The photosystem-II repair cycle: updates and open questions.
The photosystem-II (PSII) repair cycle is essential for the maintenance of photosynthesis in plants. A number of novel findings have illuminated the regulatory mechanisms of the PSII repair cycle. Photosystem II (PSII) is a large pigment-protein complex embedded in the thylakoid membrane. It plays a vital role in photosynthesis by absorbing light energy, splitting water, releasing molecular oxygen, and transferring electrons for plastoquinone reduction. However, PSII, especially the PsbA (D1) core subunit, is highly susceptible to oxidative damage. To prevent irreversible damage, plants have developed a repair cycle. The main objective of the PSII repair cycle is the degradation of photodamaged D1 and insertion of newly synthesized D1 into the PSII complex. While many factors are known to be involved in PSII repair, the exact mechanism is still under investigation. In this review, we discuss the primary steps of PSII repair, focusing on the proteolytic degradation of photodamaged D1 and the factors involved.


The role of microRNAs in cardiac development and regenerative capacity.
The mammalian heart has long been considered to be a postmitotic organ. It was thought that, in the postnatal period, the heart underwent a transition from hyperplasic growth (more cells) to hypertrophic growth (larger cells) due to the conversion of cardiomyocytes from a proliferative state to one of terminal differentiation. This hypothesis was gradually disproven, as data were published showing that the myocardium is a more dynamic tissue in which cardiomyocyte karyokinesis and cytokinesis produce new cells, leading to the hyperplasic regeneration of some of the muscle mass lost in various pathological processes. microRNAs have been shown to be critical regulators of cardiomyocyte differentiation and proliferation and may offer the novel opportunity of regenerative hyperplasic therapy. Here we summarize the relevant processes and recent progress regarding the functions of specific microRNAs in cardiac development and regeneration.


[New strategies for the treatment of thermally injured hands with regard to the epithelial substitute Suprathel].
The treatment of thermally injured hands has changed in the last 20 years. An early necrectomy and grafting with split-skin grafts is recommended by most burn specialists. The outcome in regard to cosmetic and functional results could be improved by early grafting. Meanwhile unnecessary grafts in burns with indeterminate depth can be avoided by new skin replacements. The new epithelial substitute Suprathel is marked by a considerable reduction of pain if it is applied on second degree burns. Therefore the mobilisation of the burned patient can be accelerated. Many hand burns were treated by Suprathel in our burn centre without severe scarring and without loss of function. We treated 76 inpatients with thermally injured hands in our burn centre from January 2004 to July 2006. Only 28 (25.7 %) of all 109 afflicted hands required a primary skin grafting. Suprathel was applied primarily in 78 hands (71.6 %). 3 hands were treated otherwise. 8 of the hands which were primarily treated by Suprathel (10.3 %) required a well-aimed grafting after one or two weeks, 70 (89.7 %) had a complete epithelisation without grafting. Many skin grafts could be avoided. We modified our strategy for the treatment of burned hands by our excellent experiences with Suprathel.


Histopathological effects of exogenously administered testosterone in 19 female to male transsexuals.
The effects of exogenously administered testosterone were evaluated in a group of 19 female to male transsexuals who underwent bilateral salpingo-oophorectomy after a variable period of androgen therapy. The findings were compared to those in an age-matched group of 12 patients who underwent pelvic surgery for nonendocrine reasons. The most significant findings in the 19 androgen-treated female transsexuals was the finding of enlarged or borderline enlarged ovaries in 5 subjects. In addition, we found multiple cystic follicles in 17 patients (89.5%), diffuse ovarian stromal hyperplasia in 16 patients (84.2%), collagenization of the outer cortex in 13 patients, and 4) luteinization of stromal cells in 5 patients (26.3%). Findings consistent with polycystic ovaries were thus present in 13 of the 19 patients based on the presence of 3 of the above 4 findings. The data suggest that increased blood levels and presumably increased ovarian concentrations of testosterone may produce the morphological features of polycystic ovarian disease.


Exploring fold space preferences of new-born and ancient protein superfamilies.
The evolution of proteins is one of the fundamental processes that has delivered the diversity and complexity of life we see around ourselves today. While we tend to define protein evolution in terms of sequence level mutations, insertions and deletions, it is hard to translate these processes to a more complete picture incorporating a polypeptide's structure and function. By considering how protein structures change over time we can gain an entirely new appreciation of their long-term evolutionary dynamics. In this work we seek to identify how populations of proteins at different stages of evolution explore their possible structure space. We use an annotation of superfamily age to this space and explore the relationship between these ages and a diverse set of properties pertaining to a superfamily's sequence, structure and function. We note several marked differences between the populations of newly evolved and ancient structures, such as in their length distributions, secondary structure content and tertiary packing arrangements. In particular, many of these differences suggest a less elaborate structure for newly evolved superfamilies when compared with their ancient counterparts. We show that the structural preferences we report are not a residual effect of a more fundamental relationship with function. Furthermore, we demonstrate the robustness of our results, using significant variation in the algorithm used to estimate the ages. We present these age estimates as a useful tool to analyse protein populations. In particularly, we apply this in a comparison of domains containing greek key or jelly roll motifs.


MR imaging of experimental intramuscular hemorrhage at 0.02 T. Contrast enhancement with Gd-DOTA.
Intramuscular hemorrhage was induced by injecting autologous blood into the paraspinal muscle of 8 rabbits. In order to evaluate the time-dependent changes of hemorrhage observed on MRI, the animals were imaged at different stages of blood resolution at 0.02 tesla (T), and control examined with ultrasound using a 7.5 MHz linear transducer. Six inversion recovery sequences (TR = 1,000 ms. TE = 30 ms, and TI = 18, 48, 148, 201, 302, and 398 ms) were used for the in vivo calculation of T1 relaxation times. IR 1,000 (398)/30 imaging was performed before and after the Gd-DOTA administration. The hemorrhage was evident on MR images throughout the study, especially on the T2 weighted (SE 1,000/100) images. MRI showed the healing lesion longer than ultrasound. The T1 relaxation time increased during the time of resolution. Lesions on days 4 to 7 enhanced in intensity after the injection of Gd-DOTA.


[Osteometric method of determination of ordinal localization of the ribs using discriminant analysis].
III-XI right ribs from 86 skeletons of the Caucasoid, stored in the Chair of Anthropology of Moscow State University, were examined. The ribs were measured by A. I. Turovtsev's program (1972) including 13 signs. The results have been analyzed with statistic program SPSS. Diagnostic models, based on incremental discriminant analysis, were calculated for expert practice. It is recommended to perform the expertise in 2 stages. On 1st stage group belonging of the rib has to be established. 1st group include III-V ribs, 2nd group--VI-VIII and 3rd--IX-XI ones. To determine ordinal localization of I, II and XII ribs is not difficult in view of uniqueness of its anatomic structure. Precision of classification of group localization of a rib is 99.6%. On 2nd stage individual number of the rib has to be determined. Precision of classification in case of belongings of the rib to 1st or 3rd groups is 80.2% and 85.7% respectively, to 2nd group it is lower (41.7-69%).


MR imaging and spectroscopy using hyperpolarized 129Xe gas: preliminary human results.
Using a new method of xenon laser-polarization that permits the generation of liter quantities of hyperpolarized 129Xe gas, the first 129Xe imaging results from the human chest and the first 129Xe spectroscopy results from the human chest and head have been obtained. With polarization levels of approximately 2%, cross-sectional images of the lung gas-spaces with a voxel volume of 0.9 cm3 (signal-to-noise ratio (SNR), 28) were acquired and three dissolved-phase resonances in spectra from the chest were detected. In spectra from the head, one prominent dissolved-phase resonance, presumably from brain parenchyma, was detected. With anticipated improvements in the 129Xe polarization system, pulse sequences, RF coils, and breathing maneuvers, these results suggest the possibility for 129Xe gas-phase imaging of the lungs with a resolution approaching that of current conventional thoracic proton imaging. Moreover, the results suggest the feasibility of dissolved-phase imaging of both the chest and brain with a resolution similar to that obtained with the gas-phase images.


Strong association between the dietary inflammatory index(DII) and breast cancer: a systematic review and meta-analysis.
The association between the Dietary Inflammatory Index (DII) and breast cancer risk has been widely reported in recent years, but there is still controversy about whether a pro-inflammatory diet is a risk factor for breast cancer. We conducted a meta-analysis to investigate the relationship between the DII and breast cancer risk in pre-menopausal and post-menopausal women. We comprehensively searched PubMed, Embase and the Cochrane Library in January 2021 to identify articles reporting an association between the DII and breast cancer risk. A pooled analysis was conducted with 14 studies covering 312,885 participants. Overall, women in the most pro-inflammatory diet category were at greater risk for breast cancer than those in the most anti-inflammatory category (relative risk [RR]=1.37, 95% confidence interval [CI] 1.17-1.60, P<0.001). This association was strong in both pre-menopausal women (RR=1.87, 95% CI 1.17-2.99, P=0.001) and post-menopausal women (RR=1.23, 95% CI 1.08-1.40, P<0.001). Thus, a strong and independent association was observed between a pro-inflammatory diet (assessed using the DII score) and breast cancer risk, irrespective of menopausal status. Further studies will be required to determine the relationship between a pro-inflammatory diet and different subtypes of breast cancer.


Cleavage of malyl-Coenzyme A into acetyl-Coenzyme A and glyoxylate by Pseudomonas AM1 and other C1-unit-utilizing bacteria.
1. Malyl-CoA lyase was found in high activity in extracts of Pseudomonas AM1, Pseudomonas MA, Pseudomonas MS, Hyphomicrobium X and Methylosinus trichosporium. 2. The enzyme cleaves (2S)-malyl-CoA into equimolar amounts of acetyl-CoA and glyoxylate in the presence of Mg(2+). 3. The specific activity of malyl-CoA lyase was several-fold higher in Pseudomonas AM1 when grown on C(1) compounds than when grown on C(2), C(3) or C(4) compounds. This suggests that the enzyme plays a specially important role in C(1) metabolism. 4. It is suggested that its role in C(1) metabolism, in organisms utilizing the serine pathway, is to provide the glyoxylate necessary to sustain operation of this pathway. 5. The activity of malyl-CoA lyase in extracts of Pseudomonas MA, Pseudomonas MS and Hyphomicrobium X is 27-50 times higher than the activity of ATP- and CoA-dependent cleavage of malate, suggesting that the latter activity may be due to coupling of two enzymes, malate thiokinase and malyl-CoA lyase. 6. Methane-grown Pseudomonas methanica and Methylococcus capsulatus, which are not known to use the serine pathway, possess appreciable amounts of malyl-CoA lyase. Instead of being used primarily for carbon assimilation, the enzyme may here serve as a route to glycine during biosynthesis of purines and proteins.


Effects of Grape Seed Proanthocyanidin Extract on Obesity.
Obesity is a chronic metabolic disease resulting from excessive fat accumulation and/or abnormal distribution caused by multiple factors. As a major component of metabolic syndrome, obesity is closely related to many diseases such as type 2 diabetes mellitus, hyperlipidemia, hypertension, coronary heart disease, stroke and cancer. Hence, the problem of obesity cannot be ignored, and recent studies have shown that grape seed proanthocyanidin extract (GSPE) has an antiobesity effect. This paper systematically reviews the research progress and potential mechanism of GSPE emphasizing on obesity prevention and treatment.


Association of the G403A polymorphism in the RANTES gene with coronary artery disease: a meta-analysis.
The G403A polymorphism in the RANTES (regulated on activation normal T cell expressed and secreted) gene has a key role in the expression of RANTES, which has been detected in a range of cells in atherosclerotic plaque. However, the association of this polymorphism with the risk of coronary artery disease (CAD) remains controversial. A meta-analysis was performed to assess the association of the G403A polymorphism in the RANTES gene with the risk of CAD. A comprehensive search was conducted to identify all studies published on the association of the RANTES gene G403A polymorphism with CAD risk. The fixed or random-effect pooled measure was adopted based on a heterogeneity test among studies, which was evaluated using I(2). Potential sources of between-study heterogeneity were explored using meta-regression analysis. Publication bias was estimated with Begg's rank correlation method. Eight articles were included in this meta-analysis, with 4601 CAD cases and 2522 controls. No significant association of RANTES gene G403A polymorphism with CAD was identified in any of the codominant, dominant, recessive, homozygote, or heterozygote inheritance models. No evidence of publication bias was detected. The meta-analysis suggested that the A allele of the G403A polymorphism in the RANTES gene has no effect on the risk of CAD. This relationship needs to be confirmed by further studies.


Scalding injuries in immigrant families.
From 1990 to 1996, 214 patients aged up to 6 years were treated at our inpatient burns unit. Ages ranged from 3 to 70 months. Scalding was the cause in 186 cases. The median size of the burned areas was 5.0% (range 0.5%-40%). One hundred and nine were deep dermal burns that required surgical treatment, but this was refused in seven instances. Duration of hospital stay was 11 days (2-45). The number of follow-up visits ranged from 0 to 17. Secondary reconstructions for scarring have been done for seven children so far. Ninety-eight (46%) came from immigrant families, mostly from the Middle East and the Balkans. Of the 186 scalded children, 94 (51%) were immigrants, and they also had a tendency to have more severe injuries. Explanations might be that they were more likely to cook with water and oil, they were unfamiliar with Swedish safety standards and measures, and they had difficulty in communicating (language) and a limited social network. The ensuing scar also may disturb or delay the child's adaptation to the new environment. Our preventive work is now based on a model that states that frequency, type, and severity of injury is dictated by the variables: risk, personality, supervision, and education.


Homozygous Q258X mutation in the steroidogenic acute regulatory gene in a Japanese patient with congenital lipoid adrenal hyperplasia.
Congenital lipoid adrenal hyperplasia (CLAH) is an autosomal recessive disorder characterized by impaired synthesis of all adrenal and gonadal steroid hormones. It has recently been reported that mutations in the steroidogenic acute regulatory protein (StAR) gene cause CLAH. We analyzed the nucleotide sequences of exon 7 of the StAR gene in a Japanese CLAH patient with a karyotype of 47,XYY, and her parents. The patient was homozygous for a nonsense mutation Q258X, which changed codon 258 (CAG) encoding Gln to the stop codon TAG, and the her parents were heterozygous for the Q258X mutation. Since the Q258X mutation destroys a MvaI site normally present in the StAR gene sequence, we confirmed the Q258X mutation by means of the restriction endonuclease MvaI digestion of the PCR products. Endocrinological examinations of the parents revealed normal responses of adrenal steroid hormones to exogenous adrenocorticotropin administration, confirming the failure to detect the heterozygous carriers of CLAH by hormonal evaluation.


Raising an autistic child: perspectives from Turkish mothers.
Autism is an illness with severe deficits in reciprocal social interactions, imagination, communication, and restricted or unusual behavioral repertories that affect all areas of a child's life such as daily living activities, home/school life, and relationships with family members and others. Yet, there is much to be learned about the impact of this disorder on parents' experiences, and ways in which their lives are altered and ways that they can be assisted to better manage the home environment. The purpose of this study was to explore and categorize the experiences of mothers having an autistic child using a phenomenological design in the qualitative tradition. Semistructured interviews were conducted with 43 mothers regarding their experiences with their autistic children. Data were analyzed with deductive content analysis based on coding, and were grouped into categories based on common themes. The distributions of common responses in categories were presented as percentages. Based on this qualitative study, mothers expressed feelings of burden and stress because of their child's behaviors associated with autism, as well as their own role and future expectations, and the complexity of care needed by their children at home. This study provided new knowledge about the difficulties and experiences of mothers of autistic children in Turkey. The results underscored the needs of mothers who require support from family members, healthcare organizations, and society. The findings support the need for training programs for mothers and parents conducted by nurses and other healthcare professionals who have special knowledge and skill to provide education and modeling of therapeutic interventions.


Case reports: aseptic femoral osteitis and sternocostal hyperostosis from SAPHO syndrome.
Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome are characterized by peculiar bone lesions that commonly involve the anterior chest wall. Osteitis typically is the most prominent skeletal lesion seen in synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome. We present a patient with aseptic femoral osteitis and sternocostal hyperostosis. The classic clinical, radiographic, and histologic features of this syndrome are described. Diagnosis is difficult in patients with only one symptomatic bone. The lesion often is confused with suppurative osteomyelitis because of similar clinicopathologic findings. Although the optimal treatment is unclear, it is important to consider synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome in the differential diagnosis of any lytic, sclerotic, or hyperostotic bone lesion to avoid unnecessary long-term antibiotic therapy.


The First Thousand Days: early, integrated and evidence-based approaches to improving child health: coming to a population near you?
The 'First Thousand Days' refers to the period from conception to the child's second birthday. It is increasingly gaining traction as a concept to guide public health policy. It is seen as a crucial window of opportunity for interventions that improve child and population health. This review outlines the origin and growth of the First Thousand Days concept, and the evidence behind it, particularly in the areas of brain development and cognition; mental and emotional health; nutrition and obesity; programming and economic benefits. The review then describes UK experience of use of the concept to inform policy, and a recent government inquiry that mandates more widespread implementation.


Implementation of the Article 13 WHO FCTC measures and changes in cigarette smoking among youth in 42 countries.
Despite a decline in global smoking prevalence among adolescents, around 21 million youth report current cigarette smoking. Exposure to tobacco advertising, promotion and sponsorship (TAPS) is a risk factor for smoking initiation, and therefore the Article 13 of the WHO Framework Convention on Tobacco Control (WHO FCTC) requires comprehensive TAPS bans. We examined the associations between changes in youth cigarette smoking and implementation of Article 13. We used two rounds of cross-sectional data from the Global Youth Tobacco Survey (GYTS) for 42 countries: first between 2006 and 2015, and second between 2017 and 2020. The GYTS data were linked with the WHO FCTC implementation reports from 2016 and 2018. The outcome was current smoking. Multilevel binary logistic regression models, stratified by country income level, were used to test the prevalence differences between the latest and previous GYTS rounds and their associations with TAPS bans with postestimations using marginal analyses. The percentage of students currently smoking decreased from 10.0% (95% CI 8.0 to 12.1) to 7.7% (95% CI 6.1 to 9.3) from first to second GYTS rounds (p<0.001), adjusting for country clustering. In low-income and lower-middle-income countries, the degree of decrease significantly differed between countries with versus without bans on display, partial internet TAPS ban, ban on depiction of tobacco products and by number of TAPS measures, adjusting for age and sex of the respondents. In high-income and upper-middle-income countries, the degree of decrease significantly differed by presence (or absence) of partial or full internet TAPS ban, ban on product placement and by number of TAPS measures. Implementation of TAPS bans is associated with decreased smoking among adolescents both in high-income and low-income countries. Enhanced and continuous efforts are necessary to protect youth from the promotion of tobacco and nicotine products.


Anesthetic management of a parturient with Eisenmenger's syndrome and preeclampsia during cesarean section--a case report.
It has been recommended that women with Eisenmenger's syndrome (ES) are better not to become pregnant and pregnancy may justifiably be terminated by artificial abortion to avoid high maternal mortality and coherent fetal mortality. We present a case report about a parturient with ventricular septal defect (VSD) and ES who received general anesthesia for Cesarean section (C/S) because of preeclampsia, as a result of which she finally succumbed to an episode of intraoperative hypotension in spite of vigorous cardiopulmonary resuscitation. The death was thought to be precipitated by continuous deterioration of maternal health during the 3rd trimester of gestation. The anesthetic management of pregnant ES patients in confinement was reviewed and discussed, and the possible etiological factors relevant to the tragic outcome were also explored.


An innovative approach to reducing pain in patients with peripheral neuropathy related to HIV: A single case study.
Peripheral neuropathy (PN) is the most common neurological condition seen in people living with human immunodeficiency virus (HIV) and has been estimated to be present in up to 30% of people with AIDS. Prevalence may be increasing as it appears to be related to the use of antiretroviral therapy in many cases, particularly medication containing stavudine. It is often characterised by burning and numbness in the feet. It can interfere severely with function and sufferers resort to a large number of strategies in an attempt to reduce pain. A 50-year-old man presented with severe PN and showed symptoms of extreme weakness and sensitivity of both lower limbs. His symptoms gradually worsened over a period of 18 months to such an extent that he was unable to walk. Medication had no effect on his pain or related symptoms. The authors tested the use of a Vibromat clinical vibrator to treat his PN symptoms. The patient was treated using the same modality for five evenly spaced (monthly) sessions. The patient showed marked improvement in pain, numbness and pins and needles symptoms after the first session. He was able to walk a short distance with assistance. Treatment was continued and after the third session he was able to walk unaided. Symptom relief was maintained for 4 months. This is the first case demonstrating the use of the Vibromat in successfully treating the signs and symptoms of PN. This is important for clinicians who manage patients with HIV-related PN and pain.


Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung.
One hundred fifty-three patients with limited and 167 with extensive small cell carcinoma of the lung (SCCL) were evaluable for response to treatment with six courses of chemotherapy (cyclophosphamide, doxorubicin, and vincristine), irradiation to intrathoracic disease, and prophylactic cranial irradiation (PCI). No maintenance chemotherapy was given. Fifty-two percent of patients with limited disease (LD) and 10% of extensive disease patients (ED) achieved a complete response. The median survival times for LD and ED patients were 49 and 34 weeks, respectively. These results were compared to a previous experience with 147 patients who were treated with three courses of similar induction chemotherapy and thoracic irradiation, as well as one year of maintenance chemotherapy (CCNU, procarbazine, and methotrexate) but without PCI. Although the use of PCI was found to reduce the frequency of brain metastases as the site of first relapse, detailed comparisons of response rates and survival showed no significant differences between the two study populations. Prolonged maintenance chemotherapy of the type used in the first study does not favorably influence outcome after intensive induction therapy for SCCL.


Biofunctionalized nanofibrous membranes as super separators of protein and enzyme from water.
Here, we report development of a novel biofunctionalized nanofibrous membrane which, despite its macroporous structure, is able to separate even trace amounts (as low as 2mg/L) of biomolecules such as protein and enzyme from water with an optimum efficiency of ~90%. Such an extraordinary protein selectivity at this level of pollutant concentration for a nanofibrous membrane has never been reported. In the current study, poly(acrylonitrile-co-glycidyl methacrylate) (PANGMA) electrospun nanofibers are functionalized by a bovine serum albumin (BSA) protein. This membrane is extraordinarily successful in removal of BSA protein and Candida antarctica Lipase B (Cal-B) enzyme from a water based solution. Despite a negligible non-specific adsorption of both BSA and Cal-B to the PANGMA nanofibrous membrane (8%), the separation efficiency of the biofunctionalized membrane for BSA and Cal-B reaches to 88% and 81%, respectively. The optimum separation efficiency at a trace amount of protein models is due to the water-induced conformational change of the biofunctional agent. The conformational change not only exposes more functional groups available to catch the biomolecules but also leads to swelling of the nanofibers thereby a higher steric hindrance for the solutes. Besides the optimum selectivity, the biofunctionalized membranes are highly wettable thereby highly water permeable.


Reprogramming towards totipotency is greatly facilitated by synergistic effects of small molecules.
Animal cloning has been achieved in many species by transplanting differentiated cell nuclei to unfertilized oocytes. However, the low efficiencies of cloning have remained an unresolved issue. Here we find that the combination of two small molecules, trichostatin A (TSA) and vitamin C (VC), under culture condition with bovine serum albumin deionized by ion-exchange resins, dramatically improves the cloning efficiency in mice and 15% of cloned embryos develop to term by means of somatic cell nuclear transfer (SCNT). The improvement was not observed by adding the non-treated, rather than deionized, bovine serum. RNA-seq analyses of SCNT embryos at the two-cell stage revealed that the treatment with TSA and VC resulted in the upregulated expression of previously identified reprogramming-resistant genes. Moreover, the expression of early-embryo-specific retroelements was upregulated by the TSA and VC treatment. The enhanced gene expression was relevant to the VC-mediated reduction of histone H3 lysine 9 methylation in SCNT embryos. Our study thus shows a simply applicable method to greatly improve mouse cloning efficiency, and furthers our understanding of how somatic nuclei acquire totipotency.


Natural killer cells trigger differentiation of monocytes into dendritic cells.
Circulating monocytes can differentiate into dendritic cells (moDCs), which are potent inducers of adaptive immune responses. Previous reports show that granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 induce monocyte differentiation into moDCs in vitro, but little is known about the physiological requirements that initiate moDC differentiation in vivo. Here we show that a unique natural killer (NK) cell subset (CD3(-)CD56(bright)) that accumulates in lymph nodes and chronically inflamed tissues triggers CD14(+) monocytes to differentiate into potent T-helper-1 (T(H)1) promoting DC. This process requires direct contact of monocytes with NK cells and is mediated by GM-CSF and CD154 derived from NK cells. It is noteworthy that synovial fluid (SF) from patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), but not osteoarthritis (OA), induces monocytes to differentiate into DC. However, this process occurs only in the presence of NK cells. We propose that NK cells play a role in the maintenance of T(H)1-mediated inflammatory diseases such as RA by providing a local milieu for monocytes to differentiate into DC.


Testosterone plus low-intensity physical training in late life improves functional performance, skeletal muscle mitochondrial biogenesis, and mitochondrial quality control in male mice.
Testosterone supplementation increases muscle mass in older men but has not been shown to consistently improve physical function and activity. It has been hypothesized that physical exercise is required to induce the adaptations necessary for translation of testosterone-induced muscle mass gain into functional improvements. However, the effects of testosterone plus low intensity physical exercise training (T/PT) on functional performance and bioenergetics are unknown. In this pilot study, we tested the hypothesis that combined administration of T/PT would improve functional performance and bioenergetics in male mice late in life more than low-intensity physical training alone. 28-month old male mice were randomized to receive T/PT or vehicle plus physical training (V/PT) for 2 months. Compare to V/PT control, administration of T/PT was associated with improvements in muscle mass, grip strength, spontaneous physical movements, and respiratory activity. These changes were correlated with increased mitochondrial DNA copy number and expression of markers for mitochondrial biogenesis. Mice receiving T/PT also displayed increased expression of key elements for mitochondrial quality control, including markers for mitochondrial fission-and-fusion and mitophagy. Concurrently, mice receiving T/PT also displayed increased expression of markers for reduced tissue oxidative damage and improved muscle quality. Testosterone administered with low-intensity physical training improves grip strength, spontaneous movements, and respiratory activity. These functional improvements were associated with increased muscle mitochondrial biogenesis and improved mitochondrial quality control.


The aetiology and pathogenesis of cardiopulmonary bypass-associated metabolic acidosis using polygeline pump prime.
The pathogenesis of the metabolic acidosis of cardiopulmonary bypass (CPB) is not fully understood. New quantitative methods of acid-base balance now make it possible to describe it more clearly. Accordingly, we studied acid-base changes during CPB with polygeline pump prime and defined and quantified the factors which contribute to metabolic acidosis. Prospective cohort study. Tertiary institution. 10 cardiac bypass graft surgery patients. Sampling of arterial blood at four time intervals: post-induction, on CPB during cooling and rewarming, and at skin closure. Measurement of serum Na+, K+, Mg++, Ca++, Cl-, bicarbonate, and phosphate concentrations, arterial blood gases, and serum albumin, lactate, and pyruvate concentrations at each collection point. Analysis of findings according to quantitative physicochemical principles, including calculation of the strong ion difference apparent, the strong ion difference effective, and the strong ion gap (SIG). All patients developed a mild metabolic acidosis. The median serum standard bicarbonate concentration decreased from 25.0 mEq/l post-induction to 22.3 mEq/l at cooling and 22.2 mEq/l at rewarming (p < 0.05). The standard base excess decreased from a median of 1.55 mEq/l prior to CPB, to -2.50 mEq/l at cooling, -1.65 mEq/l at rewarming and, -0.85 mEq/l at skin closure (p < 0.001). This mild metabolic acidosis occurred despite a decrease in the median serum lactate concentration from 3.20 mEq/l post-induction to 1.83, 1.80, and 1.58 mEq/l at the three other time points. The increase in the median serum chloride concentration from 104.9 mEq/l post induction to 111.0, 111.1, and 110.0 mEq/l at the subsequent time points (p < 0.0001) was the main cause of the acidosis. There was also a significant increase in the SIG of 3.8 mEq/l at cooling and rewarming (p < 0.0001), suggesting a role for other unmeasured anions (polygeline) in the genesis of this acidosis. Using quantitative biophysical methods, it can be demonstrated that, in patients receiving a pump prime rich in chloride and polygeline, the metabolic acidosis of CPB is mostly due to iatrogenic increases in serum chloride concentration and unmeasured strong anions (SIG). Its development is partially attenuated by iatrogenic hypoalbuminaemia. Changes in lactate concentrations did not play a role in the development of metabolic acidosis in our patients.


Species-specific monoclonal antibodies to Rickettsia japonica, a newly identified spotted fever group rickettsia.
A total of 192 hybridomas were developed from mice immunized with Rickettsia japonica, a newly identified spotted fever group rickettsia pathogenic for humans. Of these hybridomas, 101 were species specific, 37 were spotted fever group reactive, and the other 54 were also reactive with one or more of the other pathogenic species of spotted fever group rickettsiae, Rickettsia akari, Rickettsia australis, Rickettsia conorii, Rickettsia rickettsii, and Rickettsia sibrica. Seven of the species-specific monoclonal antibodies were characterized. These monoclonal antibodies all belong to the immunoglobulin G class and react with all five strains of R. japonica at the same immunofluorescence titers, indicating that the five strains all belong to a single species. The species-specific epitopes reactive with these monoclonal antibodies are located on the surface proteins of the organisms demonstrated as 145- and 120-kilodalton bands on Western immunoblots. These two antigenic bands were shown to be proteins, because treatment with proteinase K completely destroyed the reactivity of the bands with the monoclonal antibodies.


The radiography students' perspective of the impact of COVID-19 on education and training internationally: a across sectional survey of the UK Devolved Nations (UKDN) and the United Arab Emirates (UAE).
The overnight change in hospital practice and service delivery during the COVID-19 pandemic raises the question whether undergraduate radiography students received an adequate clinical experience. Many students had their clinical placements cancelled, deferred or replaced with simulated learning. As a way of dealing with the pandemic some hospitals were dedicated to COVID-19 patients only resulting in many elective procedures being cancelled. Many patients also chose to stay away from the hospital out of fear of infection or the desire to reduce the burden on staff. This resulted in a limited range of examinations and clinical experience for those students who were able to complete their clinical placement. This study aims to investigate the impact of COVID-19 on the education and training of radiography students internationally in the United Kingdom Devolved Nations (UKDN) and the United Arab Emirates (UAE), to determine any possible impact on their future careers. Ethical permission was sought and granted from the Research Ethics Committees (ID: 21-04-12-02 and ID:21/0032). An online survey was developed using Google Forms and link was shared with students via email. 262 students participated in the study [UAE (n = 60, 23%) and UKDN (n = 202, 77%)]. 72% stated that their clinical skills have improved and 82% were confident in the choice of radiography as a career. Participants from UAE displayed a higher tendency towards anxiety (p = 0.009). Students who were on clinical placements during the COVID-19 pandemic and worked with COVID-19 positive patients displayed less ongoing concern relating to COVID-19 (p = 0.004). 78% of the participants did not require wellbeing advice or request any type of wellbeing support from the higher education institutions (HEIs). Nevertheless, the study found that wellbeing of students was found to be negatively affected during the pandemic. Completing clinical placement during the COVID-19 pandemic allowed the continuation of education as students were allowed to improve their skills, confidence and resilience in coping with uncertainties and challenges. Undergraduate students should not be excluded from the clinical department during subsequent waves of COVID-19 or future pandemics to ensure continued workforce planning is possible. HEIs should find solutions to compensate students for the loss of practical experience and skills due to the decreased number of patients in some areas of radiography practice. Providing academic and career counselling can assist students achieve their professional objectives and decrease the risk of attrition and problems upon qualification.


Outcomes in Elderly Patients Undergoing Liver Transplantation Compared with Liver-Directed Ablative Therapy in Early-Stage Hepatocellular Carcinoma.
Orthotopic liver transplantation (OLT) is the accepted treatment in patients with unresectable, early-stage hepatocellular carcinoma (HCC) in the setting of cirrhosis. Due to increasing waitlist demand for OLT, determining optimal groups for transplant is critical. Elderly patients are known to have poorer postoperative outcomes. Considering the effectiveness of liver-directed therapies for HCC, we sought to determine whether elderly patients received survival benefit from OLT over liver-directed therapy alone. The National Cancer Database participant use file was used to analyze data between 2004 and 2017. Only patients ≥70 years of age who received OLT or liver-directed therapy alone were included. Patients with alpha-fetoprotein >500 ng/mL or missing alpha-fetoprotein values were excluded. Baseline demographic variables, model for end-stage liver disease score, and overall survival from time of diagnosis were collected. Descriptive statistics, Kaplan-Meier survival, Cox proportional hazards model, and propensity score matching were used. A total of 2,377 patients received ablative therapy alone, and 214 patients received OLT. Multivariable analysis and Kaplan-Meier showed that OLT conferred a significant survival benefit compared to liver-directed therapy alone. Age was also associated with a yearly 3% increase in risk of mortality. Propensity-matched analysis adjusting also demonstrated a significant survival benefit for elderly patients receiving OLT compared to liver-directed therapy alone. Despite increased age and associated comorbidities being factors associated with poor outcomes, OLT confers a survival advantage compared to liver-directed ablative therapies alone in selected elderly patients with HCC. OLT should be offered in medically appropriate elderly patients with HCC.


Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma.
We have investigated human gliomas that amplify and rearrange the epidermal growth factor receptor gene, with generation of an in-frame deletion mutation of 802 nucleotides in the external domain. This in-frame deletion mutation generates a local amino acid sequence at the fusion junction of what normally were distant polypeptide sequences in the intact epidermal growth factor receptor. This 14-amino acid peptide was chemically synthesized, coupled to keyhole limpet hemocyanin, and used as an immunogen in rabbits. The elicited antibody reacted specifically with the fusion peptide in ELISA. The anti-fusion junction peptide antibody was purified by passage of the antiserum over a peptide affinity column with acidic elution. The purified antibody selectively bound the glioma deletion mutant as compared to the intact epidermal growth factor receptor as assessed by immunocytochemistry, immunofluorescence, immunoprecipitation with gel electrophoresis, and binding experiments using radioiodinated antibody. These data indicate that it is feasible to generate site-specific anti-peptide antibodies that are highly selective for mutant proteins in human tumors. The anti-peptide antibody described here, and other mutation site-specific antibodies, should be ideal candidates for tumor immunoimaging and immunotherapy.


Expression of miR-31 in rectal cancer patients and its effect on proliferation ability of rectal cancer cells SW837.
This study aimed to investigate the expression of miR-31 in rectal cancer patients and its effect on the proliferation and invasion ability of human rectal cancer cells SW837. 55 rectal cancer cancerous tissue specimens and 55 corresponding adjacent tissue (tissue adjacent to carcinoma) specimens were collected from rectal cancer patients treated in The First Hospital of Jilin University from March 2014 to March 2015. Real Time-quantitative Polymerase Chain Reaction was used for detecting the expression level of miR-31 in cancerous tissue and corresponding adjacent tissues. Differences in the expression of miR-31 were compared between the two groups. Different miR-31 expression vectors were established and rectal cancer cells SW837 were transfected. MTT was used for detecting the proliferation ability of the cells in the miR-31-mimics group, miR-31-inhibitor group and miR-control group. The expression level of miR-31 was significantly higher in rectal cancer tissues than that in the adjacent tissues (p<0.05). The expression of miR-31 was higher in the miR-31-mimics group (23.6±4.6) than that in the miR-control group (1.63±0.65), while the expression of miR-31 was lower in the miR-31-inhibitor group (0.65±0.23) than that in the miR-control group. The proliferation ability of cells at the 6th, 12th, 24th, 48th, and 72nd hours was higher in the miR-31-mimics group than in the miR-31-inhibitor group, while that of cells was significantly lower in the miR-31-inhibitor group than in the miR-control group, with statistically significant differences (p<0.05). The number of invasive membrane cells (cell membrane number) counted under a microscope was (84.2±10.6) cells in the miR-31-mimics group, (12.3±4.1) cells in the miR-31-inhibitor group, and (45.2±10.6) cells in the miR-control group. The invasion ability in vitro of SW837 cells significantly increased after the overexpression of miR-31 (p<0.05). miR-31 is increasingly expressed in rectal cancer. Low expression of miR31 can inhibit the proliferation and invasion ability of the cells. MiR-31 is expected to become a current biotherapeutic target.


Burkitt's lymphoma in the femoral triangle of a white american male.
A teenage white male was recently evaluated for a rapidly enlarging mass in the right groin. Biopsy of the mass disclosed Burkitt's lymphoma. Aggressive therapy was instituted, including extirpative surgery, followed by chemotherapy and radiation therapy. Using these combined modalities, it was possible to eliminate the lymphoma. Unfortunately, severe pancytopenia and immunosuppression developed and the patient died of gram-negative sepsis. This disease should be considered in the differential diagnosis of any rapidly enlarging solid tumor in a young patient.


Epigenetic alterations and decreasing insecticide sensitivity of the Asian tiger mosquito Aedes albopictus.
A range of environmental factors, including chemicals, can affect epigenetic processes in organisms leading to variations in phenotype. Thus, epigenetics displays an important environmentally responsive element. The transgenerational impact of environmental stressors on DNA methylation and phenotype was the focus of this study. The influence of two known DNA methylation-changing agents, the phytoestrogen genistein and the fungicide vinclozolin, on the overall DNA methylation level in the Asian tiger mosquito Aedes albopictus was investigated. The experiment comprised four generations in a full life-cycle design with an exposed parental generation and three consecutive non-exposed offspring generations. Application of the methylation agents to the parental generation of the study led to an alteration of the global DNA methylation level of the exposed individuals and those in two subsequent generations. The phenotypic variability of the offspring generations was assessed by examining their insecticide sensitivity. Here, a significant decrease in sensitivity (p<0.01) towards the model insecticide imidacloprid revealed alterations of the mosquito's phenotype in two subsequent generations. Thus, the evaluation of A. albopictus from an epigenetic perspective can contribute important information to the study of the high adaptability of this invasive disease vector to new environments, and its underlying mechanisms.


Topical Products for the Protection of Periwound Skin: A Scoping Review.
The periwound skin influences the evolution of the wound. Among the mechanisms that affect it are the wound's own exudate and the use of therapeutic support devices. The objective of this scoping review is to map out topical products that have been implemented and evaluated for either the protection or treatment of injuries caused by exudate or the use of adhesives or therapeutic dressings on the periwound skin of acute or chronic wounds. The methodology for scoping reviews proposed by the Joanna Briggs Institute was adopted, and a 3-step search strategy was carried out. The first search was limited to MEDLINE and CINAHL. Subsequently, a search was conducted with the identified key words and the terms of the index for the selected databases. Finally, additional studies were sought in the references of all identified publications. Two reviewers conducted the searches independently. Literature in the English, Spanish, and Portuguese languages was included. A total of 1229 studies were identified, 12 of which met the inclusion criteria defined for this review. From the included studies, 12 products were identified for wounds of different etiologies, with the most frequent being the alcohol-free barrier film and zinc oxide. To date, the level of evidence is low. It is necessary to develop more robust research that improves the quality of the literature available for treating people with wounds.


Characterization of connexin 30.3 and 43 in thymocytes.
During maturation, thymocytes interact directly and indirectly with different cell types of the thymic microenvironment. Such a cellular communication has been basically ascribed to soluble factors and surface receptors. However, little attention has been given to cellular communication mediated by gap junctions. The existence of these intercellular channels in the immune system remained a controversial issue since the 1970s until recently, when a growing body of evidence has indicated their presence and physiological roles in the immune system. In this work, we investigated whether thymocytes express gap junction-forming proteins (connexins, Cx) and are capable of forming functional intercellular channels. Using RT-PCR, we demonstrated that thymocytes express the mRNA for two Cx isoforms: Cx30.3 and Cx43, but not for Cx26, Cx30, Cx31, Cx31.1, Cx32, Cx33, Cx36, Cx37, Cx40, Cx45, Cx46, and Cx50. In addition, the presence of Cx30.3 and Cx43 was confirmed using different techniques (RNase protection assay, western blot and immunofluorescence). However, despite the expression of these two Cxs, we did not detect functional homocellular coupling between thymocytes or between EL-4 cells (a Cx43 expressing thymic lymphoma-derived cell line) or heterocellular coupling between thymocytes and thymic epithelial cells (TEC) or between EL-4 and TEC in unstimulated conditions. Concluding, in this study, we described for the first time the expression of connexins in thymocytes, which may constitute a new molecule having a functional role in thymocytes maturation.


Non-proteolytic activation of prorenin: activation by (pro)renin receptor and its inhibition by a prorenin prosegment, "decoy peptide".
Prorenin is the enzymatically inactive precursor of renin. Recent interest has focused on the nonproteolytic activation of prorenin by antibodies and renin/prorenin receptors since markedly increased levels of circulating prorenin have been associated with both physiological and pathological changes. Prorenin has been considered to be activated in vivo proteolytically and/or non-proteolytically. It has been demonstrated in vitro the "gate" and "handle" regions in the prorenin molecule is crucial for its non-proteolytic activation by a protein-protein interaction. Prorenin was also activated by the renin/prorenin receptors. Decapeptides (10P-19P) known as "decoy" peptide and pentapeptides (11P-15P) named as "handle" region peptide, were observed to inhibit the binding of both prorenins to receptors. The "handle" region plays an important role in prorenin binding to the receptor and its enzymatic activity by non-proteolytic activation. Prorenin receptors so far revealed by animal experiments have indicated that the decoy peptide prevented diabetes nephropathy and retinopathy. It was postulated the existence of novel regulative system that stimulated signal transduction as well as that of renin-angiotensin system. These findings help to find out the clue to design useful drug with greater benefit on the end-organ damage in diabetes and hypertension than those of conventional renin-angiotensin system inhibitors.


Short term depression unmasks the ghost frequency.
Short Term Plasticity (STP) has been shown to exist extensively in synapses throughout the brain. Its function is more or less clear in the sense that it alters the probability of synaptic transmission at short time scales. However, it is still unclear what effect STP has on the dynamics of neural networks. We show, using a novel dynamic STP model, that Short Term Depression (STD) can affect the phase of frequency coded input such that small networks can perform temporal signal summation and determination with high accuracy. We show that this property of STD can readily solve the problem of the ghost frequency, the perceived pitch of a harmonic complex in absence of the base frequency. Additionally, we demonstrate that this property can explain dynamics in larger networks. By means of two models, one of chopper neurons in the Ventral Cochlear Nucleus and one of a cortical microcircuit with inhibitory Martinotti neurons, it is shown that the dynamics in these microcircuits can reliably be reproduced using STP. Our model of STP gives important insights into the potential roles of STP in self-regulation of cortical activity and long-range afferent input in neuronal microcircuits.


Peptide mimotopes as candidate vaccines.
The development of combinatorial peptide libraries, where random peptide sequences are displayed either on the surface of a phage or on a solid support, provides researchers with a powerful tool for analysis and study of the specificity of immune responses. The strength of this technology lies in the large amount of molecular diversity displayed that can be easily obtained and rapidly tested. As a result of screening peptide libraries, novel peptide sequences can be identified, which mimic native protective epitopes (mimotopes), and have the potential for use as vaccine candidates.


[The sentinel node biopsy in patients with breast cancer: recommendations for the introduction of this procedure. Dutch Working Group Sentinel Node Biopsy in Breast Cancer].
Sentinel node biopsy may be useful in the staging of breast cancer. In experienced hands presence or absence of metastasis in the sentinel node accurately predicts the nodal status and in patients with a negative sentinel node biopsy axillary dissection may be avoided. The technique, however, shows a clear learning curve and hasty introduction may lead to an unacceptable rate of false negative biopsies. Moreover, the introduction of the technique in general practice should be well coordinated in order to prevent large differences between hospitals in the staging and treatment of breast cancer patients. On the initiative of NABON (Nationaal Borstkanker Overleg Nederland; 'national breast cancer consultation') and the Nederlandse Vereniging voor Chirurgische Oncologie (Netherlands Association for Surgical Oncology) a study group was formed to co-ordinate the introduction of the sentinel node biopsy in breast cancer patients in the Netherlands. Important topics are central registration of all procedures in order to evaluate its applicability and technical variations, the performance in each centre of at least 50 procedures together with axillary node dissection to evaluate the results before clinical application is considered, and nationwide co-ordination to find the best therapy for patients with positive sentinel nodes.


Use of mental health services for anxiety, mood, and substance disorders in 17 countries in the WHO world mental health surveys.
Mental disorders are major causes of disability worldwide, including in the low-income and middle-income countries least able to bear such burdens. We describe mental health care in 17 countries participating in the WHO world mental health (WMH) survey initiative and examine unmet needs for treatment. Face-to-face household surveys were undertaken with 84,850 community adult respondents in low-income or middle-income (Colombia, Lebanon, Mexico, Nigeria, China, South Africa, Ukraine) and high-income countries (Belgium, France, Germany, Israel, Italy, Japan, Netherlands, New Zealand, Spain, USA). Prevalence and severity of mental disorders over 12 months, and mental health service use, were assessed with the WMH composite international diagnostic interview. Logistic regression analysis was used to study sociodemographic predictors of receiving any 12-month services. The number of respondents using any 12-month mental health services (57 [2%; Nigeria] to 1477 [18%; USA]) was generally lower in developing than in developed countries, and the proportion receiving services tended to correspond to countries' percentages of gross domestic product spent on health care. Although seriousness of disorder was related to service use, only five (11%; China) to 46 (61%; Belgium) of patients with severe disorders received any care in the previous year. General medical sectors were the largest sources of mental health services. For respondents initiating treatments, 152 (70%; Germany) to 129 (95%; Italy) received any follow-up care, and one (10%; Nigeria) to 113 (42%; France) received treatments meeting minimum standards for adequacy. Patients who were male, married, less-educated, and at the extremes of age or income were treated less. Unmet needs for mental health treatment are pervasive and especially concerning in less-developed countries. Alleviation of these unmet needs will require expansion and optimum allocation of treatment resources.


Anatomic predisposition to ligamentous Lisfranc injury: a matched case-control study.
Subtle, or ligamentous, Lisfranc injuries occur following low-energy trauma to the midfoot and can be debilitating. Since they are ligamentous, they may not heal, requiring arthrodesis in some cases. Certain mortise anatomic characteristics on radiographs have been shown to be associated with a predisposition to the ligamentous subtype of Lisfranc injuries. It is not known whether there are other morphometric characteristics, such as arch height or the relative length of the second metatarsal, that can similarly influence the predisposition to these injuries. The present retrospective matched case-control study involved fifty-two control subjects and twenty-six patients with ligamentous Lisfranc injuries treated from 2006 to 2010 at two institutions. Clinical and radiographic data (second metatarsal length relative to foot length, first intermetatarsal angle, navicular-cuboid overlap relative to cuboid vertical height, first metatarsal-talus angle, and calcaneal pitch angle) were examined for the existence of significant differences between control and Lisfranc subjects. Logistic regression analysis was then performed to evaluate potential risk for injury on the basis of these anatomic variables. Compared with matched controls, patients with a ligamentous Lisfranc injury were found to have a significantly smaller ratio of second metatarsal length to foot length (p < 0.001) on weight-bearing radiographs. Occurrence of a ligamentous Lisfranc injury was shown to be associated with a smaller ratio of second metatarsal length to foot length; >50% of patients in the injury group had a ratio of <29%.


The biological function of type I receptors of bone morphogenetic protein in bone.
Bone morphogenetic proteins (BMPs) have multiple roles in skeletal development, homeostasis and regeneration. BMPs signal via type I and type II serine/threonine kinase receptors (BMPRI and BMPRII). In recent decades, genetic studies in humans and mice have demonstrated that perturbations in BMP signaling via BMPRI resulted in various diseases in bone, cartilage, and muscles. In this review, we focus on all three types of BMPRI, which consist of activin-like kinase 2 (ALK2, also called type IA activin receptor), activin-like kinase 3 (ALK3, also called BMPRIA), and activin-like kinase 6 (ALK6, also called BMPRIB). The research areas covered include the current progress regarding the roles of these receptors during myogenesis, chondrogenesis, and osteogenesis. Understanding the physiological and pathological functions of these receptors at the cellular and molecular levels will advance drug development and tissue regeneration for treating musculoskeletal diseases and bone defects in the future.


The pCa-tension and force-velocity characteristics of skinned fibres isolated from fish fast and slow muscles.
1. Single fast fibres and small bundles of two to six slow fibres were dissected from the myotomal muscles of the cod, Gadus morhua, and the dogfish, Scyliorhinus canicula. Fibres were chemically skinned with the non-ionic detergent Brij 58.2. The isometric tension properties were investigated. Maximal isometric tensions (mean +/- S.E. of mean) were 18.65+/-1.18 (n = 11) and 8.34+/-0.98 (n = 13) N cm(-2) for cod fast and slow fibres, and 18.34+/-0.88 (n = 28) and 8.24+/-0.39 (n = 12) N cm(-2) for dogfish fast and slow fibres respectively. The values are comparable to those observed in mammalian and amphibian skinned fibres. The lower tensions generated by the slow fibres cannot be fully explained on the basis of their lower myofibrillar fractional volume.3. In common with previous studies, a steep sigmoid relationship between pCa and tension was observed. The threshold for tension generation was around pCa 7.2. Half-maximal pCas were 6.08 and 6.42 for cod fast and slow muscle, and 6.41 and 6.50 for dogfish fast and slow fibres respectively. Cod fibres were maximally activated at around pCa 5.18, and dogfish fibres at pCa 5.62.4. Contraction-induced residual tensions were observed in cod fast fibres after return to relaxing solution. This phenomenon is a feature common to many skinned fibre studies, but the mechanism behind it has yet to be resolved.5. The force-velocity characteristics of fast and slow fibres have been investigated (at 8 degrees C).6. Points below 0.6 P(0) on the P-V curves could be fitted to a linear form of the Hill equation. Extrapolated V(max)s were calculated as follows: cod fast fibre V(max) = 1.01 muscle length sec(-1) (Lsec(-1)) (a = 0.21 P(0); b = 0.21 Lsec(-1)). Slow fibre = 0.53 Lsec(-1) (a = 0.28P(0); b = 0.21 Lsec(-1)). Dogfish fast fibre V(max) = 2.34 Lsec(-1) (a = 0.06 P(0); b = 0.14 Lsec(-1)). Slow fibre = 0.67 Lsec(-1) (a = 0.19 P(0); b = 0.13 Lsec(-1)).7. Contraction velocity in cod slow fibres decreased continuously to produce markedly non-linear velocity transients, similar to those reported for amphibian slow fibres.8. The effect of altering Ca(2+) concentration on the shape of the isotonic velocity curve (at low loads) was studied in dogfish fast fibres (0.5-1 degrees C). Contraction velocity decreased continuously during shortening, at both maximal and half-maximal Ca(2+) concentration. The rate of decay of velocity with shortening was greater at low Ca(2+) concentration.


Studies on induced variation in the rhizobia. II. Radiation sensitivity and induction of antibiotic-resistance markers.
The relation between survival and dose of ultraviolet (UV) light or X rays was, with only one exception, nonlinear for late-log-phase cultures of four species of Rhizobium. The ld(90) for different bacterial strains ranged from 400 to 3,000 ergs per mm(2) for UV treatment, and from 3.0 to 7.5 kr for X-ray treatment. Minor existing differences in response to some antibacterial compounds (disc tests) were usable as secondary markers for genetic experiments. Spontaneous and radiation-induced mutants, resistant to high levels of several antibiotics, notably dihydrostreptomycin and erythromycin, were isolated for primary marker purposes. A significant phenotypic lag for mutation to dihydrostreptomycin resistance was noted for UV-irradiated cells. The UV-induced frequency exceeded the X-ray-induced frequency by a factor of at least three, at a comparable level of lethality. No significant change in the symbiotic capability was observed in rhizobial strains marked with antibiotics resistance.


Surgical management of vertical ocular misalignment in thyroid eye disease using an adjustable suture technique.
To report a surgical approach to managing hypotropia associated with thyroid eye disease (TED) that uses adjustable sutures. The medical records of consecutive patients with TED and hypotropia who underwent adjustable suture inferior rectus muscle recession with or without superior rectus muscle recession of the hypertropic eye were reviewed retrospectively. The initial goal was undercorrection in primary gaze and no hyperdeviation in downgaze. Outcomes were rated according to the presence of diplopia in primary and reading positions as excellent (none), good (no diplopia with <10(Δ) correction), and poor (diplopia). Fifty-four patients were included. The initial median primary position deviation was 16(Δ). Of the 54 patients, 39 (72%) underwent unilateral inferior rectus muscle recession; 15 (28%), bilateral; and 24 (44%), superior rectus muscle recession. On mean follow-up of 38 weeks, 35 patients (65%) had excellent results (30 aligned in primary and reading position, 5 of whom could fuse small deviations [average, 3(Δ)]); 17 (31%), good results (13 < 6(Δ)); and 2 (3.7%), poor results, but aligned after reoperation (6(Δ) overcorrection, 16(Δ) undercorrection). Of the 24 misaligned patients (ie, those with small deviations, good results, and poor results), 13 were undercorrected an average of 4.9(Δ) and 11 (20%) were overcorrected an average of 6.2(Δ). Adjustment timing, number of muscles recessed, preoperative deviation, and previous orbital decompression did not affect outcomes. In this series, patients with hypotropia and TED were effectively managed by the use of adjustable sutures and by surgeons operating on multiple muscles, anticipating drift toward overcorrection of the recessed inferior rectus muscle, and using prism for residual deviation.


Alternative translation initiation generates acyl-CoA synthetase 3 isoforms with heterogeneous amino termini.
ACS3 is a recently identified acyl-CoA synthetase (ACS) isozyme that preferentially utilizes laurate, myristate, arachidonate, and eicosapentaenoate among saturated and unsaturated long chain fatty acids. The ACS3 purified from COS cells transfected with the ACS3 cDNA was separated by SDS-PAGE into two major forms of 79 and 80 kDa. We report here that alternative translation initiation from ACS3 mRNA gives rise to these two isoforms of ACS3. In vitro mutagenesis of the ACS3 cDNA revealed that the translation of the 80-kDa and 79-kDa isoforms started from the first and second in-frame AUGs, respectively. The two isoforms of ACS3 expressed in COS cells exhibited similar levels of ACS activities toward palmitate and myristate. Immunocytochemistry of intact COS cells transfected with various ACS3 expression vectors suggested that the two forms are localized in the extranuclear compartment, where they exhibit a reticular pattern. In rat cerebrum, the 80-kDa isoform of ACS3 was detected mainly in the microsomal fraction. Only a trace amount of the 79-kDa isoform was detected in rat cerebrum, whereas both forms were detected in rat glioma cell line KEG1 cells.


Impact of sharing electronic health records with patients on the quality and safety of care: a systematic review and narrative synthesis protocol.
Providing patients with access to electronic health records (EHRs) has emerged as a promising solution to improve quality of care and safety. As the efforts to develop and implement EHR-based data sharing platforms mature and scale up worldwide, there is a need to evaluate the impact of these interventions and to weigh their relative risks and benefits, in order to inform evidence-based health policies. The aim of this work is to systematically characterise and appraise the demonstrated benefits and risks of sharing EHR with patients, by mapping them across the six domains of quality of care of the Institute of Medicine (IOM) analytical framework (ie, patient-centredness, effectiveness, efficiency, timeliness, equity and safety). CINAHL, Cochrane, Embase, HMIC, Medline/PubMed and PsycINFO databases will be searched from January 1997 to August 2017. Primary outcomes will include measures related with the six domains of quality of care of the IOM analytical framework. The quality of the studies will be assessed using the Cochrane Risk of Bias Tool, the ROBINS-I Tool and the Drummond's checklist. A narrative synthesis will be conducted for all included studies. Subgroup analysis will be performed by domain of quality of care domain and by time scale (ie, short-term, medium-term or long-term impact). The body of evidence will be summarised in a Summary of Findings table and its strength assessed according to the GRADE criteria. This review does not require ethical approval as it will summarise published studies with non-identifiable data. This protocol complies with the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols guidelines. Findings will be disseminated widely through peer-reviewed publication and conference presentations, and patient partners will be included in summarising the research findings into lay summaries and reports. CRD42017070092.


Spatio-temporal and stochastic modelling of severe acute respiratory syndrome.
This study describes the development of a spatio-temporal disease model based on the episodes of severe acute respiratory syndrome (SARS) that took place in Hong Kong in 2003. In contrast to conventional, deterministic modelling approaches, the model described here is predominantly spatial. It incorporates stochastic processing of environmental and social variables that interact in space and time to affect the patterns of disease transmission in a community. The model was validated through a comparative assessment between actual and modelled distribution of diseased locations. Our study shows that the inclusion of location-specific characteristics satisfactorily replicates the spatial dynamics of an infectious disease. The Pearson's correlation coefficients for five trials based on 3-day aggregation of disease counts for 1-3, 4-6 and 7-9 day forecasts were 0.57- 0.95, 0.54-0.86 and 0.57-0.82, respectively, while the correlation based on 5-day aggregation for the 1-5 day forecast was 0.55- 0.94 and 0.58-0.81 for the 6-10 day forecast. The significant and strong relationship between actual results and forecast is encouraging for the potential development of an early warning system for detecting this type of disease outbreaks.


Estimation of MERS-Coronavirus Reproductive Number and Case Fatality Rate for the Spring 2014 Saudi Arabia Outbreak: Insights from Publicly Available Data.
The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was initially recognized as a source of severe respiratory illness and renal failure in 2012. Prior to 2014, MERS-CoV was mostly associated with sporadic cases of human illness, of presumed zoonotic origin, though chains of person-to-person transmission in the healthcare setting were reported. In spring 2014, large healthcare-associated outbreaks of MERS-CoV infection occurred in Jeddah and Riyadh, Kingdom of Saudi Arabia. To date the epidemiological information published by public health investigators in affected jurisdictions has been relatively limited. However, it is important that the global public health community have access to information on the basic epidemiological features of the outbreak to date, including the basic reproduction number (R0) and best estimates of case-fatality rates (CFR). We sought to address these gaps using a publicly available line listing of MERS-CoV cases. R0 was estimated using the incidence decay with exponential adjustment ("IDEA") method, while period-specific case fatality rates that incorporated non-attributed death data were estimated using Monte Carlo simulation. 707 cases were available for evaluation. 52% of cases were identified as primary, with the rest being secondary. IDEA model fits suggested a higher R0 in Jeddah (3.5-6.7) than in Riyadh (2.0-2.8); control parameters suggested more rapid reduction in transmission in the former city than the latter. The model accurately projected final size and end date of the Riyadh outbreak based on information available prior to the outbreak peak; for Jeddah, these projections were possible once the outbreak peaked. Overall case-fatality was 40%; depending on the timing of 171 deaths unlinked to case data, outbreak CFR could be higher, lower, or equivalent to pre-outbreak CFR. Notwithstanding imperfect data, inferences about MERS-CoV epidemiology important for public health preparedness are possible using publicly available data sources. The R0 estimated in Riyadh appears similar to that seen for SARS-CoV, but CFR appears higher, and indirect evidence suggests control activities ended these outbreaks. These data suggest this disease should be regarded with equal or greater concern than the related SARS-CoV.


Structural polymorphism of the RecA protein from the thermophilic bacterium Thermus aquaticus.
The Escherichia coli RecA protein has served as a model for understanding protein-catalyzed homologous recombination, both in vitro and in vivo. Although RecA proteins have now been sequenced from over 60 different bacteria, almost all of our structural knowledge about RecA has come from studies of the E. coli protein. We have used electron microscopy and image analysis to examine three different structures formed by the RecA protein from the thermophilic bacterium Thermus aquaticus. This protein has previously been shown to catalyze an in vitro strand exchange reaction at an optimal temperature of about 60 degrees C. We show that the active filament formed by the T. aquaticus RecA on DNA in the presence of a nucleotide cofactor is extremely similar to the filament formed by the E. coli protein, including the extension of DNA to a 5.1-A rise per base pair within this filament. This parameter appears highly conserved through evolution, as it has been observed for the eukaryotic RecA analogs as well. We have also characterized bundles of filaments formed by the T. aquaticus RecA in the absence of both DNA and nucleotide cofactor, as well as hexameric rings of the protein formed under all conditions examined. The bundles display a very large plasticity of mass within the RecA filament, as well as showing a polymorphism in filament-filament contacts that may be important to understanding mutations that affect surface residues on the RecA filament.


Oxytetracycline attenuates allergic airway inflammation in mice via inhibition of the NF-κB pathway.
Oxytetracycline has been used in the treatment of acute and chronic bronchial inflammation and infectious asthma. However, its potential use for non-infectious asthma has not yet been studied. The objective of this study was to investigate the anti-inflammatory properties of oxytetracycline using a mouse asthma model. Female BALB/c mice, sensitized and challenged with ovalbumin. Naive CD4+ T cells from spleen were stimulated for 72 h with anti-CD3 (5 μg/ml) plus anti-CD28 (2.5 μg/ml) and differentiated into Th2 cells. IL-4, IL-5, IL-9, IL-13, and ovalbumin (OVA)-specific IgE production were measured by ELISA in BALF and cell supernatants. Histopathological evaluation was used to study the alterations in lung tissue. The mRNA levels of CCL5, CCL11, CCR1, and CCR3 were detected by real-time PCR. In addition, the protein levels of p-Akt, Akt, nuclear factor kappa B (NF-κB), IκBα and p-IκBα in lung tissue and cells were measured by western blot or immunofluorescence analysis. Oxytetracycline treatment caused a marked reduction in IL-4, IL-5, IL-13, immune cells, and the level of ovalbumin-specific IgE. Real-time PCR studies demonstrated that oxytetracycline can significantly reduce CCL5, CCL11 and their specific receptor CCR1 and CCR3. Histological studies demonstrated that oxytetracycline substantially inhibited ovalbumin-induced inflammatory cell infiltration in lung tissue and goblet cell hyperplasia in airway. Oxytetracycline inhibited the NF-κB activation via phosphorylation and degradation of IκBα both in vivo and in vitro. Furthermore, the increased phosphorylated Akt but not Akt protein levels in lung tissues after OVA inhalation were significantly reduced by the oral administration of oxytetracycline. These findings demonstrate an anti-inflammatory effect of oxytetracycline that might be mediated via reduction of inflammatory mediators and activation of transcription factors.


Are Dietary Indices Associated with Polycystic Ovary Syndrome and Its Phenotypes? A Preliminary Study.
Polycystic ovary syndrome (PCOS) is a complex hormonal disorder which impairs ovarian function. The adherence to healthy dietary patterns and physical exercise are the first line of recommended treatment for PCOS patients, but it is yet unclear what type of diet is more adequate. In this case-control study, we explored associations between adherence to five dietary quality indices and the presence of PCOS. We enrolled 126 cases of PCOS and 159 controls living in Murcia (Spain). Diagnostic of PCOS and its phenotypes were established following the Rotterdam criteria (hyperandrogenism (H), oligoanovulation (O), polycystic ovaries morphology (POM)). We used a validated food frequency questionnaires to calculate the scores of five dietary indices: alternate Healthy Eating index (AHEI), AHEI-2010, relative Mediterranean Dietary Score (rMED), alternate Mediterranean Dietary Score (aMED) and Dietary Approaches to Stop Hypertension (DASH). We used multivariable logistic regression to estimate adjusted odds ratios and confidence intervals. In the multivariable analysis, AHEI-2010 index was inversely associated with Hyperandrogenism + Oligoanovulation PCOS phenotype (ORQ3 vs. Q1 = 0.1; 95% CI: (0.0; 0.9); Pfor trend = 0.02). We did not find any statistical significant association between dietary indices and total anovulatory or ovulatory PCOS. However, further studies with higher sample sizes exploring these associations among the diverse phenotypes of PCOS are highly warranted.


[Allele specificity of the mutator action of bacteriophage T4 genes 43 and 32].
The substitution of tester mutant ri31 (fs-type) for transition mutants rUV30 and rUV48 allowed to reveal new mutator alleles of DNA polymerase gene of phage T4. In these conditions about 70% alleles of this gene were found to be mutators. Unlike experiments carried out with mutant-tester ri31, in experiments with mutants rUV30 and rUV48 the presence of mutator alleles in gene 32 was demonstrated. The transition pathway AT leads to GC is the preferential direction of the mutation alteration under the action of suppressed amber alleles of genes 43 and 32. The data obtained suggest allele specificity of the mutator effect in bacteriophage T4.


Inhibitory and stimulatory effects of concanavalin A on the response of mouse spleen cell suspensions to antigen. I. Characterization of the inhibitory cell activity.
The presence of concanavalin A (Con A) inhibits the immune response of mouse spleen cell suspensions to erythrocyte antigens, stimulates the incorporation of tritiated thymidine, and increases cell recovery. Con A also restores the depressed response of cell preparations treated to remove thymus-derived cells. The dose-response curve for all four effects shows peak activity at 2 microg/ml. The depressed in vitro response of spleen cell suspensions from adult thymectomized, irradiated, bone marrow-restored mice is also restored by Con A. Here the dose-response curve is quite different with activity over a much wider range of concentration. The restoration of thymus-derived cell-depleted cultures by Con A is inhibited by the addition of untreated, unirradiated, mouse spleen cell suspensions, but is not inhibited by untreated, irradiated cells. Small numbers of spleen cells that have been preincubated with Con A and washed will inhibit the response of fresh, untreated cells to antigen. If the mouse spleen cell suspensions are incubated for 24 hr before the addition of Con A, the response to antigen is no longer inhibited but is stimulated instead. The data are compatible with the hypothesis that there are at least two cell targets for the action of Con A. One cell, that mediates the inhibitor effect, is a short-lived, radiosensitive, thymus-derived cell. The other cell, that mediates the stimulating effect, cannot be identified from the data presented here but may also be of thymus origin on the basis of studies by other investigators.


Modulating Microglial Cells for Promoting Brain Recovery and Repair.
Representing the brain's innate immune cells that interact vividly with blood-derived immune cells and brain parenchymal cells, microglia set the stage for successful brain remodeling and repair in the aftermath of brain damage. With the development of pharmacological colony-stimulating factor-1 receptor inhibitors, which allow inhibiting or depleting microglial cells, and of transgenic mice, allowing the inducible depletion of microglial cells, experimental tools have become available for studying roles of microglia in neurodegenerative and neurorestorative processes. These models open fundamental insights into roles of microglia in controlling synaptic plasticity in the healthy and the injured brain. Acting as a switch from injury to repair, microglial cells might open opportunities for promoting neurological recovery in human patients upon brain injury.


Controlled ambipolar-to-unipolar conversion in graphene field-effect transistors through surface coating with poly(ethylene imine)/poly(ethylene glycol) films.
A controlled ambipolar-to-unipolar (n-type) conversion, along with a maximum fourfold increase in the electron mobility, in graphene field-effect transistors (FETs) is achieved by coating the surface of graphene with a layer of a mixed polymer system, poly(ethylene imine) (PEI) in poly(ethylene glycol) (PEG). The PEG serves as a physisorption adhesion agent for the PEI. Both unipolar and ambipolar n-type doping can be realized by adjusting the thickness of PEI films atop the graphene channel. The observed phenomena are attributed to the doping/dedoping effects of the external PEI film. The study provides a guide to engineering graphene transport properties through chemical modifications.


[Antimicrobial susceptibility in non-typable Haemophilus influenzae strains isolated from healthy children].
Antimicrobial susceptibility of 79 non-typable Haemophilus influenzae isolations obtained from healthy children that attended two day-care centers in Marianao municipality. It was found resistance to trimetoprim/sulfamethoxazole (41,77 %), tetracycline (18,99), ampicilline (17,72 %), amoxicillin/ clavulanic acid (7,59 %) and chloramphenicol (6,33 %). 25,81 % of isolates showed multiresistance. 100 % of studied cases was sensitive to ceftriaxone, cefuroxime and norfloxacin. 28,57 % of ampicilline-resistent isolates produced beta-lactamase enzyme. Chloramphenicol resistance was mediated by the production of chloramphenicol acetyltransferase enzyme.


Natural sequence variants of yeast environmental sensors confer cell-to-cell expression variability.
Living systems may have evolved probabilistic bet hedging strategies that generate cell-to-cell phenotypic diversity in anticipation of environmental catastrophes, as opposed to adaptation via a deterministic response to environmental changes. Evolution of bet hedging assumes that genotypes segregating in natural populations modulate the level of intraclonal diversity, which so far has largely remained hypothetical. Using a fluorescent P(met17)-GFP reporter, we mapped four genetic loci conferring to a wild yeast strain an elevated cell-to-cell variability in the expression of MET17, a gene regulated by the methionine pathway. A frameshift mutation in the Erc1p transmembrane transporter, probably resulting from a release of laboratory strains from negative selection, reduced P(met17)-GFP expression variability. At a second locus, cis-regulatory polymorphisms increased mean expression of the Mup1p methionine permease, causing increased expression variability in trans. These results demonstrate that an expression quantitative trait locus (eQTL) can simultaneously have a deterministic effect in cis and a probabilistic effect in trans. Our observations indicate that the evolution of transmembrane transporter genes can tune intraclonal variation and may therefore be implicated in both reactive and anticipatory strategies of adaptation.


Comparison of rates of fecal colonization with extended-spectrum beta-lactamase-producing enterobacteria among patients in different wards, outpatients and medical students.
Because asymptomatic carriage of extended-spectrum beta-lactamase (ESBL) producers is a risk factor for infection, data on colonization dynamics are important when planning infection control. This study investigated fecal colonization with ESBL producers among inpatients, outpatients and medical students and compares the characteristics of ESBL producers among these groups. Carriage rates were investigated in 5581 fecal samples; 4343 from inpatients (330, 1397, 619 and 1864 from adult ICUs [intensive care units], adult non-ICUs, pediatric ICUs and pediatric non-ICUs, respectively), 814 from outpatients and 424 from screening of medical students. ESBL producers were characterized by co-resistance, integrons carried, and aminoglycoside resistance and ESBL genes. Dynamic regression models were built to identify relationships between combinations of time series of monthly antibiotic consumption, prevalence of carriers and infected subjects. Inpatients, ICU patients and adults showed higher prevalence than outpatients, non-ICU patients or children (7.4%, 9.3% and 12.0% vs. 3.1%, 6.1% and 4.1%, respectively). Klebsiella pneumoniae was more frequent in ICU patients; dominance of CTX-M-15 producers was more marked in adult than in pediatric inpatients. ESBL carriage was shown to be a consequence of infection in adults in the time-series analysis; antibiotic consumption had little effect. The epidemiology of colonization with ESBL producers differed between pediatric ICU, adult ICU and adult non-ICU patients. In adults, carriage of ESBL producers seems to be the consequence of infection, especially in ICU patients; the main source of colonization is nosocomial acquisition. In contrast, children are less likely to acquire colonizer strains in hospitals; importation of ESBL producers by colonized children seems to be significant.


The effect of a diet with fructan-rich chicory roots on intestinal helminths and microbiota with special focus on Bifidobacteria and Campylobacter in piglets around weaning.
The restrictions on the use of antibiotic and anthelmintic treatments in organic pig farming necessitate alternative non-medical control strategies. Therefore, the antibiotic and parasite-reducing effect of a fructan-rich (prebiotic) diet of dried chicory was investigated in free-ranging piglets. Approximately half of 67 piglets from nine litters were experimentally infected with Ascaris suum and Trichuris suis in the suckling period (1 to 7 weeks of age) and 58 of the piglets were challenged daily with Eschericia coli O138:F8 for 9 days after weaning to induce weaning diarrhoea. The litters were fed either chicory (30% dry matter) or a control diet. The effect of chicory on intestinal helminths, intestinal microbiota, especially Bifidobacteria and Campylobacter spp. and E. coli post-weaning diarrhoea was assessed. The weight gain of the piglets was not impaired significantly by chicory. The intestinal A. suum worm burden was reduced by 64% (P = 0.034) in the chicory-fed piglets, whereas these same piglets had 63% more T. suis worms (P = 0.016). Feeding with chicory elicited no changes among the main bacterial groups in ileum according to terminal restriction fragment length polymorphism analysis. However, the terminal-restriction fragment (T-RF) 208 bp, which may belong to Lachnospiraceae, was stimulated by the chicory feed (P = 0.03), and T-RF 370 bp that matches Enterobacter belonging to the Enterobacteria was reduced (P = 0.004). In addition, chicory increased the level of Bifidobacteria (P = 0.001) and the faecal Campylobacter excretion level was transitorily reduced in chicory-fed piglets at 7 weeks of age (P = 0.029). Unfortunately, it was not possible to assess the effect of chicory on post-weaning diarrhoea as it did not develop. In conclusion, feeding piglets chicory around the time of weaning caused complex changes of the microbiota and parasite communities within the intestinal tract, and feeding piglets chicory may therefore serve as an animal-friendly strategy to control pathogens.


Street drug use during pregnancy: potential programming effects on preschool wheeze.
Street drug use during pregnancy is detrimental to fetal development. Although the prevalence of wheeze is high in offspring of substance-abusing mothers, nothing is known about the role of street drug use during pregnancy in its development. We investigated the impact of maternal street drug use and distress during pregnancy on the development of wheeze and allergy in preschool children. Questionnaire data were accessed from the Community Perinatal Care trial of 791 mother-child pairs in Calgary, Alberta. Using logistic regression, the association between maternal substance use and distress during pregnancy, and wheeze and allergy at age 3 years was determined in boys and girls. After adjusting for alcohol use during pregnancy, pre- and postnatal tobacco use, preterm birth, duration of exclusive breastfeeding, daycare attendance and maternal socioeconomic status, maternal street drug use during pregnancy [odds ratio (OR): 5.02, 95% confidence interval (CI): 1.30-19.4] and severe maternal distress during pregnancy (OR: 5.79, 95% CI: 1.25-26.8) were associated with wheeze in girls. In boys, an independent association was found between severe distress during pregnancy (OR: 3.85, 95% CI: 1.11-13.3) and allergies, but there was no association with maternal street drug use. In conclusion, we found an association between maternal street drug use and wheeze in preschool girls that could not be accounted for by maternal distress, smoking or alcohol use during pregnancy. Prenatal programming effects of street drugs may explain this association.


Interleukin-6 family of cytokines mediates isoproterenol-induced delayed STAT3 activation in mouse heart.
This study was aimed to determine whether beta-adrenergic receptor (beta-AR) stimulated by isoproterenol (ISO) activates signal transducers and activators of transcription (STAT) in mouse heart and, if so, to examine the underlying mechanism. We found that treatment of adult male mice by ISO (15 mg/kg body weight, intraperitoneal) caused a delayed STAT3 activation (at 60-120 min), which was fully abolished by beta-AR antagonist, propranolol. ISO-induced phosphorylation of STAT3 was markedly enhanced by phosphodiesterase inhibitor amrinone, indicating that cAMP is critically involved in beta-AR-mediated STAT3 activation. In addition, beta-AR stimulation significantly increased gene expression of interleukin-6 (IL-6) family of cytokines (IL-6, leukemia inhibitory factor, ciliary neurotrophic factor, and cardiotrophin-1). IL-6 protein levels in serum and mouse myocardium were also significantly increased in response to ISO treatment. In cultured cardiac fibroblasts, IL-6 level was enhanced significantly after ISO (10-6 mol/liter) stimulation for 2 h and then peaked at 12 h, whereas the response of IL-6 in cultured cardiomyocytes to ISO stimulation was not significant, suggesting that ISO-induced increase in IL-6 is primarily from cardiac fibroblasts rather than cardiomyocytes. Most importantly, IL-6 could activate STAT3 in a time-dependent manner in cultured cardiomyocytes, and inhibition of IL-6 level by anti-IL-6-neutralizing antibody clearly attenuated ISO-induced phosphorylation of STAT3 in myocardium. Taken together, these results indicate that beta-AR stimulation leads to a delayed STAT3 activation via an IL-6 family of cytokine-mediated pathway and that cardiac fibroblasts, but not cardiomyocytes, is probably the predominant source of IL-6 in response to ISO stimulation in mouse myocardium.


Approaches for preparation methods of Murakkab, an Unani formulation.
Murakkab drugs of Unani medicine have remained an important aspect of disease treatment since antiquity. Physicians prepared different formulations for various diseases. The formulations thus prepared have always been of two categories. One category of Murakkab drugs was those which were formulated empirically and remained in use without conceptual framework behind these formulations. These formulations were categorized as Mujarrab (tested) formulations. The other category of formulations was prepared in consideration with theoretical framework of Mizaj (temperament) and Usoole ilaj (treatment strategy) and then tested by physicians. This category forms a large chunk of formulations in the formulary sections of the literature of Unani medicine. Present paper explores various approaches for formulating Murakkab drugs of the second category keeping in view the actions of the ingredients of the drug formulation, and treatment strategy of the disease for which the formulation was prepared. It elucidates the approaches of formulating compound drug formulations with the logic of including various individual ingredients. The study exemplifies two compound formulations to illustrate the approaches used to formulate compound formulations of Unani medicine.


Local expression of interleukin-27 ameliorates collagen-induced arthritis.
To determine the mechanism of action of interleukin-27 (IL-27) against rheumatoid arthritis (RA). Adenovirus containing IL-27 transcript was constructed and was locally delivered into the ankles of mice with collagen-induced arthritis (CIA). Progression of arthritis was determined in treated and untreated mice by measuring ankle circumference and through histologic analysis. IL-17 and its downstream targets as well as cytokines promoting Th17 cell differentiation were quantified by enzyme-linked immunosorbent assay in CIA mouse ankles locally expressing adenoviral IL-27 as well as in control-treated mouse ankles. Ankles from both treatment groups were immunostained for neutrophil and monocyte migration (macrophages in the tissue). Finally, vascularization was quantified by histology and by determining ankle hemoglobin levels. Ectopic expression of IL-27 in CIA mice ameliorated inflammation, lining hypertrophy, and bone erosion as compared with control-treated CIA mice. Serum and joint levels of IL-17 were significantly reduced in the IL-27-treated group compared with the control-treated group. Two of the main cytokines that induce Th17 cell differentiation and IL-17 downstream target molecules were greatly down-regulated in CIA mouse ankles receiving forced expression of IL-27. The control mice had higher levels of vascularization and monocyte trafficking than did mice ectopically expressing IL-27. Our results suggest that increased levels of IL-27 relieve arthritis in CIA mouse ankles. This amelioration of arthritis involves a reduction in CIA mouse serum and joint levels of IL-17 and results in decreased IL-17-mediated monocyte recruitment and angiogenesis. Hence, the use of IL-27 may be a strategy for treatment of patients with RA.


[Monoclonal immunoglobulinopathy in chronic active hepatitis and liver cirrhosis].
The clinico-laboratory and morphological studies were performed to examine and characterize 15 patients with chronic active hepatitis and liver cirrhosis mainly of viral etiology, going in association with monoclonal immunoglobulinopathy. The diagnostic difficulties determined by the syndrome of monoclonal immunoglobulinopathy are demonstrated. The results of a long follow-up (up to 17 years) of the indicated patients' group are provided. A possible role is discussed of hepatitis B virus as a source of long antigenic stimulation in the origin of monoclonal immunoglobulinopathy in chronic diffuse diseases of the liver.


Deformation mechanisms based on the multiscale molecular dynamics of a gradient TA1 titanium alloy.
The heterogeneous gradient TA1 titanium alloy holds great potential for a wide range of industrial applications. Considering the influence of the gradient structure on the plastic deformation behavior of the material, the TA1 gradient polycrystalline model under uniaxial compression is established. The deformation behavior of TA1 gradient polycrystals under uniaxial compression is investigated by molecular dynamics simulation. The simulation shows that there is significant transmission during the plastic deformation of TA1 gradient polycrystals. The transmissibility of plastic deformation is specified by the alternating appearance of twinning and grain refinement. Besides, the uniaxial compression process is accompanied by active dislocation motions. Moreover, the movement of dislocations is a dynamic cyclic process. In the same uniaxial compression environment, the triggering of the plasticity mechanism in the gradient polycrystalline model is closely related to grain size. The smaller grain size crystals hardly produce plastic deformation. Grain boundary migration of medium grain size crystals dominates in plastic deformation. The proliferation of dislocations under compressive stress is the primary trigger mechanism in larger grain size crystals. In addition, the stress concentration phenomenon in regions with medium grain sizes is more significant than that in regions with larger and small grain sizes.


Prenatal sonographic diagnosis of cleidocranial dysostosis.
Cleidocranial dysostosis is an autosomal dominant disorder characterized by absence or hypoplasia of the clavicles, skull abnormalities, and abnormal dentition. The prenatal diagnosis of this condition has been reported once previously in a known high-risk pregnancy. In this report we describe the prenatal findings of cleidocranial dysostosis at 19 weeks' gestation in a woman affected with this disorder but undiagnosed before the fetal scan. This report is unique in the sense that an autosomal dominant condition diagnosed in the fetus led to a similar diagnosis in the mother.


Remarkable response to fluorouracil, leucovorin, oxaliplatin, and irinotecan therapy in urothelial cancer of the renal pelvis: a case report.
No standard chemotherapy regimen for advanced urothelial cancer has been established, except for cisplatin-based regimens. We report the case of a patient with double primary cancer, urothelial carcinoma of the upper urinary tract and colorectal cancer, who underwent oxaliplatin-based chemotherapies. A 56-year-old Japanese man presented to our hospital with the diagnosis of a left renal pelvic tumor and rectal cancer. Several examinations including ureteroscopic biopsy and computed tomography-guided biopsy were performed; however, the diagnosis of renal pelvic cancer could not be made. Because the rectal cancer had been growing during the course of examination, he underwent five cycles of neoadjuvant chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan. The volumes of both the rectal cancer and renal pelvic tumor drastically decreased. He then underwent pelvic evisceration with colostomy and ureterocutaneostomy. The histological diagnosis of the renal pelvic tumor was urothelial carcinoma. He is free of disease at 12 months after the treatment. To the best of our knowledge, this is the first report describing a remarkable response to fluorouracil, leucovorin, oxaliplatin, and irinotecan therapy for renal pelvic cancer. We suggest fluorouracil, leucovorin, oxaliplatin, and irinotecan is an effective therapy for patients with advanced urothelial cancer.