistical design was applied, considering two variables with 3 levels: 15, 30 y 45 minutes time levels: 80 degrees, 100 degrees y 121 degrees C temperature levels. Nine conditions of time-temperature were obtained. The thermal treatment caused an increase in pH and BVT. The TMA was increased since reduction of TMAO.


Hemichorea-hemiballismus as an initial manifestation in a Moroccan patient with acquired immunodeficiency syndrome and toxoplasma infection: a case report and review of the literature.
Neurologic signs and symptoms may represent the initial presentation of AIDS in 10-30% of patients. Movement disorders may be the result of direct central nervous system infection by human immunodeficiency virus (HIV) or the result of opportunistic infections. We report the case of a 59 years old woman who had hemichorea-hemiballismus subsequently found to be secondary to a cerebral toxoplasmosis infection revealing HIV infection. Movement disorders, headache and nausea were resolved after two weeks of antitoxoplasmic treatment. Brain MRI control showed a marked resolution of cerebral lesion. Occurrence of hemichorea-ballismus in patient without familial history of movement disorders suggests a diagnosis of AIDS and in particular the diagnosis of secondary cerebral toxoplasmosis. Early recognition is important since it is a treatable entity.


Shoulder dislocation in skiing: choice of surgical method depending on the degree of humeral retrotorsion.
Shoulder dislocation is one of the typical upper extremity injuries in skiing, first following a violent accident but quite frequently recurring without new trauma. This article discusses the retrotorsional angle of the humerus as an etiological factor in the occurrence of an initial dislocation and as a triggering element for its recurrence. It focuses on the consequences to be drawn for the surgical treatment of recurrent shoulder dislocation. A technique for exact determination of the humeral angle of retrotorsion by X-ray is presented. In patients with recurrent anterior dislocations of the shoulder joint, the retrotorsional angle of the humerus is pathologically reduced as compared to the control group. The method of surgical therapy is determined by the individual deviance from the average value.


Calcium, network activity, and the role of NMDA channels in synaptic plasticity in vitro.
Functionally effective neuronal circuits are constructed through a competitive process that requires patterned neuronal activity elicited by structured input from the environment. To explore the mechanisms of this activity-dependent synaptic restructuring, we have developed an in vitro preparation of mouse spinal cord neurons maintained in a 3-chambered cell-culture system. Sensory afferents that received chronic electrical stimulation for 3-5 d developed stronger synaptic connections than unstimulated afferents converging onto the same postsynaptic spinal cord neuron. Exposure to 100 microM DL-2-amino-5-phosphonovaleric acid (APV), an antagonist of the NMDA channel, during the stimulation period prevented the competitive advantage associated with electric stimulation. However, when APV was applied with a higher concentration of calcium (3 mM), activity-dependent synaptic plasticity was no longer inhibited by the NMDA receptor antagonist. This reversal of APV block of the plasticity was not impaired by reducing transmitter release with 3 mM magnesium (in addition to 3 mM calcium and APV). A suppressant effect of APV on spontaneous activity was observed, which was attributed to loss of the NMDA component of the EPSP. Activity-dependent plasticity was also blocked if spontaneous activity was suppressed with dilute tetrodotoxin (TTX; 5-10 nM), a dosage that reduces excitability of neurons but is insufficient to block sodium-dependent action potentials. These experiments bring into question how NMDA channel activation is involved in the processes of synaptic remodeling during development. The data suggest that postsynaptic activity is required for synaptic remodeling, but this activity need not involve NMDA receptor activation specifically for activity-evoked synaptic plasticity. Instead, the mechanism for plasticity appears to operate through calcium-dependent processes in general.


[What is the current age and sex-related cadmium burden of the human kidney cortex?].
55 persons of either sex in the age bracket between 0.02 and 87 years had to be examined by experts in forensic medicine. In these examinations, slices of kidney cortex were removed and prepared for cadmium(Cd)-determination by atomic absorption spectrophotometry. The samples were wet ashed by a special and quick method developed in our laboratory, using concentrated (65%) HNO3 for a short period of 1 hour at 90 degrees C. The main results of the present study were that Cd accumulation in the kidney cortex was delayed in the age group between 0.02 and 40 years. The highest Cd concentration of 27 micrograms/g wet weight was found in the age group between 50-59 years. In persons of higher age, above 60 years, the Cd concentrations were generally lower than in persons of the age group between 50-59 years; however, this decline does not seem to be significant. Summing up, we can say that the delayed increase in Cd concentrations in the kidney cortex of persons in the age group between 0.02 and 40 years might be regarded as the first positive result of the restrictive use of Cd materials, resulting in food intake with lower Cd contamination. The present study should be repeated after about 5 years to confirm whether this hopeful assumption is true.


Sarcopenia and sarcopenic obesity among men aged 80 years and older in Beijing: prevalence and its association with functional performance.
Sarcopenia and sarcopenic obesity are significant associative factors for functional impairment related to aging. The main aim of the present study was to investigate the prevalence of sarcopenia and sarcopenic obesity, and their associations with functional status among men aged 80 years and older in Beijing. A total of 75 young healthy volunteers, and 101 older men aged 80 years and older participated in the present study. Demographic characteristics, anthropometry, skeletal muscle mass measured by dual X-ray absorptiometry (DXA), 6-m gait speed and handgrip strength were collected. Relative appendicular skeletal muscle index (RASM) and percentage skeletal muscle index (SMI) were obtained. Overall, the prevalence of sarcopenia was 45.7% by using RASM. By the weight-adjusted skeletal muscle index definition (SMI), the prevalence of sarcopenia was 53.2%. The prevalence of sarcopenic obesity was lower by using RASM than SMI (4.9% vs 11.5%, P < 0.05). When we compared the sarcopenia prevalence (%) in obese participants, it was also remarkably lower by using RASM (40.0%) than SMI (95.0%). By using either RASM or SMI, gait speed was of no significant difference among the pure sarcopenia group, pure obese group and sarcopenic obesity group (0.76 ± 0.27 vs 0.82 ± 0.37 vs 0.82 ± 0.27 m/s, P > 0.05, by RASM; 0.75 ± 0.25 vs 0.92 ± 0.27 vs 0.82 ± 0.35 m/s, P > 0.05 by SMI), respectively. Multiple linear regression analyses showed that thigh skeletal muscle mass was positively correlated with gait speed independently (β = 0.221, P = 0.011), and total body fat (β = -0.216, P = 0.002) and age (β = -0.524, P = 0.000) were negatively correlated with gait speed independently. The prevalence of sarcopenia is high either based on RASM or SMI among Chinese men aged 80 years and older. Functional limitations were significantly associated with older age, skeletal muscle mass and total body fat.


Psychometric properties of the Perceived Stress Scale in a sample of German dementia patients and their caregivers.
The aim of the present study was to investigate the psychometric characteristics of the Perceived Stress Scale (PSS) in a sample of dementia patients and their spousal caregivers. We investigated the reliability and validity of the 14-item PSS in a sample of 80 couples, each including one spouse who had been diagnosed with mild to moderate dementia (mean age 75.55, SD = 5.85, 38.7% female) and one spousal caregiver (mean age 73.06, SD = 6.75, 61.3% female). We also examined the factor structure and sensitivity of the scale with regard to gender differences. Exploratory factor analysis of the PSS revealed a two-factor solution for the scale; the first factor reflected general stress while the second factor consisted of items reflecting the perceived ability to cope with stressors. A confirmatory factor analysis verified that the data were a better fit for the two-factor model than a one-factor model. The two factors of the PSS showed good reliability for patients as well as for caregivers ranging between α = 0.73 and α = 0.82. Perceived stress was significantly positively correlated with depressive symptomatology in both caregivers and patients. Mean PSS scores did not significantly differ between male and female patients nor did they differ between male and female caregivers. The present data indicate that the PSS provides a reliable and valid measure of perceived stress in dementia patients and their caregivers.


Statin-associated myasthenic weakness.
Statin-associated myasthenic weakness is uncommonly recognized. Since 2002, there have been 14 cases described in literatures. However, the underlying mechanism is still unknown. In 2007, a 50-year-old woman with generalized, limb predominated, myasthenia gravis (MG), whose MG status has been "minimal manifestation" for several years, developed moderately severe fluctuating bulbar weakness a few weeks after starting simvastatin 20 mg/day. Simvastatin was discontinued and dosage of cholinesterase inhibitor was temporarily increased. The symptoms resolved and she was back to her previous status in one month. In 2008, two weeks after re-challenge with simvastatin 10 mg/day, bulbar weakness re-occurred Antibody to acetylcholine receptors was measured 4.25 nmole/L. Serum creatine phosphokinase was normal. Electrophysiologic tests showed evidences of postsynaptic neuromuscular junction disorder without evidence of myopathy. The symptoms were again resolved after discontinuation of statin and temporarily increased dosage of cholinesterase inhibitor. She was back to previous status in two months. Hypercholesterolemia was then controlled with ezetimibe without any worsening in MG status. Because of the wide use of statins in clinical practice, physicians should be aware of this potential adverse effect. The incidence ofstatin-associated myasthenic weakness should be clearly investigated Challenge with other brands of statin or with reduced dosage is not beneficial in these patients. Non-pharmacological treatment and non-statin medication may be considered


Conditioned Medium Derived from Salidroside-Pretreated Mesenchymal Stem Cell Culture Ameliorates Mouse Lipopolysaccharide-Induced Cerebral Neuroinflammation- Histological and Immunohistochemical Study.
Neuroinflammation is involved in the pathogenesis of neurodegenerative disorders. Conditioned medium (CM) derived from bone marrow mesenchymal stem cells (MSCs) revealed substantial benefits due to its rich content of trophic factors. Salidroside (Sal), extracted from Rhodiola rosea, is known for its anti-inflammatory and neuroprotective effects. This study was designed to investigate the effect of Sal pretreated CM (CM-Sal) derived from bone marrow MSCs in lipopolysaccharide (LPS) induced neuroinflammation. Fifty adult male mice were equally divided into 5 groups: Group I (Normal Control), Group II (LPS): single 0.8 mg/kg LPS intraperitoneally; Group III (LPS-DMEM), Group IV (LPS-CM) and Group V (LPS-CM-Sal): LPS was injected as group II followed, 24 hours later, by intranasal injection of 50 μl of filtered serum- free Dulbecco's Modified Eagle's medium (DMEM), CM or CM-Sal, respectively, twice daily for 4 days. Animals were sacrificed at day 6 and paraffin cerebral sections were subjected to Hematoxylin and Eosin staining and immunohistochemistry with caspase 3 (apoptosis), glial fibrillary acidic protein GFAP (astrocytes) and CD68 (active microglia) followed by quantitative morphometric study. Examination of LPS and LPS-DMEM groups revealed neuronal apoptosis with reactive astrogliosis and increased active microglia. LPS-CM and LPS-CM-Sal groups showed less apoptosis, less astrocytes and less active microglia. The regression in neuroinflammation was more evident in LPS-CM-Sal group and the difference was statistically significant compared to other groups. CM-Sal derived from MSCs culture elicited significant histopathological improvement in LPS induced neuroinflammation which could be used as new therapeutic modality.


Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver.
Iron depletion improves insulin resistance in patients with nonalcoholic fatty liver disease and diabetes and also stabilizes the hypoxia-inducible factor (HIF)-1, resulting in increased glucose uptake in vitro. This study investigated the effect of iron depletion by deferoxamine on insulin signaling and glucose uptake in HepG2 hepatocytes and in rat liver. In HepG2 cells, deferoxamine stabilized HIF-1alpha and induced the constitutive glucose transporter Glut1 and the insulin receptor. Up-regulation of insulin receptor by deferoxamine was mimicked by the intracellular iron chelator deferasirox and the hypoxia inducer CoCl2 and required the HIF-1 obligate partner ARNT/HIF-1beta. Iron depletion increased insulin receptor activity, whereas iron supplementation had the opposite effect. Deferoxamine consistently increased the phosphorylation status of Akt/PKB and its targets FoxO1 and Gsk3beta, which mediate the effect of insulin on gluconeogenesis and glycogen synthesis, and up-regulated genes involved in glucose uptake and utilization. Iron depletion of Sprague-Dawley rats increased HIF-1alpha expression, improved glucose clearance, and was associated with up-regulation of insulin receptor and Akt/PKB levels and of glucose transport in hepatic tissue. Conversely, gluconeogenic genes were not affected. In rats with fatty liver because of a high-calorie and high-fat diet, glucose clearance was increased by iron depletion and decreased by iron supplementation. Thus, iron depletion by deferoxamine up-regulates glucose uptake, and increases insulin receptor activity and signaling in hepatocytes in vitro and in vivo.


Synthesis of P1'-functionalized macrocyclic transition-state mimicking HIV-1 protease inhibitors encompassing a tertiary alcohol.
Seven novel tertiary alcohol containing linear HIV-1 protease inhibitors (PIs), decorated at the para position of the benzyl group in the P1' side with (hetero)aromatic moieties, were synthesized and biologically evaluated. To study the inhibition and antiviral activity effect of P1-P3 macrocyclization, 14- and 15-membered macrocyclic PIs were prepared by ring-closing metathesis of the corresponding linear PIs. The macrocycles were more active than the linear precursors and compound 10f, with a 2-thiazolyl group in the P1' position, was the most potent PI of this new series (Ki 2.2 nM, EC50 0.2 μM). Co-crystallized complexes of both linear and macrocyclic PIs with the HIV-1 protease enzyme were prepared and analyzed.


Novel cyclopentadienyl tricarbonyl (99m)tc complexes containing 1-piperonylpiperazine moiety: potential imaging probes for sigma-1 receptors.
We report the design, synthesis, and evaluation of a series of novel cyclopentadienyl tricarbonyl (99m)Tc complexes as potent σ1 receptor radioligands. Rhenium compounds 3-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl)propylcarbonylcyclopentadienyl tricarbonyl rhenium (10a) and 4-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl)butylcarbonylcyclopentadienyl tricarbonyl rhenium (10b) possessed high in vitro affinity for σ1 receptors and moderate to high selectivity for σ2 receptors and the vesicular acetylcholine transporter. Biodistribution studies in mice demonstrated high initial brain uptake for corresponding (99m)Tc derivatives [(99m)Tc]23 and [(99m)Tc]24 of 2.94 and 2.13% injected dose (ID)/g, respectively, at 2 min postinjection. Pretreatment of haloperidol significantly reduced the radiotracer accumulation of [(99m)Tc]23 or [(99m)Tc]24 in the brain. Studies of the cellular uptake of [(99m)Tc]23 in C6 and DU145 tumor cells demonstrated a reduction of accumulation by incubation with haloperidol, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (SA4503), or 1,3-di-o-tolyl-guanidine (DTG). Furthermore, blocking studies in C6 glioma-bearing mice confirmed the specific binding of [(99m)Tc]23 to σ1 receptors in the tumor.


Introduction of DT40 cells into chick embryos.
To examine the transfection of exogenous genes into chick embryos, applying the characteristics of avian leukosis virus (ALV)-induced chicken B cell line DT40 to the production of chimeric birds. The DT40 cells incorporated with exogenous gene ( lacZ constructs encoding Escherichia coli beta-galactosidase: beta-gal) were introduced into chick embryos by the injection of cells into stage X blastoderm. Manipulated eggs were incubated for 3 (trial 1) or 6 (trial 2) days, and the expression of lacZ DNA was detected by a histochemical staining method of beta-galactosidase and polymerase chain reaction (PCR) analysis. The survival rates of the manipulated embryos incubated for 3 days (stage 18-20: trial 1) and 6 days (stage 28, 30: trial 2) were about 42% and 38%, respectively. The expression rates of the lacZ gene in the embryos in the trials 1 and 2 were about 60% and 23%, respectively, for the survived embryos. The rate of embryonic viability and expression rate of introduced genes were not so high, but it suggested the possibility of utilizing the DT40 cells as a vector for carrying exogenous genes into chick embryos.


Availability to lactating dairy cows of methionine added to soy lecithins and mixed with a mechanically extracted soybean meal.
We evaluated a product containing methionine mixed with soy lecithins and added to a mechanically extracted soybean meal (meSBM-Met). Lactational responses of cows, plasma methionine concentrations, and in vitro degradation of methionine were measured. Twenty-five Holstein cows were used in a replicated 5 × 5 Latin square design and fed a diet designed to be deficient in methionine or the same diet supplemented either with 4.2 or 8.3g/d of supplemental methionine from a ruminally protected source or with 2.7 or 5.3g/d of supplemental methionine from meSBM-Met. All diets were formulated to provide adequate amounts of metabolizable lysine. Concentration of milk true protein was greater when methionine was provided by the ruminally protected methionine than by meSBM-Met, but milk protein yield was not affected by treatment. Milk yields and concentrations and yields of fat, lactose, solids-not-fat, and milk urea nitrogen were not affected by supplemental methionine. Body condition scores increased linearly when methionine from meSBM-Met was supplemented, but responses were quadratic when methionine was provided from a ruminally protected source. Nitrogen retention was not affected by supplemental methionine. Plasma methionine increased linearly when methionine was supplemented from a ruminally protected source, but plasma methionine concentrations did not differ from the control when supplemental methionine from meSBM-Met was provided. In vitro degradation of supplemental methionine from meSBM-Met was complete within 3h. Data suggest that meSBM-Met provides negligible amounts of metabolizable methionine to dairy cows, and this is likely related to extensive ruminal destruction of methionine; however, cow body condition may be improved by ruminally available methionine provided by meSBM-Met.


A competitive binding assay for 2,3,7,8-tetrachlorodibenzo-p-dioxin and related ligands of the Ah receptor.
A sensitive competitive binding assay for the detection of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other ligands of the Ah receptor was developed using a stable preparation of the Ah receptor, the 40-55% ammonium sulfate fraction of liver cytosol from C57BL/6J mice, and the radioligand [125I]2-iodo-7,8-dibromodibenzo-p-dioxin (specific radioactivity, 2176 Ci/mmol, and binding affinity, KD = 6.5 pM). Conditions are described which maximize assay precision and sensitivity, while minimizing sample counting time, ensuring ligand solubility, and permitting attainment of binding equilibrium for competing ligands. Assay conditions were developed to allow calculation of the binding affinity for competing ligands and to ensure that an unknown competitor could be quantified in terms of "TCDD binding equivalents." Standard assay conditions consisted of incubation of 8 pM radioligand and 18-20 pM Ah receptor with 5-1000 pM TCDD, in a 1-ml volume, for 16 hr at 4 degrees. Statistical analysis of the standard curve of bound radioligand versus the log of the concentration of competing TCDD indicated the minimal detectable concentration of TCDD to be 10 pM (3.2 pg in a 1-ml assay alpha less than or equal to 0.01). The simplicity, sensitivity, and reproducibility of this competitive binding assay should prove useful as a screen to detect planar halogenated aromatic hydrocarbons and other ligands of the Ah receptor. The availability of this 125I-labeled dioxin congener also permitted the characterization of Ah receptor-ligand binding over a range of ligand and receptor concentrations not possible with currently available 3H-ligands.


Immunology of herpes simplex virus infection: relevance to herpes simplex virus vaccines and cervical cancer.
The immunology of herpes simplex infections has been reviewed, particularly in relation to potential herpes simplex virus (HSV) vaccines, and to the association between HSV and cervical cancer. Relevant data from humans, experimental animals, and in vitro systems implicate both specific immune mechanisms and nonspecific factors in the course of HSV infections. There appear to be complex interactions between the various populations of mononuclear cells, marcrophages, and lymphokines or other humoral factors. It is not yet possible, however, to pinpoint the crucial factors determining the different manifestations of the viral infection (primary infection, endogenous recurrence, or exogenous reinfection) in the various human hosts, although genetic factors may be important. While numerous animal models of HSV infection are available for the evaluation of HSV vaccines, models of HSV-induced cervical cancer require further exploration.


Renal vascular injuries.
Fifteen patients with injuries to the renal arteries and/or veins have been treated in the past ten years. Nine injuries were the result of gunshot wounds, and six were from blunt trauma. Twelve patients presented to the emergency department in shock; two of these did not have a palpable blood pressure. Time from admission to time of operation averaged 6.4 hr for patients with blunt trauma and 1.25 hr for patients with penetrating trauma. Seven patients had ten associated abdominal vascular injuries, and two patients had injuries to both the right renal artery and left renal vein. Associated nonvascular abdominal injuries were found in all 15 patients. Efforts were made to repair renal vascular injuries with suture or grafting of the injured vessel in eight cases (53%). These efforts were successful in four patients, but in four the repair failed and a nephrectomy could not be avoided. Two patients died in the operating room or immediately postop in spite of successful repair of their renovascular injury. One injured left renal vein was ligated and nephrectomy was not necessary. In five patients, ligation of the injured renal artery and nephrectomy were necessary. There were five deaths (33%). Three of the deaths occurred in the operating room and two were postoperative deaths. Only one of the patients who died had a renal vessel injury without other major vessels involved. He did, however, have serious liver and kidney injuries. Multiple associated vascular, nonvascular, and head injuries were present in all four of the other deaths. We have continued to take an aggressive approach to exploration, isolation of the injury, and repair of the vessel whenever possible if a renal vessel injury is suspected.(ABSTRACT TRUNCATED AT 250 WORDS)


Functional Outcome of Open Latarjet Procedure in Non-Athletic Middle-Aged Patients.
The movement and steadiness of the shoulder joint is due to both the dynamic and static stabilisers. Recurrent anterior shoulder instability is common due to the Bankart lesion or the Hill Sachs lesion. The bone loss and soft tissue failure due to these lesions causing instability is well compensated by Latarjet procedure which acts by triple blocking effect of the bone graft, the sling effect of the conjoint tendon of subscapularis and the ligament of the coracoacromial ligament stump. Middle-aged patients with recurrent anterior shoulder dislocation and a mid-range instability on clinical assessment with an isolated glenoid bone loss of 20% or Bankart lesion with engaging Hill Sachs lesion were selected for the study. The surgical procedure included a subscapularis split to expose the glenoid. The coracoid graft harvested was prefixed with Kirschner wires and placed flush over the glenoid ensuring no medial or lateral overhang and fixed with 4.0mm cancellous screws with the washer. The functional outcome was measured with the ROWE score and ASES score and the movements were evaluated. A total of 24 patients fulfilled the inclusion criteria. Post-operatively at final follow-up, the mean ROWE score was 97.08 ±8.45 and the mean ASES score was 94.4±9.10. One patient had screw breakage as a complication and another had restriction of movement which was managed with physiotherapy. Open Latarjet is an effective procedure for recurrent anterior shoulder instability in non-athletic middle-aged patients as a excellent functional outcome was achieved with this technique. We therefore recommend open Latarjet as an alternative to arthroscopic treatment in developing countries where patient affordability and the availability of the resources are the issues.


Cellular NADH and NADPH Conformation as a Real-Time Fluorescence-Based Metabolic Indicator under Pressurized Conditions.
Cellular conformation of reduced pyridine nucleotides NADH and NADPH sensed using autofluorescence spectroscopy is presented as a real-time metabolic indicator under pressurized conditions. The approach provides information on the role of pressure in energy metabolism and antioxidant defense with applications in agriculture and food technologies. Here, we use spectral phasor analysis on UV-excited autofluorescence from Saccharomyces cerevisiae (baker's yeast) to assess the involvement of one or multiple NADH- or NADPH-linked pathways based on the presence of two-component spectral behavior during a metabolic response. To demonstrate metabolic monitoring under pressure, we first present the autofluorescence response to cyanide (a respiratory inhibitor) at 32 MPa. Although ambient and high-pressure responses remain similar, pressure itself also induces a response that is consistent with a change in cellular redox state and ROS production. Next, as an example of an autofluorescence response altered by pressurization, we investigate the response to ethanol at ambient, 12 MPa, and 30 MPa pressure. Ethanol (another respiratory inhibitor) and cyanide induce similar responses at ambient pressure. The onset of non-two-component spectral behavior upon pressurization suggests a change in the mechanism of ethanol action. Overall, results point to new avenues of investigation in piezophysiology by providing a way of visualizing metabolism and mitochondrial function under pressurized conditions.


Cell surface saccharides of Trypanosoma lewis i. II. Lectin-mediated agglutination and fine-structure cytochemical detection of lectin-binding sites.
Bloodstream (BSF) and culture forms (CF) of Trypanosoma lewisi were specifically agglutinated with the plant lectins concanavalin A (Con A), soybean agglutinin (SBA), wheat germ agglutinin (WGA), and fucose-binding protein (FBP). Lectin-mediated cell agglutination was inhibited, and reversed in the presence of specific lectin-binding saccharides. Cells were agglutinated randomly with all lectins suggesting a uniform distribution in the trypanosome cell surface of the lectin-binding saccharide ligands. The BSF and CF were not agglutinated with phytohaemagglutinin-M, phytohaemagglutinin-P, or influenza virions. Living trypsinized BSF, which lacked a surface coat, gave agglutination results with the lectins identical to those obtained with living intact BSF. Glutaraldehyde- or formalin-fixed intact and trypsinized BSF gave results similar to those obtained with living cells and SBA, WGA, and FBP. However, intact, fixed BSF gave much lower agglutination levels with Con A than trypsinized-fixed, living intact, or living trypsinized BSF cells. Intact and trypsinized living and fixed CF gave identical agglutination results with each of the lectins. Living and fixed cells treated extensively with the glycoside hydrolases alpha-amylase, dextranase, and neuraminidase gave results with the lectins identical to those obtained with untreated cells. Con A bound at the cell surface was visualized with an iron-dextran (Fe-Dex) conjugate. Dense iron marker particles were distributed randomly in the intact BSF surface coat. The Con A-bound Fe-Dex marker was present on the pellicular and flagellar membrane outer lamina of trypsinized BSF and intact CF cells. Horseradish peroxidase (HRPO)-diaminobenzidine (DAB) coupled reactions also were used to visualize surface-bound Con A. Dense Con A-HRPO-DAB deposits were present uniformly in the BSF surface coat, and on the membranes of trypsinized BSF and intact CF trypanosomes. SBA and WGA were conjugated to HRPO and these used in DAB-coupled reactions at the ultrastructure level. Results obtained with the HRPO-conjugated lectins were similar in surface localization and distribution to those obtained with the Con A-HRPO-DAB preparations. Treatment of BSF and CF with the several glycoside hydrolases produced no apparent enhanced or reduced reactivity for the lectins in any of the fine-structure cytochemistry experiments. The cumulative results indicate that ligands similar or identical to alpha-D-mannose, N-acetylgalactosamine, and N-acetylglucosamine, and alpha-L-fucose are constituents in the extracellular surface coat matrix of T. lewisi BSF. Similar conclusions also pertain to the pellicular and flagellar membrane ligands of the BSF and CF cells. Moreover, results obtained with the glycoside hydrolases and influenza virions suggest that the T. lewisi cell surface ligands are not associated directly with repetitively bonded alpha-I,4- and alpha-I,6-D-glucans or sialic acid moieties.


[Treatment of trophic ulcers of lower extremities by use of boric acid-hydrocortisone mixture].
Cryostabilized boric-hydrocortisone aquaeous mixture was used in combined treatment of varicose trophic ulcers complicated by eczema and dermatitis in 70 patients. The gauze bandages, moistened by this mixture were used locality in preoperation period. In carrying out cutaneous plastic operation a free graft was preliminarily kept in the mixture for 5-7 min. During postoperation days the bandages were applied daily up to complete healing of the cutaneous flap, only upper layers of the bandage being changed. After the patient was discharged from the hospital the courses of boric-hydrocortisone applications were repeated 3-4 times for the first year. Bacterio-cytolodical examinations were carried out. The effectiveness of the use of the mixture was determined manifested by reduction of the duration of preoperative preparation and by improvement of longterm results.


The efficacy of valsartan in essential hypertension and its effects on left ventricular hypertrophy.
Recent studies demonstrate that, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers may decrease left ventricular hypertrophy (LVH) in hypertensive patients. We wanted to assess the efficacy of valsartan on echocardiographic variables of LVH in 30 mild to moderate hypertensive patients. Valsartan was found effective in controlling hypertension, also echocardiographic indices of LVH such as interventricular septum and posterior wall thickness were reduced and left ventricular mass decreased significantly. Thus valsartan favorably influences cardiac structure in hypertensive patients.


Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study.
Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined. We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology. 89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%). Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.


Fluid restriction for term infants with hypoxic-ischaemic encephalopathy following perinatal asphyxia.
Current recommendations to control the consequences of hypoxic-ischaemic encephalopathy following perinatal asphyxia include the careful management of fluids, with avoidance of fluid overload and thus avoidance of cerebral oedema. Recommendations for fluid restriction in a neonate are based on the experience of restricting fluid intake in adults or older children. The extrapolation from studies in adults, older children and animals to the human neonate is fraught with hazard due to the different physiology and mechanisms of injury. The objective of this review was to determine the effects of fluid restriction on short-term (mortality within the first 28 days of life, grade of hypoxic ischaemic encephalopathy, electrolyte disturbances, renal function, seizure activity) and long-term outcomes (death during the first year of life, CT or MRI changes, or severe neurodevelopmental disability at or equal to 12 months of age or more) in term infants following perinatal asphyxia. Subgroup analyses were planned on the basis of the severity of the resulting hypoxic-ischaemic encephalopathy, degree of fluid restriction, and length of fluid restriction. Searches were undertaken of MEDLINE October 2004 back to 1966, CINAHL back to 1966, the Oxford Database of Perinatal Trials and the Cochrane Central Register of Controlled Trial (CENTRAL, The Cochrane Library, Issue 3, 2004). Searches were made of previous reviews including cross-references and abstracts. The search was not limited to the English language; reports in foreign languages were translated. Randomised or quasi-randomised trials of fluid restriction in term newborn infants with perinatal asphyxia. No studies were found meeting the criteria for inclusion in this review. No studies were found meeting the criteria for inclusion in this review. Given that fluid restriction for the treatment of hypoxic ischaemic encephalopathy following perinatal asphyxia is recommended in standard textbooks, there is a need for randomised, controlled trials to establish if this practice affects mortality and morbidity. As it may not be ethical to include neonates with acute renal failure in a randomised trial, these babies will have to be excluded from the trial. These studies should investigate the effects of fluid management on outcomes such as mortality, seizure activity, evidence of cerebral damage on histology, and effects on renal function and electrolytes.


Nictitating membrane resection in the horse: a comparison of long-term outcomes using local vs. general anaesthesia.
Neoplasia, for which surgical excision is a frequent treatment, is the most common disease of the equine nictitating membrane. There is little long-term follow-up information available to the practitioner regarding the long-term effects of nictitating membrane excision on ocular health. No information is available to compare recurrence of primary neoplasia of the nictitating membrane after excision with local or general anaesthesia. To evaluate the long-term complications of nictitating membrane resection in horses; recurrence of neoplasia of the nictitating membrane when nictitating membrane resection is performed under local vs. general anaesthesia and if the method of anaesthesia used to permit resection of the affected membrane influences the recurrence of neoplasia of the nictitating membrane after complete nictitating membrane resection. Records of 26 horses receiving resection of the nictitating membrane for primary neoplasia of the nictitating membrane 1999-2009 were reviewed. Clinical examination findings, surgical procedure, anaesthesia type, histopathological findings and details of adjunctive treatment were recorded. Owners were contacted via telephone regarding post operative outcomes. Data were analysed using a Fisher's exact test (P<0.05). The most common long-term complication of nictitating membrane excision was mild ocular discharge. Squamous cell carcinoma was the most frequent histopathological diagnosis. Recurrence of neoplasia was uncommon (2/26 horses). No significant difference in the number of horses experiencing recurrence of neoplasia was detected between groups receiving general anaesthesia vs. those receiving local anaesthesia. Resection of the nictitating membrane in horses following local anaesthesia is not associated with increased risk of recurrence of neoplasia compared with excision under general anaesthesia. Resection of the nictitating membrane is not associated with any long-term ocular side effects and can be an effective modality for cure of primary neoplasia of the nictitating membrane in selected cases.


[The risk of the occurrence of acute nonlymphoblastic leukemia in patients with malignant neoplasms undergoing radio- and chemotherapy].
The paper discusses the results of an epidemiologic case-control study dealing with the risk of development of acute nonlymphoblastic leukemia in patients treated with radio- or chemotherapy. Out of 165 patients with primary multiple metachronous tumors, primary Hodgkin's disease, lymphosarcoma and breast, ovarian and testicular cancer, 18 developed secondary acute nonlymphoblastic leukemia; in 13, the primary tumor had been Hodgkin's disease, in 4--breast cancer and in one--testicular cancer. Relative risk (RR) of acute nonlymphoblastic leukemia proved higher in patients who had undergone radiation (RR = 6.4) or chemotherapy (RR = 1.9). Combination of those two procedures carried a higher risk, too (RR = 5.9). Relative risk of acute nonlymphoblastic leukemia proved the highest in patients treated with adriamycin (11.3) and nitrogen mustard (9.9) and much lower for cyclophosphamide (RR = 1.5).


Case Reports: Bronchial Mucosal Vasculature Is Also Involved in the Acute Vascular Distress Syndrome of COVID-19.
Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which targets the pulmonary vasculature is supposed to induce an intrapulmonary right to left shunt with an increased pulmonary blood flow. We report here what may be, to the best of our knowledge, the first videoendoscopic descriptions of an hypervascularization of the bronchial mucosa in two patients hospitalized for coronavirus disease 2019 (COVID-19) pneumonia. Cases Presentation: Two patients, 27- and 37-year-old, were addressed to our Pneumology department for suspicion of COVID-19 pneumonia. Their symptoms (fever, dry cough, and dyspnoea), associated to pulmonary ground glass opacities on thoracic CT, were highly suggestive of a COVID-19 disease despite repeated negative pharyngeal swabs RT-PCR. In both patients, bronchoscopy examination using white light was unremarkable but NBI bronchoscopy revealed a diffuse hypervascularization of the mucosa from the trachea to the sub-segmental bronchi, associated with dilated submucosal vessels. RT-PCR performed in bronchoalveolar lavage (BAL) confirmed the presence of Sars-CoV-2. Conclusions: These two case reports highlight the crucial importance of the vascular component of the viral disease. We suggest that such bronchial hypervascularization with dilated vessels contributes, at least in part, to the intrapulmonary right to left shunt that characterizes the COVID-19 related Acute Vascular Distress Syndrome (AVDS). The presence of diffuse bronchial hypervascularization in the context of COVID-19 pandemic should prompt the search for Sars-CoV-2 in BAL samples.


Clinical excellence in academia: perspectives from masterful academic clinicians.
To better understand and characterize clinical excellence in academia by exploring the perspectives of clinically excellent faculty in the top American departments of medicine. Between March 1 and May 31, 2007, 2 investigators conducted in-depth semistructured interviews with 24 clinically excellent Department of Medicine physicians at 8 academic institutions. Interview transcripts were independently analyzed by 2 investigators and compared for agreement. Content analysis identified several major themes that relate to clinical excellence in academia. Physicians hailed from a range of internal medicine specialties; 20 (83%) were associate professors or professors and 8 (33%) were women. The mean percentage of time physicians spent in clinical care was 48%. Eight domains emerged as the major features of clinical excellence in academia: reputation, communication and interpersonal skills, professionalism and humanism, diagnostic acumen, skillful negotiation of the health care system, knowledge, scholarly approach to clinical care, and passion for clinical medicine. Understanding the core elements that contribute to clinical excellence in academia represents a pivotal step to defining clinical excellence in this setting. It is hoped that such work will lead to initiatives aimed at measuring and rewarding clinical excellence in our academic medical centers such that the most outstanding clinicians feel valued and decide to stay in academia to serve as role models for medical trainees.


The Application of Gail Model to Predict the Risk of Developing Breast Cancer among Jordanian Women.
Background and Objectives. Breast cancer has been the most common cancer affecting women in Jordan. In the process of implementing breast cancer prevention and early detection programs, individualized risk assessment can add to the cost-effectiveness of such interventions. Gail model is a widely used tool to stratify patients into different risk categories. However, concerns about its applicability across different ethnic groups do exist. In this study, we report our experience with the application of a modified version of this model among Jordanian women. The Gail risk assessment model (RAM) was modified and used to calculate the 5-year and lifetime risk for breast cancer. Patients with known breast cancer were used to test this model. Medical records and hospital database were utilized to collect information on known risk factors. The mean calculated risk score for women tested was 0.65. This number, which corresponds to the Gail original score of 1.66, was used as a cutoff point to categorize patients as high risk. A total of 1786 breast cancer patients with a mean age of 50 (range: 19-93) years were included. The modified version of the Gail RAM was applied on 1213 patients aged 35-59.9 years. The mean estimated risk for developing invasive breast cancer over the following five years was 0.54 (95% CI: 0.52, 0.56), and the lifetime risk was 3.42 (95% CI: 3.30, 3.53). Only 210 (17.3%) women had a risk score >0.65 and thus categorized as high risk. First-degree family history of breast cancer was identified among 120 (57.1%) patients in this high-risk group. Among a group of patients with an established diagnosis of breast cancer, a modified Gail risk assessment model would have been able to stratify only 17% into the high-risk category. The family history of breast cancer contributed the most to the risk score.


Temporal dynamics of inducible anti-herbivory defenses in the brown seaweed Ascophyllum nodosum (Phaeophyceae)(1).
Anti-herbivory defenses support persistence of seaweeds. Little is known, however, about temporal dynamics in the induction of grazer-deterrent seaweed traits. In two induction experiments, consumption rates of the periwinkle Littorina obtusata (L.) on the brown seaweed Ascophyllum nodosum (L.) Le Jolis were measured in 3-d intervals. Changes in palatability of directly grazed A. nodosum were tested every 3 d with feeding assays using fresh and reconstituted seaweed pieces. Likewise, assays with fresh A. nodosum assessed changes in seaweed palatability in response to water-borne cues from nearby grazed conspecifics. Consumption rates of L. obtusata varied significantly during the 27-d induction phase of each experiment. Direct grazing by L. obtusata lowered palatability of fresh and reconstituted A. nodosum pieces to conspecific grazers after 15 d as well as after 6 and 12 d, respectively. After 12, 18, and 24 d, fresh A. nodosum located downstream of L. obtusata-grazed conspecifics was significantly less palatable than A. nodosum located downstream of ungrazed conspecifics. Changes in L. obtusata consumption rates and A. nodosum palatability during both induction experiments suggest temporal variation of grazer-deterrent responses, which may complicate experimental detection of inducible anti-herbivory defenses.


Emerging infectious disease, the household built environment characteristics, and urban planning: Evidence on avian influenza in Vietnam.
Recent concerns with pandemic outbreaks of human disease and their origins in animal populations have ignited concerns regarding connections between Emerging Infectious Diseases (EID) and development. As disasters, health, and infectious disease become part of planning concern (Matthew & McDonald, 2007), greater focus on household infrastructure and EID disease outbreaks among poultry is warranted. Following Spencer (2013), this study examines the relationship between the mix of household-scale water supplies, sanitation systems, and construction materials, and Highly Pathogenic Avian Influenza (HPAI) among poultry in a developing country: Vietnam. Findings of our multivariate logistic regressions suggest that a non-linear, Kuznets-shaped urban transition (Spencer, 2013) has an independent effect on the outbreak of HPAI, especially as it relates to household-level sanitation infrastructure. We conclude that the Kuznets-shape development of household infrastructure characteristics in Vietnam play a significant role in explaining where poultry outbreaks occur. Using secondary data from the Census of Population and Housing, and the Agricultural Census at the District and Commune levels for the country of Vietnam, we performed logistic regression to test the relationship between outbreaks of HPAI in poultry and newly-developed "coherence indices" (Spencer, 2013) of household water supply, sanitation, and construction materials that measure nonlinear, transitional development. Results show that district-scale coherence indices are negatively and independently correlated with HPAI outbreaks, especially for sanitation. Findings also suggest that community-scale coherence of urban infrastructures is a powerful tool for predicting where HPAI poultry outbreaks are likely to occur, thereby providing health planners new tools for efficient surveillance.


Being in the room together.
As historians have shown and political theorists have acknowledged: no viable collective is ever just the result of cool cost-benefit calculations. Rather, it is a shared vision of what it would mean to be part of a collective that surmounts hesitation and commands allegiance. What that collective vision should be for science already has a 350-odd-year history, and the work of the imagination is still ongoing.


Indoxyl Sulfate Induces Renal Fibroblast Activation through a Targetable Heat Shock Protein 90-Dependent Pathway.
Indoxyl sulfate (IS) accumulation occurs early during chronic kidney disease (CKD) progression and contributes to renal dysfunction by inducing fibrosis, inflammation, oxidative stress, and tissue remodeling. Renal toxicity of high IS concentrations (250 μM) has been widely explored, particularly in resident tubular and glomerular cells, while the effect of a moderate IS increase on kidneys is still mostly unknown. To define the effects of IS accumulation on renal fibroblasts, we first analyzed kidneys of C57BL/6 mice receiving IS (0.1%) in drinking water for 12 weeks. As a next step, we treated renal fibroblasts (NRK-49F) with IS (20 μM) with or without the HSP90 inhibitor 17-AAG (1 μM). In mouse kidneys, IS increased the collagen deposition and HSP90 and α-SMA expression (immunohistochemistry) in interstitial fibroblasts and caused tubular necrosis (histological H&E and picrosirius red staining). In NRK-49F cells, IS induced MCP1, TGF-β, collagen I, α-SMA, and HSP90 gene/protein expression and Smad2/3 pathway activation. IS had no effects on fibroblast proliferation and ROS production. 17-AAG counteracted IS-induced MCP1, TGF-β, collagen I, and α-SMA expression and Smad2/3 phosphorylation. Our study demonstrates that the IS increase promotes renal fibroblast activation by a HSP90-dependent pathway and indicates HSP90 inhibition as a potential strategy to restrain IS-induced kidney inflammation and fibrosis in CKD.


Pigmentary anomaly caused by mosaic 3q22.2q29 duplication.
A 39-year-old woman sought advice regarding potential risks to her offspring due to previous possible diagnosis of incontinentia pigmenti. She had linear hyperpigmentation along the lines of Blaschko affecting the upper and lower limbs, and skin-coloured papules on the left palm. Ophthalmoscopy revealed hypopigmented spots in the macular region of the retina in each eye due to focal areas of depigmentation of the retinal pigment epithelium. An array comparative genomic hybridization on DNA extracted from a skin biopsy revealed a 63.63-Mb duplication, arr[GRCh37] 3q22.2q29(134212001_197837069)x3, on the long arm of chromosome 3. This case is an example of genetic mosaicism resulting from a de novo genetic defect arising at some point in embryonic development. Click here for the corresponding questions to this CME article.


Surgical decision making in the setting of severe traumatic brain injury: A survey of neurosurgeons.
Surgical decision-making in severe traumatic brain injury (TBI) is complex. Neurosurgeons weigh risks and benefits of interventions that have the potential to both maximize the chance of recovery and prolong suffering. Inaccurate prognostication can lead to over- or under-estimation of outcomes and influence treatment recommendations. To evaluate the impact of evidence-based risk estimates on neurosurgeon treatment recommendations and prognostic beliefs in severe TBI. In a survey-based randomized experiment, a total of 139 neurosurgeons were presented with two hypothetical patient with severe TBI and subdural hematoma; the intervention group received additional evidence-based risk estimates for each patient. The main outcome was neurosurgeon treatment recommendation of non-surgical management. Secondary outcomes included prediction of functional recovery at six months. In the first patient scenario, 22% of neurosurgeons recommended non-surgical management and provision of evidence-based risk estimates increased the propensity to recommend non-surgical treatment (odds ratio [OR]: 2.81, 95% CI: 1.21-6.98; p = 0.02). Neurosurgeon prognostic beliefs of 6-month functional recovery were variable in both control (median 20%, IQR: 10%-40%) and intervention (30% IQR: 10%-50%) groups and neurosurgeons were less likely to recommend non-surgical management when they believed prognosis was favorable (odds ratio [OR] per percentage point increase in 6-month functional recovery: 0.97, 95% confidence interval [CI]: 0.95-0.99). The results for the second patient scenario were qualitatively similar. Our findings show that the provision of evidence-based risk predictions can influence neurosurgeon treatment recommendations and prognostication, but the effect is modest and there remains large variability in neurosurgeon prognostication.


[Consumption of cannabis among subjects with history of abuse/dependence or under an opiate maintenance therapy: OPPIDUM data in 2006 and main trends since 2004].
The data on consumption of cannabis in the young people are well documented on the other hand this consumption is less described in subjects presenting a drug dependency. The consumption of cannabis in 2006 and the principal tendencies since 2004 were studied from the OPPIDUM (Observation of Illegal Drugs and Misuse of Psychotropic Medications) program's. OPPIDUM is an annual transverse national study pharmaco-epidemiologic which recruits subjects presenting a drug dependency or benefiting of a maintenance treatment. In October 2006, 3743 subjects were included. Thirty eight per cent (n=1437) of them are consumers of cannabis, among them 27% announced consumed only cannabis and 73% consumed it with other psychoactive substances. The consumers of cannabis alone are younger, have better social-economical indicators and presented consumption of cannabis in term of abuse and dependence more important. This study underlines the problems of the polyconsommation. No change related to the characteristics of consumers of cannabis was observed between 2004 and 2006. This study underline the presence of two groups of consumers of cannabis presented in structures of care who are different on level of the social-economical indicators and its consumptions.


Two distinct non-ribosomal peptide synthetase-independent siderophore synthetase gene clusters identified in Armillaria and other species in the Physalacriaceae.
Siderophores are important for ferric iron solubilization, sequestration, transportation, and storage, especially under iron-limiting conditions such as aerobic conditions at high pH. Siderophores are mainly produced by non-ribosomal peptide synthetase-dependent siderophore pathway, non-ribosomal peptide synthetase-independent siderophore synthetase pathway, or the hybrid non-ribosomal peptide synthetases/non-ribosomal peptide synthetases-independent siderophore pathway. Outcompeting or inhibition of plant pathogens, alteration of host defense mechanisms, and alteration of plant-fungal interactions have been associated with fungal siderophores. To understand these mechanisms in fungi, studies have been conducted on siderophore biosynthesis by ascomycetes with limited focus on the basidiomycetes. Armillaria includes several species that are pathogens of woody plants and trees important to agriculture, horticulture, and forestry. The aim of this study was to investigate the presence of non-ribosomal peptide synthetases-independent siderophore synthetase gene cluster(s) in genomes of Armillaria species using a comparative genomics approach. Iron-dependent growth and siderophore biosynthesis in strains of selected Armillaria spp. were also evaluated in vitro. Two distinct non-ribosomal peptide synthetases-independent siderophore synthetase gene clusters were identified in all the genomes. All non-ribosomal peptide synthetases-independent siderophore synthetase genes identified putatively encode Type A' non-ribosomal peptide synthetases-independent siderophore synthetases, most of which have IucA_IucC and FhuF-like transporter domains at their N- and C-terminals, respectively. The effect of iron on culture growth varied among the strains studied. Bioassays using the CAS assay on selected Armillaria spp. revealed in vitro siderophore biosynthesis by all strains irrespective of added FeCl3 concentration. This study highlights some of the tools that Armillaria species allocate to iron homeostasis. The information generated from this study may in future aid in developing molecular based methods to control these phytopathogens.


Analgesic use after vaginal delivery in women with perineal lacerations: a retrospective cohort study.
Objective: To evaluate opioid consumption among parturients with varying degrees of perineal lacerations.Methods: This was a retrospective analysis of women who delivered vaginally at our institution from 1 January 2014 to 12 April 2015. We collected information regarding the degree of perineal lacerations (no lacerations, first-/second-degree, third-/fourth-degree), analgesic consumption, and postpartum pain scores. The primary outcome was opioid use from 0-48 h postpartum. Univariate and multivariable regression analyses were performed to test for the association of laceration severity with opioid use.Results: We included 5598 women in the analysis; 1948 had no lacerations, 3434 had first-/second-degree lacerations, and 216 had third-/fourth-degree lacerations. In univariate analysis, parturients with third-/fourth-degree lacerations had significantly higher use of opioids within 48 h postpartum (53.2%) compared to women with no lacerations (30.03%) or first-/second-degree lacerations (28.6%) (p < .001). In the multivariable analysis, women with third-/fourth-degree lacerations had higher odds of opioid use than those without laceration [OR (95% CI) = 2.61 (1.75-3.85), p < .001]. In pairwise comparisons, those with third-/fourth-degree lacerations had higher odds of opioid use than those without lacerations [OR (95% CI) = 3.55 (2.20-5.74)], and those with first-/second-degree lacerations [OR (95% CI) = 2.15 (1.49-3.10)] (p < .001). Oxycodone equivalent consumption was significantly different among groups with a median (IQR) of 5.00 mg (0.00-27.50), 0.00 mg (0.00-5.00) and 0.00 mg (0.00-5.00) in women with third-/fourth-degree, first-/second-degree, and no lacerations, respectively, during the 0-48 h postpartum (p < .001).Conclusion: The use of opioids and opioid doses are higher in women with third-/fourth-degree perineal lacerations compared to those with first-/second-degree or no lacerations.


[A case of rod monochromasia].
A case of rare genetic disease rod monochromasia which is often called total congenital cone dysfunction (syn. congenital cone dystrophy, congenital achromatopsia) is presented. Symptoms and signs of the disease are described in details and methods for improvement of patient's condition are indicated.


Nuclear binding of T3 and effects of QO2, Na-K-ATPase, and alpha-GPDH in liver and kidney.
Thyroid status was altered by use of a low-iodine-perchlorate (PC) regimen and either reversal with NaI or injections of L-3,5,3'-triiodothyronine (T3). The PC regimen decreased renal and hepatic oxygen consumption (QO2), alpha-glycerophosphate dehydrogenase (alpha-GPDH), and Na+-K+-dependent adenosine triphosphatase (Na-K-ATPase) to comparable extents (25 vs. 23%, 26 vs. 39%, and 41 vs. 51%, respectively). Administration of T3 to hypothyroid rats elicited dose-dependent increases in hepatic and renal cortical QO2, ouabain-sensitive oxygen consumption (QO2(t)), alpha-GPDH, and Na-K-ATPase activities. The half-maximal increases in all of the response parameters in both kidney and liver were obtained at dosages of 6-32 micrograms T3/100 g body wt. The equivalences in the renal cortical vs. hepatic responses were indicated by correlation coefficients of approximately 0.97. Kidney and liver nuclei also showed similar high-affinity binding of 125I-T3-K1/2 = 29 vs. 18 micrograms T3/100 g body wt, and Nmax = 1.8 vs. 2.1 ng T3/mg DNA. The patterns of the responses plotted as a function of T3 occupancy of the high-affinity nuclear binding sites were indistinguishable in kidney and liver. These results imply similar modes of action of T3, probably initiated at the nuclear level, in both kidney and liver.


Mutate and Conjugate: A Method to Enable Rapid In-Cell Target Validation.
Target validation remains a challenge in drug discovery, which leads to a high attrition rate in the drug discovery process, particularly in Phase II clinical trials. Consequently, new approaches to enhance target validation are valuable tools to improve the drug discovery process. Here, we report the combination of site-directed mutagenesis and electrophilic fragments to enable the rapid identification of small molecules that selectively inhibit the mutant protein. Using the bromodomain-containing protein BRD4 as an example, we employed a structure-based approach to identify the L94C mutation in the first bromodomain of BRD4 [BRD4(1)] as having a minimal effect on BRD4(1) function. We then screened a focused, KAc mimic-containing fragment set and a diverse fragment library against the mutant and wild-type proteins and identified a series of fragments that showed high selectivity for the mutant protein. These compounds were elaborated to include an alkyne click tag to enable the attachment of a fluorescent dye. These clickable compounds were then assessed in HEK293T cells, transiently expressing BRD4(1)WT or BRD4(1)L94C, to determine their selectivity for BRD4(1)L94C over other possible cellular targets. One compound was identified that shows very high selectivity for BRD4(1)L94C over all other proteins. This work provides a proof-of-concept that the combination of site-directed mutagenesis and electrophilic fragments, in a mutate and conjugate approach, can enable rapid identification of small molecule inhibitors for an appropriately mutated protein of interest. This technology can be used to assess the cellular phenotype of inhibiting the protein of interest, and the electrophilic ligand provides a starting point for noncovalent ligand development.


Per- and Polyfluoroalkyl Substance Plasma Concentrations and Bone Mineral Density in Midchildhood: A Cross-Sectional Study (Project Viva, United States).
Identifying factors that impair bone accrual during childhood is a critical step toward osteoporosis prevention. Exposure to per- and polyfluoroalkyl substances (PFASs) has been associated with lower bone mineral density, but data are limited, particularly in children. We studied 576 children in Project Viva, a Boston-area cohort of mother/child pairs recruited prenatally from 1999 to 2002. We quantified plasma concentrations of several PFASs and measured areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) in midchildhood. We used linear regression to examine associations between plasma concentrations of individual PFASs and aBMD z-score. We used weighted quantile sum (WQS) regression to examine the association of the PFAS mixture with aBMD z-score. All models were adjusted for maternal age, education, annual household income, census tract median household income, and child age, sex, race/ethnicity, dairy intake, physical activity, and year of blood draw. Children were [[Formula: see text]] [Formula: see text] of age. The highest PFAS plasma concentrations were of perfluorooctanesulfonic acid (PFOS) {median [interquartile range (IQR)]: 6.4 (5.6) ng/mL} and perfluorooctanoic acid (PFOA) [median (IQR): 4.4 (3.2) ng/mL]. Using linear regression, children with higher plasma concentrations of PFOA, PFOS, and perfluorodecanoate (PFDA) had lower aBMD z-scores [e.g., [Formula: see text]: [Formula: see text]; 95% confidence interval (CI): [Formula: see text], [Formula: see text] per doubling of PFOA]. The PFAS mixture was negatively associated with aBMD z-score ([Formula: see text]: [Formula: see text]; 95% CI: [Formula: see text], [Formula: see text] per IQR increment of the mixture index). PFAS exposure may impair bone accrual in childhood and peak bone mass, an important determinant of lifelong skeletal health. https://doi.org/10.1289/EHP4918.


Septal lesions and biting attacks in rats bidirectionally selected for emotionality.
Twenty-nine colonies composed of one female and two male rats of high or low emotional strain were established. A dominant male of each colony was identified based on its attacks on an intruder rat. It was found that dominant males of the low emotional strain colonies were significantly more aggressive than those of the high emotional strain. Septal lesions or sham operations were given to dominant males of both strain colonies. Intruder tests were followed and several aggressive behaviors were measured by VTR observation. Biting attacks of the high emotional strain decreased for 10 days after septal latencies were shortened by septal lesions. Lesions X Strain interaction was significant. These results suggest that septal lesion effects on biting attacks are influenced by artificial genetic operations.


Resolving binding pathways and solvation thermodynamics of plant hormone receptors.
Plant hormones are small molecules that regulate plant growth, development, and responses to biotic and abiotic stresses. They are specifically recognized by the binding site of their receptors. In this work, we resolved the binding pathways for eight classes of phytohormones (auxin, jasmonate, gibberellin, strigolactone, brassinosteroid, cytokinin, salicylic acid, and abscisic acid) to their canonical receptors using extensive molecular dynamics simulations. Furthermore, we investigated the role of water displacement and reorganization at the binding site of the plant receptors through inhomogeneous solvation theory. Our findings predict that displacement of water molecules by phytohormones contributes to free energy of binding via entropy gain and is associated with significant free energy barriers for most systems analyzed. Also, our results indicate that displacement of unfavorable water molecules in the binding site can be exploited in rational agrochemical design. Overall, this study uncovers the mechanism of ligand binding and the role of water molecules in plant hormone perception, which creates new avenues for agrochemical design to target plant growth and development.