Risk factors for psychosis in an ultra high-risk group: psychopathology and clinical features.
The identification of individuals at high risk of developing a psychotic disorder has long been a goal of clinicians because it is thought that early treatment of this group may prevent onset of the disorder. However, little is known of predictive factors of psychosis, even within a high-risk group. This study followed up 104 young people thought to be at 'ultra high risk' for schizophrenia and other psychotic disorders by virtue of having a family history of psychotic disorder combined with some functional decline or the presence of subthreshold or self-limiting psychotic symptoms. All subjects were therefore symptomatic, but not psychotic, at intake. Thirty-six subjects (34.6%) developed frank psychotic symptoms within 12 months. Measures of symptom duration, functioning, disability and psychopathology were made at intake, 6 and 12 months. Poor functioning, long duration of symptoms, high levels of depression and reduced attention were all predictors of psychosis. A combination of family history of psychosis, a recent significant decrease in functioning and recent experience of subthreshold psychotic symptoms was also predictive of psychosis. Combining highly predictive variables yielded a method of psychosis prediction at 12 months with good positive predictive value (80.8%), negative predictive value (81.8%) and specificity (92.6%) and moderate sensitivity (60.0%). Within our symptomatic high-risk group, therefore, it appears possible to identify those individuals who are at particularly high risk of developing a psychotic disorder such as schizophrenia. Given the very high PPV and low false positive rate with this two-step process, it may be justifiable to target these individuals for intensive monitoring of mental state and even low-dose neuroleptic medication or other biological and psychosocial treatments depending on clinical condition. This indicated prevention approach could be further developed and preventive strategies in the psychoses refined.


Effectiveness and safety of sirolimus stent implantation for coronary in-stent restenosis: the TRUE (Tuscany Registry of Sirolimus for Unselected In-Stent Restenosis) Registry.
This study sought to evaluate the effectiveness and safety of the sirolimus-eluting stent in the treatment of in-stent restenosis (ISR) in consecutive unselected patients undergoing coronary intervention in a real-world scenario. Restenosis after bare metal stenting is characterized by a high rate of re-restenosis once treated with repeated percutaneous coronary intervention. The study was designed as a prospective two-center registry. We enrolled 244 patients with ISR in a native coronary artery or saphenous vein graft who had clinical indication for repeat intervention. Sirolimus stent implantation was successful in all lesions. At 9-month follow-up, death occurred in 4 (1.6%) patients, myocardial infarction in 4 (1.6%), and ischemia-driven target lesion revascularization (TLR) in 12 (4.9%), for a cumulative event-free survival of 227 (93%). Although 9-month follow-up angiography was planned in all patients, only 150 (62%) patients completed it, and restenosis was present in 13 (8.7%) patients. Diabetes and non-ST-segment elevation acute coronary syndrome at presentation were the only independent predictors of freedom from ischemia-driven TLR and major adverse cardiac events. Sirolimus stent implantation for the treatment of ISR is effective and safe. In diabetic patients and in those with acute coronary syndrome, the higher rate of recurrence requires further evaluation.


Crovalimab treatment in patients with paroxysmal nocturnal haemoglobinuria: Long-term results from the phase I/II COMPOSER trial.
This study reports long-term outcomes from the open-label extension (OLE) period of the Phase I/II COMPOSER trial (NCT03157635) that evaluated crovalimab in patients with paroxysmal nocturnal haemoglobinuria, who were treatment-naive or switched from eculizumab at enrolment. COMPOSER consists of four sequential parts followed by the OLE. The primary OLE objective was to assess long-term crovalimab safety, with a secondary objective to assess crovalimab pharmacokinetics and pharmacodynamics. Exploratory efficacy endpoints included change in lactate dehydrogenase (LDH), transfusion avoidance, haemoglobin stabilisation and breakthrough haemolysis (BTH). A total 43 of 44 patients entered the OLE after completing the primary treatment period. Overall, 14 of 44 (32%) experienced treatment-related adverse events. Steady state exposure levels of crovalimab and terminal complement inhibition were maintained over the OLE. During the OLE, mean normalised LDH was generally maintained at ≤1.5× upper limit of normal, transfusion avoidance was achieved in 83%-92% of patients and haemoglobin stabilisation was reached in 79%-88% of patients across each 24-week interval. Five BTH events occurred with none leading to withdrawal. Over a 3-year median treatment duration, crovalimab was well tolerated and sustained C5 inhibition was achieved. Intravascular haemolysis control, haemoglobin stabilisation and transfusion avoidance were maintained, signifying long-term crovalimab efficacy.


[Severe periodontitis, edentulism and neuropathy in patients with type 2 diabetes mellitus].
Periodontitis is a frequent pathologic condition in diabetic patient, and has been associated with chronic complications like nephropathy, cardiovascular disease, peripheral artery disease or death. To document the association between severe periodontitis and edentulism with the presence of sensory-motor neuropathy in diabetic patients. Cross-sectional study in type 2 diabetic patients from the family medicine unit no. 27 of the IMSS in Tijuana, México. Patients were evaluated to identify periodontitis and sensory-motor neuropathy. Information was also obtained about sex, age, duration of diabetes, glycemic control, smoking and alcohol use. Four hundred and thirty-six patients completed all measurements. In 180 (41.3%) neuropathy was identified, and associated with age (p < 0.001); duration of diabetes (p < 0.001); fasting glucose (p < 0.001); severe periodontitis (OR: 2.7; IC 95%: 1.5-4.8);and with edentulism (OR: 4.4; IC 95%: 2.0-9.4). Logistic regression multivariable analysis kept as significative the association between severe periodontitis and edentulism with neuropathy (adjusted OR: 1.7; IC 95%: 1.1-2.6). Periodontitis and edentulism are associated with the presence of neuropathy in diabetic patients.


Multi-center investigation of the clinical and pathological characteristics of inflammatory breast cancer based on Chinese Society of Breast Surgery (CSBrs-007).
Inflammatory breast cancer (IBC) is an aggressive type of cancer with poor prognosis and outcomes. This study aimed to investigate clinicopathological features, molecular characteristics, and treatments among Chinese patients diagnosed with IBC. We collected data of 95 patients with IBC who were treated by members of the Chinese Society of Breast Surgery, from January 2017 to December 2018. The data, including demographic characteristics, pathological findings, surgical methods, systemic treatment plans, and follow-up, were obtained using a uniform electronic questionnaire. The clinicopathological features of different molecular types in patients without distant metastases were compared using the Kruskal-Wallis (H) test followed by post hoc analyses. Lymph node metastasis was noted in 75.8% of all patients, while distant metastasis was noted in 21.4%. Pathological findings indicated invasive ductal and lobular carcinomas in 86.8% and 5.3% of cases, respectively. Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (41.5%) and HR-/HER2+ (20.1%) were the most common biologic subtypes, followed by HR+/HER2+ (19.1%) and HR-/HER2- (19.1%). Stage III IBC was treated via pre-operative neoadjuvant chemotherapy in 87.7% of the cases, predominantly using anthracycline and taxanes. A total of 91.9% of patients underwent surgical treatment. Among them, 77.0% of the patients underwent modified radical mastectomy, 8.1% of whom also underwent immediate breast reconstruction. The Kruskal-Wallis test revealed that the efficacy of chemotherapy significantly differed among those with HR+/HER2- and HR-/HER2- tumors (adjusted P = 0.008), and Ki-67 expression significantly differed in HR-/HER2+ and HR+/HER2+ molecular subtypes (adjusted P = 0.008). Our study provides novel insight into clinicopathological characteristics and treatment status among patients with IBC in China, and might provide a direction and basis for further studies. chictr.org.cn, No. ChiCTR1900027179; http://www.chictr.org.cn/showprojen.aspx?proj=45030.


The mechanisms of uremic serum-induced expression of bone matrix proteins in bovine vascular smooth muscle cells.
We have previously found that uremic human serum upregulates RUNX2 in vascular smooth muscle cells (VSMCs), and that RUNX2 is upregulated in areas of vascular calcification in vivo. To confirm the role of RUNX2, we transiently transfected a dominant-negative RUNX2 (DeltaRUNX2) construct in bovine vascular smooth muscle cells (BVSMCs). Blocking RUNX2 transcriptional activity significantly decreased uremic serum induced alkaline phosphatase (ALP) activity (268+/-34 vs 188+/-9.5 U/g protein, P<0.05) and osteocalcin expression (172+/-17 vs 125+/-9 ODU, P<0.05). To determine the mechanism by which uremic serum upregulates RUNX2, we examined cell signaling pathways. BVSMCs were incubated in the presence or absence of inhibitors and RUNX2 expression and ALP activity were determined. The results demonstrate that the cyclic AMP (cAMP)/protein kinase A (PKA), but not protein kinase C, signaling pathway is involved in uremic serum-induced RUNX2 expression and ALP activity in BVSMCs. To examine potential uremic 'toxins', we measured bone morphogenetic protein (BMP)-2 concentration and found that uremic serum contained increased BMP-2 (uremic serum=169+/-33 pg/ml, normal serum=117+/-15 pg/ml, P<0.05). The incubation of BVSMCs with noggin, an inhibitor of BMP, decreased RUNX2 expression. In addition, BMP-2 secretion progressively increased during calcification and uremic serum enhanced its secretion compared to normal serum. In conclusion, this study demonstrates that RUNX2 transcriptional activity is critical in uremic serum-induced bone matrix protein expression in BVSMCs and that the cAMP/PKA pathway is involved. BMP-2 is also increased in uremic serum and can upregulate RUNX2 and calcification in vitro in VSMCs.


Generation of cytochrome P450 enzyme-polymorphic human induced pluripotent stem cell lines with CYP2D6*10/CYP3A5*3C and CYP2D6*10/CYP2C19*2.
Cytochrome P450 (CYP) reaction phenotyping has become crucial for predicting drug reactions and side effects. Single nucleotide polymorphisms (SNPs) in CYP genes alter drug metabolism capacity and cause unexpected drug-related reactions. Here, we established two human induced pluripotent stem cell (hiPSC) lines with pharmacologically important SNPs in CYP2D6 in conjunction with CYP2C19 or CYP3A5 genes. These hiPSC lines can serve as valuable resources for expanding our understanding of the relationships between genotypes and drug reactions.


Correcting delayed circadian phase with bright light therapy predicts improvement in ADHD symptoms: A pilot study.
Attention-deficit/hyperactivity disorder (ADHD) is a common condition with comorbid insomnia reported in >70% of children and adults. These patients demonstrate delays in sleep-wake rhythms, nocturnal rise in melatonin, and early morning rise in cortisol. Given that standard psychopharmacologic treatments for ADHD often do not completely control symptoms in participants with circadian rhythm delay, we sought to test whether bright light therapy (BLT) advances circadian rhythms and further reduces ADHD symptoms over standard treatments. In addition to standard of care, participants with ADHD diagnosis underwent 1 week of baseline assessment followed by 2-weeks of 30-min morning 10,000-lux BLT beginning 3 h after mid-sleep time. Participants minimized overhead light after 4 p.m., wore an actigraphy watch, and recorded BLT time on daily sleep logs. Dim Light Melatonin Onset (DLMO) was assessed at baseline and after 2-week treatment. ADHD symptoms were measured by the ADHD-Rating Scales (ADHD-RS). BLT significantly advanced the phase of DLMO by 31 min [mean time (SEM), 20:36 (0:21) advanced to 20:05 (0:20)] and mid-sleep time by 57 min [4:37 (0:22) advanced to 3:40 (0:16); paired t-tests, p = 0.002 and 0.004, respectively). Phase advances (in DLMO or mid-sleep time) were significantly correlated with decreased ADHD-RS total scores (p = 0.027 and 0.044) and Hyperactive-Impulsive sub-scores (p = 0.014 and 0.013, respectively). Actigraphy analysis for a subset of 8 participants with significant DLMO phase advance revealed no significant changes in total sleep time, sleep efficiency, wake after sleep onset, or percent wake during sleep interval. This is the first successful use of BLT for advancing melatonin phase and improving ADHD symptoms in adults. BLT may be a complementary treatment for both delayed sleep timing and ADHD symptoms in adults.


HTLV-1 subgroups associated with the risk of HAM/TSP are related to viral and host gene expression in peripheral blood mononuclear cells, independent of the transactivation functions of the viral factors.
Among human T cell leukemia virus type 1 (HTLV-1)-infected individuals, the risk of developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) across lifetime differs between ethnic groups. There is an association between HTLV-1 tax gene subgroups (subgroup-A or subgroup-B) and the risk of HAM/TSP in the Japanese population. In this study, we investigated the full-length proviral genome sequences of various HTLV-1-infected cell lines and patient samples. The functional differences in the viral transcriptional regulators Tax and HTLV-1 bZIP factor (HBZ) between each subgroup and the relationships between subgroups and the clinical and laboratory characteristics of HAM/TSP patients were evaluated. The results of these analyses indicated the following: (1) distinct nucleotide substitutions corresponding to each subgroup were associated with nucleotide substitutions in viral structural, regulatory, and accessory genes; (2) the HBZ messenger RNA (mRNA) expression in HTLV-1-infected cells was significantly higher in HAM/TSP patients with subgroup-B than in those with subgroup-A; (3) a positive correlation was observed between the expression of HBZ mRNA and its target Foxp3 mRNA in HAM/TSP patients with subgroup-B, but not in patients with subgroup-A; (4) no clear differences were noted in clinical and laboratory characteristics between HAM/TSP patients with subgroup-A and subgroup-B; and (5) no functional differences were observed in Tax and HBZ between each subgroup based on reporter gene assays. Our results indicate that although different HTLV-1 subgroups are characterized by different patterns of viral and host gene expression in HAM/TSP patients via independent mechanisms of direct transcriptional regulation, these differences do not significantly affect the clinical and laboratory characteristics of HAM/TSP patients.


Electron microscopy in tumor diagnosis: indications for its use in the immunohistochemical era.
The electron microscope reveals much more information on tumor cell structure than can be obtained with the light microscope, and some of the data are useful in diagnostic studies. In this review, major contributions of electron microscopy in the main tumor categories are discussed. To select between immunocytochemistry and electron microscopy, the probable contributions of each in the context of the particular case must be assessed. Usually, electron microscopy will only be requested after a battery of immunostaining procedures has been performed and found to be insufficient, but there are occasions when ulstrastructural study is logically the first choice after routine light microscopy. It is worth taking tissue for possible electron microscopy from any tumor that is known or anticipated to be a diagnostic problem.


RCAN1.4 attenuates renal fibrosis through inhibiting calcineurin-mediated nuclear translocation of NFAT2.
Chronic kidney disease (CKD) is thus deemed to a global health problem. Renal fibrosis, characterized by accumulation of extracellular matrix (ECM) components in the kidney, is considered a common pathway leading to CKD. Regulator of calcineurin1 (RCAN1), identified as a competitive endogenous inhibitor of the phosphatase calcineurin, participates in ECM deposition in various organs. However, the role of RCAN1 in renal fibrosis remains unclear. Here, unilateral ureteral obstruction (UUO), a well-known model to induce renal fibrosis in vivo, was performed on mice for a week. To overexpress RCAN1.4 in vivo, recombinant adeno-associated virus 9-packed RCAN1.4 over-expression plasm was employed in mice kidney. Lentivirus-packed RCAN1.4 over-expression plasm was employed to transfer into HK-2 and NRK-49F cells in vitro. The results indicated that RCAN1.4 expression was impaired both in UUO-induced renal fibrosis in vivo and TGF-β1-induced renal fibrosis in vitro. However, knocking in of RCAN1.4 suppressed the production of extracellular matrix (ECM) both in vivo and in vitro. Furthermore, in vitro, the apoptosis-related proteins, including the ratio of Bax/Bcl-2 and cleaved-caspase3, were elevated in cells transfected with RCAN1.4 overexpression plasmid. In addition, we found that RCAN1.4 could rugulated NFAT2 nuclear distribution by inhibiting calcineurin pathway. So overexpression of RCAN1.4 could reverse renal fibrosis, attenuate ECM related protein accumulation, promote apoptosis of myofibroblast via inhibiting Calcineurin/NFAT2 signaling pathway. Taken together, our study demonstrated that targeting RCAN1.4 may be therapeutic efficacy in renal fibrosis.


Perlman syndrome--a cause of enlarged, hyperechogenic kidneys.
Perlman syndrome is a rare overgrowth syndrome, thought to be inherited in the autosomal recessive fashion. We describe the sonographic features in two cases, and review the literature.


Distinct taxonomic and functional profiles of high Arctic and alpine permafrost-affected soil microbiomes.
Global warming is affecting all cold environments, including the European Alps and Arctic regions. Here, permafrost may be considered a unique ecosystem harboring a distinct microbiome. The frequent freeze-thaw cycles occurring in permafrost-affected soils, and mainly in the seasonally active top layers, modify microbial communities and consequently ecosystem processes. Although taxonomic responses of the microbiomes in permafrost-affected soils have been widely documented, studies about how the microbial genetic potential, especially pathways involved in C and N cycling, changes between active-layer soils and permafrost soils are rare. Here, we used shotgun metagenomics to analyze the microbial and functional diversity and the metabolic potential of permafrost-affected soil collected from an alpine site (Val Lavirun, Engadin area, Switzerland) and a High Arctic site (Station Nord, Villum Research Station, Greenland). The main goal was to discover the key genes abundant in the active-layer and permafrost soils, with the purpose to highlight the potential role of the functional genes found. We observed differences between the alpine and High Arctic sites in alpha- and beta-diversity, and in EggNOG, CAZy, and NCyc datasets. In the High Arctic site, the metagenome in permafrost soil had an overrepresentation (relative to that in active-layer soil) of genes involved in lipid transport by fatty acid desaturate and ABC transporters, i.e. genes that are useful in preventing microorganisms from freezing by increasing membrane fluidity, and genes involved in cell defense mechanisms. The majority of CAZy and NCyc genes were overrepresented in permafrost soils relative to active-layer soils in both localities, with genes involved in the degradation of carbon substrates and in the degradation of N compounds indicating high microbial activity in permafrost in response to climate warming. Our study on the functional characteristics of permafrost microbiomes underlines the remarkably high functional gene diversity of the High Arctic and temperate mountain permafrost, including a broad range of C- and N-cycling genes, and multiple survival and energetic metabolisms. Their metabolic versatility in using organic materials from ancient soils undergoing microbial degradation determine organic matter decomposition and greenhouse gas emissions upon permafrost thawing. Attention to their functional genes is therefore essential to predict potential soil-climate feedbacks to the future warmer climate.


Integration of SCP1, a giant linear plasmid, into the Streptomyces coelicolor chromosome.
SCP1, coding for the methylenomycin biosynthetic genes in Streptomyces coelicolor, is a giant linear plasmid of 350 kb. Extensive physical characterization revealed that SCP1 has unusually long terminal inverted repeats (TIR) of about 80 kb on both ends and an insertion sequence, IS466, at the end of the right TIR (TIR-R), and the 5'-ends are attached to a terminal protein. In the NF strain S. coelicolor 2612, SCP1 is integrated into the chromosome at the 9-o'clock position. Analysis of the two junctions between the SCP1 DNA and the chromosomal DNA revealed that the left junction had an almost intact left terminus of SCP1, while the right junction was composed of IS466, completely deleting TIR-R. Based on these results, we presented a possible formation mechanism of the NF strain, which is characterized by integration of SCP1 into the chromosome via an interaction of the target site and the combined ends of the racket-frame structure of SCP1 followed by deletion of TIR-R. We also hypothesized that this type of integration of a giant linear plasmid might be involved in the origin and distribution of the chromosomal antibiotic biosynthetic gene clusters in microorganisms.


Veterinary anthropology explored.
Veterinary and social scientists came together at the Centre for Medical Anthropology at the University of Edinburgh in April to discuss areas of common interest and the possibility of defining a new interdisciplinary field of 'veterinary anthropology'. Andrew Gardiner, one of the organisers of the international meeting, reports.


[Internal medicine and psychosomatic medicine between dualism and monism].
This paper investigates the possibility that psychosomatics could overcome the dualistic concept of a human being divided into mind and body. According to S. Freud's theories about the individual uniqueness and to G. A. Kelly's personal construct theory, the authors try to determine a monistic concept of the human being also from the clinical standpoint.


Endoscopic ultrasound-guided drainage of peripancreatic fluid collections: What impacts treatment duration?
Peripancreatic fluid collections (PFCs) are complications resulting from acute or chronic pancreatitis and require treatment in certain clinical conditions. The present study aimed to identify the factors influencing the duration of endoscopic ultrasound (EUS)-guided drainage of symptomatic pancreatic pseudocysts (PPCs), walled-off necrosis (WON), and acute necrotic collections (ANCs). This was a retrospective cohort study of 68 patients with PFCs who underwent EUS-guided drainage. The timing and duration of EUS-guided drainage of various PFCs (ANC, WON, and PPCs) were compared, and the factors influencing the duration of endoscopic treatment were identified. The mean time to first EUS-guided PFC drainage since the acute pancreatitis episode was 372.0, 505.0, and 18.7 days for WON, PPC, and ANC, respectively, and the mean duration of treatment was 90, 60, and 63 days, respectively. A disconnected pancreatic duct, a history of percutaneous drainage, and an infected PFC were identified as factors influencing the treatment duration. A positive correlation was observed between the treatment duration and patients' age. Patients with a disconnected pancreatic duct had to undergo more procedures. In patients with PPC, clinically successful drainage was more frequently achieved after a single procedure without the need for repeated procedures than in those with WON (90% vs. 59%, P = 0.01). Patients with a history of percutaneous drainage, disconnected pancreatic duct, or PFC infection may require longer endoscopic treatment.


Effect of phospholipids on fluorescence polarization and lifetimes of fluorescein-labeled phospholipase A2.
Phospholipids and divalent metal ions induce changes in the fluorescence polarization of fluorescein-labeled phospholipase A2 from the Indian cobra (Hazlett, T.L. and Dennis, E.A. (1985) Biochemistry 24, 6152-6158) which may be indicative of enzyme aggregation. Lifetimes and rotational correlation times of the conjugate in the presence of these and other ligands are now reported. The correlation times of monomeric phospholipase A2 were shorter than expected for a hydrated, 13,000 molecular weight protein, indicating a high degree of probe mobility. The increase in the enzyme correlation time upon phospholipid addition was found to be consistent with the formation of a phospholipase A2 dimer or higher-order aggregate. It was found that activator lipids, such as phosphatidylcholine, increase the correlation time and probably the size of the enzyme, while nonactivator lipids, such as phosphatidylethanolamine, did so to a lesser extent. This suggests a possible link between aggregation and phosphatidylcholine-induced activation of this enzyme.


In Vivo and In Vitro Comparison of Internal and Marginal Fit of Digital and Conventional Impressions for Full-Coverage Fixed Restorations: A Systematic Review and Meta-analysis.
This study aims to evaluate digital and conventional impressions for full-coverage restorations in terms of marginal and internal discrepancies. The analysis included in vivo and in vitro studies reporting the marginal or internal gap of full-coverage restorations that provide both the conventional and digital impression. The PubMed, Cochrane Trials, and Scopus databases were searched. The quality of clinical trials was rated using Cochrane Collaboration's tool, and the quality of the evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation tool. Heterogeneity among the studies was evaluated, and a meta-analysis with subgroup analysis was conducted whenever it was possible. Thirty-three articles (8 prospective clinical trials and 26 in vitro studies) were selected to extract data after applying the predefined selection criteria. The standard mean difference (SMD) of the meta-analysis for marginal adaptation was -0.76 (95% confidence interval: -1.23 to -0.29) and -0.59 (95% confidence interval: -0.93 to -0.24) for in vitro and in vivo studies, respectively, indicating digital impressions provided significantly less marginal gap than conventional impressions in in vitro studies (P = .002). The impression technique did not significantly influence the internal adaptation. Differences in marginal adaptation between the digital and conventional groups are not significant for in vivo studies, but for in vitro studies, the digital impression resulted in better marginal adaptation. Based on the Grading of Recommendations, Assessment, Development, and Evaluation approach for marginal adaptation, clinical studies were classified as high confidence and in vitro studies were graded moderate because of the inconsistency. Furthermore, high-quality studies are needed to confirm our results (the International Prospective Register of Systematic Reviews; CRD42017077925).


A pilot study on intermittent every other days of 5-dose Filgrastim compared with single Pegfilgrastim in breast Cancer patients receiving adjuvant Docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy.
Aim To compare the efficacy and safety of intermittent every other days 5-dose filgrastim with single pegfilgrastim in patients with breast cancer receiving adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy. Methods In this pilot study, Korean patients who had undergone complete resection for breast cancer and scheduled for adjuvant TAC chemotherapy were enrolled. Patients were randomized to receive either intermittent 5 doses of filgrastim (5 mcg/kg/day) or once-a-cycle pegfilgrastim (6 mg) as primary prophylaxis during the first three cycles of the TAC chemotherapy. Absolute neutrophil count (ANC) was analyzed as well. Results A total of 22 patients were randomly and equally divided into filgrastim or pegfilgrastim arms. Febrile neutropenia (FN) occurred in 1 patient in the pegfilgrastim arm (1 of 33 cycles) and none in the filgrastim arm. G3 neutropenia occurred in 1 patient (1 of 33 cycles) in the filgrastim arm and 2 patients (4 of 33 cycles) in the pegfilgrastim arm (P = 0.476). G4 neutropenia occurred in 11 patients (28 of 33 cycles) in the filgrastim arm and 9 patients (18 of 33 cycles) in the pegfilgrastim arm (P = 0.476). Except for on day 9 in cycle 3, there was no significant difference between the two groups in terms of ANC. Conclusion We observed no significant differences between the two methods of prophylaxis in terms of FN and G3/4 neutropenia incidence in patients receiving adjuvant TAC chemotherapy. Intermittent every other days 5-dose filgrastim may be available alternative to pegfilgrastim.


Emerging roles of astrocytes in neural circuit development.
Astrocytes are now emerging as key participants in many aspects of brain development, function and disease. In particular, new evidence shows that astrocytes powerfully control the formation, maturation, function and elimination of synapses through various secreted and contact-mediated signals. Astrocytes are also increasingly being implicated in the pathophysiology of many psychiatric and neurological disorders that result from synaptic defects. A better understanding of how astrocytes regulate neural circuit development and function in the healthy and diseased brain might lead to the development of therapeutic agents to treat these diseases.


Retinoscopy and chromatic aberration.
The origin of the apparent farsightedness as revealed by retinoscopy in smaller eyes was investigated by using monochromatic retinoscopy on wild rabbits. Our results indicate that a combination of long wavelength light and chromatic aberration of the subject's dioptrics is the major source of this artifact.


HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis.
Cellular aspartate drives cancer cell proliferation, but signaling pathways that rewire aspartate biosynthesis to control cell growth remain largely unknown. Hypoxia-inducible factor-1α (HIF1α) can suppress tumor cell proliferation. Here, we discovered that HIF1α acts as a direct repressor of aspartate biosynthesis involving the suppression of several key aspartate-producing proteins, including cytosolic glutamic-oxaloacetic transaminase-1 (GOT1) and mitochondrial GOT2. Accordingly, HIF1α suppresses aspartate production from both glutamine oxidation as well as the glutamine reductive pathway. Strikingly, the addition of aspartate to the culture medium is sufficient to relieve HIF1α-dependent repression of tumor cell proliferation. Furthermore, these key aspartate-producing players are specifically repressed in VHL-deficient human renal carcinomas, a paradigmatic tumor type in which HIF1α acts as a tumor suppressor, highlighting the in vivo relevance of these findings. In conclusion, we show that HIF1α inhibits cytosolic and mitochondrial aspartate biosynthesis and that this mechanism is the molecular basis for HIF1α tumor suppressor activity.


Estimating and Using Block Information in the Thurstonian IRT Model.
Multidimensional forced-choice (MFC) tests are increasing in popularity but their construction is complex. The Thurstonian item response model (Thurstonian IRT model) is most often used to score MFC tests that contain dominance items. Currently, in a frequentist framework, information about the latent traits in the Thurstonian IRT model is computed for binary outcomes of pairwise comparisons, but this approach neglects stochastic dependencies. In this manuscript, it is shown how to estimate Fisher information on the block level. A simulation study showed that the observed and expected standard errors based on the block information were similarly accurate. When local dependencies for block sizes [Formula: see text] were neglected, the standard errors were underestimated, except with the maximum a posteriori estimator. It is shown how the multidimensional block information can be summarized for test construction. A simulation study and an empirical application showed small differences between the block information summaries depending on the outcome considered. Thus, block information can aid the construction of reliable MFC tests.


Effects of mesotocin manipulation on the behavior of male and female common waxbills.
The oxytocin family of neuropeptides is implicated in the regulation of sociality across vertebrates. Non-mammalian homologs of oxytocin, such as isotocin in fish and mesotocin in amphibians, reptiles and birds, all play crucial roles modulating social and reproductive behavior. In this study, we exogenously manipulated the mesotocinergic system in a highly social bird, the common waxbill Estrild astrild, and tested the effects on affiliative and aggressive behavior by performing tests of competition over food. Birds treated with mesotocin decreased almost all the behaviors we studied (movement, feeding, allopreening), while birds treated with an oxytocin antagonist showed a reduction only in social behaviors (aggressions and allopreening). We also found two sex-specific effects: mesotocin reduced allopreening more in males than females, and the oxytocin antagonist reduced aggressiveness only in females. Our results suggest sex-specific effects in the modulation of affiliative and aggressive behaviors via mesotocinergic pathways.


Not Baseline Atrial Fibrillation but New-Onset Atrial Fibrillation and the Loss of Left Atrial Function Are Essential for Predicting Poor Outcomes in Non-ischemic Cardiomyopathy.
Aims: The clinical impact of the type of atrial fibrillation (AF) has not been completely elucidated in non-ischemic cardiomyopathy (NICM). Although the structure and function of the left atrium (LA) provide prognostic information in patients with heart failure, the relationship of the AF type with LA structure and function in NICM is unclear. Methods: Consecutive patients with NICM who underwent cardiac magnetic resonance were evaluated and followed. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for major adverse cardiovascular events (MACE) related to the AF type, such as paroxysmal AF, chronic AF, and new-onset AF (NOAF). Results: Among 625 patients with NICM (mean age, 64.4 ± 14.2 years; women, 39.7%), 133 had a history of AF at baseline; of these, 60 had paroxysmal AF. Each baseline AF type was associated with higher LA volume and lower LA emptying fraction but not with an increased incidence of MACE (p = 0.245). New-onset AF developed in 5.9% of patients with sinus rhythm over a median follow-up period of 609 days, and maximum LA volume was a strong and independent predictor [p < 0.001, area under the ROC curve (AUC): 0.795]. Maximum LA volume was superior to LA emptying fraction and B-type natriuretic peptide (AUC: 0.683 and 0.680, respectively). The use of β-blocker and the age of the patient were associated with the incidence of NOAF (HR: 0.37, 95% CI: 0.16-0.84 and HR: 1.05, 95% CI: 1.01-1.09, respectively). Kaplan-Meier analysis showed that patients with NOAF had a higher incidence of MACE than those with sinus rhythm or baseline AF (p = 0.002). NOAF and LA emptying fraction were independent predictors of MACE (HR: 2.28, 95% CI: 1.20-3.97 and HR: 0.98, 95% CI: 0.96-0.99, respectively) after adjusting for age, sex, body mass index, and diagnosis. Conclusions: Paroxysmal and chronic AF in patients with NICM were not associated with an increased incidence of MACE despite their association with LA volume and function. NOAF was independently associated with poor prognosis. Higher maximum LA volume predicted the onset and lower LA emptying fraction was independently associated with poor prognosis.


[Health and justice coordination in prisons].
The question of health-justice coordination has been present since the law of 18th January 1994. Since then, professional relations between prison staff and health carers have been regularly questioned in terms of their aims. The texts structuring this interinstitutional health-justice coordination constitutes a framework which the various professionals must appropriate and implement by drawing on specific knowledge and skills. It is an invitation to work together around the same population, on their respective and different missions. The implementation of a structured therapeutic group with sex offenders constitutes a positive experience.


Antiviral activity of Inonotusin A an active compound isolated from Boletus bellinii and Boletus subtomentosus.
Mushrooms produce various classes of secondary metabolites that could be used as antivirals in the future. The aim of this study was to determine the antiviral activity of methanolic extracts obtained from two edible mushrooms, Boletus bellinii (B. bellinii) and Boletus subtomentosus (B. subtomentosus), collected from the north forests of Tunisia, against Herpes Simplex Virus type 2 and Coxsackie Virus B type 3. In vitro micro-inhibition assays and cytotoxicity screening were performed on Vero cells. The tested Boletus methanolic extracts were found to be non-cytotoxic at high doses (50% cytotoxic concentration - CC50 > 1 mg/mL) and exhibited relevant viral inhibition with 50% inhibitory concentration, i.e., IC50 of 3.60 ± 0.66 µg/mL and 35.70 ± 7.42 µg/mL for B. bellinii, and 5.67 ± 1.02 µg/mL and 56.88 ± 9.56 µg/mL for B. subtomentosus, against HSV-2 and CVB-3, respectively. Interestingly, Boletus methanolic extracts showed high selectivity index (SI) values against both viruses, with the highest values against HSV-2 (SI > 800). Both viral strains were inhibited when treated with extracts during the early stages of virus replication. Inonotusin A was isolated and identified as the compound responsible for these activities. The latter is a novel antiviral agent that may have clinical utility or serve as a lead compound for further development. This study is the first attempt to investigate the antiviral activity of inonotusin A, isolated from the genus Boletus. The information from the present work should be a valuable reference for future studies on the antiviral activity of inonotusin A.


Hyperhidrosis treatment with bornaprine in the acute phase of spinal cord-injured patients.
Original article. To test the use of bornaprine in the hyperhidrosis treatment in the acute phase of spinal cord-injured patients. Patients with acute spinal cord lesions in the Spinal Unit of Pietra Ligure, Savona, Italy. In 4 years, 12 patients have been treated, for a maximum period of 75 days, with dosages ranging from 2 to 4 mg day(-1). All of them reported long-lasting subjective benefits, without side effects, even after the interruption of the therapy. The bornaprine treatment, at 2 or 4 mg day(-1) dosage, has been effective and safe to contrast hyperhidrosis, in the acute phase of spinal cord-injured patients. This positive experience would require additional trials and a larger number of cases to gain a more solid support.


Outbreak of acute gastroenteritis in young children with death due to rotavirus genotype G9 in Rio Branco, Brazilian Amazon region, 2005.
An epidemic of acute gastroenteritis occurred in Rio Branco City, Acre State, in Brazil's Amazon region in 2005. An investigation was conducted to confirm the etiology and identify possible risk factors for death. Rio Branco municipality surveillance data for the period May to October 2005 were reviewed. In a case-control study, children who died following acute gastroenteritis were compared to age-matched controls with acute gastroenteritis who survived. Rotavirus A (RV-A) was investigated in 799 stool samples and genotyped by reverse transcription polymerase chain reaction (RT-PCR). The cumulative incidence of diarrhea in children aged <5 years was 21%. A fatal outcome was significantly associated with uncovered household water storage containers. RV-A was identified in 88% of samples and G9 was the prevalent genotype (71%). Oral rehydration solution and boiling or chlorinating drinking water likely limited mortality. This epidemic was caused by RV-A genotype G9. After the outbreak, a rotavirus vaccine was introduced into the official childhood immunization schedule in Brazil.


Antioxidant evaluation and computational prediction of prospective drug-like compounds from polyphenolic-rich extract of Hibiscus cannabinus L. seed as antidiabetic and neuroprotective targets: assessment through in vitro and in silico studies.
Reports have implicated diabetes mellitus (DM) and Alzheimer's disease (AD) as some of the global persistent health challenges with no lasting solutions, despite of significant inputs of modern-day pharmaceutical firms. This study therefore, aimed to appraise the in vitro antioxidant potential, enzymes inhibitory activities, and as well carry out in silico study on bioactive compounds from polyphenolic-rich extract of Hibiscus cannabinus seed (PEHc). In vitro antioxidant assays were performed on PEHc using standard methods while the identification of phytoconstituents was carried out with high performance liquid chromatography (HPLC). For the in silico molecular docking using Schrodinger's Grid-based ligand docking with energetics software, seven target proteins were retrieved from the database ( https://www.rcsb.org/ ). HPLC technique identified twelve chemical compounds in PEHc, while antioxidant quantification revealed higher total phenolic contents (243.5 ± 0.71 mg GAE/g) than total flavonoid contents (54.06 ± 0.09 mg QE/g) with a significant (p < 0.05) inhibition of ABTS (IC50 = 218.30 ± 0.87 µg/ml) and 1, 1-diphenyl-2-picrylhydrazyl free radicals (IC50 = 227.79 ± 0.74 µg/ml). In a similar manner, the extract demonstrated a significant (p < 0.05) inhibitory activity against α-amylase (IC50 = 256.88 ± 6.15 µg/ml) and α-glucosidase (IC50 = 183.19 ± 0.23 µg/ml) as well as acetylcholinesterase (IC50 = 262.95 ± 1.47 µg/ml) and butyrylcholinesterase (IC50 = 189.97 ± 0.82 µg/ml), respectively. Furthermore, In silico study showed that hibiscetin (a lead) revealed a very strong binding affinity energies for DPP-4, (PDB ID: 1RWQ) and α-amylase (PDB ID: 1SMD), gamma-tocopherol ( for peptide-1 receptor; PDB ID: 3C59, AChE; PDB ID: 4EY7 and BChE; PDB ID: 7B04), cianidanol for α-glucosidase; PDB ID: 7KBJ and kaempferol for Poly [ADP-ribose] polymerase 1 (PARP-1); PDB ID: 6BHV, respectively. More so, ADMET scores revealed drug-like potentials of the lead compounds identified in PEHc. As a result, the findings of this study point to potential drug-able compounds in PEHc that could be useful for the management of DM and AD.


An ultrasensitive and stable potentiometric immunosensor.
We describe a novel quantitative polypyrrole based potentiometric biosensor that provides broad-spectrum assay capability. The biosensor allows for capture of analytes of interest from complex real samples such as serum and whole blood, and subsequent measurement in a controlled matrix environment. The technology is rapid (<15 min), ultrasensitive (<50 fM) and reproducible (CV<5% at 0.1 ng/ml). In addition the system has shown a wide dynamic range (four to five orders of magnitude), and good stability, 37 degrees C for at least 4 months. This potentiometric biosensor detects enzyme labelled immuno-complexes formed at the surface of a polypyrrole coated, screenprinted gold electrode. Detection is mediated by a secondary reaction that produces charged products (a 'charge-step' procedure). A shift in potential is measured at the sensor surface, caused by local changes in redox state, pH and/or ionic strength. The magnitude of the difference in potential is related to the concentration of the formed receptor-target complex. The potentiometric sensing technology has been demonstrated in assays for hepatitis B surface antigen (HBsAg) (Mw>300 kDa), Troponin I (Mw approximately 23 kDa), Digoxin (Mw 780 Da) and tumour necrosis factor (hTNF-alpha) (Mw approximately 23 kDa). These model targets were chosen to represent analytes of a range of molecular weights, and because of their requirement for assays of high analytical sensitivity and precision. All these assays were performed using complex fluid samples and the presence of any non-specific binding has no significant effect on the final measurement. New assays can be transferred and optimised readily.


Computational biomechanics of a lumbar motion segment in pure and combined shear loads.
Anterior shear has been implicated as a risk factor in spinal injuries. A 3D nonlinear poroelastic finite element model study of a lumbar motion segment L4-L5 was performed to predict the temporal shear response under various single and combined shear loads. Effects of nucleotomy and facetectomy as well as changes in the posture and facet gap distance were analyzed as well. Comparison of the predicted anterior displacement and stiffness response with available measurements indicates satisfactory agreement. Under shear loads up to 400 N, the model predicted an almost linear displacement response. With increasing shear load and/or compressive preload, the stiffening behavior becomes evident, primarily due to stretched collagen fibers and greater facet interactions. Removal of the facets markedly decreases the segmental stiffness in shear and thus highlights the importance of the facets in resisting shear force; 61-87% of the applied shear force is transmitted through the facets depending on the magnitude of the applied shear and compressive preload. Fluid exudation during the day as well as reduced facet gap distance and a more extended posture yielded higher facet joint forces. The shear resistance of the motion segment remains almost the same with time despite the transfer of load sharing from the disc to facets. Large forces on facet joints are computed especially under greater compression preloads, shear forces and extension rotations, as time progresses and with smaller gap distances. The disc contribution on the other hand increases under larger shear loads, smaller compression preloads, flexed postures, larger facet gap distances and at transient periods.


Augmented baseplates yield optimum outcomes when compared with bone graft augmentation for managing glenoid deformity during reverse total shoulder arthroplasty: a retrospective comparative study.
The purpose of this study was to compare the outcomes of primary reverse total shoulder arthroplasty (rTSA) using glenoid bone grafting (BG rTSA) with primary rTSA using augmented glenoid baseplates (Aug rTSA) with a minimum 2-year follow-up. A total of 520 primary rTSA patients treated with 8° posterior glenoid augments (n = 246), 10° superior glenoid augments (n = 97), or combined 10° superior/8° posterior glenoid augments (n = 177) were compared with 47 patients undergoing glenoid bone grafting for glenoid bone insufficiency. The mean follow-up was 37.0(±16) and 53.0(±27) months, respectively. Outcomes were analyzed preoperatively and at the latest follow-up using conventional statistics and stratification by minimum clinically important difference (MCID) and substantial clinical benefit (SCB) thresholds where applicable. Radiographs were analyzed for baseplate failure, and the incidences of postoperative complications and revisions were recorded. The glenoid Aug rTSA cohort had greater improvements in patient-reported outcome measures (PROMs) and range of motion when compared with the BG rTSA group at a minimum of 2-year follow-up, including Simple Shoulder Test, Constant score, American Shoulder and Elbow Surgeons score, University of California Los Angeles score, Shoulder Pain and Disability Index score, shoulder function, Shoulder Arthroplasty Smart score, abduction, and external rotation (P < .05). Patient satisfaction was higher in the Aug rTSA group compared with the BG rTSA group (P = .006). The utilization of an augmented glenoid component instead of glenoid bone grafting resulted in approximately 50% less total intraoperative time (P < .001), nearly 33% less intraoperative blood loss volume (P < .001), approximately 3-fold less scapular notching (P < .01), and approximately 8-fold less adverse events requiring revision (P < .01) when compared with the BG rTSA cohort. Aside from SCB for abduction, the Aug rTSA cohort achieved higher rates of exceeding MCID and SCB for every PROM compared with BG rTSA. More specifically, 77.6% and 70.2% of the Aug rTSA achieved SCB for American Shoulder and Elbow Surgeons and Shoulder Pain and Disability Index vs. 55% and 48.6% in the BG rTSA, respectively (P = .003 and P = .013). The present midterm clinical and radiographic study demonstrates that the utilization of an augmented baseplate for insufficient glenoid bone stock is superior as judged by multiple PROMs and range of motion metrics when compared with bone graft augmentation at minimum 2-year follow-up. In addition, when analyzed according to MCID and SCB thresholds, the use of augmented baseplates outperforms the use of glenoid bone grafting. Complication and revision rates also favor the use of augmented glenoid baseplates over glenoid bone grafting. Long-term clinical and radiographic follow-up is necessary to confirm that these promising midterm results are durable.


Treatment termination variables, MMPI scores and frequencies of relapse in alcoholics.
MMPI scores failed to predict treatment completion in alcoholics, but successful completion of treatment was related to lower relapse rates.


The role of nailfold capillaroscopy in pediatric patients with Kawasaki disease.
Nailfold capillaroscopy has been used as a non-invasive diagnostic method for microvasculature evaluation in various rheumatological disorders. The present study aimed to determine the utility of nailfold capillaroscopy in the diagnosis of Kawasaki Disease (KD). In this case-control study nailfold capillaroscopy was performed in 31 patients with KD and 30 healthy controls. All nailfold images were evaluated for capillary distribution and capillary morphology such as enlargement, tortuosity, and dilatation of the capillaries. Abnormal capillaroscopic diameter was identified in 21 patients from the KD group and 4 patients in the control group. The most common abnormality in capillary diameter was irregular dilatation in 11 (35.4%) KD patients and in 4 people (13.3%) in the control group. Distortions of the normal capillary architecture was commonly seen in the KD group (n=8). A positive correlation was observed between coronary involvement and abnormal capillaroscopic results (r=.65, P<.03). The sensitivity and specificity of capillaroscopy for the diagnosis of KD were 84.0% (95%CI: 63.9-95.5%) and 72.2% (95%CI: 54.8-85.8%), respectively. The PPV and NPV of capillaroscopy for KD were 67.7% (95%CI: 48.6-83.3) and 86.7% (95% CI: 69.3-96.2), respectively. Capillary alterations are more common in KD patients compared to control group. Thus, nailfold capillaroscopy can be useful in detecting these alterations. Capillaroscopy is a sensitive test for detecting capillary alternations in KD patients. It could be used as a feasible diagnostic modality for evaluating microvascular damage in KD.


A review of malaria vaccine clinical projects based on the WHO rainbow table.
Development and Phase 3 testing of the most advanced malaria vaccine, RTS,S/AS01, indicates that malaria vaccine R&D is moving into a new phase. Field trials of several research malaria vaccines have also confirmed that it is possible to impact the host-parasite relationship through vaccine-induced immune responses to multiple antigenic targets using different platforms. Other approaches have been appropriately tested but turned out to be disappointing after clinical evaluation. As the malaria community considers the potential role of a first-generation malaria vaccine in malaria control efforts, it is an apposite time to carefully document terminated and ongoing malaria vaccine research projects so that lessons learned can be applied to increase the chances of success for second-generation malaria vaccines over the next 10 years. The most comprehensive resource of malaria vaccine projects is a spreadsheet compiled by WHO thanks to the input from funding agencies, sponsors and investigators worldwide. This spreadsheet, available from WHO's website, is known as "the rainbow table". By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of malaria vaccine projects to be published in the last several years is provided below.


Association of chest tube position with phrenic nerve palsy after neonatal and infant cardiac surgery.
Diaphragm paralysis (DP) complicates the postoperative course of neonates and infants undergoing cardiac surgery. Events causing DP remain poorly understood, and preventive strategies remain elusive. This retrospective cohort analysis aims to test the hypothesis that chest tubes in contact with the phrenic nerve in the pleural apex may cause pressure palsy. In late 2018, the chest tube positioning strategy was changed so as to avoid a putative "danger zone" configuration, defined as (1) the chest tube looping apicomedially at the level of the second right intercostal space, and (2) wedging of chest tube tip against pericardium. A preintervention and postintervention analysis of 531 patients from 2012 to 2019 was performed to evaluate any association of chest tube position or duration in place with DP. Univariable and multivariable analyses were carried out, with significance set a priori at P < .05. The preintervention group comprised 488 patients, of whom 32 (6.6%) had RDP. The postintervention group comprised 43 patients, none of whom had DP. Multivariable analysis of the entire cohort revealed chest tube positioning in the danger zone as the only significant association with RDP (odds ratio, 4.22; 95% confidence interval, 1.57-11.33; P < .05). Chest tubes that occupy the right superior pleural space are associated with increased risk of DP.


Isolation and functional diversification of dihydroflavonol 4-Reductase gene HvDFR from Hosta ventricosa indicate its role in driving anthocyanin accumulation.
Anthocyanins are natural colorants are synthesized in a branch of the flavonoid pathway. Dihydroflavonol-4reductase (DFR) catalyzes dihydroflavonoids into anthocyanins biosynthesis, which is a key regulatory enzyme of anthocyanin biosynthesis in plants. Hosta ventricosa is an ornamental plant with elegant flowers and rich colorful leaves. How the function of HvDFR contributes to the anthocyanins biosynthesis is still unknown. In this study, the DFR homolog was identified from H. ventricosa and sequence analysis showed that HvDFR possessed the conserved NADPH binding and catalytic domains. A phylogenetic analysis showed that HvDFR was close to the clade formed with MaDFR and HoDFR in Asparagaceae. Gene expression analysis revealed that HvDFR was constitutive expressed in all tissues and expressed highly in flower as well as was positively correlated with anthocyanin content. In addition, the subcellular location of HvDFR showed that is in the nucleus and cell membrane. Overexpression of HvDFR in transgenic tobacco lines enhanced the anthocyanins accumulation along with the key genes upregulated, such as F3H, F3'H, ANS, and UFGT. Our results indicated a functional activity of the HvDFR, which provide an insight into the regulation of anthocyanins content in H. ventricosa.


Adrenal cysts: diagnostic value of "intravenous viscerogram".
Two cases of adrenal pseudocysts are presented, one secondary to the necrosis of an adenoma and the other a hemorrhagic pseudocyst. The diagnosis of these tumors is usually made radiologically owing to the vagueness of symptoms and nonexistent specific laboratory examinations, so that preoperative diagnosis is uncommon. We present a radiologic technique, intravenous viscerogram, which may be useful in the diagnosis of adrenal cysts. This procedure is easy to carry out and has almost no complications for the patient. The classification, clinical findings, and surgical treatment of adrenal cysts are discussed.


Genetic labeling of both the axons of transduced, glutamatergic neurons in rat postrhinal cortex and their postsynaptic neurons in other neocortical areas by herpes simplex virus vectors that coexpress an axon-targeted β-galactosidase and wheat germ agglutinin from a vesicular glutamate transporter-1 promoter.
Neuronal circuits comprise the foundation for neuronal physiology and synaptic plasticity, and thus for consequent behaviors and learning, but our knowledge of neocortical circuits is incomplete. Mapping neocortical circuits is a challenging problem because these circuits contain large numbers of neurons, a high density of synapses, and numerous classes and subclasses of neurons that form many different types of synapses. Expression of specific genetic tracers in small numbers of specific subclasses of neocortical neurons has the potential to map neocortical circuits. Suitable genetic tracers have been established in neurons in subcortical areas, but application to neocortical circuits has been limited. Enabling this approach, Herpes Simplex Virus (HSV-1) plasmid (amplicon) vectors can transduce small numbers of neurons in a specific neocortical area. Further, expression of a particular genetic tracer can be restricted to specific subclasses of neurons; in particular, the vesicular glutamate transporter-1 (VGLUT1) promoter supports expression in VGLUT1-containing glutamatergic neurons in rat postrhinal (POR) cortex. Here, we show that expression of an axon-targeted β-galactosidase (β-gal) from such vectors supports mapping specific commissural and associative projections of the transduced neurons in POR cortex. Further, coexpression of wheat germ agglutinin (WGA) and an axon-targeted β-gal supports mapping both specific projections of the transduced neurons and identifying specific postsynaptic neurons for the transduced neurons. The neocortical circuit mapping capabilities developed here may support mapping specific neocortical circuits that have critical roles in cognitive learning.


Discussion on basic equations for a flow in human air passages and their representation.
Basic equations of time-dependent flow are discussed in the case of rigid or elastic branches and according to the airway representation pattern, both continuous and discontinuous. Two relevant fundamental continuous functions are defined: the 'order of generation' G(x) and the cumulative bronchial diameter D(x). A numerical solution is outlined in the former case, then in the latter case, and the system of equations which completely describes the flow is solved.


Species-specific immunostaining of embryonic corneal nerves: techniques for inactivating endogenous peroxidases and demonstration of lateral diffusion of antibodies in the plane of the corneal stroma.
Species-specific and species-common monoclonal antibodies (MAbs) to nerve-specific cell surface epitopes were used to compare pre-treatment techniques for nerve staining. Endogenous peroxidases were inactivated in four ways: (1) 0.3% hydrogen peroxide (H2O2); (2) 1% periodic acid (PA) (pH 1.85-1.95); (3) sodium meta-periodate (10-40 mM, pH 4.5); or (4) HCl (pH 1.80). Staining of chick and quail corneal nerves and dorsal root ganglia (DRG) nerves with the MAbs was species-specific. Staining of chick and quail corneal nerves was unaffected by pre-treatment with 0.3% H2O2, but was eliminated by pre-treatment with 1% PA. Chick and quail DRG nerve staining tolerated 0.3% H2O2, and at least one epitope also tolerated 1% PA. Corneal nerves of both chick and quail displayed concentration-dependent sensitivity to pre-treatment with sodium meta-periodate; DRG nerves were not sensitive to such pre-treatment. Corneal nerves tolerated pre-treatment with HCI (pH 1.80), whereas DRG nerves did not. These findings indicate sensitivity of corneal nerve epitopes to oxidation, in contrast with sensitivity of DRG nerve epitopes to low pH. Results also indicate that tissue trimming regulated whole-mount staining of corneal nerves, suggesting that antibodies cannot diffuse across corneal basement membranes, even after detergent extraction. However, antibodies are able to diffuse laterally into the stroma from any cut edge.


Women's body dissatisfaction, social class, and social mobility.
Several studies indicate that socially advantaged women are more dissatisfied with their bodies than socially disadvantaged women. These findings have been based on women's current social class, and no attention has been paid to the social class of her family of origin or to intergenerational social mobility. In the present research 912 54-year-old women from a prospective birth cohort study provided self-report data on current body esteem (appearance and weight dimensions). Childhood and adult social class (manual versus non-manual) were defined based on father's occupation and own or partner's occupation, respectively. This information and the highest educational qualifications recorded by age 26 were gathered prospectively. Indicators of current and adolescent body mass index (BMI) were computed from height and weight values collected at ages 15 (or 11) and 53-54 years. Multiple regression was used to examine the relationship between midlife body esteem and childhood social class, adult social class, educational qualifications, and social mobility, unadjusted and adjusted for BMI. Women from the non-manual classes as adults were more dissatisfied with their weight than women from the manual classes as adults, for a given BMI. Adjusting for BMI, downwardly mobile women were more satisfied with their appearance than stable non-manual women. Adjusting for BMI, higher educational qualifications were associated with more dissatisfaction with weight and with appearance, and education appears to be more important than occupationally defined social class in explaining body dissatisfaction. A clearer understanding of the relationship between socio-economic position and body dissatisfaction demands that the following distinctions are made: weight versus appearance satisfaction, education versus occupation, and current social class versus intergenerational social mobility.


Newborn infants differently process adult directed and infant directed speech.
Infant directed speech (IDS) may serve important functions in language acquisition and in adult-infant communication. The processing of IDS evolves during the first years of life. In order to serve as an effective tool of language acquisition, already very young infants should be able to distinguish IDS from adult directed speech (ADS). We tested whether the ability to discriminate these two speech registers is functional in neonates, by recording EEG from 98 newborn infants in response to Hungarian words naturally spoken in the IDS and the ADS register. Words presented in the ADS register elicited a centro-parietal slow positivity in the 200-600 ms time window whereas words in IDS register elicited a small frontal negativity in the 700-900 ms time window. We conclude that newborn infants differentiate natural speech sounds based on speech register.


Immunocytochemical location of oxytocin and mesotocin within the hypothalamus of two Australian marsupials, the bandicoot Isoodon macrourus and the brushtail possum Trichosurus vulpecula.
The presence of oxytocin and mesotocin in the hypothalamus of two Australian marsupials, the bandicoot (Isoodon macrourus) and the brushtail possum (Trichosurus vulpecula), was examined by immunocytochemistry. Tissue was fixed in paraformaldehyde in phosphate buffer and immunoreactive cells were detected using highly specific rabbit antioxytocin and sheep anti-mesotocin as primary antisera. Immunoreactive oxytocin cells were demonstrated in the paraventricular and supraoptic nuclei of bandicoot and possum hypothalami, with greater density being observed in paraventricular nuclei. Immunoreactive mesotocin cells were also found in both hypothalamic nuclei of the possum but not of the bandicoot. The same cells appeared to stain for both peptides.


Cough ability measurements and recurrent respiratory symptoms in individuals with Ataxia Telangiectasia.
Ataxia-Telangiectasia (A-T) individuals often present with respiratory muscle weakness, causing recurrent respiratory system infections, asthma-like symptoms, and chronic cough life-threatening events. The cough flow volume maneuver may reveal powerless airflow needed for efficient cough. The study aims to explore cough ability in relation to the flow/volume maneuver. Data collected retrospectively from clinical charts of 35 A-T patients (age 12.7 ± 4.9 years) included forced expiratory and cough flow/volume maneuvers performed on the same day. Analysis compared among the maneuvers matching indices, numbers of cough-spikes, flow rate decay, and the reference data of similar ages. Adjusted to age, BMI, and number of hospitalizations prior to the tests, values were correlated with the cough indices. Cough peak-flow (C-PF) was propagated within 90 ± 20 ms compared with peak expiratory flow (PEF > 200 ms). C-PF measured values were higher than expiratory peak-flow measured values (3.27 ± 1.53 L/s versus 3.02 ± 1.52 L/s, respectively, but C-PF (%predicted) values were significantly lower than expiratory peak-flow (%predicted) (46 ± 15 versus 68 ± 20 %predicted, respectively, p < 0.002). The number of spikes/maneuver was low when compared with reference (2.0 ± 0.8 versus 6-12 spikes) and cough vital-capacity was lower than expiratory vital capacity (0.95 ± 0.43 versus 1.03 ± 0.47; p < 0.01). Inefficient C-PF was more prevalent in patients suffering from recurrent respiratory illness. The length of wheelchair confinement duration mostly influenced the C-VC level. The cough flow-volume curve can be applied as a method to follow cough ability in patients with A-T who showed a significantly reduced cough capacity. Further studies are needed to establish if the findings may aid decisions regarding cough assistance.


New PEPPSI-Pd-NHC complexes bearing 4-hydroxyphenylethyl group: Synthesis, characterization, molecular docking, and bioactivity properties.
Five 4-hydroxyphenylethyl substituted pyridine enhanced, precatalyst, preparation, stabilization, and initiation-Pd-N-heterocyclic carbene (PEPPSI-Pd-NHC) complexes are synthesized in a straightforward way. All PEPPSI-Pd-NHC complexes were prepared by mixing 4-hydroxyphenylethyl substituted NHC precursors, palladium chloride, potassium carbonate, and potassium bromide in pyridine. All complexes were screened for human carbonic anhydrase I (hCA I) and hCA II, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase (α-Glu) inhibitory activities. The ChE inhibitory activities of the new PEPPSI-Pd-NHC complexes bearing the 4-hydroxyphenylethyl group (1a-e) against α-Glu, AChE, and BChE were determined by the Tao and Ellman methods. The results indicated that all the synthetic complexes exhibited potent inhibitory activities against all targets as compared to the standard inhibitors, revealed by IC50 values. The Ki values of the new PEPPSI-Pd-NHC complexes 1a-e for hCA I, hCA II, AChE, BChE, and α-Glu were obtained in the ranges of 18.98-32.65, 22.95-38.13, 3.67-11.65, 4.09-9.36, 186.92-287.45 µM, respectively. Among the synthesized complexes, the most potent complexes were 1c toward hCA I and II with Ki values 18.98 and 22.95 µM, and 1d toward AChE and BChE with Ki = 3.67 and 4.09 µM, respectively.


A new inactivated tissue culture rabies vaccine for use in man. Evaluation of PCEC-vaccine by laboratory tests.
A new inactivated rabies vaccine (purified chick embryo cell vaccine) has been developed using the Flury LEP-C 25 strain of rabies virus propagated in primary chick embryo cell cultures. The antigen was purified and concentrated by continuous density gradient centrifugation and inactivated by betapropiolactone. This vaccine was tested for innocuity, tolerability and protective capacity in a series of laboratory tests and compared with human diploid cell strain (HDC)-vaccines of similar antigenicity. The results indicated that this new vaccine was excellently tolerated and that its protective activity met the high standard of HDC-vaccine, conditions which were imposed on this vaccine before entering clinical trials in man.


[The surgical anatomy of the rectal and anal blood vessels].
The authors examined 40 rectum specimens by angiography, preparation and staining methods to show the exact arterial vessel supply of the rectum and tried to find out whether a reason could be found for the relatively high rate of suture leaks after low resection of the rectum or not. The insertion of the levator muscle is a sort of vessel divide: caudal to the levator muscle the inferior rectal artery is the main supplying vessel, cranially the superior rectal artery. Here a vessel deficient-area always remains in the dorso-caudal sector of the rectal ampulla which cannot be compensated by another rectum-supplying vessel. The middle rectal artery supplies the rectum accessorily. The results are able to explain why the suture leaks are constantly observed in the dorso-caudal ampulla after profound anterior resection of the rectum. Furthermore the results account for the good healing tendency of coloanal anastomoses: the inferior rectal artery amply supplies the anal canal; there is not the same vessel-deficient area as found cranial to the levator muscle.


The chloroplast division protein FtsZ is encoded by a nucleomorph gene in cryptomonads.
Guillardia theta is a cryptomonad alga, whose phototrophic symbiont was acquired by secondary endocytobiosis. The nucleomorph, the vestigial nucleus of the eukaryotic endosymbiont, harbors three linear chromosomes with a total coding capacity of 515 kb. Sequencing of the nucleomorph genome reveals that it encodes an ORF homologous to the bacterial cell division protein FtsZ, supporting the hypothesis that FtsZ is common in chloroplasts. We show that the nucleomorph-encoded ftsZ gene is transcribed. The transcript is polyadenylated and therefore shows features typical of eukaryotic transcripts. However, 3' processing of nucleomorph mRNA is inaccurate. Transcripts of nucleomorph genes in G. theta overlap with neighboring UTRs and coding regions. We demonstrate that the reading frame encoding NmFtsZ is not interrupted by introns. Subcellular localization of the protein reveals that FtsZ is localized exclusively in the chloroplast of G. theta, demonstrating that FtsZ is imported into the organelle.


Parametric analysis of the influence of texture on human dental surface hardness.
Tooth wear is one of the dental abnormalities commonly found in different populations. The objective of this work is to conduct a parametric analysis to evaluate the texture influence on the human dental surface hardness, considered here as the ratio between contact force and contact area, obtained through homogenization procedure. A code was implemented using the statistical package R for parametric analysis. The computational approach consists of three routines: numerical generation of surfaces, based on Pearson system; the second, a script coupled to the Finite Element program Abaqus, for the modelling of the micro-contacts; the third for homogenization and statistical analysis of results. The average curvature of the roughness exerts the greatest influence on the surface hardness. The parameters that most influence the development of contact forces are kurtosis followed by skewness.


Clinical significance of slow paroxysmal atrial tachycardia.
This study examines the clinical setting, characteristics, and follow-up of 173 patients who had slow paroxysmal atrial tachycardia (SPAT) (greater than 4 beats, rate less than 150 bpm) during 24-hour Holter monitoring. These episodes were classified by probable mechanism according to recognized ECG criteria and included AV nodal reentry (AVNR), sinoatrial nodal reentry (SANR), and automatic (A). There were 76 males (44%) with a mean age of 72 years and 97 females (56%) with a mean age of 73 years. The indications for Holter recording revealed that the SANR and A subgroups had a higher frequency of cerebral symptoms compared to AVNR (p less than 0.01). Chest pain was more common in the SANR group as compared to the other two groups (p less than 0.01). There was no difference in the frequency of palpitation in the three subgroups. The mean rate of SPAT for the entire group was 115.2 +/- 14 and these episodes had a mean duration of 5.58 +/- 3.07 seconds. The SANR subgroup had a significantly slower rate (107.1 +/- 9.2) as compared to the AVNR subgroup (p less than 0.01). One hundred fourteen patients were available for follow-up. The average period of follow-up was similar for all three groups. At follow-up the frequency of sick sinus syndrome as determined clinically and permanent pacemaker insertion was significantly greater in the SANR subgroup (p less than 0.01) as compared to the other subgroups which did not differ from each other.


TGF-β1 upregulates secreted protein acidic and rich in cysteine expression in human granulosa-lutein cells: a potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome.
Ovarian hyperstimulation syndrome (OHSS) is a serious complication during in vitro fertilization (IVF) treatment. The upregulation of ovarian transforming growth factor-beta 1 (TGF-β1) is involved in the development of OHSS. The secreted protein acidic and rich in cysteine (SPARC) is a secreted multifunctional matricellular glycoprotein. Although the regulatory effects of TGF-β1 on SPARC expression have been reported, whether TGF-β1 regulates SPARC expression in the human ovary remains unknown. In addition, the role of SPARC in the pathogenesis of OHSS is unclear. A steroidogenic human ovarian granulosa-like tumor cell line, KGN, and primary culture of human granulosa-lutein (hGL) cells obtained from patients undergoing IVF treatment were used as experimental models. OHSS was induced in rats, and ovaries were collected. Follicular fluid samples were collected from 39 OHSS and 35 non-OHSS patients during oocyte retrieval. The underlying molecular mechanisms mediating the effect of TGF-β1 on SPARC expression were explored by a series of in vitro experiments. TGF-β1 upregulated SPARC expression in both KGN and hGL cells. The stimulatory effect of TGF-β1 on SPARC expression was mediated by SMAD3 but not SMAD2. The transcription factors, Snail and Slug, were induced in response to the TGF-β1 treatment. However, only Slug was required for the TGF-β1-induced SPARC expression. Conversely, we found that the knockdown of SPARC decreased Slug expression. Our results also revealed that SPARC was upregulated in the OHSS rat ovaries and in the follicular fluid of OHSS patients. Knockdown of SPARC attenuated the TGF-β1-stimulated expression of vascular endothelial growth factor (VEGF) and aromatase, two markers of OHSS. Moreover, the knockdown of SPARC reduced TGF-β1 signaling by downregulating SMAD4 expression. By illustrating the potential physiological and pathological roles of TGF-β1 in the regulation of SPARC in hGL cells, our results may serve to improve current strategies used to treat clinical infertility and OHSS. Video Abstract.


Development of a transformation and selection system for the glycolipid-producing yeast Candida bombicola.
Sophorolipids are surface-active compounds synthesized by the non-pathogenic yeast Candida bombicola. Over recent decades much effort has been spent to optimize culture conditions in order to improve the yield and production process. As far as we know, however, hardly any attention has been given to the genetics of the producing yeast strain itself and there are no published results available on the genetic engineering of C. bombicola. Nevertheless, this can be a useful tool for the study of the sophorolipid synthesis pathway and open up perspectives for improved production. A first step is the development of a suitable transformation and selection method. This article describes the creation and selection of an uracil auxotrophic C. bombicola mutant, which can be transformed back to prototrophy with the species' own orotidine 5'-phosphate decarboxylase or URA3 gene. Successful transformation was confirmed by a PCR-based method discriminating between the wild-type and mutated URA3 gene.


Major ABO-incompatible BMT: isohemagglutinin reduction with plasma exchange is safe and avoids graft manipulation.
The impact of donor-recipient ABO incompatibility on long-term BMT outcomes remains controversial. A common strategy is to deplete the donor marrow of red cells, although this variably reduces the number of CD34+ cells. This 10-year retrospective study assessed the impact of recipient plasma exchange in major ABO-incompatible allogeneic BMT on outcomes and survival. Target Ab titres were ≤ 1:4 for anti-A and ≤ 1:8 for anti-B. Patients with higher titres underwent plasma exchange before marrow infusion. Of 133 patients who underwent allogeneic BMT, 34 had a major ABO-incompatible donor. The median number of exchanges was 2 (range 1-4). There were no acute haemolytic transfusion reactions. Engraftment times, transfusion requirements and acute and chronic GVHD were no different from those of patients with an ABO-identical donor. Treatment-related mortality at 100 days was 21% in the group with a major ABO-incompatible donor and 17% in the group with an identical donor (P=0.8). Plasma exchange of the recipient is a safe method of managing donor-recipient major ABO incompatibility before BMT without the risk of haematopoietic progenitor cell loss associated with red cell depletion of the graft.


Patterns of ontogenetic evolution across extant marsupials reflect different allometric pathways to ecomorphological diversity.
The relatively high level of morphological diversity in Australasian marsupials compared to that observed among American marsupials remains poorly understood. We undertake a comprehensive macroevolutionary analysis of ontogenetic allometry of American and Australasian marsupials to examine whether the contrasting levels of morphological diversity in these groups are reflected in their patterns of allometric evolution. We collate ontogenetic series for 62 species and 18 families of marsupials (n = 2091 specimens), spanning across extant marsupial diversity. Our results demonstrate significant lability of ontogenetic allometric trajectories among American and Australasian marsupials, yet a phylogenetically structured pattern of allometric evolution is preserved. Here we show that species diverging more than 65 million years ago converge in their patterns of ontogenetic allometry under animalivorous and herbivorous diets, and that Australasian marsupials do not show significantly greater variation in patterns of ontogenetic allometry than their American counterparts, despite displaying greater magnitudes of extant ecomorphological diversity.


Relief of persistent postamputation stump and phantom limb pain with intrathecal fentanyl.
Two patients with postamputation stump and phantom limb pain respectively responded favorably to intrathecal fentanyl which temporarily abolished the pain, normalized sensations and produced euphoria without supraspinal effects. One of the patients subsequently received intrathecal, extradural and intravenous fentanyl as well as intrathecal lidocaine. The neuraxial (intrathecal and epidural) fentanyl temporarily abolished the pain. Intravenous fentanyl and intrathecal lidocine were unable to reproduce this effect. Neuraxial fentanyl apparently produced its effects by a segmental spinal action. Spinal modulation of postamputation pain was important in these patients.


Iatrogenic genetic damage of spermatozoa.
Various factors that negatively influence male fertility can affect sperm morphology and physiology. Many studies on humans and animals suggest that both radiation and chemotherapy alter the sperm chromatin, inducing significant damage to sperm DNA, and decrease the level of protamination, thereby altering DNA compaction. Spermatozoa from cancer survivors are affected by chemotherapy even years after the end of treatment. We are exposed to various toxicants present in the environment (e.g., products of air pollution, pesticides, and plasticizers) whose impact on human male reproduction has not yet been established.This chapter aims to update our knowledge on how the sperm chromatin structure is modified by external agents and to describe the different strategies available to better study this complex structure in infertile men.


Assessment of the urodynamic diagnosis in patients with urinary incontinence associated with normal pressure hydrocephalus.
To assess the urodynamic patterns present in patients with adult normal pressure hydrocephalus (NPH) in our institution. Retrospectively conducted study on patients diagnosed with NPH by the Neurosurgery Department of our institution, without etiological treatment or urogynecological disorders, who underwent an urodynamic study (UDS) performed according to methods proposed by the International Society of Continence (ICS). Clinical information, complementary tests and UDS were collected, and descriptive analysis was performed, with special focus in urodynamic final diagnosis. Eighty-one UDS performed between 2003 and 2013. Fifty-one Males (63%). Mean age: 74.89 ± 8.58 years old (range 52-88 years). Classical triad of symptoms: gait disturbance, dementia, and urinary incontinence (UI) presented in 48.1%. Urinary urgency in 80.9% and UI in 70%. In two cases (2.5%) UDS was not valuable. Urodynamic features of the 79 remaining studies revealed overactive detrusor (OD) in 56 patients (70.9%), being associated with Stress UI (SUI) in one case and with bladder outlet obstruction (BOO) in 19. SUI in six patients (7.6%) and BOO in five (6.3%). Detrusor underactivity in four cases (5%) and normal study in eight (10.1%). About 47.1% of males presented BOO. Cerebrospinal fluid shunt surgery was performed on 32 patients during follow-up, with subsequent clinical improvement in 90.6% of them. OD was the most frequent diagnosis within UDS conducted on adult NPH patients in our institution, with BOO in an elevated percentage of them. Etiological treatment led to symptomatic improvement in most of patients.


Long chain fatty acyl-CoA synthetase 5 expression is induced by insulin and glucose: involvement of sterol regulatory element-binding protein-1c.
In a screen for sterol regulatory element-binding protein (SREBP)-1c target genes in the liver, we identified long chain fatty acyl-CoA synthetase 5 (ACS-5). Hepatic ACS-5 mRNA is poorly expressed during fasting and diabetes and strongly induced by carbohydrate refeeding and insulin treatment. In cultured hepatocytes, insulin and a high glucose concentration induce ACS-5 mRNA. Adenoviral overexpression of a nuclear form of SREBP-1c in liver of diabetic mice or in cultured hepatocytes mimics the effect of insulin to induce ACS-5. By contrast, a dominant negative form of SREBP-1c abolishes the effect of insulin on ACS-5 expression. The dietary and SREBP-1c-mediated insulin regulation of ACS-5 expression indicate that ACS-5 is involved in the anabolic fate of fatty acids.


Effects of nitrogen/bismuth-doping on the photocatalyst composite of carbon dots/titanium dioxide nanoparticles (CDs/TNP) for enhanced visible light-driven removal of diclofenac.
The present work demonstrates the coupling of titanium dioxide, TiO2 nanoparticles (TNP) with N-doped, Bi-doped, and N-Bi co-doped rice husk-derived carbon dots (CDs) via a facile dispersion method, forming respective photocatalyst composites of CDs/TNP, N-CDs/TNP, Bi-CDs/TNP and N-Bi-CDs/TNP. Characterization analyzes verified the successful incorporation of respective CDs samples into TNP, forming photocatalyst composite with narrowed band gap and quenched photoluminescence intensity. Photocatalytic activity of TNP and the respective composites was investigated for photodegradation of diclofenac (DCF) under both simulated sunlight and natural sunlight irradiation. The as-prepared N-Bi-CDs/TNP composite showed the best photocatalytic performance among all composites, able to completely degrade 5 ppm of DCF within 60 min and 180 min under both types of visible light irradiation, respectively. The N-Bi-CDs/TNP composite also showed a TOC removal efficiency up to 87.63%. N-Bi-CDs, worked as photosensitizer and electron reservoir, contributed to the outstanding photocatalytic activity of N-Bi-CDs/TNP, whereby the recombination was prolonged and light absorption was shifted towards the visible light region. Furthermore, the composite of N-Bi-CDs/TNP also demonstrated good stability and reusability over repeated degradation cycles. The photodegradation of DCF resulted into several intermediates, which were identified from LC-MS analysis. The present work could provide an insight on the application of heteroatoms doped and co-doped carbon dots in semiconductor oxide as high performance photocatalysts.


Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid.
Cyclophosphamide (CP), a chemotherapeutic agent, is restricted due to its side effects, especially hepatotoxicity. Ginseng has often been clinically used with CP in China, but whether and how ginseng reduces the hepatotoxicity is unknown. In this study, the hepatoprotective effects and mechanisms under the combined usage were investigated. It was found that ginseng could ameliorate CP-induced elevations of ALP, ALT, ALS, MDA and hepatic deterioration, enhance antioxidant enzymes' activities and GSH's level. Metabolomics study revealed that 33 endogenous metabolites were changed by CP, 19 of which were reversed when ginseng was co-administrated via two main pathways, i.e., GSH metabolism and primary bile acids synthesis. Furthermore, ginseng could induce expression of GCLC, GCLM, GS and GST, which associate with the disposition of GSH, and expression of FXR, CYP7A1, NTCP and MRP 3, which play important roles in the synthesis and transport of bile acids. In addition, NRF 2, one of regulatory elements on the expression of GCLC, GCLM, GS, GST, NTCP and MRP3, was up-regulated when ginseng was co-administrated. In conclusion, ginseng could alleviate CP-induced hepatotoxicity via modulating the disordered homeostasis of GSH and bile acid, which might be mediated by inducing the expression of NRF 2 in liver.


Quantitative analysis of 17 amino acids in the connective tissue of patients with pelvic organ prolapse using capillary electrophoresis-tandem mass spectrometry.
The simultaneous determination of 17 amino acids in connective tissue using capillary electrophoresis is described in this study. Separation was carried out on a fused silica capillary column (80 cm x 50 mm i.d.) with 1M formic acid as the running electrolyte. The detection was conducted on a mass spectrometer by selective reaction monitoring (SRM) mode via an electrospray ionization source. Tissue samples were prepared by reduction and acid hydrolysis to extract amino acids; over 84.3% recovery was seen for all compounds. The method allowed for sensitive, reproducible, and reliable quantification, and all 17 amino acids were separated using this method. Good linearity over the investigated concentration ranges was observed, with values of R higher than 0.993 for all the analytes. Precision and accuracy examined at three concentration levels ranged from 0.2% to 19.5% and 84.1% to 120.0%, respectively. Matrix effects were also tested and ranged from -9.1% to 15.4%. The validated method was applied to the quantitation of 17 amino acids in pelvic connective tissue of pelvic organ prolapsed patients. Methionine, glutamine, and histidine were significantly higher in the experimental patients compared to the controls. This suggests that changes in the amino acid concentrations within the connective tissue could be a factor in the genesis of pelvic organ prolapse. Therefore, this method is potentially applicable for amino acid analysis in tissue, providing a more complete understanding of pelvic organ prolapse.


PDI inhibitor LTI6426 enhances panobinostat efficacy in preclinical models of multiple myeloma.
The histone deacetylase inhibitor (HDACi), panobinostat (Pano), is approved by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of relapsed/refractory multiple myeloma (MM). Despite regulatory approvals, Pano is used on a limited basis in MM due largely to an unfavorable toxicity profile. The MM treatment landscape continues to evolve, and for Pano to maintain a place in that paradigm it will be necessary to identify treatment regimens that optimize its effectiveness, particularly those that permit dose reductions to eliminate unwanted toxicity. Here, we propose such a regimen by combining Pano with LTI6426, a first-in-class orally bioavailable protein disulfide isomerase (PDI) inhibitor. We show that LTI6426 dramatically enhances the anti-MM activity of Pano in vitro and in vivo using a proteasome inhibitor resistant mouse model of MM and a low dose of Pano that exhibited no signs of toxicity. We go on to characterize a transcriptional program that is induced by the LTI6426/Pano combination, demonstrating a convergence of the two drugs on endoplasmic reticulum (ER) stress pathway effectors ATF3 (Activating Transcription Factor 3), DDIT3/CHOP (DNA Damage Inducible Transcript 3, a.k.a. C/EBP Homologous Protein), and DNAJB1 (DnaJ homolog subfamily B member 1, a.k.a. HSP40). We conclude that LTI6426 may safely enhance low-dose Pano regimens and that ATF3, DDIT3/CHOP, and DNAJB1 are candidate pharmacodynamic biomarkers of response to this novel treatment regimen.


Distribution and transport characteristics of fine particulate matter in beijing with mobile lidar measurements from 2015 to 2018.
Accurately quantifying the concentration and transport flux of atmospheric fine particulate matter (PM2.5) is vital when attempting to thoroughly identify the pollution formation mechanism. In this study, the mobile lidar measurements in Beijing on heavily polluted days in December from 2015 to 2018 are presented. The lidar was mounted on a vehicle, which could perform measurements along designated routes. On the basis of mobile lidar measurements along closed circuits of the 6th Ring Road around Beijing, the spatial distribution and transport flux of PM2.5 in Beijing were determined with information of wind field. In the spatial distribution, both the concentration and transport of PM2.5 were revealed to be more significant in the southern section of Beijing. The regional transport layer at heights < 1.3 km plays an important role in pollution formation. The maximum transport flux reached 1600 μg/(m2*sec) on 11 December 2016. With the aerosol boundary layer height determined from the image edge detection (IED) method, the inter-annual variations of the aerosol boundary layer height (ABLH) were also analysed. The ABLH decreased from 0.73 to 0.46 km during the same heavy pollution period from 2015 to 2018. Increasingly adverse aerosol boundary layer (ABL) meteorological factors, including lower ABLH, light winds, temperature inversions, and accumulated moisture, have become necessary for pollution formation in Beijing.


Kaposi's sarcoma-associated herpesvirus infection promotes proliferation of SH-SY5Y cells by the Notch signaling pathway.
The cancer caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection is one of the major causes of death in AIDS patients. Some patients have neurological symptoms, which appear to be associated with KSHV infection, based on the neurotropic tendency of this virus in recent years. The objectives of this study were to investigate the effects of KSHV infection on neuronal SH-SY5Y cells and to identify differentially expressed genes. KSHV was collected from islk.219 cells. Real-time PCR was used to quantify KSHV copy numbers. KSHV was used to infect SH-SY5Y cells. The KSHV copy number in the supernatants and mRNA levels of latency-associated nuclear antigen (LANA), ORF26, K8.1 A, and replication and transcriptional activator (RTA) were detected by real-time PCR. Proteins were detected by immunohistochemistry. The effect of KSHV infection on cell proliferation was detected by MTT and Ki-67 staining. Cell migration was evaluated by Transwell and wound healing assays. The cell cycle was analyzed by flow cytometry. The expression of CDK4, CDK5, CDK6, cyclin D1, and p27 were measured by western blotting. The levels of cell cycle proteins were re-examined in LANA-overexpressing SH-SY5Y cells. Transcriptome sequencing was used to identify differentially expressed genes in KSHV-infected cells. The levels of Notch signaling pathway proteins were measured by western blotting. RNA interference was used to silence Notch1 and proliferation were analyzed again. SH-SY5Y cells were successfully infected with KSHV, and they maintained the ability to produce virions. KSHV-infected SH-SY5Y expressed LANA, ORF26, K8.1 A, and RTA. After KSHV infection, cell proliferation was enhanced, but cell migration was suppressed. KSHV infection accelerated the G0/G1 phase. CDK4, CDK5, CDK6, and cyclin D1 expression was increased, whereas p27 expression was decreased. After LANA overexpression, CDK4, CDK6 and cyclin D1 expression was increased. Transcriptome sequencing showed that 11,258 genes were upregulated and 1,967 genes were downregulated in KSHV-infected SH-SY5Y. The Notch signaling pathway played a role in KSHV infection in SH-SY5Y, and western blots confirmed that Notch1, NICD, RBP-Jĸ and Hes1 expression was increased. After silencing of Notch1, the related proteins and cell proliferation ability were decreased. KSHV infected SH-SY5Y cells and promoted the cell proliferation. KSHV infection increased the expression of Notch signaling pathway proteins, which may have been associated with the enhanced cell proliferation.


Determinants of breast cancer in Saudi women from Makkah region: a case-control study (breast cancer risk factors among Saudi women).
There are various factors that play a major role in influencing the overall health conditions of women diagnosed with breast cancer. The population of women in Makkah region are diverse, therefore it is significant to highlight the possible determinants of breast cancer in this population. This is a case-control study that assessed determinants of breast cancer including socioeconomic factors, health-related characteristics, menstrual histories and breastfeeding among postmenopausal women in Makkah region in Saudi Arabia. A total of 432 female participants (214 cases and 218 controls) were recruited for this study. A validated questionnaire was completed by trained dietitians at King Abdullah Medical City Hospital in the Makkah region of Saudi Arabia. Results displayed that determinants of breast cancer were associated significantly (P < 0.05) with unemployment, large family size, lack of knowledge and awareness about breast cancer, obesity, sedentary lifestyle, smoking, starting menarche at an early age, as well as hormonal and non-hormonal contraceptive use. There was no effect of diabetes, hypertension, hyperlipidemia, and duration of breastfeeding on the incidence of breast cancer. In summary, the results of this study accentuate the possible effect of socioeconomic factors, health-related characteristics and menstrual history on the incidence of breast cancer in postmenopausal women in the Makkah region. Education programs should be applied to increase breast cancer awareness and possibly decrease its incidence.


Childhood overweight and obesity in the UK--a comparison of two environmentally distinct populations of 7-year-old children.
The proportions of overweight and obesity in seven-year-old children in two environmentally different UK based centres: Avon and the Isle of Man (IOM) have been compared. Children in the IOM (particularly boys) were more likely to be overweight and obese, when classified by body mass index (weight [kg]/height(2) [m]) (BMI), and waist circumference (WC).


A proton therapy system in Nagoya Proton Therapy Center.
The purpose of this paper is to describe an outline of a proton therapy system in Nagoya Proton Therapy Center (NPTC). The NPTC has a synchrotron with a linac injector and three treatment rooms: two rooms are equipped with a gantry and the other one is equipped with a fixed horizontal beamline. One gantry treatment room has a pencil beam scanning treatment delivery nozzle. The other two treatment rooms have a passive scattering treatment delivery nozzle. In the scanning treatment delivery nozzle, an energy absorber and an aperture system to treat head and neck cancer have been equipped. In the passive treatment delivery nozzle, a multi-leaf collimator is equipped. We employ respiratory gating to treat lung and liver cancers for passive irradiation. The proton therapy system passed all acceptance tests. The first patient was treated on February 25, 2013, using passive scattering fixed beams. Respiratory gating is commonly used to treat lung and liver cancers in the passive scattering system. The MLCs are our first choice to limit the irradiation field. The use of the aperture for scanning irradiation reduced the lateral fall off by half or less. The energy absorber and aperture system in scanning delivery is beneficial to treat head and neck cancer.