Modified Delphi Study on Nursing Practice and Science in Fetal Care.
To identify essential structures, processes, outcomes, and challenges of nursing practice in fetal care and to identify research priorities for nurses in fetal care. We used a modified Delphi method to achieve consensus. A secure online survey platform. The expert panel included nurses from the Fetal Therapy Nurse Network. In addition, a multidisciplinary research jury included members of the North American Fetal Therapy Network (NAFTNet). We collected data in three consecutive rounds with online questionnaires that were e-mailed to panelists. We used content analysis to generate statements from an initial round of open-ended questions. Statements met consensus if 75% of the panelists ranked it as greater than or equal to 6 on a 1-to-7 Likert scale. The 48 nurse panelists and 11 multidisciplinary jury members described a range of nursing processes. Consensus was reached on 96 statements related to the structure, processes, outcomes, and research priorities of nurses in fetal care. The participants agreed that an expert fetal care nursing team is necessary to provide care to women and families during fetal diagnosis and treatment. Ideally, these nurses should coordinate care and provide direct clinical care (e.g., patient counseling) in outpatient prenatal settings and inpatient settings when fetal surgery is involved. Nurses should be supported to take on leadership roles in program development, research, quality improvement, and professional development with relevant professional organizations.


Home death--the caregivers' experiences.
The objectives of this study were to evaluate caregivers' experiences concerning the care of a terminally ill loved one at home, and to compare the death experiences of caregivers with and without access to homecare programs. The primary caregivers of all the patients who died of cancer 6-18 months before the study period (1999-2001) in the Negev area were contacted. This group included 240 caregivers of patients who died in the home palliative care program and 404 caregivers of patients who died with no access to a home palliative care program. A total of 159 caregivers were interviewed, 76 from the home palliative program and 83 who had no access to a palliative care program. Death at home occurred for 80.3% of patients with access to homecare and 20.5% of those without access. Despite the fact that caring for a loved one at home was a greater financial and emotional burden, there was a greater overall satisfaction with the caring experience of those whose loved ones died at home and had access to the homecare program. Given appropriate professional support systems, home-based care at the end of life is preferable to most caregivers.


Antitumor activity of a novel STAT3 inhibitor and redox modulator in non-small cell lung cancer cells.
NSC-743380 is a novel STAT3 inhibitor that suppresses the growth of several NCI-60 cancer cell lines derived from different tissues and induces regression of xenograft tumors in vivo at various doses. To evaluate the antitumor activity of NSC-743380 in lung cancer cells, we analyzed the susceptibility of 50 NSCLC cell lines to this compound using cell viability assay. About 32% (16 of 50) of these cell lines were highly susceptible to this compound, with a 50% inhibitory concentration (IC₅₀) of < 1 μM. In mechanistic studies, the increased numbers of apoptotic cells as well as increased PARP cleavage showed that cytotoxic effects correlate with apoptosis induction. Treatment with NSC-743380 inhibited transcription factor STAT3 activation and induced ROS production in sensitive human lung cancer cell lines but not in resistant cells. Blocking ROS generation with the antioxidant NDGA dramatically abolished NSC-743380-induced growth suppression and apoptosis, but had minimal effect on NSC-743380-induced STAT3 inhibition, suggesting that STAT3 inhibition is not caused by ROS production. Interestingly, knockdown of STAT3 with use of shSTAT3 induced ROS generation and suppressed tumor cell growth. Moreover, scavenging ROS induced by STAT3 inhibition also diminished antitumor activity of STAT3 inhibition. In vivo administration of NSC-743380 suppressed tumor growth and p-STAT3 in lung tumors. Our results indicate that NSC-743380 is a potent anticancer agent for lung cancer and that its apoptotic effects in lung cancer cells are mediated by induction of ROS through STAT3 inhibition.


Pressure-strain loops unveil haemodynamics behind mechanical circulatory support systems.
Mechanical circulatory support (MCS) systems are increasingly employed in cardiogenic shock and advanced heart failure. A thorough understanding of the complex interactions occurring among heart, vasculature, and device is essential to optimize patient's management. The aim of this study is to explore non-invasive haemodynamic profiling of patients undergoing MCS based on pressure-strain (PS) analysis. Clinical and echocardiographic data from consecutive patients undergoing different MCS systems positioning/implantation admitted to the third level cardiological intensive care unit of Siena Hospital from August 2021 to November 2021 were retrospectively reviewed. Patients without a useful echocardiographic exam or without arterial blood pressure recording at the time of echocardiography were excluded. Myocardial work analysis was performed in the included patients. We reviewed 18 patients, of which nine were excluded. Included patients were three patients with intra-aortic balloon pump (IABP), two patients with durable left ventricular assist device (dLVAD), two patients with Impella®, one patient with extracorporeal membrane oxygenation (ECMO), and one patient with ECMO and IABP. Myocardial work analysis was feasible in each included patient. The use of IABP shifted the PS curve rightward and downward. Global work index (GWI) and global wasted work (GWW) decreased after IABP positioning, whereas global work efficiency (GWE) increased. The use of continuous-flow pumps, whether temporaneous (Impella®) or long term (dLVAD), induced a change in the PS loop morphology, with a shift towards a triangular shape. ECMO positioning alone resulted in a narrowing of the PS loop, with a decrease in GWI and GWE and an increase in GWW and mean arterial pressure. The combined used of IABP with ECMO widened the PS loop and improved GWI and GWE. PS loops analysis in patients undergoing MCS seems to be feasible and may unveil MCS-induced haemodynamic variations. Myocardial work could be used to monitor ventricular-arterial-device coupling and guide tailored MCS management.


The nerve growth factor receptor: a multicomponent system that mediates the actions of the neurotrophin family of proteins.
Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3) are members of a family of structurally related proteins termed neurotrophins that promote the growth and survival of neurons in the central and peripheral nervous systems. Each of these proteins bind to at least two membrane receptors. One is the low affinity nerve growth factor receptor (p75), which binds each member of the neurotrophin family. The other is one of a family of tyrosine kinase receptors--trkA binds only NGF, the related trkB receptor binds BDNF and NT-3, and trkC binds NT-3 alone. This article reviews kinetic and biochemical information on p75 and its relationship to the trk gene products.


Exercise-induced pneumomediastinum.
A sudden onset of chest pain, which often reflects a life-threatening disease, requires prompt diagnosis in the emergency department. A 12-year-old boy presented with sustained chest pain and dyspnea after diving into a swimming pool and was transferred to our emergency department. A chest examination noted a crunching and rasping sound at the precordium, synchronous with the heartbeat. Chest radiography showed lucent streaks and the mediastinal pleura at the left cardiac outline. Additionally, computed tomography showed massive pneumomediastinum surrounding the heart. Thus, he was diagnosed with spontaneous pneumomediastinum. Spontaneous pneumomediastinum should be considered in the differential diagnosis of chest pain. In addition to medical history-taking, careful physical examination, which can identify the characteristic finding of a friction sound synchronous with the heartbeat (Hamman's sound), will help in the immediate diagnosis of spontaneous pneumomediastinum.


Silent ischemia predicts infarction and death during 2 year follow-up of unstable angina.
Silent myocardial ischemia as detected on Holter electrocardiographic (ECG) monitoring is present in greater than 50% of patients with unstable angina despite intensive medical therapy. The presence and the extent of silent ischemia have been correlated with an increased risk of early (1 month) unfavorable outcome including myocardial infarction and need for coronary revascularization for persistent symptoms. Seventy patients with unstable angina who had undergone continuous ECG monitoring for silent ischemia were followed up for 2 years; 37 patients (Group I) had Holter ECG evidence of silent ischemia at bed rest in the coronary care unit during medical treatment with nitrates, beta-receptor blockers and calcium channel antagonists; the other 33 patients (Group II) had no ischemic ST segment changes (symptomatic or silent) on Holter monitoring. Over a 2 year follow-up period, myocardial infarction occurred in 10 patients in Group I (in 2 it was fatal) compared with one nonfatal infarction in Group II (p less than 0.01 by Kaplan-Meier analysis); revascularization with either coronary bypass surgery or angioplasty for symptomatic ischemia was performed in 11 Group I and 5 Group II patients (p less than 0.05). Multivariate Cox's hazard analysis demonstrated that the presence of silent ischemia was the best predictor of 2 year outcome. Therefore, persistent silent myocardial ischemia despite medical therapy in patients with unstable angina carries adverse prognostic implications that persist over a 2 year period.


Organometallic photonucleases: a novel class of DNA-cleaving agents.
The first demonstration of DNA cleavage by an organic radical generated via homolysis of a metal-alkyl bond in a Cp-metal complex is presented. Irradiation of CpW(CO)3CH3 (1.5 molecules/base pair) produced methyl radical, giving single-strand cleavage of pBR322 DNA. This process was inhibited by the general radical trap cysteine and by TEMPO, which traps carbon radicals but not oxygen-centered radicals.


Matrine alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial dysfunction and inflammation via SIRT3/OPA1 pathway.
Cisplatin is extensively used to treat malignancies. However, its clinical use is always limited due to the serious side effects, especially the nephrotoxicity. Matrine (MAT), a tetracyclic quinolizine alkaloid found in sophora genus, exerts multiple pharmacological roles, including anti-oxidative stress, anti-inflammation and anti-apoptosis, but the role of MAT on acute kidney injury (AKI) has not been evaluated. Here, we found that MAT potently inhibited cell injury induced by cisplatin in HK2 cells in vitro, which was associated with the inhibition of oxidative injury and NF-κB-mediated inflammation. Moreover, MAT treatment could activate the SIRT3/OPA1 axis and subsequently suppress the mitochondrial fragmentation and improve mitochondrial function. More importantly, SIRT3 knockdown suppressed the deacetylation of OPA1, which blocked the protective role of MAT on cisplatin-induced cell injury. In vivo, MAT treatment alleviated renal dysfunction, histological damage and inflammation induced by cisplatin in mice. Furthermore, consistent with the founding in vitro, MAT also activated SIRT3-mediated deacetylation of OPA1 and alleviated mitochondrial dysfunction in AKI mice. Our study proved that MAT protected against cisplatin-induced AKI by synergic anti-oxidative stress and anti-inflammation actions via SIRT3/OPA1-mediated improvement of mitochondrial function, suggesting that MAT may be a novel and effective strategy for AKI.


Bioequivalence evaluation of two brands of lisinopril tablets (Lisotec and Zestril) in healthy human volunteers.
The bioequivalence of two brands of lisinopril 20 mg tablets was demonstrated in 28 healthy human volunteers after a single oral dose in a randomized cross-over study, conducted at ACDIMA Center for Bioequivalence and Pharmaceutical Studies, Amman, Jordan. Reference (Zestril, AstraZeneca, UK) and test (Lisotec, Julphar, UAE) products were administered to fasting volunteers on 2 treatment days separated by a 2-week washout period; blood samples were collected at specified time intervals, and the plasma was separated and analysed for lisinopril using a validated LC-MS/MS method at ACDIMA Laboratory. The pharmacokinetic parameters AUC(0-t), AUC(0- proportional), C(MAX), T(MAX), T(1/2) and the elimination rate constant were determined from the plasma concentration-time profiles for both formulations and were compared statistically to evaluate bioequivalence between the two brands, using the statistical modules recommended by the FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetic profiles and that Julphar's Lisotec is bioequivalent to Zestril of AstraZeneca, UK.


Intensive, Manual-based Intervention for Pediatric Feeding Disorders: Results From a Randomized Pilot Trial.
The aim of this pilot study was to investigate feasibility and preliminary efficacy of an intensive, manual-based behavioral feeding intervention for children with chronic food refusal and dependence on enteral feeding or oral nutritional formula supplementation. Twenty children ages 13 to 72 months (12 boys and 8 girls) meeting criteria for avoidant/restrictive food intake disorder were randomly assigned to receive treatment for 5 consecutive days in a day treatment program (n = 10) or waitlist (n = 10). A team of trained therapists implemented treatment under the guidance of a multidisciplinary team. Parent training was delivered to support generalization of treatment gains. We tracked parental attrition and attendance, as well as therapist fidelity. Primary outcome measures were bite acceptance, disruptions, and grams consumed during meals. Caregivers reported high satisfaction and acceptability of the intervention. Three participants (1 intervention; 2 waitlist) dropped out of the study before endpoint. Of the expected 140 treatment meals for the intervention group, 137 (97.8%) were actually attended. The intervention group showed significantly greater improvements (P < 0.05) on all primary outcome measures (d = 1.03-2.11) compared with waitlist (d = -1.13-0.24). A 1-month follow-up suggested stability in treatment gains. Results from this pilot study corroborate evidence from single-subject and nonrandomized studies on the positive effects of behavioral intervention. Findings support the feasibility and preliminary efficacy of this manual-based approach to intervention. These results warrant a large-scale randomized trial to test the safety and efficacy of this intervention.


Administering Parenteral Nutrition in the Neonatal Intensive Care Unit: Logistics, Existing Challenges, and a Few Conundrums.
Use of parenteral nutrition (PN) in the neonatal intensive care unit (NICU) requires evaluating the need for central venous catheters, potential drug incompatibilities, unintentional exposures, and suboptimal energy and nutrient intake during the transition to full enteral nutrition. Risks of photooxidation reactions in PN components, refeeding syndrome, and excess early amino acid intake should prompt the reevaluation of routine practices. The goal of this paper is to review the practicalities, challenges, and conundrums of administering PN in the NICU.


[Mental Health Residents: Knowledge on prices and availability of drugs they prescribe].
The cost and availability of psychiatric drugs is an important aspect for patient adherence to treatment. Therefore, Psychiatry Residents were interviewed about what drugs were most usually prescribed by them, their estimated price, free availability in their hospitals and access to literature about drug costs in the services. During the VI Congress of Residents in Mental Health of the Metropolitan Area of Buenos Aires, a structured interview was administered to Psychiatry Residents. A form was used containing open and close questions. The questionnaire was not self administered. Sixty eight Psychiatry Residents of fourteen Public Hospitals of the Capital and Province of Buenos Aires were interviewed. The drugs most frequently chosen in each pharmacological group were: haloperidol 24 percent, fluoxetine 43 per cent, clonazepan 39 percent and carbamazepine 34 per cent 82 percent of the questions regarding the knowledge about prescribed drug costs were incorrect. 57 per cent of the drugs chosen were not available at the Hospitals whereas 69 per cent of the drugs that were never selected were available. In this descriptive study, we found an important lack of knowledge on drug costs, little access to literature about this subject and availability of drugs not adequated to the Residents choices.


Subcellular localization of epidermal growth factor in human submandibular gland.
Epidermal growth factor in human submandibular gland was localized at the subcellular level by means of an immunogold staining method. Labelling was observed in serous acini and ducts. In the acini, gold particles were found within secretory granules, indicating that the growth factor is released into the saliva through granule exocytosis. In the ductal system, the most intense reactivity was revealed in the principal cells of striated ducts. In these cells, an abundant population of small cytoplasmic vesicles was specifically stained. Immunoreactive vesicles were found both apically and basally, suggesting that ductal cells can release their products not only into the saliva but also into the interstitium.


Epidermal growth factor activates calcium channels by phospholipase A2/5-lipoxygenase-mediated leukotriene C4 production.
Epidermal growth factor (EGF) induces a Ca2+ influx in many cell types, but the underlying mechanisms are so far unresolved. We report that: EGF-induced Ca2+ channel activity is eliminated by lipoxygenase inhibition and is mimicked by artificial induction of lipoxygenase activity; addition of leukotriene C4 can fully mimic EGF in its ability to activate Ca2+ channels; and EGF induces a rapid accumulation of intracellular leukotriene C4. In addition, we show that EGF-induced, Ca(2+)-dependent membrane hyperpolarization and junB proto-oncogene expression are dependent on lipoxygenase activity, whereas EGF-induced cytoplasmic alkalinization is not. We conclude that PLA2/5-lipoxygenase-mediated leukotriene C4 production constitutes a novel and specific signal transduction pathway in growth factor action.


Predictors of anxiety and depression in Egyptian thalassemic patients: a single center study.
Thalassemic patients are vulnerable to emotional and behavioral problems. Each patient age group exhibits problems unique to that stage of development, and although up to 80 % of thalassemic patients are likely to have psychological disorders, e.g., anxiety and depression, predictors of these disorders remain poorly understood. The present study was designed to assess the prevalence of anxiety and depression in a sample of Egyptian thalassemic patients and to identify predictors of these psychiatric disorders. A case-control study was conducted in 218 thalassemic patients, with 244 healthy subjects as a control. All patients and control subjects were subjected to thorough evaluation of medical history and clinical examination, and examined by a psychiatrist using the clinician version of the structured clinical interview for DSM-IV (SCID-CV), hospital anxiety and depression scale and Coopersmith self-esteem inventory. Abnormal and borderline anxieties were reported by 36.7 and 20.6 % of thalassemic patients, respectively, while abnormal and borderline depressions were reported by 32.1 and 16.1 % of patients, respectively. Hospitalization, low self-esteem, diabetes mellitus and heart failure were independent predictors of anxiety. The independent predictors of depression were heart failure, hospitalization, diabetes mellitus, short stature and delayed puberty. Thalassemic patients were more vulnerable to anxiety and depression, indicating that screening and management for such psychiatric disorders should be considered in treating all such patients.


Commentary: U.S. mortality, geography, and the anti-social determinants of health.
Drug-related overdoses appear to be a major factor behind an historic pause or even a reversal in the predominant downward trend over time in U.S. mortality rates, a departure that is especially evident among non-Hispanic white females of middle age. The new geography of accidental poisoning deaths and their covariates suggests that we should reassess traditional policies and perspectives in order to combat this threat to public health.


The mitochondrial cascade hypothesis for Parkinson's disease.
During the past decades, we have witnessed significant advances in our understanding of the molecular etiology of Parkinson's disease (PD). The unearthing of the causative genes for hereditary PD accelerated not only the studies of the molecular mechanisms underlying this pathology, but also set mitochondria at the center of PD pathology. In this review we revisit mitochondrial key role and propose a hypothesis for PD, that allows the unification of both sporadic and familial PD forms. In light of this we also discuss new promising disease-modified therapies.


Changes in circulating sirtuin 1 after bariatric surgery.
Obesity is associated with chronic inflammation and oxidative stress. Weight loss after bariatric surgery improves the inflammatory state and risk of cardiovascular disease. Improvement in metabolic dysfunction might be associated with changes in the activity of sirtuin 1 (SIRT1) and we aimed to investigate the effect of bariatric surgery on its circulating levels. This is a sub-study of a prospective cohort study, including 110 subjects with morbid obesity. The surgical procedure was either laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Blood was sampled at inclusion and six and 12 months after surgery. SIRT1 was measured in EDTA plasma with an enzyme-linked immunosorbent assay. The mean age in the population was 43 years, 80% were women and mean body mass index (BMI) was 38.8 kg/m2. RYGB and SG were performed in 89 and 21 subjects, respectively. SIRT1 concentration was significantly reduced from baseline to six and 12 months after surgery, with mean values (SD) 156.8 (82.6), 119.5 (65.6) and 94.9 (45.6) ng/mL, respectively, (p ≤ 0.002, all), accompanied by significant reductions in C-reactive protein (CRP), BMI and triglycerides from inclusion (p < 0.001, all). Type of surgery did not differently modify SIRT1 levels (p = 0.09). CRP and triglycerides were both positively predictive of SIRT1 levels (p ≤ 0.001, both). SIRT1 concentration was significantly lower six and 12 months after bariatric surgery. CRP and triglycerides independently predicted SIRT1 levels, suggesting that reduction in SIRT1 levels might not intrinsically be related to weight reduction, but to improvement in metaflammation.


A Tissue Engineering Approach to Metastatic Colon Cancer.
Colon cancer remains the third most common cause of cancer in the US, and the third most common cause of cancer death. Worldwide, colon cancer is the second most common cause of cancer and cancer deaths. At least 25% of patients still present with metastatic disease, and at least 25-30% will develop metastatic colon cancer in the course of their disease. While chemotherapy and surgery remain the mainstay of treatment, understanding the fundamental cellular niche and mechanical properties that result in metastases would facilitate both prevention and cure. Advances in biomaterials, novel 3D primary human cells, modelling using microfluidics and the ability to alter the physical environment, now offers a unique opportunity to develop and test impactful treatment.


Cell-free foetal DNA in maternal plasma does not appear to be derived from the rich pool of cell-free foetal DNA in amniotic fluid.
Large quantities of cell-free foetal DNA have been detected in amniotic fluid, and it has been proposed that this material may contribute to the pool of cell-free foetal DNA in maternal plasma. Twelve maternal blood samples were obtained from pregnant women about to undergo an amniocentesis. Cell-free DNA was extracted from the maternal plasma samples and the matched amniotic fluid samples. The amount of cell-free foetal DNA was quantified by real-time PCR assays for the SRY and RHD genes. Amniotic fluid was found to contain vast quantities of cell-free DNA (median concentration = 3,978 copies/ml amniotic fluid). The concentration of cell-free foetal DNA in maternal plasma was much lower (median concentration = 96.6 copies/ml maternal plasma). No significant correlation could, however, be determined between these two pools of cell-free foetal DNA. Our data confirm that amniotic fluid contains prodigious quantities of cell-free foetal DNA, but as no relationship exists between this material and that in the maternal circulation, it is unlikely that the amnion contributes to the presence of cell-free foetal DNA in maternal plasma.


Synthesis of pregnenoic acid derivatives possessing structural elements of prostaglandins.
Pregneoic acid derivative V in which the character of functional groups and distances between them (expressed in terms of C-C bonds) resemble those occurring in prostaglandins has been synthetised. 3beta-Hydroxyandrost-5-en-17-one acetate VII was converted to ethyl 3beta-acetoxypregn-5-en-21-oate XIIa via a Reformatsky reaction followed by dehydration of adduct VIIIa and selective hydrogenation of the diene X. Compound XIIa was then transformed into trienone XIII by oxidation of the 3beta-hydroxy-5-ene XIIc with DDQ. The trienone XIII was subsequently epoxidised with alkaline hydrogen peroxide and m-chloroperbenzoic acid to give diepoxide XV which was reduced with aluminum amalgam to the final product V.


Purification of equine IgG3 by lectin affinity and an interaction analysis via microscale thermophoresis.
The availability of purified antibodies is a prerequisite for many applications and the appropriate choice(s) for antibody-purification is crucial. Numerous methods have been developed for the purification of antibodies from different sources with affinity chromatography-based methods being the most extensively utilized. These methods are based on high specificity, easy reversibility and biological interactions between two molecules (e.g., between receptor and ligand or antibody and antigen). However, no simple techniques have yet been described to characterize and purify subclasses of immunoglobulins (Ig) from some animals of biotechnology importance such as equines, which are frequently used to produce biotherapeutic antibodies. The sera of these animals present a large number of Ig classes that have a greater complexity than other animals. The implementation of an effective protocol to purify the desired antibody class/subclasses requires meticulous planning to achieve yields at a high purity. The IgG3 subclass of equine-Ig has recently been used as antigen in a new diagnostic test for allergic responses to horse sera-based therapies. Here, we defined a simple method using Jacalin lectin immobilized on Sepharose beads to prepare highly pure equine IgG3 antibodies with a determination of the affinity constants for Jacalin lectin and horse IgG3.


Dissecting the catalytic triad of a serine protease.
Serine proteases are present in virtually all organisms and function both inside and outside the cell; they exist as two families, the 'trypsin-like' and the 'subtilisin-like', that have independently evolved a similar catalytic device characterized by the Ser, His, Asp triad, an oxyanion binding site, and possibly other determinants that stabilize the transition state (Fig. 1). For Bacillus amyloliquefaciens subtilisin, these functional elements impart a total rate enhancement of at least 10(9) to 10(10) times the non-enzymatic hydrolysis of amide bonds. We have examined the catalytic importance and interplay between residues within the catalytic triad by individual or multiple replacement with alanine(s), using site-directed mutagenesis of the cloned B. amyloliquefaciens subtilisin gene. Alanine substitutions were chosen to minimize unfavourable steric contacts and to avoid imposing new charge interactions or hydrogen bonds from the substituted side chains. In contrast to the effect of mutations in residues involved in substrate binding, the mutations in the catalytic triad greatly reduce the turnover number and cause only minor effects on the Michaelis constant. Kinetic analyses of the multiple mutants demonstrate that the residues within the triad interact synergistically to accelerate amide bond hydrolysis by a factor of approximately 2 X 10(6).


Cognitive functions in severe congestive heart failure before and after an exercise training program.
Congestive heart failure is associated with cognitive impairment, particularly of attentional skills. We assessed, in a hypothesis-generating study, the effect of an exercise training program on cognitive functions among patients with severe congestive heart failure. Patients with severe congestive heart failure (n=20; New York Heart Association functional class III; left ventricular ejection fraction < or =35%) were evaluated before and following a standardized and supervised exercise training program (x2/week for 18 weeks; exercise group), while 5 additional patients did not undergo an exercise training program (control group). A battery of cognitive tests was used to assess cognitive functions. Physical performance was assessed by the 6-min walk test and the modified Bruce exercise test, cardiac index and systemic vascular resistance using thoracic electrical bioimpedance, and cerebral vasomotor reactivity to hypercapnia by means of the breath-holding index using transcranial Doppler. Time of completion of the trail making A (105+/-116 to 75+/-52; p=0.02) and B (169+/-100 to 119+/-65; p=0.002) tests, and of the Stroop part A (40+/-13 to 37+/-13; p=0.04) was shorter in patients completing the exercise training program, but not in control patients, while the other neuropsychological measures remained unchanged in both groups. Cerebral vasomotor reactivity to hypercapnia remained diminished (breath-holding index 0.64+/-0.27 vs. 0.68+/-0.37) despite significant improvements in exercise capacity (6-min walk test 308+/-87 to 423+/-91 m, p<0.001; modified Bruce exercise test 5.6+/-3.8 to 9.8+/-3.4 min, p<0.001). Patients with severe congestive heart failure undergoing an exercise training program improve in some measures of cognitive functions that are limited to general attention and psychomotor speed. Based on these preliminary findings, further evaluations are designed within the framework of a larger controlled clinical trial.


Why nobody discusses the adverse psychiatric effects of chloroquine in case it might become the future treatment against COVID-19?
Chloroquine represents at least a basic prototype antimalarial drug, widely applied in several branches of medicine and also recently against a new zoonotic origin coronavirus. At present, there is little awareness of chloroquine's psychiatric side effects, which appear to be overlooked by the Scientific Committee, although they may manifest in a worryingly wide range of symptoms. This is likely to interfere with the course of specifically long-term (high-dose) COVID-19 treatment in some aggravated forms (25% of coronavirus patients were still carrying the virus 6 days after taking hydroxychloroquine). Besides, symptoms of infection, adverse effects from the 600 mg hydroxychloroquine daily plus azithromycin, including insomnia, headaches, skin reactions, digestive upset with nausea, vomiting, and diarrhea, blurred vision, and local pain, may lead to increased anxiety and mental distress.


Developing a Clinico-Molecular Test for Individualized Treatment of Ovarian Cancer: The interplay of Precision Medicine Informatics with Clinical and Health Economics Dimensions.
We report recent progress in the development of a precision test for individualized use of the VEGF-A targeting drug bevacizumab for treating ovarian cancer. We discuss the discovery model stage (i.e., past feasibility modeling and before conversion to the production test). Main results: (a) Informatics modeling plays a critical role in supporting driving clinical and health economic requirements. (b) The novel computational models support the creation of a precision test with sufficient predictivity to reduce healthcare system costs up to $30 billion over 10 years, and make the use of bevacizumab affordable without loss of length or quality of life.


Prognostic value of right ventricular two-dimensional global strain in patients referred for cardiac surgery.
Right ventricular (RV) function is a strong predictor of patient outcome after cardiac surgery. Limited studies have compared the predictive value of RV global longitudinal strain (RV-GLS) with tricuspid annular plane systolic excursion (TAPSE) and RV fractional area change (RVFAC) in this setting. The study included 250 patients (66 ± 13 years old, LVEF = 52% ± 12%) referred for cardiac surgery (EuroSCORE-II = 4.8% ± 8.0%). RV function before surgery was assessed by RV-GLS by using speckle-tracking analysis (3-segment from the RV free wall), RVFAC and TAPSE was compared with postoperative outcome defined by 1-month mortality. Overall, 19 patients (7.6%) had RVFAC < 35%, 34 (13.6%) had TAPSE < 16 mm, and 99 (39.6%) had impaired RV-GLS > -21% (35% with normal RVFAC ≥ 35%). Postoperative death (n = 25) was higher in patients with abnormal RV-GLS > -21% (22% vs 3%; P < .0001), TAPSE < 16 mm (24% vs 8%; P = .007), and RVFAC < 35% (32% vs 9%; P = .001). Mortality was 3% in patients with preserved RV-GLS. In patients with preserved RVFAC ≥ 35% but abnormal RV-GLS, mortality was similar to that of those with RVFAC < 35% (20% vs 32%; P = .12). Among RV systolic indexes, only RV-GLS was associated with patient outcome by multivariate analysis adjusted to EuroSCORE-II and cardiopulmonary bypass duration. RV-GLS is a sensitive marker of RV dysfunction and correlates with postoperative mortality.


Phenylthiocarbamide (PTC) taste sensitivity in selected populations of the Isle of Man and Cumbria.
PTC taste thresholds were determined using a modification of the Harris and Kalmus sorting technique for 854 Cumbrian schoolchildren and 699 individuals from the Isle of Man. A non-taster frequency of 19.7 percent was observed in the Cumbrian sample compared with a frequency of 27.8 per cent in that from the Isle of Man. Analysis of taste threshold distributions revealed significant variability, both within and between these two samples. Evidence of significant regional heterogeneity was detected in Cumbria but not in the Isle of Man. Finally, these two series were compared with data from neighbouring regions of the British Isles and Scandinavian populations.


In vivo animation of auditory-language-induced gamma-oscillations in children with intractable focal epilepsy.
We determined if high-frequency gamma-oscillations (50- to 150-Hz) were induced by simple auditory communication over the language network areas in children with focal epilepsy. Four children (aged 7, 9, 10 and 16 years) with intractable left-hemispheric focal epilepsy underwent extraoperative electrocorticography (ECoG) as well as language mapping using neurostimulation and auditory-language-induced gamma-oscillations on ECoG. The audible communication was recorded concurrently and integrated with ECoG recording to allow for accurate time lock on ECoG analysis. In three children, who successfully completed the auditory-language task, high-frequency gamma-augmentation sequentially involved: i) the posterior superior temporal gyrus when listening to the question, ii) the posterior lateral temporal region and the posterior frontal region in the time interval between question completion and the patient's vocalization, and iii) the pre- and post-central gyri immediately preceding and during the patient's vocalization. The youngest child, with attention deficits, failed to cooperate during the auditory-language task, and high-frequency gamma-augmentation was noted only in the posterior superior temporal gyrus when audible questions were given. The size of language areas suggested by statistically significant high-frequency gamma-augmentation was larger than that defined by neurostimulation. The present method can provide in vivo imaging of electrophysiological activities over the language network areas during language processes. Further studies are warranted to determine whether recording of language-induced gamma-oscillations can supplement language mapping using neurostimulation in presurgical evaluation of children with focal epilepsy.


Phase-I trial of 4-demethoxydaunorubicin in acute leukaemias.
Eleven patients with heavily pretreated acute leukaemia were treated with 4-demethoxydaunorubicin. Dosages were escalated from 7 mg/m2/d to 15 mg/m2/d for 3 consecutive days. One patient achieved a partial remission and antitumor activity was seen in most other patients. Stomatitis was dose-limiting at 15 mg/m2. Phase II trials are warranted and we propose a schedule of 12 mg/m2/d for 3 consecutive days.


Angiographic, operative, and histologic findings after embolization of craniofacial angiomas.
After pre- or intraoperative angiography and Gelfoam embolization in patients with deforming vascular malformations in the craniofacial region, the angiographic findings and the results of embolization were controlled by operation and histology. In arteriovenous hemangiomas the disfigurations of the craniofacial region originate from the shunt vessels themselves, in capillary hemangiomas exclusively from neoplastic, pathologically dilated and convoluted veins which could be demonstrated only by percutaneous punctures. Lymphatic hemangiomas also could be radiologically shown only after direct punctures and without any feeding or draining vessels. During operation vast necrosis of the fatty tissue in the region of embolization and massive phlebolithiasis in the draining veins were found. Histologically, arterial obliterations could be shown in the former shunt area. The reconstructive operations could be done in bloodless surgical regions and always showed good cosmetic results, which were regarded as constant because of the embolization of the shunt area.


Geriatric neurosurgery.
The "elderly," aged 65 and over, represent a rapidly growing proportion of the American population. Their percentage among the neurosurgical admissions at Henry Ford Hospital increased from 14.4% in 1978 to 22.4% in 1984. Occlusive cerebrovascular disease was the most frequent pathology seen, representing 40% of the population studied. Spinal degenerative myeloradiculopathy represented 14%, tumors 7%, trauma 5.4%, and intracranial hematomas represented 4% of the population. Vascular anomalies represented 3.3% of the patient group, with almost the same number of patients presenting with intracranial hemorrhage. The percentage of patients who were surgically treated was 58%. Mortality was 6.5%, with only 2.5% of the patients requiring special-care-facility placement following release from the hospital. An older group, aged 85 and over, represented 4% of our geriatric population. In the age 85+ group, occlusive cerebrovascular disease was the leading pathology (18% of the population), followed by subdural hematomas (15%), spinal degenerative myeloradiculopathy (11.6%), trigeminal neuralgias (7%), hydrocephalus (4%), vascular anomalies (4%), and tumors (4%). Patients in the age 85+ group were surgically treated in 41% of the cases, with a mortality of less than 10%. In the past, older age (greater than 65 years) was believed to be a contraindication to surgery, however, the increased life expectancy, number, and health of this population made reconsideration of this arbitrary age limit essential. We feel that age alone is not a barrier to proper neurosurgical treatment when other risk factors are adequately managed.


Growth of diploid, Epstein-Barr virus-carrying human lymphoblastoid cell lines heterotransplanted into nude mice under immunologically privileged conditions.
Human Epstein-Barr virus-carrying lymphoid cell lines which have been classified on the basis of studies on clonality and morphological, chromosomal and functional parameters as lymphoblastoid cell lines (LCL) of presumed non-neoplastic origin were inoculated intracerebrally into nude mice. All eighteen of them grew, killing the host mice within 7 to 25 days, except for 2 which grew more slowly. At autopsy, the brain of the nudes was found to be invaded by infiltrating lymphomas. Sixteen of these lymphomas, when recultured in vitro, gave rise to cell lines with growth properties and morphology indistinguishable from those of the inoculated LCL. Chromosomal examinations showed that 3/7 cell lines injected, which grew as lymphomas in the brain, were still normal diploid on reexplantation whereas the remaining four had become aneuploid. Four lines derived from intracerebral lymphomas (2 diploid, 1 aneuploid and 1 untested) were inoculated subcutaneously into adult nude mice. None of them grew. When the corresponding four original LCL lines were inoculated subcutaneously into newborn nude mice, they grew rapidly, but failed to do so in newborn normal mice or intracerebrally in adult normal mice. One such line, U-1450, was treated with anti-lymphocyte serum (ALS). Small nodules developed at the site of inoculation. From one nodule a cell line was cultured, 1450 ALSAD. It was morphologically indistinguishable from the line of origin. The lines obtained from nude mice inoculated with polyclonal LCL seem to have a restricted clonal representation, but were not monoclonal, as evidenced by analyses of their pattern of immunoglobulin synthesis.


Evaluating the presence of Mycoplasma hyorhinis, Fusobacterium nucleatum, and Helicobacter pylori in biopsies of patients with gastric cancer.
Gastric cancer is the third leading cause of cancer-related deaths worldwide and has been associated with infections that may promote tumour progression. Accordingly, we analysed the presence of Mollicutes, Mycoplasma hyorhinis, Fusobacterium nucleatum and Helicobacter pylori in gastric cancer tissues and evaluated their correlation with clinicopathological factors. Using a commercial kit, DNA were extracted from 120 gastric samples embedded in paraffin: 80 from patients with gastric cancer and 40 from cancer free patients, dating from 2006 to 2016. Mollicutes and H. pylori were detected by PCR; F. nucleatum and M. hyorhinis were detected by qPCR, together with immunohistochemistry for the latter bacteria. Mollicutes were detected in the case and control groups (12% and 2.5%) and correlated with the papillary histologic pattern (P = 0.003), likely due to cell transformation promoted by Mollicutes. M. hyorhinis was detected in the case and control group but was not considered a cancer risk factor. H. pylori was detected at higher loads in the case compared to the control group (8% and 22%, P = 0.008) and correlated with metastasis (P = 0.024), lymphatic invasion (P = 0.033), tumour of diffused type (P = 0.028), and histopathological grading G1/G2 (P = 0.008). F. nucleatum was the most abundant bacteria in the case group, but was also detected in the control group (26% and 2.5%). It increased the cancer risk factor (P = 0.045, OR = 10.562, CI95% = 1.057-105.521), and correlated with old age (P = 0.030) and tumour size (P = 0.053). Bacterial abundance was significantly different between groups (P = 0.001). Our findings could improve the control and promote our understanding of opportunistic bacteria and their relevance to malignant phenotypes.


Microscopic localization of mercury-selenium interaction products in liver, kidney, lung and brain of Mediterranean striped dolphins (Stenella Coeruleoalba) by silver enhancement kit.
Microscopic observation, using physical development of silver, was carried out to localize the mercury-selenium interaction products in the organs of Mediterranean striped dolphins. The silver-metal reaction products were located mainly in hepatocytes and macrophages for liver, in proximal tubules for kidney. They were less abundant in lung than in liver and kidney. The result of semi-quantitative histochemistry tests showed that silver staining deposits were more abundant at relatively high metal concentrations than low metal contents, but independent of the metal contents. Comparisons with the most concentrated metal contents suggested that there might be a new complex of mercury and selenium, which could not be stainable by physical silver development.


Corrigendum to "Minimizing Glucose Excursions (GEM) With Continuous Glucose Monitoring in Type 2 Diabetes: A Randomized Clinical Trial".
[This corrects the article DOI: 10.1210/jendso/bvaa118.].


Variations in diurnal rhythm of leucocytes in white Leghorn chicks of two different ages.
Blood leucocytes in 4-week-old and 5-7-month-old White Leghorn cockerels show a diurnal rhythm. This diurnal rhythm has been observed to vary with age. The variations observed may be due to the different hormonal status of the two groups of birds. The effects of drugs at different phases of the diurnal rhythm will be of great interest in medical practice and should be considered during clinical treatment.


Looking backwards: a birthday card for the double helix.
This 'birthday' paper outlines very briefly the history of the discovery of the DNA double helix, the way it was received and how it was confirmed. The paper also discusses why, at that time, we foresaw so little of the rapid progress produced by the techniques of recombinant DNA. The key feature of the nucleic acids--discovered by Jim Watson--is their ability to form specific base pairs.


West Nile virus encephalitis with myositis and orchitis.
This report documents the hospital course and autopsy findings of a 43-year-old man with a renal allograft who died of West Nile virus (WNV) encephalitis. Central nervous system (CNS) findings were those of severe necrotizing and hemorrhagic encephalitis affecting gray matter regions limited to the diencepahlon, rhombencephalon, spinal cord, and limbic system. The bilateral process exhibited preferential involvement of motor neurons. Brain imaging obtained 6 days before death demonstrated an unusual pattern of involvement corresponding with the autopsy findings, confirming that imaging may be a specific diagnostic guide in WNV encephalitis. Extra-CNS findings include myositis with T-lymphocyte infiltration of nerve fibers, suggesting that the virus may reach the CNS via peripheral nerves. Orchitis with dense T-lymphocyte infiltration and syncytial cell formation thought to be due to WNV were also noted.


Evaluation of pleural lesions after pleurodesis with OK-432 by fluorodeoxyglucose-positron emission tomography/CT.
This study aimed to determine changes in FDG-PET/CT after pleurodesis with OK-432 and to investigate differences in the changes between non-malignant and malignant lesions. Study participants were 17 patients with a history of malignant chest disease who underwent FDG-PET/CT after pleurodesis using OK-432 and in whom pleural lesions were determined to be non-malignant (n = 8) or malignant (n = 9). FDG uptake (SUVmax) was counted on all pleural lesions. CT findings (CT attenuation, shape) of pleural lesions with increased FDG uptake were evaluated. The number of patients with increased FDG uptake in the pleura differed significantly between the non-malignant group (3/8) and malignant group (9/9) (p < 0.01) The mean SUVmax of non-malignant lesions with increased FDG uptake was 2.3 ± 0.7 vs. 6.2 ± 2.2 in malignant lesions, for a significant difference (p < 0.01). The mean CT attenuation of lesions was 36 ± 11 HU in the non-malignant group and 34 ± 14 HU in the malignant group, a difference that was not significant (p = 0.91). There was a significant difference in nodular and linear shapes between non-malignant and malignant lesions (p < 0.01). All non-malignant lesions were linear. Positive FDG uptake was shown in non-malignant pleural lesions as well as in malignant pleural lesions after pleurodesis using OK-432. Combined analysis of FDG accumulation and CT morphology is helpful to distinguish between benign and malignant lesions.


Faster and more diverse de novo molecular optimization with double-loop reinforcement learning using augmented SMILES.
Using generative deep learning models and reinforcement learning together can effectively generate new molecules with desired properties. By employing a multi-objective scoring function, thousands of high-scoring molecules can be generated, making this approach useful for drug discovery and material science. However, the application of these methods can be hindered by computationally expensive or time-consuming scoring procedures, particularly when a large number of function calls are required as feedback in the reinforcement learning optimization. Here, we propose the use of double-loop reinforcement learning with simplified molecular line entry system (SMILES) augmentation to improve the efficiency and speed of the optimization. By adding an inner loop that augments the generated SMILES strings to non-canonical SMILES for use in additional reinforcement learning rounds, we can both reuse the scoring calculations on the molecular level, thereby speeding up the learning process, as well as offer additional protection against mode collapse. We find that employing between 5 and 10 augmentation repetitions is optimal for the scoring functions tested and is further associated with an increased diversity in the generated compounds, improved reproducibility of the sampling runs and the generation of molecules of higher similarity to known ligands.


Rejuvenation of the aging hand.
This article reviews aging of the hand and the treatment options for cosmetic rejuvenation. Options available for cutaneous rejuvenation include microdermabrasion, chemical peeling, intense light sources, and laser therapy, including pigment lasers, ablative resurfacing, and noninvasive rejuvenation. Protuberant veins of the aging hand can be treated effectively with sclerotherapy. The soft tissue atrophy of the aging hand is best treated with fat augmentation. The article concludes with a mention of new fillers that are just beginning to be used for soft tissue atrophy of the hand.


Endogenous plant nitroxyl, a new component of nitric oxide biology.
Nitroxyl (HNO), a one-electron reduced and protonated congener of nitric oxide (•NO), was recently discovered in Arabidopsis thaliana. Due to its distinct chemical properties, we believe HNO must be further studied to determine how many physiological processes it impacts.


Influence of fish skin gelatin-sodium alginate complex stabilized emulsion on benzyl isothiocyanate stability and digestibility in vitro and in vivo.
An emulsion delivery system for benzyl isothiocyanate (BITC) was prepared using fish skin gelatin (FSG) and sodium alginate (Alg). The effects of the FSG-Alg complex on the emulsion stability and BITC release pattern from the emulsion were investigated in vitro and in vivo. The storage stability and embedding rate of the 10 g kg-1 FSG and 2.5 g kg-1 Alg (FSG-Alg) emulsion were the highest among all samples. The FSG-Alg complex provided BITC a better protection during in vitro digestion. The microstructure of the FSG-Alg emulsions was more stable during in vitro digestion, and the bioaccessibility and retention rate of BITC were much higher compared to those of the FSG emulsion. The results of the ex vivo everted gut sac of rat intestine study showed that the FSG-Alg emulsion significantly increased the BITC absorption rate in the duodenum. The FSG-Alg emulsion delivery system is a highly stable system for the delivery of BITC that improves the bioaccessibility of BITC and promotes its absorption in the duodenum. © 2022 Society of Chemical Industry.


Influence of alcohol consumption and various beverages on waist girth and waist-to-hip ratio in a sample of French men and women.
The goal of the present study was to assess the association between alcohol consumption and abdominal fat deposition in France, a country where wine is the most commonly consumed alcoholic beverage. We analyzed the association between alcohol consumption and various markers of body weight, in a population sample recruited in three distinct geographical areas of France (MONICA centers). This sample included men (n = 1778) and women (n = 1730) aged 35- 64 y, randomly selected from electoral rolls. Alcohol consumption was assessed with a quantitative frequency questionnaire. Alcohol intake ranged from 0-1655 ml of alcohol per week. Wine was the main source of alcohol, representing 67% of total alcohol intake in both genders. In men, there was no association between alcohol intake and body mass index (BMI) or body weight, whereas in women, alcohol consumption was inversely correlated with BMI (P < 0.0001) and body weight (P < 0.0002). In men, total alcohol consumption was positively associated with waist-to-hip ratio (WHR, P < 0.0002) and waist girth (P < 0.004), independently of BMI. Similarly, in women, positive associations were found between alcohol intake and WHR (P < 0.0001) as well as waist girth (P < 0.0001), independently of BMI. In a linear regression model including types of beverages and usual confounders, reporting consumption of either wine, beer or spirit was poorly associated with WHR in men, whereas wine (P < 0.0008) and beer (P < 0.0001) consumptions were both positively associated with WHR in women. However, there was no evidence of a statistically significant heterogeneous effect of wine, beer and spirits on WHR in both genders. In a sample of representative French people, in whom wine is the most common alcoholic beverage, alcohol consumption is associated with greater WHR independently of BMI in both men and women.


The impact of climate change on ski resorts in China.
Although ski tourism in China is experiencing a boom, and the number of operating ski areas has significantly increased, the influence of climate change on the future development of China's ski industry has so far largely been overlooked. This paper addresses this important gap by applying the ski season simulation model SkiSim 2.0 at 116 ski areas. Four main indicators of climate change impact were examined: ski season length, operational ski days in economically important season segments, technically produced snow and snowmaking requirements. For all ski resorts in China and all climate change scenarios, average ski seasons are projected to shorten (- 4 to - 61% RCP 4.5; - 6 to - 79% RCP 8.5 in the 2050s) while snowmaking needs increase (27 to 51% RCP 4.5; 46 to 80% RCP 8.5 in the 2050s). The results indicate that high regional differences in climate change vulnerability exist. The implications for altered competitiveness and development potential of the ski industry in China are discussed.


Burden, patterns, and impact of multimorbidity in North India: findings from a rural population-based study.
To estimate the prevalence, socio-demographic determinants, common disease combinations, and health impact of multimorbidity among a young rural population. We conducted a cross-sectional survey among participants aged ≥30 years in rural Punjab, North India, from Jan 2019 to April 2019. Multimorbidity was defined as the coexistence of ≥two conditions using a 14-condition tool validated in India. We also calculated a multimorbidity-weighted index (MWI), which provides a weight to each disease based on its impact on physical functioning. Logistic regression was conducted to evaluate the association with sociodemographic variables, mental health (PHQ-9), physical functioning (ADL scale), and self-rated health (SRH). We analyzed data from 3213 adults [Mean age 51.5 (±13), 54% women]. Prevalence of single chronic condition, multimorbidity, and MWI was 28.6, 18% and - 1.9 respectively. Age, higher wealth index and ever use alcohol were significantly associated with multimorbidity. Overall, 2.8% of respondents had limited physical functioning, 2.1% had depression, and 61.5% reported low SRH. Poorer health outcomes were more prevalent among the elderly, women, less educated, and those having lower wealth index and multimorbidity, were found to be significantly associated with poor health outcomes. The burden of multimorbidity was high in this young rural population, which portends significant adverse effects on their health and quality of life. The Indian health system should be reconfigured to address this emerging health priority holistically, by adopting a more integrated and sustainable model of care.


Icosapent Ethyl Reduces Ischemic Events in Patients With a History of Previous Coronary Artery Bypass Grafting: REDUCE-IT CABG.
Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63-0.92]; P=0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56-0.87]; P=0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50-0.81]; P=0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%-10.2%) in first events, with a number needed to treat of 16 (95% CI, 10-44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P=0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.


Atypical Lumbar Scheuermann's Disease: A Rare Entity and Literature Review.
Atypical Scheuermann disease involves one or two vertebral bodies which result in kyphosis. An 18-year-old male presented in OPD with a complaint of chronic lower back pain without any lower limb pain and neurological deficit. Radiological imaging and blood parameters were in favor of atypical Scheuermann disease. Radiological and blood investigations are required to rule out other possible causes of chronic back pain to make a diagnosis of atypical Scheuermann disease which should be treated conservatively initially.


Hypoglycemia in blood glucose level in type 2 diabetic Japanese patients by continuous glucose monitoring.
Hypoglycemia is associated with cardiovascular diseases, increased risk of death. Therefore, it is important to avoid hypoglycemia. The aim of this study was to characterize hypoglycemia according to glycated hemoglobin (HbA1c) level and determine the contributing factors in type 2 diabetes mellitus (T2DM), using continuous glucose monitoring (CGM). T2DM patients (n = 293) receiving inpatient care were divided into five groups according to HbA1c level on admission (Group 1: ≥ 6 to < 7%, Group 2: ≥ 7 to < 8%, Group 3: ≥ 8 to < 9%, Group 4: ≥ 9 to < 10%, and Group 5: ≥ 10%). The frequency of hypoglycemia and factors associated with hypoglycemia were analyzed. Hypoglycemia occurred in 15 patients (5.1%), including 4 (8%), 4 (6%), and 7 (10%) patients of Groups 1, 2, and 3, respectively, but in none of groups 4 and 5. Patients with hypoglycemia of Groups 1 had low insulin secretion and were high among insulin users, those of Groups 2 had low homeostasis model assessment of insulin resistance (HOMA-IR). Those of Group 2 and 3 had significantly lower mean blood glucose levels, those of Group 3 only had significantly lower maximum blood glucose level and percentage of AUC > 180 mg/dL. In any of the HbA1c groups, variations in blood glucose level were significantly larger in patients with hypoglycemia than without. Hypoglycemia occurred in patients with a wide range of HbA1c on admission (range 6-9%), suggesting that prediction of hypoglycemia based on HbA1c alone is inappropriate. Among patients with low HbA1c, strict control sometimes induce hypoglycemia. Among patients with high HbA1c, the possibility of hypoglycemia should be considered if there is a marked discrepancy between HbA1c and randomly measured blood glucose level. Larger variations in blood glucose level induce hypoglycemia in any of the HbA1c groups. The treatment to reduce variations in blood glucose level is important to prevent hypoglycemia.


Influence of stretch on the target phenomenon in the tenotomized and immobilized gastrocnemius muscle of the rat.
The influence of traction on the target phenomenon was analysed in the tenotomized gastrocnemius muscle of Wistar rats. Target fibres were constantly observed at the medial side of the heads of the non-immobilized and tenotomized gastrocnemius muscles used as control. In the muscles fixed in flexion, no target fibres could be detected, while in the muscles fixed in hyperextension some target fibres were seen. The latter were less numerous than those present in the non-immobilized muscles. This experiment proves the importance of stretch mechanisms in the pathogenesis of the target phenomenon.


Palliative Radiotherapy Produced Spectacular Improvement in a Terminally Ill Colorectal Carcinoma Patient With Severe Pain and Duodenal Bleeding.
Colorectal cancer has a devastating effect on the quality of life, and the treatment of active intestinal bleeding in colorectal cancer is a real challenge at the end of life. This case report presents a spectacular effect of an unusual palliative treatment strategy in a middle-aged home hospice patient with severe pain and persistent duodenal bleeding secondary to its neoplastic infiltration. Palliative radiotherapy (RT) significantly improved pain control, terminated the duodenal bleeding, and allowed successful treatment of deep vein thrombosis, previously impossible because of the bleeding. It also made the patient independent of otherwise unavoidable transfusions, thus improving his quality of life. In our patient, RT played a leading role in restoring general fitness and, accordingly, mental state improvement. Our case demonstrates that palliative RT may be a valuable treatment option in cases similar to ours. Still, careful assessment of risks and benefits is always mandatory.


Memristive characteristic of an amorphous Ga-Sn-O thin-film device.
We have found a memristive characteristic of an α-GTO thin-film device. The α-GTO thin-film layer is deposited using radio-frequency (RF) magnetron sputtering at room temperature and sandwiched between the Al top and bottom electrodes. It is found that the hysteresis loop of the flowing current (I) and applied voltage (V) characteristic becomes larger and stable after the one hundredth cycle. The electrical resistances for the high-resistance state (HRS) and low-resistance state (LRS) are clearly different and relatively stable. Based on various analysis, it is suggested that the memristive characteristic is due to the chemical reaction between the SnO2 and SnO blocked by AlOx on the Al bottom electrode. It is marvelous that the memristive characteristic can be realized by such common materials, simple structures, and easy fabrication.


[Non-secretory plasmacytoma. Bibliographic review and immunohistochemical study of a case].
After a brief examination of the recent literature on non-secretory multiple myeloma, the Authors describe the immunohistologic study (peroxidase-antiperoxidase method) of a case of truly non producing plasmacytoma, interesting because of the presence of a small polyclonal plasma cell population within the neoplastic clone. Several possible explanations are considered.


Activating the delivery of a model drug to lipid membrane by encapsulation of cyclodextrin: Combined experimental and molecular docking studies.
Drug delivery science is always an important topic as it studies the delivery of therapeutic payloads to the desired target cells without affecting the healthy tissues/cells, thus minimizing drug-induced toxicity. Aiming towards the targeted drug delivery, the present project deals with the delivery of a polarity-sensitive solvatochromic model drug, namely, salt of 8-anilinonaphthalene-1-sulphonic acid (ANSA) to the model bio-membrane (which mimic several aspects of the real cell membrane), more precisely at the lipid-water interface of L-α-Dipalmitoylphosphatidylcholine (DPPC) phospholipid. The drug delivery process has been activated through the binding of dye with cyclodextrin, acting as a drug transporter. Detailed steady-state and time-resolved spectroscopic studies including molecular docking analysis imply the targeted drug delivery of dye, ANSA, towards the lipid-water interface region of lipid bilayers through encapsulation within the cyclodextrin void. Stronger binding interaction of the dye with the lipid bilayers relative to β-cyclodextrin (β-CD) is the foremost reason for the targeted delivery. The present biophysical interaction studies of drug-lipid interaction, thus, may provide a cordial approach for drug formulation and drug delivery.


Synthesis and characterization of bismuth(III) and antimony(V) porphyrins: high antileishmanial activity against antimony-resistant parasite.
Two bismuth(III) porphyrins-5,10,15,20-tetrakis(phenyl)porphyrinatobismuth(III) nitrate, [Bi(III)(TPP)]NO3, and the unprecedent 5,10,15,20-tetrakis(4-carbomethoxyphenyl)porphyrinatobismuth(III) nitrate, [Bi(III)(T4CMPP)]NO3, and two unprecedented antimony(V) porphyrins dichlorido(5,10,15,20-tetrakis(phenyl)porphyrinato)antimony(V) bromide, [Sb(V)(TPP)Cl2]Br, and dibromido(5,10,15,20-tetrakis(4-carbomethoxyphenyl)porphyrinato)antimony(V) bromide, [Sb(V)(T4CMPP)Br2]Br,-were synthesized by reacting the corresponding porphyrin ligand with Bi(NO3)3·5H2O or SbCl3. All compounds were characterized by UV-vis, (1)H NMR spectroscopy, and mass spectrometry. The new compounds were also characterized by elemental analysis. Because antimony and bismuth compounds have been widely applied in medicine, the activity of these complexes was tested against Sb-sensitive and -resistant Leishmania amazonensis parasites. [Sb(V)(T4CMPP)Br2]Br was more active against the promastigote form of Sb-resistant mutant strain as compared to the sensitive parental strain, with IC50 in the micromolar range. These data contrasted with those obtained using the Sb(III) drug potassium antimony tartrate, which displayed IC50 of 110 μmol L(-1) against the Sb-sensitive parasite and was almost inactive against the Sb-resistant strain. The H2T4CMPP ligand also showed antileishmanial activity against Sb-resistant and -sensitive strains, but with IC50 at least tenfold greater than that of the complex. The Sb(V)-porphyrin complex was also active against intracellular amastigotes and showed a higher selectivity index than the conventional Sb(V) drug glucantime, in both Sb-sensitive and -resistant strains. The greater antileishmanial activity of this complex could be attributed to an increased cellular uptake of Sb. Thus, [Sb(V)(T4CMPP)Br2]Br constitutes a new antileishmanial drug candidate.


Quantification and kinetics of purine catabolism in Dalmatian dogs at low and high purine intakes.
1. In eight Dalmatian dogs low and high purine intakes resulted in plasma urate levels from 25 to 185 mumol/l. 2. The relationship between purine intake and excretion of uric acid and allantoin per day was described by linear regression equations. 3. The elimination of endogenous purines was 1.8 mmol/day for urate and 1.7 mmol/day for allantoin. Exogenous purines increased renal excretion by 0.57 mmol/mmol. 4. Kinetic measurements with [2(-14)C]uric acid infused continuously into each of two dogs on low and high purine revealed increases of plasma pool (urate + allantoin) of 3.3 fold and entry rate of 4.0 fold. Conversion of urate into allantoin increased from 20 to 36%. 5. Renal elimination of catabolites increased 3.3 fold and exhalation rate of purine-CO2 379 fold. Extra-renal elimination at high purine intake was quantitatively similar to humans and closely related to pool size.


Comparison of oil-in-water emulsions prepared by ultrasound, high-pressure homogenization and high-speed homogenization.
This study was designed to compare the properties of myofibrillar protein (MP) stabilized soybean oil-in-water emulsions fabricated by ultrasound-assisted emulsification (UAE), high-pressure homogenization (HPH) and high-speed homogenization (HSH). The emulsion properties, droplet characteristics, interfacial proteins, protein exposure extent, microrheological properties, multiple light scattering results, and 7 d storage stabilities of the three emulsions were specifically investigated. Our results indicate that UAE and HPH were better emulsification methods than HSH to obtain high-quality emulsions with higher emulsifying activity index (UAE 20.73 m2·g-1, HPH 11.76 m2·g-1 and HSH 6.80 m2·g-1), whiteness (UAE 81.05, HPH 80.67 and HSH 74.09), viscosity coefficient (UAE 0.44 Pa·sn, HPH 0.49 Pa·sn and HSH 0.22 Pa·sn), macroscopic viscosity index (UAE 2.31 nm-2·s, HPH 0.38 nm-2·s and HSH 0.34 nm-2·s), and storage stability, especially for the UAE. Furthermore, UAE was a more efficient emulsification method than HPH to prepare the fine MP-soybean oil emulsion. The protein-coated oil droplets were observed in the three emulsions. The emulsion droplet size of the UAE-fabricated emulsion was the lowest (0.15 μm) while the interfacial protein concentration (93.37%) and the protein exposure extent were the highest among the three emulsions. During the 7 d storage, no separation was observed for the UAE-fabricated emulsion, while the emulsions fabricated by HPH and HSH were separated after storage for 5 d and 2 h. Therefore, this work suggests that UAE could be a better method than HPH and HSH to fabricate MP-soybean oil emulsion.


Neurochemical pathology in Korsakoff's psychosis: implications for other cognitive disorders.
There seems to be an anatomic correspondence between pathways of monoamine-containing neurons and the brainstem and diencephalic lesions associated with Korsakoff's psychosis. In 25 patients with Korsakoff's disease, we found that CSF levels of metabolites of norepinephrine, dopamine, and serotonin were significantly lower than in controls. Norepinephrine metabolite levels were reduced more consistently and extensively than those of dopamine and serotonin. The 25 patients had circumscribed cognitive deficits, but were not demented. We argue that norepinephrine-containing neurons are selectively damaged in Korsakoff's psychosis and that lesions of brain monoamine-containing neurons cause specific cognitive impairments, not global dementia.


Profile of and risk factors for early unplanned readmissions in patients with acute necrotizing pancreatitis.
Acute necrotizing pancreatitis (ANP) complicates up to 15% of acute pancreatitis cases. ANP has historically been associated with a significant risk for readmission, but there are currently no studies exploring factors that associate with risk for unplanned, early (<30-day) readmissions in this patient population. We performed a retrospective review of all consecutive patients presenting to hospitals in the Indiana University (IU) Health system with pancreatic necrosis between December 2016 and June 2020. Patients younger than 18 years of age, without confirmed pancreatic necrosis and those that suffered in-hospital mortality were excluded. Logistic regression was performed to identify potential predictors of early readmission in this group of patients. One hundred and sixty-two patients met study criteria. 27.7% of the cohort was readmitted within 30-days of index discharge. The median time to readmission was 10 days (IQR 5-17 days). The most frequent reason for readmission was abdominal pain (75.6%), followed by nausea and vomiting in (35.6%). Discharge to home was associated with 93% lower odds of readmission. We found no additional clinical factors that predicted early readmission. Patients with ANP have a significant risk for early (<30 days) readmission. Direct discharge to home, rather than short or long-term rehabilitation facilities, is associated with lower odds of early readmission. Analysis was otherwise negative for independent, clinical predictors of early unplanned readmissions in ANP.


AMPA receptor stimulation within the central nucleus of the amygdala elicits a differential activation of central dopaminergic systems.
Appetitive and aversive arousing stimuli increase rates of dopamine (DA) release, particularly within the prefrontal cortex (PFC). Evidence suggests an activating influence of both the central (CeA) and basolateral (BlA) nuclei of the amygdala on DA neurotransmission. For example, lesions of CeA block stressor-induced increases in DA release. Additionally, electrical stimulation of BlA increases DA release in select terminal fields. Previous studies indicate that glutamatergic AMPA receptors modulate CeA and BlA output. However, the extent to which AMPA receptors participate in amygdala-dependent activation of DA neurotransmission is unknown. The current studies examined the effects of bilateral AMPA infusions within CeA or BlA on post-mortem and in vivo microdialysis indices of DA release. Additionally, stress is associated with moderate increases in serotonin (5-HT) neurotransmission that are also blocked by CeA lesions. Thus, the current studies also examined the impact of AMPA infusions on post-mortem indices of 5-HT utilization. AMPA infusion into CeA, but not BlA, increased post-mortem indices of DA and 5-HT release in a pattern comparable to that observed under appetitive/aversive conditions. In vivo microdialysis studies confirmed that AMPA infusions into CeA, but not BlA, increase extracellular PFC DA levels. When infused into sleeping animals, CeA-AMPA infusion also elicited a rapid-onset transition into waking. Thus, CeA-AMPA receptors exert an excitatory influence on DA and 5-HT neurotransmission and on behavioral state. Combined, these results suggest that CeA-AMPA receptors may participate in the coordination of neural systems involved in the regulation of behavioral state under high-arousal conditions.


Radiation-induced skin toxicity: prophylaxis or management?
This editorial aims to provide context for changing skin care interventions for radiation-induced skin toxicities over several decades.


Drug Testing US Student-Athletes for Performance-Enhancing Substance Misuse: A Flawed Process.
The author argues that drug testing of U.S. high school students for performance-enhancing substance misuse is invasive, expensive, and the low number of positive test results do not justify the costs, especially in financially strapped school districts where this money would be better spent on injury prevention for athletes and the education of all students.


Factors determining the distribution of the sea pansy, Renilla kollikeri, in a subtidal sand-bottom habitat.
The biological and physical factors that affect the distribution of the subtidal, epibenthic, sand-dwelling cnidarian Renilla kollikeri along a depth gradient from 2 to 13 m were determined by manipulative field and laboratory experiments. The sea pansy's nearshore distributional limit (2.5 m in depth) was set by the animal's inability to remain anchored on the bottom in the face of increasing wave surge associated with shallow water. Renilla was outcompeted for space by the sand dollar Dendraster excentricus in an area between 6 and 9 m in depth and was largely excluded from the substrate when sand dollar densities exceeded 350/m2. Predator-prey interactions also influence the Renilla distribution. The asteroid Astropecten brasiliensis feeds on and removes Renilla 40 mm and less in diameter from areas seaward of the sand dollar bed (9 m in depth). Astropecten did not forage in the shallow area where Renilla was most abundant because of its intolerance to wave surge and because of its difficulty in crossing the sand dollar bed. The nudibranch Armina californica fed on Renilla throughout the depth gradient but did not remove colonies greater than 20 mm in diameter because of the Armina- specific escape behavior of Renilla. The foraging behavior of Armina was also curtailed by strong surge conditions. The nearshore area (3-6 m in depth) of high Renilla density was a refuge in which animals that had settled from the plankton could escape predation. As the animals grow they lose their ability to anchor in the substrate in shallow water and thus move into deeper water. The results of multiway interactions among sets of three species, particularly the beneficial results of the competitive interaction with Dendraster in light of the activities of the predators are discussed with reference to the abundance and distribution of Renilla.


A simple but quantitative method for non-destructive monitoring of myoglobin redox forms inside the meat.
This study aims at exploring a simple and quantitative method for non-destructive monitoring of the myoglobin redox forms inside of beef. The modified Beer-Lambert law was employed to derive an equation that delineates a relationship between attenuance differences and oxy-, deoxy-, and met-myoglobin proportions. An experiment with forty-three well-bled muscle beef samples during 7 days of storage was performed to validate the equation. Firstly, the reflection spectra were collected from the beef samples using a probe consisting of a light source and a light detector. Secondly, the attenuance differences, A630-615 and A578-567, were calculated from the measured spectra. Finally, these attenuance differences were placed into the derived equation to determine the proportions of the three myoglobin redox forms. Both the met-myoglobin proportion and meat oxygenation computed via the attenuance differences established a strong correlation with the ones estimated using the whole spectrum (R2 > 0.88). The experimental results suggest the potential of using the attenuance at five wavelengths (524, 567, 578, 615, and 630 nm) to monitor oxy-, deoxy-, and met-myoglobin inside of beef in a simple and fast manner with little to no sample preparation.


[Intravenous re-infusion of ascitic fluid in patients with treatment-resistant cirrhotic ascites (author's transl)].
Unmodified ascitic fluid was re-infused into 14 patients with treatment-resistant cirrhotic ascites. Re-infusion lasted for 41 hours, divided over five days, with an average duration of 8 3/4 hours per day. Weight reduction averaged 10.5 kg, decrease in abdominal circumference 13 cm. Urine production rose by an average of + 23.7%. Azotaemia and abnormal serum electrolytes levels tended towards normal.


Regulation of GATA-3, c-maf and T-bet mRNA expression in bronchoalveolar lavage cells and bronchial biopsies after segmental allergen challenge.
GATA-3 (GATA binding protein 3) and the proto-oncogene c-maf are Th2-regulating transcription factors that control the expression of interleukin (IL)-4 and IL-5, while T-bet (T-box expressed in T cells) is a Th1-specific transcription factor that controls the expression of interferon (IFN-gamma). Allergen provocation in asthmatics induces a Th2-dominated cytokine profile, but so far it is unknown whether the skewed cytokine expression is reflected by the expression of the respective transcriptional regulators. The aim of this study was to determine the regulation of Th1- and Th2-specific transcription factors and cytokines in 10 atopic subjects with mild asthma and 5 nonatopic healthy controls at baseline and after segmental sham and allergen challenge. The mRNA expression of GATA-3, c-maf and T-bet was determined by real-time polymerase chain reaction in bronchoalveolar lavage (BAL) cells and bronchial biopsies. The percentage of IL-4+, IL-5+ and IFN-gamma+ BAL T cells was determined by flow cytometry, and BAL levels of these cytokines were measured by ELISA. In BAL cells of asthmatics, the mRNA expression of all transcription factors was increased after allergen challenge. In bronchial biopsies, the basal expression of GATA-3 was increased in asthmatics compared to healthy controls but decreased after allergen challenge. Compared to sham challenge, the percentage of IL-5+/CD4+ BAL T cells was increased after allergen challenge in asthmatics while the percentage of IFN-gamma+/CD4+ and IFN-gamma+/CD8+ T cells was decreased. Expression of c-maf mRNA in BAL cells correlated with IL-4+/CD4+ BAL cells and BAL IL-5 levels. Segmental allergen challenge in asthmatics leads to increased GATA-3, c-maf and T-bet expression in BAL cells but not in bronchial biopsies.


Is anisotropic propagation of polarized molecular distribution the common mechanism of swirling patterns of planar cell polarization?
Mutations in multiple planar cell polarity (PCP) genes can cause swirling patterns indicated by whorls and tufts of hairs in the wings and the abdomen of Drosophila and in the skin of vertebrates. Damaged global directional cue caused by mutations in four-jointed, fat, and dachsous, impaired cellular hexagonal packing caused by mutations in frizzled, or weakened intracellular signaling caused by mutations in disheveled, inturned, and prickle all make hair patterns globally irregular yet locally aligned, and in some cases, typically swirling. Why and how mutations in different genes all lead to swirling patterns is unexplored. Although the mechanisms of molecular signaling remain unclear, the features of molecular distribution are evident-most PCP molecules develop the polarized distribution in cells and this distribution can be induced by intercellular signaling. Does this suggest something fundamental to swirling patterns beyond the particular functions of genes, proteins, and signaling? A simple model indeed indicates this. Disregarding detailed molecular interactions, the induced polarization of molecular distribution in an epithelial cell can be modeled as the induced polarization of positive and negative charge distribution in a dielectric molecule. Simulations reveal why and how mutations in different genes all lead to swirling patterns, and in particular, the conditions for generating typical swirling patterns. The results show that the anisotropic propagation of polarized molecular distribution may be the common mechanism of swirling patterns caused by different mutations. They also suggest that at the cell level, as at the molecular level, a simple mechanism can generate complex and diverse patterning phenotypes in different molecular contexts. The similarity between the induced polarization and its propagation in both the epithelial cells and the dielectric molecules also interestingly suggests some commonalities between pattern formation in the biological and physical systems.


Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: do conditioning stimulus painfulness, gender and personality variables matter?
Descending modulation of pain can be demonstrated psychophysically by dual pain stimulation. This study evaluates in 31 healthy subjects the association between parameters of the conditioning stimulus, gender and personality, and the endogenous analgesia (EA) extent assessed by diffuse noxious inhibitory control (DNIC) paradigm. Contact heat pain was applied as the test stimulus to the non-dominant forearm, with stimulation temperature at a psychophysical intensity score of 60 on a 0-100 numerical pain scale. The conditioning stimulus was a 60s immersion of the dominant hand in cold (12, 15, 18 degrees C), hot (44 and 46.5 degrees C), or skin temperature (33 degrees C) water. The test stimulus was repeated on the non-dominant hand during the last 30s of the conditioning immersion. EA extent was calculated as the difference between pain scores of the two test stimuli. State and trait anxiety and pain catastrophizing scores were assessed prior to stimulation. EA was induced only for the pain-generating conditioning stimuli at 46.5 degrees C (p=0.011) and 12 degrees C (p=0.003). EA was independent of conditioning pain modality, or personality, but a significant gender effect was found, with greater EA response in males. Importantly, pain scores of the conditioning stimuli were not correlated with EA extent. The latter is based on both our study population, and on additional 82 patients, who participated in another study, in which EA was induced by immersion at 46.5 degrees C. DNIC testing, thus, seems to be relatively independent of the stimulation conditions, making it an easy to apply tool, suitable for wide range applications in pain psychophysics.


Crystallization and preliminary X-ray diffraction study of a xylanase from Trichoderma harzianum.
A 20,000 Mr xylanase from Trichoderma harzianum has been purified and crystallized from 20% (w/v) saturated ammonium sulphate solutions. The unit cell is orthorhombic, space group P2(1)2(1)2(1), with unit cell lengths a = 44.2 A, b = 94.1 A, c = 51.6 A. Data from native crystals and several potential heavy-atom derivatives have been collected. An X-ray analysis to at least 2.8 A resolution appears to be feasible.


How Sensitive Are Transdermal Transport Predictions by Microscopic Stratum Corneum Models to Geometric and Transport Parameter Input?
While predictive models of transdermal transport have the potential to reduce human and animal testing, microscopic stratum corneum (SC) model output is highly dependent on idealized SC geometry, transport pathway (transcellular vs. intercellular), and penetrant transport parameters (e.g., compound diffusivity in lipids). Most microscopic models are limited to a simple rectangular brick-and-mortar SC geometry and do not account for variability across delivery sites, hydration levels, and populations. In addition, these models rely on transport parameters obtained from pure theory, parameter fitting to match in vivo experiments, and time-intensive diffusion experiments for each compound. In this work, we develop a microscopic finite element model that allows us to probe model sensitivity to variations in geometry, transport pathway, and hydration level. Given the dearth of experimentally-validated transport data and the wide range in theoretically-predicted transport parameters, we examine the model's response to a variety of transport parameters reported in the literature. Results show that model predictions are strongly dependent on all aforementioned variations, resulting in order-of-magnitude differences in lag times and permeabilities for distinct structure, hydration, and parameter combinations. This work demonstrates that universally predictive models cannot fully succeed without employing experimentally verified transport parameters and individualized SC structures.


[Reconstruction of the lower alveolar nerve during mandible resection due to benign tumors].
Development of a method for reconstruction of the inferior alveolar nerve and evaluation of its effectiveness in resection of the lower jaw for benign tumors. In the period from 2018 to 2020, 10 resections were performed for benign odontogenic neoplasms (myxoma, ameloblastoma, osteoblastoclastoma) at the age of 18 to 60 years. Tactile, pain and temperature sensitivity were subjectively studied. The assessment of subjective sensitivity was carried out five times: before the operation, after 21 days, after 3.6 months and a year after the operation, an electromyograph «SYNAPSIS» was used for an objective assessment of sensitivity. The studies were conducted twice: 21 days after the operation and 12 months later. Reinervation was carried out by two methods. Method I: by transferring the insertion from the calf nerve and applying end-to-end neuroanastomoses between the proximal and distal ends of the inferior alveolar nerve (5 patients); method II: transferring the insertion from the calf nerve to the lingual nerve. Neuroanastomoses are applied periepineurally between the distal end of the inferior alveolar nerve and the lingual nerve «end to side» (5 patients). After 12 months, all types of sensitivity were restored in the control group in all patients, and in the second group in 80%. All patients had areas of hyposthesia in terms of temperature and tactile sensitivity. The results of trigeminal evoked potentials were negative in all patients 21 days after surgery, and peaks of evoked potentials were recorded in 9 (90%) patients 12 months later. These reconstruction techniques are effective both when the proximal end of the inferior alveolar nerve is preserved, and when it is impossible to preserve it. With minimal donor damage, the sensitivity of the lower lip is restored, which significantly improves the quality of life of patients and their social adaptation.


Sex influences the effect of body mass index on the vascular response to angiotensin II in humans.
Sex influences the cardiorenal risk associated with body mass index (BMI). The role of the renin-angiotensin-aldosterone system in adiposity-mediated cardiorenal risk profiles in healthy, non-obese men and women was investigated. Systemic and renal hemodynamic responses to angiotensin-II (AngII) as a function of BMI, waist and hip circumference, waist-hip ratio, as well as fat and lean mass were measured in 18 men and 25 women in high-salt balance, stratified by BMI (<25 kg/m2 (ideal body weight (IBW)) vs. ≥25 kg/m2 overweight)). In men (n = 7, BMI 23 ± 1 kg/m2) and women (n = 14, BMI 22 ± 2 kg/m2) of IBW, BMI was not associated with the systolic blood pressure (SBP) response to AngII. In contrast, overweight men (n = 11, 29 ± 2 kg/m2) demonstrated a progressively more blunted vasoconstrictor SBP response to AngII challenge as BMI increased (P = 0.007), even after adjustment for covariates. Women maintained the same relationship between BMI and the SBP response to AngII irrespective of weight status (P = 0.2, IBW vs. overweight women). Compared to BMI, other adiposity measures showed similar associations to systemic AngII responsiveness in men but not in women. Increasing BMI was associated with a blunted renovasoconstrictor response to AngII in all subjects, but was more pronounced in men. Sex influences the effect of adiposity on vascular angiotensin-responsiveness.


In utero exposure to gestational diabetes mellitus and long term endocrine morbidity of the offspring.
Gestational diabetes mellitus (GDM) is a worldwide public health problem. Few studies investigated the association of intra uterine exposure to GDM and long-term endocrine morbidity of offspring. To assess whether in utero exposure to GDM increases the risk for long-term endocrine morbidity of the offspring. A retrospective cohort study was conducted including all singleton born to women who delivered between 1988 and 2014. All births occurred in a tertiary medical center. Data were collected from the computerized perinatal database of the obstetrics and gynecology department and the computerized hospitalization database. The exposure variables were: diet-controlled GDM (GDMA1) and treated GDM (GDMA2). Multivariate generalized estimating equation (GEE) logistic regression model analysis was used to control for confounders and for maternal clusters. During the study period 231,271 deliveries met the inclusion criteria, of which 12,642 deliveries (5.4%) were diagnosed with GDM. During the follow-up period, children exposed in utero to GDM had a higher rate of long- term hospitalizations with diagnoses of endocrine morbidity (such as diabetes mellitus and obesity) compared to those unexposed. Using a GEE model, controlling for confounders such as maternal age, follow up-time, obesity and birthweight, in-utero exposure to GDMA1 (adjusted OR = 2.1; 95% CI 1.7-2.7; P < 0.001) and especially to GDMA2 (adjusted OR = 3.1; 95% CI 2.2-4.4, P < 0.001) were found as risk factors for long-term endocrine disease during childhood. Exposure to GDM is a risk factor for long-term endocrine morbidity in the offspring.


COVID-19 outcomes of venovenous extracorporeal membrane oxygenation for acute respiratory failure vs historical cohort of non-COVID-19 viral infections.
Veno-venous extracorporeal membrane oxygenation (VV ECMO) has become a support modality for patients with acute respiratory failure refractory to standard therapies. VV ECMO has been increasingly used during the current COVID-19 pandemic for patients with refractory respiratory failure. The object of this study was to evaluate the outcomes of VV ECMO in patients with COVID-19 compared to patients with non-COVID-19 viral infections. We retrospectively reviewed all patients supported with VV ECMO between 8/2014 and 8/2020 whose etiology of illness was a viral pulmonary infection. The primary outcome of this study was to evaluate in-hospital mortality. The secondary outcomes included length of ECMO course, ventilator duration, hospital length of stay, incidence of adverse events through ECMO course. Eighty-nine patients were included (35 COVID-19 vs 54 non-COVID-19). Forty (74%) of the non-COVID-19 patients had influenza virus. Prior to cannulation, COVID-19 patients had longer ventilator duration (3 vs 1 day, p = .003), higher PaCO2 (64 vs 53 mmHg, p = .012), and white blood cell count (14 vs 9 ×103/μL, p = .004). Overall in-hospital mortality was 33.7% (n = 30). COVID-19 patients had a higher mortality (49% vs. 24%, p = .017) when compared to non-COVID-19 patients. COVID-19 survivors had longer median time on ECMO than non-COVID-19 survivors (24.4 vs 16.5 days p = .03) but had a similar hospital length of stay (HLOS) (41 vs 48 Extracorporeal Membrane Oxygenationdays p = .33). COVID-19 patients supported with VV ECMO have a higher mortality than non-COVID-19 patients. While COVID-19 survivors had significantly longer VV ECMO runs than non-COVID-19 survivors, HLOS was similar. This data add to a growing body of literature supporting the use of ECMO for potentially reversible causes of respiratory failure.


Unexpected new roles for heparanase in Type 1 diabetes and immune gene regulation.
Heparanase (Hpse) is an endo-β-d-glucuronidase that degrades the glycosaminoglycan heparan sulfate (HS) in basement membranes (BMs) to facilitate leukocyte migration into tissues. Heparanase activity also releases HS-bound growth factors from the extracellular matrix (ECM), a function that aids wound healing and angiogenesis. In disease states, the degradation of HS in BMs by heparanase is well recognized as an invasive property of metastatic cancer cells. Recent studies by our group, however, have identified unexpected new roles for heparanase and HS. First, we discovered that in Type 1 diabetes (T1D) (i) HS in the pancreatic islet BM acts as a barrier to invading cells and (ii) high levels of HS within the insulin-producing islet beta cells themselves are critical for beta cell survival, protecting the cells from free radical-mediated damage. Furthermore, catalytically active heparanase produced by autoreactive T cells and other insulitis mononuclear cells was shown to degrade intra-islet HS, increasing the susceptibility of islet beta cells to free radical damage and death. This totally novel molecular explanation for the onset of T1D diabetes opens up new therapeutic approaches for preventing disease progression. Indeed, administration of the heparanase inhibitor, PI-88, dramatically reduced T1D incidence in diabetes-prone NOD mice, preserved islet beta cell HS and reduced islet inflammation. Second, in parallel studies it has been shown that heparanase and HS can be transported to the nucleus of cells where they impact directly or indirectly on gene transcription. Based on ChIP-on-chip studies heparanase was found to interact with the promoters and transcribed regions of several hundred genes and micro-RNAs in activated Jurkat T cells and up-regulate transcription, with many of the target genes/micro-RNAs being involved in T cell differentiation. At the molecular level, nuclear heparanase appears to regulate histone 3 lysine 4 (H3K4) methylation by influencing the recruitment of demethylases to transcriptionally active genes. These studies have unveiled new functions for heparanase produced by T lymphocytes, with the enzyme mediating unexpected intracellular effects on T cell differentiation and insulin-producing beta cell survival in T cell-dependent autoimmune T1D.