Future drugs for the treatment of benign prostatic hyperplasia.
For at least a decade, no new drug principles have been added to the therapeutic armamentarium for the treatment of lower urinary tract symptoms (LUTS) associated with or suggestive of benign prostatic hyperplasia (BPH). Theoretically, there seem to be several possibilities to improve the current treatment, which is based mainly on alpha1-adrenoceptor (AR) antagonists, 5alpha-reductase inhibitors and phytotherapy. It cannot be dismissed that subtype selective alpha1-AR antagonists can further improve treatment, but convincing evidence is still lacking. Muscarinic receptor antagonists are currently evaluated in BPH patients, but their eventual place in therapy, as a single treatment or in combination with alpha1-AR antagonists, has to be established. Endothelin receptor antagonists, alone or together with alpha1-AR antagonists, seem to offer a new attractive approach; however, proof of concept studies are lacking. The L-arginine/NO/cGMP pathway awaits further exploration; nitric oxide (NO) donors or phosphodiesterase (PDE) inhibitors may be clinically useful. Purinoceptors are currently the focus of interest as treatment targets in the lower urinary tract and inhibitors of P2X3 (and P2X1) subtypes may offer new opportunities. If a treatment based on desensitising C-fibres in the bladder and urethra is effective, not only in neurogenic bladders, but also for treating LUTS, it would be a viable option. For new treatments of LUTS, targets within the central nervous system (CNS) may offer exciting opportunities.


Apathogenic proxies for transmission dynamics of a fatal virus.
Identifying drivers of transmission-especially of emerging pathogens-is a formidable challenge for proactive disease management efforts. While close social interactions can be associated with microbial sharing between individuals, and thereby imply dynamics important for transmission, such associations can be obscured by the influences of factors such as shared diets or environments. Directly-transmitted viral agents, specifically those that are rapidly evolving such as many RNA viruses, can allow for high-resolution inference of transmission, and therefore hold promise for elucidating not only which individuals transmit to each other, but also drivers of those transmission events. Here, we tested a novel approach in the Florida panther, which is affected by several directly-transmitted feline retroviruses. We first inferred the transmission network for an apathogenic, directly-transmitted retrovirus, feline immunodeficiency virus (FIV), and then used exponential random graph models to determine drivers structuring this network. We then evaluated the utility of these drivers in predicting transmission of the analogously transmitted, pathogenic agent, feline leukemia virus (FeLV), and compared FIV-based predictions of outbreak dynamics against empirical FeLV outbreak data. FIV transmission was primarily driven by panther age class and distances between panther home range centroids. FIV-based modeling predicted FeLV dynamics similarly to common modeling approaches, but with evidence that FIV-based predictions captured the spatial structuring of the observed FeLV outbreak. While FIV-based predictions of FeLV transmission performed only marginally better than standard approaches, our results highlight the value of proactively identifying drivers of transmission-even based on analogously-transmitted, apathogenic agents-in order to predict transmission of emerging infectious agents. The identification of underlying drivers of transmission, such as through our workflow here, therefore holds promise for improving predictions of pathogen transmission in novel host populations, and could provide new strategies for proactive pathogen management in human and animal systems.


The importance of light in the anti-HIV effect of hypericin.
The requirement for light in the anti-HIV-1 activity of hypericin was investigated. The hypericin concentration-dependence and light dosage-dependence of the reaction were measured. Under conditions in which hypericin caused substantial inactivation of HIV-1, there was a strict requirement for visible light. Only when the concentration of hypericin approached the cytotoxic level was there an apparent light-independent antiviral effect. This strict light-requirement for the antiviral effect could explain some of the apparently discrepant results reported by other workers. Furthermore if hypericin is contemplated for use in humans, the importance of light must be considered.


Heat shock protein 20 (HSPB6) regulates TNF-α-induced intracellular signaling pathway in human hepatocellular carcinoma cells.
We previously demonstrated that the expression of HSP20, a small heat shock protein, is inversely correlated with the progression of HCC. Inflammation is associated with HCC, and numerous cytokines, including TNF-α, act as key mediators in the progression of HCC. In the present study, we investigated whether HSP20 is implicated in the TNF-α-stimulated intracellular signaling in HCC using human HCC-derived HuH7 cells in the presence of TNF-α. In HSP20-overexpressing HCC cells, the cell growth was retarded compared with that in the control cells under long-term exposure of TNF-α. Because NF-κB pathway is the main intracellular signaling system activated by TNF-α, we investigated the effects of HSP20-overexpression of this pathway. The protein levels of IKK-α, but not IKK-β, in the HSP20-overexpressing cells were decreased. Short-term exposure to TNF-α-induced phosphorylation and degradation of IκB, and the phosphorylation and transactivational activity of NF-κB were suppressed in the HSP20-overexpressing HCC cells. Furthermore, the increase in IKK-α levels was accompanied by a decrease in the HSP20 levels in human HCC tissues. These findings strongly suggest that HSP20 might decrease the IKK-α protein level and that it down-regulates the TNF-α-stimulated intracellular signaling in HCC, thus resulting in the suppression of HCC progression.


Expression of c-myc oncogene in rat liver by a dietary manipulation.
After rats deprived of protein for several days are fed a meal containing protein, hepatic DNA replication is induced. When nuclear DNA synthesis is stimulated in the normally quiescent rat liver by a dietary manipulation, we examined the changes of the steady-state levels of messenger RNA for c-myc. Levels of c-myc mRNA are gradually elevated approximately 4 to 5-fold above normal in the livers of rats that are fed for several days a diet that lacks protein. After a nutritional shift from a protein-free diet to a diet containing 50% casein, the levels of c-myc mRNA decrease rapidly by 2 h and returned to approximately basal levels after 8 h. Our results suggest that c-myc expression during the prereplicative stage of liver is likely to reflect events associated with entry and progression of hepatocytes into the cell cycle.


Infection of newborn and fetal hamsters induced by inoculation of LuIII parvovirus.
The LuIII parvovirus was adapted to the newborn hamster and produced a systemic infection with massive intestinal hemorrhage. Inoculation of pregnant hamsters lead to transplacental infection of the fetuses and abortion. Most fetal deaths were observed in animals inoculated on days 8 and 10 of gestation. Virus was recovered from dead fetuses, placentas, and viable fetuses. Histological lesions were found in the heart, liver, kidney and CNS of infected fetuses.


Eccentric Versus Concentric Exercises in Patients With Rheumatoid Arthritis and Rotator Cuff Tendinopathy: A Randomized Comparative Study.
To determine the efficacy of concentric vs. eccentric exercise in improving shoulder function, pain, and tendon characteristics for patients with rheumatoid arthritis and rotator cuff tendinopathy. Forty patients with rheumatoid arthritis and rotator cuff tendinopathy were divided into either concentric or eccentric exercise groups, with 20 patients in each group. Patients received 12 sessions at a pace of 3 sessions per week. Shoulder Pain and Disability Index (SPADI), the visual analogue scale (VAS), supraspinatus and subscapularis thickness, echo pixels, and the Disease Activity Score-28-erythrocyte sedimentation rate (DAS-28-ESR) were assessed at baseline and post-treatment. There was a significant difference between the concentric and eccentric groups regarding SPADI and VAS scores in favor of the eccentric group. However, there was no significant difference between the two groups regarding tendon thickness, echo pixels, or DAS-28-ESR. Eccentric exercises were more effective than concentric exercises in improving shoulder function and pain intensity. However, neither of the two types of exercises was superior in improving tendon characteristics or disease activity.


Intraoperative conversion from laparoscopic gastrectomy to an open procedure: a decade of experience in a Japanese high-volume center.
Although laparoscopic gastrectomy (LG) is a widely accepted treatment for gastric cancer, conversion to laparotomy is sometimes required. The current study aimed to review the time trends of intraoperative conversions to open procedures during the decade in which the LG procedure was being developed. Cases in which LG was attempted at the Cancer Institute Hospital from 2005 to 2018 were retrospectively reviewed, and the details regarding conversions to open surgery were examined. Twenty-two (0.63%) of 3,498 patients required conversion to open surgery due to technical difficulties. The major reasons for conversions were difficulties in reconstruction (seven patients; 0.20%) and intraoperative bleeding (six patients; 0.17%). All conversions due to difficulties in reconstruction occurred in the introduction period of LG during the performance of esophagojejunostomy or esophagogastrostomy in laparoscopic total gastrectomy or proximal gastrectomy using a circular stapler. Five (71.4%) of the seven patients in whom conversion was performed due to difficulties in reconstruction developed postoperative severe complications. No conversions due to difficulties in reconstruction have been experienced since 2011, possibly due to the decrease in the number of laparoscopic total gastrectomy procedures and the introduction of the use of a linear stapler in esophagojejunostomy. To manage intraoperative bleeding in LG, hemostatic procedures were systematized and conversions were considered if visualization was not maintained following the procedures. None of the six patients who required laparotomy due to intraoperative bleeding required surgical or radiological intervention postoperatively. Over a decade of experience and procedural changes have markedly decreased the incidence of conversion to open surgery in LG. The main causes of conversion during the early period of LG introduction were difficulties in reconstruction and intraoperative bleeding; the incidences of these complications have been decreased by employing the appropriate procedures for LG.


Flame Synthesis of Cu/ZnO-CeO2 Catalysts: Synergistic Metal-Support Interactions Promote CH3OH Selectivity in CO2 Hydrogenation.
The hydrogenation of CO2 to CH3OH is an important reaction for future renewable energy scenarios. Herein, we compare Cu/ZnO, Cu/CeO2, and Cu/ZnO-CeO2 catalysts prepared by flame spray pyrolysis. The Cu loading and support composition were varied to understand the role of Cu-ZnO and Cu-CeO2 interactions. CeO2 addition improves Cu dispersion with respect to ZnO, owing to stronger Cu-CeO2 interactions. The ternary Cu/ZnO-CeO2 catalysts displayed a substantially higher CH3OH selectivity than binary Cu/CeO2 and Cu/ZnO catalysts. The high CH3OH selectivity in comparison with a commercial Cu-ZnO catalyst is also confirmed for Cu/ZnO-CeO2 catalyst prepared with high Cu loading (∼40 wt %). In situ IR spectroscopy was used to probe metal-support interactions in the reduced catalysts and to gain insight into CO2 hydrogenation over the Cu-Zn-Ce oxide catalysts. The higher CH3OH selectivity can be explained by synergistic Cu-CeO2 and Cu-ZnO interactions. Cu-ZnO interactions promote CO2 hydrogenation to CH3OH by Zn-decorated Cu active sites. Cu-CeO2 interactions inhibit the reverse water-gas shift reaction due to a high formate coverage of Cu and a high rate of hydrogenation of the CO intermediate to CH3OH. These insights emphasize the potential of fine-tuning metal-support interactions to develop improved Cu-based catalysts for CO2 hydrogenation to CH3OH.


Transpedicular fixation for the treatment of isthmic spondylolisthesis in adults.
This study analyzed the fusion rate and clinical success rate in adult patients undergoing surgical treatment for symptomatic, low grade, isthmic spondylolisthesis. A postoperative questionnaire and grading scale were used to judge clinical success. Successful fusion was judged using radiographic criteria. To evaluate the clinical success and fusion success in a group of adult patients undergoing instrumented posterolateral arthrodesis for symptomatic isthmic spondylolisthesis. Seventeen consecutive adult patients with symptomatic low grade isthmic spondylolisthesis underwent the identical surgical procedure consisting of Gill laminectomy, L5 nerve root decompression, Luque pedicle-screw plate instrumentation, and posterolateral arthrodesis at L5-S1 using autogenous iliac crest bone graft. Results were analyzed at an average 30-month follow-up. An independent observer reviewed the results using a postoperative questionnaire to determine rates of return to work, symptom relief, and analgesic medication usage. Radiographs were evaluated to determine the fusion status. Seventeen patients were evaluated at an average of 30 months after the index procedure. Sixteen of 17 had solid fusions using radiographic criteria. Sixteen of 17 had satisfactory clinical results. Eight of 13 (62%) employed patients, including three of six patients with worker's compensation, returned to their usual jobs. An instrumented posterolateral arthrodesis in combination with a Gill procedure and L5 nerve root decompression results in a high rate of fusion, satisfactory clinical success, and a high rate of return to work.


"De novo" familial adenomatous polyposis (FAP) presenting as rectal cancer.
Familial adenomatous polyposis is an autosomal dominant disorder with familial predisposition. 25%-30% cases arise "de novo," without any clinical or genetic evidence.


Promoting appropriate midline catheter and PICC placement through implementation of an EHR-based clinical decision support tool: An interrupted time-series analysis.
Inappropriate use of peripherally inserted central catheters (PICCs), including multilumen PICCs, may increase the risk of patient complications. Implement computerized decision support to: (a) increase the use of midline catheters over PICCs when appropriate and (b) decrease PICC lumens when a PICC is necessary. Quasi-experimental, interrupted time series. Single tertiary academic medical center. Hospitalized adults who received a midline or PICC during clinical care. Decision support on appropriate vascular access device choice via a set of electronic orders embedded within the electronic health record. Proportion of midline catheter and single-lumen PICCs placed between January 2, 2017 and November 19, 2017 (preintervention) versus November 20, 2017 to December 1, 2019 (postintervention). A total of 8758 midline and PICCs were inserted during the study period. A statistically significant increase in the insertion of midline catheters was observed during the intervention (p = .006). In parallel, single-lumen PICC insertion as a proportion of all PICCs also increased after the intervention (p = .035). Results were consistent across multiple disciplines, including internal medicine, surgery, and intensive care. After considering the hospital census, total PICC and midline utilization rates and rates of complications did not change over time. However, an increase in catheter exchanges from less to more invasive devices occurred. In this single-center study, the implementation of electronic decision support to inform appropriate catheter use led to a more appropriate midline catheter and single-lumen PICC insertion. Dissemination of this single, effective intervention to examine efficacy in other hospital settings would be welcomed.


Spinal epidural abscess caused by Aspergillus spp masquerading as spinal tuberculosis in a person with HIV.
Spinal epidural abscess caused by Aspergillus spp is a debilitating form of invasive aspergillosis that can easily be misdiagnosed as spinal tuberculosis due to shared risk factors and clinical features. In this Grand Round, we describe a case of thoracic aspergillus spinal epidural abscess in a patient with underlying HIV infection. The initial diagnostic consideration was that of spinal tuberculosis. Consequently, despite positive microbiological cultures of Aspergillus fumigatus, antifungal therapy was delayed until histopathological evaluation of the affected tissue confirmed the presence of fungal hyphae. The patient showed an initial favourable response after surgical removal of the infected focus, but unfortunately never returned to premorbid functioning. This case highlights the importance of early diagnosis, urgent surgery, and prompt antifungal therapy for the management of aspergillus spinal epidural abscesses. Associated morbidity and mortality can be substantially increased if physicians fail to recognise this condition and do not institute appropriate and timely surgical and medical treatment.


De novo mutations in SCN1A are associated with classic Rett syndrome: a case report.
Rett syndrome (RTT) is a neurodevelopmental disorder. In more than 95% of females with classic RTT a pathogenic mutation in MECP2 has been identified. This leaves a small fraction of classic cases with other genetic causes. So far, there has not been reported any other gene that may account for the majority of these cases. We describe two females who fulfill the diagnostic criteria for classic RTT, with pathogenic de novo mutations in SCN1A, which usually leads to Dravet syndrome. The developmental history and clinical features of these two females fits well with RTT, but they do have an unusual epileptic profile with early onset of seizures. Investigation of mRNA from one of the females showed a significantly reduced level of MECP2 mRNA. To our knowledge, this is the first report suggesting that SCN1A mutations could account for a proportion of the females with classic RTT without MECP2 mutations. As a consequence of these findings SCN1A should be considered in the molecular routine screening in MECP2-negative individuals with RTT and early onset epilepsy.


Opioid peptide effects on feeding in rabbits.
The food intake of rabbits was measured after intracerebroventricular injections of several opioid agonists and naloxone. The preferential kappa agonist dynorphin A increased intake, while naloxone, [D-Ser2,Leu5]enkephalin-Thr6 and Tyr-D-Ala-Gly-(Me)Phe-Gly-ol reduced intake or had no effect. These results suggest that kappa receptors have a role in the control of feeding in rabbits.


Mature human neutrophils constitutively express the transcription factor EGR-1.
The immediate early response gene, Early Growth Response 1 (EGR-1) has emerged as a central regulator of early inflammatory and immune processes by rapidly regulating the transcription of a wide array of downstream effector genes. Neutrophils, which are among the first circulating leukocytes to respond to inflammatory signals, exhibit a broad set of transcriptional changes immediately upon exposure to inflammatory and pathogenic stimuli. Such transcriptional changes are likely to be controlled by early gene transcription factors such as EGR-1. We therefore examined the regulation and role of EGR-1 in mature human neutrophils exposed to the inflammatory stimuli fMLP and IL-8. We report that human neutrophils rapidly and transiently up-regulate EGR-1 mRNA upon stimulation with fMLP or IL-8. However in contrast to that seen in other cells, EGR-1 mRNA expression profiles were not predictive of protein expression. Instead, we show that human neutrophils constitutively express EGR-1 protein. The cellular content of EGR-1 did not change over time or upon neutrophil activation. Confocal microscopy revealed that EGR-1 was present in both the cytoplasm and nuclei of un-stimulated neutrophils and that activation did not change this subcellular localization or promote nuclear translocation. Using chromatin immunoprecipitation, we demonstrate that EGR-1 is associated with the promoter regions of the immune regulatory genes IL-1 beta, TGFbeta-1 and MIF in both resting and activated neutrophils with increased promoter association observed upon cell activation. This novel pattern of EGR-1 protein expression may underlie the ability of the neutrophil to respond rapidly to inflammatory stimuli.


Influence of spiral topographies on human limbal-derived immortalized corneal epithelial cells.
Cells migrate from the limbus to the corneal epithelium following a centripetal pathway. Corneal epithelial cells tend to orientate in spiral or vortex patterns. However, when cultured in-vitro, limbal derived corneal epithelia do not tend to align or migrate in a spiral pattern. Here, we used soft lithography to create silk fibroin substrates with spiral topographies that direct the human limbal-derived immortalized corneal epithelial cells (hTCEpi) to form a spiral orientation. The impact of this topography on the cells was then characterized. The spiral patterns affected cytoskeletal organization, cell spreading, and nuclei shapes. Spiral width and numbers had a significant impact on proliferation of cells, their focal adhesion, their chromatin condensation, and number of actin filaments. Immunocytochemical staining showed that the spiral pattern enhanced the expression of markers associated with limbal stem cells. The current work illustrates micro spiral patterns can serve to control the nature of limbal derived epithelial cells by providing relevant biophysical cues.


Biological and social influences on cognitive control processes dependent on prefrontal cortex.
Cognitive control functions ("executive functions" [EFs] such as attentional control, self-regulation, working memory, and inhibition) that depend on prefrontal cortex (PFC) are critical for success in school and in life. Many children begin school lacking needed EF skills. Disturbances in EFs occur in many mental health disorders, such as ADHD and depression. This chapter addresses modulation of EFs by biology (genes and neurochemistry) and the environment (including school programs) with implications for clinical disorders and for education. Unusual properties of the prefrontal dopamine system contribute to PFC's vulnerability to environmental and genetic variations that have little effect elsewhere. EFs depend on a late-maturing brain region (PFC), yet they can be improved even in infants and preschoolers, without specialists or fancy equipment. Research shows that activities often squeezed out of school curricula (play, physical education, and the arts) rather than detracting from academic achievement help improve EFs and enhance academic outcomes. Such practices may also head off problems before they lead to diagnoses of EF impairments, including ADHD. Many issues are not simply education issues or health issues; they are both.


Large differences in global transcriptional regulatory programs of normal and tumor colon cells.
Dysregulation of transcriptional programs leads to cell malfunctioning and can have an impact in cancer development. Our study aims to characterize global differences between transcriptional regulatory programs of normal and tumor cells of the colon. Affymetrix Human Genome U219 expression arrays were used to assess gene expression in 100 samples of colon tumor and their paired adjacent normal mucosa. Transcriptional networks were reconstructed using ARACNe algorithm using 1,000 bootstrap replicates consolidated into a consensus network. Networks were compared regarding topology parameters and identified well-connected clusters. Functional enrichment was performed with SIGORA method. ENCODE ChIP-Seq data curated in the hmChIP database was used for in silico validation of the most prominent transcription factors. The normal network contained 1,177 transcription factors, 5,466 target genes and 61,226 transcriptional interactions. A large loss of transcriptional interactions in the tumor network was observed (11,585; 81% reduction), which also contained fewer transcription factors (621; 47% reduction) and target genes (2,190; 60% reduction) than the normal network. Gene silencing was not a main determinant of this loss of regulatory activity, since the average gene expression was essentially conserved. Also, 91 transcription factors increased their connectivity in the tumor network. These genes revealed a tumor-specific emergent transcriptional regulatory program with significant functional enrichment related to colorectal cancer pathway. In addition, the analysis of clusters again identified subnetworks in the tumors enriched for cancer related pathways (immune response, Wnt signaling, DNA replication, cell adherence, apoptosis, DNA repair, among others). Also multiple metabolism pathways show differential clustering between the tumor and normal network. These findings will allow a better understanding of the transcriptional regulatory programs altered in colon cancer and could be an invaluable methodology to identify potential hubs with a relevant role in the field of cancer diagnosis, prognosis and therapy.


Psychological distress among postpartum women who took opioids during pregnancy: the role of perceived stigma in healthcare settings.
This study examined the relationship between perceived stigma in healthcare settings during pregnancy and psychological distress and well-being in the postpartum period among individuals who took opioids while pregnant. Analyses included 134 birth mothers of opioid-exposed infants. At 0-1 months postpartum, perceived stigma and psychological distress were measured using the Prenatal Opioid use Perceived Stigma scale and measures from the Patient-Reported Outcome Measurement Information System (PROMIS). Food insecurity, housing instability, and Adverse Childhood Experiences (ACEs) were also assessed. Linear and generalized linear mixed-effect models were conducted to compare PROMIS scale scores and unmet needs by stigma, adjusting for site/location, age, race/ethnicity, marital status, education, public insurance, and parity. More than half of participants (54%) perceived stigma in healthcare settings. Individuals reporting stigma had higher depression, anxiety, and anger scores (p < 0.001) indicating greater psychological distress in the postpartum period compared to those reporting no stigma, after controlling for demographic characteristics. In addition, they scored significantly lower on the PROMIS meaning and purpose scale, an indicator of well-being (p = 0.002). Those reporting stigma were more likely to have food insecurity (p = 0.003), three or more ACEs (p = 0.040), verbal or physical abuse during pregnancy (p < 0.001), and less emotional support (p = 0.006) than those who did not. An association was observed between perceived stigma in the prenatal period and psychological distress in the postpartum period, providing support for stigma reduction interventions and education for healthcare providers on trauma-informed care.


Systemic amyloidosis presenting as splenic tumor.
We report a case of amyloidosis manifesting as a splenic tumor and pleural effusion. Only one case of a splenic amyloid tumor has been reported in the literature, but its radiological findings were not described. Therefore, we present the computed tomographic (CT), sonographic, and angiographic features of splenic amyloid tumor.


Basics of breastfeeding. Part II: the anatomy and psychophysiology of lactation.
The major anatomical structures of the lactating breast are identified and related to the psychophysiologic mechanisms of lactation. Hand expression of breast milk is explained in a practical manner and some causes of lactation dysfunction are described.


Trends in Academic Misrepresentation in Neurological Surgery Residency Applicants: A 2-Year Analysis.
Academic misrepresentation is not an unknown phenomenon, with recent reports in neurosurgery detecting a 45% misrepresentation rate in prospective neurosurgical residents. The purpose of this study was to determine current rates of academic misrepresentation by prospective neurosurgical residents at a single institution across 2 distinct application cycles. We retrospectively reviewed all Electronic Residency Application Service applications to 1 institution's neurosurgical residency program in the 2015 (n = 320) and 2020 (n = 355) application cycles. Reported academic works were verified through an extensive Web search of PubMed, Google Scholar, and the individual journal Web sites. Misrepresentation was defined in our study as listing work that does not exist, self-promotion to primary authorship, self-promotion (excluding primary authorship), incorrectly listing online-only publications, and listing non-peer-reviewed work as peer-reviewed. In 2015, 253 (79.1%) applicants reported a total of 2097 citations and 305 (85.9%) applicants reported a total of 3018 citations in 2020 (P < 0.05). Median peer-reviewed articles per applicant rose significantly in 2020 (3.0 vs. 4.0, P < 0.001). Misrepresentation rates decreased dramatically in 2020 to 18.4% from a previously reported misrepresentation rate of 45% in 2012 (P < 0.0001). Increased United States Medical Licensing Exam Step 2 scores were associated with a decreased likelihood of misrepresentation (odds ratio = 0.97, P < 0.001). Misrepresentation rates within neurosurgical residency candidates have significantly decreased despite an increase in reported citations. A variety of steps including education, modifying reporting methods, and increased screening may help even further decrease misrepresentation.


Comparison of in vitro Susceptibilities of Talaromyces marneffei in Mold and Yeast Forms in Malaysia.
This study was aimed to determine minimum inhibitory concentration (MIC) differences between yeast and mold forms of T. marneffei in Malaysia. Ninety-seven clinical strains of T. marneffei were received from various Malaysian hospitals from the year 2020 until 2022. Their identities were determined using microscopic, macroscopic and molecular methods. Next, the susceptibility of yeast and mold forms of each isolate against amphotericin B, itraconazole, voriconazole, posaconazole, ketoconazole, isavuconazole, terbinafine, caspofungin and micafungin were tested according to the broth microdilution according to the Clinical and Laboratory Standards Institute (CLSI) M38 and M27 guidelines. The geometric means of minimal inhibitory concentration (GM MIC), MIC50, and MIC90 were determined for each antifungal. Additionally, Wilcoxon signed-rank test was used to compare the significant difference of GM MICs for each antifungal, GM MIC, MIC50 and MIC90 for the combined nine antifungals against different growth forms of T. marneffei. The significance was set at p<0.05. Micafungin had the highest GM MIC, MIC50 and MIC90 for mold form of T. marneffei. For yeast form, amphotericin B achieved the highest GM MIC and MIC50 while micafungin achieved the highest MIC90. However, the GM MIC, MIC50 and MIC90 of terbinafine and azole antifungals on T. marneffei were similar to each other, namely between 0.03 and 0.60µg/mL. The difference of GM MIC of all tested antifungals except caspofungin and micafungin was insignificant. Overall, GM MIC, MIC50 and MIC90 of the combined nine antifungals against two growth forms were insignificant. The findings suggested either yeast or mold form can be used in the susceptibility testing of T. marneffei against amphotericin B, itraconazole, voriconazole, posaconazole, ketoconazole, isavuconazole and terbinafine.


[Experiences with a subcutaneous, fully resorbable bridge in construction a double loop ileo- and colostomy].
Our experience with the subcutaneous absorbable bridge for constructing a temporary loop ileostomy and loop colostomy is described. The use of this subcutaneous absorbable bridge in 15 patients - 6 with loop ileostomy and 9 with loop colostomy - was almost without complications. The absorbable bridge is a progress for maturation of the stoma and for immediate postoperative as prospective fitting of a watertight appliance. The actual trend substituting the temporary loop colostomy by the loop ileostomy may be advanced by the unlimited use of the subcutaneous absorbable bridge for constructing a temporary loop ileostomy.


Design and synthesis of benzoxazole containing indole analogs as peroxisome proliferator-activated receptor-γ/δ dual agonists.
A series of benzoxazole or benzothiazole containing indole analogs, 6-alkoxyindole-2-carboxylic acids and 5-alkoxy-3-indolylacetic acids, were synthesized as novel candidates of PPARγ/δ dual agonists and their ligand activities for PPAR subtypes (α, γ, and δ) were investigated. In transient transactivation assay, several compounds activated PPARγ and δ with little activity of PPARα. Putative binding mode of the compounds 1a and 2a in the active site of PPARγ was similar with that of rosiglitazone and the molecular modeling provides molecular insight to the observed activity.


Synthesis and in vitro anticancer activities of selenium N-heterocyclic carbene compounds.
Fourteen novel selenium N-heterocyclic carbene (Se-NHC) compounds derived from 4,5-diarylimidazole were designed, synthesized, and evaluated as antiproliferative agents. Most of them were more effective toward A2780 ovarian cancer cells than HepG2 hepatocellular carcinoma cells. Among them, the most active compound 2b was about fourfold more active than the positive control ebselen against A2780 cells. In addition, this compound displayed twofold higher cytotoxicity to A2780 cells than to IOSE80 normal ovarian epithelial cells. Further studies revealed that 2b could induce reactive oxygen species production, damage mitochondrial membrane potential, block the cells in the G0/G1 phase, and finally promote A2780 cell apoptosis.


Paracrine and autocrine interactions in the human islet: more than meets the eye.
The pancreatic islet secretes the hormones insulin and glucagon to regulate glucose metabolism. To generate an adequate secretory response, islet endocrine cells must receive multiple regulatory signals relaying information about changes in the internal and external environments. Islet cells also need to be made aware about the functional status of neighboring cells through paracrine interactions. All this information is used to orchestrate a hormonal response that contributes to glucose homeostasis. Several neurotransmitters have been proposed to work as paracrine signals in the islet. Most of these, however, have yet to meet the criteria to be considered bona fide paracrine signals, in particular in human islets. Here, we review recent findings describing autocrine and paracrine signaling mechanisms in human islets. These recent results are showing an increasingly complex picture of paracrine interactions in the human islet and emphasize that results from other species cannot be readily extrapolated to the human context. Investigators are unveiling new signaling mechanisms or finding new roles for known paracrine signals in human islets. While it is too early to provide a synthesis, the field of islet research is defining the paracrine and autocrine components that will be used to generate models about how islet function is regulated. Meanwhile, the identified signaling pathways can be proposed as therapeutic targets for treating diabetes, a devastating disease affecting millions worldwide.


Fostamatinib Inhibits Neutrophils Extracellular Traps Induced by COVID-19 Patient Plasma: A Potential Therapeutic.
Neutrophil extracellular traps (NETs) contribute to immunothrombosis and have been associated with mortality in coronavirus disease 2019 (COVID-19). We stimulated donor neutrophils with plasma from patients with COVID-19 and demonstrated that R406 can abrogate the release of NETs. These data provide evidence for how fostamatinib may mitigate neutrophil-associated mechanisms contributing to COVID-19 immunopathogenesis.


Soluble lipase-catalyzed synthesis of methyl esters using a blend of edible and nonedible raw materials.
This work investigates the use of blends of edible and nonedible raw materials as an alternative feedstock to fatty acid methyl esters (FAME) production through enzymatic catalysis. As biocatalyst, liquid lipase from Thermomyces lanuginosus (Callera™ Trans L), was used. Under reaction conditions of 35 °C, methanol to feedstock molar ratio of 4.5:1 and 1.45% of catalyst load, the best process performance was reached using 9% of water concentration in the medium-yield of 79.9% after 480 min of reaction. In terms of use of tallow mixed with soybean oil, the best yield was obtained when 100% of tallow was used in the process-84.6% after 480 min of reaction-behavior that was associated with the degree of unsaturation of the feedstock, something by that time, not addressed in papers of the area. The results show that tallow can be used as an alternative to FAME production, catalyzed by soluble lipase.


Host cell factor CD59 restricts complement lysis of Plasmodium falciparum-infected erythrocytes.
Here we demonstrate that components of the entire complement cascade are fixed on the surface of erythrocytes infected with the human malarial parasite Plasmodium falciparum. Despite the activation of lytic complement factors, no complement-mediated lysis of P. falciparum-infected erythrocytes occurred only in the absence of functional intrinsic CD59. These data suggest that the restriction of the complement attack of P. falciparum-infected erythrocytes is principally mediated by intrinsic host cell factors, in particular CD59.


Isolation and functional reconstitution of the aspartate/glutamate carrier from mitochondria.
The aspartate/glutamate carrier from beef heart mitochondria was solubilized by the detergent dodecyloctaoxyethylene ether (C12E8) in the presence of high concentrations of ammonium acetate. After separating the bulk amount of contaminating proteins by differential solubilization and by hydroxyapatite centrifugation chromatography, the aspartate/glutamate carrier was purified by high-performance liquid chromatography on hydroxyapatite. During the purification process, the aspartate/glutamate carrier as well as other transport proteins was identified by functional reconstitution. In sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis the purified aspartate/glutamate carrier protein appears as a protein band with an apparent molecular mass of 68 kDa. Small amounts of some contaminating proteins mainly at 31 kDa were also found. Since the ADP/ATP carrier has an apparent molecular mass of 31 kDa in SDS-gel electrophoresis, possible contamination by the nucleotide carrier was analyzed by immunological methods. The enrichment of the aspartate/glutamate carrier--based on functional reconstitution--was about 570-fold, the protein yield was 0.1%.


Migraine attacks among medical students in Soochow University, Southeast China: a cross-sectional study.
Migraine is one of the most common primary headache disorders and is burdensome to both the individual and society, influencing the academic performance and quality of daily lives of medical students worldwide. This study aimed to investigate the migraine prevalence in a sample of university medical students in China and to examine the features and typical trigger factors of migraine among these students. From May 2016 to August 2016, a total of 1,060 medical students who were enrolled in Soochow University in Jiangsu Province in China were chosen through stratified random sampling. A self-administered questionnaire that included the ID Migraine™ for screening of migraine cases was used to collect data. The frequency, severity, duration of migraine attacks, and relevant trigger factors were measured for migraine cases. In total, 986 students completed the questionnaire. The overall migraine prevalence among students was 7.91%, with 4.64% in male and 9.84% in female students. Junior-grade students had a higher migraine prevalence than senior students (prevalence of migraine of year 1 to year 5 undergraduates: 10.83%, 8.9% vs. 6.25%, 4.42%, 5.33%, P<0.05; prevalence of migraine of year 1 to year 3 graduates: 9.68%, 9.71% vs. 6.38%, P<0.05). Students with a positive family history were more likely to suffer migraine than those without (OR=8.48, 95% CI: 4.33-16.59). Stress (n=73, 93.59%), lack of sleep (n=72, 92.31%), and change of sleeping time (n=68, 87.18%) were the top three trigger factors among the students. Migraine was common among medical students from a university in China, and especially higher in female and junior-grade students, and those with a family history of migraine. Reducing stress and improving sleep quality might be effective to reduce migraine attacks in this population.


Pyridine nucleotide synthesis in normal and neoplastic human pituitary cells in culture.
14C-Nicotinic acid (NA) incorporation into nicotinamide adenine dinucleotide (NAD) was studied in cultures from 7 normal human pituitaries and 13 chromophobe adenomas. 14C-NA (7.2 microM) was incubated with both normal and tumor cell cultures for periods up to 48 hours. Cells and culture media were examined separately for metabolites at 24 and 48 hours. NAD was the major labeled metabolite found in both normal and tumor cells, accounting for 65.4% for normal cells and 56.8% for tumor cells of the total cellular label at 48 hours. Nicotinamide (NAm), a product arising from NAD, was the only labeled metabolite found in the culture medium, aside from the 14C-NA added initially. Total incorporation of 14C-NA into NAD was estimated by adding the cellular 14C-NAD and labeled products of NAD (NMN, NAm and NADP) to the 14C-NAm found in the medium for each culture. Cultures derived from adenomas demonstrated greater than twice the rate of incorporation of 14C-NA into NAD as did normal cell cultures (P less than 0.01 at 24 hours and less than 0.001 at 48 hours). This difference did not appear to be related to the secretory status of the tumor, since both secreting and nonsecreting tumors demonstrated increased rates when compared to normal cells. This difference also persisted in two different culture media and with cells that had been maintained in culture for different lengths of time (6-day dispersed cell cultures and 6- to 16-week fragment cultures).


Accuracy of Estimating Chronological Age from Nolla's Method of Dental Age Estimation in a Population of Southern Saudi Arabian Children.
The aim of this study was to test the accuracy of estimating chronological age using Nolla's method of dental age assessment in a Saudi Arabian population considering sex and age group variables. This cross-sectional study involved a retrospective evaluation of 458 orthopantomographs (187 males and 271 females) of 5-11 years old healthy Saudi children. Seven permanent left mandibular teeth were assessed as per Nolla's method to record dental age. The mean difference between dental age and chronological age was calculated using a paired t-test. Correlation between chronological age and dental age was analyzed using Pearson's correlation coefficient. There was a statistically significant difference (P < 0.05) between the estimated dental age and chronological age in all age groups irrespective of gender. The mean difference between estimated dental age and chronological age in males ranged from -2.68 to -6 months and -2.17 to -4.24 months in females. Pearson's correlation coefficient showed a strong positive correlation (r = 0.95 for males and r = 0.94 for females) between estimated dental age and chronological age. Nolla's method is suitable for estimating chronological age in Southern Saudi children, as the mean difference between estimated dental age and chronological age was within an acceptable range.


Macular hemorrhages associated with posterior vitreous detachment.
We treated three patients with small, macular-area hemorrhages associated with posterior vitreous detachment. All patients were young and had no associated systemic illness or associated retinal vascular disease. Visual acuity returned to normal without treatment as the hemorrhages resolved.


Antibody-independent detection of virus-specific glycoprotein synthesis is oncornavirus-infected cells.
A method is described for detecting the synthesis of avian and murine oncornavirus-specific glycoproteins without the use of antibodies raised against viral structural proteins. As applied to cells infected with avian tumor virus, the method served to resolve pr90, the precursor of the major envelope glycoprotein. A virus-specific glycoprotein of about 85,000 daltons, which has several properties expected to a precursor to gp69/71, was detected in cells infected with murine leukemia virus.


Case report: A novel PPP3CA truncating mutation within the regulatory domain causes severe developmental and epileptic encephalopathy in a Chinese patient.
Developmental and epileptic encephalopathy 91 (DEE91; OMIM#617711) is a severe neurodevelopmental disorder caused by heterozygous PPP3CA variants. To the best of our knowledge, only a few DEE91 cases have been reported. This study reports a boy who experienced recurrent afebrile convulsions and spasms at the age of 2 months. After being given multiple antiepileptic treatments with levetiracetam, adrenocorticotropic hormone (ACTH), prednisone, topiramate, and clonazepam, his seizures were not completely relieved. At the age of 4 months, the patient exhibited delayed neuromotor development and difficulty in feeding; at the age of 6 months, he was diagnosed with developmental regression with recurrent spasms and myoclonic seizures that could respond to vigabatrin. At the age of 1 year and 4 months, the patient showed profound global developmental delay (GDD) with intermittent absence seizures. Whole-exome sequencing (WES) identified a novel loss-of-function variant c.1258_1259insAGTG (p. Val420Glufs*32) in PPP3CA. This finding expands the genetic spectrum of the PPP3CA gene and reinforces the theory that DEE91-associated truncating variants cluster within a 26-amino acid region in the regulatory domain (RD) of PPP3CA.


Effect of nitrogen source on biosynthesis of rapamycin by Streptomyces hygroscopicus.
Six non-amino acid nitrogen compounds were examined as nitrogen source for growth of Streptomyces hygroscopicus and biosynthesis of rapamycin. Of the nitrogen sources studied, ammonium sulfate was the best with respect to formation of rapamycin, and supported cell growth comparable to the organic nitrogen sources used in the control chemically defined medium, i.e., aspartate, arginine plus histidine. In the new chemically defined medium, which is buffered with 200 mM 2-(N-morpholino)ethanesulfonic acid to prevent decline of pH during fermentation, an ammonium sulfate concentration of 40 mM was optimal for biosynthesis of rapamycin. Rapamycin production increased by more than 30% on both volumetric and specific bases as compared to the previous medium containing the three amino acids as nitrogen source.


Spatial Localization of Two Enzymes at Pickering Emulsion Droplet Interfaces for Cascade Reactions.
Developing biocatalytic cascades in abiological conditions is of utmost significance, but such processes often suffer from low reaction efficiency because of incompatible reaction environments and suppressed intermediate transportation. Herein we report a new type of biocatalytic cascade by localizing two different enzymes separately in the outer and inner interfacial layers of Pickering emulsion droplets. This versatile approach enables the localization of two enzymes in their preferred reaction microenvironments and simultaneously in nanoscale proximity of each other. The thus-designed interfacial biocatalytic cascades show outstanding catalytic efficiency in alkene epoxidation and thioether oxidation with in situ generation of hydrogen peroxide under mild conditions, 6.9-13.6 times higher than the catalytic efficiency of the free enzymes in solution and their multi-enzymatic counterparts. The remarkable interfacial effect of Pickering droplets was found to be responsible for the significantly enhanced cascading efficiency.


Beginning to understand high-density lipoproteins.
This article reconciles the classic view of high-density lipoproteins (HDL) associated with low risk for cardiovascular disease (CVD) with recent data (genetics studies and randomized clinical trials) casting doubt over the widely accepted beneficial role of HDL regarding CVD risk. Although HDL cholesterol has been used as a surrogate measure to investigate HDL function, the cholesterol content in HDL particles is not an indicator of the atheroprotective properties of HDL. Thus, more precise measures of HDL metabolism are needed to reflect and account for the beneficial effects of HDL particles. Current and emerging therapies targeting HDL are discussed.


Henipaviruses: emerging paramyxoviruses associated with fruit bats.
Two related, novel, zoonotic paramyxoviruses have been described recently. Hendra virus was first reported in horses and thence humans in Australia in 1994; Nipah virus was first reported in pigs and thence humans in Malaysia in 1998. Human cases of Nipah virus infection, apparently unassociated with infection in livestock, have been reported in Bangladesh since 2001. Species of fruit bats (genus Pteropus) have been identified as natural hosts of both agents. Anthropogenic changes (habitat loss, hunting) that have impacted the population dynamics of Pteropus species across much of their range are hypothesised to have facilitated emergence. Current strategies for the management of henipaviruses are directed at minimising contact with the natural hosts, monitoring identified intermediate hosts, improving biosecurity on farms, and better disease recognition and diagnosis. Investigation of the emergence and ecology of henipaviruses warrants a broad, cross-disciplinary ecosystem health approach that recognises the critical linkages between human activity, ecological change, and livestock and human health.


Extracellular vesicles as next generation immunotherapeutics.
Extracellular vesicles (EVs) function as a mode of intercellular communication and molecular transfer to elicit diverse biological/functional response. Accumulating evidence has highlighted that EVs from immune, tumour, stromal cells and even bacteria and parasites mediate the communication of various immune cell types to dynamically regulate host immune response. EVs have an innate capacity to evade recognition, transport and transfer functional components to target cells, with subsequent removal by the immune system, where the immunological activities of EVs impact immunoregulation including modulation of antigen presentation and cross-dressing, immune activation, immune suppression, and immune surveillance, impacting the tumour immune microenvironment. In this review, we outline the recent progress of EVs in immunorecognition and therapeutic intervention in cancer, including vaccine and targeted drug delivery and summarise their utility towards clinical translation. We highlight the strategies where EVs (natural and engineered) are being employed as a therapeutic approach for immunogenicity, tumoricidal function, and vaccine development, termed immuno-EVs. With seminal studies providing significant progress in the sequential development of engineered EVs as therapeutic anti-tumour platforms, we now require direct assessment to tune and improve the efficacy of resulting immune responses - essential in their translation into the clinic. We believe such a review could strengthen our understanding of the progress in EV immunobiology and facilitate advances in engineering EVs for the development of novel EV-based immunotherapeutics as a platform for cancer treatment.


Normalisation of haemodynamics in patients with end-stage heart failure with continuous-flow left ventricular assist device therapy.
New generation continuous-flow left ventricular assist devices (LVADs) utilise centrifugal pumps. Data concerning their effect on patient haemodynamics, ventricular function and tissue perfusion is limited. We aimed to document these parameters following HeartWare centrifugal continuous-flow LVAD (HVAD) implantation and to assess the impact of post-operative right heart failure (RHF). We reviewed 53 consecutive patients (mean age 49.5 ± 14.1 yrs) with HVAD implanted in the left ventricle, at St. Vincent's Hospital, Sydney, between January 2007 and August 2012. Available paired right heart catheterisation (n=35) and echocardiography (n=39) data was reviewed to assess response of invasive haemodynamics and ventricular function to LVAD support. A total of 28 patients (53%) were implanted from interim mechanical circulatory support. Seventeen patients (32%) required short-term post-implant veno-pulmonary artery extracorporeal membrane oxygenation. At 100 ± 61 days post-implant, mean pulmonary artery pressure and mean pulmonary capillary wedge pressure decreased from 38.8 ± 7.7 to 22.9 ± 7.7 mmHg and 28.3 ± 6.4 to 13.4 ± 5.4 mmHg respectively (p<0.001). LV end diastolic diameter decreased from 71.3 ± 12.7 to 61.1 ± 13.7 mm and LV end-systolic diameter from 62.7 ± 12.3 to 53.9 ± 14.4mm (p<0.001). Aortic regurgitation remained trivial. Serum sodium increased from 133.3 ± 5.7 to 139.3 ± 2.8 mmol/L and creatinine decreased from 109.1 ± 42.5 to 74.3 ± 26.2 μmol/L (p<0.001). Across the entire cohort, the six-month survival/transplant rate was significantly lower for RHF patients (72.2%, n=18) compared to those without (96.9%, n=35, p=0.01). HVAD support improves haemodynamics, LV dimensions and renal function. Following implantation with a centrifugal continuous-flow LVAD, RHF remains a significant risk with a tendency to worse outcomes in the short to medium term.


Perceived reasons for depression among low income women of Mexican descent.
From a larger cross-sectional study of 315 women of Mexican descent, this secondary analysis focused on short answers to open-ended questions related to reasons given by 107 women at risk for depression (>16 on CES-D) for feelings of sadness, hopelessness, or depression within the last month. Data were analyzed using grounded theory techniques. Six categories of reasons were derived from data including: (1) partner issues, (2) family issues, (3) feelings of being alone, (4) inability to provide for material needs, (5) bodily symptoms and experiences, and (6) vague nonspecific reasons. Results are useful for designing future treatment programs.


Integration of the delta-endotoxin gene of Bacillus thuringiensis into the chromosome of root-colonizing strains of pseudomonads using Tn5.
The delta-endotoxin gene (tox) from Bacillus thuringiensis subsp. kurstaki HD-1 was cloned into Tn5 and the resulting Tn5-tox element transposed from a vector plasmid into the chromosome of six corn-root-colonizing strains of Pseudomonas fluorescens and Agrobacterium radiobacter. Chromosomal integration of the tox gene maximized stability and minimized the potential for horizontal transfer of the tox gene to other bacterial species. Expression of the tox gene was demonstrated by Western blot analysis and by toxicity against larvae of the tobacco hornworm (Manduca sexta). The method described illustrates how a given gene can be stably integrated into the chromosome of diverse bacterial species.


Evaluating real-world COVID-19 vaccine effectiveness using a test-negative case-control design.
Aim: It is important to assess if clinical trial efficacy translates into real-world effectiveness for COVID-19 vaccines. Materials & methods: We conducted a modified test-negative design (TND) to evaluate the real-world effectiveness of three COVID-19 vaccines. We defined cases in two ways: self-reported COVID-19-positive tests, and self-reported positive tests with ≥1 moderate/severe COVID-19 symptom. Results: Any vaccination was associated with a 95% reduction in subsequently reporting a positive COVID-19 test, and a 71% reduction in reporting a positive test and ≥1 moderate/severe symptom. Conclusion: We observed high effectiveness across all three marketed vaccines, both for self-reported positive COVID-19 tests and moderate/severe COVID-19 symptoms. This innovative TND approach can be implemented in future COVID-19 vaccine and treatment real-world effectiveness studies. Clinicaltrials.gov identifier: NCT04368065.


Comparison of PAX6 and PAX8 as immunohistochemical markers for pancreatic neuroendocrine tumors.
To compare the utility of PAX6 and PAX8 as immunohistochemical markers for neuroendocrine tumors (NETs) of pancreatic origin, we performed PAX6 and PAX8 immunostains on 178 NETs, including 110 primary NETs (26 pancreatic, 10 gastric, 12 duodenal, 22 jejuno-ileal, 10 rectal, 30 pulmonary) and 68 NETs metastatic to the liver (24 pancreatic, 1 duodenal, 37 jejuno-ileal, 1 rectal, 5 pulmonary). Among primary NETs, PAX6 and PAX8 were positive in 65 % (17/26) and 73 % (19/26) of pancreatic, 0 % (0/10) and 10 % (1/10) of gastric, 92 % (11/12) and 92 % (11/12) of duodenal, 0 % (0/22) and 0 % (0/22) of jejuno-ileal, 90 % (9/10) and 80 % (8/10) of rectal, and 0 % (0/30) and 23 % (7/30) of pulmonary NETs, respectively. PAX6 and PAX8 positivity was seen in 46 % (11/24) and 50 % (12/24) of metastatic pancreatic NETs to the liver, respectively. None of the nonpancreatic NETs metastatic to the liver were immunoreactive for either PAX6 or PAX8. PAX6 showed a slightly but statistically significant higher specificity for pancreatic NETs than did PAX8 (P = 0.039), while the sensitivities were similar (P = 0.51). PAX6 had the additional advantages over PAX8 of not exhibiting nonspecific cytoplasmic staining of tumor cells and only infrequently staining background lymphocytes. Since rectal NETs rarely present with metastatic disease, positive staining of a metastatic NET of unknown primary origin for PAX6 and/or PAX8 favors a pancreatic or duodenal origin. This information may be helpful in directing further diagnostic studies to identify the primary site of the metastatic tumor.


Effects of an organic carbon source on the coupling of sulfur(thiosulfate)-driven denitration with Anammox process.
The sulfur(thiosulfate)-driven autotrophic denitrification coupled with Anammox (SDDA) process is proposed as an emerging technology for wastewater containing NH4+-N and NO3--N. However, the influence of organic matter on the SDDA process is not fully understood. A long-term experiment has shown that a moderate organic (acetate) (<140 mg/L COD) can accelerate the heterotrophic/autotrophic denitrification and Anammox activity, to reach as high as 92.8% ± 0.3% total nitrogen at a loading rate of 1.34 kg-N/(m3·d). Batch test results showed that Anammox made the largest contribution to the removal of nitrogen, even in an SDDA system with COD addition. Additionally, organics can promote the bioavailability of solid sulfur through reaction with sulfide to form polysulfides, which increased nitrite accumulation to forward Anammox process. Sulfur-oxidizing bacteria (e.g., Thiobacillus and Denitratisoma) coexisted with Anammox bacteria (e.g., Ca. Brocadia and Ca. Kuenenia) in the SDDA system despite the addition of exogenous COD.


The effect of repeated instillations of antiseptics on catheter-associated urinary tract infections: a study in a physical model of the catheterized bladder.
The activity of three antiseptic bladder washout solutions was examined in a physical model of the catheterized bladder. Tests were performed against cultures of four common urinary tract pathogens that had established themselves in the model and colonized the surfaces with biofilm. Double instillations of chlorhexidine (0.02% w/v) at 6-h intervals failed to eliminate Pseudomonas aeruginosa, Proteus mirabilis, and Providencia stuartii from the bladder model. Escherichia coli, however, was susceptible to a second instillation provided that it was performed within 12 h. Supplementing chlorhexidine with EDTA and TRIS potentiated its activity against E. coli. Mandelic acid (1.0% w/v) was the most effective of the agents, double instillations eliminating all but Pr. mirabilis infections.


Characterization of antigen-specific suppressor factors induced by staphylococcal enterotoxin B.
Previous studies from this laboratory have shown that staphylococcal enterotoxin B (SEB) has the capacity to nonspecifically induce multiple T suppressor cell populations which are capable of regulating both primary and secondary in vitro antibody responses. Additional studies have revealed that the suppressive activity of these cells is mediated, at least in part, by an I-J-restricted suppressor-inducer factor. Efforts to characterize the specificity of this inducer molecule have demonstrated the presence of multiple antigen-specific suppressor factors within SEB-stimulated supernatants. Antigen-binding molecules present within these SEB-induced factor preparations were isolated and concentrated over antigen-coupled columns. The results have demonstrated that eluates from trinitrophenyl-ovalbumin and trinitrophenyl-keyhole limpet hemocyanin-coupled columns significantly suppress both primary and secondary anti-TNP plaque-forming colony responses, whereas the filtrates from these columns demonstrated little to no inhibitory activity. The filtrates, but not eluates, from these columns exhibited significant suppressive activity for anti-poly(L-Phe,L-Glu)-poly-DL-Ala-poly-L-Lys, anti-azobenzenearsonate, and anti-sheep red blood cell antibody responses. Additional studies using eluates and filtrates from a variety of antigen-coated columns have demonstrated that suppressor factors of multiple antigenic specificities are present within SEB-induced supernatants. These studies suggest that SEB polyclonally activates antigen-specific suppressor cells which produce suppressor factors which specifically regulate the antibody response.


Hopeahainol C monohydrate.
In the structure of the title compound, C(28)H(16)O(6)·H(2)O [systematic name 3,11-bis(4-hydroxyphenyl)-4,12-dioxapentacyclo[220.127.116.11(2,5).0(13,17).0(9,18)]octadeca-1(16),2,5(18),6,8,10,13(17),14-octaene-7,15-diol monohydrate], the hopeahainol C mol-ecule lies about an inversion center with the solvent water mol-ecule located on a crystallographic twofold axis. Hopeahainol C is an oligostillbenoid compound and was isolated from the bark of Shorea roxburghii G. Don. The five central fused rings are essentially planar with an r.m.s. deviation of 0.0173 (3) Å. The 4-hy-droxy-phenyl ring is twisted with respect to this plane, with the dihedral angle between the phenyl ring and the fused-ring system being 41.70 (10)°. The crystal features inter-molecular O-H⋯O hydrogen bonds. These inter-actions link the hopeahainol C mol-ecules into chains along the b axis. Water mol-ecules are located inter-stitially between the hopeahainol C mol-ecules linked by O(water)-H⋯O(hy-droxy) and O(hy-droxy)-H⋯O(water) hydrogen bonds. π-π inter-actions are also observed with centroid-centroid distances of 3.6056 (17) and 3.5622 (17) Å. Short O⋯O contacts [2.703 (2)-2.720 (3) Å] are also present in the crystal.


Relations Among Suicidal Ideation, Depressive Symptoms, and Functional Independence During the 10 Years After Traumatic Brain Injury: A Model Systems Study.
To investigate relative causality in relations among suicidal ideation (SI), depressive symptoms, and functional independence over the first 10 years after traumatic brain injury (TBI). Prospective longitudinal design with data collected through the Traumatic Brain Injury Model Systems (TBIMS) network at acute rehabilitation hospitalization as well as 1, 2, 5, and 10 years after injury. United States Level I/II trauma centers and inpatient rehabilitation centers with telephone follow-up. Individuals enrolled into the TBIMS National Database (N=9539) with at least 1 SI score at any follow-up data collection (72.1% male; mean age, 39.39y). Not applicable. Patient Health Questionnaire-9 and FIM at years 1, 2, 5, and 10 post injury. A cross-lagged panel structural equation model, which is meant to indirectly infer causality through longitudinal correlational data, suggested that SI, depressive symptoms, and functional independence each significantly predicted themselves over time. Within the model, bivariate correlations among variables were all significant within each time point. Between years 1 and 2 and between years 2 and 5, depressive symptoms had a larger effect on SI than SI had on depressive symptoms. Between years 5 and 10, there was reciprocal causality between the 2 variables. Functional independence more strongly predicted depressive symptoms than the reverse between years 1 and 2 as well as years 2 and 5, but its unique effects on SI over time were extremely marginal or absent after controlling for depressive symptoms. A primary goal for rehabilitation and mental health providers should be to monitor and address elevated symptoms of depression as quickly as possible before they translate into SI, particularly for individuals with TBI who have reduced functional independence. Doing so may be a key to breaking the connection between low functional independence and SI.


Characterization of the 3' terminus of RNA isolated from vesicular stomatitis virus and from its defective interfering particles.
The 3' termini of RNA from vesicular stomatitis virus and from three widely dissimilar defective interfering particles of the virus are PypGpU-OH. The possible relevance of these findings to autointerference and to replication of vesicular stomatitis virus is discussed.


Current trends in radiographic caries imaging.
Caries prevalence, lesion site, and lesion behavior have changed over the past decade. This review looks at the impact of these changes on radiographic caries imaging.


Special Issue "Pediatric Viral Infection Long-Term Consequences".
This Special Issue was focused on advancing our understanding of the long-term consequences of pediatric viral infections [...].


Outbreak of tungiasis following a trip to Ethiopia.
Tungiasis is a skin disease caused by the ectoparasite sand flea Tunga penetrans. Although tungiasis is an important health problem in endemic areas, mainly South America and sub-Saharan Africa, it is reported uncommonly in travelers. We describe an outbreak of tungiasis in a group of travelers to Ethiopia. Following the diagnosis of tungiasis in a member of a group of 17 Israeli travelers to Ethiopia, other affected members were identified by photograph assisted self diagnosis. The characteristics, including relevant demographic and epidemiologic data were recorded using a telephone interview and computerized questionnaire, and analyzed subsequently. The attack rate of tungiasis in the travel group was 53% (9 patients). Most of the patients (89%) wore open sandals during prolonged periods of their journey, but the pattern of shoeware use was similar in unaffected group members. An insect bite was not felt by any patient. The median number of skin lesions was one, and most lesions were located on the foot (7 of 9 travelers), but the hands were also affected in 2 travelers. All skin lesions healed without a need for a major intervention and without major sequela within 5 weeks of their appearance. Tungiasis may be underdiagnosed in travelers. Medical personnel should include tungiasis in pre-travel recommendations, and post-travel assessment.


Dermal epidermal junction detection for full-field optical coherence tomography data of human skin by deep learning.
Full-field optical coherence tomography (FF-OCT) has been developed to obtain three-dimensional (3D) OCT data of human skin for early diagnosis of skin cancer. Detection of dermal epidermal junction (DEJ), where melanomas and basal cell carcinomas originate, is an essential step for skin cancer diagnosis. However, most existing DEJ detection methods consider each cross-sectional frame of the 3D OCT data independently, leaving the relationship between neighboring frames unexplored. In this paper, we exploit the continuity of 3D OCT data to enhance DEJ detection. In particular, we propose a method for noise reduction of the training data and a multi-directional convolutional neural network to predict the probability of epidermal pixels in the 3D OCT data, which is more stable than one-directional convolutional neural network for DEJ detection. Our crosscheck refinement method also exploits the domain knowledge to generate a smooth DEJ surface. The average mean error of the entire DEJ detection system is approximately 6 μm.


Endometrial carcinoma: a comparative analysis of the therapeutic results and causes of failure after treatment by radiation combined with surgery or radiation therapy alone.
At the present time endometrial carcinoma is considered to be among the most frequent of gynecological tumors and its incidence is now reaching that of cervix carcinoma. In this paper, we present the results of two series of treatment for endometrial carcinoma, one using the combination of surgery and radiation, the second one using radiation treatment alone. Indeed, due to our recruitment criteria between 1968 and 1978 at the Montpellier Cancer Institute, the proportion of patients treated exclusively by physical agents was more or less equal to those receiving combined treatment. In many cases, either because of the poor condition of the patient, or due to local involvement, irradiation alone was used. The report of the results explain the therapeutic failures and show by means of two sequential series how techniques have been developed. Previously treated patients were excluded (44 cases).


Can we overcome the effect of conflicts in rendering palliative care? An introduction to the Middle Eastern Cancer Consortium (MECC).
The Middle East has been experiencing an ongoing political conflict for the past several decades. This situation has been characterized by hostility often leading to violence of all sources. At times, such a conflict led to the outbreak of a military war, which was followed by an enmity between religious, ethnic, cultural, and national populations. In such environmental situations, palliative care professionals often confront major challenges including bias, mistrust, and mutual suspicion between patients and their treating clinicians. In order to overcome such obstacles, while rendering palliative care services, all professionals involved need careful planning and execution of their treatment plans. The latter is however possible, and sometimes successful even across lines of conflict, thereby promoting understanding, mutual respect, and tolerance between the involved communities and individuals.


A Novel In Vitro Mouse Model to Study Mycobacterium tuberculosis Dissemination Across Brain Vessels: A Combination Granuloma and Blood-Brain Barrier Mouse Model.
In vitro culture models of the blood-brain barrier (BBB) provide a useful platform to test the mechanisms of cellular infiltration and pathogen dissemination into the central nervous system (CNS). We present an in vitro mouse model of the BBB to test Mycobacterium tuberculosis (Mtb) dissemination across brain endothelial cells. One-third of the global population is infected with Mtb, and in 1%-2% of cases bacteria invade the CNS through a largely unknown process. The "Trojan horse" theory supports the role of a cellular carrier that engulfs bacteria and carries them to the brain without being recognized. We present for the first time a protocol for an in vitro BBB-granuloma model that supports the Trojan horse mechanism of Mtb dissemination into the CNS. Handling of bacterial cultures, in vivo and in vitro infections, isolation of primary astroglial and endothelial cells, and assembly of the in vitro BBB model is presented. These techniques can be used to analyze the interaction of adaptive and innate immune system cells with brain endothelial cells, cellular transmigration, BBB morphological and functional changes, and methods of bacterial dissemination. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Isolation of primary mouse brain astrocytes and endothelial cells Basic Protocol 2: Isolation of primary mouse bone marrow-derived dendritic cells Support Protocol 1: Validation of dendritic cell purity by flow cytometry Basic Protocol 3: Isolation of primary mouse peripheral blood mononuclear cells Support Protocol 2: Isolation of primary mouse spleen cells Support Protocol 3: Purification and validation of CD4+ T cells from PBMCs and spleen cells Basic Protocol 4: Isolation of liver granuloma supernatant and determination of organ load Support Protocol 4: In vivo and in vitro infection with mycobacteria Basic Protocol 5: Assembly of the BBB co-culture model Basic Protocol 6: Assembly of the combined in vitro granuloma and BBB model.


Indoor UV tanning operator opinion regarding youth access: an electronic survey.
Adolescents frequently use indoor tanning facilities, but little is known about tanning facility operator opinions regarding this use. Objective To assess indoor tanning operator attitudes and stated practices regarding youth access. We electronically surveyed 89 indoor tanning facilities and 130 spas with active e-mail addresses. The survey response rate was 21% for both indoor tanning facilities (19/89) and spas (27/130). Most tanning operators (92%) felt that a client can be too young to receive indoor tanning, and most felt that written parental permission should be required (80%). Most facilities required adult accompaniment (92%), and most operators had discouraged a customer from receiving indoor tanning based on age (77%). The reported age of the youngest patron receiving indoor tanning ranged from 5 to 21 years. Our sample of indoor tanning facility operators believed that minimum age and parental consent regulations for indoor tanning should be required.


An ultrasonic assisted extraction method to release heavy metals from untreated sewage sludge samples.
A rapid ultrasound accelerated sequential extraction procedure has been used to develop sequential extraction proposed by BCR protocol (the community Bureau of Reference now the European Union "Measurement and Testing Programme"). The effects of the ultrasonic treatment on the extraction of Cu, Cd, Cr, Pb, Ni and Zn from untreated sewage sludge collected from industrial site of Hyderabad city (Pakistan) were compared with those obtained from conventional sequentional extraction procedure of modified BCR protocol. In BCR method, each extraction steps takes 10h, where as with the use of compromise sonication conditions in ultrasonic bath, steps 1-3 of the sequential extraction (excluding the hydrogen peroxide digestion in step 3, which was not performed with sonication) could be completed in 30, 30 and 30 min, respectively. Extractable Cd, Cr, Pb and Ni contents were obtained by both comparable methodologies were measured by electrothermal atomic absorption spectrometry (ETAAS), while for Cu and Zn Flame atomic absorption spectrometry (FAAS) was used. The validations of both methods were compared by the analysis of certified reference material of soil amended with sewage sludge (BCR 483). According to statistical evaluation of the results, the proposed accelerated extraction method is valid alternative to conventional shaking with much shorter extraction time with p value <0.05. The overall metal recoveries in steps 1-3 (excluding residual step) were 95-100% of those obtained with the conventional BCR protocol, except for Cu extracted (91.6%) as related to indicative values of Cu in BCR 483 obtained in 1-3 steps. The results of the partitioning study of untreated industrial waste water sewage sludge, indicate that more easily mobilized forms (acid exchangeable) were predominant for Cd and Zn, in contrast, the largest amount of Pb and Cr was associated with the iron/manganese oxide and organic matter/sulphide fractions.


Highly sensitive detection of melanoma at an early stage based on the increased serum secreted protein acidic and rich in cysteine and glypican-3 levels.
There are no available tumor markers detecting primary melanoma at an early stage. The identification of such serum markers would be of significant benefit for an early diagnosis of melanoma. We recently identified glypican-3 (GPC3) as a novel tumor marker but could diagnose only 40% of melanomas. Thereby, we focused out attention on secreted protein acidic and rich in cysteine (SPARC) overexpressed in melanoma as another candidate for tumor marker. Secreted SPARC protein was quantified using ELISA in the sera from 109 melanoma patients, five patients with large congenital melanocytic nevus, 61 age-matched healthy donors, and 13 disease-free patients after undergoing a surgical removal. We also quantified GPC3 and 5-S-cysteinyldopa in the same serum samples and compared these markers for their diagnostic value. The serum SPARC concentrations in melanoma patients were greater than those in healthy donors (P = 0.001). When we fixed a cutoff value at the mean concentration plus 2 SD of the healthy donors, the serum SPARC was found to have increased in the sera of 36 of the 109 (33%) melanoma patients, whereas there were three (4.9%) false-positive cases of 61 healthy donors. Surprisingly, 19 of 36 patients showing increased SPARC levels were in stages 0 to II. The serum SPARC level decreased under the cutoff level in 10 of 13 patients after surgical removal. Using SPARC and GPC3 in combination thus enabled us to diagnose 47 of 75 (66.2%) melanoma patients at an early stage (0-II). SPARC or its combination with GPC3 is thus considered a potentially useful tumor marker, especially for melanoma at an early stage.


Strategies to deliver RNA by nanoparticles for therapeutic potential.
The use of a variety of RNA molecules, including messenger RNA, small interfering RNA, and microRNA, has shown great potential for prevention and therapy of many pathologies. However, this therapeutic promise has historically been limited by short in vivo half-life, lack of targeted delivery, and safety issues. Nanoparticle (NP)-mediated delivery has been a successful platform to overcome these limitations, with multiple formulations already in clinical trials and approved by the FDA. Although there is a diversity of NPs in terms of material formulation, size, shape, and charge that have been proposed for biomedical applications, specific modifications are required to facilitate sufficient RNA delivery and adequate therapeutic effect. This includes optimization of (i) RNA incorporation into NPs, (ii) specific cell targeting, (iii) cellular uptake and (iv) endosomal escape ability. In this review, we summarize the methods by which NPs can be modified for RNA delivery to achieve optimal therapeutic effects.


Design, synthesis and biological evaluation of novel thiosemicarbazones as cruzipain inhibitors.
Based on the activity of 23 TSCs on CZ taken from the literature, we have developed a QSAR model for predicting the activity of TSCs. New TSCs were designed and then tested against CZP, resulting in inhibitors with IC50 values in the nanomolar range. The modelling of the corresponding TSC-CZ complexes by molecular docking and QM/QM ONIOM refinement indicates a binding mode compatible with what was expected for active TSCs, according to a geometry-based theoretical model previously developed by our research group. Kinetic experiments on CZP suggest that the new TSCs act by a mechanism that involves the formation of a reversible covalent adduct with slow association and dissociation kinetics. These results demonstrate the strong inhibitory effect of the new TSCs and the benefit of the combined use of QSAR and molecular modelling techniques in the design of new and potent CZ/CZP inhibitors.


Generation of Red Blood Cell Nanovesicles as a Delivery Tool.
Extracellular vesicles (EVs) are natural membranous vesicles with immense potential as drug delivery tools. However, their large-scale production remains a huge technical challenge, is time consuming, and expensive. Thus, EV mimetics (nanovesicles) generated from easily sourced red blood cells (RBCs) have gained vested interest as an effective and scalable drug delivery system. Their surface proteins (e.g., CD47) inherited from parental RBCs also improve their biocompatibility and bioavailability. Here, we outline a step-by-step guide for large-scale production of RBC nanovesicles using one-step extrusion method coupled to rapid density-cushion centrifugation. We also outline protocol for their extensive biophysical characterization (size and morphology using single particle analysis and cryogenic electron microscopy), and in-depth mass spectrometry-based proteome characterization. Finally, we outline two strategies (active loading during extrusion vs. passive loading via diffusion) to incorporate pharmacological compound(s) into nanovesicles and detect their loading using spectrophotometry.


Three dimensional/four dimensional ultrasound-guided embryo transfer using the maximal implantation potential point.
To evaluate the use of maximal implantation potential (MIP) point in conjunction with a 3D/4D ultrasound in order to facilitate embryo transfers and potentially improve pregnancy rate. Retrospective, observational study. IVF Center. Between October 1, 2002, and August 27, 2004, 1,222 patients who underwent 3D/4D-ultrasound guided embryo transfers. Ultrasound-guided embryo transfer using a 3D/4D ultrasound machine and the MIP point. Procedure feasibility with improved visibility. Embryo transfers were performed at the MIP point and the pregnancy rate was 36.66% (average patient age, 37.6 years). Physicians reported improved visualization and a greater accuracy in the placement of embryos within the uterine cavity. The MIP point can be immediately identified and individualized for each patient. Embryo transfers at the MIP were associated with good implantation and pregnancy rates.


Impact of the Patient Protection and Affordable Care Act on 1-year survival in glioblastoma patients.
Glioblastoma (GBM) treatment requires access to complex medical services, and the Patient Protection and Affordable Care Act (ACA) sought to expand access to health care, including complex oncologic care. Whether the implementation of the ACA was subsequently associated with changes in 1-year survival in GBM is not known. A retrospective cohort study was performed using the Surveillance, Epidemiology, and End Results (SEER) database. We identified patients with the primary diagnosis of GBM between 2008 and 2016. A multivariable-adjusted Cox proportional hazards model was developed using patient and clinical characteristics to determine the main outcome: the 1-year cumulative probability of death by state expansion status. A total of 25 784 patients and 14 355 deaths at 1 year were identified and included in the analysis, 49.7% were older than 65 at diagnosis. Overall 1-year cumulative probability of death for GBM patients in non-expansion versus expansion states did not significantly worsen over the 2 time periods (2008-2010: hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.04-1.19; 2014-2016: HR 1.18, 95% CI 1.09-1.27). In GBM patients younger than age 65 at diagnosis, there was a nonsignificant trend toward the poorer 1-year cumulative probability of death in non-expansion versus expansion states (2008-2010: HR 1.09, 95% CI 0.97-1.22; 2014-2016: HR 1.23, 95% CI 1.09-1.40). No differences were found over time in survival for GBM patients in expansion versus non-expansion states. Further study may reveal whether GBM patients diagnosed younger than age 65 in expansion states experienced improvements in 1-year survival.


Comparison of contact lens-assisted and transepithelial corneal crosslinking with standard epithelium-off crosslinking for progressive keratoconus: 24-month clinical results.
To compare the outcomes of contact lens-assisted corneal crosslinking (CACXL) and transepithelial CXL (TECXL) with standard epithelium-off (epi-off) CXL for progressive keratoconus. Advanced Eye Center, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Retrospective, comparative study. Patients with progressive keratoconus undergoing CXL with a minimum follow-up of 24 months were included. CACXL and TECXL were performed in patients with epithelium-on minimal pachymetry between 350 μm and 450 μm. The main outcome measures included change in maximum keratometry (Kmax), corrected distance visual acuity (CDVA), and efficacy in halting progression (increase in Kmax ≥1 diopter [D]). Standard epi-off CXL, CACXL, and TECXL were performed in 34, 14, and 10 eyes, respectively. Baseline Kmax and CDVA were comparable for all groups. Kmax reduced significantly by -2.83 ± 3.35 D, -3.18 ± 2.74 D, and -2.02 ± 1.66 D in the standard epi-off CXL (P < .01), CACXL (P = .001), and TECXL (P = .004) groups, respectively; the reduction was comparable for all groups (P = .63). CDVA improved by -0.14 ± 0.24, -0.04 ± 0.19, and -0.12 ± 0.17 logMAR in the standard epi-off CXL (P = .006), CACXL (P = .42), and TECXL (P = .05) groups, respectively; the reduction was comparable for all groups (P = .46). Progression was documented in 2 eyes (6%) in the standard epi-off CXL group and in 0 eyes of the CACXL and TECXL groups (P = .61). CACXL and TECXL were comparable with the standard epi-off CXL for progressive keratoconus.


Healthcare Professionals' Perceptions of Infographics Within Medical Information Response Letters.
In a continuing effort to provide innovative formats of presenting medical information in a digestible and comprehensive manner, infographics were created and included in select standard letters created by the Medical Information team. Qualitative and quantitative feedback on the ease of comprehension, flow, layout, and value of infographics within Standard Response Documents (SRDs) was obtained from healthcare professionals (HCPs). A qualitative survey (n = 47) was conducted to assess the ease of comprehension and effectiveness of infographics. The qualitative market research consisted of 25 individual 60-min phone interviews with HCPs focused around two SRDs. It was found that 87% (n = 41) of respondents agreed or strongly agreed that the infographic was easy to comprehend. Additionally, 85% (n = 40) of the respondents agreed or strongly agreed that the infographic was useful in answering their product question. It was found that most HCPs (20/25) appreciated the presentation of the infographics and found them visually appealing. Additionally, most agreed that the infographic provided content that was sufficient in addressing their product inquiries and impactful for clinical decision making. Infographics have proved to be a valuable resource within response letters to address HCP inquiries and provide an option to pharmaceutical companies to evolve the way medical information is presented.


Metropolitan Detroit's network. A step-by-step discard program.
Rationale and planning leading to a successful discard program, capable of being accomplished a little at a time, are described for a hospital library.


Accuracy of the three-window sampling method in morphometric analysis of human sural nerve.
Morphometry has an important role in the assessment of sural nerve biopsies as a part of early detection of structural abnormalities in peripheral nerve. Various sampling methods have been used to reduce time and effort needed in the analysis of total nerve fibers but their accuracy remains controversial. We examined the accuracy of three-window sampling method in the morphometric evaluation of human sural nerve biopsies by comparing with the total fiber quantification. Three windows (0.012 mm(2) each) were placed in every possible fascicle in the sections and data from all windows were pooled and analyzed for the number of myelinated axons, myelinated fiber diameter, axon diameter, myelin thickness, g ratio as well as myelinated fiber density. Means and ranges of the data from the two techniques were similar and the agreement was further confirmed by intraclass correlation analysis. These findings indicate that the three-window sampling method can be used to evaluate human sural nerve with accuracy.


Radiographic appearance of extracorporeal membrane oxygenations versus left ventricular assist device.
Chest radiography compares left ventricular decompression in the same patient supported with extracorporeal membrane oxygenation with atrial septal fenestration and subsequently supported with left ventricular assist device with apical cannulation.


Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes.
Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that is associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure. We previously observed an unexpected proliferation-independent telomere shortening in cardiomyocytes of a DMD mouse model. Here, we provide mechanistic insights using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using traction force microscopy, we show that DMD hiPSC-CMs exhibit deficits in force generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels. Furthermore, we observed a progressive post-mitotic telomere shortening in DMD hiPSC-CMs coincident with downregulation of shelterin complex, telomere capping proteins, and activation of the p53 DNA damage response. This telomere shortening is blocked by blebbistatin, which inhibits contraction in DMD cardiomyocytes. Our studies underscore the role of fibrotic stiffening in the etiology of DMD cardiomyopathy. In addition, our data indicate that telomere shortening is progressive, contraction dependent, and mechanosensitive, and suggest points of therapeutic intervention.


Biological dysrhythm in remitted bipolar I disorder.
Recent treatment guidelines support treatment of biological rhythm abnormalities as a part of treatment of bipolar disorder, but still, literature examining various domains (Sleep, Activity, Social, and Eating) of biological rhythm and its clinical predictors are less. The main aim of our study is to compare various domains of biological rhythm among remitted bipolar I subjects and healthy controls. We also explored for any association between clinical variables and biological rhythm among bipolar subjects. 40 subjects with Bipolar I disorder and 40 healthy controls who met inclusion and exclusion criteria were recruited for the study. Diagnoses were ascertained by a qualified psychiatrist using MINI 5.0. Sociodemographic details, biological rhythm (BRIAN-Biological Rhythm Interview of assessment in Neuropsychiatry) and Sleep functioning (PSQI- Pittsburgh Sleep Quality Index) were assessed in all subjects. Mean age of the Bipolar subjects and controls were 41.25±11.84years and 38.25±11.25 years respectively. Bipolar subjects experienced more biological rhythm disturbance when compared to healthy controls (total BRIAN score being 34.25±9.36 vs 28.2±6.53) (p=0.002). Subsyndromal depressive symptoms (HDRS) had significant positive correlation with BRIAN global scores(r=0.368, p=0.02). Linear regression analysis showed that number of episodes which required hospitalization (β=0.601, t=3.106, P=0.004), PSQI (β=0.394, t=2.609, p=0.014), HDRS (β=0.376, t=2.34, t=0.036) explained 31% of variance in BRIAN scores in remitted bipolar subjects. Biological rhythm disturbances seem to persist even after clinical remission of bipolar illness. More studies to look into the impact of subsyndromal depressive symptoms on biological rhythm are needed.


Developing Signs of Safety: A Deaf-accessible counselling toolkit for trauma and addiction.
The U.S. Deaf community-more than half a million Americans who communicate using American Sign Language (ASL)-experiences higher rates of trauma exposure and substance use disorder (SUD) than the general population. Yet there are no evidence-based treatments for any behavioural health condition that have been evaluated for use with Deaf people. The driving aim of our work, therefore, has been to develop and formally evaluate a Deaf-accessible trauma/SUD counselling approach. Here we describe our initial intervention development work and a single-arm pilot that evaluated the feasibility, acceptability, and preliminary clinical efficacy of Signs of Safety-a Deaf-accessible toolkit to be used with an existing, widely adopted protocol for trauma and addiction (Seeking Safety). Preliminary efficacy results indicated clinically significant reductions in PTSD symptoms and frequency of alcohol use for the Seeking Safety/Signs of Safety model. Frequency of drug use did not change significantly-likely attributable to the mid-study legalization of recreational marijuana in our state. Next steps include the redesign and refilming of Signs of Safety based on pilot participant feedback, again using a Deaf-engaged development and production process. This new toolkit will be tested via a pilot randomized controlled trial designed based on present methodological lessons learned.


Sorocea guilleminiana Gaudich.: Wound healing activity, action mechanisms, and chemical characterization of the leaf infusion.
Sorocea guilleminina Gaudich. is a tree or shrub endemic to Brazil. Its leaves are used in Brazilian folk medicine for the healing of wounds, stomach problems, inflammation and as diuretic. The present study evaluates the activity and action mechanisms of the healing properties of the aqueous extract of S. guilleminiana leaves (AESg), in experimental models in vivo and in vitro, as well as performs a phytochemical analysis of the extract. The AESg was prepared by infusion: Ten g of dry leaves powder in 1 L hot water, soaked for 15 min, filtered, lyophilized, and stored at -30 °C. Phytochemical analyses were realized by colorimetry and HPLC/ESI/MS. Its' in vitro cytotoxicity was evaluated on fibroblastic N3T3 cells. The potential of the wound healing activity in vivo was evaluated using excision and incision wound rat models, by histopathology of the injured skin along with the determination of nitric oxide, cytokines (IL-1β, IL-10, and TNF-α), and antioxidant parameters (GSH, MPO and CAT). In vitro wound healing activity was also demonstrated in scratched N3T3 cells, by measuring the proliferation/migration rate. The phytochemical analysis of the AESg revealed a strong presence of polar compounds, especially flavonoids (4 majoritarian), as well as terpenes and/or sterols (2 majoritarian). The AESg showed no toxicity in the N3T3 cell line (IC50 > 800 μg/mL). Topical treatment with the AESg showed an increase (p < 0.05) in wound contraction with 2 mg/g cream on days 5 and 9 (43.56% and 6.70% increase, respectively), and with 50 mg/g on days 7 and 9 (10.88% and 7.91%, respectively), compared to the vehicle (non-ionic neutral cream). Topical application of AESg (2 or 50 mg/g non-ionic cream) in incised wounds caused an increase in the force necessary for the rupture of the wound when compared to the vehicle group. No changes in cytokines (IL-1β, IL-10, or TNF-α) or NO accumulation was found with up to 50 mg/g AESg treatment. For antioxidant activity on the incision wound, an increase in GSH levels was denoted with the AESg use, at the lowest and highest dose (2 and 50 mg/g) by 75.86% and 61.20% respectively, when compared to the vehicle. Also, the CAT activity was accentuated by AESg at the highest dose (50 mg/g) by 85.87%. Finally, the AESg at all doses attenuated MPO activity significantly in the incision wound by 71.35%, 73.21%, 78.08%, respectively. In the scratch test on N3T3 cells, the treatment with AESg resulted also in an increase in fibroblast proliferation/migration rate, compared to the vehicle. AESg is not cytotoxic. The results confirm the popular use of the leaf infusion of S. guilleminiana for the treatment of cutaneous wounds, possibly by stimulating the proliferation of fibroblasts with a consequent deposition of collagen, fastening rearrangement of collagen fibers, and greater transformation into myofibroblasts, essential in the healing process. Preliminary chemical analyzes of AESg revealed the presence mainly of phenolic compounds, being salicylic acid, gallic acid, pinocembrin and isoquercitrin the majoritarian ones.


[The extracorporeal correction of disorders in the blood aggregate state in patients with acute infectious destructions of the lungs and pleura].
Positive hemorheological effect was found in using therapeutical plasmapheresis in combination with extracorporeal blood oxygenation. Indications and contraindications for therapeutical plasmapheresis are discussed in the paper.


Homogeneously and heterogeneously structured biofilm models for wastewater treatment.
Biofilm, a layer comprising extracellular polymeric substances, is the platform where the embedded living cells degrade the substances in the wastewaters. Biofilm models have been developed as part of the comprehensive models for the wastewater treatment process. This review summarizes the biofilm models applied in contemporary literature based on the spatial dimensions adopted for model build-up. The most commonly applied biofilm models are null-dimensional, considering the biofilm active biomass for the substrate sink's biological reaction. The one-dimensional, multi-species models are the second standard models for contemporary studies, providing transport and reaction resistances of substrates in the biofilm matrix and the interactions of competing or collaborating strains in the biofilm. The structural homogeneity of the biofilm challenges the validity of the uniformly structured models, highlighting the need to re-examine the validity of the uniformly structured models. The challenges and prospects of biofilm model developments and applications are outlined.


Granule and mitral cell densities are unchanged following early olfactory preference training.
Early olfactory preference training causes both an increased number of juxtaglomerular cells and an increased number of such cells expressing Fos protein. In contrast, there are fewer cells expressing Fos protein in the granule cell layer after training. Here, we report no change in the number or size of granule and mitral cells as a consequence of these early olfactory experiences.