[Effect of gamma-aminobutyric acid on audiogenic seizures and conditioned reflexes in the rat].
The influence of GABA injection (intraperiotoneal) on the sensitivity to sound and behaviour was studied on KM line rats, in which a strong sound produces epileptiform seizures, and on sound-resistant Wistar line rats. It was shown that in the KM line rats the previously elaborated motor alimentary conditioned reflex was impaired for several hours after the seizures. The two first GABA injections to the rats of both lines reduce the number of adequate reactions to a signal stimulus. As GABA injections are repeated, conditioned activity is restored. A four-time GABA injection results in blocking of the audiogenic seizures in a number of rats of the KM line and in the maintenance of normal behaviour after the action of the epileptogenic stimulus.


Cholecystectomy in patients with mild cirrhosis. A more favorable situation.
A conservative approach toward elective cholecystectomy in the patient with cirrhosis has been suggested because of the strong likelihood of excessive bleeding, sepsis, and multiple organ failure. We reviewed this problem in two medical centers, studying 27 patients with cirrhosis who had undergone nonemergency biliary tract surgery. Most patients had adequate liver function preoperatively. Most operations were cholecystectomies without duct exploration. Among factors analyzed were liver function tests, coagulation tests, and Child's classification. Prothrombin time was less than 2.5 s above control in 18 patients, more than 2.5 s above control in four patients, and not recorded in five patients. All survived the operation with benign postoperative courses. Only one patient had excessive bleeding; this patient had an elevated prothrombin time preoperatively. We conclude that elective cholecystectomy can be performed safely in patients with cirrhosis who have relatively normal liver function.


Use of biosensors for rapid and sensitive detection of pesticides in food samples for food safety chemical risk assessment.
The utility of pesticides in the agricultural field is unquestionable, but at the same time pesticide use presents serious hazards to the environment and the human health. For that reason, detection of pesticides and their biotransformation products in food is of utmost importance. According to previous studies, esterase-based biosensors have been proposed as a viable and efficient solution for the detection of organophosphate pesticides. In this project, a double mutant of the thermostable esterase-2 (EST2) from Alicyclobacillus acidocaldarius was studied as a potential biosensor, for its ability to detect residual amounts of pesticides. Initial characterisation of the enzyme was performed, that included determination of optimal pH, thermophilicity, as well as kinetic analysis. Subsequently, the enzyme was studied by enzymatic activity assays with and without the presence of various organophosphate compounds. The effect of the organophosphates on the enzymatic activity was measured and complete inhibition of the enzyme was observed after incubation with paraoxon. These experiments were followed by an additional method involving labelling of the enzyme with a fluorescent probe. In this case, the effect of different pesticides on the EST2 enzyme was monitored by measuring the fluorescence quenching upon addition to the enzyme. Fourteen compounds were screened with this method and significant fluorescence quenching was observed in the presence of paraoxon and methyl-paraoxon when used in equimolar amounts with the enzyme in the range of nanomolar. This biosensor has been also used to test the presence of pesticides in real food samples, like fruits and juices. This research represents a starting point to develop effective fluorescence-based biosensors aiming at the screening of mutants with different pesticide selectivity profiles. The use of this enzyme-based biosensor can have applications in the field of food traceability as well as environmental monitoring, to control the presence of toxic chemicals, in particular organophosphate pesticides.


Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes.
To examine the effects of bronchopulmonary dysplasia (BPD) and very low birth weight (VLBW) on the cognitive and academic achievement of a large sample of 8-year-old children. Infants who were VLBW and had BPD (n = 98) or did not have BPD (n = 75) and term infants (n = 99) were followed prospectively to age 8. Groups were compared on measures assessing 4 broad areas of functioning: intelligence, achievement, gross motor, and attentional skills. Measures included the Wechsler Intelligence Scale for Children III, the Woodcock Johnson Test of Achievement-Revised, the Bruininks-Oseretsky Test of Motor Proficiency, the Tactual Performance Test (spatial memory), and the Continuous Performance Test (attention). School outcomes were assessed by parent and teacher report, as well as from school records. Groups were comparable on socioeconomic status, sex, and race. The total sample of BPD, VLBW, and term children was compared on all outcome measures. In addition, neurologic risk was assessed in the present sample and included the following: intraventricular hemorrhage, echodense lesions, porencephaly, hydrocephalus, ventriculoperitoneal shunt, meningitis, and periventricular leukomalacia. Individual difference analyses were conducted for neurologically intact children in all 3 groups. Finally, treatment effects were examined by comparing BPD children who had received steroids as part of their treatment with BPD children who had not. The BPD group demonstrated deficits compared with VLBW and term children in intelligence; reading, mathematics, and gross motor skills; and special education services. VLBW children differed from term children in all of the above areas, except reading recognition, comprehension, and occupational therapy. Attentional differences were obtained between BPD and term children only. The BPD group (54%) was more likely to be enrolled in special education classes than VLBW (37%) or term children (25%). In addition, more BPD children (20%) achieved full-scale IQ scores <70, in the mental retardation range, compared with either VLBW (11%) or term (3%) children, with all VLBW children significantly more likely than term children to achieve IQs in the subaverage category. After controlling for birth weight and neurologic problems, BPD and/or duration on oxygen predicted lower performance IQ, perceptual organization, full-scale IQ, motor and attentional skills, and special education placement. The qualitative classification of BPD (present or absent) was a significant predictor for lower scores on measures of applied problems; motor skills; and incidence of speech-language, occupational, and physical therapies. Individual difference analyses were performed to ascertain whether differences between the risk groups were primarily attributable to neurologic complications. Even with the neurologically intact sample of BPD and VLBW children, differences between the term comparison group and both the BPD and VLBW groups were found for many outcome measures. When birth weight and neurologic complications were controlled, BPD and severity of BPD were associated with lower performance and full-scale IQ, poorer perceptual organization, attention, and motor skills, as well as lower school achievement and greater participation in special education, including occupational, physical, and speech-language therapies. Treatment protocol may in part be responsible for differences observed in our BPD sample. Steroid and nonsteroid groups of BPD children differed significantly in performance IQ (72.8 vs 84.8) and full-scale IQ (77.0 vs 85.2); perceptual organization (74.0 vs 85.2); Bruininks-Oseretsky Test of Motor Proficiency score (36.6 vs 44.7); and participation in special education (78% vs 48%), occupational therapy (71% vs 44%), and physical therapy (71% vs 41%). In every instance, BPD children who received steroids fared more poorly than BPD children who did not receive steroids. BPD and duration on oxygen have long-term adverse effects on cognitive and academic achievement above and be beyond the effects of VLBW. The problems that have been identified at 8 years of age highlight the need for continued monitoring of the learning, behavior, and development of BPD children to intervene with children who are at risk for school problems.


Serum anti-tissue transglutaminase IgA and prediction of duodenal villous atrophy in adults with suspected coeliac disease without IgA deficiency (Bi.A.CeD): a multicentre, prospective cohort study.
Whether coeliac disease in adults can be diagnosed with serology alone remains controversial. We aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA (tTG-IgA) in the diagnosis of coeliac disease. In this multicentre, prospective cohort study, adult participants (aged ≥18 years) with suspected coeliac disease without IgA deficiency who were not on a gluten-free diet and who had a local serum tTG-IgA measurement, were enrolled from Feb 27, 2018, to Dec 24, 2020, by 14 tertiary referral centres (ten from Europe, two from Asia, one from Oceania, and one from South America) to undergo local endoscopic duodenal biopsy. Local serum tTG-IgA was measured with 14 different test brands and concentration expressed as a multiple of each test's upper limit of normal (ULN), and defined as positive when greater than 1 times the ULN. The main study outcome was the reliability of serum tests for the diagnosis of coeliac disease, as defined by duodenal villous atrophy (Marsh type 3 or Corazza-Villanacci grade B). Histology was evaluated by the local pathologist, with discordant cases (positive tTG-IgA without duodenal villous atrophy or negative tTG-IgA with duodenal villous atrophy) re-evaluated by a central pathologist. The reliability of serum tests for the prediction of duodenal villous atrophy was evaluated according to sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic curve (AUC) for categorical and continuous data. We enrolled 436 participants with complete local data on serum tTG-IgA and duodenal histology (296 [68%] women and 140 [32%] men; mean age 40 years [SD 15]). Positive serum tTG-IgA was detected in 363 (83%) participants and negative serum tTG-IgA in 73 (17%). Of the 363 participants with positive serum tTG-IgA, 341 had positive histology (true positives) and 22 had negative histology (false positives) after local review. Of the 73 participants with negative serum tTG-IgA, seven had positive histology (false negatives) and 66 had negative histology (true negatives) after local review. The positive predictive value was 93·9% (95% CI 89·2-98·6), the negative predictive value was 90·4% (85·5-95·3), sensitivity was 98·0% (95·3-100·0), and specificity was 75·0% (66·6-83·4). After central re-evaluation of duodenal histology in 29 discordant cases, there were 348 true positive cases, 15 false positive cases, 66 true negative cases, and seven false negative cases, resulting in a positive predictive value of 95·9% (92·0-99·8), a negative predictive value of 90·4% (85·5-95·3), a sensitivity of 98·0% (95·3-100·0), and a specificity of 81·5% (73·9-89·1). Either using the local or central definition of duodenal histology, the positive predictive value of local serum tTG-IgA increased when the serological threshold was defined at increasing multiples of the ULN (p<0·0001). The AUC for serum tTG-IgA for the prediction of duodenal villous atrophy was 0·87 (95% CI 0·81-0·92) when applying the categorical definition of serum tTG-IgA (positive [>1 × ULN] vs negative [≤1 × ULN]), and 0·93 (0·89-0·96) when applying the numerical definition of serum tTG-IgA (multiples of the ULN). Additional endoscopic findings included peptic gastritis (nine patients), autoimmune atrophic gastritis (three), reflux oesophagitis (31), gastric or duodenal ulcer (three), and Barrett's oesophagus (one). In the 1-year follow-up, a midgut ileum lymphoma was diagnosed in a woman on a gluten-free diet. Our data showed that biopsy could be reasonably avoided in the diagnosis of coeliac disease in adults with reliable suspicion of coeliac disease and high serum tTG-IgA. None.


Dielectric properties of ocular tissues in the supercooled and frozen states.
Values of the relative permittivity and conductivity of the rabbit retina and lens have been measured between 10 MHz and 10 GHz over the temperature range 20 to -20 degrees C. As the temperature was lowered from 20 degrees C the dielectric parameters changed smoothly until -9 degrees C where freezing occurred. At this temperature a sharp transition was observed in both conductivity and relative permittivity, the latter falling to a value of below 10 over most of the frequency range. Analysis shows that this is due to the unfreezable water, from which a value of lens hydration is calculated. This value agrees with that obtained previously at 37 degrees C using conventional dielectric mixture theory, but the associated margin of error is much smaller.


The use of sprint tests for assessment of speed qualities of elite Australian rules footballers.
The purpose of this study was to determine the relationships between split times within sprint tests over 30 m and 40 m in elite Australian Rules footballers. Data were analyzed from two Australian Football League (AFL) clubs. The first club (n = 35) conducted a 40-m sprint test and recorded split times at 10 m and 20 m. The second club (n = 30) conducted a 30-m sprint test and recorded splits at 10 m and 20 m. Analyses included calculation of Pearson correlations and common variances between all the split times as well as "flying" times (20-40 m for the first club and 20 to 30 m for the second club). There was a high correlation (r = 0.94) between 10-m time and 20-m time within each club, indicating these measures assessed very similar speed qualities. The correlations between 10-m time and times to 30 m and 40 m decreased, but still produced common variances of 79% and 66% respectively. However when the "flying" times (20-40 m and 20-30 m) were correlated to 10-m time, the common variances decreased substantially to 25% and 42% respectively, indicating uniqueness. It was concluded that 10-m time is a good reflection of acceleration capabilities and either 20 to 40 m in a 40-m sprint test or 20 to 30 m in a 30-m sprint test can be used to estimate maximum speed capabilities. It was suggested that sprint tests over 30 m or 40 m can be conducted indoors to provide useful information about independent speed qualities in athletes.


Whipworm (Trichuris discolor) infection in dairy replacement heifers.
Trichuriasis caused by Trichuris discolor was diagnosed in a 19-month-old Holstein heifer examined because of emaciation, diarrhea, recumbency, and oral ulceration. The heifer's problem was representative of a herd problem involving pastured replacement heifers. Euthanasia was elected due to the heifer's moribund state and poor prognosis. Gross necropsy revealed subcutaneous edema and diffuse edema of the colon, with hundreds of adult Trichuris discolor in the cecum and colon. Histologic examination revealed multifocal subacute necrotizing colitis, with many adult Trichuris discolor embedded in the mucosa. Treatment instituted on the farm consisted of levamisole hydrochloride at a dosage of 6 mg/kg of body weight. Favorable response was documented by clinical improvement and elimination of fecal shedding of trichurid eggs.


Stop-transfer regions do not halt translocation of proteins into chloroplasts.
Protein targeting in eukaryotic cells is determined by several topogenic signals. Among these are stop-transfer regions, which halt translocation of proteins across the endoplasmic reticulum membrane. Two different stop-transfer regions were incorporated into precursors for a chloroplast protein, the small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase. Both chimeric proteins were imported into chloroplasts and did not accumulate in the envelope membranes. Thus, the stop-transfer signals did not function during chloroplast protein import. These observations support the hypothesis that the mechanism for translocation of proteins across the chloroplast envelope is significantly different from that for translocation across the endoplasmic reticulum membrane.


Adherence of acanthamoeba to lens cases and effects of drying on survival.
To compare the effects of drying the lens case with tissue on the presence of Acanthamoeba with cases left wet and to determine adherence to the lens case of varying concentrations of Acanthamoeba suspensions. The effect of drying on viability of Acanthamoeba in new, used, and soiled lens cases was compared over a 24 h period. New (16) and scratched (16) lens cases were rinsed with a range of Acanthamoeba suspensions. Eight of each group were dried with tissue and the presence of Acanthamoeba was determined in all cases using polymerase chain reaction. To examine effects of drying, forty-two lens case wells were scratched to simulate use and 21 of these were artificially soiled with serum Bovine albumin. These cases and a further 21 unused wells were contaminated with Acanthamoeba (×10/ml) and then left to dry in a cool, dry environment. Three wells of each group were sampled at time 0, 2, 4, 6, 8, 12, and 24 h, and the number of viable Acanthamoeba were determined. Acanthamoeba were more likely to adhere to used than unused lens cases (p < 0.05). Detection of Acanthamoeba in wiped lens cases was at 2-log dilutions less than in cases left wet for both new and used lens cases. Adherence were significantly different between rinse and rinse/dried cases (p = 0.015). Air drying significantly reduced the numbers of viable amoebic cysts and trophozoites and the effect was time dependent. Survival was significantly higher in used and soiled wells. Drying with tissue after rinsing significantly reduces numbers of adhering Acanthamoeba. Acanthamoeba were found to be able to adhere even to new unused cases, so the importance of proper cleaning and disinfection of lens cases cannot be underestimated. Air drying reduces viability but some viable cells were present at 24 h in soiled cases, confirming the role of biofilm in protecting organisms from desiccation.


Flower-like CdSe ultrathin nanosheet assemblies for enhanced visible-light-driven photocatalytic H2 production.
Flower-like CdSe architectures composed of ultrathin nanosheets were prepared via a facile solvothermal method. A relationship was established between the solvothermal temperature and the product structure, and thus the photocatalytic activity. When compared with well-studied CdSe quantum dots, the ultrathin nanosheet assemblies exhibited a better photocatalytic H2 evolution activity under visible light irradiation.


Is anemia of chronic renal failure related to secondary hyperparathyroidism?
A pathogenetic role of secondary hyperparathyroidism in the anemia of chronic renal failure has been suggested. To investigate this relationship, the biochemical factors of secondary hyperparathyroidism (calcium, phosphorus, alkaline phosphatase, and immunoreactive parathyroid hormone) were correlated with hematocrit levels in 96 long-term hemodialysis patients. We also compared hematocrit values before and after parathyroidectomy in 18 patients. No correlation between hematocrit level and biochemical indices of secondary hyperparathyroidism could be found. However, in 44% of the patients with parathyroidectomies, the hematocrit reading increased after surgery. The importance and possible cause of this improvement of anemia in this group is discussed.


Prevalence of cerebral microbleeds in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia: A systematic review and meta-analysis.
Cerebral microbleeds (CMB) are often associated with vascular risk factors and/or cerebral amyloid angiopathy and are frequently identified in people with dementia. The present study therefore aimed to estimate the pooled prevalence and associations of CMB in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), using meta-analytic methods. Sixty-five MRI studies were included after a systematic search on major electronic databases. We found that the prevalence of CMB was comparable across the three dementia subtypes (31-36%) and was highly influenced by the MRI techniques used. CMB in AD were associated with a history of hypertension and amyloid-β burden. In contrast, CMB in DLB, despite being predominantly lobar, were associated with hypertension, but not amyloid-β burden. These findings suggest that the underlying pathophysiology of CMB in DLB might differ from that of AD. There was substantially larger number of AD studies identified and more studies evaluating CMB in Lewy body dementias are warranted.


Malignant hypertension: a rare problem or is it underdiagnosed?
Malignant hypertension (MHT) is the most severe form of hypertension which is clinically defined as the presence of high blood pressure in association with bilateral retinal haemorrhages and/or exudates, with or without papilloedema. The aim of this review article is to discuss whether MHT is a problem which is truly becoming a rarity, or is it simply a problem with underdiagnosis. Despite the improvements in the general management of hypertension, we have no strong evidence of a declining incidence of MHT. In contrast, this disorder may appear to become even more common worldwide taking into account the growing hypertensive population in the developing countries. Although the diagnostic criteria of MHT appear to be simple and straightforward, the prompt diagnose of MHT may be difficult in substantial proportion of patients who often present with clinical symptoms only at a late stage of irreversible target organ changes. Furthermore, MHT and the accompanying ocular changes may gradually resolve making retrospective diagnosis problematic, whilst persistent target organ damage can drive the development of complications and have a negative prognosis in these patients. Clearly, MHT should not yet be forgotten nor ignored by clinicians.


Recent progress in understanding PAMP- and effector-triggered immunity against the rice blast fungus Magnaporthe oryzae.
Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is one of the most destructive diseases of rice worldwide. The rice-M. oryzae pathosystem has become a model in the study of plant-fungal interactions because of its scientific advancement and economic importance. Recent studies have identified a number of new pathogen-associated molecular patterns (PAMPs) and effectors from the blast fungus that trigger rice immune responses upon perception. Interaction analyses between avirulence effectors and their cognate resistance proteins have provided new insights into the molecular basis of plant-fungal interactions. In this review, we summarize the recent research on the characterization of those genes in both M. oryzae and rice that are important for the PAMP- and effector-triggered immunity recognition and signaling processes. We also discuss future directions for research that will further our understanding of this pathosystem.


Longitudinal time-lapse in vivo micro-CT reveals differential patterns of peri-implant bone changes after subclinical bacterial infection in a rat model.
Subclinical infection associated with orthopedic devices can be challenging to diagnose. The goal of this study was to evaluate longitudinal, microcomputed tomography (microCT) imaging in a rat model of subclinical orthopedic device-related infection caused by Staphylococcus epidermidis and four different Cutibacterium (previously Propionibacterium) acnes strains, and compare outcomes with non-inoculated and historical S. aureus-inoculated controls. Sterile screws or screws colonized with bacteria were placed in the tibia of 38 adult Wistar rats [n = 6 sterile screws; n = 6 S. epidermidis-colonized screws; n = 26 C. acnes-colonized screws (covering all three main subspecies)]. Regular microCT scans were taken over 28 days and processed for quantitative time-lapse imaging with dynamic histomorphometry. At euthanasia, tissues were processed for semiquantitative histopathology or quantitative bacteriology. All rats receiving sterile screws were culture-negative at euthanasia and displayed progressive bony encapsulation of the screw. All rats inoculated with S. epidermidis-colonized screws were culture-positive and displayed minor changes in peri-implant bone, characteristic of subclinical infection. Five of the 17 rats in the C. acnes inoculated group were culture positive at euthanasia and displayed bone changes at the interface of the screw and bone, but not deeper in the peri-implant bone. Dynamic histomorphometry revealed significant differences in osseointegration, bone remodeling and periosteal reactions between groups that were not measurable by visual observation of still microCT images. Our study illustrates the added value of merging 3D microCT data from subsequent timepoints and producing inherently richer 4D data for the detection and characterization of subclinical orthopedic infections, whilst also reducing animal use.


Nagaoka ferromagnetism observed in a quantum dot plaquette.
Engineered, highly controllable quantum systems are promising simulators of emergent physics beyond the simulation capabilities of classical computers1. An important problem in many-body physics is itinerant magnetism, which originates purely from long-range interactions of free electrons and whose existence in real systems has been debated for decades2,3. Here we use a quantum simulator consisting of a four-electron-site square plaquette of quantum dots4 to demonstrate Nagaoka ferromagnetism5. This form of itinerant magnetism has been rigorously studied theoretically6-9 but has remained unattainable in experiments. We load the plaquette with three electrons and demonstrate the predicted emergence of spontaneous ferromagnetic correlations through pairwise measurements of spin. We find that the ferromagnetic ground state is remarkably robust to engineered disorder in the on-site potentials and we can induce a transition to the low-spin state by changing the plaquette topology to an open chain. This demonstration of Nagaoka ferromagnetism highlights that quantum simulators can be used to study physical phenomena that have not yet been observed in any experimental system. The work also constitutes an important step towards large-scale quantum dot simulators of correlated electron systems.


Results of the national program for prevention of beta-thalassemia major in the Iranian Province of Mazandaran.
Prevention programs are considered to be a top priority in Iran because beta-thalassemia (beta-thal) major (TM) is the most common autosomal disorder in Iran, and in the Mazandaran Province in particular. The main strategies comprise providing appropriate information for the public and professionals, screening and counseling of families at-risk and screening of general population prior to marriage. Providing laboratories for prenatal diagnosis was the most recent step in the program. We report the results of our prevention campaign for the period 1993-2006 in order to assess the effectiveness of all actions in controlling thalassemia major. In 1993, 500 TM patients were registered at the clinic of the Boo Ali Sina Hospital, Sari, Mazandaran, Iran. From 1993 to 1996, on average of 50 new cases were added to the cohort annually, whereas from 1995 to 2005 the number of new cases declined to 35 per year. Furthermore, the patients' average age increased. Overall, 51% of couples at-risk, who received genetic counseling, decided not to marry. All at-risk couples who are married were counseled for prevention of unplanned pregnancies. Currently, 64% are using safe contraceptive methods of family planning, and 14% are no longer at-risk for further pregnancies, the rest remained at-risk for unplanned pregnancies. In conclusion, at the relatively low cost of premarital screening and genetic counseling, we have offered at-risk couples the possibility of preventing the birth of at least 600 undesired TM patients. Thus, a great deal of suffering and an unbearable financial burden has been prevented to patients and their families.


Association of spontaneous abortion with bipolar disorder and major depression based on inverse probability treatment weighting of multigroup propensity scores: Evidence from the UK Biobank.
Few studies have explored the association between the number of SAs and bipolar disorder and major depression (BDMD). This study aims to investigate the association between SA and BDMD, and the possible dose-response relationship between them. We conducted a cross-sectional study of 13,200 female UK Biobank participants. Participants were classified into BDMD and no-BDMD groups based on their BDMD status. The number of SAs was grouped into non-SA, occasional SA (OSA), and recurrent SA (RSA). Baseline characteristics of the three groups were balanced using inverse probability treatment weighting (IPTW) based on propensity scores. The three-knots restricted cubic spline regression model was utilized to assess the dose-response relationship between the number of SAs and BDMD. The IPTW-adjusted multivariate logistic regression revealed that SA was an independent risk factor for BDMD, with adjusted OR of 1.12 (95 % CI: 1.07-1.19) and 1.32 (95 % CI: 1.25-1.40) in the OSA and RSA groups, respectively. The strength of this association amplified as the number of SAs (P for trend <0.001). There was a nonlinear relationship between the number of SAs and the risk of BDMD, with an approximately inverted L-shaped curve. The information of the SA and BDMD status relied on self-reported by volunteers, and the study sample was mostly of European descent. Women who reported experiencing multiple SAs are more likely to have BDMD. Therefore, it is imperative to provide psychological care and interventions for women in the postpartum period.


Three of 7 hemoglobin A1c point-of-care instruments do not meet generally accepted analytical performance criteria.
In 2009, we investigated the conformance of 8 hemoglobin A(1c) (Hb A(1c)) point-of-care (POC) instruments. Since then, instruments have improved and new devices are available on the market. In this second study, we evaluated the performance of DCA Vantage, Afinion, InnovaStar, Quo-Lab, Quo-Test, Cobas B101, and B-analyst Hb A(1c) POC instruments. Clinical and Laboratory Standards Institute protocols EP-5 and EP-9 were applied to investigate imprecision, accuracy, and bias. We assessed bias using the mean of 3 certified secondary reference measurement procedures (SRMPs). Assay conformance with the National Glycohemoglobin Standardization Program (NGSP) certification criteria was also evaluated. Interference of common Hb variants was investigated for methods that could work with hemolysed material. The total CVs for all instruments, except for the DCA Vantage at a high Hb A(1c) value, were ≤3.1% in SI units and ≤2.1% in Diabetes Control and Complications Trial (DCCT) units. Afinion, DCA Vantage, B-analyst, and Cobas B101 instruments passed the NGSP criteria with 2 different reagent lot numbers. Quo-Test, Quo-Lab, and InnovaStar instruments had a negative bias compared to the mean of the 3 SRMPs and failed NGSP criteria. Most of the common Hb variants did not interfere with the investigated instruments, except Hb AE for the Cobas B101. Afinion, DCA Vantage, Cobas B101, and B-analyst instruments met the generally accepted performance criteria for Hb A(1c). Quo-Test, Quo-Lab, and InnovaStar met the criteria for precision but not for bias. Proficiency testing should be mandated for users of Hb A1c POC assays to ensure quality.


Recess and Overweight and Obesity in Children 5-11 Years of Age: 2013-2016 National Health and Nutrition Examination Survey.
Recess has been shown to increase total daily energy expenditure, which may favorably impact body mass index by decreasing adiposity. This study examines associations between recess participation and adiposity. The study sample included male (N = 1434) and female (N = 1409) children 5 to 11 years of age participating in the 2013-2016 National Health and Nutrition Examination Survey. Overweight and obesity were defined using age- and sex-specific percentiles. Recess participation interview questions were answered via proxy response. Compared to a referent group participating in recess 5 days/week for >30 minutes/day and independent of demographic and behavioral factors, analysis revealed significantly greater odds of obesity in females reporting no recess participation (odds ratio 1.80; 95% confidence interval, 1.03-3.15, p = .03). Furthermore, minority females were consistently found to possess greater odds of overweight and obesity independent of recess participation time. Only Mexican American boys were found to have greater odds of obesity independent of participation recess time. In a large nationally representative sample of US children, reporting no recess was associated with significantly greater odds of obesity in females. Minority females were also more likely to be overweight and obese and Mexican American boys are more likely to be obese independent of recess participation time.


Chimeric antigen receptor therapy for cancer.
Improved outcomes for patients with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, synthetic biology, and cell-processing technologies has paved the way for clinical applications of chimeric antigen receptor-based therapies. This new form of targeted immunotherapy merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and on elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of cancer.


Future supply of boreal forest ecosystem services is driven by management rather than by climate change.
Forests provide a wide variety of ecosystem services (ES) to society. The boreal biome is experiencing the highest rates of warming on the planet and increasing demand for forest products. To foresee how to maximize the adaptation of boreal forests to future warmer conditions and growing demands of forest products, we need a better understanding of the relative importance of forest management and climate change on the supply of ecosystem services. Here, using Finland as a boreal forest case study, we assessed the potential supply of a wide range of ES (timber, bilberry, cowberry, mushrooms, carbon storage, scenic beauty, species habitat availability and deadwood) given seven management regimes and four climate change scenarios. We used the forest simulator SIMO to project forest dynamics for 100 years into the future (2016-2116) and estimate the potential supply of each service using published models. Then, we tested the relative importance of management and climate change as drivers of the future supply of these services using generalized linear mixed models. Our results show that the effects of management on the future supply of these ES were, on average, 11 times higher than the effects of climate change across all services, but greatly differed among them (from 0.53 to 24 times higher for timber and cowberry, respectively). Notably, the importance of these drivers substantially differed among biogeographical zones within the boreal biome. The effects of climate change were 1.6 times higher in northern Finland than in southern Finland, whereas the effects of management were the opposite-they were three times higher in the south compared to the north. We conclude that new guidelines for adapting forests to global change should account for regional differences and the variation in the effects of climate change and management on different forest ES.


A novel motif in geminivirus replication proteins interacts with the plant retinoblastoma-related protein.
The geminivirus replication factor AL1 interacts with the plant retinoblastoma-related protein (pRBR) to modulate host gene expression. The AL1 protein of tomato golden mosaic virus (TGMV) binds to pRBR through an 80-amino-acid region that contains two highly predicted alpha-helices designated 3 and 4. Earlier studies suggested that the helix 4 motif, whose amino acid sequence is strongly conserved across geminivirus replication proteins, plays a role in pRBR binding. We generated a series of alanine substitutions across helix 4 of TGMV AL1 and examined their impact on pRBR binding using yeast two-hybrid assays. These experiments showed that several helix 4 residues are essential for efficient pRBR binding, with a critical residue being a leucine at position 148 in the middle of the motif. Various amino acid substitutions at leucine-148 indicated that both structural and side chain components contribute to pRBR binding. The replication proteins of the geminiviruses tomato yellow leaf curl virus and cabbage leaf curl virus (CaLCuV) also bound to pRBR in yeast dihybrid assays. Mutation of the leucine residue in helix 4 of CaLCuV AL1 reduced binding. Together, these results suggest that helix 4 and the conserved leucine residue are part of a pRBR-binding interface in begomovirus replication proteins.


Ovarian and uterine carcinosarcomas: a comparative analysis of prognostic variables and survival outcomes.
Carcinosarcomas (malignant mixed Mullerian tumor) of the female genital tract are rare tumors associated with poor outcome. The objective of this study was to identify site-specific differences by comparing carcinosarcomas originating in the uterus and the ovaries. Data on patients with uterine and ovarian carcinosarcomas were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Kaplan-Meier log rank and Cox proportional hazards models were used for survival analysis and for identification of possible predictors for survival. The identified cohort included 3683 women of whom 2759 (75%) have uterine carcinosarcoma and 924 (25%) have ovarian carcinosarcomas. The patients with uterine carcinosarcoma were older than the patients with ovarian carcinosarcoma (median age, 67 vs 65 years; P < 0.001). The women with uterine carcinosarcoma compared with those with ovarian carcinosarcoma were more often African American (17.3% vs 6%; P < 0.001) and presented more often with localized disease (47% vs 10.8%; P < 0.001). Uterine carcinosarcoma compared with ovarian carcinosarcoma differed significantly with regard to the performance of lymphadenectomy (62.6% vs 41.2%; P < 0.001) and the administration of radiotherapy (38.2% vs 4.8%; P < 0.001). When controlled for the extent of disease spread, uterine carcinosarcoma had a more aggressive clinical course and shorter survival compared with ovarian carcinosarcoma. Although age (P < 0.001), race (P = 0.01), stage (P < 0.001), lymphadenectomy (P < 0.001), and radiation (P < 0.001) were all significant prognostic factors in uterine carcinosarcoma, only age (P < 0.001), stage (P < 0.001), and lymphadenectomy (P < 0.001) were significant predictors in ovarian carcinosarcoma. Although uterine carcinosarcoma presents at an earlier stage than ovarian carcinosarcoma, it has a worse prognosis compared with ovarian carcinosarcoma, with a similar extent of disease spread. Improved survival observed in lymphadenectomy group lends support to its routine performance in patients with uterine and ovarian carcinosarcomas.


Agonist binding and protein kinase C activation stimulate phosphorylation of the gastrin-releasing peptide receptor at distinct sites.
Gastrin-releasing peptide and other bombesin-like peptides stimulate secretion, cell proliferation, and smooth muscle contraction via a family of G protein-coupled receptors that activate phospholipase C. Second messenger formation by one of these receptors, called BR1, is rapidly desensitized after treatment of cells with either agonists or the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA). To determine whether receptor phosphorylation was involved in BR1 desensitization, we generated antibodies to a peptide corresponding to a unique sequence within the COOH terminus of this receptor. One antibody (BR1-517) immunoprecipitated 60% of the solubilized [125I-Tyr4]bombesin/receptor complex prepared from either Swiss 3T3 fibroblasts or CHO-K1 cells transfected to express high levels of mouse BR1 (CHO-mBR1). Furthermore, immunoprecipitation of photoaffinity-labeled receptors yielded the expected 87-kDa radiolabeled band on gel electrophoresis. Phosphorylation of this immunoprecipitated receptor protein was markedly stimulated when [32P]orthophosphate-labeled Swiss 3T3 cells or CHO-mBR1 cells were treated with 100 nM bombesin for 5 min. 32PO4 incorporation into immunoprecipitated receptor was detectable after 2 min and maximal after 15 min of bombesin treatment. Phosphoamino acid analysis showed 32P labeling of serine and theonine but not tyrosine residues. Pretreatment of CHO-mBR1 cells with 100 nM TPA for 30 min also desensitized bombesin stimulation of inositol-1,4,5-trisphosphate formation. However, TPA did not increase 32PO4 incorporation into the immunoprecipitated receptor, although protein kinase C inhibition potentiated bombesin-induced receptor phosphorylation. Subsequent studies showed that TPA did stimulate receptor phosphorylation, but the antibody did not recognize this phosphorylated state of the receptor. Thus, TPA decreased the efficiency of receptor immunoprecipitation, and subsequent incubation of receptor with alkaline phosphatase reversed this TPA inhibition. The differential specificity of the antibody for various phosphorylated forms of BR1 demonstrates that agonist-induced and TPA-induced phosphorylations of the receptor occur at distinct sites.


Macrophage migration inhibitory factor is essential for osteoclastogenic mechanisms in vitro and in vivo mouse model of arthritis.
Macrophage migration inhibitory factor (MIF) enhances activation of leukocytes, endothelial cells and fibroblast-like synoviocytes (FLS), thereby contributing to the pathogenesis of rheumatoid arthritis (RA). A MIF promoter polymorphism in RA patients resulted in higher serum MIF concentration and worsens bone erosion; controversially current literature reported an inhibitory role of MIF in osteoclast formation. The controversial suggested that the precise role of MIF and its putative receptor CD74 in osteoclastogenesis and RA bone erosion, mediated by locally formed osteoclasts in response to receptor activator of NF-κB ligand (RANKL), is unclear. We reported that in an in vivo K/BxN serum transfer arthritis, reduced clinical and histological arthritis in MIF(-/-) and CD74(-/-) mice were accompanied by a virtual absence of osteoclasts at the synovium-bone interface and reduced osteoclast-related gene expression. Furthermore, in vitro osteoclast formation and osteoclast-related gene expression were significantly reduced in MIF(-/-) cells via decreasing RANKL-induced phosphorylation of NF-κB-p65 and ERK1/2. This was supported by a similar reduction of osteoclastogenesis observed in CD74(-/-) cells. Furthermore, a MIF blockade reduced RANKL-induced osteoclastogenesis via deregulating RANKL-mediated NF-κB and NFATc1 transcription factor activation. These data indicate that MIF and CD74 facilitate RANKL-induced osteoclastogenesis, and suggest that MIF contributes directly to bone erosion, as well as inflammation, in RA.


Weight of salivary gland ultrasonography compared to other items of the 2016 ACR/EULAR classification criteria for Primary Sjögren's syndrome.
Major salivary gland ultrasonography (SGUS) is widely used for the diagnosis of primary Sjögren's syndrome (pSS). Our objective was to assess the contribution of SGUS compared to other items of the 2016 ACR/EULAR pSS classification criteria, based on expert opinion. A secure web-based relational database was used by 24 experts from 14 countries to assess 512 realistic vignettes developed from data of patients with suspected pSS. Each vignette provided classification criteria items and information on history, clinical symptoms and SGUS findings. Each expert assessed 64 vignettes, and each vignette was assessed by 3 experts. A diagnosis of pSS was defined according to at least 2 of 3 experts. Validation was performed in the independent French DiapSS cohort of patients with suspected pSS. A criteria-based pSS diagnosis and SGUS findings were independently associated with an expert diagnosis of pSS (P < 0.001). The derived diagnostic weights of individual items in the 2016 ACR/EULAR criteria including SGUS were as follows: anti-SSA, 3; focus score ≥ 1, 3; SGUS score ≥ 2, 1; positive Schirmer's test, 1; dry mouth, 1; and salivary flow rate < 0.1 mL/min, 1. The corrected C statistic area under the curve for the new weighted score was 0.96. Adding SGUS improves the sensitivity from 90.2 % to 95.6% with a quite similar specificity 84.1% versus 82.6%. Results were similar in the DiapSS cohort: adding SGUS improves the sensitivity from 87% to 93%. SGUS had similar weight compared to minor items, and its addition improves the performance of the 2016 ACR/EULAR classification criteria.


Tumor Microenvironment-Responsive Nanodrug for Clear-Cell Renal Cell Carcinoma Therapy via Triggering Waterfall-Like Cascade Ferroptosis.
The most common type of kidney tumor, clear-cell renal cell carcinoma (ccRCC) with relatively insidious development and easily metastatic characteristics is generally insensitive to cytotoxic chemotherapy. The abundant polyunsaturated fatty acids (PUFAs) content in advanced ccRCC allows it to be intrinsically vulnerable to ferroptosis-based therapeutic strategies. Nevertheless, the strategy to cause the "iron overload" by administration with iron-based nanomaterials has limited therapeutic efficacy. And the classic ferroptosis agonist (RSL3) with low specificity for tumors, short half-life in the blood, poor water solubility and deficient accumulation at the tumor site prevents its reliable application in vivo. In this study, iron-based metal-organic framework nanoparticles (MIL-101(Fe) NPs) delivered RSL3 to ccRCC tumors, and then released the iron ions and RSL3 accompanied by the degradation of MIL-101(Fe) NPs in the acidic tumor microenvironment. The MIL-101(Fe)@RSL3 as a pH-responsive nanodrug causes cellular iron overload and promotes the hydroxyl radical (•OH) generation by Fenton reaction to attack PUFAs, leading to the aberrant accumulation of lipid peroxides (L-OOH). Additionally, RSL3 directly inhibits glutathione peroxidase 4 (GPX4) to detoxify L-OOH, and ferrous ions further catalyze the irreversible conversion of highly reactive lipid alkoxyl radicals (L-O•) from L-OOH to triggering waterfall-like cascade ferroptosis. In contrast to the limited antitumor efficiency of free RSL3, MIL-101(Fe)@RSL3 with high encapsulation efficiency (88.7%) shows a significant ccRCC-specific antitumor effect and negligible side effects. Taken together, MIL-101(Fe)@RSL3 could aggravate ferroptosis and be expected to be a promising nanodrug for ccRCC systemic therapy due to the targeted delivery and responsive release of RSL3 and iron ions.


Neurochemical and Neuroendocrine Effects of Ibogaine in Rats: Comparison to MK-801.
Ibogaine (IBO) is a naturally-occurring indole compound that is being evaluated as a potential medication for substance use disorders. Although the precise mechanism of IBO action is unclear, recent in vitro data show this drug displays properties similar to the noncompetitive N-methyl-d-aspartate (NMDA) antagonist MK-801. The purpose of the present work was to compare In Vivo neurobiological effects of IBO and MK-801 in rats. Groups of male rats (n = 6-8/group) were decapitated 30 and 60 min after receiving intraperitoneal (i.p.) IBO (10 & 100 mg/kg), MK-801 (0.1 & 1.0 mg/kg) or vehicle. Trunk blood was collected for the analysis of plasma prolactin and corticosterone; brains were harvested and dissected for determination of dopamine (DA), serotonin (5-HT) and their metabolites. Both IBO and MK-801 increased corticosterone secretion, but only IBO elevated plasma prolactin. IBO produced dramatic reductions in tissue DA levels with concurrent increases in the metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of IBO-induced changes in DA transmission was observed in the striatum, olfactory tubercle, and hypothalamus. The effects of MK-801 on DA metabolism did not mimic IBO, as MK-801 tended to increase DA and its metabolites. Neither drug appreciably affected 5-HT systems. Our results suggest that the effects of IBO on neuroendocrine function and DA transmission are not due to MK-801-like properties of IBO. Thus, the In Vivo mechanism of IBO action cannot be explained simply on the basis of antagonism at NMDA receptors.


[Glutamate dehydrogenase activity in the structures of the rabbit brain limbic system].
The activity of glutamate dehydrogenase (EC 18.104.22.168) is studied in homogenates and subcellular fractions of five limbic structures: regio superior, regio inferior of hippocampus, fascia dentata, septum and corpora mamillaria. The lowest activity of the enzyme is found in regio superior of hippocampus. 80% of the total enzyme activity of primary fractions is found in "crude" mitochondria. After centrifugation of the latter within the linear sucrose density gradient the distribution of the enzume activity is similar for different structures and the highest activity is found in the region of sucrose molarity from 1.44 up to 1.50 M which corresponds to the mitochondria distribution region. 50% of the total found activity is in the fraction enriched by mitochondria, 30% is in the fraction enriched by nerve endings with the high activity of glutamate decarboxylase. It was found for different fractions that 1 mM of ADF with 0.2 mM NAD-H+ produces about 10-fold increase in the enzyme activity. Pyridoxal-5'-phosphate inhibits the enzyme from inactivation. The results are discussed in connection with the possible role of pyridoxal-5'-phosphate in regulation of the glutamate dehydrogenase activity in vivo.


[Significance of radionuclide study in early diagnosis of chronic pleural empyemas].
Forty-five patients aged 17 to 70 years with exudative pleurisy were examined. Among them there were 31 patients with exudative pleurisy of tuberculous etiology, 7 with parapneumonic pleurisy and 7 with malignant pleurisy. In addition to clinical and X-ray examination, all the patients were studied for the functional status of the parietal pleura by using the radionuclide technique. The study indicated that the peripheral blood levels of radio pharmaceuticals (RP) ranged in relation to the duration of the disease: 0.33%, 0.31, 0.29, and 0.26% with a duration of 1-3, 4-6, 7-9, and over 10 months, respectively. With the least changes in the parietal pleura, the peripheral blood content of RP was highest and in pleural cirrhosis it was the lowest. The study showed that 66% were diagnosed as having early pleural empyema and 13 underwent pleurectomy.


Bronchial epithelial compression regulates MAP kinase signaling and HB-EGF-like growth factor expression.
Airway smooth muscle constriction leads to the development of compressive stress on bronchial epithelial cells. Normal human bronchial epithelial cells exposed to an apical-to-basal transcellular pressure difference equivalent to the computed stress in the airway during bronchoconstriction demonstrate enhanced phosphorylation of extracellular signal-regulated kinase (ERK). The response is pressure dependent and rapid, with phosphorylation increasing 14-fold in 30 min, and selective, since p38 and c-Jun NH(2)-terminal kinase phosphorylation remains unchanged after pressure application. Transcellular pressure also elicits a ninefold increase in expression of mRNA encoding heparin-binding epidermal growth factor-like growth factor (HB-EGF) after 1 h, followed by prominent immunostaining for pro-HB-EGF after 6 h. Inhibition of the ERK pathway with PD-98059 results in a dose-dependent reduction in pressure-induced HB-EGF gene expression. The magnitude of the HB-EGF response to transcellular pressure and tumor necrosis factor (TNF)-alpha (1 ng/ml) is similar, and the combined mechanical and inflammatory stimulus is more effective than either stimulus alone. These results demonstrate that compressive stress is a selective and potent activator of signal transduction and gene expression in bronchial epithelial cells.


New molecular staging with G-factors (VEGF-C and Reg IV) by supplementing TNM classification in colorectal cancers.
Staging classification of colorectal cancers is performed by the UICC/TNM classification system, which is the global gold standard. However, we often experience in clinical practice that there are considerable differences in prognoses between patients who have the same classification particularly in stage II and III cancers. The aim of this study was to propose a new TNM-G classification to predict prognosis and recurrence by supplementing the conventional TNM classification. A total of 220 cases of colorectal cancer, including 77 at stage II and 143 at stage III, were registered from four independent facilities. Immunohistochemical staining for 7 molecules, such as p53, vascular endothelial growth factor (VEGF)-A, VEGF-C, regenerating islet-derived family, member 4 (Reg IV), olfactomedin 4, Claudin-18 and matrix metalloproteinase-7 (MMP‑7), was performed to investigate the correlation between clinicopathological factors and expression of each molecule. Based on the results, no significant correlation was observed between the immunostaining expression of these 7 factors and recurrence in total colorectal cancer. Recurrence in stage II (77 cases) was significantly higher in cases positive for Reg IV expression (P=0.042). On analysis of overall survival (OS) and disease‑free survival (DFS), VEGF-C and Reg IV expression had a correlation with poor prognosis, therefore, these factors were selected and applied to G-factor classifications so that cases negative for both could be classified as G0, cases positive for either of the factors could be classified as G1, and cases positive for both factors could be classified as G2. While no significant correlation was observed in the recurrence rates between G0 and G2, OS and DFS in stage II cases were significantly poorer for G2 cases in comparison with G0 or G1 cases. The survival curves of OS and DFS in stage II G2 were similar to that of stage III cases. According to these results, prognosis of VEGF-C/Reg IV both positive G2 cases in stage II colorectal cancer was found to be almost equal to the poor survival in stage III cases, and the advancement of one stage up migration based on G-factors may be supposed to be highly feasible for clinical application. In conclusion, the combination of VEGF-C and Reg IV may be a promising factor for clinical staging to supplement the classical TNM classification system, and it may suggest a good indication of adjuvant chemotherapy for G2 cases in stage II colorectal cancers.


Three-year Outcomes of an Expanded Asynchronous Virtual Glaucoma Clinic in Singapore.
Virtual glaucoma clinics can help increase health care capacity, easing the disease burden of glaucoma. This study assesses the safety, rate of glaucoma progression, time efficiency, and cost-savings of our expanded Glaucoma Observation Clinic (GLOC) at the Singapore National Eye Centre over 3 years. All patients seen at GLOC between July 2018 and June 2021 were included. Visual acuity, intraocular pressure, and visual fields or optic nerve head imaging were recorded, followed by a virtual review of the data by an ophthalmologist. An objective review of the management of 100 patients was conducted by 2 senior consultants independently as a safety audit. Patient outcomes including the rate of instability (due to worsening of clinical parameters necessitating a conventional clinic visit), glaucoma progression, the consultation review time efficiency, and cost-savings of GLOC were measured. Of 3458 patients, 16% had glaucoma, and the others had risk factors for glaucoma. The safety audit demonstrated a 95% interobserver agreement. The rate of instability was 14.6%, of which true progression was observed in 3.12%. The time taken for a glaucoma specialist to review a GLOC patient was 5.75±0.75 minutes compared with 13.7±2.3 minutes in a conventional clinic. The per capita manpower cost per GLOC patient per visit was $36.77 compared with $65.62 in the conventional clinic. This translates to a cost-saving of $280.65 over the lifetime of a hypothetical patient. Our expanded virtual glaucoma clinic is a safe, time-efficient, and cost-effective model with low rates of glaucoma progression, which could allow for significant health care capacity expansion.


Tertiary contact vaccinia in a breastfeeding infant.
On May 4, 2003, a US Army soldier received primary smallpox vaccination and experienced a primary uptake reaction at the inoculation site on days 6 through 8. The vaccinee reported observing all of the standard precautions to avoid household spread. In mid May, his breastfeeding wife developed vesicles on both areolas. On May 29, their infant daughter developed a papule on her philtrum. Contact vaccinia was confirmed by positive polymerase chain reaction and culture for vaccinia of both the maternal and infant lesions. This is the first documented case of inadvertent contact vaccinia transmission from a mother to her infant through direct skin-to-skin and skin-to-mucous membrane contact while breastfeeding. The mechanism of transfer from the vaccinee to the spouse is uncertain. This report demonstrates that breastfeeding infants living in close contact with smallpox vaccinees are at potential risk for contact vaccinia, even if the vaccinee is not the breastfeeding mother, and highlights the need for special precautions to prevent secondary transfer to breastfeeding mothers.


Differential regulation of the mu-, delta-, and kappa-opiate receptor subtypes by guanyl nucleotides and metal ions.
The effects of Na+, guanyl-5'-yl imidodiphosphate (Gpp(MH)p), and Mn2+ on the binding of dihydromorphine, ethylketocyclazocine, D-Ala2, D-Leu5-enkephalin, and diprenorphine to the opiate receptor were investigated. Three distinct binding sites, mu, delta, and kappa sites, were identified with the use of multiple tracer displacement curves. Moreover, this approach was used to determine the effects of Gpp (NH)p and metal ions on each individual binding site. At the mu and delta sites, Na+ and Gpp(NH)p each decreased and Mn2+ increased agonist binding affinities, with the exception of D-Ala2, D-Leu-enkephalin affinity which was not affected by Gpp(NH)p. None of these conditions markedly altered dihydromorphine and D-Ala2, Leu5-enkephalin binding to kappa sites, whereas the affinity of ethylke-tocyclazocine for kappa sites was decreased by Gpp(NH)p. Sodium ions lowered the capacity of mu sites and Gpp(NH)p reduced that of delta sites, while both agents increased the capacity of apparent kappa sites. These results demonstrate that each of the kinetically distinguishable binding sites is regulated differentially by metal ions and guanyl nucleotides. Simultaneous addition of Na+ and Gpp(NH)p greatly reduced the binding affinity of all three agonists at their respective high affinity sites (dihydromorphine at the mu site, D-Ala2, D-Leu5-enkephalin at the delta site, and ethylketocyclazocine at the kappa and mu sites). This result confirms previous observations that agonist binding is characterized by a large affinity reduction in the presence of both Na+ and guanyl nucleotides, and it extends this concept to each of the opiate receptor subtypes.


Simulation of human luteal endocrine function with granulosa lutein cell culture.
Human granulosa cells collected from in vitro fertilization have previously been cultured to provide a system to simulate the granulosa lutein cells of the corpus luteum. In most of these systems, the cultures have been relatively short term, and attempts to simulate the normal pattern of hormone production observed during the luteal phase of the cycle have not been reported. Additionally, the hormone relaxin has generally been absent from the endocrine analysis of these systems. In this report, methods were used that supported secretion of ovarian steroids and relaxin that mimics the profiles of these hormones in vivo. This system was used to observe the endocrine responses of the granulosa lutein cells to three different protocols of CG administration designed to mimic the normal luteal phase, early pregnancy, and early pregnancy followed by pregnancy loss. The normal luteal phase was simulated by a constant baseline (0.02 IU/mL) CG model to simulate a nonconceptive cycle (baseline). The second model was baseline CG until day 8 of culture, followed by daily doubling from days 9-17 to simulate an early pregnancy (rescue-plateau). CG concentrations were then held constant from days 17-20 (5.12 IU/mL). A third model (rescue-drop) was used that was identical to the early pregnancy model except that on day 17 CG was returned to baseline concentrations (0.02 IU/mL) to simulate an early pregnancy loss. Baseline CG stimulation resulted in profiles of estrogen, progesterone, and relaxin secretion in culture that were closely related to secretory profiles previously reported in serum during the nonconceptive luteal phase. The timing of appearance of relaxin secretion and later declines in steroid and relaxin secretion paralleled that observed in serum. In the CG rescue protocols, ovarian steroids rose in response to daily doubling of CG and fell when CG either plateaued or fell. Relaxin did not show an increase in response to increasing CG, but its secretion did not drop when CG concentrations plateaued or dropped. This cell culture system model mimics the profile of ovarian steroids and relaxin seen in serum during the nonconceptive luteal phase, although the relative magnitude of the hormones was not the same as seen in vivo. It was also used to investigate responses to luteal rescue protocols designed to simulate early pregnancy and pregnancy loss. This culture system may be useful to study differences in endocrine response in granulosa cells collected from different patients and to provide information of clinical relevance. This culture system provides a model to study luteal function and its response to different protocols of luteal rescue and thus may provide insight into early pregnancy and pregnancy loss.


Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?
Many small-molecule agonists also display allosteric properties. Such ago-allosteric modulators act as co-agonists, providing additive efficacy--instead of partial antagonism--and they can affect--and often improve--the potency of the endogenous agonist. Surprisingly, the apparent binding sites of several ordinary allosteric enhancers and ago-allosteric modulators seem to overlap with those of the endogenous agonists. Different molecular scenarios are proposed to explain this discrepancy from classical allosteric models. In one scenario, the ago-allosteric modulator can interchange between different binding modes. In another, dimeric, receptor scenario, the endogenous agonist binds to one protomer while the ago-allosteric modulator binds to the other, 'allosteric' protomer. It is suggested that testing for ago-allosteric properties should be an integral part of the agonist drug discovery process because a compound that acts with--rather than against--the endogenous agonist could be an optimal agonist drug.


Changes in Absolute Contents of Compounds Affecting the Taste and Nutritional Properties of the Flesh of Three Plum Species Throughout Development.
The characteristics of plum fruits of three different species were investigated throughout their development (including over-ripening). The content of primary and secondary metabolites was expressed as amount per gram DW (dry weight) and per fruit in order to obtain information about the balance between their synthesis and dissimilation at different stages of fruit development. In all the plums, during the first stages of development, glucose was the most abundant sugar, whereas sucrose increased during ripening. There was no decrease in malate content per fruit before the commercial harvesting time of any of the plums, whereas a decrease was observed during over-ripening. In general, both the total phenol content and the contents of individual phenols in the flesh expressed on gram DW decreased throughout development, whereas their content per fruit increased, indicating that these decreases were due to a dilution effect arising from the expansion of the flesh. During the development of the flesh, the increase in the contents of the investigated metabolites per fruit shows that there was no net dissimilation of malate up to commercial harvest and of phenols throughout fruit development. Good correlations between the content of phenols to antioxidant activity were found. Shiro flesh, during the last part of fruit development, had lower total carbohydrate and polyphenol contents, lower antioxidant activities, and a higher malate content than the flesh of the other two genotypes.


Complete Dosage Compensation in Anopheles stephensi and the Evolution of Sex-Biased Genes in Mosquitoes.
Complete dosage compensation refers to hyperexpression of the entire X or Z chromosome in organisms with heterogametic sex chromosomes (XY male or ZW female) in order to compensate for having only one copy of the X or Z chromosome. Recent analyses suggest that complete dosage compensation, as in Drosophila melanogaster, may not be the norm. There has been no systematic study focusing on dosage compensation in mosquitoes. However, analysis of dosage compensation in Anopheles mosquitoes provides opportunities for evolutionary insights, as the X chromosome of Anopheles and that of its Dipteran relative, D. melanogaster formed independently from the same ancestral chromosome. Furthermore, Culicinae mosquitoes, including the Aedes genus, have homomorphic sex-determining chromosomes, negating the need for dosage compensation. Thus, Culicinae genes provide a rare phylogenetic context to investigate dosage compensation in Anopheles mosquitoes. Here, we performed RNA-seq analysis of male and female samples of the Asian malaria mosquito Anopheles stephensi and the yellow fever mosquito Aedes aegypti. Autosomal and X-linked genes in An. stephensi showed very similar levels of expression in both males and females, indicating complete dosage compensation. The uniformity of average expression levels of autosomal and X-linked genes remained when An. stephensi gene expression was normalized by that of their Ae. aegypti orthologs, strengthening the finding of complete dosage compensation in Anopheles. In addition, we comparatively analyzed the differentially expressed genes between adult males and adult females in both species, investigated sex-biased gene chromosomal distribution patterns in An. stephensi and provided three examples where gene duplications may have enabled the acquisition of sex-specific expression during mosquito evolution.


Efficient algorithm for discrete sinc interpolation.
A new computing method for discrete-signal sinc interpolation suitable for use in image and signal processing and the synthesis of holograms is described. It is shown to be superior to the commonly used zero-padding interpolation method in terms of interpolation accuracy, flexibility, and computational complexity.


Multiparameter behavioral analyses provide insights to mechanisms of cyanide resistance in Caenorhabditis elegans.
Environmental toxicants influence development, behavior, and ultimately survival. The nematode Caenorhabditis elegans has proven to be an exceptionally powerful model for toxicological studies. Here, we develop novel technologies to describe the effects of cyanide toxicity with high spatiotemporal resolution. Importantly, we use these methods to examine the genetic underpinnings of cyanide resistance. Caenorhabditis elegans that lack the EGL-9 oxygen sensing enzyme have been shown to be resistant to hydrogen cyanide (HCN) gas produced by the pathogen Pseudomonas aeruginosa PAO1. We demonstrate that the cyanide resistance exhibited by egl-9 mutants is completely dependent on the HIF-1 hypoxia-inducible factor and is mediated by the cysl-2 cysteine synthase, which likely functions in metabolic pathways that inactivate cyanide. Further, the expression of cysl-2 correlates with the degree of cyanide resistance exhibited in each genetic background. We find that each mutant exhibits similar relative resistance to HCN gas on plates or to aqueous potassium cyanide in microfluidic chambers. The design of the microfluidic devices, in combination with real-time imaging, addresses a series of challenges presented by mutant phenotypes and by the chemical nature of the toxicant. The microfluidic assay produces a set of behavioral parameters with increased resolution that describe cyanide toxicity and resistance in C. elegans, and this is particularly useful in analyzing subtle phenotypes. These multiparameter analyses of C. elegans behavior hold great potential as a means to monitor the effects of toxicants or chemical interventions in real time and to study the biological networks that underpin toxicant resistance.


Community responses to communication campaigns for influenza A (H1N1): a focus group study.
This research was a part of a contestable rapid response initiative launched by the Health Research Council of New Zealand and the Ministry of Health in response to the 2009 influenza A pandemic. The aim was to provide health authorities in New Zealand with evidence-based practical information to guide the development and delivery of effective health messages for H1N1 and other health campaigns. This study contributed to the initiative by providing qualitative data about community responses to key health messages in the 2009 and 2010 H1N1 campaigns, the impact of messages on behavioural change and the differential impact on vulnerable groups in New Zealand. Qualitative data were collected on community responses to key health messages in the 2009 and 2010 Ministry of Health H1N1 campaigns, the impact of messages on behaviour and the differential impact on vulnerable groups. Eight focus groups were held in the winter of 2010 with 80 participants from groups identified by the Ministry of Health as vulnerable to the H1N1 virus, such as people with chronic health conditions, pregnant women, children, Pacific Peoples and Māori. Because this study was part of a rapid response initiative, focus groups were selected as the most efficient means of data collection in the time available. For Māori, focus group discussion (hui) is a culturally appropriate methodology. Thematic analysis of data identified four major themes: personal and community risk, building community strategies, responsibility and information sources. People wanted messages about specific actions that they could take to protect themselves and their families and to mitigate any consequences. They wanted transparent and factual communication where both good and bad news is conveyed by people who they could trust. The responses from all groups endorsed the need for community based risk management including information dissemination. Engaging with communities will be essential to facilitate preparedness and build community resilience to future pandemic events. This research provides an illustration of the complexities of how people understand and respond to health messages related to the H1N1 pandemic. The importance of the differences identified in the analysis is not the differences per se but highlight problems with a "one size fits all" pandemic warning strategy.


Effect of pilates exercises on premenstrual syndrome symptoms: a quasi-experimental study.
This study was done to identify the effect of pilates exercises on the symptoms of premenstrual syndrome. A quasi experimental was conducted on university student with premenstrual syndrome. Population of the study included midwifery students with premenstrual syndrome at Istanbul University Faculty of Health Sciences (N = 286) and 50 of them became the sample (25 in experimental group and 25 in control group). Non-probablistic sampling method was used. While the students in experimental group were asked to practice the pilates exercises for three months, the students in control group were told to maintain their routine habits. At the end of the three months, premenstrual syndrome problem of experimental and control group was diagnosed and the effect of pilates on premenstrual syndrome was evaluated. Premenstrual Syndrome symptoms were evaluated through Premenstrual Syndrome Scale (PMSS). The high score received from PMSS shows that the symptoms are intensive. It was seen that the students in the experimental and control group were similar in terms of their aspects which were individual, health and could affect premenstrual syndrome (p > 005). A statistical significant difference was not found between total scores and sub-dimension scores of PMSS in experimental and control group (p < 0.05). It was seen that PMSS total score of experimental group was significantly lower than that of control group (p < 0.001). When in-group comparisons were examined, it was identified that PMSS scores of control group did not change at the beginning and end of exercise, but PMSS score of experimental group at the end of exercise was lower than their score received at the beginning of exercise and, the difference was statistically significant to the highest degree (p < 0.001). It was seen that the pilates exercises, which were practiced in this research, decreased the PMS symptoms considerably. In this regard, the pilates exercises have an important role in healing the PMS symptoms.


Insights into tRNA-dependent amidotransferase evolution and catalysis from the structure of the Aquifex aeolicus enzyme.
Many bacteria form Gln-tRNA(Gln) and Asn-tRNA(Asn) by conversion of the misacylated Glu-tRNA(Gln) and Asp-tRNA(Asn) species catalyzed by the GatCAB amidotransferase in the presence of ATP and an amide donor (glutamine or asparagine). Here, we report the crystal structures of GatCAB from the hyperthermophilic bacterium Aquifex aeolicus, complexed with glutamine, asparagine, aspartate, ADP, or ATP. In contrast to the Staphylococcus aureus GatCAB, the A. aeolicus enzyme formed acyl-enzyme intermediates with either glutamine or asparagine, in line with the equally facile use by the amidotransferase of these amino acids as amide donors in the transamidation reaction. A water-filled ammonia channel is open throughout the length of the A. aeolicus GatCAB from the GatA active site to the synthetase catalytic pocket in the B-subunit. A non-catalytic Zn(2+) site in the A. aeolicus GatB stabilizes subunit contacts and the ammonia channel. Judged from sequence conservation in the known GatCAB sequences, the Zn(2+) binding motif was likely present in the primordial GatB/E, but became lost in certain lineages (e.g., S. aureus GatB). Two divalent metal binding sites, one permanent and the other transient, are present in the catalytic pocket of the A. aeolicus GatB. The two sites enable GatCAB to first phosphorylate the misacylated tRNA substrate and then amidate the activated intermediate to form the cognate products, Gln-tRNA(Gln) or Asn-tRNA(Asn).


A review on traditional uses, phytochemistry, pharmacology, pharmacokinetics and toxicology of the genus Peganum.
The plants of the genus Peganum have a long history as a Chinese traditional medicine for the treatment of cough, hypertension, diabetes, asthma, jaundice, colic, lumbago, and many other human ailments. Additionally, the plants can be used as an amulet against evil-eye, dye and so on, which have become increasingly popular in Asia, Iran, Northwest India, and North Africa. The present paper reviewed the ethnopharmacology, phytochemistry, analytical methods, biological activities, metabolism, pharmacokinetics, toxicology, and drug interaction of the genus Peganum in order to assess the ethnopharmacological use and to explore therapeutic potentials and future opportunities for research. Information on studies of the genus Peganum was gathered via the Internet (using Google Scholar, Baidu Scholar, Elsevier, ACS, Pudmed, Web of Science, CNKI and EMBASE) and libraries. Additionally, information was also obtained from some local books, PhD and MS's dissertations. The genus Peganum has played an important role in traditional Chinese medicine. The main bioactive metabolites of the genus include alkaloids, flavonoids, volatile oils, etc. Scientific studies on extracts and formulations revealed a wide range of pharmacological activities, such as cholinesterase and monoamine oxidase inhibitory activities, antitumor, anti-hypertension, anticoagulant, antidiabetic, antimicrobial, insecticidal, antiparasidal, anti-leishmaniasis, antioxidant, and anti-inflammatory. Based on this review, there is some evidence for extracts' pharmacological effects on Alzheimer's and Parkinson's diseases, cancer, diabetes, hypertension. Some indications from ethnomedicine have been confirmed by pharmacological effects, such as the cholinesterase, monoamine oxidase and DNA topoisomerase inhibitory activities, hypoglycemic and vasodilation effects of this genus. The available literature showed that most of the activities of the genus Peganum can be attributed to the active alkaloids. Data regarding many aspects of the genus such as mechanisms of actions, metabolism, pharmacokinetics, toxicology, potential drug interactions with standard-of-care medications is still limited which call for additional studies particularly in humans. Further assessments and clinical trials should be performed before it can be integrated into medicinal practices.


Beta(2)-adrenergic and several other G protein-coupled receptors in human atrial membranes activate both G(s) and G(i).
Cardiac G protein-coupled receptors that couple to Galpha(s) and stimulate cAMP formation (eg, beta-adrenergic, histamine, serotonin, and glucagon receptors) play a key role in cardiac inotropy. Recent studies in rodent cardiac myocytes and transfected cells have revealed that one of these receptors, the beta(2)-adrenergic receptor (AR), also couples to the inhibitory G protein Galpha(i) (activation of which inhibits cAMP formation). If beta(2)ARs could be shown to couple to Galpha(i) in the human heart, it would have important ramifications, because levels of Galpha(i) increase with age and in failing human heart. Therefore, we investigated whether beta(2)ARs in the human heart activate Galpha(i). By photoaffinity labeling human atrial membranes with [(32)P]azidoanilido-GTP, followed by immunoprecipitation with antibodies specific for Galpha(i), we found that Galpha(i) is activated by stimulation of beta(2)ARs but not of beta(1)ARs. In addition, we found that other Galpha(s)-coupled receptors also couple to Galpha(i), including histamine, serotonin, and glucagon. When coupling of these receptors to Galpha(i) is disrupted by pertussis toxin, their ability to stimulate adenylyl cyclase is enhanced. These data provide the first evidence that beta(2)AR and many other Galpha(s)-coupled receptors in human atrium also couple to Galpha(i) and that abolishing the coupling of these receptors to Galpha(i) increases the receptor-mediated adenylyl cyclase activity.


The surgical option in the management of acute pulmonary embolism.
Massive or submassive pulmonary embolism (PE) carries a high mortality. Traditionally this condition has been treated with thrombolysis or anticoagulation and support measures. Surgical embolectomy is carried out in situations of hemodynamic instability or contraindication for thrombolysis. We present our results of surgical embolectomy in patients with massive and submassive PE. Over a three-year period, we have carried out 20 surgical embolectomies for acute PE. The mean age was 66 years, and there were 11 males. In all cases, the diagnosis had been made by a computerized tomography (CT) pulmonary artery angiography. Nine patients (45%) arrived to the operating theater on inotropes, and two of them (10%) with ventilatory support. All patients underwent a median sternotomy, bicaval cannulation for institution of cardiopulmonary bypass (CPB), and main pulmonary arteriotomy for the removal of the thrombus. The mean bypass time was 45 minutes. Two patients (12%) died after being unable to wean off CPB due to right heart failure. Among the 15 survivors, the median ventilation time in the intensive care unit was 24 hours. Twelve patients (60%) required inotropic support postoperatively for right heart failure. All but one survivor (94%) underwent an insertion of a permanent inferior vena cava filter and were anticoagulated with coumarin. The mean follow-up is 9.8 months and is 100% complete, with a survival of 94.5%. All patients were in the World Health Organization (WHO) functional class I, with no re-admissions for respiratory failure. In patients with acute massive or submassive PE, surgical embolectomy offers a valid therapeutic strategy. A right-sided heart failure is the main complication of this condition.


Avirulent uracil auxotrophs based on disruption of orotidine-5'-monophosphate decarboxylase elicit protective immunity to Toxoplasma gondii.
The orotidine-5'-monophosphate decarboxylase (OMPDC) gene, encoding the final enzyme of the de novo pyrimidine biosynthesis pathway, was deleted using Toxoplasma gondii KU80 knockouts to develop an avirulent nonreverting pyrimidine auxotroph strain. Additionally, to functionally address the role of the pyrimidine salvage pathway, the uridine phosphorylase (UP) salvage activity was knocked out and a double knockout of UP and OMPDC was also constructed. The nonreverting DeltaOMPDC, DeltaUP, and DeltaOMPDC DeltaUP knockout strains were evaluated for pyrimidine auxotrophy, for attenuation of virulence, and for their ability to elicit potent immunity to reinfection. The DeltaUP knockout strain was replication competent and virulent. In contrast, the DeltaOMPDC and DeltaOMPDC DeltaUP strains were uracil auxotrophs that rapidly lost their viability during pyrimidine starvation. Replication of the DeltaOMPDC strain but not the DeltaOMPDC DeltaUP strain was also partially rescued in vitro with uridine or cytidine supplementation. Compared to their hypervirulent parental type I strain, the DeltaOMPDC and DeltaOMPDC DeltaUP knockout strains exhibited extreme attenuation in murine virulence (approximately 8 logs). Genetic complementation of the DeltaOMPDC strain using a functional OMPDC allele restored normal replication and type I parental strain virulence phenotypes. A single immunization of mice with either the live critically attenuated DeltaOMPDC strain or the DeltaOMPDC DeltaUP knockout strain effectively induced potent protective immunity to lethal challenge infection. The avirulent nonreverting DeltaOMPDC and DeltaOMPDC DeltaUP strains provide new tools for the dissection of the host response to infection and are promising candidates for safe and effective Th1 vaccine platforms that can be easily genetically engineered.


Suppressed cutaneous endothelial vascular control and hemodynamic changes in paretic extremities with edema in the extremities of patients with hemiplegia.
To investigate peripheral circulatory function and its underlying mechanisms in the paretic upper extremity after a stroke. Case-control study. A department of physical medicine and rehabilitation in Taiwan. A total of 53 hemiplegic patients (28 men, 25 women; mean age +/- standard deviation; 58.2+/-3.8y) were studied. Subjects were divided into edema and nonedema groups. The edema group included 29 hemiplegic patients with edematous paretic upper extremities. Twenty-four hemiplegic patients in the nonedema group did not suffer from limb edema in the paretic upper extremity. Not applicable. Cutaneous microvascular perfusion responses to 3 grade levels of iontophoretically applied 1% acetylcholine (ACh), 1% ACh plus 1% N(G)-monomethyl-L-arginine (L-NMMA), and 1% sodium nitroprusside (SNP) in the skin of subjects' forearms were determined by laser Doppler perfusion measurements. Moreover, hemodynamic characteristics in the arterial and venous vessels were measured by impedance plethysmography. Resting arterial inflow and venous capacity, tone, and outflow in paretic extremities did not significantly differ from nonparetic extremities, but the hyperemic arterial inflow was lower in paretic extremities than in nonparetic extremities, and paretic extremities were associated with lower ACh- and ACh plus L-NMMA-induced cutaneous perfusions than nonparetic extremities. ACh-induced cutaneous perfusions also decreased much more significantly in edematous paretic extremities than in nonedematous paretic extremities, and skin vascular responses to SNP do not differ significantly between paretic and nonparetic extremities. Cutaneous microcirculatory function in the paretic upper extremity after stroke may be impaired. The impairment may occur because of decreased endothelium-dependent dilation in skin vasculature. Dysfunction in cutaneous microcirculation tends to be more pronounced in the edematous than in the nonedematous extremities.


Spondylolisthesis in children and adolescents.
A study of spondylolysis and spondylolisthesis in 142 children and adolescents is reported. In twelve of the seventy-nine patients followed for over a year the affected vertebra slipped further by 10 per cent or more. Increasing slip occurred mainly during the adolescent growth spurt, and was greater when spinal bifida or other vertebral anomalies were present. If at presentation the slip is less than 30 per cent then further slip beyond 30 per cent is unlikely. Decompression posteriorly is advised when signs of nerve pressure are present. Indications for spinal fusion are suggested; the intertransverse method of fusion was used in sixty-nine patients.


[Helping physicians arrive at medical diagnoses: how and why (author's transl)].
In the majority of the medical disciplines the diagnosis still constitutes the corner-stone of medicine. Every year this function becomes increasingly difficult and time-consuming and it is felt that the doctor should be able to benefit easily and rapidly from the most recent findings. A simple analysis of the natural process of decision-making, followed by a critical inventory of the various methods used to diagnose, has led us to develop our method for computer-assisted diagnosis (ADM). In our presentation of the methodology of diagnostic decision-making we examine the natural process, the analytical and synthetic methods as well as the difficulties and errors liable to occur. Four methods used in arriving at a diagnosis are analysed and criticized: those based on probability, those based on pattern recognition, those based on logic, and those based on classification methods. Finally a case is made for a computer-assisted diagnostic system based on a logical method of the documentation type.


Keratinocyte Expression of A20/TNFAIP3 Controls Skin Inflammation Associated with Atopic Dermatitis and Psoriasis.
Keratinocytes are key players in chronic inflammatory skin diseases. A20 regulates NF-κB-dependent expression of proinflammatory genes and cell death, but the impact of its expression in keratinocytes on systemic inflammation and skin disorders has not been determined. Comparative transcriptomic analysis of microdissected epidermis showed that A20 is down-regulated in involved epidermis, but not in dermis, of psoriasis and atopic dermatitis patients, suggesting that loss of A20 expression in keratinocytes increases the vulnerability for psoriasis/atopic dermatitis induction. We have previously shown that epidermis-specific A20 knockout mice (A20EKO) develop mild epidermal hyperplasia but no macroscopic skin inflammation. We now show that various cytokines and chemokines are up-regulated in A20EKO mouse skin. A20EKO mice also display systemic proinflammatory changes, even in the absence of skin immune cell infiltration, and an exacerbated disease severity upon induction of experimental psoriasis, atopic dermatitis, or skin barrier disruption. Keratinocytes showed increased proinflammatory gene expression in the absence of A20 in unstimulated and IL-17A-stimulated conditions, in part resulting from uncontrolled MyD88-dependent signaling. Our findings indicate that absence of A20 in keratinocytes leads to systemic inflammation at homeostatic conditions and is sufficient to exacerbate inflammatory skin disorders associated with different immune profiles by increasing cytokine and chemokine expression.


Association Between Patient Age and Lymph Node Positivity in Thin Melanoma.
More than half of all new melanoma diagnoses present as clinically localized T1 melanoma, yet sentinel lymph node biopsy (SLNB) is controversial in this population given the overall low yield. Guidelines for SLNB have focused on pathologic factors, but patient factors, such as age, are not routinely considered. To identify indicators of lymph node (LN) metastasis in thin melanoma in a large, generalizable data set and to evaluate the association between patient age and LN positivity. A retrospective cohort study using the National Cancer Database, an oncology database representing patients from more than 1500 hospitals throughout the United States, was performed (2010-2013). Data analysis was conducted from October 1, 2016, to January 15, 2017. A total of 8772 patients with clinical stage I 0.50 to 1.0 mm thin melanoma undergoing wide excision and surgical evaluation of regional LNs were included for study. The primary outcome of interest was presence of melanoma in a biopsied regional LN. Clinicopathologic factors associated with LN positivity were characterized, using logistic regression. Age was categorized as younger than 40 years, 40 to 64 years, and 65 years or older for multivariable analysis. Classification tree analysis was performed to identify high-risk groups for LN positivity. Among the study cohort (n = 8772), 333 patients had nodal metastases, for an overall positivity rate of 3.8% (95% CI, 3.4%-4.2%). A total of 4087 (54.0%) patients were women. Median age was 56 years (interquartile range [IQR], 46-67) in patients with negative LNs and 52 years (IQR, 41-61) in those with positive LNs (P < .001). In multivariable analysis, younger age, female sex, thickness of 0.76 mm or larger, increasing Clark level, mitoses, ulceration, and lymphovascular invasion were independently associated with LN positivity. In decision tree analysis, patient age was identified as an important risk stratifier for LN metastases, after mitoses and thickness. Patients younger than 40 years with category T1b tumors 0.50 to 0.75 mm, who would generally not be recommended for SLNB, had an LN positivity rate of 5.6% (95% CI, 3.3%-8.6%); conversely, patients 65 years or older with T1b tumors 0.76 mm or larger, who would generally be recommended for SLNB, had an LN positivity rate of only 3.9% (95% CI, 2.7%-5.3%). Patient age is an important factor in estimating lymph node positivity in thin melanoma independent of traditional pathologic factors. Age therefore should be taken into consideration when selecting patients for nodal biopsy.


[The lipid peroxidation processes and the antioxidant system in the dynamics of an experimental Pseudomonas aeruginosa intoxication].
Lipid peroxidation and antioxidant defense processes have been studied over the course of experimental Pseudomonas aeruginosa intoxication in albino rats injected with a lethal dose of exotoxin A. The development of intoxication is associated with intensification of lipid peroxidation, manifested by accumulation of malonic dialdehyde and diene conjugates and decreased peroxide resistance of erythrocytes. Superoxide dismutase and catalase activities were inhibited and the concentration of vitamin B dropped. Injection of antioxidant alpha-tocopherol or antihypoxant gutimine at the late stage of intoxication did not notably modify the studied parameters.


Flat histogram version of the pruned and enriched Rosenbluth method.
In this Letter we present a flat histogram algorithm based on the pruned and enriched Rosenbluth method. This algorithm incorporates in a straightforward manner microcanonical reweighting techniques, leading to "flat histogram" sampling in the chosen parameter space. As an additional benefit, our algorithm is completely parameter free and, hence, easy to implement. We apply this algorithm to interacting self-avoiding walks, the generic lattice model of polymer collapse.


[Patient expectations regarding methods and outcomes of their rehabilitation--a controlled study of back pain- and cancer patients].
Although patient expectations are important factors of the success of rehabilitation, they have not yet received much attention in research. In the present cross-sectional study, n = 248 rehabilitation patients, n = 160 suffering from chronic back pain and n = 88 suffering from oncological diseases (breast cancer, cervical cancer, ovarian cancer, colorectal cancer), were assessed at the time of admission to a rehabilitation clinic, using a newly developed self-report questionnaire to evaluate their expectations regarding the process and outcome of their rehabilitation. Results show on an item level that non-specific process expectations such as balneophysical treatments or features of the surroundings of the clinic were most prevailing. Across both diagnostic groups, common goals of rehabilitation such as reduction of complaints, physical fitness and recreation scored highest. On the basis of factor analysis, 10 scales of process expectations were constructed: medical attention, physical training, vocational counselling, balneophysical treatment, health information, stress management training, support groups, relief from the strains of everyday life, alternative medicine, and pleasant surroundings. Nine dimensions of outcome expectations were detected: ability for work, physical fitness, reduction of complaints, behaviour change, reduction of body weight, positive body feeling, vitality, enjoyment of life, and social contact. In the univariate analysis, orthopaedical patients scored higher on balneophysical treatments and vocational counselling (process expectations) as well as reduction of complaints and ability for work (outcome expectations). However, there were effects of age, gender and working status, too. Thus these differences between diagnostic groups turned out to be nonsignificant after controlling for the effects of age, gender, and working status. On the other hand, some effects of the medical condition had been hidden in the univariate comparison and were only revealed when adjusting for the moderator variables. Those differences show that oncological patients had higher expectations than back pain patients. Patients' expectations were correlated with functional status and, to a lesser degree, emotional distress and locus of control. To conclude, our study demonstrated that medical condition, sociodemographic factors, working status and functional capacity are important determinants of patient expectations regarding the process and outcome of rehabilitation.


The Cumulative Prevalence of Congregate Care Placement for U.S. Children by Race/Ethnicity, 2019.
Congregate care placement is among the most consequential forms of foster care placement that youth can experience, as it means a removal from both the family of origin and a family setting more broadly. Unfortunately, little research has estimated how common this intervention is. In this article, we use data from the Adoption and Foster Care Analysis Reporting System (AFCARS) and synthetic cohort life tables to show what proportion of children ever placed in foster care will ever be placed in congregate care, what proportion of children in the entire population will ever be placed in congregate care, and how these proportions vary by state of residence and race/ethnicity. Our results support four main conclusions. First, roughly 15% of all children ever placed in foster care will experience congregate care placement. Second, among children who will ever be placed in foster care, the risk of congregate care placement peaks at age 16. Third, congregate care placement is highly stratified by race/ethnicity. Finally, there are vast geographic differences in both congregate care placement and ethno-racial disparities therein. Taken together, these findings enhance our understanding of the demography of the child welfare system with implications for research, policy, and practice.