MRI based morphological examination of the placenta.
Ultrasound is widely used as the initial diagnostic imaging modality during pregnancy with both high spatial and temporal resolution. Although MRI in pregnancy has long focused on the fetus, its use in placental imaging has greatly increased over recent years. In addition to the possibilities of evaluating function, MRI with a wide field of view and high contrast resolution allows characterization of placental anatomy, particularly in situations that are difficult to specify with ultrasound, especially for suspected placenta accreta. MRI also appears to be a particularly useful examination for the anatomical evaluation of the placenta independent of maternal body habitus or fetal position. Indeed, surprisingly little attention is paid to the placenta in MRI when the indication for the examination is fetal. Thus, some aspects of the placenta seem to us to be important to be recognized by the radiologist and to be described on the MRI report. In this review, we will describe MRI sequences used for, and common features seen in, imaging of i) the normal placenta, ii) abnormal aspects of the placenta that should be identified on MRI performed for fetal reason, and iii) placental anomalies for which placental MRI may be indicated.


[Successful therapy of secondary melanoma of the orbit with DTIC].
The authors report on cytostatic treatment of a secondary malignant melanoma of the left orbit in a 68-year-old patient. It was an inoperable tumor, extending parabulbarly and retrobulbarly, with erosion of the bone of the orbital roof and deep infiltration into the frontal sinus. The regression of the tumor following intravenous administration of Dacarbacine (6 series of 5 X 200 mg DTIC) is shown on computerized tomograms. A year after completion of chemotherapy there had been no recurrence; the patient then died suddenly from the sequelae of an apoplexy.


cDNA cloning, sequence analysis and seasonal expression of lignin-bispecific caffeic acid/5-hydroxyferulic acid O-methyltransferase of aspen.
A cDNA clone (Ptomt 1) encoding a lignin-bispecific O-methyltransferase (OMT) was isolated by immunological screening of a lambda gt11 expression library prepared from mRNA of developing secondary xylem of aspen (Populus tremuloides). Nucleotide sequence analysis of Ptomt1 revealed an open reading frame of 1095 bp which encodes a polypeptide with a predicted molecular weight of 39,802, corresponding well with the size of the OMT polypeptide estimated by SDS-PAGE. Authenticity of Ptomt1 was demonstrated in part by detection of OMT activity and protein in extracts of Escherichia coli cultures transformed with a plasmid construct containing Ptomt1. In addition, peptides produced from a proteolytic digest of purified OMT and sequenced by automated Edman degradation matched to portions of the deduced amino acid sequence of Ptomt1. Comparison of this sequence to amino acid sequences of OMTs of diverse species identified regions of similarity which probably contribute to the binding site of S-adenosyl-L-methionine. Tissue-specific expression was demonstrated by northern analysis which showed that Ptomt1 hybridized to a 1.7 kb transcript from aspen developing secondary xylem and by tissue printing of aspen stems in which only the outer layer of xylem bound the antibody. A biphasic pattern of gene expression and enzyme activity for OMT was observed from xylem samples of aspen during the growing season which suggests linkage between gene expression for a monolignol biosynthetic enzyme and seasonal regulation of xylem differentiation in woody plants.


New Tools for Molecular Therapy of Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer, arising from neoplastic transformation of hepatocytes or liver precursor/stem cells. HCC is often associated with pre-existing chronic liver pathologies of different origin (mainly subsequent to HBV and HCV infections), such as fibrosis or cirrhosis. Current therapies are essentially still ineffective, due both to the tumor heterogeneity and the frequent late diagnosis, making necessary the creation of new therapeutic strategies to inhibit tumor onset and progression and improve the survival of patients. A promising strategy for treatment of HCC is the targeted molecular therapy based on the restoration of tumor suppressor proteins lost during neoplastic transformation. In particular, the delivery of master genes of epithelial/hepatocyte differentiation, able to trigger an extensive reprogramming of gene expression, could allow the induction of an efficient antitumor response through the simultaneous adjustment of multiple genetic/epigenetic alterations contributing to tumor development. Here, we report recent literature data supporting the use of members of the liver enriched transcription factor (LETF) family, in particular HNF4α, as tools for gene therapy of HCC.


No evidence for conspecific recruitment for cooperative hunting in lionfish Pterois miles.
Lionfish are common piscivores in the Indo-Pacific and invasive in the Caribbean. A fin flaring pattern, involving a rapid undulation of the caudal fin and sequential turning of both pectoral fins, was described in zebra lionfish as a signal to initiate cooperative hunting, and it was hypothesized that such hunting tactics may also exist in other lionfish species and contribute to their successful invasion in the Caribbean. Here, we investigated one of those invasive species, Pterois miles, in its natural range in the Red Sea. We did not observe evidence for cooperative hunting in the field. We complemented field observations with a laboratory experiment aimed at inducing subjects to recruit partners for cooperative hunts, exposing subjects to inaccessible prey in transparent housing as well as to a potential partner. We regularly observed the fin flaring pattern, but importantly, it was not directed at the partner. Thus, rather than being a signal, the fin flaring movement pattern seems to be a swimming mode in a confined environment. Furthermore, the two lionfish did not aggregate at the prey housing, reinforcing the field results that this species in the Red Sea does not depend on cooperation to hunt fish.


Role of vitamins in determining apoptosis and extent of suppression by bcl-2 during hybridoma cell culture.
The identification of cell culture media components that may instigate apoptosis in cell lines used for the production of commercial antibodies and recombinant proteins, is crucial to aid the development of improved media for reduced cell death and to understand the role of nutrient components in cell survival and maintenance. Here we determine the impact of depriving all or individual B-group media vitamins either, D-CaPantothenate (DCaP), choline chloride (CC), riboflavin (Rb), i-inositol, nicotinamide (NAM), pyridoxal hydrochloride (PyrHCl), folic acid (FA), or thiamine hydrochloride (ThHCl) on hybridoma cell growth and viability using fluorescence microscopy techniques. Cultivation in media deprived of all these vitamins prevented cell proliferation from reaching maximum capacity while increasing cell death rate, predominantly via apoptosis. Deletion of either DCaP, CC, or Rb showed that these components were most likely responsible for the development of apoptosis. Exclusion of either i-inositol, NAM or PyrHCl failed to inhibit cell growth and viability, while marginal improvements in viability were noted by ThHCl deprivation and more so by FA exclusion. Over-expression of the anti-apoptotic gene bcl-2 suppressed cell death initiated by all or single vitamin (either DCaP, CC or Rb) deprivation. The involvement of bcl-2 activity, established a close association between small vitamin molecules particularly DCaP, CC or Rb and the biochemical activation of apoptosis.


Validity of the neck disability index, Northwick Park neck pain questionnaire, and problem elicitation technique for measuring disability associated with whiplash-associated disorders.
The Neck Disability Index (NDI) and Northwick Park Neck Pain Questionnaire (NPQ) were developed to measure self-perceived disability from neck pain, including that which may arise from whiplash injury. However, there is little data specifically concerning their validity for whiplash-associated disorders (WAD). The aim of this study was to assess the validity of the NDI and NPQ as measures of outcome in WAD by comparing them to a patient preference questionnaire, the problem elicitation technique (PET), which identifies problems that are of most importance to the individual patient. A cross-sectional study of 71 patients with varying severity and duration of WAD were recruited from a private physiotherapy practice. All patients completed a standardized self-administered questionnaire that included demographic and clinical details as well as self-perceived pain and severity of symptoms, NDI and NPQ. A trained interviewer administered the PET. Construct validity of the disability measures was examined by determining their correlation with each other and with pain and severity of symptoms by calculating Pearson's correlation coefficients. Content validity of the NDI and NPQ was assessed by comparing the items of both questionnaires to the problems identified by the PET. Participants' mean age was 40.1 years (SD=14.3) and 59 were women (83.1%). Most patients were in WAD category I (n=23, 32.1%), or II (n=42, 59.2%). Mean NDI, NPQ, and PET scores were 40.7 (SD=17.0), 38.7 (SD=15.8), and 160.2 (SD=92.0, range 6.0-509.5), respectively. Correlations between the NDI and PET, NPQ and PET, and NDI and NPQ were r=0.57, 0.56 and 0.88, respectively. The PET identified an average of 7.7 problems per patient (SD=4.2, range 1-17 problems). Problems most commonly identified were work for wages (52.1%), fatigued during the day (50.7%), participation in sports (47.9%), depression (43.7%), drive a car (43.7%), socialize with friends (33.8%), sleep through the night (31.0%), frustration (31.0%), and anger (28.2%). Only three of these problems are included in the NDI (work, driving, and sleeping) and only four are included in the NPQ (work, driving, sleeping, and social activities). While both the NDI and NPQ include some problems that are common in patients with WAD, frequently identified problems, such as emotional and social items are absent. In contrast to the PET, neither instrument captures the full spectrum of disabilities judged to be important by the patient.


The prognostic role of immune checkpoint markers programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) in a large, multicenter prostate cancer cohort.
Programmed cell death protein 1 (PD-1) and its ligand Programmed death ligand 1 (PD-L1) have gained massive attention in cancer research due to recent availability and their targeted antitumor effects. Their role in prostate cancer is still undetermined. We constructed tissue microarrays from prostatectomy specimens from 535 prostate cancer patients. Following validation of antibodies, immunohistochemistry was used to evaluate the expression of PD-1 in lymphocytes and PD-L1 in epithelial and stromal cells of primary tumors. PD-L1 expression was commonly seen in tumor epithelial cells (92% of cases). Univariate survival analysis revealed a positive association between a high density of PD-1+ lymphocytes and worse clinical failure-free survival, limited to a trend (p = 0.084). In subgroups known to indicate unfavorable prostate cancer prognosis (Gleason grade 9, age < 65, preoperative PSA > 10, pT3) patients with high density of PD-1+ lymphocytes had a significantly higher risk of clinical failure (p = < 0.001, p = 0.025, p = 0.039 and p = 0.011, respectively). In the multivariate analysis, high density of PD-1+ lymphocytes was a significant negative independent prognostic factor for clinical failure-free survival (HR = 2.48, CI 95% 1.12-5.48, p = 0.025).


[Dynamics and ultrastructural characteristics of osteoclast formation].
Using electron microscopy and 3H-thymidine autoradiography it has been shown that osteoclasts of rats and rabbits are formed by fusion of cell precursors which become members of the osteoclasts 14 hours following S-phase. Monoblasts and promonocytes are considered as DNA-synthesizing forms. A single injection of parathormone in a dose of 10 units/100 g of body weight leads to an increase in the fractions of DNA-synthesizing cells. Monocytes and macrophages appear to be direct osteoclast precursors in resorption zones. As a result of their fusion there appear "unfixed" polynuclear macrophages (young osteoclasts). The number of osteoclast nuclei increases also at the expense of little-differentiated phagocytes, the inclusion of the latter takes place at different stages of the life span of osteoclasts depending on the intensity of bone resorption processes. The structural characteristics of fusion of cell precursors are considered.


N-Heterocyclic borneol derivatives as inhibitors of Marburg virus glycoprotein-mediated VSIV pseudotype entry.
There is currently no approved antiviral therapy for treatment of Marburg virus disease (MVD). Although filovirus infection outbreaks are quite rare, the high mortality rates in such outbreaks make the development of anti-filoviral drugs an important goal of medical chemistry and virology. Here, we performed screening of a large library of natural derivatives for their virus entry inhibition activity using pseudotype systems. The bornyl ester derivatives containing saturated N-heterocycles exhibited the highest antiviral activity. It is supposed that compounds with specific inhibitory activity toward MarV-GP-dependent virus entry will inhibit the rVSIV-ΔG-MarV-GP pseudotype much more efficiently than the control rVSIV-ΔG-G pseudotype. At the same time, the compounds similarly inhibiting both pseudotypes will likely affect rVSIV capsid replication or the cellular mechanisms common to the entry of both viruses. Borneol itself is not active against both pseudotypes and is nontoxic, whereas its derivatives have varying toxicity and antiviral activity. Among low-toxic borneol derivatives, six compounds turned out to be relatively specific inhibitors of MarV-GP-mediated infection (SC > 10). Of them, compound 6 containing a methylpiperidine moiety exhibited the highest virus-specific activity. Notably, the virus-specific activity of this compound is twice as high as that of the reference.


Causes and consequences of higher Leishmania infantum burden in patients with kala-azar: a study of 625 patients.
An infected host's Leishmania infantum load in blood is considered to be an estimate of his or her total parasite burden. Therefore, the measurement of blood parasite burden is important in the identification of factors involved in parasite control. Quantitative polymerase chain reaction was performed on blood samples from 625 patients with kala-azar consecutively admitted to a reference hospital in Teresina, Brazil. Primers were used to amplify a segment of kDNA using the TaqMan system. Non-parametric statistical tests were applied. The median blood parasite burden was 499.2 amastigote equivalents (AE)/ml. Children <1 year old (yo) had a high parasite burden, which dropped sharply after the first year of life (192.8, AE/ml at 1 < 2 yo) and remained lower until adolescence. Following adolescence, the parasite burden increased with age, peaking among elderly individuals. Men had a higher parasite burden than women. HIV-infected patients had a much higher parasite burden than non-infected patients. The parasite burden of children under 5 years with acute moderate to severe malnourishment (weight-for-age and body mass index z-scores <-2) was almost three times greater than that of better-nourished children. The parasite burden identified in deceased patients was more than twice that of surviving patients; those with a higher risk of death, sepsis, pneumonia and jaundice also had increased parasite burdens. All of these differences were statistically significant at P-values <0.05. These data indicate that the parasite burden in patients with kala-azar was associated with age- and gender-associated factors and with HIV infection status. Acute malnutrition could be either a cause or a consequence of a higher parasite burden. An individual's parasite burden influences his or her clinical profile, disease severity and mortality risk. The best explanation for the presence of a higher parasite burden in individuals with these immunoregulatory conditions and severe disease is the occurrence of acquired immunosuppression followed by heightened innate immunity.


Relationship of breast volume, obesity and central obesity with different prognostic factors of breast cancer.
The objective of this study was to investigate whether the BC tumor biology in women with larger breast volume, in obese women and especially in women with central adiposity at the moment of diagnosis of BC is more aggressive than in those women without these characteristics. 347 pre- and postmenopausal women with a recent diagnosis of BC were analyzed. In all patients, anthropometric measurements at the time of diagnosis was collected. In 103 of them, the breast volume was measured by the Archimedes method. The Breast volume, BMI, WHR and the menopausal status were related to different well-known pathological prognostic factors for BC. At the time of diagnosis, 35.4% were obese (BMI > 30 kg/m2), 60.2% had a WHR ≥ 0.85, 68.8% were postmenopausal and 44.7% had a breast volume considered "large" (> 600 cc). Between patients with a large breast volume, only a higher prevalence of ER (+) tumors was found (95.3% vs. 77.2%; p = 0.04) compared to those with small breast volumes. The obese BC patients showed significantly higher rates of large tumors (45.5% vs. 40.6%; p = 0.04), axillary invasion (53.6% vs. 38.8%; p = 0.04), undifferentiated tumors (38.2% vs. 23.2%) and unfavorable NPI (p = 0.04) than non-obese women. Those with WHR ≥ 0.85 presented higher postsurgical tumor stages (61.7% vs. 57.8%; p = 0.03), higher axillary invasion (39.9% vs. 36.0%; p = 0.004), more undifferentiated tumors (30.0% vs. 22.3%; p = 0.009), higher lymphovascular infiltration (6.5% vs. 1.6%; p = 0.02), and a higher NPI (3.6 ± 1.8 vs. 3.2 ± 1.8; p = 0.04). No statistically significant differences were found according to menopausal status. We conclude that obesity, but especially central obesity can be associated with a more aggressive tumour phenotype. No relation between breast volume and tumoral prognostic factors was found, except for a higher proportion of ER (+) tumor in women with higher breast volume.


Predictors of Quality Improvement in Pediatric Asthma Care.
Little is known about what hospital and emergency department (ED) factors predict performance in pediatric quality improvement efforts. Identify site characteristics and implementation strategies associated with improvements in pediatric asthma care. In this secondary analysis, we used data from a national quality collaborative. Data on site factors were collected via survey of implementation leaders. Data on quality measures were collected via chart review of children with a primary diagnosis of asthma. ED measures included severity assessment at triage, corticosteroid administration within 60 minutes, avoidance of chest radiographs, and discharge from the hospital. Inpatient measures included early administration of bronchodilator via metered-dose inhaler, screening for tobacco exposure, and caregiver referral to smoking cessation resources. We used multilevel regression models to determine associations between site factors and changes in mean compliance across all measures. Sixty-four EDs and 70 inpatient units participated. Baseline compliance was similar by site characteristics. We found significantly greater increases in compliance in EDs within nonteaching versus teaching hospitals (12% vs 5%), smaller versus larger hospitals (10% vs 4%), and rural and urban versus suburban settings (6%-7% vs 3%). In inpatient units, we also found significantly greater increases in compliance in nonteaching versus teaching hospitals (36% vs 17%) and community versus children's hospitals (23% vs 14%). Changes in compliance were not associated with organizational readiness or number of audit and feedback sessions or improvement cycles. Specific hospital and ED characteristics are associated with improvements in pediatric asthma care. Identifying setting-specific barriers may facilitate more targeted implementation support.


Hexaazatriphenylene (HAT) derivatives: from synthesis to molecular design, self-organization and device applications.
Dipyrazino[2,3-f:2′,3′-h]quinoxaline also known as 1,4,5,8,9,12-hexaazatriphenylene (HAT) is an electron deficient, rigid, planar, aromatic discotic system with an excellent π–π stacking ability. Because it is one of the smallest two-dimensional N-containing polyheterocyclic aromatic systems, it has been used as the basic scaffold for larger 2D N-substituted polyheterocyclic aromatics. Furthermore, it is the building block of choice in a plethora of molecular, macromolecular and supramolecular systems for a variety of applications. This review is aimed to critically review the research performed during the almost three decades of research based on HAT from the synthetic, theoretical and application points of view. The design principles and synthetic strategies towards HAT derivatives will be established and their use in n-type semiconductors, sensors, nonlinear optical chromophores, liquid crystals, microporous polymers for energy storage and nano and microstructures will reveal the relevance of HAT as a basic scaffold in the areas of organic materials and nanoscience.


Sequence alteration in the enhancer contributes to the heterochronic Sox9 expression in marsupial cranial neural crest.
Neonates of marsupial mammals are altricial at birth, because their gestation period is relatively short compared to placental mammals. Yet, as they need to travel to the teat from the birth canal, and suckle on the mother's milk, forelimbs and jaws develop significantly early. Previous studies in opossum (Monodelphis domestica), an experimental marsupial model, have revealed that cranial neural crest cells are generated significantly early compared to those in placental mammals, such as mouse, leading to an early development of jaw primordia. We have previously found that Sox9, an important neural crest-specifier gene, is expressed in the future cranial neural crest of the opossum embryonic ectoderm significantly earlier than that in mouse or quail embryos. As Sox9 is essential for neural crest formation in various vertebrates, it seems likely that the heterochronic expression of Sox9 is critical for the early cranial neural crest formation in the marsupial embryos. In this study, we show a marsupial-specific sequence in the Sox9 neural crest enhancer E3. We also reveal that the mouse E3 enhancer is activated in the cranial neural crest cells of quail embryos, that the E3 enhancer with marsupial-specific sequence is activated earlier in the Pax7-expressing neural border prior to the onset of endogenous Sox9 expression, and that a misexpression of cMyb, which is also a transcriptional activator of Pax7, in the neural border can ectopically activate the "marsupialized" enhancer. Thus, we suggest that the modification of the E3 enhancer sequence in the marsupial ancestor would have promoted the early expression of Sox9 in the neural border, facilitating the early formation of the cranial neural crest cells and the subsequent heterochronic development of the jaw primordia.


Assessing the Quality of Burkina Faso Soybeans Based on Fatty Acid Composition and Pesticide Residue Contamination.
Soybean is widely used in the food industry because of its high fatty acid and protein content. However, the increased use of pesticides to control pests during cultivation, in addition to being a public health concern, may influence the nutritional quality of soybeans. This study aimed to assess the nutritional quality of soybeans with respect to fatty acid profile and pesticide residue contamination. The levels of fatty acids and pesticides in soybean varieties G196 and G197 were determined by gas chromatography and by the QuEChERS method, respectively. The results showed a significant variation in the quantitative and qualitative fatty acid composition of the two varieties, with 18.03 g/100 g and 4 fatty acids detected for the G196 variety and 21.35 g/100 g and 7 fatty acids for the G197 variety, respectively. In addition, 12 active pesticide compounds were found, and among them, imazalil, quintozene, cyfluthrin and lindane exceeded their maximum limits. The G197 variety had a better nutritional profile compared to G196. The profile of fatty acids and the content of pesticide residues were used as important determinants for soybean utilization in human nutrition.


[Plasmids of Bacillus thuringiensis var. galleriae strain 612].
We studied Bacillus thuringiensis var galleriae, strain 612 plasmids. B. thuringiensis cells contain double-stranded plasmid DNA molecules (ranging of about 12% from total DNA content) with buoyant density 1.59 g/cm3. Plasmid DNA content was constant during the exponential and stationary phases of bacterial growth. The plasmid fractions consist of DNA molecules with molecular weights of 5.9 x 10(6), 10.0 x 10(6), and 110.9 x 10(6) daltons (pVD1, pVD2 pVD3, respectively). Endonuclease EcoRI cuts the plasmids pVD2 and pVD3 into two and four fragments, respectivelyy, but pVDI seemed to be resistent to EcoRI treatment. We found that pVD2 and pVD3 plasmids contain a common DNA fragment with the molecular weight of 6.7 x 10(6) dalton as it was shown by restriction analysis. In contrast, the same plasmids contain the common fragment with molecular weight of 7.5 x 10(6) dalton as shown by heteroduplex analysis. Plasmid pVD3 has a transposon-like structure.


Degradation of ornithine transcarbamylase in sporulating Bacillus subtilis cells.
When Bacillus subtilis cells grew and sporulated on glucose-nutrient broth, ornithine transcarbamylase (OTCase) was synthesized in the early stationary phase and then inactivated. The loss of OTCase activity was much slower in a mutant that was deficient in a major intracellular serine protease (ISP). Immunochemical analysis showed that synthesis of OTCase decreased to a low, but detectable, level during its inactivation and that loss of activity was paralleled by loss of cross-reactive protein. Because the antibodies were capable of detecting denatured and fragmented forms of OTCase, we conclude that inactivation involved or was rapidly followed by degradation in vivo. Native OTCase was not degraded in crude extracts or when purified ISP and OTCase were incubated together under a variety of conditions. Synthesis of OTCase was not shut off normally in the ISP-deficient mutant. When the effects of continued synthesis were minimized, OTCase was degraded only slightly slower in the mutant than in its parent. Thus, the mutant had unanticipated pleiotropic characteristics, and it was unlikely that ISP played a major role in the degradation of OTCase in vivo.


Optimal treatment of femoral neck fractures according to patient's physiologic age: an evidence-based review.
For decades, the basic tenets of managing displaced femoral neck fractures have not changed, but the optimal treatment choice continues to be highly debated. The contemporary controversies associated with the treatment principles of displaced femoral neck fractures are distinct between young and old patients and are considered individually in this article about the current evidence. Although fixation constructs all seem to have similar complication rates, there is increasing evidence suggesting that total hip replacement improves patient functional outcomes for healthy, independent, elderly patients compared with hemiarthroplasty and should be considered as the treatment of choice for these patients.


Addressing the mental health impact of COVID-19 through population health.
The COVID-19 pandemic has and will continue to result in negative mental health outcomes such as depression, anxiety and traumatic stress in people and populations throughout the world. A population mental health perspective informed by clinical psychology, psychiatry and dissemination and implementation science is ideally suited to address the broad, multi-faceted and long-lasting mental health impact of the pandemic. Informed by a systematic review of the burgeoning empirical research on the COVID-19 pandemic and research on prior coronavirus pandemics, we link pandemic risk factors, negative mental health outcomes and appropriate intervention strategies. We describe how social risk factors and pandemic stressors will contribute to negative mental health outcomes, especially among vulnerable populations. We evaluate the scalability of primary, secondary and tertiary interventions according to mental health target, population, modality, intensity and provider type to provide a unified strategy for meeting population mental health needs. Traditional models, in which evidence-based therapies delivered are delivered in-person, by a trained expert, at a specialty care location have proved difficult to scale. The use of non-traditional models, tailoring preventive interventions to populations based on their needs, and ongoing coordinated evaluation of intervention implementation and effectiveness will be critical to refining our efforts to increase reach.


Bladder outlet obstruction causes up-regulation of nicotinic acetylcholine receptors in bladder-projecting pelvic ganglion neurons.
Pelvic ganglion (PG) neurons relay sympathetic and parasympathetic signals to the lower urinary tract, comprising the urinary bladder and bladder outlet, and are thus essential for both storage and voiding reflexes. Autonomic transmission is mediated by activation of the nicotinic acetylcholine receptor (nAChR) in PG neurons. Previously, bladder outlet obstruction (BOO), secondary to benign prostatic hyperplasia, was found to increase soma sizes of bladder-projecting PG neurons. To date, however, it remains unknown whether these morphological changes are accompanied by functional plasticity in PG neurons. In the present study, we investigated whether BOO alters acetylcholine receptor (nAChR) transcript expression and current density in bladder PG neurons. Partial ligation of the rat urethra for six weeks induced detrusor overactivity (DO), as observed during cystometrical measurement. In rats exhibiting DO, membrane capacitance of parasympathetic bladder PG neurons was selectively increased. Real-time PCR analysis revealed that BOO enhanced the expression of the transcripts encoding the nAChR α3 and β4 subunits in PG neurons. Notably, BOO significantly increased ACh-evoked current density in parasympathetic bladder PG neurons, whereas no changes were observed in sympathetic bladder and parasympathetic penile PG neurons. In addition, other ligand-gated ionic currents were immune to BOO in bladder PG neurons. Taken together, these data suggest that BOO causes upregulation of nAChR in parasympathetic bladder PG neurons, which in turn may potentiate ganglionic transmission and contribute to the development of DO.


Characterization and genetic analysis of Drosophila melanogaster photobehavior during larval development.
In Drosophila melanogaster, during the mid third instar of development larvae cease foraging and commence a period of increased locomotor activity referred to as wandering behavior. In this study, we quantified the wild type larval response to light during the foraging (first, second, and early third instars) and wandering (late third instar) stages of development. Foraging larvae in the first, second and early third instars exhibited a robust and marked aversion to light (negative phototaxis). From the mid larval third instar larvae showed a decrease in photonegative behavior, until just before pupation when the response of wandering larvae to light became random. The photobehavior of several strains known to affect the adult visual system were also studied. All but four exhibited normal phototaxis in the foraging and wandering stages. gl mutant larvae failed to respond to light during the foraging stage likely due to lack of larval photoreceptors. Larvae carrying three different mutations in the rhodopsin RH1 gene continued to express negative phototaxis throughout both the foraging and wandering stages. These results suggest that the transition from negative phototaxis toward photoneutral behavior characteristic of the wandering third instar larva requires vision.


RESIDUAL INTRARETINAL EDEMA AFTER 25-GAUGE VITRECTOMY AND MACULAR PUCKER REMOVAL: Is Intraoperative Sustained-release Dexamethasone a Real Treatment Option?
To investigate the efficacy and safety of intraoperative slow-release dexamethasone implant and 25-gauge (G) vitrectomy plus epiretinal membrane removal in patients affected by idiopathic macular pucker. In this randomized, clinical, multicenter study, 60 eyes of 60 pseudophakic eyes having idiopathic macular pucker were enrolled. Thirty eyes underwent 25-G pars plana vitrectomy and internal limiting membrane peeling ("Control group"), whereas 30 eyes underwent 25-G pars plana vitrectomy and internal limiting membrane peeling combined with dexamethasone implant ("DEX group"). Best-corrected visual acuity was investigated using Snellen visual acuity ratio. Anatomical outcomes (foveal thickness and total macular volume) were analyzed with spectral domain optical coherence tomography. After 6-month follow-up, best-corrected visual acuity significantly increased in each group (P < 0.05), but there were no significant differences between groups (P = 0.60). Foveal thickness showed a significant decrease in both groups (P < 0.05), but no differences were seen between groups (P = 0.80). Finally, also total macular volume decreased significantly in both groups at the last follow-up visit (P < 0.05), but both groups a showed similar trend (P = 0.12). Intraoperative sustained-release dexamethasone implant, a powerful antiinflammatory agent with significant efficacy in vitrectomized eyes, did not result in a significant change in macular thickness and volume compared with the vitrectomy alone without dexamethasone implant at 6-month follow-up. These data support the hypothesis that its etiology does not seem to be mainly related to an inflammatory process.


Role of smoke-free legislation on emergency department admissions for smoking-related diseases in Kocaeli, Turkey.
Legislation banning smoking in all indoor public places was introduced in Turkey in July 2009. The aim of this study was to evaluate the role of smoke-free legislation on the number of emergency department admissions for smoking-related diseases in Kocaeli city. A retrospective analysis was made of hospital records from the first 6 months of 2009 and 2010 (before and after legislation). Total admissions for smoking-related diseases were 83 089 in 2009 and 64 314 in 2010, a 22.6% decrease. Time-series analysis showed that the decreases were significant for bronchitis and lower respiratory tract infections. Emergency admissions for chronic obstructive pulmonary disease, myocardial infarction and allergic rhinitis were lower but not significantly so. The number of patients admitted with asthma showed a non-significant increase. Smoke-free legislation might have important short-term effects on emergency department admissions, but further studies are needed in order to evaluate the long-term effects of legislation on smoking-related diseases.


[Laxigal effectiveness in constipation of various etiology].
The efficiency of laxigal (sodium picosulfate) was evaluated in 66 patients aged 38-73 years with the irritated bowel syndrome (IBS), inert colon, and dolichocolon. Twenty-eight patients had defecations twice a week, 26 once a week or less. Twelve patients had no spontaneous defecations. Laxigal was administered in a dose of 10-24 droplets before sleeping. Good effect was attained in 42 (64%) patients and satisfactory in 24 (36%). Good effect is more often observed in patients with IBS and dolichocolon, while in patients with inert colon the results were usually no better than satisfactory. After long (3 weeks and longer) therapy with laxigal its dose could be reduced by 30-50% without loss of effect. Laxigal induces no diarrhea, abdominal pain, decrease in electrolyte composition or other serum shifts, does not disorder hepatorenal functions.


EBI2 guides serial movements of activated B cells and ligand activity is detectable in lymphoid and nonlymphoid tissues.
EBV-induced gene 2 (EBI2) was recently shown to direct the delayed movement of activated B cells to interfollicular and outer follicular regions of secondary lymphoid organs and to be required for mounting a normal T-dependent Ab response. In this study, we show that EBI2 promotes an early wave of Ag-activated B cell migration to the outer follicle in mice. Later, when B cells have moved to the T zone in a CCR7-dependent manner, EBI2 helps distribute the cells along the B zone-T zone boundary. Subsequent EBI2-dependent movement to the outer follicle coincides with CCR7 downregulation and is promoted by CD40 engagement. Using a bioassay, we identify a proteinase K-resistant, hydrophobic EBI2 ligand activity in lymphoid and nonlymphoid tissues. Production of EBI2 ligand activity by a cell line is sensitive to statins, suggesting production in a 3-hydroxy-3-methyl-glutaryl-CoA reductase-dependent manner. CD40-activated B cells show sustained EBI2-dependent responsiveness to the bioactivity. These findings establish a role for EBI2 in helping control B cell position at multiple stages during the Ab response and they suggest that EBI2 responds to a broadly distributed lipid ligand.


Liquid exfoliation of 2D MoS2 nanosheets and their utilization as a label-free electrochemical immunoassay for subclinical ketosis.
We report the step-by-step fabrication of a 2D MoS2 nanostructure-based disposable electrochemical immunosensor to detect β-hydroxybutyrate (βHBA), a novel subclinical ketosis biomarker. The MoS2 nanosheets were exfoliated in the liquid phase by ultrasonication, and then followed by deposition on gold colloid modified screen-printed electrodes (Au-SPE). The MoS2-modified electrodes were thoroughly characterized by physical, electrochemical as well as spectroscopic techniques, and the obtained results indicate the successful and irreversible electrodeposition of MoS2 nanosheets. These MoS2-modified disposable electrodes were subsequently bioconjugated with anti-βHBA antibodies and then employed for the label-free immunosensing of the βHBA biomarker to detect subclinical ketosis. A simple electrochemical Differential Pulse Voltammetry (DPV) technique based immunodetection was realized for the sensing of varying concentrations of βHBA antigen. The bioassay demonstrated remarkable sensitivity and specificity having a dynamic linear response range of 0.7 mM to 10 mM for βHBA in standard antigen solutions, spiked serum, blood, milk and clinical samples, with linear results being obtained with R2 ∼ 0.9923. The sensor electrodes were also studied with other relative interferents to investigate cross reactivity and non-specificity. These electrodes showed a linear, specific, reproducible and stable response towards the βHBA antigen over a wide range of concentrations.


The receptor encoded by the human c-MET oncogene is expressed in hepatocytes, epithelial cells and solid tumors.
The human c-MET oncogene encodes a transmembrane tyrosine kinase (p190c-met) with structural and functional features of a growth-factor receptor. Monoclonal antibodies (MAbs) have been used to investigate the distribution of the c-Met protein in human normal and neoplastic tissues. By immunofluorescence microscopy homogeneous expression was detected in normal hepatocytes as well as in epithelial cells lining the stomach, the small and the large intestine. Positive staining was also found in epithelial cells of the endometrium and ovary, and in basal keratinocytes of esophagus and skin. By Northern blot analysis, high levels of c-met messenger RNA were detected in specimens of liver, gastro-intestinal tract and kidney. c-met-specific mRNA was also found in thyroid, pancreas and placenta, in which organs c-Met protein was barely detectable by immunofluorescence. The antibodies revealed expression of c-MET protein in hepatomas (11/14), carcinomas of colon and rectum (19/21), stomach (11/22), kidney (16/19), ovary (9/17) and skin (7/17). Carcinomas of the lung (13/20), thyroid (11/13) and pancreas (5/7) were also positive. In these last cases (lung, thyroid and pancreas) tumor cells were homogeneously stained by the antibodies, whereas in their normal counterparts staining was barely detectable. These data suggest that the receptor encoded by c-MET plays a physiological role in epithelial cell growth and that its expression is altered in human carcinomas.


Nanoparticles as drug delivery systems in the treatment of oral squamous cell carcinoma: current status and recent progression.
Oral squamous cell carcinoma (OSCC) is a common human malignancy with an estimated incidence of around 377,713 new cases worldwide in 2020. Despite the advance in clinical management, some of OSCC patients still miss the opportunity of completable resection of tumor, and have to accept medical therapies, e.g., chemotherapy, radiotherapy, or immunotherapy when the disease develops into the advanced stage. However, these therapies have been reported to be far from ideal due to the low efficiency of conventional delivery approaches. To obtain a better therapeutic effect, considerable attempts have been made toward to develop an effective drug delivery system (DDS). Nanoparticles (NPs) including inorganic NPs, polymer NPs, lipid NP, extracellular vesicles and cell membrane-based NPs have been evaluated as the better DDS candidates that can specifically accumulate in the tumor microenvironment along with a large amount of blood vessels. Emerging evidence suggested that NPs formulated with anticancer drugs including chemotherapeutic drugs, radiotherapy and immunotarget antibodies could remarkably improve the release and increase concentration of these drugs at the tumor site and show a better therapeutic efficacy, suggesting that NPs might serve as promising DDSs in the treatment of OSCC. Therefore, we have conducted this review to summarize recent progression and current status of diverse NPs as DDSs in this research field.


Epidural anesthesia in elective lumbar microdiscectomy surgery: is it safe and effective?
The aim of this study was to evaluate effectiveness and safety of epidural anesthesia in elective lumbar microdiscectomy surgery. Twenty-seven patients (78%, female), who were admitted for single level simple microdiscectomy surgery between May 2012 and December 2013 in single spine center of a university hospital, were enrolled into the study. Clinical evaluations with demographical and per-operative data were collected prospectively. Mean age was 60.04 years. Mean weight, height, and BMI of the study population were 77.7 kg, 160.22 cm, 30.26; respectively. Mean operation duration was 45.56 minutes. Mean VAS score for pain was 0.78 at immediate post-op, 0.52 at 4th hour, and 0.35 at post-operative 24th hour. Ramsay sedation scale (RSS) scores steadily decreased from 2.07 in the immediate post-operative time to 1.93 at 4th hour and 1.88 at 24th hour. The only correlation seen between patient demographics and RSS was body weight seen in immediate post-operative period. Improvements for VAS scores for pain at 4th and 24th hours were 28% and 31%; respectively. Three patients had nausea, one of them vomited after the surgery. All patients were satisfied and would consider epidural anesthesia in future similar surgeries. Epidural anesthesia provides a safe and effective method for elective lumbar microdiscectomy surgery.


International priorities for home care education, research, practice, and management: Qualitative content analysis.
Despite growing demand for home care nursing, there is a growing home care workforce shortage, due in part to hospital-centric nursing curricula that lead students to undervalue of home care and community practice setting (Van Iersel et al., 2018a, 2018b). Articulate an international vision for the future of home care education, research, practice, and management shared by experienced home care nurses working in leadership roles. Qualitative content analysis. The sample included 50 home care professionals from 17 countries. Home care nurse leaders (in education, research, practice, and management roles) were recruited through professional international nursing networks to participate in a structured online survey about priorities for the future of home care in 2014. Responses were open coded by two independent researchers. Preliminary categories and sub-themes were developed by the research team and revised after a modified member-checking process that included presentation and discussion of preliminary findings at three international nursing meetings in 2015 and 2016. Four major themes emerged reflecting international priorities for the future of home care education, research, practice, and management: 1) Build the evidence base for home care; 2) Design better systems of care; 3) Develop leaders at all levels; and 4) Address payment and policy issues. Collectively, the findings provide a major call to action for nurse educators to re-design existing pre- and post-licensure educational programs to meet the growing demand for home care nurses. Innovations in education that focus on filling gaps in the evidence-base for community nursing practice, and improving access to continuing education and evidence-based resources for practicing home care nurses and nurse managers should be prioritized.


p53-dependent apoptosis is essential for the antitumor effect of paclitaxel response to DNA damage in papillary thyroid carcinoma.
A functional p53 protein plays an important role in killing tumor cells. Previous studies showed that chemotherapeutic drug, paclitaxel (PTX), showed anti-tumor activity through inducing G2/M arrest and apoptosis by targeting microtubules in tumor cells. However, PTX was not sensitive to p53-inactivated papillary thyroid carcinoma (PTC) cells by inducing G2/M arrest only. Recombinant adenovirus-p53 (rAd-p53) was used to increase the level of p53, which significantly increased the sensitivity of PTC cells to PTX by inducing S arrest, G2/M arrest and apoptosis. To discuss the anti-tumor mechanism of rAd-p53 + PTX and found p53 activation was necessary for anti-tumor effect of PTX in PTC cells. There was high level of p53 in rAd-p53-treated PTC cells. rAd-p53 + PTX increased the level of p21, p-ATM and γ-H2AX and decreased the level of Cyclin D1/E1, suggesting p53 activated p21 which negatively regulated cyclins to induce S arrest response to DNA damage in PTC cells. rAd-p53 + PTX increased the levels of cleaved-PARP-1, cleaved -Caspase 3, and BAX and decreased the level of BCL-XL, suggesting p53 regulates the expression of BAX/BCL-XL to mediate DNA damage-induced apoptosis in PTC cells. Furthermore, rAd-p53 + PTX showed significant tumor inhibition in TPC-1 xenograft model, with an inhibitory rate of 79.39%. TUNEL assay showed rAd-p53 + PTX induced notable apoptosis in tumor tissues. rAd-p53 showed good sensitization of PTX in vitro and in vivo through inducing DNA damage induced-apoptosis indicated p53-dependent apoptosis was essential for the antitumor effect of PTX in PTC.


Early screening for post-stroke depression, and the effect on functional outcomes, quality of life and mortality: a protocol for a systematic review and meta-analysis.
Post-stroke depression (PSD) is a severe complication of cerebrovascular stroke affecting about one-third of stroke survivors. Moreover, PSD is associated with functional recovery and quality of life (QOL) in stroke survivors. Screening for PSD is recommended. There are, however, differences in the literature on the impact of early screening on functional outcomes. In this systematic review, we synthesise the currently available literature regarding the associations between timing and setting of PSD screening and mortality, QOL and functional outcomes in stroke survivors. We will systematically search electronic databases including PubMed, Embase, APA PsycINFO, Web of Science, Scopus and CINAHL from inception to August 2021. Four reviewers will screen the title and abstract and full-text level records identified in the search in a blinded fashion to determine the study eligibility. Any selection disagreements between the reviewers will be resolved by the study investigator. Data extraction of eligible studies will be conducted by two reviewers using a predefined template. We will complete the quality assessment of included articles independently by two reviewers using the Newcastle Ottawa Scale. Eventual discrepancies will be resolved by the principal investigator. Due to the nature of the study design, ethical approval is not required. The systematic review and meta-analysis findings will be published and disseminated in a peer-reviewed journal. Our results will also be disseminated through posters and presentations at appropriate scientific conferences. CRD42021235993.


An open trial of mindfulness-based cognitive therapy for the prevention of perinatal depressive relapse/recurrence.
Pregnant women with histories of depression are at high risk of depressive relapse/recurrence during the perinatal period, and options for relapse/recurrence prevention are limited. Mindfulness-based cognitive therapy (MBCT) has strong evidence among general populations but has not been studied among at-risk pregnant women to prevent depression. We examined the feasibility, acceptability, and clinical outcomes of depression symptom severity and relapse/recurrence associated with MBCT adapted for perinatal women (MBCT-PD). Pregnant women with depression histories were recruited from obstetrics clinics in a large health maintenance organization at two sites and enrolled in MBCT-PD (N = 49). Self-reported depressive symptoms and interview-based assessments of depression relapse/recurrence status were measured at baseline, during MBCT-PD, and through 6-months postpartum. Pregnant women reported interest, engagement, and satisfaction with the program. Retention rates were high, as were rates of completion of daily homework practices. Intent to treat analyses indicated a significant improvement in depression symptom levels and an 18 % rate of relapse/recurrence through 6 months postpartum. MBCT-PD shows promise as an acceptable, feasible, and clinically beneficial brief psychosocial prevention option for pregnant women with histories of depression. Randomized controlled trials are needed to examine the efficacy of MBCT-PD for the prevention of depressive relapse/recurrence during pregnancy and postpartum.


Zinc improves the filterability of sickle erythrocytes at intermediate oxygen partial pressures.
1. The deformability of erythrocytes from patients with sickle-cell anaemia was measured with a St George's blood filtrometer at a range of oxygen partial pressures and at four levels of zinc loading. 2. When incubated in buffered saline containing zinc and the chelator ethyl maltol, erythrocytes rapidly accumulated zinc and thus their oxygen affinity was increased. 3. Neither the oxygen partial pressure nor zinc loading affected the filtration of normal erythrocytes. 4. Deoxygenation of sickle erythrocytes greatly impaired filtration, although the initial filtration rate declined sharply at different oxygen partial pressures (between 70 and 35 mmHg) in different patients. 5. Low levels of zinc (0.03 +/- 0.003 mol of zinc/mol of haemoglobin tetramer) were without effect on sickle cells, but at zinc/haemoglobin ratios of 0.6:1 and above, the sharp fall in filtration rate occurred at oxygen partial pressures 8-25 mmHg below the oxygen partial pressure that impaired filtration of untreated cells. 6. Hence, the deformability of sickle erythrocytes in vitro can be improved by increasing the intracellular content of zinc to 20-fold above normal. Further studies are now required to examine the stability of zinc in erythrocytes, the effects of high intracellular zinc concentrations on erythrocyte viability, and the toxicity of zinc released from zinc-laden cells.


NMR imaging shows water distribution and transport in plant root systems in situ.
Images of Vicia faba L. root systems at 0.6-mm resolution, undisturbed and within the soil medium in which they were grown, have been obtained by using a 1.5-Tesla proton ((1)H) NMR medical imaging research system. Images of root systems in seven soil media (Cahaba soil, vermiculite, sand, perlite, fritted clay, potting soil, and peatlite) exhibited variable but useful quality owing to a diversity of magnetic properties of the soils. Root structure and pathology in the form of partial decay of hypogeal cotyledons were easily discernible. Water transport in roots with light-stressed foliage was demonstrated by using water doped with a paramagnetic NMR contrast agent, and the process of plant-wilt and recovery was monitored in situ. Images of germinated seeds within soil media indicated that dynamic observations of germination and growth are possible. The results suggest that NMR imaging can be an effective noninvasive tool for studying plants in situ.


Turning the table: plants consume microbes as a source of nutrients.
Interactions between plants and microbes in soil, the final frontier of ecology, determine the availability of nutrients to plants and thereby primary production of terrestrial ecosystems. Nutrient cycling in soils is considered a battle between autotrophs and heterotrophs in which the latter usually outcompete the former, although recent studies have questioned the unconditional reign of microbes on nutrient cycles and the plants' dependence on microbes for breakdown of organic matter. Here we present evidence indicative of a more active role of plants in nutrient cycling than currently considered. Using fluorescent-labeled non-pathogenic and non-symbiotic strains of a bacterium and a fungus (Escherichia coli and Saccharomyces cerevisiae, respectively), we demonstrate that microbes enter root cells and are subsequently digested to release nitrogen that is used in shoots. Extensive modifications of root cell walls, as substantiated by cell wall outgrowth and induction of genes encoding cell wall synthesizing, loosening and degrading enzymes, may facilitate the uptake of microbes into root cells. Our study provides further evidence that the autotrophy of plants has a heterotrophic constituent which could explain the presence of root-inhabiting microbes of unknown ecological function. Our discovery has implications for soil ecology and applications including future sustainable agriculture with efficient nutrient cycles.


The NHS as a learning organization: aspirations beyond the rainbow?
It is the intention of this paper to review the issues and challenges organizations face when aspiring to embrace and enact the tenets of a learning organization; and in particular the perceived impact on management strategy, structure and leadership styles. The paper is predicated on the premise that learning and knowledge act as vital strategic resources, crucial not only to organizations in terms of competitive advantage but to ethical enterprise per se. Modern life is characterized by change, against the backdrop of this continual turmoil, organizational learning has emerged as a dominant theme within contemporary management theory, with many commentators increasingly locating the capacity of an aspiring organization to accommodate the ethos of organizational learning, as the vital component in ensuring enduring efficiency, innovation and competitiveness. However, the utility of such learning needs to be scrutinized and evaluated in terms of service need and expectation. The paper will expand upon wider theoretical debates extant within the literature, by considering the concept and utility of the learning organization with specific reference to management reform extant within the British National Health Service (NHS). During the course of the review the various the theoretical positions contributing to the notion of the learning organization will be analysed, the practical ramifications of which will be examined in the context of reflective practice, clinical supervision and the wider cultural background of nursing and the NHS. The paper concludes that the NHS needs to reorientate management perspectives to focus attention more acutely on systems which are deliberately designed to facilitate shared learning, to unravel the ambiguities of organizational life, to affirm management belief in the nursing contribution and to achieve an as yet unrealized potential in terms of patient care and advanced nursing practice.


FLUORIDE CONTENT OF COMMERCIALLY AVAILABLE SOY MILK PRODUCTS IN THAILAND.
Abstract. In Thailand, the consumption of soy milk products is common but there is limited data about their fluoride content. The purpose of this study was to es- timate the fluoride content of soy milk products available in Thailand. Fluoride content was determined for 76 brands of soy milk using a F-ion-specific electrode. The fluoride concentrations ranged from 0.01 to 3.78 μg/ml. The fluoride content was not related to sugar content, soy bean content or the sterilization process. Among 3 brands of soy milk containing tea powder extract, the fluoride content was high (1.25 to 3.78 μg/ml). Most brands of soy milk tested in our study had fluoride content below the optimal daily intake but brands containing tea powder extract if consumed by children may increase their risk for fluorosis.


Autophagy gene ATG7 regulates albumin transcytosis in renal tubule epithelial cells.
Receptor-mediated albumin transport in proximal tubule epithelial cells (PTECs) is important to control proteinuria. Autophagy is an evolutionarily conserved degradation pathway, and its role in intracellular trafficking through interactions with the endocytic pathway has recently been highlighted. Here, we determined whether autophagy regulates albumin transcytosis in PTECs and suppresses albumin-induced cytotoxicity using human proximal tubule (HK-2) cells. The neonatal Fc receptor (FcRn), a receptor for albumin transcytosis, is partially colocalized with autophagosomes. Recycling of FcRn was attenuated, and FcRn accumulated in autophagy-related 7 (ATG7) knockdown HK-2 cells. Colocalization of FcRn with RAB7-positive late endosomes and RAB11-positive recycling endosomes was reduced in ATG7 knockdown cells, which decreased recycling of FcRn to the plasma membrane. In ATG7 or autophagy-related 5 (ATG5) knockdown cells and Atg5 or Atg7 knockout mouse embryonic fibroblasts, albumin transcytosis was significantly reduced and intracellular albumin accumulation was increased. Finally, the release of kidney injury molecule-1, a marker of tubule injury, from ATG7 or ATG5 knockdown cells was increased in response to excess albumin. In conclusion, suppression of autophagy in tubules impairs FcRn transport, thereby inhibiting albumin transcytosis. The resulting accumulation of albumin induces cytotoxicity in tubules.NEW & NOTEWORTHY Albumin transport in proximal tubule epithelial cells (PTECs) is important to control proteinuria. The neonatal Fc receptor (FcRn), a receptor for albumin transcytosis, is partially colocalized with autophagosomes. Recycling of FcRn to the plasma membrane was decreased in autophagy-related 7 (ATG7) knockdown cells. In addition, albumin transcytosis was decreased in ATG7 or autophagy-related 5 (ATG5) knockdown PTECs. Finally, release of kidney injury molecule-1 from ATG7 or ATG5 knockdown cells was increased in response to excess albumin.


Apoptosis of retinal ganglion cells in anterior ischemic optic neuropathy.
We identified retinal ganglion cells undergoing apoptosis, a form of programmed cell death, in an eye of a 70-year-old man with anterior ischemic optic neuropathy. The TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin end nick labeling) staining and the presence of condensed, fragmented nuclear bodies were used to identify apoptotic cells. Examination of TUNEL-stained retinal sections revealed occasional cells in the ganglion cell layer with pyknotic nuclei and brown reaction product, representing positive staining for chromosomal DNA breaks. Positive cells were sparsely distributed, consistent with the limited time in which apoptotic cells are identifiable before they are removed. The most likely explanation for these results is that injury to the retinal ganglion cell axon induces apoptosis. To our knowledge, this is the first report of human retinal ganglion cell apoptosis in an acute optic neuropathy.


Outcomes of robotic versus laparoscopic surgery for mid and low rectal cancer after neoadjuvant chemoradiation therapy and the effect of learning curve.
Randomized controlled trials have demonstrated that laparoscopic surgery for rectal cancer is safe and can accelerate recovery without compromising oncological outcomes. However, such a surgery is technically demanding, limiting its application in nonspecialized centers. The operational features of a robotic system may facilitate overcoming this limitation. Studies have reported the potential advantages of robotic surgery. However, only a few of them have featured the application of this surgery in patients with advanced rectal cancer undergoing neoadjuvant chemoradiation therapy (nCRT).From January 2012 to April 2015, after undergoing nCRT, 40 patients with mid or low rectal cancer were operated using the robotic approach at our institution. Another 38 patients who were operated using the conventional laparoscopic approach were matched to patients in the robotic group by sex, age, the body mass index, and procedure. All operations were performed by a single surgical team. The clinicopathological characteristics and short-term outcomes of these patients were compared. To assess the effect of the learning curve on the outcomes, patients in the robotic group were further subdivided into 2 groups according to the sequential order of their procedures, with an equal number of patients in each group. Their outcome measures were compared.The robotic and laparoscopic groups were comparable with regard to pretreatment characteristics, rectal resection type, and pathological examination result. After undergoing nCRT, more patients in the robotic group exhibited clinically advanced diseases. The complication rate was similar between the 2 groups. The operation time and the time to the resumption of a soft diet were significantly prolonged in the robotic group. Further analysis revealed that the difference was mainly observed in the first robotic group. No significant difference was observed between the second robotic and laparoscopic groups.Although the robotic approach may offer potential advantages for rectal surgery, comparable short-term outcomes may be achieved when laparoscopic surgery is performed by experienced surgeons. However, our results suggested a shorter learning curve for robotic surgery for rectal cancer, even in patients who exhibited more advanced disease after undergoing nCRT.


Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner.
Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4+ T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naïve Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORγt in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4+ T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4+ T cell-mediated diseases.


Mortality in nondemented subjects with cognitive impairment: the influence of health-related factors.
Nondemented older subjects with cognitive impairment are at higher risk of death than are mentally intact persons. It is unknown whether the effect of cognitive impairment on mortality is independent or mediated by poorer health or other factors. To address this issue, the authors used a prospective population-based cohort study with 8 years of follow-up started in 1987 in the urban district of Kungsholmen, Stockholm, Sweden. Subjects were all 75- to 95-year-old subjects nondemented at baseline (n = 1,435). Data on cognition, health (mental and subjective health, physical diseases and comorbidity, nutritional status, and disability), and apolipoprotein E genotype were collected at baseline as was time of death at follow-up. Cognitive impairment was defined on the basis of age- and education-specific cutoffs on the Mini-Mental State Examination. When compared with cognitively unimpaired subjects (n = 1,210), those cognitively impaired (n = 225) had poorer health conditions, were more frequently apolipoprotein E epsilon4 carriers, and had greater mortality risk (hazard ratio = 1.7; 95% confidence interval: 1.5, 2.1). Neither health nor apolipoprotein E genotype accounted for the association of cognitive impairment with mortality (adjusted hazard ratio = 1.6; 95% confidence interval: 1.3, 1.9). The functional and behavioral consequences associated with the progression of cognitive impairment may mediate the increased mortality risk.


Sojourn-time-corrected receiver operating characteristic curve (ROC) for prostate specific antigen (PSA) test in population-based prostate cancer screening.
Evaluating the performance of serum prostate-specific antigen (PSA) test in population-based screening with receiver operating characteristics (ROC) curve often neglects the time dimension. Asymptomatic cases with negative PSA test would have been missed if sojourn time is not taken into account to allow for cases surfacing into the clinical phase. Data included 20,796 men with PSA test at the first screening round was used from population-based Finnish prostate cancer screening trial during 1996-1999. Cancers detected at the first screen, together with interval cancers ascertained during 4-year follow-up were expediently used to estimate sensitivity and specificity. A sojourn-time-corrected model was applied to estimating the possible false negative cases for those with PSA < 4 ng/ml for correcting the ROC curve. The estimated sensitivity estimate was reduced from 94.4% without correction to 68.8% with correction but the estimated specificity was identical (89.4% vs. 89.2%) at cutoff of 3 ng/ml. The corrected area under curve (AUC) [77.0% (74.9-79.1%)] of the PSA test was significantly lower than the uncorrected AUC [95.9% (95.3-96.6%)]. The failure of considering the time since last negative screen due to incomplete ascertainment for asymptomatic cancer led to the overestimation of PSA test performance that further affects the cut-off value of PSA tests for population-based prostate cancer screening.


When does mass screening for open neural tube defects in low-risk pregnancies result in cost savings?
Using a decision analysis model, we estimated the savings that might be derived from a mass prenatal screening program aimed at detecting open neural tube defects (NTDs) in low-risk pregnancies. Our baseline analysis showed that screening v. no screening could be expected to save approximately $8 per pregnancy given a cost of $7.50 for the maternal serum alpha-feto-protein (MSAFP) test and a cost of $42,507 for hospital and rehabilitation services for the first 10 years of life for a child with spina bifida. When a more liberal estimate of the costs of caring for such a child was used, the savings with the screening program were more substantial. We performed extensive sensitivity analyses, which showed that the savings were somewhat sensitive to the cost of the MSAFP test and highly sensitive to the specificity (but not the sensitivity) of the test. A screening program for NTDs in low-risk pregnancies may result in substantial savings in direct health care costs if the screening protocol is followed rigorously and efficiently.


Influence of chromatin structure and radical scavengers on yields of radiation-induced 8-oxo-dG and DNA strand breaks in cellular model systems.
Radiation-induced formation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) and DNA strand breaks was studied in cultured cells with normal or modified chromatin structure. Human fibroblasts were irradiated as cellular monolayers (intact cells), nuclear monolayers (permeabilized cells with intact chromatin structure), and nucleoid monolayers (permeabilized and salt-treated cells with histone-free DNA). 8-oxo-dG was assayed with reverse-phase HPLC coupled to an electrochemical detector and strand breaks with the alkali unwinding assay. Depletion of low-molecular-weight nuclear components increased the radiation-induced formation of 8-oxo-dG fivefold compared to twofold for the formation of strand breaks. Removal of both low-molecular-weight components and histones increased the yield of 8-oxo-dG 46-fold and the yield of strand breaks 43-fold. Removal of only the histones thus leads to a two times greater increase in the yield of strand breaks compared to 8-oxo-dG. Addition of radical scavengers to nuclear and nucleoid monolayers provided a significantly better protection against the formation of 8-oxo-dG relative to the formation of strand breaks. These results suggest that in intact cells, 8-oxo-dG is preferentially formed in histone-free structures of chromatin, indicating a larger role for the indirect effect of radiation in the formation of 8-oxo-dG than in the formation of strand breaks.


In vitro effects of phosphatidylcholine and transgalactooligosaccharides on the production of 1,2-sn-diacylglycerol by Bifidobacterium longum biovar infantis.
To investigate the production of the tumour promoter 1,2-sn-diacylglycerol (DAG) by a human gut isolate of Bifidobacterium longum biovar infantis. Bifidobacterium longum biovar infantis was grown in vitro using anaerobic static batch cultures in the presence of phosphatidylcholine (PC) and trans-galactooligosaccharides (TOS). Production of DAG was found to be dependent upon the presence of PC, while TOS had a reducing effect. Considerable differences in morphology, growth and metabolic end products from the micro-organism were observed under the different culture conditions. Our results have provided evidence that B. longum biovar infantis can produce DAG in vitro and that a prebiotic exerted a reducing effect upon this production. The results presented in this study demonstrate an ability of ostensibly beneficial member of the colonic environment to produce unwanted compounds under certain conditions. Therefore, it may be important that a combination of substrates and other factors are assessed when studying the behaviour of any bacterial group or species, especially when designing the dietary interventions.


Investigating the origin of tomatoes and triple concentrated tomato pastes through multielement determination by inductively coupled plasma mass spectrometry and statistical analysis.
The concentration of 32 elements (Al, As, Ba, Be, Ca, Cd, Ce, Cu, Dy, Fe, K, La, Lu, Mg, Mn, Na, Nd, Pb, Rb, Sm, Sr, Th, U, V, Zn) was determined in tomatoes harvested in different four Italian regions and in triple concentrated tomato paste samples coming from Italy, China, Greece and California. The resulting multielement profiles were processed using three chemometric techniques to evaluate the possibility of discrimination between different cultivation areas. The closed-vessel microwave digested samples were diluted and analyzed by DRC-ICP-MS with CH(4) as reaction gas. The accuracy of the proposed method was considered acceptable (values in the range 75-120%) for 25 out of the 35 elements of the reference material NCS ZC85006 Tomato. The origin of tomato fruits and the areas of production as "Italy" and "non-Italy" of the triple concentrated pastes were evaluated by three supervised pattern recognition procedures, linear discriminant analysis (LDA), soft independent modeling of class analogy (SIMCA) and K-nearest neighbors (KNN).


Stem cells and the kidney: a new therapeutic tool?
In the past few years, a number of studies have shown that stem cells can be found in virtually every organ of the adult organism. The kidney is not an exception, and resident stem cells have been identified both in the papilla and along the tubules. Of interest, kidney-bound stem cells have been identified also in the bone marrow. When injected, both resident and bone marrow-derived stem cells are able to reach the injured renal tissue and, once there, to differentiate into renal cells. The evidence that, in humans, some of the acute and most of the chronic renal damages lead to ESRD suggests that in normal conditions, the reservoir of stem cells (considering both resident and bone marrow-derived stem cells) is insufficient to allow a major renal regeneration. Probably the number of stem cells that are ready to intervene in an adult kidney are sufficient to compensate for the normal cell turnover but largely inadequate to counteract a major injury. This is confirmed further by the finding that, even by transplanting a syngenic bone marrow in rats with ablation of 5/6 of the renal function, it is not possible to increase the life expectancy of the animals. Altogether, this evidence suggests that, to clarify the potentiality of a stem cell therapy for renal diseases, experiments that aim to clarify the ideal concentration of stem cells to be injected and to identify the best way of administration are needed.


[Space radiation biology].
Astronauts were constantly exposed to space radiation containing various kinds of energy with a low-dose rate during long-term stays in space. Therefore, it is important to judge correctly the biological effect of space radiation for human health. In addition, research for space radiation might give us useful information concerning birth and evolution of lives on the earth. Here, we described a view of the future about space experiments at an International Space Station. Therefore, we desire to educate the space researcher of the next generation for importance of research for space radiation.


The drug resistance suppression induced by curcuminoids in colon cancer SW-480 cells is mediated by reactive oxygen species-induced disruption of the microRNA-27a-ZBTB10-Sp axis.
Mechanisms involving the curcuminoids effects in decreasing the prooncogenic specificity protein (Sp) transcription factors, and Sp-regulated genes in SW-480 colon cancer cells and how the multidrug resistance protein (MDR1) inhibition is mediated by Sp suppression. HT-29 and SW-480 colon cancer and normal CCD-18Co colon fibroblast cells were treated with curcuminoids previously analyzed by HPLC. Gene and protein expression regulation were assessed by RT-PCR, transfections with expression constructs, and Western blots. Curcuminoids (2.5-10 μg/mL) suppressed preferentially the growth of SW-480 and HT-29 compared to CCD-18Co cells and enhanced the anticancer activity of the chemotherapeutic drug 5-fluorouracil due to the suppression of MDR1. Additionally, Sp1, Sp3, and Sp4 and Sp-regulated genes were downregulated by curcuminoids in SW-480 and this was accompanied by suppression of microRNA-27a (miR-27a) and induction of ZBTB10, an mRNA target of miR-27a and a transcriptional repressor of Sp expression. This mechanism was mediated by the induction of ROS. RNA-interference and transfection with ZBTB10-expression plasmid demonstrated that MDR1 was regulated by Sp1 and Sp3 and the disruption of the miR-27a-ZBTB10-Sp axis. Colon cancer treatment with curcuminoids will enhance the therapeutic effects of drugs in patients who have developed drug resistance.


The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study.
The study aimed to estimate the risk of cardiac events in immune checkpoint inhibitor (ICI)-treated patients with lung cancer or malignant melanoma. The study included consecutive patients with lung cancer or malignant melanoma in 2011-17 nationwide in Denmark. The main composite outcome was cardiac events (arrhythmia, peri- or myocarditis, heart failure) or cardiovascular death. Absolute risks were estimated and the association of ICI and cardiac events was analysed in multivariable Cox models. We included 25 573 patients with lung cancer. Of these, 743 were treated with programmed cell death-1 inhibitor (PD1i) and their 1-year absolute risk of cardiac events was 9.7% [95% confidence interval (CI) 6.8-12.5]. Of the 13 568 patients with malignant melanoma, 145 had PD1i and 212 had cytotoxic T-lymphocyte-associated protein-4 inhibitor (CTLA-4i) treatment. Their 1-year risks were 6.6% (1.8-11.3) and 7.5% (3.7-11.3). The hazard rates of cardiac events were higher in patients with vs. without ICI treatment. Within 6 months from 1st ICI administration, the hazard ratios were 2.14 (95% CI 1.50-3.05) in patients with lung cancer and 4.30 (1.38-13.42) and 4.93 (2.45-9.94) in patients with malignant melanoma with PD1i and CTLA-4i, respectively. After 6 months, HRs were 2.26 (1.27-4.02) for patients with lung cancer and 3.48 (1.91-6.35) for patients with malignant melanoma and CTLA-4i. Among patients with lung cancer and malignant melanoma, ICI treated had increased rates of cardiac events. The absolute risks were higher in these data compared with previous pharmacovigilance studies (e.g. 1.8% peri-/myocarditis 1-year risk).


Mutation of cytochrome P-45017 alpha gene (CYP17) in a Japanese patient previously reported as having glucocorticoid-responsive hyperaldosteronism: with a review of Japanese patients with mutations of CYP17.
A 17-yr-old female Japanese patient, who was reported in 1968 as having glucocorticoid-responsive hyperaldosteronism but was presumed to have a defect of 17 alpha-hydroxylation mainly in the adrenal glands as the etiology of her illness, was followed. The relationship between clinical manifestations and molecular abnormalities in cytochrome P-45017 alpha gene (CYP17) was also reviewed based on the literature on Japanese patients with 17 alpha-hydroxylase deficiency. She has been treated with dexamethasone, resulting in normal blood pressure and normokalemia for 28 yr. She had almost normal gonadal function with regular menstruation on her first admission. Because of sustained genital bleeding, however, she underwent total hysterectomy with an ovarian biopsy at the age of 42 yr. No follicles or corpus luteum were detected in the ovarian specimen. At the age of 45 yr, the basal levels of sex steroids were decreased, while those of gonadotropins were increased. A genetic study on CYP17 revealed a homozygous deletion of phenylalanine (Phe) codon (TTC) at either amino acid position 53 or 54 in exon 1. A review of the literature revealed 4 patients with this type of CYP17 mutation, including the present patient, out of a total of 11 young adult Japanese patients. The clinical manifestations caused by congenitally deficient gonadal function were not marked in any of these 4 patients, but were marked in 5 of the 7 patients with different mutations of CYP17. The remaining 2 female patients had irregular menstruation. The pretreatment urine/plasma values of aldosterone were variable, normal to high, in individual patients, regardless of the structural abnormalities of CYP17. The following conclusions were suggested: 1) this type of CYP17 mutation is associated with well preserved gonadal function in young adult patients, but it likely causes early reduction of gonadal function with increasing age in these patients; 2) the prevalence of this type of CYP17 mutation is quite high in Japanese patients; and 3) the pretreatment hyperaldosteronism observed in the present patient seems not to be related to the mutation of CYP17.


Microbulbifer marinus sp. nov. and Microbulbifer yueqingensis sp. nov., isolated from marine sediment.
Two Gram-negative, aerobic strains, Y215(T) and Y226(T), were isolated from sediment from Yueqing Bay, Zhejiang Province, China. The two novel strains were both positive for oxidase activity, nitrate reduction, and aesculin and casein decomposition, but negative for gelatin and tyrosine decomposition. Catalase activity, and starch and Tween 80 decomposition differed between the two strains. Cells of both novel strains were rod-shaped in young cultures and ovoid in older cultures. Optimum NaCl concentration and pH range for growth of both strains were 2.0-3.0% (w/v) and 7.0-8.0, respectively, whereas the optimum growth temperature for strain Y215(T) (25-30 °C) was lower than that for strain Y226(T) (30-37 °C). The genomic DNA G+C contents of strains Y215(T) and Y226(T) were 54.0 and 56.7 mol%, respectively. The major fatty acids in both isolates were iso-C(15:0) and iso-C(17:1)ω9c, which was also the case in the reference strains apart from Microbulbifer salipaludis, which possessed C(18:1)ω7c as the predominant fatty acid. The predominant isoprenoid quinone was Q-8 and the major polar lipids of both strains were phosphatidylethanolamine, phosphatidylglycerol and an unknown glycolipid. Both strains had highest 16S rRNA gene sequence similarity to members of the genus Microbulbifer. Strain Y215(T) was closely related to the type strains of Microbulbifer maritimus (97.6%) and Microbulbifer donghaiensis (97.5%), whereas strain Y226(T) was closely related to the type strain of M. salipaludis (97.6%). Phylogenetic analysis based on 16S rRNA gene sequences showed that strains Y215(T) and Y226(T) fell into two separate clusters. The DNA-DNA relatedness values of strain Y215(T) with M. maritimus TF-17(T) and M. donghaiensis CN85(T) were 34.1 and 32.8%, respectively, whereas that between strain Y226(T) and M. salipaludis SM-1(T) was 38.0%; these values are significantly lower than the threshold value for the delineation of bacterial species. On the basis of their distinct taxonomic characteristics, the two isolates represent two novel species of the genus Microbulbifer, for which the names Microbulbifer marinus sp. nov. and Microbulbifer yueqingensis sp. nov. are proposed; the type strains are Y215(T) (=CGMCC 1.10657(T)=JCM 17211(T)) and Y226(T) (=CGMCC 1.10658(T)=JCM 17212(T)), respectively.


Revisiting the bonding of the pentagonal-pyramidal C6H62+ and C6(CH3)62+ dications.
This work delves into the bonding nature of the pentagonal-pyramidal benzene and hexamethylbenzene dications, C6R62+ (R = H and CH3), which contain a hexacoordinate carbon. The study employs a range of methodologies to analyze a series of scalar fields, including electron density, electron localization function, local momentum representation, and the evaluation of the Coulomb hole through information theory-derived functions. The findings unveil that electron density undergoes transfer from the pentagonal ring to the apical group. As a result, the base of the complex accumulates the positive charge. Moreover, an extended electron density domain emerges between the carbon pentagon and the apical carbon atom. This phenomenon is related to the molecular orbitals with a dipolar character aligned with the principal axis of the molecule. The results also indicate an electron density polarization towards the apical carbon, coupled with an exclusion of electron density surrounding both the apical carbon and the lower portion of the pentagonal ring. These provide valuable insights into the complex bonding nature of hexacoordinate carbon and its implications for organic chemistry.


Differentially Expressed Tear Proteins in Sjögren's Syndrome Keratoconjunctivitis Sicca.
The purpose of this study was to determine if there are significant differences in the concentrations of tear proteins in Sjögren's syndrome keratoconjunctivitis sicca (SS KCS) compared to healthy controls. Tear samples were collected with unmarked Schirmer strips from 15 patients with SS KCS and 21 healthy controls. Tear protein was eluted and the concentration measured. Inflammatory mediators were assayed with a Raybiotech L-507 glass slide array and normalized by strip wetting length. All patients underwent an ocular surface exam to evaluate tear break-up time (TBUT), corneal fluorescein (CF) staining, and conjunctival (CJ) staining. The symptom assessment questionnaire in dry eye (SANDE) scores were collected for all patients. Two hundred fifty-three of the 507 tear proteins analyzed were significantly different in patients with SS compared to controls. Two hundred forty-one if the proteins were upregulated and 12 were downregulated. One hundred eighty-one differentially expressed proteins were significantly correlated with all four clinical parameters: TBUT, CF staining, CJ staining, and SANDE score. These findings indicate that hundreds of factors can be assayed in tear proteins collected from a Schirmer strip. The results suggest tear protein concentrations are altered in patients with SS KCS compared to controls. The upregulated tear proteins correlated with clinical measures of dry eye symptoms and disease severity. Tear proteins could serve as important biomarkers for studying pathogenesis and in clinical diagnosis and management of SS KCS.


The efficacy and safety of acupuncture-related therapy in the treatment of rheumatoid arthritis: A protocol for systematic review and network meta-analysis.
Rheumatoid arthritis (RA) has seriously affected the quality of life of patients with its refractory, recurrent, and disabled characteristics, and has become a major public health problem. Previous studies have confirmed that acupuncture and moxibustion have a reliable effect on RA, but there are many forms of acupuncture and moxibustion, and the efficacy of each form is different. This study is to evaluate the clinical efficacy of different acupuncture-related therapies in the treatment of RA by means of network meta-analysis. According to the retrieval strategy, we retrieved the randomized controlled studies on acupuncture-related therapy for RA from China National Knowledge Infrastructure, Wanfang, VIP, China Biomedicine, PubMed, Embase, Web of Science, and The Cochrane Library databases from the establishment of the database to July 2021. We assessed the quality of the studies using the Cochrane Risk Bias Assessment Tool and assessed the strength of the evidence using the Grading of Recommendation Assessment, Development, and Evaluation methodology. All data analyses were performed by Revman5.3, Gemtc 0.14.3, and Stata 14.0. This study is to evaluate the efficacy of different acupuncture-related therapies in the treatment of RA by evaluating the total effective rate, pain scores, joint function scores, quality of life scores, laboratory indicators, adverse reactions, etc. This study will provide a reliable evidence-based basis for the selection of the best acupuncture form for the treatment of RA. Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval will not be required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.


Context-dependent requirement for dE2F during oncogenic proliferation.
The Hippo pathway negatively regulates the cell number in epithelial tissue. Upon its inactivation, an excess of cells is produced. These additional cells are generated from an increased rate of cell division, followed by inappropriate proliferation of cells that have failed to exit the cell cycle. We analyzed the consequence of inactivation of the entire E2F family of transcription factors in these two settings. In Drosophila, there is a single activator, dE2F1, and a single repressor, dE2F2, which act antagonistically to each other during development. While the loss of the activator dE2F1 results in a severe impairment in cell proliferation, this defect is rescued by the simultaneous loss of the repressor dE2F2, as cell proliferation occurs relatively normally in the absence of both dE2F proteins. We found that the combined inactivation of dE2F1 and dE2F2 had no significant effect on the increased rate of cell division of Hippo pathway mutant cells. In striking contrast, inappropriate proliferation of cells that failed to exit the cell cycle was efficiently blocked. Furthermore, our data suggest that such inappropriate proliferation was primarily dependent on the activator, de2f1, as loss of de2f2 was inconsequential. Consistently, Hippo pathway mutant cells had elevated E2F activity and induced dE2F1 expression at a point when wild-type cells normally exit the cell cycle. Thus, we uncovered a critical requirement for the dE2F family during inappropriate proliferation of Hippo pathway mutant cells.


Epigenetic reprogramming to prevent genetic cardiomyopathy.
Mutations in the gene that codes for lamin A/C (LMNA) are a common cause of adult-onset cardiomyopathy and heart failure. In this issue of the JCI, Guénantin and Jebeniani et al. identify impaired cardiomyocyte development and maturation as a prenatal feature in a model of laminopathy. Cardiomyocytes carrying the Lmna point mutation H222P misexpressed genes involved in the epithelial-mesenchymal transition and showed decreased methylation at the fourth lysine of histone H3 (H3K4). Notably, inhibiting lysine-specific demethylase 1 in the LMNA H222P mouse model treated this congenital form of cardiomyopathy and improved survival in utero. These data highlight early epigenomic modifications in lamin A/C-mediated pathology and indicate a unique therapeutic strategy for cardiomyopathy.


Does growth require suffering? A systematic review and meta-analysis on genuine posttraumatic and postecstatic growth.
Previous literature on growth after major life events has primarily focused on negative experiences and operationalized growth with measures which rely on the post hoc self-perception of change. Because this method is prone to many biases, two questions have become increasingly controversial: Is there genuine growth after major life events and does growth require suffering? The present meta-analysis is the first synthesis of longitudinal research on the effects of life events on at least one subdomain of psychological well-being, posttraumatic, or postecstatic growth. Studies needed to have a longitudinal design, assess changes through independent measures over time, and provide sufficient data to estimate change scores. The present meta-analysis comprises 364 effect sizes from 154 independent samples (total N = 98,436) in 122 longitudinal studies. A positive trend has been found for self-esteem, positive relationships, and mastery in prospective studies after both positive and negative events. We found no general evidence for the widespread conviction that negative life events have a stronger effect than positive ones. No genuine growth was found for meaning and spirituality. In the majority of studies with control groups, results did not significantly differ between event and control group, indicating that changes in the outcome variables cannot simply be attributed to the occurrence of the investigated life events. More controlled prospective studies are necessary to validate the genuine nature of postevent growth. Overall, the meta-analysis provides a systematic overview of the state of life event research and delineates important guidelines for future research on genuine growth. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


[Study of the clinical features of psychopathy-like schizophrenia in childhood and adolescence].
As a result of comparing the clinical course in 230 cases with psychopathlike schizophrenia, followed up on an average for 10 years, with 600 cases of psychopathies which are formed in adolescents, basic clinical characteristics, differentiating the first group from the second were detected and described. Age-associated time-course of morbid disorders in psychopathlike schizophrenia with an early onset, depending upon age crisis and phases of pubertal period was demonstrated. With the aid of special programmes, designed to solve the question of classification by a computer, a combination of factors comprising an optimal diagnostic complex for psychopathlike schizophrenia in adolescence was demonstrated.


The 'critical trochanter angle': a predictor for stem alignment in total hip arthroplasty.
Stem malalignment can affect offset reconstruction and may result in gluteal muscle insufficiency. In this retrospective study, a novel geometric angle named 'critical trochanter angle' (CTA) is described and investigated towards the risk of malposition of a collarless straight tapered hydroxyapatite-coated stem in primary total hip arthroplasty (THA). A total of 100 cementless THA were implanted in patients with unilateral coxarthrosis via the direct anterior (n = 50) or direct lateral Hardinge approach (n = 50) in a two surgeon setting using the Corail® or Trendhip® stem (DePuy Synthes or Aesculap). Stem alignment was analysed in postoperative AP pelvic radiographs and correlated to the CTA: the angle crest was defined by the intersection of the femoral shaft and neck axis and the angle was measured between the shaft axis and a leg intersecting the vertex between the lateral and superoposterior facet of the trochanter. Forty-seven stems were implanted in varus (≥ + 1°), 42 in neutral (< + 1°/> - 1°) and 11 in valgus position (≤ - 1°). The mean critical trochanter angle was 25.0° (SD ± 7.5°), and there was a negative and statistically significant correlation to stem alignment (r = - 0.52; p ≤ 0.001) independent from the surgical approach. For stem malposition of 2° and above (n = 23), mean CTA was 17.2° for varus (n = 20) and 31.6° for valgus (n = 3). A CTA lesser or equal to 22.75° had a sensitivity of 90% and specificity of 80% for varus stem position of 2° or greater. Specificity raised to 100% with a cutoff CTA of 12.5° or lesser. Varus stem alignment in THA is associated with coxa vara deformity and a radiological low CTA. In preoperative planning, the critical trochanter angle can help to evaluate the risk for intraoperative stem malpositioning. If navigation or robotic assistance is not available when using this stem design, we recommend an intraoperative x-ray to verify correct implant positioning in patients with a CTA under 20° or above 30°.


Spatial control of the βAR system in heart failure: the transverse tubule and beyond.
The beta1-adrenoceptors (β(1)AR) and beta-2 (β(2)AR) adrenoceptors represent the predominant pathway for sympathetic control of myocardial function. Diverse mechanisms have evolved to translate signalling via these two molecules into differential effects on physiology. In this review, we discuss how the functions of the βAR are organized from the level of secondary messengers to the whole heart to achieve this. Using novel microscopy and bio-imaging methods researchers have uncovered subtle organization of the control of cyclic adenosine monophosphate (cAMP), the predominant positively inotropic pathway for the βAR. The β(2)AR in particular is demonstrated to give rise to highly compartmentalized, spatially confined cAMP signals. Organization of β(2)AR within the T-tubule and caveolae of cardiomyocytes concentrates this receptor with molecules which buffer and shape its cAMP signal to give fine control. This situation is undermined in various forms of heart failure. Human and animal models of heart failure demonstrate disruption of cellular micro-architecture which contributes to the change in response to cardiac βARs. Loss of cellular structure has proved key to the observed loss of confined β(2)AR signalling. Some pharmacological and genetic treatments have been successful in returning failing cells to a more structured phenotype. Within these cells it has been possible to observe the partial restoration of normal β(2)AR signalling. At the level of the organ, the expression of the two βAR subtypes varies between regions with the β(2)AR forming a greater proportion of the βAR population at the apex. This distribution may contribute to regional wall motion abnormalities in Takotsubo cardiomyopathy, a syndrome of high sympathetic activity, where the phosphorylated β(2)AR can signal via Gi protein to produce negatively inotropic effects.