Operative and Obstetric Outcomes after Single-port Laparoscopic Myomectomy: A Retrospective Single-center Analysis of 504 Cases.
To analyze the obstetric and operative outcomes of 504 cases of single-port laparoscopic myomectomy (SPLM). Single-center retrospective study. A tertiary university hospital. A total of 502 patients (504 SPLM procedures) who underwent SPLM for symptom relief or growing myomas between October 2009 and April 2020. Data on patient demographics, operative variables (estimated blood loss, hemoglobin decrease, operation time, perioperative complications, and postoperative hospital stay), and obstetric outcomes (the surgery-to-pregnancy interval and birth-related outcomes) were obtained from medical records and analyzed. The mean age of the patients was 40.6 ± 6.6 years. The patients had had an average of 2.3 ± 2.2 myomas removed; the largest myoma size was 6.8 ± 2.4 cm. The mean operation time, postoperative hemoglobin decrease, and postoperative hospital stay duration were 112.9 ± 45.3 minutes, 1.7 ± 1.1 g/dL, and 2.2 ± 1.4 days, respectively. The overall rate of postoperative complications was 7.7% (39/504), and the common complications were transfusions (16/504, 3.1%) or wound problems (15/504, 3.0%). Conversion to multiport or open myomectomy was required in 0.8% of the cases (4/504). A total of 376 women were of child-bearing age, and 56 attempted to become pregnant after surgery. The mean interval from surgery to pregnancy was 15.6 ± 12.2 months. The obstetric outcomes were pregnancy (42/56, 75.0%), live birth (39/56, 69.6%), and miscarriage (2/56, 3.6%). One pregnant woman was lost to follow-up. The 39 live births predominantly involved full-term delivery (36/39, 92.3%), mostly through cesarean section (36/39, 92.3%). No postpartum complications were reported. The 2 most common obstetric complications were preterm labor (7.6%) and gestational diabetes (5.1%). SPLM seems to be an effective procedure with good operative and postoperative obstetric outcomes for women with myomas who require surgery and may wish to subsequently become pregnant.


Entanglement in a 20-Qubit Superconducting Quantum Computer.
The ability to prepare sizeable multi-qubit entangled states with full qubit control is a critical milestone for physical platforms upon which quantum computers are built. We investigate the extent to which entanglement is found within a prepared graph state on the 20-qubit superconducting quantum computer IBM Q Poughkeepsie. We prepared a graph state along a path consisting of all twenty qubits within the device and performed full quantum state tomography on all groups of four connected qubits along this path. We determined that each pair of connected qubits was inseparable and hence the prepared state was entangled. Additionally, a genuine multipartite entanglement witness was measured on all qubit subpaths of the graph state and we found genuine multipartite entanglement on chains of up to three qubits. These results represent a demonstration of entanglement in one of the largest solid-state qubit arrays to date and indicate the positive direction of progress towards the goal of implementing complex quantum algorithms relying on such effects.


Implementation of Imaging Methods in Evaluation of T2DM-Correlated Brain Alterations and Cognitive Dysfunction.
There has been mounting evidence that type 2 diabetes mellitus (T2DM) populations are prone to aberrant brain functionality and cognitive deficits. Hyperglycemic status and insulin resistance, among other factors, have been associated with compromised brain neural congruity, leading to lower cognitive performance. The aim of the present paper is to provide a comprehensive review of imaging techniques and their applicability in detection of brain changes in the setting of T2DM. A search of PubMed electronic database was followed. Primary search terms included "imaging methods", "type 2 diabetes" and "cognitive impairment". A range of imaging modalities that can be of value in depiction of diabetes-mediated structural and functional brain aberrations. An increasingly body of research points to the adverse effect T2DM exerts on brain integrity and higher cognitive skills. Findings support the role of imaging techniques in delineation of brain divergence in middle-aged and older diabetic populations.


The Hidden Intricacies of Aquaporins: Remarkable Details in a Common Structural Scaffold.
Evolution turned aquaporins (AQPs) into the most efficient facilitators of passive water flow through cell membranes at no expense of solute discrimination. In spite of a plethora of solved AQP structures, many structural details remain hidden. Here, by combining extensive sequence- and structural-based analysis of a unique set of 20 non-redundant high-resolution structures and molecular dynamics simulations of four representatives, key aspects of AQP stability, gating, selectivity, pore geometry, and oligomerization, with a potential impact on channel functionality, are identified. The general view of AQPs possessing a continuous open water pore is challenged and it is depicted that AQPs' selectivity is not exclusively shaped by pore-lining residues but also by the relative arrangement of transmembrane helices. Moreover, this analysis reveals that hydrophobic interactions constitute the main determinant of protein thermal stability. Finally, a numbering scheme of the conserved AQP scaffold is established, facilitating direct comparison of, for example, disease-causing mutations and prediction of potential structural consequences. Additionally, the results pave the way for the design of optimized AQP water channels to be utilized in biotechnological applications.


Alteration of a human lymphoblastoid cell line, REH6 during subsequent cultivation.
Chromosomal and isoenzyme alteration of a human leukemia cell line, REH6, is shown during 80 subsequent passages. No correlation between these properties could be found.


Severe Pancytopenia After COVID-19 Revealing a Case of Primary Bone Marrow Diffuse Large B Cell Lymphoma.
BACKGROUND Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). While bone marrow (BM) involvement is common in lymphoma, primary bone marrow (PBM) DLBCL is extremely rare. We present a case of PBM DLBCL discovered in a patient with COVID-19. CASE REPORT An 80-year-old man presented with generalized abdominal pain, weight loss, fever, fatigue, anorexia, and watery diarrhea over a 3-month period. Physical examination was unremarkable. Laboratory workup revealed anemia, thrombocytopenia, and elevated inflammation markers. SARS-COV-2 PCR was positive, while blood cultures were negative. A rapid decline in the white blood cell count in the following days prompted a BM biopsy, confirming the diagnosis of PBM DLBCL. Computed tomography (CT) did not show thoracic or abdominal lymphadenopathy. The patient received packed red blood cell and platelet transfusions, granulocyte colony-stimulating factor (G-CSF) for pancytopenia, and empirical antibiotics for suspected infection. Due to active COVID-19 and advanced age, cytotoxic chemotherapy was delayed. Rituximab and prednisone were initiated on day 9, followed by an infusion reaction, which led to treatment discontinuation. He died 2 days later. CONCLUSIONS Diagnosing PBM malignancy is challenging, especially with coexisting infection. It is essential to suspect underlying BM malignancy in patients with clinical deterioration and worsening pancytopenia despite adequate treatment. The diagnosis of PBM DLBCL requires the absence of lymphadenopathy, and the presence of histologically confirmed DLBCL. Prompt management with combination chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with/without hematopoietic stem cell transplant can improve the prognosis.


Medical students' clinical performance in general practice - Triangulating assessments from patients, teachers and students.
Formative assessment of medical students' clinical performance during general practice clerkship is necessary to learn consultation skills. Our aim was to triangulate feedback using patient questionnaires, written self-assessment and teachers' observation-based assessment, and to describe the content of this feedback. We developed StudentPEP, a 15-item version of EUROPEP, a tool for measuring patients' evaluation of quality in general practice. The teacher and student forms consisted of five StudentPEP-items and open-ended questions asking for approval and improvement needed on four aspects. Quantitative scores were analyzed statistically. Free-text comments were analyzed and categorized into 'specific and concrete' versus 'general and unspecific'. One hundred seventy-three students returned data from 2643 consultations. Mean patients' scores for 15 items were 4.3-4.8 on a five-point Likert scale. Mean teacher scores were 4.4 on five items, while students' mean self-assessments were 3.6-3.8. In an analysis of 380 consultations, students were more specific and concrete in their self-evaluation compared with teachers (p < 0.01). Patients scored students' performance high compared with students' self-assessments. Teachers' scores were in accordance with patients' scores. Teachers' written evaluations of students were often general. There is a potential for improving teachers' feedback in terms of more specific and concrete comments.


Association between plant-based diets and metabolic health status in adolescents with overweight and obesity.
The association of plant-based diets with health status is underestimated in pediatrics. We aimed to examine the relation between plant-based diets (including overall plant-based index (PDI), healthy plant-based (hPDI) and unhealthy plant-based (uPDI)) and metabolic health status in Iranian adolescents with overweight/obesity. We conducted a cross-sectional study on 203 adolescents with overweight/obesity (12-18 years old) selected by a multistage cluster random-sampling method. Usual dietary intakes were assessed through a validated 147-item food frequency questionnaire (FFQ). Anthropometric indices and blood pressure values were measured and fasting blood samples were drawn. For classification of participants into metabolically healthy obese (MHO) or metabolically unhealthy obese (MUO) groups, two methods of International Diabetes Federation (IDF) and combination of IDF with Homeostasis Model Assessment Insulin Resistance (HOMA-IR) were applied. No significant association was observed between higher adherence to PDI and odds of MUO status defined by both IDF and IDF/HOMA-IR strategies. After adjustments for all potential confounders, adolescents in the highest tertile of hPDI, compared with those in the lowest tertile, had 85% (95% CI 0.05-0.43) and 84% (95% CI 0.05, 0.52) lower odds of being MUO based on IDF and IDF/HOMA-IR criteria, respectively. Greater adherence to uPDI was associated with odd of 3.95 (95% CI 1.41, 11.12) and 4.06 (95% CI 1.31, 12.57) of being MUO based on IDF and IDF/HOMA-IR definitions, after considering all potential confounders. Stratified analysis revealed that these associations were stronger in girls and overweight subjects. Adherence to healthy plant-based foods was inversely associated with odds of MUO status in Iranian adolescents. In contrast, unhealthy plant-based diets was directly associated with MUO in pediatrics. Further studies with prospective nature, are required to affirm these results.


Delayed Development of Aneurysmal Dilatations in Patients with Extracranial Carotid Artery Dissections.
Dissection of the carotid artery (CaAD) may result in aneurysm formation. The present study was undertaken to evaluate the time of onset of post-dissection extracranial carotid artery aneurysms (ECAA) following CaAD, and to analyse independent risk factors for the development of these aneurysms. From four European stroke centres, 360 patients with extracranial CaAD were included. The time between the estimated dissection onset and aneurysm formation was analysed, and the clinical risk factors increasing the probability of aneurysm were assessed. The median duration of follow up was 5.2 months (range 0 - 24 months). A total of 75 post-dissection ECAAs were identified in 70 patients (19.4%, 95% confidence interval [CI] 15.7 - 23.8). In 52 of 70 (74%) patients, the ECAA was diagnosed at the initial clinical work up of CaAD diagnosis, with the median estimated time of dissection onset to ECAA diagnosis being six days (interquartile range [IQR] 0 - 25). In the remaining 18 (26%) patients who had normal carotid arteries at the initial imaging, the aneurysm diagnosis was made a median of 6.2 months (189 days) from the original imaging (IQR 128 - 198). A Cox proportional hazards model showed that both multiple artery dissections (hazard ratio [HR] 2.58, 95% CI 1.54 - 4.33) and arterial tortuosity (HR 1.79, 95% CI 1.08 - 2.95) were associated with presence of ipsilateral ECAA. This post hoc cohort analysis showed substantially delayed development of ipsilateral ECAA in patients with CaAD, months after baseline. Multiple dissections and arterial tortuosity are associated with the presence of ECAA and can be used in future prediction models of ECAA development in patients with CaAD.


Movement of personnel and wound contamination.
We studied the association between the movement of operating room personnel and bacterial contamination of the operative field during 12 clean operations. Settle plates placed on the patient's chest and instrument table were exposed during the operation. As a control, settle plates were exposed in the same locations when no personnel and patients were in the room. Bacterial contamination of the aseptic field was categorized as disseminating (Group A: greater than 42 combined movements) and nondisseminating (Group B: less than 42 combined movements). There were 24 persons in each group. There was a highly significant difference between the two groups in the colony counts on settling plates. More vigorous movement was associated with increased bacterial contamination of the operative field. Low bacterial colony counts were found in the control plates, ruling out environmental sources of contamination. Bacterial fallout correlated with the movement of personnel. Measures to reduce excessive movement in the OR are recommended.


In vivo oestrogenicity and binding characteristics of alpha-zearalanol (P-1496) to different classes of oestrogen binding proteins in rat liver.
It is now well established that the mycotoxin zearalenone and some of its derivatives possess oestrogenic activity. In the present study, the binding characteristics of [3H]zearalanol (P-1496) to different classes of sites including [1] the oestrogen receptor, [2] the higher capacity lower affinity (HCLA) sites, [3] the antioestrogen sites and [4] a new class of binding sites apparently specific for P-1496 were examined in rat liver. Analysis of the binding by sucrose density gradient centrifugation confirmed that P-1496 binds to the oestrogen receptor but not to the higher capacity lower affinity sites for oestradiol-17 beta. Furthermore, saturation experiments using partially-purified fractions showed that P-1496 binds to the oestrogen receptor with an affinity very similar to that of oestradiol-17 beta (apparent dissociation constants ranged from 0.1-0.3 nM). Competition studies using partially purified cytosolic oestrogen receptor suggested that P-1496 binds to a second high affinity site distinct from the oestrogen receptor. This binding site was further characterized as selective for P-1496 by saturation analysis following the complete occupancy of oestrogen receptor by oestradiol-17 beta. The in vitro binding characteristics of P-1496 were then compared with in vivo effects on concentrations of serum triglycerides. Treatment of ovariectomized female rats daily with 1.5 or 2 mg P-1496/kg body weight resulted in marked increases in the concentrations of serum triglycerides associated with the very low density lipoprotein (VLDL) fraction. Dose-response studies indicated that there was no sex difference with respect to the dose necessary to produce significant increases in serum triglycerides. The present study shows striking similarities between the binding of P-1496 and oestradiol-17 beta to liver oestrogen receptor in vitro. However, differences are observed with respect to their binding to other cytoplasmic components of liver. In addition, although P-1496 is capable of eliciting in vivo oestrogenic effects in liver, it is much less potent than oestradiol-17 beta.


Prognostic outcomes after direct percutaneous endoscopic jejunostomy in elderly patients: comparison with percutaneous endoscopic gastrostomy.
Direct percutaneous endoscopic jejunostomy (DPEJ) is an alternative method of enteral feeding to percutaneous endoscopic gastrostomy (PEG). Although long-term outcomes of PEG have been reported, little is known regarding the outcomes of DPEJ. A retrospective cohort study was conducted including 115 and 651 consecutive attempts of DPEJ and PEG, respectively, in a total of 766 elderly patients between April 2004 and March 2019. Patients' clinical background, procedural and long-term outcomes, survival analysis, and cause of death were analyzed. Successful placement rates were 93.9% and 97.1% for DPEJ and PEG, respectively. There was no significant difference in procedure-related adverse events (AEs) between the DPEJ and PEG groups. Rates of pneumonia, vomiting, and upper GI bleeding were significantly lower, whereas those of fistula enlargement and ileus were significantly higher in the DPEJ group as long-term AEs. The median survival periods were 694 and 734 days for DPEJ and PEG, respectively, with no significant differences between the 2 groups. Multivariate analysis revealed that age 80 years old or older, C-reactive protein level of 1.0 mg/dL or higher, and the presence of diabetes were independent risk factors for mortality after DPEJ. Respiratory tract infection was the primary cause of death in both groups. DPEJ is considered a safe and feasible method of access for enteral feeding as well as PEG. Although the survival period after DPEJ may be expected to be as long as that with PEG, DPEJ-specific AEs should be kept in mind on long-term feeding.


Does the Periprosthetic Fracture Pattern Depend on the Stem Fixation Method in Total Hip Arthroplasty?
Management of periprosthetic femoral fractures (PFFs) is reportedly challenging. Different patterns of PFFs would occur based on whether stem fixation was primarily cemented or cementless and whether these patterns would be associated with clinical outcomes, such as subsidence, fracture union, and complications, after stem revision. A retrospective comparative study was performed, involving 52 PFF patients treated with tapered fluted modular stems (TFMSs). In the 52 patients with Vancouver B2 or B3, including 21 cemented stems and 31 cementless stems, fracture patterns and bone stock were analyzed. Clinical outcomes after revision surgery using the TFMSs were compared between the two groups. Transverse or short oblique type PFFs occurred around the cemented stem with loosening at the bone-cement interface. The Paprosky type III femoral deficiency and Vancouver type B3 fracture were observed more frequently in the cemented stem group. Otherwise, spiral fractures occurred more frequently in the cementless group (p < 0.001). Excessive subsidence of > 5 mm was observed more frequently in the cemented stem group (p < 0.001). The re-revision rates were higher in the cemented group than in the cementless group (p = 0.047). In our study, it was found that the patterns of transverse or oblique PFFs were more frequently produced with cemented stems, while long spiral fractures were more frequent with cementless stems. Stem subsidence and reoperation related to complications were more common in patients with PFFs around cemented stems than those with PFFs around cementless stems.


Mechanism of signal sequence handover from NAC to SRP on ribosomes during ER-protein targeting.
The nascent polypeptide-associated complex (NAC) interacts with newly synthesized proteins at the ribosomal tunnel exit and competes with the signal recognition particle (SRP) to prevent mistargeting of cytosolic and mitochondrial polypeptides to the endoplasmic reticulum (ER). How NAC antagonizes SRP and how this is overcome by ER targeting signals are unknown. Here, we found that NAC uses two domains with opposing effects to control SRP access. The core globular domain prevented SRP from binding to signal-less ribosomes, whereas a flexibly attached domain transiently captured SRP to permit scanning of nascent chains. The emergence of an ER-targeting signal destabilized NAC's globular domain and facilitated SRP access to the nascent chain. These findings elucidate how NAC hands over the signal sequence to SRP and imparts specificity of protein localization.


[Impulsivity in adolescents with attention deficit hyperactivity disorder].
To study impulsivity in adolescents with attention deficit hyperactivity disorder (ADHD) and evaluate the efficacy of noophen in dosage 500 mg daily for 45 days in the treatment of this disorder. The results of the clinical, psychological and psycho-physiological study of 60 adolescents with ADHD, aged 12 to 15 years, have been analyzed. A comparative analysis of the clinical picture of the disease and the data of psychophysiological examination of ADHD predominantly hyperactive (ADHD-H) and the combined type of the disease are presented as well. The study shows significantly higher levels of anxiety and impulsivity in children with ADHD-H. The efficacy of noophen in the treatment of this group of patients has been evaluated. The high clinical efficacy of noophen is shown. After treatment, the improvement has been obtained in 63.3% of patients.


Identification of key genes in calcific aortic valve disease via weighted gene co-expression network analysis.
Calcific aortic valve disease (CAVD) is the most common subclass of valve heart disease in the elderly population and a primary cause of aortic valve stenosis. However, the underlying mechanisms remain unclear. The gene expression profiles of GSE83453, GSE51472, and GSE12644 were analyzed by 'limma' and 'weighted gene co-expression network analysis (WGCNA)' package in R to identify differentially expressed genes (DEGs) and key modules associated with CAVD, respectively. Then, enrichment analysis was performed based on Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, DisGeNET, and TRRUST database. Protein-protein interaction network was constructed using the overlapped genes of DEGs and key modules, and we identified the top 5 hub genes by mixed character calculation. We identified the blue and yellow modules as the key modules. Enrichment analysis showed that leukocyte migration, extracellular matrix, and extracellular matrix structural constituent were significantly enriched. SPP1, TNC, SCG2, FAM20A, and CD52 were identified as hub genes, and their expression levels in calcified or normal aortic valve samples were illustrated, respectively. This study suggested that SPP1, TNC, SCG2, FAM20A, and CD52 might be hub genes associated with CAVD. Further studies are required to elucidate the underlying mechanisms and provide potential therapeutic targets.


Comparison of the Effects of Govarcin Herbal Capsule and Metoclopramide for Alleviating Gastrointestinal Symptoms in Patients with Functional Dyspepsia: A Randomized Double-blind Clinical Trial.
Functional dyspepsia (FD) is felt as a discomfort or pain on the center line or upper abdomen. In this study, we investigated the effect of Govarcin herbal capsule on FD so that if it is effective, it can be used in the treatment of patients with this disease. Totally, 106 patients enrolled in a double-blind, clinical trial study. The participants had FD and were divided into two groups receiving Govarcin and Metoclopramide by block randomization. The patients were treated for four weeks, taking one Govarcin capsule or Metoclopramide tablet after each meal. The rate of improvement in patients was assessed by mitigation of clinical symptoms, including epigastric pain, fullness, discomfort, nausea, vomiting and heartburn. Also, before and after intervention, we used Nepin questionnaire and ROME III. SPSS statistics 25 software was used for data analyzing. Clinical symptom score changes between Govarcin and Metoclopramide patients' groups showed that there was no significant difference in any of the clinical symptom scores (except for heartburn, p-vale=0.012) between the study groups. Nepean score in Govarcin group before and after treatment was 19.3±4.8 and 8.9±2.8, respectively (p-value<0.001). For Metoclopramide group, these values were 19.8±3.5 and 9.4±2.1 respectively (p-value<0.001). No significant difference was found in terms of Nepean score between the Govarcin and Metoclopramide groups (p-value=0.995). Govarcin herbal capsule can be used to remedy symptoms in patients with FD. It seems that Guarcin is as effective as metoclopramide in fighting symptoms of FD as no significant difference in efficacy has been demonstrated between them.


Micromachined detectors for an enzyme-based FIA.
Micromachining techniques were applied to construct biosensor systems. The micromachined biosensors have small size, low production cost, and good reproducibility. We made some detection units for flow injection analysis (FIA). An electrochemical flow cell was fabricated, and both the enzyme immobilized column and electrochemical detector were integrated onto the same chip. A chemiluminescence detector was also fabricated and applied to the determination of glucose and lactic acid contained in human serum and urine.


Polysomnography in children scheduled for adenotonsillectomy.
Several studies suggest that a reliable diagnosis of childhood sleep-disordered breathing (SDB) requires polysomnography (PSG). We compared clinical and PSG-based diagnoses in children scheduled for adenotonsillectomy (AT). Parent responses on a validated Pediatric Sleep Questionnaire were used to determine which symptoms could help identify children with clinical diagnoses of SDB but normal PSG. Thirty-four children aged 5.0 to 12.9 years and scheduled for AT to treat clinically diagnosed sleep-disordered breathing underwent laboratory-based PSG. Results were scored by 3 different criteria: 1) >1 obstructive apnea (2 breaths or longer) per hour of sleep; 2) >5 apneas or hypopneas per hour of sleep; or 3) >1 apnea, hypopnea, or respiratory event-related arousal per hour of sleep. Depending on the criterion used, the PSG documented SDB from a minimum of 18/34 subjects (53%, for criterion I) to as many as 30/34 subjects (88%, for criterion III). Among symptoms studied, absence of daytime mouth breathing and habitual snoring were most helpful in identification of children who had no evidence of SDB on PSG, by criterion I (Chi-square, P < 0.05). The absence of other common symptoms, such as "loud snoring" or "trouble breathing" at night, were not helpful. Children with clinical diagnoses of SDB may not consistently meet PSG criteria for this disorder. Questions about daytime mouth breathing and habitual snoring might help clinicians recognize children who would not have SDB on objective testing. Clinical identification of SDB confirmable on PSG could be improved. However, available outcome data do not yet clarify whether clinical or PSG criteria best identify children likely to suffer morbidity from SDB. C.


Raman spectroscopy based diagnosis of dermatofibrosarcoma protuberans: Case report.
Dermatofibrosarcoma protuberans is a rare disease and this pathology provokes insufficient oncological alertness among clinicians. A possible way to increase the accuracy of early diagnosis of rare skin neoplasms is "optical biopsy" using Raman spectroscopy tissue response. This case report of a 32-year-old woman with a dermatofibrosarcoma protuberans demonstrates that Raman spectroscopy based "optical biopsy" can help to diagnose rare tumors.


Structural Studies of the Phage G Tail Demonstrate an Atypical Tail Contraction.
Phage G is recognized as having a remarkably large genome and capsid size among isolated, propagated phages. Negative stain electron microscopy of the host-phage G interaction reveals tail sheaths that are contracted towards the distal tip and decoupled from the head-neck region. This is different from the typical myophage tail contraction, where the sheath contracts upward, while being linked to the head-neck region. Our cryo-EM structures of the non-contracted and contracted tail sheath show that: (1) The protein fold of the sheath protein is very similar to its counterpart in smaller, contractile phages such as T4 and phi812; (2) Phage G's sheath structure in the non-contracted and contracted states are similar to phage T4's sheath structure. Similarity to other myophages is confirmed by a comparison-based study of the tail sheath's helical symmetry, the sheath protein's evolutionary timetree, and the organization of genes involved in tail morphogenesis. Atypical phase G tail contraction could be due to a missing anchor point at the upper end of the tail sheath that allows the decoupling of the sheath from the head-neck region. Explaining the atypical tail contraction requires further investigation of the phage G sheath anchor points.


Constipation and diarrhea: the neglected symptoms.
To review the symptom experience of constipation and diarrhea related to cancer and its treatment. Published articles and book chapters relating to constipation and diarrhea in patients with cancer. Constipation and diarrhea often represent a major concern and source of discomfort for the cancer patients. Research is needed to establish prevention and treatment protocols for patients at risk for constipation or diarrhea. Oncology nurses are in an excellent position to recognize individuals who are at high risk for constipation and diarrhea. Preventive strategies and treatment protocols are of utmost importance.


Poikilodermatous mycosis fungoides: a study of its clinicopathological, immunophenotypic, and prognostic features.
Poikilodermatous mycosis fungoides (MF) is a variant of MF, and its clinicopathological, immunophenotypic, molecular, and prognostic features have not previously been defined in the literature. The purpose of this study was to improve the data available for this variant of MF thus enabling clinicians to apply the appropriate treatment and follow-up. In a retrospective single center study we evaluated the clinical, histopathological, immunohistochemical, and molecular characteristics of patients with predominant (>50%) poikilodermatous lesions of MF. In all, 49 patients were identified. The median age at diagnosis was 44 years (15-81 years). Of 49 patients, 43 (88%) had early stage disease (≤IIA) at diagnosis. No patients had stage IV disease at presentation. A frequent association was coexistence of lymphomatoid papulosis (9/49; 18%). Histopathology review showed a high number of cases with CD8(+) CD4(-) atypical lymphocytes (38%). After diagnosis most patients were treated with expectant or skin-directed therapy. Psoralen plus ultraviolet A therapy was most frequently used and had high response rates (83%). Five (10%) of 49 received systemic therapy. The mean follow-up was 11 years, 10 months (1->40 years). In all, 47 (96%) of 49 patients had stable disease and two (4%) of 49 had progressive disease. No patients died during follow-up. As a tertiary center our patient cohort may be expected to have more advanced and aggressive disease. Poikilodermatous MF represents a distinct clinicopathological entity from classic patch/plaque MF. It presents at a younger age and is more frequently associated with lymphomatoid papulosis. There is an increased number of cases with predominantly CD8(+) CD4(-) atypical lymphocytes. Overall there is a good response to phototherapy and the overall prognosis appears favorable.


Genetic risks in Perthes' disease.
A population study of Perthes' disease in South Wales over a 25-year period has shown a low risk of the disorder in relatives. The risk of Perthes' disease in sibs is under 1% (2 in 323), while the risk to children of an children of an affected parent is about 3% (1 in 35) when adjusted for age of onset. No increased risk was found in relatives of patients with bilateral as compared with unilateral Perthes' disease. A mating between two affected individuals resulted in monozygotic twins concordant for Perthes' disease, but no familial concentration to suggest the action of a single major gene was found. The importance of excluding generalised disorders which may mimic Perthes' disease and may show Mendelian inheritance is emphasised, but it is concluded that true Perthes' disease has a relatively minor genetic component.


Isolation and structure (X-ray analysis) of ent-norsecurinine, an alkaloid from Phyllanthus niruri.
The isolation and structure determination of the alkaloid ent-norsecurinine (4) from Phyllanthus niruri L. is described. The structure and absolute stereochemistry have been confirmed by an X-ray analysis of ent-norsecurinine hydrochloride.


Correlates of Physical Activity Among Disadvantaged Groups: A Systematic Review.
Socioeconomically disadvantaged adults have lower engagement in leisure-time physical activity than those who are more affluent. Identification of correlates of physical activity can inform the design of effective interventions. The aim of this systematic review was to identify consistent correlates of unspecified physical activity and leisure-time physical activity among socioeconomically disadvantaged adults. PubMed and Scopus were searched up to May 2018, and titles/abstracts and full texts were screened against eligibility criteria. Methodologic quality was assessed, and correlates were synthesized from July to September 2018. Seventy-three studies were selected for synthesis; 48 examined unspecified physical activity and 31 examined leisure-time physical activity (6 examined both). Self-rated health, functional capacity, and physical activity self-efficacy were consistently, positively associated with unspecified physical activity. Mental health status and perceived benefits and enjoyment of physical activity were consistently, positively associated with leisure-time physical activity. Most studies were cross-sectional and used validated self-report measures of physical activity; few reported response rates >50%. Few factors were consistently associated with either unspecified physical activity or leisure-time physical activity. Based on available evidence, strategies to increase physical activity should consider the needs of, and focus on, those with poor self-rated health and functional capacity and should use strategies to improve physical activity self-efficacy. Strategies to increase leisure-time physical activity should focus on simultaneously addressing leisure-time physical activity and mental health concerns and improving perceptions of physical activity benefits and enjoyment. It is recommended that future studies focus on leisure-time physical activity, focus on men, use longitudinal design, examine variables related to behavioral attributes and skills, and carefully consider and plan recruitment strategies.


The biophysical limitations in physiological transport and exchange in plants grown in microgravity.
This paper describes how changes in the physical behavior of fluids and gases in microgravity can limit the physiological transport and exchange in higher plants. These types of effects are termed indirect effects of microgravity because they are not due to gravity interacting with the mass of the plant body itself. The impact of limiting gravity-dependent transport phenomena has been analyzed by the use of mathematical modeling to simulate and compare biophysical transport in the 1g and spaceflight environments. These data clearly show that the microgravity environment induces significant limitations on basic physiological and biochemical processes within the aerial and rootzone portions of the plant. Furthermore, this mathematical model provides a solid foundation for explaining the physiological effects that have been noted in past spaceflight experiments.


Improving enzyme activity, thermostability and storage stability of β-1,3-1,4-glucanase with poly-γ-glutamic acid produced by Bacillus sp. SJ-10.
β-1,3-1,4-glucanase (BG) is an industrially important enzyme owing to its stringent specificity for β-glucan cleavage. In this study, poly-γ-glutamic acid (γ-PGA) was added to BG to investigate its effect on improving the activity and stability of the enzyme. The effect of γ-PGA was investigated by analyzing kinetic and thermodynamic parameters. Compared to control, significant differences (P < .05) in enzyme activity were observed when 1.0 %, 1.5 %, and 2.0 % γ-PGA was added, and the activities were increased 1.23 ± 0.05, 1.23 ± 0.07, and 1.31 ± 0.07-fold, respectively. Regarding thermostability, residual BG activity after a 1 h incubation at 60 °C was 12.53 ± 0.06 % without γ-PGA and 79.02 ± 5.76 % with 1% γ-PGA. The storage stability at 25 °C and 50 °C also increased when γ-PGA was present. The kinetics and thermodynamic investigations indicated that the increased activity and stability of BG when γ-PGA was added were due to increased values of the Vmax, Kcat, and activation energy for denaturation. The findings of this study suggest that adding γ-PGA to BG increases the application value of this enzyme in the food and feed industries.


Infertile couples still undergo assisted reproductive treatments without initial andrological evaluation in the real-life setting: A failure to adhere to guidelines?
The EAU guidelines on male sexual and reproductive health state that both partners of the infertile couple should undergo simultaneous investigation. To assess the prevalence and the characteristics of infertile men who were referred for an andrological evaluation after failed attempts of Assisted Reproductive Technology (ART) with those who were evaluated at the beginning of their infertility pathway at a single academic centre over a 17-year period. Data of 3213 primary infertile couples assessed between 2003 and 2020 were analysed. Descriptive statistics compared the overall characteristics of male partners of couples with (+ART) or without (-ART) previous ART prior to andrological consultation. Logistic regression models analysed variables associated with +ART. Local polynomial regression models explored the probability of +ART over the analysed time frame. Of all, 493 (15.3%) participants were +ART. Patients and female partners' age was higher in +ART couples (all p ≤ 0.04). Sperm concentration, progressive sperm motility and normal sperm morphology were lower in +ART than in -ART patients (all p < 0.001), along with a greater percentage of non-obstructive azoospermia in +ART compared to -ART men (p < 0.0001). At univariable analysis, patient age and partner age >35 years and a less recent assessment were associated with +ART status (all p ≤ 0.04). Male age and less recent years of assessment were also independent predictors of +ART, after accounting for partner's age >35 years (all p < 0.01). A not significant decrease of this pattern was observed throughout the last 7 years at local polynomial regression models. Overall awareness towards the importance of a comprehensive evaluation for the male partner of every infertile couple should therefore be further strengthened. Approximately 15% of couples still undergo ART without any initial andrological evaluation in the real-life setting. A not significant decrease in this trend was observed over most recent years.


An improved procedure for the isolation and purification of nicotinic acetylcholine receptor from Torpedo fuscomaculata electric organ.
The nicotinic acetylcholinergic receptor has been isolated and purified from extracts of the electric organ of the fish Torpedo fuscomaculata. The isolation procedure involves (a) a series of purification steps including preparation of membrane fragments, extraction of receptors with non-ionic detergents and chromatofocusing; (b) a novel fluorimetric titration assay. The purified receptor is isolated following a 9-fold purification with an overall yield of 12% and a specific activity of 4027 nM.g-1. Gel electrophoresis in the presence of sodium dodecylsulphate produced only one major band with molecular weight of 44,600 associated with the alpha-subunit. A comparison is made with other established procedures. Affinity chromatography on cobratoxin CNBr-Sepharose CL4B produced a 6.8-fold purification, 5% yield and 2900 nM.g-1 specific activity, while in ion-exchange chromatography on DEAE Sepharose 6B gave a 4.7-fold purification, 3% yield and specific activity of 1988 nM.g-1.


Antibiotic-associated colitis due to Clostridium difficile: double-blind comparison of vancomycin with bacitracin.
A randomized double-blind study was carried out in patients with unresolving antibiotic-associated colitis due to Clostridium difficile, to compare the effect of bacitracin (80,000 U/day) with vancomycin (500 mg/day) on the resolution of symptoms, clearance of organism, and prevention of relapse. Forty-two patients with colitis, 9 of whom had a pseudomembrane, were randomized, 21 patients to each treatment group. The two groups were comparable in age, disease severity, and antibiotic exposure. For a 50% reduction in stool frequency the mean times (+/- SE) were 4.1 +/- 0.4 days for bacitracin and 4.2 +/- 0.4 days for vancomycin. Sixteen patients (76%) had symptom resolution after 7 days of treatment with bacitracin, compared with 18 patients (86%) given vancomycin. Patients who failed to respond were crossed over (blind) to the alternative antibiotic, but tended to be refractory to the alternative medication as well. Vancomycin-treated patients had negative toxin (83% vs. 53%, p = 0.04) and negative stool cultures (81% vs. 52%, p = 0.02) more frequently than did those patients given bacitracin. Similar numbers of patients in each group had symptomatic relapse during 1 mo of follow-up, but most of them relapsed yet again after blinded crossover therapy. Although bacitracin was significantly less effective than vancomycin in clearing C. difficile from the stools, both were of similar value in the control of symptoms in a group of patients with predominantly nonpseudomembranous colitis. In view of its low cost, bacitracin is a reasonable first-line alternative to vancomycin in the treatment of antibiotic-associated colitis.


Structural features and antitumor activity of a purified polysaccharide extracted from Sargassum horneri.
A polysaccharide fraction (SHPSA) was obtained from Sargassum horneri by hot-water extraction and sequential purification of anion-exchange chromatography and gel-filtration chromatography. SHPSA was found to be a neutral polysaccharide fraction with an average molecular weight of 5.78×10(5) Da and composed of T-D-Glcp, 1,3-D-Glcp, 1,6-D-Glcp and 1,3,6-D-Glcp in a molar percentage of 1.00:4.17:1.17:0.89, respectively. Based on the results from chemical analysis, NMR, and SHPSA was determined to be a glucan with β-(1→6) side chains linked to a β-(1→3) backbone with relatively few branch points. Moreover, SHPSA could inhibit the growth of human colon cancer DLD cells in a dose-dependent manner by inducing the apoptosis of DLD cells. So, SHPSA was promising for future use as a natural antitumor agent.


Genes Related to Oxytocin and Arginine-Vasopressin Pathways: Associations with Autism Spectrum Disorders.
Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorders characterized by impaired social interactions, communication deficits, and repetitive behavior. Although the mechanisms underlying its etiology and manifestations are poorly understood, several lines of evidence from rodent and human studies suggest involvement of the evolutionarily highly-conserved oxytocin (OXT) and arginine-vasopressin (AVP), as these neuropeptides modulate various aspects of mammalian social behavior. As far as we know, there is no comprehensive review of the roles of the OXT and AVP systems in the development of ASD from the genetic aspect. In this review, we summarize the current knowledge regarding associations between ASD and single-nucleotide variants of the human OXT-AVP pathway genes OXT, AVP, AVP receptor 1a (AVPR1a), OXT receptor (OXTR), the oxytocinase/vasopressinase (LNPEP), and ADP-ribosyl cyclase (CD38).


New cannulation technique for the severely calcified ascending aorta.
Severe calcific atherosclerosis involving the femoral arteries, ascending aorta, right subclavian artery, and aortic arch precluded standard cannulation techniques for a patient requiring emergency revascularization. A cannula was passed from the apex of the left ventricle across the aortic valve to lie in the proximal ascending aorta, and successful cardiopulmonary bypass was achieved to allow revascularization.


Recruitment of synapses in the neurosecretory process during long-term facilitation at the lobster neuromuscular junction.
We investigated long-term facilitation at the lobster neuromuscular synapse employing a combination of FM1-43 staining of synaptic vesicles, electron microscopy analysis, and electrical recordings of synaptic activity. Synaptic terminals were loaded with the fluorescent dye FM1-43 producing clusters of activity-dependent fluorescent spots. Electron microscopy analysis of synaptic ultrastructure suggested that fluorescent spots represent compartments of synaptic terminals filled with vesicles. Excitatory postsynaptic currents were recorded from the stained synaptic terminals using focal macropatch electrodes. Terminals were stained during the nerve stimulation at a low stimulation frequency (2, 5 or 10 Hz) before and after long-term facilitation was elicited by high-frequency stimulation (20 or 30 Hz for 5 min). We found that staining after long-term facilitation results in the appearance of new fluorescent spots, as well as in the increase in fluorescence of the spots that appeared before long-term facilitation. This increase in fluorescence accounted for the increase in quantal release. Activation of individual fluorescent spots was found to be non-uniform. In spite of overall increase in fluorescence, some synaptic compartments decreased their staining after long-term facilitation. Thus, our study demonstrates that long-term facilitation produces non-uniform activation of FM1-43 uptake in synaptic compartments that correlates with the increase in quantal neurosecretion.


Mitomycin-C-induced sister-chromatid exchanges and cell-cycle kinetics in lymphocytes from patients with Klinefelter syndrome.
The chromosomal sensitivity to mitomycin-C (MMC) and cell-cycle kinetics in cells from patients with Klinefelter syndrome, a sex chromosomal disorder giving a high risk of malignant tumor, were studied by techniques of sister-chromatid exchanges (SCEs). The frequencies of MMC-induced SCEs increased in proportion to the increase in MMC concentration in both patient and normal control cells. At low levels of MMC there were no significant differences in SCE frequencies between the patient and normal control cells, but at MMC concentrations of 3 X 10(-8) M (p less than 0.05) and 1 X 10(-7) M (p less than 0.01), significant increases in the frequency of MMC-induced SCEs were observed in cells from patients compared to cells from normal controls. Although the analysis of cell-cycle kinetics both after various culture times and after treatment with MMC revealed that there were no significant differences between the patient and normal control cells, patients with Klinefelter syndrome showed a tendency to cell-cycle delays after treatment with MMC in comparison with normal controls.


[Concentration of minocycline in human aqueous humor after oral administration (author's transl)].
For antibacterial prophylaxis in intraocular surgery minocycline was administered in oral dosage in 22 cataract-patients. The concentration levels reached in the aqueous humor were determined. The detected levels ranged in some cases from 0.08 to 0.2 mcg/ml, the majority was below 0.06 mcg/ml.


Deep brain stimulation electrode anchoring using BioGlue((R)), a protective electrode covering, and a titanium microplate.
The authors present an easily applicable deep brain stimulation (DBS) electrode anchoring technique for use in human and experimental animals. The anchoring technique combines the use of fibrin glue, a two-component surgical adhesive (BioGlue), a protective electrode covering, and a titanium microplate. The BioGlue (CryoLife International, Inc., Kennesaw, GA, USA) hinders unwanted electrode movement during the electrode fixation step and seals the burr hole, while the protective electrode covering protects the electrode under the titanium microplate which keeps the electrode in a permanent position. The described technique further has the advantage of being cosmetically acceptable to the human patient, and furthermore it perfectly adapts to the smaller and irregular-shaped skull in experimental animals. The described technique has clinically been used to implant DBS-electrodes in the subthalamic nucleus for Parkinson disease and is the preferred DBS-electrode anchoring technique for our experimental DBS-studies in the Göttingen minipig.


Design, synthesis and antifungal activity of novel amide derivatives containing a pyrrolidine moiety as potential succinate dehydrogenase inhibitors.
To discover new succinate dehydrogenase inhibitors (SDHI) fungicides, a series of amide derivatives containing a pyrrolidine moiety were designed and synthesized, and their antifungal activities were evaluated against Monilinia fructicola (M. fructicola), Rhizoctonia solani (R. solani), Fusarium graminearum schw (F. graminearum), Fusarium oxysporum (F. oxysporum), and Phytophthora infestans (P. infestans). Some compounds showed excellent antifungal activities against the five fungi. Among them, compound 6 showed broad-spectrum inhibitory activities. The EC50 of compound 6 against M. fructicola, R. solani, F. graminearum, F. oxysporum, and P. infestans were 2.13, 14.42, 1.69, 27.79, and 27.12 mg/L, respectively. In addition, compound 6 can effectively inhibit the spore germination of M. fructicola and has moderate damage to the cell membrane. Compound 6 can effectively inhibit succinate dehydrogenase (SDH) of M. fructicola, and can significantly increase the expression levels of SDHC and SDHD. Compound 6 can be used as a lead structure for developing new SDH inhibitors.


Implementation, utilization, and evaluation of a pharmacist-driven romiplostim dosing service for patients with immune thrombocytopenia at a multisite cancer centre.
Romiplostim is a thrombopoietin receptor agonist approved for the treatment of patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immune globulin, or splenectomy. Dose adjustments of romiplostim are based on platelet counts and follow a dosing schema that requires frequent monitoring. As a quality improvement initiative to increase clinical efficiency and promote clinical pharmacy services at our institution, we developed a collaborative practice agreement and implemented a novel pharmacist-driven romiplostim dosing protocol. A retrospective chart review was conducted to evaluate the acceptance, utilization, and impact of the pharmacist-driven romiplostim dosing service. The primary outcome of our analysis was the adoption rate by providers of the romiplostim pharmacist dosing service. Secondary endpoints were focused on patients newly initiating romiplostim on the dosing service and included platelet responses and number of dose adjustments by a pharmacist. A total of 54 patients received romiplostim in our analysis: 25 patients who had already been receiving romiplostim and 29 patients who newly initiated romiplostim during the study period. Of the 29 patients newly initiating romiplostim, 27 (93%) had their dosing managed by a pharmacist Twenty-one patients (84%) and 18 patients (75%) achieved an initial and durable response with romiplostim, respectively. Pharmacists made a median of 3 dose adjustments to romiplostim per patient. The implementation of a pharmacist-driven romiplostim dosing service led to a significant adoption and utilization by physicians at our health system.


Pulmonary amyloidosis in Sjögren's syndrome: a rare diagnosis for nodular lung lesions.
Lung involvement in Sjögren's syndrome (SS) can affect trachea, bronchus, small airways, pleura and may cause interstitial lung injury. It may also be associated with malignancies, particularly non-Hodgkin's lymphoma, which is a well-recognized complication of this disease. Here we describe the occurrence of localized amyloidosis presenting as pulmonary nodules in a patient with newly diagnosed SS. We highlight this rare occurrence as a diagnostic possibility that should be considered in the evaluation of pulmonary involvement in this disease.


Expression of nestin mRNA is a differentiation marker in thyroid tumors.
Nestin is a maker that identifies stem cells in some adult tissues, and its expression is believed to relate to malignancy in cancer cells. In this study, we measured the expression levels of nestin mRNA in various kinds of thyroid tumor by the real-time quantitative reverse transcription-polymerase chain reaction. Unexpectedly, nestin mRNA was detected in almost all differentiated thyroid tumors and normal thyroid tissues, whereas extremely decreased expression was observed in anaplastic carcinomas, which are the most malignant of the thyroid follicular cell-derived tumors. These results suggest that nestin mRNA is a differentiation marker, and its expression does not relate to malignant characteristics in thyroid tumors.


Predictive value of the cardio-ankle vascular index for recurrence of atrial fibrillation after catheter ablation.
The predictive value of the cardio-ankle vascular index (CAVI) for estimating the efficacy outcome of catheter ablation (CA) in atrial fibrillation (AF) patients is unclear. We aimed to examine the predictive performance of the CAVI for recurrences of atrial arrhythmias after CA. We enrolled a total of 193 patients with AF (paroxysmal 126 and non-paroxysmal 67) who underwent initial CA procedures at our institute, and CAVI measurements were conducted between January 2016 and March 2017. We evaluated recurrences of atrial arrhythmias after the first CA procedure as a clinical outcome. The CAVI value was assessed and the enrolled patients were divided according to the optimal CAVI value cut-off point (9.5) in the atrial arrhythmia recurrence group. During a mean follow-up of 31.3 (17.5-43.0) months, 74 (32.5%; PaAF 41 and 49.3%; non-PaAF 33) patients had recurrences of atrial arrhythmias. The recurrence ratio of atrial arrhythmias was significantly higher in patients with a high CAVI (≥9.5) than those with a low CAVI (<9.5) (log rank test; p = 0.018). A univariate analysis showed the association between higher CAVI values and recurrences of atrial arrhythmias (p = 0.072). Multivariate analyses using a Cox proportional hazard model after adjusting for other clinical factors revealed that the CAVI value was determined to be a significant predictive factor of a recurrence of atrial arrhythmias after CA (Hazard ratio: 1.44, 95% confidence interval: 1.17-1.78, p < 0.01). The CAVI was significantly associated with a recurrence of atrial arrhythmias after CA in AF patients.


SARS-CoV-2 Nucleocapsid Plasma Antigen for Diagnosis and Monitoring of COVID-19.
Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid antigen in blood has been described, but the diagnostic and prognostic role of antigenemia is not well understood. This study aimed to determine the frequency, duration, and concentration of nucleocapsid antigen in plasma and its association with coronavirus disease 2019 (COVID-19) severity. We utilized an ultrasensitive electrochemiluminescence immunoassay targeting SARS-CoV-2 nucleocapsid antigen to evaluate 777 plasma samples from 104 individuals with COVID-19. We compared plasma antigen to respiratory nucleic acid amplification testing (NAAT) in 74 individuals with COVID-19 from samples collected ±1 day of diagnostic respiratory NAAT and in 52 SARS-CoV-2-negative individuals. We used Kruskal-Wallis tests, multivariable logistic regression, and mixed-effects modeling to evaluate whether plasma antigen concentration was associated with disease severity. Plasma antigen had 91.9% (95% CI 83.2%-97.0%) clinical sensitivity and 94.2% (84.1%-98.8%) clinical specificity. Antigen-negative plasma samples belonged to patients with later respiratory cycle thresholds (Ct) when compared with antigen-positive plasma samples. Median plasma antigen concentration (log10 fg/mL) was 5.4 (interquartile range 3.9-6.0) in outpatients, 6.0 (5.4-6.5) in inpatients, and 6.6 (6.1-7.2) in intensive care unit (ICU) patients. In models adjusted for age, sex, diabetes, and hypertension, plasma antigen concentration at diagnosis was associated with ICU admission [odds ratio 2.8 (95% CI 1.2-6.2), P=.01] but not with non-ICU hospitalization. Rate of antigen decrease was not associated with disease severity. SARS-CoV-2 plasma nucleocapsid antigen exhibited comparable diagnostic performance to upper respiratory NAAT, especially among those with late respiratory Ct. In addition to currently available tools, antigenemia may facilitate patient triage to optimize intensive care utilization.


Narcissistic T cells: reactivity to self makes a difference.
It has been appreciated for more than three decades that the interactions between the T-cell antigen receptor and self-antigens are the major determinants of the cell fates of developing thymocytes and the establishment of central tolerance. However, recent evidence shows that the level of self-reactivity substantially contributes to fate choices of positively selected mature T cells in homeostasis, as well as during immune responses. This implies that individual clones of peripheral T cells are predisposed to specific functional properties based on the self-reactivity of their antigen receptors. Overall, the relative difference in the self-reactivity among peripheral T cells is an important factor contributing to the diversity of T-cell responses to foreign antigens.


Therapy of primary hypothyroidism with L-triiodothyronine: discordant cardiac and pituitary responses.
Cardiac systolic time intervals were studied in ten patients with primary hypothyroidism before and during therapy with increasing doses of oral L-triiodothyronine (L-T3). Therapy was increased sequentially from 10, 20, 25 to 50 microgram of L-T3 daily on a monthly basis. On L-T3, 20 to 25 microgram/day, cardiac systolic time intervals and other peripheral responses to thyroid hormone including serum cholesterol concentration, serum creatine phosphokinase (CPK) activity, and basal metabolic rate had normalized. However, serum thyrotrophin (TSH) levels and peak TSH responses to thyrotrophin-releasing hormone (TRH) remained elevated on these doses of L-T3. As the dose of L-T3 was increased from 20 to 50 microgram/day, mean basal serum TSH levels decreased from 55 to 16 microunits/ml, and the peak TSH response to TRH decreased from 243 to 58 microunits/ml (P less than 0.001) while systolic time intervals did not decrease further. Changing to L-thyroxine (L-T4) therapy at this point resulted in further suppression of TSH secretion, without significantly altering systolic time intervals or the other peripheral responses to thyroid hormone. These data suggest (a) that some biological responses to thyroid hormone were normalized on lower doses of L-T3 than were required to normalize TSH secretion, and (b) that higher doses of L-T3 or substituting L-T4 therapy could suppress TSH secretion further without altering the other peripheral responses to thyroid hormone.


Malignant transformation of osteoblastoma: study using image analysis microdensitometry.
To determine if the malignant transformation, as perceived histologically, in a case of osteoblastoma from the right femur, was also expressed as a quantitative change in nuclear DNA during tumour progression over five months. Nuclear DNA microdensitometry by computer image analysis was used to acquire relative DNA distribution patterns. Tissue had been removed on four separate occasions from a lesion in the right femur of an 18 year old man. Retrospective DNA analysis was performed on formalin fixed, paraffin wax-embedded tissue. The DNA profile of the initial biopsy specimen, which was histologically diagnosed as osteoblastoma, was euploid with a near diploid (2c) modal DNA. The second biopsy specimen taken one month later also resembled osteoblastoma but showed an aneuploid DNA profile with a diploid modal DNA and some nuclei with ploidy greater than 5c. The third biopsy specimen taken four months later showed histological evidence of osteosarcoma and a near pentaploid (5c) modal DNA with large number of nuclei exceeding 5c. DNA microdensitometry confirmed the initial and final diagnosis. The technique also seems to be capable of detecting aneuploidy before malignancy is morphologically evident.


Is Mammographic Breast Density an Endophenotype for Breast Cancer?
Mammographic breast density (MBD) is a strong and highly heritable predictor of breast cancer risk and a biomarker for the disease. This study systematically assesses MBD as an endophenotype for breast cancer-a quantitative trait that is heritable and genetically correlated with disease risk. Using data from the family-based kConFab Study and the 1994/1995 cross-sectional Busselton Health Study, participants were divided into three status groups-cases, relatives of cases and controls. Participant's mammograms were used to measure absolute dense area (DA) and percentage dense area (PDA). To address each endophenotype criterion, linear mixed models and heritability analysis were conducted. Both measures of MBD were significantly associated with breast cancer risk in two independent samples. These measures were also highly heritable. Meta-analyses of both studies showed that MBD measures were higher in cases compared to relatives (β = 0.48, 95% CI = 0.10, 0.86 and β = 0.41, 95% CI = 0.06, 0.78 for DA and PDA, respectively) and in relatives compared to controls (β = 0.16, 95% CI = -0.24, 0.56 and β = 0.16, 95% CI = -0.21, 0.53 for DA and PDA, respectively). This study formally demonstrates, for the first time, that MBD is an endophenotype for breast cancer.


Challenging stereotypes improves understanding of canine behavioral genetics.
A recent study by Morrill et al. (2022) highlights important connections between genetics and behavior in domestic dogs (Canis familiaris), while also contesting the idea that common breed stereotypes accurately predict individual dog behavior. These findings challenge scientists and dog professionals to deepen our understanding of dog behavior, moving past generalizations and toward approaches that better account for the behavior of individuals.


Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells.
Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic β cells. In the present study, we have identified the expression of TGR5 in pancreatic β cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated Gα(s) and caused an increase in intracellular cAMP and Ca(2+). OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective Gα(s) inhibitor) or U73122 (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, U73122 or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G(s)/cAMP/Ca(2+) pathway. 8-pCPT-2'-O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic β cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.


Cajanolactone A, a stilbenoid from Cajanus cajan, inhibits energy intake and lipid synthesis/storage, and promotes energy expenditure in ovariectomized mice.
We had reported that cajanolactone A (CLA) from Cajanus cajan dose-dependently inhibited ovariectomy-induced obesity and liver steatosis in mice, showing potential to prevent postmenopausal obesity and fatty liver. In this study, the role of CLA in the regulation of energy and lipid homeostasis was investigated. Ovariectomized mice treated with CLA or vehicle for 12 weeks were performed a 48 h monitoring for energy metabolism and food uptake. After that, hypothalami, perigonadal (pWATs), inguinal (iWATs) and brown (BATs) adipose tissues, livers, sera, and fecal and cecal contents were collected and analyzed. In CLA-treated mice, we observed reduced food uptake; increased energy expenditure; inhibited expression of orexigenic genes (ORX, ORXR2, pMCH and Gal) in the hypothalami, of lipogenic genes (CD36, SREBP-1c, ChREBP, PPARγ) in the livers, and of lipid storage proteins in the WATs (FSP27, MEST and caveolin-1) and livers (FSP27, Plin2 and Plin5); stimulated expression of metabolism-related proteins (pATGL and Echs1) in the adipose tissues and of thermogenic protein (UCP1) in the inguinal WATs; increased BAT content; increased mitochondria in the pWATs and livers; inhibited angiogenesis in the pWATs; and altered gut microbiome diversity with an increased abundance of Bacteroides. CLA prevents ovariectomy-induced obesity and liver steatosis via regulating energy intake and lipid synthesis/storage, promoting UCP1-dependent heat production, and protecting the mitochondrial function of hepatocytes and adipocytes. The improved gut microecology and inhibited angiogenesis may also contribute to the anti-obese activity of CLA.


Sleep Pharmacotherapy for Common Sleep Disorders in Pregnancy and Lactation.
Sleep disturbances are common in pregnancy, and sleep disorders may worsen or present de novo in the course of gestation. Managing a pregnant patient is complicated by the risk of teratogenicity, pharmacokinetic changes, and the dynamic nature of pregnancy. Although nonpharmacologic interventions are likely safest, they are often ineffective, and a patient is left dealing with frustrations of the sleep disturbance, as well as the negative outcomes of poor sleep in pregnancy. As with any other condition in pregnancy, management requires an understanding of pregnancy physiology, knowledge of the impact of a given condition on pregnancy or fetal and neonatal outcomes, and an ability to weigh the risk of the exposure to an untreated, or poorly treated condition, against the risk of a given drug. In partnership with the pregnant patient or couple, options for therapy should be reviewed in the context of the impact of the condition on pregnancy and offspring outcomes, while understanding that data (positive or negative) on the impact of therapy on perinatal outcomes are lacking. This article reviews the epidemiology of sleep disorders in pregnancy, general principles of prescribing in pregnancy and lactation, and safety surrounding therapeutic options in pregnancy.


Military medicine and the ethics of war: British colonial warfare during the Seven Years War (1756-63).
This article examines 18th-century European warfare, tracing the first formal codifications of conventions of war, frequently introduced by military physicians and initially regarding the treatment of the sick and wounded. It outlines to what extent these conventions were followed in practice, particularly in the challenging environment of American irregular warfare, with a focus on the most well-known incident of "biological warfare" in the period: the deliberate spread of smallpox by British officers among Amerindians in 1763. More broadly, it demonstrates that the history of military medicine provides a fruitful method with which to uncover assumptions about the ethics of war.


Switching to Lurasidone following 12 months of treatment with Risperidone: results of a 6-month, open-label study.
Patients with a diagnosis of schizophrenia are at an increased risk for developing metabolic syndrome, which is associated with greater cardiovascular morbidity and mortality. Treatment with some commonly used antipsychotic medications may increase the risk of developing metabolic syndrome. The aim of the study was to evaluate the safety of lurasidone in patients who continued lurasidone or switched from risperidone to lurasidone. A secondary aim was assessment of the effect of long-term lurasidone on the Positive and Negative Syndrome Scale (PANSS). The treatment sample in the current study consisted of clinically stable patients with schizophrenia (N = 223) who had completed a 12-month, double-blind study of lurasidone vs. risperidone. In the current extension study, all patients received 6 months of open-label treatment with lurasidone, either continuing lurasidone assigned during the preceding double-blind trial, or switching from double-blind risperidone to lurasidone. Safety and tolerability parameters included body weight, prolactin, and metabolic laboratory tests. Six months of OL treatment with lurasidone was generally well-tolerated, with a low incidence of parkinsonism (4.5%) and akathisia (3.1%). Overall, few adverse events were rated as severe (4.9%), and discontinuation due to an adverse event was low in the lurasidone continuation vs. risperidone switch groups (3.7% vs. 6.9%). In the lurasidone continuation versus risperidone switch groups, change from OL baseline to 6-month endpoint (observed case) was observed in mean body weight (- 0.6 vs. -2.6 kg), median total cholesterol (- 4.0 vs. + 4.5 mg/dL), triglycerides (- 4.5 vs. -5.5 mg/dL), glucose (0.0 vs. -3.0 mg/dL) and prolactin (males, + 0.15 vs. -11.2 ng/mL; females, + 1.3 vs. -30.8 ng/mL). Improvement in PANSS total score was maintained, from OL baseline to endpoint in the continuation vs. switch groups (+ 1.0 vs. -1.0; OC). In this 6-month extension study, lurasidone treatment was generally well-tolerated and associated with minimal effects on weight, metabolic parameters, and prolactin levels. Patients who switched from risperidone to lurasidone experienced reductions in weight, metabolic parameters and prolactin levels commensurate with increases in these safety parameters experienced during the previous 12 months of treatment with risperidone. ClinicalTrials.gov NCT00641745 (Date of Registration: March 24, 2008).


Incidence and outcomes of protamine reactions in patients undergoing catheter ablation of atrial fibrillation.
Aggressive anticoagulation with heparin to maintain an activated clotting time (ACT) >300 s is required during catheter ablation of atrial fibrillation (AF) to reduce the risk of systemic thromboembolism. The purpose of this study is to describe the incidence and outcome of protamine reactions and analyze the risk factors in patients undergoing catheter ablation of AF. The patient population included 242 consecutive patients (193 men, age 57.6 +/- 10.8 years) with drug refractory AF who underwent catheter ablation and received protamine immediately following catheter ablation to reverse the effects of heparin. Fifty eight of these patients had prior exposure to protamine. Three of the 242 patients in our study developed an adverse reaction to protamine (1.2%). Although each of the three protamine reaction presented in a dramatic fashion with profound hypotension, all three patients responded to medical treatment and did not experience clinical sequelae. Age, gender, type of AF, number of ablations, prior exposure, diabetes mellitus, and ejection fraction did not predict the occurrence of these reactions. This study reports, for the first time, the incidence and outcomes of protamine reaction in patients undergoing catheter ablation of AF. The results of this study reveal that protamine reactions present in a dramatic fashion often with profound hypotension. Although the incidence of protamine reactions in this setting is low (1.2%), they do occur. Electrophysiologists who use protamine need to be aware of this reaction and the appropriate therapeutic interventions.


Human genetic defect in leukotriene C4 synthesis.
Normal human platelets metabolise [3H]-LTA4 into [3H]-LTC4. Platelets from patients with glutathione synthetase deficiency possessing 10-30% of normal levels of cellular glutathione showed marked reduction in capacity to form [3H]-LTC4 (8-10% of normal) even though exogenous reduced glutathione was added to the incubation medium. To our knowledge this is the first demonstration of a genetic defect in LTC4 synthetase coupled to a defect in cellular glutathione levels.


Review article: impact of cigarette smoking on intestinal inflammation-direct and indirect mechanisms.
The inflammatory bowel diseases, Crohn's disease and ulcerative colitis are related multifactorial diseases. Their pathogenesis is influenced by each individual's immune system, the environmental factors within exposome and genetic predisposition. Smoking habit is the single best-established environmental factor that influences disease phenotype, behaviour and response to therapy. To assess current epidemiological, experimental and clinical evidence that may explain how smoking impacts on the pathogenesis of inflammatory bowel disease. A Medline search for 'cigarette smoking', in combination with terms including 'passive', 'second-hand', 'intestinal inflammation', 'Crohn's disease', 'ulcerative colitis', 'colitis'; 'intestinal epithelium', 'immune system', 'intestinal microbiota', 'tight junctions', 'mucus', 'goblet cells', 'Paneth cells', 'autophagy'; 'epigenetics', 'genes', 'DNA methylation', 'histones', 'short noncoding/long noncoding RNAs'; 'carbon monoxide/CO' and 'nitric oxide/NO' was performed. Studies found evidence of direct and indirect effects of smoking on various parameters, including oxidative damage, impairment of intestinal barrier and immune cell function, epigenetic and microbiota composition changes, that contribute to the pathogenesis of inflammatory bowel disease. Cigarette smoking promotes intestinal inflammation by affecting the function and interactions among intestinal epithelium, immune system and microbiota/microbiome.


Diagnostic Yield of Incremental Biopsy Cores and Second Lesion Sampling for In-Gantry MRI-Guided Prostate Biopsy.
BACKGROUND. In-gantry MRI-guided biopsy (MRGB) of the prostate has been shown to be more accurate than other targeted prostate biopsy methods. However, the optimal number of cores to obtain during in-gantry MRGB remains undetermined. OBJECTIVE. The purpose of this study was to assess the diagnostic yield of obtaining an incremental number of cores from the primary lesion and of second lesion sampling during in-gantry MRGB of the prostate. METHODS. This retrospective study included 128 men with 163 prostate lesions who underwent in-gantry MRGB between 2016 and 2019. The men had a total of 163 lesions sampled with two or more cores, 121 lesions sampled with three or more cores, and 52 lesions sampled with four or more cores. A total of 40 men underwent sampling of a second lesion. Upgrade on a given core was defined as a greater International Society of Urological Pathology (ISUP) grade group (GG) relative to the previously obtained cores. Clinically significant prostate cancer (csPCa) was defined as ISUP GG 2 or greater. RESULTS. The frequency of any upgrade was 12.9% (21/163) on core 2 versus 10.7% (13/121) on core 3 (p = .29 relative to core 2) and 1.9% (1/52) on core 4 (p = .03 relative to core 3). The frequency of upgrade to csPCa was 7.4% (12/163) on core 2 versus 4.1% (5/121) on core 3 (p = .13 relative to core 2) and 0% (0/52) on core 4 (p = .07 relative to core 3). The frequency of upgrade on core 2 was higher for anterior lesions (p < .001) and lesions with a higher PI-RADS score (p = .007); the frequency of upgrade on core 3 was higher for apical lesions (p = .01) and lesions with a higher PI-RADS score (p = .01). Sampling of a second lesion resulted in an upgrade in a single patient (2.5%; 1/40); both lesions were PI-RADS category 4 and showed csPCa. CONCLUSION. When performing in-gantry MRGB of the prostate, obtaining three cores from the primary lesion is warranted to optimize csPCa diagnosis. Obtaining a fourth core from the primary lesion or sampling a second lesion has very low yield in upgrading cancer diagnoses. CLINICAL IMPACT. To reduce patient discomfort and procedure times, operators may refrain from obtaining more than three cores or second lesion sampling.


Exploring the resistance mechanisms in Trichosporon asahii: Triazoles as the last defense for invasive trichosporonosis.
Trichosporon asahii has recently been recognized as an emergent fungal pathogen able to cause invasive infections in neutropenic cancer patients as well as in critically ill patients submitted to invasive medical procedures and broad-spectrum antibiotic therapy. T. asahii is the main pathogen associated with invasive trichosporonosis worldwide. Treatment of patients with invasive trichosporonosis remains a controversial issue, but triazoles are mentioned by most authors as the best first-line antifungal therapy. There is mounting evidence supporting the claim that fluconazole (FLC) resistance in T. asahii is emerging worldwide. Since 2000, 15 publications involving large collections of T. asahii isolates described non-wild type isolates for FLC and/or voriconazole. However, very few papers have addressed the epidemiology and molecular mechanism of antifungal resistance in Trichosporon spp. Data available suggest that continuous exposure to azoles can induce mutations in the ERG11 gene, resulting in resistance to this class of antifungal drugs. A recent report characterizing T. asahii azole-resistant strains found several genes differentially expressed and highly mutated, including genes related to the Target of Rapamycin (TOR) pathway, indicating that evolutionary modifications on this pathway induced by FLC stress may be involved in developing azole resistance. Finally, we provided new data suggesting that hyperactive efflux pumps may play a role as drug transporters in FLC resistant T. asahii strains.


Early parental loss and depression history: associations with recent life stress in major depressive disorder.
Although exposure to early adversity and prior experiences with depression have both been associated with lower levels of precipitating life stress in depression, it is unclear whether these stress sensitization effects are similar for all types of stress or whether they are specific to stressors that may be particularly depressogenic, such as those involving interpersonal loss. To investigate this issue, we administered structured, interview-based measures of early adversity, depression history, and recent life stress to one hundred adults who were diagnosed with major depressive disorder. As predicted, individuals who experienced early parental loss or prolonged separation (i.e., lasting one year or longer) and persons with more lifetime episodes of depression became depressed following lower levels of life stress occurring in the etiologically-central time period of three months prior to onset of depression. Importantly, however, additional analyses revealed that these effects were unique to stressors involving interpersonal loss. These data highlight potential stressor-specific effects in stress sensitization and demonstrate for the first time that individuals exposed to early parental loss or separation, and persons with greater histories of MDD, may be selectively sensitized to stressors involving interpersonal loss.


Synthesis, DFT calculations, linear and nonlinear optical properties of binuclear phthalocyanine gallium chloride.
The axially substituted binuclear GaCl/GaCl phthalocyanine 1 with an unsymmetrical pattern of substitution has been prepared and its nonlinear optical (NLO) properties determined. The resulting binuclear complex retains approximately the same transition energies of monomeric (RO)8PcGaCl as far as the linear optical spectrum is concerned, although 1 has a double concentration of central atoms per molecule and an enlarged conjugated ligand. The lack of significant spectral shifts in passing from mononuclear to binuclear complexes has been rationalized theoretically by means of density functional theory calculations. The purpose of the present study is to determine whether binuclearity affects the optical limiting behavior of 1 with respect to monomeric (RO)8PcGaCl in the NLO regime determined by nanosecond laser pulses.


The clinical role of combined serum C1q and hsCRP in predicting coronary artery disease.
C1q has been shown to be associated with coronary heart disease (CAD) and can co-deposit with C-reactive protein (CRP) in atherosclerotic plaques. However, few studies have been conducted between C1q, CRP parameters and CAD. The aim of this study is to explore the relationship between C1q and CRP parameters and assess their clinical significance in CAD. 238 total patients who underwent coronary artery angiography were enrolled and divided into control group (n = 65), stable CAD group (n = 47) and unstable angina group (UA group, n = 126). Patients' data were collected from self-administered questionnaires and electrical medical records. The severity of coronary stenosis was presented by Gensini score. The relationship between C1q, CRP parameters and CAD were evaluated by multivariate regression analysis and their predicting performance were assessed by ROC analysis and odds ratio analysis. Compared with control group, C1q was showed significantly lower in stable CAD (P = 0.004) and UA groups (P = 0.008), while hsCRP was higher in UA group (P = 0.024). Serum C1q was weakly positively associated with hsCRP (r = 0.24, P < 0.001) but not correlated with Gensini score. Logistic regression identified C1q (OR: 0.87 per 10 mg/L, 95% CI: 0.79-0.95, P = 0.001) and hsCRP (OR: 1.08 mg/L, 95% CI: 1.01-1.15, P = 0.032) as independent determinants of CAD. Furthermore, combined C1q and hsCRP level showed higher discriminatory accuracy in predicting CAD than C1q (AUC: 0.676 vs 0.585, P = 0.101; NRI: 10.4%, P = 0.049; IDI: 3.9%, P < 0.001) or hsCRP (AUC: 0.676 vs 0.585, P = 0.101; NRI: 16.7%, P = 0.006; IDI: 5.8%, P < 0.001). Reduced serum C1q and increased hsCRP are independently associated with CAD and could be potential predictors for CAD diagnosis. Furthermore, combined C1q and hsCRP showed better performance in predicting CAD than using single one.


Establishing an environment in which rigorous scientific inquiry is practiced: a personal journey.
For more than three decades, Ionis Pharmaceutics has pursued the challenging mission of creating a new platform for drug discovery. To overcome the numerous challenges faced required the integration of innovation across many scientific areas, despite many disappointments and failures. The approaches implemented to create and maintain a scientific environment to achieve the mission demanded the rigorous practice of science over three decades. The approaches taken are discussed in this perspective.


Evaluation of auditory perception development in neonates by event-related potential technique.
To investigate auditory perception development in neonates and correlate it with days after birth, left and right hemisphere development and sex using event-related potential (ERP) technique. Sixty full-term neonates, consisting of 32 males and 28 females, aged 2-28days were included in this study. An auditory oddball paradigm was used to elicit ERPs. N2 wave latencies and areas were recorded at different days after birth, to study on relationship between auditory perception and age, and comparison of left and right hemispheres, and males and females. Average wave forms of ERPs in neonates started from relatively irregular flat-bottomed troughs to relatively regular steep-sided ripples. A good linear relationship between ERPs and days after birth in neonates was observed. As days after birth increased, N2 latencies gradually and significantly shortened, and N2 areas gradually and significantly increased (both P<0.01). N2 areas in the central part of the brain were significantly greater, and N2 latencies in the central part were significantly shorter in the left hemisphere compared with the right, indicative of left hemisphere dominance (both P<0.05). N2 areas were greater and N2 latencies shorter in female neonates compared with males. The neonatal period is one of rapid auditory perception development. In the days following birth, the auditory perception ability of neonates gradually increases. This occurs predominantly in the left hemisphere, with auditory perception ability appearing to develop earlier in female neonates than in males. ERP can be used as an objective index used to evaluate auditory perception development in neonates.


The New S7B/E14 Question and Answer Draft Guidance for Industry: Contents and Commentary.
In August 2020, the International Council on Harmonisation (ICH) released a new draft document, which for the first time combined nonclinical (S7B) and clinical (E14) Questions and Answers (Q&As) into 1 document. FDA describes the revision as a "value proposition": if the human ether-à-go-go assay and the in vivo study are performed in a standardized way, the number of dedicated thorough QT (TQT) studies can be reduced. In this article, we describe and discuss the Q&As that relate to clinical ECG evaluation. If supported by negative standardized nonclinical assays, Q&A 5.1 will obviate the need for a TQT study in the case that a >2-fold exposure margin vs high clinical scenario cannot be obtained. Q&A 6.1 addresses drugs that are poorly tolerated in healthy subjects and cannot be studied at high doses or in placebo-controlled studies; it therefore mainly applies to oncology drugs. It will enable sponsors to claim that a new drug has a "low likelihood of proarrhythmic effects" in the case that the mean corrected QT effect is <10 milliseconds at the time of market application. The E14 2015 revision allowed application of concentration-corrected QT analysis on data from routinely performed clinical pharmacology studies, for example, the first-in-human study and the proportion of dedicated TQT studies has since steadily decreased. It can be foreseen that the proposed new revision will further reduce the number of TQT studies. To achieve harmonization across regulatory regions, it seems important to reach consensus within the International Council on Harmonisation group on the new threshold proposed in 6.1. For this purpose, the Implementation Working Group has asked for public comments.


Infection of a ventriculoatrial shunt with phenotypically variable Staphylococcus epidermidis masquerading as polymicrobial bacteremia due to various coagulase-negative Staphylococci and Kocuria varians.
The diagnosis of bloodstream infection with coagulase-negative staphylococci is frequently based on the isolation of the same organism from more than one blood culture. Phenotypic variation is a common characteristic of pathogenic strains of Staphylococcus epidermidis which may affect species identification by the microbiology laboratory. We describe a patient with a new onset of nephritis and gram-positive bacteremia. Gram-positive cocci grew in multiple blood cultures and were identified by the Vitek 2 system as Kocuria varians, Staphylococcus hyicus, and S. epidermidis. Bacterial isolates grew on blood agar and Congo red agar plates as two distinct morphotypes and exhibited phenotypic variation. Neither morphotype could be identified by the API-Staph assay. Cellular fatty acid analysis identified one of the morphotypes as S. epidermidis but could not identify the other morphotype. All isolates were found to be identical by pulsed-field gel electrophoresis, and both colonial morphotypes were identified as S. epidermidis by 16S ribosomal gene sequencing. Phenotypic variation of S. epidermidis may affect identification to the species level by phenotype-based identification systems. Caution should be exercised when differentiating between true infection and contamination based on strain identification.


A cysteine-based molecular code informs collagen C-propeptide assembly.
Fundamental questions regarding collagen biosynthesis, especially with respect to the molecular origins of homotrimeric versus heterotrimeric assembly, remain unanswered. Here, we demonstrate that the presence or absence of a single cysteine in type-I collagen's C-propeptide domain is a key factor governing the ability of a given collagen polypeptide to stably homotrimerize. We also identify a critical role for Ca2+ in non-covalent collagen C-propeptide trimerization, thereby priming the protein for disulfide-mediated covalent immortalization. The resulting cysteine-based code for stable assembly provides a molecular model that can be used to predict, a priori, the identity of not just collagen homotrimers, but also naturally occurring 2:1 and 1:1:1 heterotrimers. Moreover, the code applies across all of the sequence-diverse fibrillar collagens. These results provide new insight into how evolution leverages disulfide networks to fine-tune protein assembly, and will inform the ongoing development of designer proteins that assemble into specific oligomeric forms.


Differential roles of JIP scaffold proteins in the modulation of amyloid precursor protein metabolism.
We previously found that the JNK-interacting proteins JIP1b and JIP2 associate with the cytoplasmic domain of the Alzheimer's amyloid precursor protein (APP) (Taru, H., Iijima, K., Hase, M., Kirino, Y., Yagi, Y., and Suzuki, T. (2002) J. Biol. Chem. 277, 20070-20078). This interaction involves the carboxyl-terminal phosphotyrosine interaction (PI) domain of JIP1b or JIP2 and the GYENPTY motif in the APP cytoplasmic domain. The expression of JIP1b stabilizes immature APP and suppresses the production of a secreted large extracellular amino-terminal domain of APP, the generation of a cleaved intracellular carboxyl-terminal fragment of APP, and the secretion of beta-amyloid 40 and 42. Deletion of the PI domain or alteration of PI amino acid residues prevents JIP1b from interacting with APP and affecting its metabolism, but deletion of the JNK-binding domain of JIP1b has no effect. JIP2, a weaker APP-binding protein, does not influence the processing of APP, although it is known that both JIP1b and JIP2 equally regulate the JNK signaling cascade. The present results suggest that JIP1b can directly modulate APP metabolism by interacting with the APP cytoplasmic domain, independent of its regulation of the JNK signaling cascade.


Correction to: A framework of genetic algorithm-based CNN on multi-access edge computing for automated detection of COVID-19.
[This corrects the article DOI: 10.1007/s11227-021-04222-4.].


Maternal prolactin secretion is phasic during induced term and post-term labor.
We hypothesized that regimens of labor induction do not alter the biphasic secretion of maternal prolactin (PRL) seen during spontaneous labor. Serial blood samples drawn from 12 women before, during, and after induced labor were assayed for PRL and hCG and compared with cervical dilatation and uterine contraction frequency (UCF). Induction methods were cervical ripening with dinoprostone gel (Prepidil) followed by oxytocin infusion (n = 1), amniotomy followed by oxytocin (n = 4), oxytocin followed by amniotomy (n = 3), amniotomy only (n = 2), and oxytocin only (n = 2). Regardless of the induction method, PRL decreased with advancing cervical dilatation during the first stage of labor and reached a nadir at full dilatation. Prolactin levels then increased rapidly during the second stage, correlating significantly with the increase in UCF, and peaked at 1 hour postpartum before decreasing. Levels of hCG increased during labor and peaked just before or at delivery before rapidly decreasing. The biphasic secretion of maternal PRL is a fundamental characteristic of active term labor and occurs regardless of the method used to induce labor.


Relationship of blood heavy metals and osteoporosis among the middle-aged and elderly adults: A secondary analysis from NHANES 2013 to 2014 and 2017 to 2018.
This study aimed to assess the relationship between blood heavy metals and a higher prevalence of osteoporosis in middle-aged and elderly US adults using the National Health and Nutritional Examination Surveys (NHANES). The secondary data analysis was performed using the data of NHANES 2013-2014 and 2017-2018. We used the information, including physical examination, laboratory tests, questionnaires, and interviews, provided by participants in NHANES. Logistic regression and weighted quantile sum (WQS) regression models were used to explore the relationships between levels of blood heavy metals and a higher prevalence of osteoporosis. A total of 1,777 middle-aged and elderly participants were analyzed in this study, comprising 115 participants with osteoporosis and 1,662 without osteoporosis. Adjusted model 1 showed a significant positive relationship between cadmium (Cd) levels and a higher prevalence of osteoporosis (quartile 2, OR = 7.62; 95% CI, 2.01-29.03; p = 0.003; quartile 3, OR = 12.38; 95% CI, 3.88-39.60; p < 0.001; and quartile 4, OR = 15.64; 95% CI, 3.22-76.08; p = 0.001). The fourth quartile of selenium (Se) level (OR = 0.34; 95% CI, 0.14-0.39; p < 0.001) led to a lower prevalence of osteoporosis and exerted a protective effect on model 1. Other models produced similar results to those of model 1. A subgroup analysis showed that Cd levels were positively related to a higher prevalence of osteoporosis in all three models in women, while this relationship was not found in men. The fourth quartile of the Se level was related to a lower prevalence of osteoporosis in both male and female analyses. A significant positive relationship was found between the blood Cd level and a higher prevalence of osteoporosis in the non-smoking subgroup. Blood Se level showed a protective effect on the fourth quartile in both the smoking and non-smoking subgroups. Blood Cd level aggravated the prevalence of osteoporosis, while blood Se level could be a protective factor in osteoporosis among the US middle-aged and older populations.


Current drug development portfolio for antimalarial therapies.
In response to the emergence of parasite drug resistance to currently deployed antimalarials, the scientific community, in partnership with the pharmaceutical industry and public organizations, has fashioned an antimalarial drug development portfolio for the sustained development and registration of safe, effective and cheap antimalarial medicines. The management of this portfolio is being driven by MMV (Medicines for Malaria Venture), with a number of projects recently reaching the clinical end of this drug development pipeline.


Exercise training increases endothelial progenitor cells and decreases asymmetric dimethylarginine in peripheral arterial disease: a randomized controlled trial.
Supervised exercise training (SET) is recommended as initial treatment to improve walking capacity in peripheral arterial disease (PAD) patients with intermittent claudication. Various mechanisms by which SET yields beneficial effects are postulated, however data regarding its influence on angiogenesis are scarce. Thus, we designed a prospective randomized controlled trial to study the impact of SET on markers of angiogenesis and endothelial function in PAD. Forty PAD patients were randomized to SET on top of best medical treatment (SET+BMT) for 6 months versus best medical treatment (BMT) only. Endothelial progenitor cells (EPC) were assessed by whole-blood flow cytometry (co-expression of CD34+ CD133+ KDR+) and cell culture assays (endothelial cell-colony forming units, circulating angiogenic cells, migration assay) at baseline, 3, 6 and 12-months after inclusion. Changes of plasma levels of asymmetric dimethylarginine (ADMA), vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1) and maximum walking distance were determined. EPC - measured by flow cytometric and cell culture techniques - increased significantly upon training paralleled by a significant decrease of ADMA when compared to the BMT group (p<0.05). Six months after training cessation, the beneficial effect of SET on EPC diminished, but maximum walking distance was significantly improved compared to baseline and controls (p<0.05). No significant changes were observed for VEGF and SDF-1 plasma levels in time course. SET increases circulating EPC counts and decreases ADMA levels reflecting enhanced angiogenesis and improved endothelial function, which might contribute to cardiovascular risk reduction.