Cesarean delivery rates and neonatal morbidity in a low-risk population.
To estimate the relationship between case-mix adjusted cesarean delivery rates and neonatal morbidity and mortality in infants born to low-risk mothers. This retrospective cohort study used vital and administrative data for 748,604 California singletons born without congenital abnormalities in 1998-2000. A total of 282 institutions was classified as average-, low-, or high-cesarean delivery hospitals based on their cesarean delivery rate for mothers without a previous cesarean delivery, in labor at term, with no evidence of maternal, fetal, or placental complications. Neonatal mortality, diagnoses, and therapeutic interventions determined by International Classification of Diseases, 9th Revision, Clinical Modification codes, and neonatal length of stay were compared across these hospital groupings. Compared with average-cesarean delivery-rate hospitals, infants born to low-risk mothers at low-cesarean delivery hospitals had increased fetal hemorrhage, birth asphyxia, meconium aspiration syndrome, feeding problems, and electrolyte abnormalities (P <.02). Infused medication, pressors, transfusion for shock, mechanical ventilation, and length of stay were also increased (P <.001). This suggests that some infants born in low-cesarean delivery hospitals might have benefited from cesarean delivery. Infants delivered at high-cesarean delivery hospitals demonstrated increased fetal hemorrhage, asphyxia, birth trauma, electrolyte abnormalities, and use of mechanical ventilation (P <.001), suggesting that high cesarean delivery rates themselves are not protective. Neonatal morbidity is increased in infants born to low-risk women who deliver at both low- and high-cesarean delivery-rate hospitals. The quality of perinatal care should be assessed in these outlier hospitals. III


Columnar cell lesions of the breast: mammographic and US features.
Columnar cell lesions are being encountered with increasing frequency in breast biopsies performed. The purpose of our study was to determine whether columnar cell lesions of the breast have any distinctive imaging characteristics. We retrospectively reviewed our institutional database for all records of breast pathology obtained in a 17-month period. Columnar cell lesion was diagnosed in 53 lesions and 12 of these 53 lesions contained columnar cell lesions as the sole histopathologic findings. These 12 lesions in nine patients made up our study population. They included columnar cell change (n=4), columnar cell hyperplasia (n=5), and columnar cell hyperplasia with atypia (n=3). All nine patients underwent mammography and sonography within 1 month of each other. Of the mammograms in nine patients, nine lesions (75%) appeared as clustered amorphous or indistinct (n=5), fine pleomorphic (n=3), or round (n=1) microcalcifications. The tenth lesion showed a focal mass without microcalcifications and the remaining two lesions showed no abnormal findings. At sonography, not-circumscribed masses were depicted in six lesions and microcalcifications were visible in four lesions, of which three lesions were concurrent with masses. There were no sonographically focal lesions in the remaining five. Overall 11 lesions were classified as BI-RADS category 4 (92%) and one as category 3. Of the three lesions with atypia, two were classified as category 4a and one was classified as category 4c, and they showed no distinct imaging appearance from those without atypia. Columnar cell lesions usually present as nonpalpable, clustered indeterminate or suspicious microcalcifications on mammography. They are indistinguishable from other causes of suspicious microcalcifications such as atypical ductal hyperplasia or ductal carcinoma in situ and require needle biopsy or excisional biopsy for diagnosis.


Changes in sexual function among midlife women: "I'm older… and I'm wiser".
Women experience a variety of changes at midlife that may affect sexual function. Qualitative research approaches can allow a deeper understanding of women's experiences. We conducted 20 individual interviews and three focus groups among sexually active women aged 45 to 60 years (total n = 39) to explore how sexual function changes during midlife. Interviews and focus groups were conducted by a trained facilitator using a semistructured guide. All data were audio-recorded and transcribed. Two investigators used a subsample of data to iteratively develop a codebook. The primary investigator coded all data. A second investigator coded a randomly selected 25% of interviews. Codes regarding changes in sexual function were examined and key themes emerged. The mean age was 52, and most women were peri- or postmenopausal. Fifty-four per cent of women were white, 36% black, and 10% of another race. Participants discussed positive and negative changes in sexual function. The most common negative changes were decreased frequency of sex, low libido, vaginal dryness, and anorgasmia. Participants attributed negative changes to menopause, partner issues, and stress. Most participants responded to negative changes with adaptation, including changing sexual behavior and prioritizing different aspects of sex. Participants also reported positive changes, attributed to higher self-confidence, increased self-knowledge, and better communication skills with aging. In this qualitative study, women described experiencing both positive and negative changes in sexual function during midlife. When negative changes occurred, women often adapted behaviorally and psychologically. Providers should recognize that each woman's experience is unique and nuanced, and they should provide tailored care regarding sexual function at midlife.


Effects of D-002, a product isolated from beeswax, on gastric symptoms of patients with osteoarthritis treated with piroxicam: a pilot study.
Non-steroidal anti-inflammatory drugs (NSAIDs) are indicated for treatment of rheumatoid arthritis and osteoarthritis, but often induce gastric adverse experiences (AE), including gastric ulcers and complications. Inhibitors of proton pump and H(2) antagonists are very effective for duodenal ulcer; meanwhile, cytoprotective drugs are more effective for gastric ulcer. D-002 is a mixture of higher aliphatic alcohols obtained from beeswax, wherein triacontanol is the most abundant. D-002 induces anti-ulcer effects through a cytoprotective mechanism, being more effective in protecting against ethanol- and NSAID-induced ulcers. The present double-blind, placebo-controlled clinical study was undertaken to investigate the effects of D-002 on gastric symptoms associated to piroxicam use on patients suffering osteoarthritis. Fifty-nine patients, all taking piroxicam, 20 mg/day, were randomized to placebo or D-002 (40 or 100 mg/day) for 14 days. The primary efficacy variable was the reduction on the frequency of patients with gastric AE compared with placebo. Pain evolution was investigated to discard any influence on D-002 on the analgesic effect of piroxicam. The frequency of patients treated with D-002, 40 and 100 mg/day, reporting acidity [0 of 18 (0%) and 1 of 21 (4.8%), respectively] was lower (P < .05) than in placebo [6 of 20 (30%)]. Also, the frequency of patients treated with 100 mg/day reporting some gastric AE [5 of 21 (23.8%)] was lower (P < .05) than in placebo [13 of 20 (65.0%)]. The analgesic effect of piroxicam was unaffected with D-002. Treatment was well tolerated. Two patients discontinued from the study because of gastrointestinal AE: one in the placebo group and the other treated with D-002, 40 mg/day. Other three patients discontinued because of other AE: mildly uncontrolled hypertension (one in the placebo group, one treated with D-002, 40 mg/day) and headache (one treated with D-200, 100 mg/day). It is concluded that D-002 could be useful for controlling gastric AE of patients treated with NSAIDs, although further studies with a larger sample size and longer follow-up are needed for definitive conclusions.


Vision therapy improves binocular visual dysfunction in patients with mild traumatic brain injury.
To evaluate benefits of binocular vision and ocular motility training in patients with long-term sequelae after mild traumatic brain injury (mTBI). Twenty-eight mTBI (concussion) patients from 25 to 61 years of age with oculomotor dysfunction were selected by optometric examination. The vision therapy was designed to improve convergence, pursuit and saccades as well as to increase fusional reserves. The vision therapy was conducted by a neurooptometrist and a speech therapist, and took place weekly for 1 hour during 10 continuous weeks. Between vision training sessions, patients trained at home for 15-20 minutes daily. Before and after vision therapy, patients completed a test battery including the Groffman Visual Tracing Test, King-Devick test (K-D), a reading speed test, Multidimensional Fatigue Inventory (MFI-20) and patient interviews based on a modified version of the Canadian Occupational Performance Measure (COPM). Twenty-seven patients completed the vision therapy. After the therapy, improvements were measured on all test parameters, e.g. Groffman Visual Tracing Test (p < 0.05), K-D-Test (p = 0.01), Reading Speed Test (p < 0.01) and MFI-20 total (p < 0.05). The results for the modified COPM were significantly improved for both performance and satisfaction (0.0001 < p < 0.01). Vision therapy improved fixation stability and endurance. Reading speed measured by the numbers of saccades and regressions time consumption per read word increased. There was also an improvement in visual attention, possibly making patients safer in traffic and outdoor activities.


Evaluation of a differentiation model of preschoolers' executive functions.
Despite the prominent role of executive functions in children's emerging competencies, there remains debate regarding the structure and development of executive functions. In an attempt to reconcile these discrepancies, a differentiation model of executive function development was evaluated in the early years using 6-month age groupings. Specifically, 281 preschoolers completed measures of working memory, inhibition, and shifting. Results contradicted suggestions that executive functions follow a single trajectory of progressive separation in childhood, instead suggesting that these functions may undergo a period of integration in the preschool years. These results highlight potential problems with current practices and theorizing in executive function research.


SIDMA as a criterion for psychiatric compulsion: An analysis of compulsory treatment orders in Scotland.
Scottish mental health legislation includes a unique criterion for the use of compulsion in the delivery of mental health care and treatment. Under the Mental Health (Care and Treatment) (Scotland) Act, 2003, patients must exhibit 'significantly impaired decision-making ability' (SIDMA) in order to be eligible for psychiatric detention or involuntary psychiatric treatment outside the forensic context. The SIDMA requirement represents a distinctive strategy in ongoing international efforts to rethink the conditions under which psychiatric compulsion is permissible. We reconstruct the history of the Scottish SIDMA requirement, analyse its differences from so-called 'fusion law,' and then examine how the SIDMA standard actually functions in practice. We analyse 100 reports that accompany applications for Compulsory Treatment Orders (CTOs). Based on this analysis, we provide a profile of the patient population that is found to exhibit SIDMA, identify the grounds upon which SIDMA is attributed to individual patients, and offer an assessment of the quality of the documentation of SIDMA. We demonstrate that there are systemic areas of poor practice in the reporting of SIDMA, with only 12% of CTOs satisfying the minimum standard of formal completeness endorsed by the Mental Welfare Commission. We consider what lessons might be drawn both for the ongoing review of mental health legislation in Scotland, and for law reform initiatives in other jurisdictions.


[Anatomical aspects of the arteria inferior posterior cerebelli for posterior fossa surgery].
As the arteria inferior posterior cerebelli sometimes causes surprises of grave consequence at surgical approaches, its origin and course had to be described in detail. For this aim, we especially considered the local relationships of this artery with the medulla oblongata and the cranial nerves of the posterior fossa. Branches of the a. inferior posterior cerebelli supplying the medulla oblongata have been noticed in relation to the arterial supply of the medulla oblongata by corresponding vessels and the aa. spinales lateralis and posterior with special reference to all the possible collateralizations.


Bioassay-Guided Isolation, Metabolic Profiling, and Docking Studies of Hyaluronidase Inhibitors from Ravenala madagascariensis.
Hyaluronidase enzyme (HAase) has a role in the dissolution or disintegration of hyaluronic acid (HA) and in maintaining the heathy state of skin. Bioassay-guided fractionation of Ravenala madagascariensis (Sonn.) organ extracts (leaf, flower, stem, and root) testing for hyaluronidase inhibition was performed followed by metabolic profiling using LC-HRMS. Additionally, a hyaluronidase docking study was achieved using Molecular Operating Environment (MOE). Results showed that the crude hydroalcoholic (70% EtOH) extract of the leaves as well as its n-butanol (n-BuOH) partition showed higher HAase activity with 64.3% inhibition. Metabolic analysis of R. madagascariensis resulted in the identification of 19 phenolic compounds ranging from different chemical classes (flavone glycosides, flavonol glycosides, and flavanol aglycones). Bioassay-guided purification of the leaf n-BuOH partition led to the isolation of seven compounds that were identified as narcissin, rutin, epiafzelechin, epicatechin, isorhamnetin 7-O-glucoside, kaempferol, and isorhamnetin-7-O-rutinoside. The docking study showed that narcissin, rutin, and quercetin 3-O-glucoside all interact with HAase through hydrogen bonding with the Asp111, Gln271, and/or Glu113 residues. Our results highlight Ravenala madagascariensis and its flavonoids as promising hyaluronidase inhibitors in natural cosmetology preparations for skin care.


Spontaneous and evoked glutamate release activates two populations of NMDA receptors with limited overlap.
In a synapse, spontaneous and action-potential-driven neurotransmitter release is assumed to activate the same set of postsynaptic receptors. Here, we tested this assumption using (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801), a well characterized use-dependent blocker of NMDA receptors. NMDA-receptor-mediated spontaneous miniature EPSCs (NMDA-mEPSCs) were substantially decreased by MK-801 within 2 min in a use-dependent manner. In contrast, MK-801 application at rest for 10 min did not significantly impair the subsequent NMDA-receptor-mediated evoked EPSCs (NMDA-eEPSCs). Brief stimulation in the presence of MK-801 significantly depressed evoked NMDA-eEPSCs but only mildly affected the spontaneous NMDA-mEPSCs detected on the same cell. Optical imaging of synaptic vesicle fusion showed that spontaneous and evoked release could occur at the same synapse albeit without correlation between their kinetics. In addition, modeling glutamate diffusion and NMDA receptor activation revealed that postsynaptic densities larger than approximately 0.2 microm(2) can accommodate two populations of NMDA receptors with nonoverlapping responsiveness. Collectively, these results support the premise that spontaneous and evoked neurotransmissions activate distinct sets of NMDA receptors and signal independently to the postsynaptic side.


[Dynamics of the microvessel responses in the projection areas of the rat somatosensory cortex].
A mosaic distribution of local cerebral blood flow was found in the rat border cells of the somatosensory brain cortes, as well as development of local functional hyperemia during whisker stimulation. The more intensive the stimulation the shorter were latency and amplitude of the hyperemia. The early phase of the hyperemia seems to be associated with neuronal factors, whereas the late component depended on the endothelium.


Immune consequences of kinase inhibitors in development, undergoing clinical trials and in current use in melanoma treatment.
Metastatic malignant melanoma is a frequently fatal cancer. In recent years substantial therapeutic progress has occurred with the development of targeted kinase inhibitors and immunotherapeutics. Targeted therapies often result in rapid clinical benefit however responses are seldom durable. Immune therapies can result in durable disease control but responses may not be immediate. Optimal cancer therapy requires both rapid and durable cancer control and this can likely best be achieved by combining targeted therapies with immunotherapeutics. To achieve this, a detailed understanding of the immune consequences of the various kinase inhibitors, in development, clinical trial and currently used to treat melanoma is required.


Neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data.
Neuraxial drugs provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improves analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by the addition of clonidine, ketamine, neostigmine, or tramadol to single-shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side effects, and follow-up. Current data related to benefits and complications in neonates and infants are summarized, but variability in current neuraxial drug use reflects the relative lack of high-quality evidence. Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. However, the developing spinal cord is also vulnerable to drug-related toxicity, and although there are well-established preclinical models and criteria for assessing spinal cord toxicity in adult animals, until recently there had been no systematic evaluation during early life. Therefore, in the second half of this review, we present preclinical data evaluating age-dependent changes in the pharmacodynamic response to different spinal analgesics, and recent studies evaluating spinal toxicity in specific developmental models. Finally, we advocate use of neuraxial drugs with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation before adoption of new analgesics or preparations into routine clinical practice.


[Pathophysiology of acute lung injury in severe burn and smoke inhalation injury].
This review article describes the pathophysiological aspects of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), induced by combined burn and smoke inhalation and examines various therapeutic approaches. The injury results in a fall in arterial oxygenation as a result of airway obstruction, increased pulmonary transvascular fluid flux and loss of hypoxic pulmonary vasoconstriction. The changes in cardiopulmonary function are mediated by reactive oxygen and nitrogen species. Nitric oxide (NO) is generated by both inducible and constitutive isoforms of nitric oxide synthase (NOS). Recently, neuronal NOS emerged as a major component within the pathogenesis of ARDS. NO rapidly combines with the oxygen radical superoxide to form reactive and highly toxic nitrogen species such as peroxynitrite. The control of NO formation involves poly(ADP-ribose) polymerase and its ability to up-regulate the activity of nuclear transcription factors through ribosylation. In addition, present data support a major role of the bronchial circulation in the injury, as blockage of bronchial blood flow will also minimize the pulmonary injury. Current data suggest that cytotoxins and activated cells are formed in the airway and carried to the parenchyma.


[Biosynthesis of immunoglobin G in a cell-free system].
Optimal conditions are selected to study biosynthesis of proteins by the microsomal cell-free system. It is established that incorporation of the radioactive precursor into anew synthesized proteins by microsomes decreases in a series: the liver, spleen, lymph nodes, bone marrow. It is shown that under malignant growth considerably higher amount of protein with the antigenic properties of immunoglobulin C is synthesized in the spleen of leukemic rats than in other organs of control leukemic animals.


[Polychemotherapy combined with low-intensity laser therapy in treating patients with renal tuberculosis].
A prospective study of 150 patients with verified nephrotuberculosis has demonstrated feasibility of essential expansion of the therapeutic limit and of 1/3 reduction in the number of operations due to adjuvant radiation with low-intensity laser beam used in a complex of etiopathogenetic treatment of the urinary system.


Accelerometer-Measured Moderate to Vigorous Physical Activity and Incidence Rates of Falls in Older Women.
To examine whether moderate to vigorous physical activity (MVPA) measured using accelerometry is associated with incident falls and whether associations differ according to physical function or history of falls. Prospective study with baseline data collection from 2012 to 2014 and 1 year of follow-up. Women's Health Initiative participants living in the United States. Ambulatory women aged 63 to 99 (N = 5,545). Minutes of MVPA per day measured using an accelerometer, functional status measured using the Short Physical Performance Battery (SPPB), fall risk factors assessed using a questionnaire, fall injuries assessed in a telephone interview, incident falls ascertained from fall calendars. Incident rate ratios (IRRs) revealed greater fall risk in women in the lowest quartile of MVPA compared to those in the highest (IRR = 1.18, 95% confidence interval = 1.01-1.38), adjusted for age, race and ethnicity, and fall risk factors. Fall rates were not significantly associated with MVPA in women with high SPPB scores (9-12) or one or fewer falls in the previous year, but in women with low SPPB scores (≤ 8) or a history of frequent falls, fall rates were higher in women with lower MVPA levels than in those with higher levels (interaction P < .03 and < .001, respectively). Falls in women with MVPA above the median were less likely to involve injuries requiring medical treatment (9.9%) than falls in women with lower MVPA levels (13.0%) (P < .001). These findings indicate that falls are not more common or injurious in older women who engage in higher levels of MVPA. These findings support encouraging women to engage in the amounts and types of MVPA that they prefer. Older women with low physical function or frequent falls with low levels of MVPA are a high-risk group for whom vigilance about falls prevention is warranted.


Arsenic induces oxidative stress, sphingolipidosis, depletes proteins and some antioxidants in various regions of rat brain.
To seek an interrelationship, if any, between oxidant stress and neurochemical changes in various rat brain regions after arsenic exposure. This study was carried out at the Department of Biochemistry, Al Arab Medical University, Benghazi, Libya. Seventy five male Spraque-Dawley rats were divided into three groups: Rats were administered 2 ml of normal saline solution/kg body weight (b.wt.) daily for 20 days by intraperitoneal (i.p.) route. ARSENIC-TREATED GROUP: Rats received elemental arsenic (as sodium arsenate) 2.0 mg/kg b.wt. daily for 20 days by i.p. route. RECOVERY GROUP: Rats received 2.0 mg/kg b.wt. elemental arsenic daily for 20 days by i.p. route and were allowed to recover for 20 days. Rats were sacrificed and brains were dissected into cerebral cortex, corpus striatum, cerebellum and brain stem. Tissue homogenized in respective mediums. And were analyzed for lipid classes, oxidative stress, concentration of proteins, glutathione and ascorbic acid by utilizing standard colorimetric procedures. Arsenic exposure increased the oxidant stress because lipid peroxidation was enhanced. And decreased the contents of lipid classes, proteins, glutathione and the ascorbic acid in various rat brain regions. However, thins-layer chromatography exhibited regional variations in phospholipids classes. These results suggested that arsenic-initiated oxidant stress by increasing lipid peroxidation. The losses of lipid classes, ascorbic acid and glutathione may be attributed to peroxidative damage and binding of arsenic with sulfhydryl groups of enzymes. Recovery of animals showed reversibility in most of studied parameters, but gangliosides and cerebrosides over shooted. And speculated "Sphingolipidosis". It is then likely that repeated exposures of humans to arsenic may result in hampering of cell signalling, apoptosis and mutagenesis.


Comparison of metabolic effects of orlistat and sibutramine treatment in Type 2 diabetic obese patients.
The aim of our study was to comparatively evaluate the efficacy and safety of orlistat and sibutramine treatment in obese diabetic patients of both sexes, with specific attention to metabolic pattern-induced changes and cardiovascular effects. Patients were enrolled, evaluated, and followed in 3 Italian Centres of Internal Medicine. We evaluated 144 obese diabetic patients. All were required to have been diagnosed as being diabetic for at least 6 months, and had glycaemic control with diet alone or diet and oral hypoglycaemic agents. We administered orlistat (360 mg/d) or sibutramine (10 mg/d) in a randomized, controlled, double-blind clinical study, and evaluated anthropometric variables, glycaemic control, blood pressure and heart rate (HR) during 12 months of this treatment. A total of 141 (69 males and 72 females; 35 males and 36 females, aged 53 +/- 5 yr with orlistat; 34 males and 36 females, aged 51 +/- 4 yr with sibutramine) completed the 4 weeks on controlled-energy diet and were randomized to double-blind treatment with orlistat (n=71) or sibutramine (n=70). Significant body mass index (BMI) improvement was present after 6 (p<0.05), 9 (p<0.02), and 12 (p<0.01) months in both groups. Significant waist circumference (WC), hip circumference (HC), and waist/hip ratio (W/H ratio) improvement was observed after 12 months (p<0.05, respectively) in both groups. Significant HbA1c decrease was obtained after 6 (p<0.05), 9 (p<0.02), and 12 (p<0.01) months in both groups. After 9 and 12 months, mean fasting plasma glucose (FPG) and post-prandial plasma glucose (PPG) levels were significantly decreased in both groups (p<0.05 andp<0.02, respectively). Significant systolic blood pressure (SBP) and diastolic blood pressure (DBP) improvement (p<0.05) was present in the orlistat group after 12 months. No significant change in blood pressure measurements was observed in the sibutramine group during the study. No significant HR variation was obtained during the study in either group. Of the 133 patients who completed the study, 33.8% of patients in the orlistat group and 13.2% of patients in the sibutramine group had side effects (p<0.05 vs orlistat group). Side effect profiles were different in the two treatmen groups. All orlistat side effects were gastrointestinal events. Sibutramine caused an increase in blood pres sure (both SBP and DBP) in one patient, but it was controlled by anti-hypertensive treatment. The vita min changes were small and all mean vitamin and beta-carotene values stayed within reference ranges. No patients required vitamin supplementation. Both orlistat and sibutramine were effective on anthropometric variables and on metabolic pattern during the 12-month treatment; in our sample, orlistat appears to be slightly more efficacious as an anti-obesity drug, while sibutramine intake was not associated to any cardiovascular effect and was generally better tolerated than orlistat.


Characterization of the Medicago truncatula cell wall proteome in cell suspension culture upon elicitation and suppression of plant defense.
In addition to establishing methods for proteome analysis of cell wall proteins (CWPs) for the model plant Medicago truncatula, this work highlights the presence of several protein classes in cell culture. Using a combination of two-dimensional gel electrophoresis (2D-PAGE) and/or liquid chromatography-tandem mass spectrometry (LC-MS/MS), we established the proteome reference map of M. truncatula cell wall proteins. CWPs extracted from purified cell wall fragments resulted in the identification of 46 (2D-PAGE) and 65 (LC-MS/MS) proteins, respectively, with a total of 111 proteins. The identified proteins are involved in various processes, including cell wall modifications, signaling, defense mechanisms, membrane transport, protein synthesis and processing. Further, we conducted comparative proteome analysis to identify changes in protein composition during interaction of M. truncatula cell suspension culture with a pathogen-derived yeast elicitor (YE) and suppressor using Sinorhizobium meliloti LPS. 2D-PAGE analysis for the CWPs after YE and LPS treatment resembled the proteome map of YE alone, with a few up-regulated proteins involved in defense, and in the case of the LPS-treated cell wall proteome, there was no significant difference observed. Using this approach, proteins involved in defense, such as l-ascorbate peroxidase, specifically targeted proteins to the cell wall during defense, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and proteins that play an important role during growth and development were identified. Also, some defense-related proteins were absent in the same gel after YE treatment, suggesting that oxidant protection is regulated by these proteins.


Diabetes clinical trials: helped or hindered by the current shift in regulatory requirements?
Glycaemic control is an inadequate surrogate marker of cardiovascular event reduction in patients with type 2 diabetes. Clinical trials to date have been unsuccessful in identifying a therapeutic approach that addresses the underlying problem in diabetes (glycaemic control) and reduces cardiovascular risk. The potential for some agents to increase the risk of cardiovascular events has led to substantial changes in regulatory requirements for new anti-diabetic therapies. These requirements, while key to ensuring the cardiovascular safety of new agents, fail to emphasize the need to show clinical benefits, such as less visual impairment, less need for dialysis, or fewer cardiovascular events and deaths. Changes in test results such as glycaemic control, serum creatinine, micro-albuminuria, or retinopathy are inadequate surrogates. Regulators should consider the potential advantages of offering extended patent protection in order to encourage companies to conduct long-term trials in diabetes and many other chronic medical conditions. Cooperative efforts among physicians, clinical trialists, regulators, and sponsors are needed to address unresolved issues including re-defining therapeutic targets that are meaningful to patients with diabetes, determining the appropriate length of follow-up for future trials, and considering the ethical and operational challenges of non-inferiority designs.


[Intrathoracic migration of Kirschner wires].
Orthopedic surgeons apply metallic pins to stabilize the clavicule and humerus on a daily basis. Migration of these pins into the thoracic cavity is rare. We present the case of an elderly female patient, whose right humeroscapular joint was fixed with Kirschner wires due to recurrent luxation. Six weeks later, a follow-up X-ray revealed that the pins have migrated into the right thoracic cavity, confirmed by a CT chest. Videothoracoscopic removal of the metallic pins was not possible because of dense adhesions. Right anterolateral thoracotomy was carried out, and after pneumolysis one pin was taken out from the 2nd lung segment. The other one, which was running along the cupola and entering the spinal cord, was also removed. There was no postoperative surgical complication. The authors review the literature of this rare complication and point out that pins migrating into the thoracic cavity should be removed to avoid life threatening complications.


Leptin regulates the reward value of nutrient.
We developed an assay for quantifying the reward value of nutrient and used it to analyze the effects of metabolic state and leptin. In this assay, mice chose between two sippers, one of which dispensed water and was coupled to optogenetic activation of dopaminergic (DA) neurons and the other of which dispensed natural or artificial sweeteners. This assay measured the reward value of sweeteners relative to lick-induced optogenetic activation of DA neurons. Mice preferred optogenetic stimulation of DA neurons to sucralose, but not to sucrose. However, the mice preferred sucralose plus optogenetic stimulation versus sucrose. We found that food restriction increased the value of sucrose relative to sucralose plus optogenetic stimulation, and that leptin decreased it. Our data suggest that leptin suppresses the ability of sucrose to drive taste-independent DA neuronal activation and provide new insights into the mechanism of leptin's effects on food intake.


A theoretical model for the Gla-TSR-EGF-1 region of the anticoagulant cofactor protein S: from biostructural pathology to species-specific cofactor activity.
Protein S (PS), which functions as a species-specific anticoagulant cofactor to activated protein C (APC), is a mosaic protein that interacts with the phospholipid membrane via its gamma-carboxyglutamate-rich (Gla) module. This module is followed by the thrombin-sensitive region (TSR), sensitive to thrombin cleavage, four epidermal growth factor (EGF)-like modules and a last region referred to as the sex hormone binding globulin (SHBG) domain. Of these, the TSR and the first EGF-like regions have been shown to be important for the species-specific interaction with APC. Difficulties in crystallising PS have so far hindered its study at the atomic level. Here, we report theoretical models for the Gla and EGF-1 modules of human PS constructed using prothrombin and factor X experimental structures. The TSR was built interactively. Analysis of the model linked with the large body of biochemical literature on PS and related proteins leads to suggestions that (i) the TSR stabilises the calcium-loaded Gla module through hydrophobic and ionic interactions and its conformation depends on the presence of the Gla module; (ii) the TSR does not form a calcium binding site but is protected from thrombin cleavage in the calcium-loaded form owing to short secondary structure elements and close contact with the Gla module; (iii) the PS missense mutations in this region are consistent with the structural data, except in one case which needs further investigation; and (iv) the two PS 'faces' involving regions of residues Arg49-Gln52-Lys97 (TSR-EGF-1) and Thr103-Pro106 (EGF-1) may be involved in species-specific interactions with APC as they are richer in nonconservative substitution when comparing human and bovine protein S. This preliminary model helps to plan future experiments and the resulting data will be used to further validate and optimise the present structure.


A Middle Jurassic 'sphenosuchian' from China and the origin of the crocodylian skull.
The skull of living crocodylians is highly solidified and the jaw closing muscles are enlarged, allowing for prey capture by prolonged crushing between the jaws. Living species are all semi-aquatic, with sprawling limbs and a broad body that moves mainly from side-to-side; however, fossils indicate that they evolved from terrestrial forms. The most cursorial of these fossils are small, gracile forms often grouped together as the Sphenosuchia, with fully erect, slender limbs; their relationships, however, are poorly understood. A new crocodylomorph from deposits in northwestern China of the poorly known Middle Jurassic epoch possesses a skull with several adaptations typical of living crocodylians. Postcranially it is similar to sphenosuchians but with even greater adaptations for cursoriality in the forelimb. Here we show, through phylogenetic analysis, that it is the closest relative of the large group Crocodyliformes, including living crocodylians. Thus, important features of the modern crocodylian skull evolved during a phase when the postcranial skeleton was evolving towards greater cursoriality, rather than towards their current semi-aquatic habitus.


Modified Criteria for Diagnosing "Cognitive Frailty".
The concept of cognitive frailty has recently been proposed by an International Consensus Group as the presence of physical frailty and cognitive impairment [defined using the Clinical Dementia Ratings (CDR)=0.5], without concurrent dementia. However, CDR is difficult to implement and not often available in epidemiologic studies or busy clinical settings, and an alternative to CDR is required. We suggest an alternative definition of cognitive frailty as: 1) physical frailty, 2) more than 1.5 standard deviation below the mean for age-, gender-, and education-adjusted norms on any cognitive function test (e.g., the Montreal Cognitive assessment test, the Alzheimer's disease assessment scale-cognitive subscale, verbal learning test, Digit Span, Boston Naming Test, Trail Making Test, and Frontal Assessment Battery), and 3) no dependency in instrumental activities of daily living. The redefined criteria for cognitive frailty would be more feasible to implement and thus more applicable in epidemiologic studies and busy clinical settings.


Clinical Outcomes of Inside Stents and Conventional Plastic Stents as Bridge-to-Surgery Options for Malignant Hilar Biliary Obstruction.
The appropriate method of preoperative endoscopic biliary drainage (EBD) for cholangiocarcinoma with hilar biliary obstruction remains controversial. The inside-stent technique is a method of placing plastic stents entirely inside the bile duct. Several studies of patients with unresectable stage have reported longer stent patency compared with conventional endoscopic biliary stenting (EBS). Inside-stent techniques have been introduced as a bridge-to-surgery option and as an alternative to conventional EBS. We aimed to evaluate the clinical outcomes of inside stent use and conventional EBS. During this retrospective multicenter study, we reviewed consecutive patients with cholangiocarcinoma who underwent radical surgery after conventional EBS or inside-stent insertion. Adverse event (AE) rates after EBD and post-surgical AEs were compared. A multivariable analysis was performed to identify factors affecting cholangitis after EBD. Conventional EBS and inside-stent procedures were performed for 56 and 73 patients, respectively. Patient backgrounds were similar between groups, except for percutaneous transhepatic portal vein embolization. The waiting time before surgery was similar between groups (28.5 days vs. 30 days). There were no significant differences in the cholangitis rate (21.4% vs. 26.0%; P = 0.68) and all AEs (25.0% vs. 30.1%; P = 0.56) between groups. The post-surgical AE rate was similar between the groups. The multivariable analysis found that preprocedural cholangitis was a risk factor for cholangitis after EBD (odds ratio: 5.67; 95% confidence interval: 1.61-19.9). The outcomes of inside-stent techniques and conventional EBS for the management of preoperative EBD are comparable for patients with cholangiocarcinoma.


Deletion of the Gene for the Type I Interferon Inhibitor I329L from the Attenuated African Swine Fever Virus OURT88/3 Strain Reduces Protection Induced in Pigs.
Live attenuated vaccines are considered to be the fastest route to the development of a safe and efficacious African swine fever (ASF) vaccine. Infection with the naturally attenuated OURT88/3 strain induces protection against challenge with virulent isolates from the same or closely related genotypes. However, adverse clinical signs following immunisation have been observed. Here, we attempted to increase the OURT88/3 safety profile by deleting I329L, a gene previously shown to inhibit the host innate immune response. The resulting virus, OURT88/3ΔI329L, was tested in vitro to evaluate the replication and expression of type I interferon (IFN) and in vivo by immunisation and lethal challenge experiments in pigs. No differences were observed regarding replication; however, increased amounts of both IFN-β and IFN-α were observed in macrophages infected with the deletion mutant virus. Unexpectedly, the deletion of I329L markedly reduced protection against challenge with the virulent OURT88/1 isolate. This was associated with a decrease in both antibody levels against VP72 and the number of IFN-γ-producing cells in the blood of non-protected animals. Furthermore, a significant increase in IL-10 levels in serum was observed in pigs immunised with OURT88/3ΔI329L following challenge. Interestingly, the deletion of the I329L gene failed to attenuate the virulent Georgia/2007 isolate.


The Foldback-like element Galileo belongs to the P superfamily of DNA transposons and is widespread within the Drosophila genus.
Galileo is the only transposable element (TE) known to have generated natural chromosomal inversions in the genus Drosophila. It was discovered in Drosophila buzzatii and classified as a Foldback-like element because of its long, internally repetitive, terminal inverted repeats (TIRs) and lack of coding capacity. Here, we characterized a seemingly complete copy of Galileo from the D. buzzatii genome. It is 5,406 bp long, possesses 1,229-bp TIRs, and encodes a 912-aa transposase similar to those of the Drosophila melanogaster 1360 (Hoppel) and P elements. We also searched the recently available genome sequences of 12 Drosophila species for elements similar to Dbuz\Galileo by using bioinformatic tools. Galileo was found in six species (ananassae, willistoni, peudoobscura, persimilis, virilis, and mojavensis) from the two main lineages within the Drosophila genus. Our observations place Galileo within the P superfamily of cut-and-paste transposons and extend considerably its phylogenetic distribution. The interspecific distribution of Galileo indicates an ancient presence in the genus, but the phylogenetic tree built with the transposase amino acid sequences contrasts significantly with that of the species, indicating lineage sorting and/or horizontal transfer events. Our results also suggest that Foldback-like elements such as Galileo may evolve from DNA-based transposon ancestors by loss of the transposase gene and disproportionate elongation of TIRs.


Telomere length de novo assembly of all 7 chromosomes and mitogenome sequencing of the model entomopathogenic fungus, Metarhizium brunneum, by means of a novel assembly pipeline.
More accurate and complete reference genomes have improved understanding of gene function, biology, and evolutionary mechanisms. Hybrid genome assembly approaches leverage benefits of both long, relatively error-prone reads from third-generation sequencing technologies and short, accurate reads from second-generation sequencing technologies, to produce more accurate and contiguous de novo genome assemblies in comparison to using either technology independently. In this study, we present a novel hybrid assembly pipeline that allowed for both mitogenome de novo assembly and telomere length de novo assembly of all 7 chromosomes of the model entomopathogenic fungus, Metarhizium brunneum. The improved assembly allowed for better ab initio gene prediction and a more BUSCO complete proteome set has been generated in comparison to the eight current NCBI reference Metarhizium spp. genomes. Remarkably, we note that including the mitogenome in ab initio gene prediction training improved overall gene prediction. The assembly was further validated by comparing contig assembly agreement across various assemblers, assessing the assembly performance of each tool. Genomic synteny and orthologous protein clusters were compared between Metarhizium brunneum and three other Hypocreales species with complete genomes, identifying core proteins, and listing orthologous protein clusters shared uniquely between the two entomopathogenic fungal species, so as to further facilitate the understanding of molecular mechanisms underpinning fungal-insect pathogenesis. The novel assembly pipeline may be used for other haploid fungal species, facilitating the need to produce high-quality reference fungal genomes, leading to better understanding of fungal genomic evolution, chromosome structuring and gene regulation.


High-Performance Production of N-Acetyl-d-Neuraminic Acid with Whole Cells of Fast-Growing Vibrio natriegens via a Thermal Strategy.
High performance is the core objective that biotechnologists pursue, of which low efficiency, low titer, and side products are the chief obstacles. Here, a thermal strategy is proposed for simultaneously addressing the obstacles of whole-cell catalysis that is widely applied in the food industry. The strategy, by combining fast-growing Vibrio natriegens, thermophilic enzymes, and high-temperature whole-cell catalysis, was successfully applied for the high-performance production of N-acetyl-d-neuraminic acid (Neu5Ac) that plays essential roles in the fields of food (infant formulas), healthcare, and medicine. By using this strategy, we realized the highest Neu5Ac titer and productivity of 126.1 g/L and up to 71.6 g/(L h), respectively, 7.2-fold higher than the productivity of Escherichia coli. The major byproduct acetic acid was also eliminated via quenching complex metabolic side reactions enabled by temperature elevation. This study offers a broadly applicable strategy for producing chemicals relevant to the food industry, providing insights for its future development.


Overexpression of Jagged-1 and its intracellular domain in human mesenchymal stromal cells differentially affect the interaction with hematopoietic stem and progenitor cells.
Mesenchymal stromal cells (MSC) are an important component of the bone marrow microenvironment. Notch ligands expressed by MSC are known to play a regulatory role for hematopoietic stem and progenitor cells (HSPC) and in support of bone marrow homeostasis. While the role of Notch signaling in HSPC, their progeny, and MSC has been relatively well studied, little is known about the Notch-independent regulatory impact of Notch ligands on MSC themselves. In the present study, we used genetically engineered bone marrow-derived human MSC to study the function role of Jagged-1 and the Jagged-1 intracellular domain (JICD) with regard to the interaction with HSPC. We demonstrate that Jagged-1 in human MSC undergoes cleavage to produce an intracellular domain that translocates into the nucleus. JICD but not Jagged-1 overexpression was associated with an increased expression of stromal cell-derived factor-1. Short-term co-culture (7 days) of HSPC with JICD-overexpressing MSC, but not with Jagged-1-overexpressing MSC, led to increased proliferation of CD34(+) progenitors. In contrast, long-term co-culture of HSPC with Jagged-1-overexpressing MSC (up to 6 weeks) led to a significantly better support of cobblestone area-forming cells and long-term culture-initiating cells (LTC-ICs) compared with JICD-overexpressing MSC. Taken together, results of this study indicate that full-length Jagged-1 and JICD have differential effects on MSC and on their interaction with HSPC ex-vivo. JICD-overexpressing MSC induce proliferation of HSPCs in short-term culture at the expense of immature precursors (LTC-ICs), whereas Jagged-1 overexpressing MSC favor LTC-IC formation.


A Secure ZUPT-Aided Indoor Navigation System Using Blockchain in GNSS-Denied Environments.
This paper proposes a novel Blockchain-based indoor navigation system that combines a foot-mounted dual-inertial measurement unit (IMU) setup and a zero-velocity update (ZUPT) algorithm for secure and accurate indoor navigation in GNSS-denied environments. The system estimates the user's position and orientation by fusing the data from two IMUs using an extended Kalman filter (EKF). The ZUPT algorithm is employed to detect and correct the error introduced by sensor drift during zero-velocity intervals, thus enhancing the accuracy of the position estimate. The proposed Low SWaP-C blockchain-based decentralized architecture ensures the security and trustworthiness of the system by providing an immutable and distributed ledger to store and verify the sensor data and navigation solutions. The proposed system is suitable for various indoor navigation applications, including autonomous vehicles, robots, and human tracking. The experimental results provide clear and compelling evidence of the effectiveness of the proposed system in ensuring the integrity, privacy, and security of navigation data through the utilization of blockchain technology. The system exhibits an impressive ability to process more than 680 transactions per second within the Hyperledger-Fabric framework. Furthermore, it demonstrates exceptional accuracy and robustness, with a mean RMSE error of 1.2 m and a peak RMSE of 3.2 during a 20 min test. By eliminating the reliance on external signals or infrastructure, the system offers an innovative, practical, and secure solution for indoor navigation in environments where GNSS signals are unavailable.


Continuous ambulatory peritoneal dialysis in children: comparison with hemodialysis.
The clinical and biochemical effects of continuous ambulatory peritoneal dialysis in 20 children and of hemodialysis in 16 children were compared over a 2 1/2-year period. Statistically significant differences between the treatment groups included higher hematocrit, higher serum carbon dioxide and cholesterol levels, large intake of calories and protein, and lower systolic blood pressure and rates of transfusion in the patients receiving continuous ambulatory peritoneal dialysis. These patients had more complications than the patients receiving hemodialysis, but hospitalization rates in the two groups were similar. The cost of continuous ambulatory peritoneal dialysis was +19,600 per patient-year; the cost of hemodialysis was +54,300 per patient-year; the cost of hemodialysis was +54,300 per patient-year. There were four treatment failures with continuous ambulatory peritoneal dialysis and one with hemodialysis. Patients treated with both forms of dialysis preferred continuous ambulatory peritoneal dialysis. We conclude that continuous ambulatory peritoneal dialysis is an important alternative to hemodialysis in children.


Comparison of matrix frequency-doubling technology perimetry and standard automated perimetry in monitoring the development of visual field defects for glaucoma suspect eyes.
Perimetry is indispensable for the clinical management of glaucoma suspects. Our goal is to compare the performance of standard automated perimetry (SAP) and Matrix frequency-doubling technology (FDT) perimetry in monitoring the development of visual field (VF) defects in glaucoma suspect eyes. Longitudinal data of paired SAP and FDT from 221 eyes of 155 glaucoma suspects enrolled in the Diagnostic Innovations in Glaucoma Study or the African Descent and Glaucoma Evaluation Study were included. All eyes had glaucomatous optic neuropathy or ocular hypertension, but normal SAP and FDT results at baseline. The development of glaucomatous VF defects was defined as the presence of a cluster of ≥ 3 (less conservative) or ≥ 4 (more conservative) locations confirmed on ≥ 2 additional consecutive tests. Risk factors for the development of VF defects were analyzed by COX proportional hazard models. After conversion into common logarithmic units, the rates of change of global VF indices were fitted with linear mixed models. FDT detected more eyes that developed VF defects than SAP using the less conservative criterion, and no significant difference was observed using the more conservative criterion. For those eyes detected by both SAP and FDT, FDT detected the development of VF defects either earlier than SAP or simultaneously in most cases. Baseline structural measurements were not significantly associated with an increased risk for the development of glaucomatous VF defects on either SAP or FDT. Older age was significantly associated with the development of VF defects on FDT but not on SAP. Both SAP and FDT detected a progressing worsening trend of pattern standard deviation over time with a similar rate of change between these test types. Matrix FDT would be useful to monitor the onset of VF defects in glaucoma suspects and may outperform SAP in the early stage of glaucomatous VF damage.


Evolution of a mating preference for a dual-utility trait used in intrasexual competition in genetically monogamous populations.
The selection pressures by which mating preferences for ornamental traits can evolve in genetically monogamous mating systems remain understudied. Empirical evidence from several taxa supports the prevalence of dual-utility traits, defined as traits used both as armaments in intersexual selection and ornaments in intrasexual selection, as well as the importance of intrasexual resource competition for the evolution of female ornamentation. Here, we study whether mating preferences for traits used in intrasexual resource competition can evolve under genetic monogamy. We find that a mating preference for a competitive trait can evolve and affect the evolution of the trait. The preference is more likely to persist when the fecundity benefit for mates of successful competitors is large and the aversion to unornamented potential mates is strong. The preference can persist for long periods or potentially permanently even when it incurs slight costs. Our results suggest that, when females use ornaments as signals in intrasexual resource competition, males can evolve mating preferences for those ornaments, illuminating both the evolution of female ornamentation and the evolution of male preferences for female ornaments in monogamous species.


Sensitive test for ion-cyclotron resonant heating in the solar wind.
Plasma carrying a spectrum of counterpropagating field-aligned ion-cyclotron waves can strongly and preferentially heat ions through a stochastic Fermi mechanism. Such a process has been proposed to explain the extreme temperatures, temperature anisotropies, and speeds of ions in the solar corona and solar wind. We quantify how differential flow between ion species results in a Doppler shift in the wave spectrum that can prevent this strong heating. Two critical values of differential flow are derived for strong heating of the core and tail of a given ion distribution function. Our comparison of these predictions to observations from the Wind spacecraft reveals excellent agreement. Solar wind helium that meets the condition for strong core heating is nearly 7 times hotter than hydrogen on average. Ion-cyclotron resonance contributes to heating in the solar wind, and there is a close link between heating, differential flow, and temperature anisotropy.


Simultaneous nitrate and chromium removal mechanism in a pyrite-involved mixotrophic biofilter.
Microbially mediated NO3--N and Cr(VI) reduction is being recognized as an eco-friendly and cost-effective remediation strategy. Iron sulfide mineral, as a natural inorganic electron donor, has a strong influence on NO3--N and Cr(VI) transformation, respectively. However, little is known about the simultaneous nitrate and chromium removal performance and underlying mechanism in an iron sulfide mineral-involved mixotrophic biofilter. This study demonstrated that the NO3--N and Cr(VI) removal efficiencies were stable at 62 ± 8% and 56 ± 10%, and most of them were eliminated in the 0-100-mm region of the biofilter. Cr(VI) was reduced to insoluble Cr(III) via microbial and chemical pathways, which was confirmed by the SEM-EDS morphology and the XPS spectra of biofilm and pyrite particles. SO42- was as a main byproduct of pyrite oxidation; however, the bacterial SO42- reduction synchronously occurred, evidenced by the variations of TOC and SO42- concentrations. These results suggested that there were complicated and intertwined biochemical relations between NO3--N/Cr(VI)/SO42-/DO (electron acceptors) and pyrite/organics (electron donors). Further investigation indicated that both the maximal biomass and greatest denitrifiers' relative abundances in microbial sample S1 well explained why the pollutants were removed in the 0-100-mm region. A variety of denitrifiers such as Pseudoxanthomona, Acidovorax, and Simplicispira were enriched, which probably were responsible for both NO3--N and Cr(VI) removal. Our findings advance the understanding of simultaneous nitrate and chromium removal in pyrite-involved mixotrophic systems and facilitate the new strategy development for nitrate and chromium remediation.


Telepsychiatry in Chennai, India: the SCARF experience.
India, with its huge population and limited mental health resources, must find alternative ways of delivering its mental healthcare services. Telepsychiatry seems to be a promising option even with no regulatory authority in place or specific laws in India that deal with telemedicine practice, there has been a mushrooming of telemedicine services in India. Healthy cooperation between government organizations such as the Indian Space Research Organization (ISRO) and institutions in the non-government and private sectors is another key feature in India. The experience of the Schizophrenia Research Foundation (SCARF), at Chennai, in South India, in running and establishing a telepsychiatry network is presented in this article. We identified the following tasks as essential to ensure an efficient intervention using telemedicine: identifying a suitable technology, a suitable location, and a local collaborator; providing training and creating awareness; establishing peripheral telepsychiatry centers and ensuring case documentation; and accountability.


Analysis of the Effect of Fast Recovery Surgery Concept on Perioperative Nursing Care of Patients with Radical Resection of Cervical Cancer and Its Influence on Psychological Status.
To explore the applied effect of fast-track surgery concept in the perioperative nursing of patients undergoing radical cervical cancer surgery and its influence on mental state. The clinical data of 110 patients undergoing radical cervical cancer surgery in our hospital from May 2015 to May 2017 were retrospectively analyzed, and they were randomly divided into a research group (n = 55) and a reference group (n = 55). The reference group received routine clinical nursing, and the research group received fast-track surgical nursing. Then, we compared their nursing effect and influence on the mental state of patients in the two groups. The Karnofsky performance status (KPS) scores of patients in the two groups after intervention were significantly lower than those before the intervention (P < 0.001), and after intervention, patients in the research group had significantly lower KPS scores as compared to patients in the reference group (P < 0.001). There was a significant decrease in the self-rating anxiety scale (SAS) scores and self-rating depression scale (SDS) scores of patients in the two groups after intervention in comparison with before intervention (P < 0.001), and patients in the research group after intervention had significantly lower SAS and SDS scores compared to the reference group (P < 0.001). Patients in the research group spent short time on expelling gas, eating, and getting out of bed as compared to the reference group (P < 0.001); after intervention, compared to patients in the reference group, patients in the research group had significantly higher scores in cognitive function, emotional function, social function, and physical function (P < 0.05). There was no significant difference in IgA, IgM, and IgG levels before intervention (P > 0.05). After intervention, the IgA, IgM, and IgG levels of patients in the two groups were all lower than before intervention, and patients in the research group had significantly higher IgA, IgM, and IgG levels as compared to the reference group (P < 0.001); the complication rate of patients in the research group was significantly lower than that in the reference group (P < 0.05). The fast-track surgery concept effectively helps improve the negative emotion of patients, shorten recovery time, improve quality of life, and reduce the impact on immune function in the radical cervical cancer surgery, and it is worthy of promotion and application, with a high safety.


Early-life exposure to the endocrine disruptor 17-α-ethinylestradiol induces delayed effects in adult brain, liver and ovotestis proteomes of a self-fertilizing fish.
Early-life represents a critically sensitive window to endocrine disrupting chemicals, potentially leading to long-term repercussions on the phenotype later in life. The mechanisms underlying this phenomenon, referred to as the Developmental Origins of Health and Disease (DOHaD), are still poorly understood. To gain molecular understanding of these effects, we exposed mangrove rivulus (Kryptolebias marmoratus) for 28 days post hatching (dph) to 4 and 120 ng/L 17-α-ethinylestradiol, a model xenoestrogen. After 28 days, fish were raised for 140 days in clean water and we performed quantitative label-free proteomics on brain, liver and ovotestis of 168 dph adults. A total of 820, 888 and 420 proteins were robustly identified in the brain, liver and ovotestis, respectively. Effects of 17-α-ethinylestradiol were tissue and dose-dependent: a total of 31, 51 and 18 proteins were differentially abundant at 4 ng/L in the brain, liver and ovotestis, respectively, compared to 20, 25 and 39 proteins at 120 ng/L. Our results suggest that estrogen-responsive pathways, such as lipid metabolism, inflammation, and the innate immune system were affected months after the exposure. In addition, the potential perturbation of S-adenosylmethionine metabolism encourages future studies to investigate the role of DNA methylation in mediating the long-term effects of early-life exposures. SIGNIFICANCE: The Developmental Origins of Health and Disease (DOHaD) states that early life stages of humans and animals are sensitive to environmental stressors and can develop health issues later in life, even if the stress has ceased. Molecular mechanisms supporting DOHaD are still unclear. The mangrove rivulus is a new fish model species naturally reproducing by self-fertilization, making it possible to use isogenic lineages in which all individuals are highly homozygous. This species therefore permits to strongly reduce the confounding factor of genetic variability in order to investigate the effects of environmental stress on the phenotype. After characterizing the molecular phenotype of brain, liver and ovotestis, we obtained true proteomic reaction norms of these three organs in adults after early life stages have been exposed to the common endocrine disruptor 17-α-ethinylestradiol (EE2). Our study demonstrates long-term effects of early-life endocrine disruption at the proteomic level in diverse estrogen-responsive pathways 5 months after the exposure. The lowest tested and environmentally relevant concentration of 4 ng/L had the highest impact on the proteome in brain and liver, highlighting the potency of endocrine disruptors at low concentrations.


Internet-Delivered Health Interventions That Work: Systematic Review of Meta-Analyses and Evaluation of Website Availability.
Due to easy access and low cost, Internet-delivered therapies offer an attractive alternative to improving health. Although numerous websites contain health-related information, finding evidence-based programs (as demonstrated through randomized controlled trials, RCTs) can be challenging. We sought to bridge the divide between the knowledge gained from RCTs and communication of the results by conducting a global systematic review and analyzing the availability of evidence-based Internet health programs. The study aimed to (1) discover the range of health-related topics that are addressed through Internet-delivered interventions, (2) generate a list of current websites used in the trials which demonstrate a health benefit, and (3) identify gaps in the research that may have hindered dissemination. Our focus was on Internet-delivered self-guided health interventions that did not require real-time clinical support. A systematic review of meta-analyses was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO Registration Number CRD42016041258). MEDLINE via Ovid, PsycINFO, Embase, Cochrane Database of Systematic Reviews, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched. Inclusion criteria included (1) meta-analyses of RCTs, (2) at least one Internet-delivered intervention that measured a health-related outcome, and (3) use of at least one self-guided intervention. We excluded group-based therapies. There were no language restrictions. Of the 363 records identified through the search, 71 meta-analyses met inclusion criteria. Within the 71 meta-analyses, there were 1733 studies that contained 268 unique RCTs which tested self-help interventions. On review of the 268 studies, 21.3% (57/268) had functional websites. These included evidence-based Web programs on substance abuse (alcohol, tobacco, cannabis), mental health (depression, anxiety, post-traumatic stress disorder [PTSD], phobias, panic disorders, obsessive compulsive disorder [OCD]), and on diet and physical activity. There were also evidence-based programs on insomnia, chronic pain, cardiovascular risk, and childhood health problems. These programs tended to be intensive, requiring weeks to months of engagement by the user, often including interaction, personalized and normative feedback, and self-monitoring. English was the most common language, although some were available in Spanish, French, Portuguese, Dutch, German, Norwegian, Finnish, Swedish, and Mandarin. There were several interventions with numbers needed to treat of <5; these included painACTION, Mental Health Online for panic disorders, Deprexis, Triple P Online (TPOL), and U Can POOP Too. Hyperlinks of the sites have been listed. A wide range of evidence-based Internet programs are currently available for health-related behaviors, as well as disease prevention and treatment. However, the majority of Internet-delivered health interventions found to be efficacious in RCTs do not have websites for general use. Increased efforts to provide mechanisms to host "interventions that work" on the Web and to assist the public in locating these sites are necessary.


Human freezing in response to affective films.
Human freezing has been objectively assessed using a passive picture viewing paradigm as an analog for threat. These results should be replicated for other stimuli in order to determine their stability and generalizability. Affective films are used frequently to elicit affective responses, but it is unknown whether they also elicit freezing-like defense responses. To test whether this is the case, 50 participants watched neutral, pleasant and unpleasant film fragments while standing on a stabilometric platform and wearing a polar band to assess heart rate. Freezing-like responses (indicated by overall reduced body sway and heart rate deceleration) were observed for the unpleasant film only. The unpleasant film also elicited early reduced body sway (1-2 s after stimulus onset). Heart rate and body sway were correlated during the unpleasant film only. The results suggest that ecologically valid stimuli like films are adequate stimuli in evoking defense responses. The results also underscore the importance of including time courses in human experimental research on defense reactions in order to delineate different stages in the defense response.


Heterogeneous expression of connexin 36 in the olfactory epithelium and glomerular layer of the olfactory bulb.
Gap junctions regulate a variety of cell functions by directly connecting two cells through intercellular channels. Connexins are gap junction channel-forming protein subunits. In this study, we studied the expression of connexin 36 (Cx36) in the olfactory epithelium and olfactory bulb of adult mice. In situ hybridization revealed that mRNA for Cx36 was expressed in the olfactory sensory epithelium, main olfactory bulb and accessory olfactory bulb. Expression of mRNA encoding Cx36 was observed in the olfactory epithelium mainly in ventral and lateral regions of the turbinates. Immunohistochemical determination of Cx36 protein expression showed sparse punctuate staining in the olfactory epithelial layer. Intense Cx36-like immunostaining was found in the olfactory nerve bundles underlying the olfactory epithelium and in the olfactory nerve layer and glomerular layer of the olfactory bulb. Mapping of the intensity of Cx36-like immunofluorescence in glomeruli throughout the main olfactory bulb indicated a heterogeneous distribution. A set of approximately 50 glomeruli located in the anterior and posterior limits of the olfactory bulb was more intensely labeled than other glomeruli. There was intense immunofluorescence signal in the glomerular layer of the accessory olfactory bulb and in the vomeronasal nerve. beta-Galactosidase distribution in the olfactory epithelium and olfactory bulb in Cx36 knockout mice (Deans et al. [2001] Neuron 31:477-485) supported the findings with immunofluorescence. Cx36-like immunofluorescence was absent in the olfactory nerve bundles in Cx36 knockout mice. The immunolocalization of Cx36 to the olfactory and vomeronasal nerves, and a subset of olfactory glomeruli suggest a functional role for Cx36 in odor coding.


Lymphocytes in patients with variable immunodeficiency and panhypogammaglobulinemia. Evaluation of B and T cell surface markers and a proposed classification.
Peripheral blood lymphocytes from 15 patients with variable immunodeficiency and severe panhypogammaglobulinemia were evaluated for B and T cell surface markers. B cells were enumerated by immunofluorescent detection of both surface immunoglobulin (Ig) and the ability to bind aggregated Ig complexes. T cells were identified by their ability to form nonimmune rosettes with sheep red blood cells. Four distinct patterns were observed which were designated types I-IV. Type I: six patients had normal percentages (8.5-19.0%) of Ig-bearing B lymphocytes. Type II: four patients were observed to have B lymphocytes (4.5-15.0%) which lacked fluorescence-detectable surface Ig. Type III: the peripheral blood of these four patients contained a subpopulation (11.3-20.0%) of lymphocytes which apparently lacked both B and T cell markers ("null" cells). Type IV: one patient's blood was characterized by a subpopulation (18.0-22.0%) of lymphocytes which bore both B and T cell markers. Patients of each type had some clinical features in common. It is concluded that evaluation of lymphocyte surface markers provides a means of separating patients with variable immunodeficiency and panhypogammaglobulinemia into distinct groups which appear to differ in the nature of their fundamental defect.


An item response theory analysis of the Prodromal Questionnaire-Brief Child Version: Developing a screening form that informs understanding of self-reported psychotic-like experiences in childhood.
The Prodromal Questionnaire-Brief Child Version (PQ-BC) has been developed as a tool for identifying psychotic-like experiences (PLEs) in school-age children. The current study examined the psychometric properties of the PQ-BC, examined how well the PQ-BC estimates the latent construct of PLEs (θ̂), and began the process of developing a screening form informed by item response theory (IRT). Utilizing the baseline (N = 11,129) sample from the Adolescent Brain Cognitive Development study, we examined which PQ-BC items provide the most information and best discriminate individuals experiencing PLEs. Using hierarchical linear models (HLMs), we found that θ̂ scores were significantly associated with several previously identified predictors of psychosis spectrum symptoms (i.e., history of psychosis, internalizing symptoms, cognitive impairments, developmental milestone delays, and resting-state functional connectivity impairments) at baseline and Year 1 (n = 5,532). Using item-level information and discrimination parameters of the PQ-BC from the baseline sample, we created a 7-item screening form. HLMs generally found significant associations between screening form scores for both baseline and Year 1 with the aforementioned predictors. The analyses provide evidence for the validity of a screening form derived from the PQ-BC using IRT-derived parameters. This screening form could prove useful when the full measure is not feasible. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


An automatic medication self-management and monitoring system for independently living patients.
This paper describes the development, prototyping, and evaluation of RMAIS (RFID-based Medication Adherence Intelligence System). Previous work in this field has resulted in devices that are either costly or too complicated for general (especially elderly) patients to operate. RMAIS provides a practical and economical means for ordinary patients to easily manage their own medications, taking the right dosage of medicine at the prescribed time in a fully automatic way. The system design has the following features: (1) fully automatic operation for easy medication by using the built-in scale for dosage measurement and a motorized rotation plate to deliver the right medicine container in front of a patient, (2) various medication reminder messages for patients, and noncompliance alerts for caregivers (such as doctors, relatives or social workers who take care of the patients), and (3) incremental and economical adoption by pharmacies, patients, and insurance companies.


Introduction of moribund category to OECD fish acute test and its effect on suffering and LC50 values.
It has become common practice in many laboratories in Europe to introduce the criterion "moribund" to reduce the suffering in fish acute lethality tests. Fish with severe sublethal symptoms might be declared moribund and are removed from the test as soon as this occurs (premature discontinuation of experiment). Moribund fish affect main study outcomes as the median lethal concentration (LC50) derived on fish declared as moribund may be lower than the conventional LC50. This was evaluated by a retrospective analysis of 328 fish acute toxicity tests of an industry laboratory based on five different definitions of moribund, and of 111 tests from 10 other laboratories from Europe and the United States. Using the criterion of moribund 10 to 23% of the fish were being declared as moribund in 49 to 79% of the studies. In 36 to 52% of the studies, the LC50(moribund) was lower than the conventional LC50 depending on the definitions of moribund. An inclusion of the moribund criterion in an updated Organisation for Economic Cooperation and Development guideline for the acute fish toxicity test would reduce the period of suffering by up to 92 h, lowering the value of the main toxicity endpoint by a factor of approximately 2, and maximal by a factor of approximately 16.


[Spontaneous pneumomediastinum and idiopathic pulmonary fibrosis].
The association between pulmonary fibrosis and pneumomediastinum is infrequent. Computed tomography is the suited method for the detection of small pneumomediastinum, which is difficult to detect by chest radiography. A case of idiopathic pulmonary fibrosis, with frequent and violent cough, with pneumomediastinum and cervical subcutaneous emphysema, without pneumothorax, probably caused by rupture of bullae is presented. The outcome was favourable with symptomatic treatment.


Tuning the photophysical properties of 4'-substituted terpyridines - an experimental and theoretical study.
Several 2,2':6',2''-terpyridines substituted in the 4'-position were synthesized and their photophysical properties were investigated by absorption and photoluminescence spectroscopy in dilute solutions and solid state. The studies confirmed that the absorption and emission wavelengths, fluorescence quantum yields and lifetimes of 1-R(1-16) are strongly structure-related, demonstrating a decisive role of the nature of the substituent in determining the photophysical properties of 4'-functionalized terpyridines. Additionally, the density functional theory (DFT) calculations were performed for 1-R(1-16) to get insight into their electronic structure and spectroscopic properties.


Influence of Different Kinematics on Apical Extrusion of Irrigant and Debris during Canal Preparation Using K3XF Instruments.
This in vitro study was designed to evaluate the amount of apically extruded irrigant and debris during root canal preparation using K3XF instruments (SybronEndo, Orange, CA) with different kinematics and using hand files with a step-back technique. A total of 80 extracted mandibular premolars were selected and randomly assigned to 4 groups (n = 20). The root canals were instrumented with K-type stainless steel instruments using a step-back technique and with the K3XF system using the following kinematics: reciprocating motion, adaptive motion, and continuous rotation. Bidistilled water was used as an irrigant. Preweighed Eppendorf tubes were used to collect apically extruded debris during instrumentation. Extruded irrigant was collected from the drainage cannula using a plastic insulin syringe, and the volumes were recorded. After complete evaporation of the liquid inside the tube, the weight of extruded debris was determined for each specimen. Data were analyzed statistically using the Kruskal-Wallis and Mann-Whitney U tests at a significance level of P < .05. Hand file instrumentation was associated with a significantly greater extrusion of debris compared with the K3XF groups (P < .05). Among the different kinematics, the highest mean debris extrusion value was obtained with reciprocating motion and the least with continuous rotation, but this difference was not significant (P > .05). No significant differences were observed between groups in terms of irrigant extrusion (P > .05). Hand instrumentation extruded more debris than K3XF instruments that were used with different kinematics. All instrumentation kinematics were associated with apical debris and irrigant extrusion.


Acoustic Localization of Bragg Peak Proton Beams for Hadrontherapy Monitoring.
Hadrontherapy makes it possible to deliver high doses of energy to cancerous tumors by using the large energy deposition in the Bragg-peak. However, uncertainties in the patient positioning and/or in the anatomical parameters can cause distortions in the calculation of the dose distribution. In order to maximize the effectiveness of heavy particle treatments, an accurate monitoring system of the deposited dose depending on the energy, beam time, and spot size is necessary. The localized deposition of this energy leads to the generation of a thermoacoustic pulse that can be detected using acoustic technologies. This article presents different experimental and simulation studies of the acoustic localization of thermoacoustic pulses captured with a set of sensors around the sample. In addition, numerical simulations have been done where thermo-acoustic pulses are emitted for the specific case of a proton beam of 100 MeV.


The clpP multigene family for the ATP-dependent Clp protease in the cyanobacterium Synechococcus.
In the cyanobacterium Synechococcus sp. strain PCC 7942 a multigene family of three different isozymes encodes the proteolytic subunit ClpP of the ATP-dependent Clp protease. In contrast to the monocistronic clpPI gene, clpPII and clpPIII are part of two bicistronic operons with clpX and clpR, respectively. Unlike most bacterial Clp proteins, the Synechococcus ClpP2, ClpP3, ClpR and ClpX proteins were not highly inducible by high temperatures, or by other stresses such as cold, high light or oxidation, although slower gradual rises occurred for all four proteins during high light, and for ClpP3, ClpR and ClpX at low temperature. Attempts to inactivate the clpPII, clpIII, clpR or clpX genes were only successful for clpPII, suggesting the others are essential for Synechococcus cell viability. The DeltaclpPII mutant exhibited no significant phenotypic changes from the wild-type, including no change in ClpX content. Despite the apparent bicistronic arrangement of both clpPII-clpX and clpR-clpPIII, all four genes primarily produce monocistronic transcripts, although polycistronic transcripts were detected. Mapping of 5' ends for the clpX and clpPIII monocistronic transcripts revealed promoters situated within the 3' region of clpPII and clpR, respectively. Transcriptional and translational studies further showed differences in the expression and regulation between the clpP-clpR-clpX genes. Inactivation of clpPI caused a significant decrease in ClpP2 protein concomitant to small increases in both ClpP3 and ClpR. Inactivation of clpPII resulted in a large rise in clpPI transcripts but to a lesser extent in ClpP1 protein. Similar small increases in ClpP3, ClpR and ClpX proteins also occurred in DeltaclpPII. These results highlight the regulatory complexity of these multiple clp genes and their functional importance in cyanobacteria.


Moral assessment in indirect reciprocity.
Indirect reciprocity is one of the mechanisms for cooperation, and seems to be of particular interest for the evolution of human societies. A large part is based on assessing reputations and acting accordingly. This paper gives a brief overview of different assessment rules for indirect reciprocity, and studies them by using evolutionary game dynamics. Even the simplest binary assessment rules lead to complex outcomes and require considerable cognitive abilities.


PROBLEMS OF COMMUNITY PSYCHIATRY.
An analysis of existing psychiatric facilities in the community reveals their heterogeneity and fragmentation. Parallel, overlapping and non-communicating, they deal with treatment in a piecemeal fashion and with prevention only by default. Divorce between the different therapeutic phases of what is often the same illness violates any continuity of care. The provincial mental hospital, which arose in part out of social pressure to isolate the "mad" patient, finds itself, often enough, isolated in turn from the community it serves.Greater integration of available treatment resources for the psychiatric patient would serve both his interest and the general concepts of preventive and rehabilitative medicine. An understanding of how this may be achieved may engender social and professional impetus toward the accomplishment. The general hospital is a logical coordinating focus for these facilities and when it has adopted this role this might lead to a greater acceptance of emotional illness by both patients and doctors.


Canine parvovirus immunoprophylaxis: a review.
The presently available data on canine parvovirus is reviewed with particular emphasis on the degree of immunity provided by the various types of vaccines commercially available, the interference of active immunisation by maternally-derived antibody, and the recommendations as to age of vaccination.


Readout and control of the spin-orbit states of two coupled acceptor atoms in a silicon transistor.
Coupling spin qubits to electric fields is attractive to simplify qubit manipulation and couple qubits over long distances. Electron spins in silicon offer long lifetimes, but their weak spin-orbit interaction makes electrical coupling challenging. Hole spins bound to acceptor dopants, spin-orbit-coupled J = 3/2 systems similar to Si vacancies in SiC and single Co dopants, are an electrically active spin system in silicon. However, J = 3/2 systems are much less studied than S = 1/2 electrons, and spin readout has not yet been demonstrated for acceptors in silicon. Here, we study acceptor hole spin dynamics by dispersive readout of single-hole tunneling between two coupled acceptors in a nanowire transistor. We identify m J = ±1/2 and m J = ±3/2 levels, and we use a magnetic field to overcome the initial heavy-light hole splitting and to tune the J = 3/2 energy spectrum. We find regimes of spin-like (+3/2 to -3/2) and charge-like (±1/2 to ±3/2) relaxations, separated by a regime of enhanced relaxation induced by mixing of light and heavy holes. The demonstrated control over the energy level ordering and hybridization are new tools in the J = 3/2 system that are crucial to optimize single-atom spin lifetime and electrical coupling.


Modulation of CTP:phosphocholine cytidylyltransferase by membrane curvature elastic stress.
The activity of CTP:phosphocholine cytidylyltransferase, a rate-limiting enzyme in phosphatidylcholine biosynthesis, is modulated by its interaction with lipid bilayers [Kent, C. (1997) Biochim. Biophys. Acta 1348, 79-90]. Its regulation is of central importance in the maintenance of membrane lipid homeostasis. Here we show evidence that the stored curvature elastic stress in the lipid membrane's monolayer modulates the activity of CTP:phosphocholine cytidylyltransferase. Our results show how a purely physical feedback signal could play a key role in the control of membrane lipid synthesis.


Isolated bicuspid pulmonary valve: an unusual finding.
Whilst the pulmonary valve is a tricuspid valve, very few reports exist of bicuspid pulmonary valves, the majority of which are associated with congenital heart disease. Isolated bicuspid valves not associated with congenital abnormalities are even more rare. Herein, the case is described of a 65-year-old man who died from a stroke, and in whom a bicuspid pulmonary valve was found during post-mortem dissection for tissue donation.


Add-on therapies to metformin for type 2 diabetes.
As of 2010, approximately 285 million people worldwide have diabetes; that number is estimated to increase to 439 million by 2030. The majority of these individuals (> 90%) have type 2 diabetes, a chronic and progressive disease. Metformin monotherapy is a safe and effective option. However, its effects on glycemia are typically of limited durability. Progressive loss of β-cell function and failure of metformin monotherapy to control glucose adequately prompt the addition of other oral antidiabetic drugs, such as sulfonylureas and thiazolidinediones, which have their own limitations. Evidence suggests that incretin-based agents can successfully achieve glycemic control while potentially providing cardiovascular and β-cell-function benefits. Knowledge of the available clinical evidence on the incretin-based therapies and other pharmacotherapeutic options for patients with type 2 diabetes who fail first-line therapy with metformin, through an analysis of improved glycemic parameters and overall risk:benefit profiles. Traditional oral antidiabetic agents, recommended as first- and second-line therapies in patients with type 2 diabetes inadequately controlled with diet/exercise or monotherapy, have limited durability of effect and are associated with an increased risk of adverse events. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors provide glycemic control and are promising additions to the pharmacotherapeutic armamentarium.


Is there a role for "watch and wait" in follicular lymphoma in the rituximab era?
The paradigm of "watch and wait" for low-tumor-burden follicular lymphoma (LTB-FL) was established in an era when the treatment options were more limited. With the introduction of rituximab, it appears that the natural history of this incurable disease has changed. However, most of the contemporary treatment data have been generated in patients with high tumor burden, and it is unclear whether the improvements in outcome also apply to the LTB population. There are no published trials evaluating rituximab-chemotherapy combinations and just a few studies evaluating single-agent rituximab in this population. As a result, there are many unknowns in the management of LTB-FL. Would the application of rituximab-chemotherapy combination cure a fraction of patients? Would the application of rituximab-chemotherapy combination improve the overall survival of the population? Would treatment with single-agent rituximab improve the psychologic quality of life by avoiding a watch and wait interval or by delaying the time to first chemotherapy? This review, a mixture of data and opinion, will discuss goals of therapy for an LTB-FL patient, summarize existing data, and propose a management algorithm.


A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: a randomized controlled trial with 2 year follow-up.
Cell-based therapies have shown promise for the treatment of knee osteoarthritis (OA). The current study compared exercise therapy to autologous bone marrow concentrate (BMC) and platelet products for knee OA treatment. Patients with symptomatic knee OA (N = 48) were randomized into either an exercise therapy control group or treatment group with injection of autologous BMC and platelet products. Patients in the control group could crossover to BMC treatment after 3 months. Clinical outcomes were documented at baseline and at 6-weeks, 3, 6, 12 and 24 months, including the Knee Society Score (KSS), Pain Visual Analogue Scale, Short Form-12 Scales (SF-12), and Lower Extremity Activity Scale (LEAS). All patients in the exercise group crossed over to receive BMC treatment after 3 months (N = 22 crossover). At 3 months, KSS-knee, SF-12 Physical, and LEAS improved significantly in the crossover group compared to exercise, similar to significant improvements on KSS-knee and LEAS for the treatment group (N = 26) compared to exercise group at 3 months. After BMC treatment, patients' clinical outcome scores (except SF-12 Mental Health), were significantly improved through the 2-year follow-up compared to baseline. No serious adverse events were reported. The use of image-guided percutaneous BMC with platelet products yielded better results than exercise therapy as an effective alternative therapy for patients with symptomatic moderate to moderate-severe osteoarthritis of the knee. Trial registration NCT02034032. https://clinicaltrials.gov/ct2/show/NCT02034032 . Registered 13 January 2014.


Correlation of iron overload and glomerular filtration rate estimated by cystatin C in patients with β-thalassemia major.
Historically, renal involvement has not been a commonly recognized complication in patients with β-thalassemia major (β-TM). Herein, we studied the impact of iron overload on glomerular filtration rate (GFR) estimated by cystatin C based GFR (Cyst C eGFR). We enrolled 149 patients with β-TM in a cross sectional study in a single center in Oman. We investigated the correlation between measurement of serum ferritin and Cyst C eGFR. We used univariable linear regression to study the impact of serum ferritin on Cyst C eGFR and backwards stepwise regression to adjust for potential confounders. We included 78 males and 71 females with a mean age of 17.3 ± 9 years (range 2.5-38.5). Seventeen patients had diabetes mellitus. Patients were taking deferiprone (DFP) and deferoxamine (DFO) (26 patients), DFP (58 patients), deferasirox (DFX) (62 patients) and one patient was taking only DFO. There was a very weak negative linear relationship between serum ferritin and Cyst C eGFR (correlation coefficient -0.25). In the univariable analyses, serum ferritin (p = 0.004), diabetes status (p < 0.001) and chelation therapy (p < 0.001) were statistically significant. In the multivariable model, age (p = 0.033), chelation with DFX (p = 0.05) and diabetes status (p < 0.001) were statistically significant. We found a very weak inverse linear correlation between serum ferritin and Cyst C eGFR. However, when concomitant use of chelation therapy was considered, serum ferritin did not associate with glomerular function. Prospective and larger studies are needed to confirm these findings.


Association of six polymorphisms of the NOTCH4 gene with schizophrenia in the Japanese population.
The NOTCH4 gene is located at 6p21.3 and involved in the development and patterning of the central nervous systems. Recently, Wei and Hemmings [2000] observed that the gene was associated with schizophrenia. Subsequent to the report, several studies investigated the gene in schizophrenia, with controversial and inconclusive results. In the present study, we investigated six polymorphisms (SNPs 1-5 and a CTG repeat) of the gene in Japanese subjects with schizophrenia (n = 284) and the same number of controls. The polymorphisms include SNP5, which has been observed to be associated with schizophrenia in a Chinese population and two new SNPs 3-4 adjacent to SNP5, in addition to the SNPs 1-2 and the CTG repeat, which were suggested for the association with the disease in the previous study. As a result, no significant difference in genotypic distributions or allelic frequencies of the six polymorphisms of the gene was observed between the patients and the controls. Also, no significant difference was found in frequencies of haplotypes of the six polymorphisms between the patients and the controls. However, the distribution of SNP2 was significantly deviated from Hardy-Weinberg equilibrium in the patients (P = 0.000986), not in the controls, which could be a chance or due to an association of SNP2 with the disease. In conclusion, the present study provided no clear evidence for an association between the NOTCH4 gene and schizophrenia in the Japanese population.


Vitamin D across growth hormone (GH) disorders: From GH deficiency to GH excess.
The interplay between vitamin D and the growth hormone (GH)/insulin-like growth factor (IGF)-I system is very complex and to date it is not fully understood. GH directly regulates renal 1 alpha-hydroxylase activity, although the action of GH in modulating vitamin D metabolism may also be IGF-I mediated. On the other hand, vitamin D increases circulating IGF-I and the vitamin D deficiency should be normalized before measurement of IGF-I concentrations to obtain reliable and unbiased IGF-I values. Indeed, linear growth after treatment of nutritional vitamin D deficiency seems to be mediated through activation of the GH/IGF-I axis and it suggests an important role of vitamin D as a link between the proliferating cartilage cells of the growth plate and GH/IGF-I secretion. Vitamin D levels are commonly lower in patients with GH deficiency (GHD) than in controls, with a variable prevalence of insufficiency or deficiency, and this condition may worsen the already known cardiovascular and metabolic risk of GHD, although this finding is not common to all studies. In addition, data on the impact of GH treatment on vitamin D levels in GHD patients are quite conflicting. Conversely, in active acromegaly, a condition characterized by a chronic GH excess, both increased and decreased vitamin D levels have been highlighted, and the interplay between vitamin D and the GH/IGF-I axis becomes even more complicated when we consider the acromegaly treatment, both medical and surgical. The current review summarizes the available data on vitamin D in the main disorders of the GH/IGF-I axis, providing an overview of the current state of the art.


Evaluation of Simulation Models that Estimate the Effect of Dietary Strategies on Nutritional Intake: A Systematic Review.
Background: Dietary simulation modeling can predict dietary strategies that may improve nutritional or health outcomes.Objectives: The study aims were to undertake a systematic review of simulation studies that model dietary strategies aiming to improve nutritional intake, body weight, and related chronic disease, and to assess the methodologic and reporting quality of these models.Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guided the search strategy with studies located through electronic searches [Cochrane Library, Ovid (MEDLINE and Embase), EBSCOhost (CINAHL), and Scopus]. Study findings were described and dietary modeling methodology and reporting quality were critiqued by using a set of quality criteria adapted for dietary modeling from general modeling guidelines.Results: Forty-five studies were included and categorized as modeling moderation, substitution, reformulation, or promotion dietary strategies. Moderation and reformulation strategies targeted individual nutrients or foods to theoretically improve one particular nutrient or health outcome, estimating small to modest improvements. Substituting unhealthy foods with healthier choices was estimated to be effective across a range of nutrients, including an estimated reduction in intake of saturated fatty acids, sodium, and added sugar. Promotion of fruits and vegetables predicted marginal changes in intake. Overall, the quality of the studies was moderate to high, with certain features of the quality criteria consistently reported.Conclusions: Based on the results of reviewed simulation dietary modeling studies, targeting a variety of foods rather than individual foods or nutrients theoretically appears most effective in estimating improvements in nutritional intake, particularly reducing intake of nutrients commonly consumed in excess. A combination of strategies could theoretically be used to deliver the best improvement in outcomes. Study quality was moderate to high. However, given the lack of dietary simulation reporting guidelines, future work could refine the quality tool to harmonize consistency in the reporting of subsequent dietary modeling studies.