Density Functional and Semiempirical Molecular Orbital Methods Including Dispersion Corrections for the Accurate Description of Noncovalent Interactions Involving Sulfur-Containing Molecules.
We describe the use of density functional theory (DFT-D) and semiempirical (AM1-D and PM3-D) methods having an added empirical dispersion correction, to treat noncovalent interactions between molecules involving sulfur atoms. The DFT-D method, with the BLYP and B3LYP functionals, was judged against a small-molecule database involving sulfur-π, S-H···S, and C-H···S interactions for which high-level MP2 or CCSD(T) estimates of the structures and binding or interaction energies are available. This database was also used to develop appropriate AM1-D and PM3-D parameters for sulfur. The DFT-D, AM1-D, and PM3-D methods were further assessed by calculating the structures and binding energies for a set of eight sulfur-containing base pairs, for which high-level ab initio data are available. The mean absolute deviations (MAD) for both sets of structures shown by the DFT-D methods are 0.04 Å for the intermolecular distances and less than 0.7 kcal mol(-)(1) for the binding and interaction energies. The corresponding values are 0.3 Å and 1.5 kcal mol(-)(1) for the semiempirical methods. For the complexes studied, the dispersion contributions to the overall binding and interaction energies are shown to be important, particularly for the complexes involving sulfur-π interactions.


Characterization and developmental expression of lactotriosylceramide:galactosyltransferase for the synthesis of neolactotetraosylceramide in the nervous system.
Neolactoglycolipids are derived from neolactotetraosylceramide (nLcOse4Cer). They are found during the embryonic and neonatal developmental periods in the rat cerebral cortex and disappear shortly after birth. These glycolipids are, however, abundant in the adult cerebellum. Lactotriosylceramide (LcOse3Cer):galactosyltransferase (GT), which catalyzes the terminal step in the biosynthesis of nLcOse4Cer, was characterized in mammalian brain. The enzyme was highly specific for LcOse3Cer, with a terminal GlcNAc beta 1-3Gal-residue, and it did not catalyze the transfer of galactose to other glycolipids studied with alternate carbohydrate residues. The microsomal membrane enzyme required Mn2+ and a detergent for in vitro activity. The optimal pH was 7.4, and the Km value for LcOse3Cer was 34 microM (Vmax = approximately 2 nmol/mg/h). The LcOse3Cer:GT was shown to be different from the GM2:GT and the soluble enzyme lactose synthase A. The specific activity of LcOse3Cer:GT was enriched fivefold higher in the white matter than in the gray matter of young adult rat brain, whereas GM2:GT was enriched only about 1.5-fold higher in the white matter. The developmental expression of LcOse3Cer:GT in the cerebral cortex and cerebellum was not correlative with the levels of nLcOse4Cer in these neural areas. Despite the complete absence of nLcOse4Cer in the cerebral cortex of animals older than 5 days, significant activity of the LcOse3Cer:GT was found even in the adult cortex. In cerebellum, the levels of nLcOse4Cer increased with development, but the specific activity of the enzyme was reduced by 50% soon after birth and then remained practically the same with development.(ABSTRACT TRUNCATED AT 250 WORDS)


A de novo mutation in sporadic nocturnal frontal lobe epilepsy.
Autosomal dominant nocturnal frontal lobe epilepsy is sometimes due to mutations in CHRNA4. The commoner presentation of sporadic nocturnal frontal lobe epilepsy has not been associated with genetic defects. A 30-year-old woman diagnosed as having sporadic nocturnal frontal lobe epilepsy was found to have a de novo Ser252Leu CHRNA4 mutation. A pattern is emerging of site-specific mutation within the second transmembrane domain of CHRNA4 in association with autosomal dominant nocturnal frontal lobe epilepsy and sporadic nocturnal frontal lobe epilepsy in families with different ethnic backgrounds.


The majority of atypical cpb2 genes in Clostridium perfringens isolates of different domestic animal origin are expressed.
This study examined the prevalence and expression of the "consensus" and the "atypical"cpb2 genes in Clostridium perfringens isolates from cattle, chickens, dogs, goats, horses, pigs and sheep using polymerase chain reaction (PCR), sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by Western blotting. Almost all porcine isolates (12/14) carried and expressed the consensus form of cpb2 but, when present in 108 non-porcine isolates, the gene was usually the atypical form (40 atypical versus 9 consensus). Western blotting showed expression in 30 of 40 (75%) atypical cpb2-positive isolates, considerably more frequently than reported previously. CPB2 was expressed by almost all (20/21) the consensus cpb2-positive isolates, regardless of source.


Parry Romberg Syndrome: A Case Report and an Insight Into Etiology.
Parry-Romberg syndrome (PRS) is a rare degenerative disorder of unknown cause that causes slow, progressive atrophy on one side of the face. The cause may be a malfunction of the sympathetic nervous system, with or without neurological symptoms. Atrophy usually begins in childhood and progresses gradually over several years. Stabilization can take up to 20 years. There is no definitive cure for this condition, but once the condition is stabilized, reconstructive surgery of the damaged skin and soft tissue can correct the deformity. The objective of this article is to present an insight into the etiology of PRS with a case report of a 15-year-old male patient, who was diagnosed with PRS due to trauma and developed progressive hemifacial atrophy without neurological manifestations. PRS is a progressive disease that severely affects one side of the face. Because of its devastating effects on the entire body, treatment requires a multidisciplinary approach. Further research is needed to clearly understand the etiology and provide patients with accurate treatment plans.


Paraganglioma in the posterior mediastinum: a case report.
Paragangliomas are tumors that arise from extra-adrenal chromaffin cells. Herein, we present a rare case of a functional paraganglioma in the posterior mediastinum. A 36-year-old man presented with paroxysms of chest pain and headache. At presentation, the patient's blood pressure was 190/120 mmHg. Chest computed tomography and magnetic resonance imaging revealed a left paravertebral mass in the posterior mediastinum. 123I-metaiodobenzylguanidine scanning revealed focally high tracer uptake in the left paravertebral area. The metanephrine level in the urine was elevated, confirming a rare, catecholamine-producing, functional paraganglioma in the posterior mediastinum. Before surgery, the patient was prepared by orally administering α- and β-adrenergic blockers. The mass was then resected via a lateral thoracotomy. The metanephrine level in urine was normal 24 h after surgery. Paragangliomas in the posterior mediastinum are very rare, but more than half of all cases are functional. The associated symptoms are curable with complete resection, and long-term follow-up for recurrence is important.


An unexpected interactive pattern of visual field asymmetries revealed by faster/slower response partitioning.
Subjects were presented with unilaterally-exposed schematic, outline faces in one condition, and three-letter single-syllable first names in another. In either case there was an ensemble of four items which were to be partitioned, by the subjects making a manual choice-reaction-time response, into two subsets. No easy rule permitted the partitioning either of the faces or of the names (DEN, LES versus LEN, DES). While no clear pattern of asymmetries emerged from an overall analysis, or from a simple comparison of the two types of response, when the subjects' individual responses were instead partitioned into faster and slower, a striking pattern of interactive asymmetries emerged which was consistent for both sexes and both tasks. Thus the slower of the two responses was associated with a left field superiority, and the faster with a right. These findings were discussed in the context of perceived or covert task demands, which are not always immediately recognizable from a superficial or conventional analysis of response data, and the effect of positive (target) and negative (nontarget) processing upon behavioral asymmetries.


Proposal and validation of a new model to estimate survival for hepatocellular carcinoma patients.
The survival of hepatocellular carcinoma (HCC) patients is heterogeneous. We aim to develop and validate a simple prognostic model to estimate survival for HCC patients (MESH score). A total of 3182 patients were randomised into derivation and validation cohort. Multivariate analysis was used to identify independent predictors of survival in the derivation cohort. The validation cohort was employed to examine the prognostic capabilities. The MESH score allocated 1 point for each of the following parameters: large tumour (beyond Milan criteria), presence of vascular invasion or metastasis, Child-Turcotte-Pugh score ≥6, performance status ≥2, serum alpha-fetoprotein level ≥20 ng/ml, and serum alkaline phosphatase ≥200 IU/L, with a maximal of 6 points. In the validation cohort, significant survival differences were found across all MESH scores from 0 to 6 (all p < 0.01). The MESH system was associated with the highest homogeneity and lowest corrected Akaike information criterion compared with Barcelona Clínic Liver Cancer, Hong Kong Liver Cancer (HKLC), Cancer of the Liver Italian Program, Taipei Integrated Scoring and model to estimate survival in ambulatory HCC Patients systems. The prognostic accuracy of the MESH scores remained constant in patients with hepatitis B- or hepatitis C-related HCC. The MESH score can also discriminate survival for patients from early to advanced stages of HCC. This newly proposed simple and accurate survival model provides enhanced prognostic accuracy for HCC. The MESH system is a useful supplement to the BCLC and HKLC classification schemes in refining treatment strategies.


Rasnitsynala sigambrorum gen. et sp. n., a small odonatopterid ("Eomeganisoptera", "Erasipteridae") from the early Late Carboniferous of Hagen-Vorhalle (Germany).
Besides Erasipteroides valentini (Brauckmann in Brauckmann, Koch & Kemper, 1985), Zessinella siope Brauckmann, 1988, and Namurotypus sippeli Brauckmann & Zessin, 1989, Rasnitsynala sigambrorumgen. et sp. n. is the fourth species of the Odonatoptera from the early Late Carboniferous (Early Pennsylvanian: Namurian B, Marsdenian) deposits of the important Hagen-Vorhalle Konservat-Lagerstätte in Germany. With its wing-span of about 55 mm it is unusually small even for the "Eomeganisoptera". Its venation resembles other small "Eomeganisoptera", in particular Zessinella siope. This is why it is here assigned to the probably paraphyletic "Erasipteridae" Carpenter, 1939.


Menstruation-Induced Psychosis in a Pediatric Patient: A Case Report.
Menstruation-induced psychosis (MIP) is a rare disorder with limited documentation in the medical literature. Most cases have been described in case reports, although multiple literature reviews have demonstrated the relationship between menses and psychosis. Here, we describe 2 episodes of rapid-onset psychosis in a healthy 15-year-old girl. Written informed consent was obtained from the patient and their father. On first evaluation, autoimmune encephalitis was the leading diagnosis of consideration. The patient received intravenous immune globulin, returning to baseline within 24 hours of administration. Extensive neurological workup was unrevealing, aside from mild cerebrospinal fluid pleocytosis, serum anti-thyroid peroxidase (TPO) antibodies, and a fluid-attenuated inversion recovery (FLAIR) splenial lesion on magnetic resonance imaging. Psychotic symptoms began around the start of the patient's menstrual cycle, and both episodes were less than 1 week in duration. This report reviews the characteristics of MIP, details a case of recurrent psychosis that fits these characteristics, and adds a well-documented case to the growing series of reports. Given the rarity of MIP, it is essential to thoroughly document such cases. This case provides an example of the clinical presentation and disease course for pediatric patients presenting with MIP, and may serve as a reference for future work in understanding MIP. MIP is characterized by psychotic symptoms of acute onset and short duration that occur in association with the menstrual cycle.1,2 MIP can present in any individual capable of menstruation, including those who do not identify as female. Per previous reports, patients generally have no history of mental illness prior to their first psychotic episode and completely recover their baseline functioning.1 In this case, the patient's presentation is consistent with the characteristics previously described for MIP.1.


Enabling factors and barriers for the use of health impact assessment in decision-making processes.
To identify key stakeholders' views of factors that may enable or limit the use of health impact assessment (HIA) in the decision-making processes within their organizations. In-depth interviews were carried out with 14 key informants from local and regional stakeholder organizations. North East of England, 2005. Three emergent themes were identified: leadership in HIA; integration of HIA with existing organizational structures; and joint working between key stakeholder organizations. With the exception of a 'leadership vacuum' that had not been described previously, the present findings on factors that enable or limit the use of HIA in decision making by organizations in the region are consistent with those reported previously in the literature. In the absence of a nationally defined regulatory and organizational framework for HIA practice, key stakeholders' views on factors that promote or hinder the use of HIA in the decision-making process of their organizations may be pivotal in advancing HIA practice in the region.


Effectiveness of Coupled Application of AmpFℓSTR Yfiler Kit and Reduced Size Y-chromosomal Short Tandem Repeat Analysis for Archeological Human Bones.
The AmpFℓSTR Yfiler PCR Amplification (Yfiler) kit continues to be improved for a better analytical efficiency in cases of highly degraded DNA. The authors endeavored to determine whether coupling of the Yfiler kit with supplemental multiplex amplification of some Y-STR loci is a more efficient analytical mode for poorly preserved human femurs (n = 15) discovered at Korean archeological sites. To reveal locus profiles not easily obtained by Yfiler analysis, custom-designed primers were adopted for the DYS390, DYS391, DYS392, DYS438, DYS439, and DYS635 loci. The success rate for 16 Y-STR locus profiles obtained from the 15 femurs was improved from 18.33% (in the use of Yfiler kit only) to 49.17% (the coupled use of Yfiler and custom-designed primers). In this study, the authors established that the custom-designed primers offer a markedly improved success rate for obtainment of Y-STR profiles from degraded aDNA not easily identified by sole use of the Yfiler assay.


Single point mutations enhance activity of cis-epoxysuccinate hydrolase.
To enhance activity of cis-epoxysuccinate hydrolase from Klebsiella sp. BK-58 for converting cis-epoxysuccinate to tartrate. By semi-saturation mutagenesis, all the mutants of the six important conserved residues almost completely lost activity. Then random mutation by error-prone PCR and high throughput screening were further performed to screen higher activity enzyme. We obtained a positive mutant F10D after screening 6000 mutations. Saturation mutagenesis on residues Phe10 showed that most of mutants exhibited higher activity than the wild-type, and the highest mutant was F10Q with activity of 812 U mg(-1) (k cat /K m , 9.8 ± 0.1 mM(-1) s(-1)), which was 230 % higher than that of wild-type enzyme 355 U mg(-1) (k cat /K m , 5.3 ± 0.1 mM(-1) s(-1)). However, the thermostability of the mutant F10Q slightly decreased. The catalytic activity of a cis-epoxysuccinate hydrolase was efficient improved by a single mutation F10Q and Phe10 might play an important role in the catalysis.


Quality of life and sexual function evaluation in women with urogynecological diseases analyzed with telemedicine during the COVID-19 period: the beginning of a new era?
The aim of this study was to demonstrate that the implementation of remote medical care in the management of patients suffering from specific urogynecological diseases can be a valid alternative to outpatient visits leading to a huge saving of resources which can be used for real emergencies. Therefore, the primary aim of this study was to demonstrate that patients treated with telehealth had the same improvement in symptoms and Quality of Life as those treated with outpatient visits. Observational analysis on women with urogynecological diseases was performed during restrictive measures period. One group of patients was assessed in the clinic and one group by video consultations. The population answered Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS), the Overactive Bladder Questionnaire Symptoms and Health-Related Quality of Life Short-Form Symptoms (OAB-Q), Prolapse Quality of Life Questionnaire (P-QoL), the Pelvic Pain and Urinary/Frequency Patient Symptom Scale (PUF) scores, the Short Form Health Survey questionnaires (SF-36) during the first visit and after 12 weeks. The primary endpoint was to evaluate the change in symptoms after the outpatient and telemedicine visit. The secondary endpoint was the evaluation of the telemedicine impact on the Quality of Life and sexual function. One hundred twenty-five patients were considered. Symptoms of overactive bladder, genitourinary syndrome, and recurrent urinary infections improved significantly in both groups with no significant differences. Sexual activity increased significantly in both groups with a significant change in FSFI and FSDS values. The SF-36 showed a significant change 12 weeks after the visit in both groups. Telemedicine is equally useful and effective as the outpatient visits in patients suffering from urogynecological diseases.


Reference intervals for hematological and biochemical analytes in a single herd of clinically healthy gelding donkeys in Saint Kitts.
There is a large population of donkeys in Saint Kitts; however, hematological and biochemical reference intervals (RIs) are lacking. This study addressed this deficiency by following the American Society for Veterinary Clinical Pathology RI guidelines. Sixty-six healthy, gelding standard donkeys with a median and interquartile range age of 5 years (3.5 - 8 years) and a mean ± standard deviation body weighed of 156 ± 16.7 kg were used to produce a five-part differential complete blood count using an impedance-based analyzer. Clinical chemistry analytes were quantified using a photometric-based analyzer utilizing two reagent rotors that determined 14 and 11 analytes, respectively. An electrochemical-based analyzer quantified chloride, sodium and potassium. Reference intervals were computed using Reference Value Advisor. Results of analytes determined using different rotors/analyzers were assessed using Passing-Bablok regression and Bland-Altman plot analyses. Reference intervals for 43 hematological and biochemical analytes were generated. Reference intervals for hematocrit, red blood cells, white blood cells, total protein, glucose, blood urea nitrogen, and creatinine were 23.67% - 38.08%, 4.08 - 6.42 1012/L, 4.7 - 12.34 109/L, 5.84 - 6.93 g/dL, 64.7 - 130.9 mg/dL, 11.1 - 13.4 mg/dL, and 0.67 - 1.36 mg/dL, respectively. There was good agreement between detection system for albumin, aspartate aminotransferase, gamma glutamyl transferase, total protein, globulin, and potassium, but not for blood urea nitrogen, calcium, creatinine kinase, and sodium. This study is the first to establish hematological and biochemical RIs in donkeys in Saint Kitts. These values will be useful for clinical decision-making.


Phase 1b clinical trial of pucotenlimab (HX008), a novel anti-PD-1 monoclonal antibody, combined with gemcitabine and cisplatin in the first-line treatment of metastatic triple-negative breast cancer.
Pucotenlimab, also called HX008, is a humanized anti-PD-1 antagonist IgG4 mAb. It blocks programmed cell death protein 1 (PD-1), programmed-death ligand 1 (PD-L1), and programmed death ligand-2 (PD-L2). In the CBCSG 006 trial, gemcitabine plus cisplatin (GP) has shown impressive antitumor activity as first-line therapy for metastatic triple-negative breast cancer (mTNBC). The phase 1b study was conducted to assess the safety and preliminary antitumor activity of pucotenlimab when combined with GP in patients with mTNBC in the first-line setting. Eligible patients with mTNBC with ≥6 months of DFI (disease-free interval) who have never received antitumor therapy for metastatic disease were screened. Participants received pucotenlimab at 3 mg/kg (d1, q3w) plus gemcitabine at 1,250 mg/m2 (d1, 8, q3w) and cisplatin at 75 mg/m2 (d1, q3w). Eligible patients received up to six cycles of pucotenlimab along with GP chemotherapy, while pucotenlimab could be maintained until disease progression or unacceptable toxicity occurred or withdrawal of informed consent. This study was registered in China under registration number CTR20191353. Between July 2019 and March 2020, 31 patients were enrolled in this study. The median age was 50 (range 28-68) years. Among 31 patients who were evaluated, 25 (80.6%) experienced objective response and the other six (19.4%) experienced stable disease (SD). As of 4 August, the median progression-free survival (PFS) was 9.0 months (95% CI, 6.2-9.2). The most common grade 3 or 4 treatment-related adverse events included neutropenia (74.1%), anemia (35.5%), thrombocytopenia (32.3%), hypocalcemia (9.7%), hypokalemia (9.7%), and alanine aminotransferase increased (6.5%). There were no treatment-related deaths. Pucotenlimab plus GP demonstrated promising activity and a manageable safety profile in patients with mTNBC in the first-line setting.


Comparison of activity, structure, and dynamics of SF-1 and LRH-1 complexed with small molecule modulators.
Steroidogenic factor-1 (SF-1) is a phospholipid-sensing nuclear receptor expressed in the adrenal glands, gonads, and hypothalamus which controls steroidogenesis and metabolism. There is significant therapeutic interest in SF-1 because of its oncogenic properties in adrenocortical cancer. Synthetic modulators are attractive for targeting SF-1 for clinical and laboratory purposes due to the poor pharmaceutical properties of its native phospholipid ligands. While small molecule agonists targeting SF-1 have been synthesized, no crystal structures have been reported of SF-1 in complexes with synthetic compounds. This has prevented the establishment of structure-activity relationships that would enable better characterization of ligand-mediated activation and improvement in current chemical scaffolds. Here, we compare the effects of small molecules in SF-1 and its close homolog, liver receptor homolog-1 (LRH-1), and identify several molecules that specifically activate LRH-1. We also report the first crystal structure of SF-1 in complex with a synthetic agonist that displays low nanomolar affinity and potency for SF-1. We use this structure to explore the mechanistic basis for small molecule agonism of SF-1, especially compared to LRH-1, and uncover unique signaling pathways that drive LRH-1 specificity. Molecular dynamics simulations reveal differences in protein dynamics at the pocket mouth as well as ligand-mediated allosteric communication from this region to the coactivator binding interface. Our studies, therefore, shed important insight into the allostery driving SF-1 activity and show potential for modulation of LRH-1 over SF-1.


Targeting helminths: The expanding world of type 2 immune effector mechanisms.
In this new review, Rick Maizels and Bill Gause summarize how type 2 immune responses combat helminth parasites through novel mechanisms, coordinating multiple innate and adaptive cell and molecular players that can eliminate infection and repair-resultant tissue damage.


B-type natriuretic peptide for the treatment of congestive heart failure.
Since their discovery 20 years ago, the natriuretic peptides have emerged as an important endocrine response to excessive increases in intravascular volume. In a cGMP-dependent fashion, the natriuretic peptides induce a balanced vasodilation, decreasing preload and afterload in states of cardiac impairment and stimulating the excretion of salt and water by the kidneys. Recombinant B-type natriuretic peptide (nesiritide), identical to the principle natriuretic peptide produced by human cardiac ventricles, has just been approved for the treatment of acute decompensated congestive heart failure. Nesiritide has been shown in controlled trials in congestive heart failure to decrease pulmonary capillary wedge pressure, improve cardiac output, stimulate natriuresis and diuresis, and rapidly induce symptomatic relief. As a naturally occurring stress hormone of the heart, with particular rectifying effects on the pulmonary, cardiac and renal vasculatures, B-type natriuretic peptide may prove useful in a variety of cardiovascular disease states.


Familial subacute necrotizing encephalomyelopathy of the adult form (adult Leigh syndrome).
A family--mother and 2 sons--with a heredodegenerative neurological disease is described. The disease started with bilateral optic atrophy, central scotoma, and color blindness during the second decade. This was followed by a quiescent period until additional neurological symptoms appeared, around the age of 50 years in the case of the mother and 40 and 30 years, respectively, in the sons. The additional symptoms were ataxia, spastic paresis, clonic jerks, grand mal seizures, psychia lability, and slight dementia. The disease was progressive, resulting in permanent hospitalization within a few years. The mother died at the age of 63 years and the sons at 46 and 43 years of age. Neuropathological examination revealed lesions histopathologically characteristic of subacute necrotizing encephalomyelopathy (SNE, Leigh disease), and their distribution in the brain and brainstem also conformed to this disease. On the basis of the clinical course and neuropathological findings, we consider that these 3 patients represent the first reported familial cases of the adult form of SNE.


Pre-treatment and post-treatment evaluation of prostatic adenocarcinoma for prostatic specific acid phosphatase and prostatic specific antigen by immunohistochemistry.
Prostatic specific acid phosphatase and prostatic specific antigen have been used as specific markers of prostatic adenocarcinoma in immunohistochemical studies, particularly when seeking the primary site of a poorly differentiated metastasis. We herein evaluate the effect of therapy on the persistence of these markers in surgically obtained tissues. Prostatic biopsies from 30 patients with adenocarcinoma of the prostate gland before and after treatment with orchiectomy alone, diethylstilbestrol, external beam radiation or combined radiation and diethylstilbestrol were studied for prostatic specific acid phosphatase and prostatic specific antigen using the indirect immunoperoxidase technique. The interval between biopsies ranged from 3 to 72 months, with an average of 28 months. All pre-treatment biopsies stained positively for prostatic specific acid phosphatase and prostatic specific antigen. Staining for prostatic specific antigen and prostatic specific acid phosphatase was seen easily in 29 of 30 post-treatment biopsies, while in 1 case infiltrating anaplastic cells surrounded by stroma showed staining for these antigens in an extremely small percentage of cells, which were overlooked easily unless examined carefully. In view of this small number of positively staining cells this case was designated as equivocal. While some cases demonstrated less intense staining in post-treatment biopsies compared to pre-treatment, this finding was by no means constant. With these primary antisera a higher percentage of cytologically malignant cells stained positively for prostatic specific acid phosphatase than for prostatic specific antigen in adjacent tissue sections in some cases. Prostatic specific acid phosphatase and prostatic specific antigen appear to be sensitive and persistent markers of prostatic adenocarcinoma despite morphologic changes accompanying various therapies.


Kidney transplant recipients with functioning grafts for more than 15 years.
Renal transplantation is the best renal replacement therapy because it significantly improves patient survival. The developments in transplantation and increasing number of patients with end-stage renal disease (ESRD) have unmasked long-term complications secondary to immunosuppressive drugs and chronic renal failure. Eighty-six renal transplant recipients with grafts that have functioned more than 15 years were included in the study. This cross-sectional retrospective analysis of demographic, clinical, and laboratory findings was conducted in 3 Turkish transplantation centers. The mean age was 30.4 ± 10.2 years at the time of the transplantation. The mean time between the transplantation and the study was 19.1 ± 3.6 years. At the time of the study, mean creatinine level was 1.52 ± 0.60 mg/dL, 70.09% of the patients displayed glomerular filtration rates <60 mL/min/1.73 m(2). Urinary protein excretion was 0.57 ± 0.65 g/d. Hypertension and hyperlipidemia were the most common comorbid diseases. Twelve patients had diabetes and 9 cardiovascular disease. Seventeen patients had been diagnosed with skin and 5 with non-skin cancer. As the number of recipients with long-term functioning grafts increases, long-term complications become evident, particularly chronic renal failure. Survivors should be evaluated regularly and treated early for risk factors and complications to improve long-term graft and patient survival.


Systematic assessment of bone resorption, collagen synthesis, and calcification in chick embryonic calvaria in vitro: effects of prostaglandin E2.
A systematic method has been developed to assess bone resorption, matrix formation, and calcification in a single calvarial culture from 20-day-old chick embryos. The bones were prelabeled with 45Ca by an injection into the egg white before culture. In the last 2 h of incubation, the bones were further labeled with both 3H-proline and 3H-tetracycline. Bone resorption was assessed as 45Ca release into the medium. Collagen synthesis was measured by the incorporation of 3H-proline into collagenase-digestible protein (CDP). Since tetracycline has been commonly used as an in vivo marker for osteoid calcification, we assessed in vitro calcification as the uptake of 3H-tetracycline into bone. By using this method, we studied the effects of prostaglandin E2 (PGE2) and indomethacin, which inhibits biosynthesis of PGE2, on bone resorption and formation. The cultured bone synthesized approximately 300 ng of PGE2 during every 24 h of incubation, and indomethacin (10(-6) M) completely inhibited the synthesis. In indomethacin-treated cultures, % 45Ca release and the labeling of CDP were significantly reduced. These reductions were not seen when exogenous PGE2 (10(-9) M) comparable to its endogenous level was added along with the indomethacin. Furthermore, 10(-8) to 10(-5) M PGE2 increased % 45Ca release and the CDP labeling. In addition, the uptake of 3H-tetracycline into the cultured bone was also enhanced by PGE2. In devitalized calvaria, PGE2 had no effect on 3H-tetracycline uptake, suggesting that the stimulative effect on PGE2 was cell-mediated.(ABSTRACT TRUNCATED AT 250 WORDS)


The epidemiology of animal trichinellosis in China.
The epidemiology of animal trichinellosis in China based mainly upon original Chinese literature published between 1937 and 2004 is reviewed. The seroprevalence of Trichinella infection in herbivores was 0.7% (2/300) in cattle and 0.8% (4/500) in sheep. The prevalence of trichinellosis in naturally infected cattle was 1.2% (2/163). Trichinella larvae were detected in 1.4% (3/215) of sheep and in 2.1% (1/47) of beef cattle sold at markets. Canine trichinellosis was recorded in 13 Provinces, Autonomous Regions or Municipalities (P/A/M) and the average prevalence of the infection in dogs slaughtered in abattoirs was 16.2% (5654/34,983) ranging from 1.2% to 44.8%, with the highest prevalence located in northeast China. The prevalence in dog meat sold at markets was 3.5% (988/27,898) in 5 P/A. Feline Trichinella infection was reported in 10 P/A/M. The prevalence of Trichinella infection in rats varied from 1.1% (51/459) to 15.1% (50/332). Trichinella larvae were detected in 1.5% (9/587) of house rats (Rattus norvegicus) as well as in 0.8% (3/369) of wild rats (Apodemus chevrieri), and the infection was recorded also in other wildlife (foxes, bears, wild boar, weasels, raccoon dogs, muntjak and bamboo rats). Trichinella larvae were detected in 2.6% (4/156) of weasels (Mustela sibirica), 1.5% (2/135) of shrews (Tupaia belangeri) and 7.7% (1/13) of moles (Parascapter leucurus). All Trichinella isolates from domestic pigs were identified as T. spiralis. Some Trichinella isolates from dogs in north-eastern China were identified as T. nativa, which has muscle larvae that are highly resistant to freezing. Twenty-seven outbreaks of human trichinellosis associated with mutton, dog and game meat occurred in China between 1964 and 2004, but the quarantine of Trichinella larvae in such meat is not mandatory in China at present.


High adsorptive γ-AlOOH(boehmite)@SiO2/Fe3O4 porous magnetic microspheres for detection of toxic metal ions in drinking water.
γ-AlOOH(boehmite)@SiO(2)/Fe(3)O(4) porous magnetic microspheres with high adsorption capacity toward heavy metal ions were found to be useful for the simultaneous and selective electrochemical detection of five metal ions, such as ultratrace zinc(II), cadmium(II), lead(II), copper(II), and mercury(II), in drinking water.


Presbycusis: reversible with anesthesia drugs?
Age-related hearing impairment, or presbycusis, is a degenerative condition not currently treatable by medication. It is therefore significant that the author, as a patient, experienced a reversal of high-frequency hearing loss during a 2-day period following abdominal surgery with general anesthesia. This report documents the surgery and the subsequent restoration of hearing, which was bilateral and is estimated to have exceeded 50dB at 4kHz. A possible role is noted for anesthetic agents such as lidocaine, propofol, or fentanyl. This experience may hold a clue for research toward the development of medical treatments for presbycusis.


Predicting cumulative lead (Pb) exposure using the Super Learner algorithm.
Chronic lead (Pb) exposure causes long term health effects. While recent exposure can be assessed by measuring blood lead (half-life 30 days), chronic exposures can be assessed by measuring lead in bone (half-life of many years to decades). Bone lead measurements, in turn, have been measured non-invasively in large population-based studies using x-ray fluorescence techniques, but the method remains limited due to technical availability, expense, and the need for licensing radioactive materials used by the instruments. Thus, we developed prediction models for bone lead concentrations using a flexible machine learning approach--Super Learner, which combines the predictions from a set of machine learning algorithms for better prediction performance. The study population included 695 men in the Normative Aging Study, aged 48 years and older, whose bone (patella and tibia) lead concentrations were directly measured using K-shell-X-ray fluorescence. Ten predictors (blood lead, age, education, job type, weight, height, body mass index, waist circumference, cumulative cigarette smoking (pack-year), and smoking status) were selected for patella lead and 11 (the same 10 predictors plus serum phosphorus) for tibia lead using the Boruta algorithm. We implemented Super Learner to predict bone lead concentrations by calculating a weighted combination of predictions from 8 algorithms. In the nested cross-validation, the correlation coefficients between measured and predicted bone lead concentrations were 0.58 for patella lead and 0.52 for tibia lead, which has improved the correlations obtained in previously-published linear regression-based prediction models. We evaluated the applicability of these prediction models to the National Health and Nutrition Examination Survey for the associations between predicted bone lead concentrations and blood pressure, and positive associations were observed. These bone lead prediction models provide reasonable accuracy and can be used to evaluate health effects of cumulative lead exposure in studies where bone lead is not measured.


Potential effectiveness of quality assurance screening using large but imperfect databases.
To examine the effect of imprecise classification of patient risk (severity of illness) on an otherwise highly accurate quality assurance screening technique, data on clinical outcomes were generated for a simulated hospital system consisting of 108 facilities treating approximately 565,000 patients a year. In these simulations, marked differences in facility size, casemix distribution, and quality of care were combined with random variations in outcome. Pooled data for all 108 facilities were used to create algorithms that combined 468 discrete patient risk classifications into either ten or three groups with broad, overlapping ranges of patient-specific risks of unfavorable clinical results. When derived algorithms were applied to independently generated facility-specific data, the ability to identify hospital systems with and without quality of care problems was maintained with ten, but not with three, risk groups. However, even three moderately heterogeneous risk groups were sufficient to preserve a high degree of sensitivity and specificity in screening for potential quality of care problems within individual facilities. Thus, outcome-based quality assurance screening can be highly accurate in actual health care situations in which only imprecise estimations of patient-specific risk can be achieved.


High-performance liquid chromatography as a technique to determine protein adsorption onto hydrophilic/hydrophobic surfaces.
The purpose of this study is to evaluate the potential of simple high performance liquid chromatography (HPLC) setup for quantification of adsorbed proteins on various type of plane substrates with limited area (<3 cm(2)). Protein quantification was investigated with a liquid chromatography chain equipped with a size exclusion column or a reversed-phase column. By evaluating the validation of the method according to guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), all the results obtained by HPLC were reliable. By simple adsorption test at the contact of hydrophilic (glass) and hydrophobic (polydimethylsiloxane: PDMS) surfaces, kinetics of adsorption were determined and amounts of adsorbed bovine serum albumin, myoglobin and lysozyme were obtained: as expected for each protein, the amount adsorbed at the plateau on glass (between 0.15 μg/cm(2) and 0.4 μg/cm(2)) is lower than for hydrophobic PDMS surfaces (between 0.45 μg/cm(2) and 0.8 μg/cm(2)). These results were consistent with bicinchoninic acid protein determination. According to ICH guidelines, both Reversed Phase and Size Exclusion HPLC can be validated for quantification of adsorbed protein. However, we consider the size exclusion approach more interesting in this field because additional informations can be obtained for aggregative proteins. Indeed, monomer, dimer and oligomer of bovine serum albumin (BSA) were observed in the chromatogram. On increasing the temperature, we found a decrease of peak intensity of bovine serum albumin as well as the fraction of dimer and oligomer after contact with PDMS and glass surface. As the surface can act as a denaturation parameter, these informations can have a huge impact on the elucidation of the interfacial behavior of protein and in particular for aggregation processes in pharmaceutical applications.


Biofeedback applications to migraine and tension headaches: a double-blinded outcome study.
The efficacy of progressive relaxation, fingertip temperature training, and EMG training of the frontalis muscles was tested against chronic migraine and tension headaches in a double-blinded 3 X 2 design. All 56 subjects reported being conditioned in the course of the nine 1/2-hour training sessions. Detailed records of perceived severity and duration of the headaches were maintained by the subjects before the study and for at least 3 months after the training period. While even a conservative F revealed a diminution of perceived severity, of hours/month of headache, and of an index conceived by Budzynski, Stoyva, Adler, and Mullaney (1973), across time, at beyond the .05 level of significance, no specific treatment emerged as clearly most effective for either type of headache. Over time, however, progressive relaxation was not as good as the other procedures in reducing the number of hours/month of headache.


Synthesis and biological evaluation of novel 5,6-dihydropyrimido[4,5-f]quinazoline derivatives as potent CDK2 inhibitors.
As serine/threonine kinase, the cyclin dependent kinase 2 (CDK2) is a promising target for various diseases such as cerebral hypoxia, cancer, and neurodegenerative diseases. Here we reported the structure-based synthesis and biological evaluation of novel 5,6-dihydropyrimido[4,5-f]quinazoline derivatives as CDK2 inhibitors, which exhibited potent CDK2 inhibitory activities, as well as anticancer activities in low concentration against two human cancer cell lines (MCF-7 and HCT116). In particular, compounds 11a and 11f (IC50 values of 0.11 and 0.09 μM for CDK2, respectively) have demonstrated significantly inhibitory potency against CDK2 and have showed great inhibitory activities against MCF-7 and HCT116 cell lines.


Clinical decision support increases diagnostic yield of computed tomography for suspected pulmonary embolism.
Determine effects of evidence-based clinical decision support (CDS) on the use and yield of computed tomographic pulmonary angiography for suspected pulmonary embolism (CTPE) in Emergency Department (ED) patients. This multi-site prospective quality improvement intervention conducted in three urban EDs used a pre/post design. For ED patients aged 18+years with suspected PE, CTPE use and yield were compared 19months pre- and 32months post-implementation of CDS intervention based on the Wells criteria, provided at the time of CTPE order, deployed in April 2012. Primary outcome was the yield (percentage of studies positive for acute PE). Secondary outcome was utilization (number of studies/100 ED visits) of CTPE. Chi-square and statistical process control chart assessed pre- and post-intervention differences. An interrupted time series analysis was also performed. Of 558,795 patients presenting October 2010-December 2014, 7987 (1.4%) underwent CTPE (mean age 52±17.5years, 66% female, 60.1% black); 34.7% of patients presented pre- and 65.3% post-CDS implementation. Overall CTPE diagnostic yield was 9.8% (779/7987 studies positive for PE). Yield increased a relative 30.8% after CDS implementation (8.1% vs. 10.6%; p=0.0003). There was no statistically significant change in CTPE utilization (1.4% pre- vs. 1.4% post-implementation; p=0.25). A statistical process control chart demonstrated immediate and sustained improvement in CTPE yield post-implementation. Interrupted time series analysis demonstrated the slope of PE findings versus time to be unchanged before and after the intervention (p=0.9). However, there was a trend that the intervention was associated with a 50% increased probability of PE finding (p=0.08), suggesting an immediate rather than gradual change after the intervention. Implementing evidence-based CDS in the ED was associated with an immediate, significant and sustained increase in CTPE yield without a measurable decrease in CTPE utilization. Further studies will be needed to assess whether stronger interventions could further improve appropriate use of CTPE.


N-acetyl-transferase phenotype and risk for preeclampsia.
This study was undertaken to determine whether the N-acetyltransferase (NAT) phenotype contributes to the susceptibility for the development of preeclampsia. The NAT acetylator status was determined by measuring urinary caffeine metabolites in 134 nonpregnant women with a history of preeclampsia and in 109 control women with uncomplicated pregnancy. The chi(2) and logistic regression analyses were used for statistical evaluation of differences in acetylator status. Significantly more fast acetylators were found among the women with a history of preeclampsia (46.3%) than among the controls (25.4%). Fast acetylators showed an odds ratio of 2.5 (95% CI 1.4-4.3) for preeclampsia. No differences in the acetylator status were found between women with a history of preeclampsia only and those with the HELLP syndrome as well. The fast NAT acetylator status, which may result in altered NAT detoxification capacity, is associated with preeclampsia.


Prognostic factors in Spanish COVID-19 patients: A case series from Barcelona.
In addition to the lack of COVID-19 diagnostic tests for the whole Spanish population, the current strategy is to identify the disease early to limit contagion in the community. To determine clinical factors of a poor prognosis in patients with COVID-19 infection. Descriptive, observational, retrospective study in three primary healthcare centres with an assigned population of 100,000. Examination of the medical records of patients with COVID-19 infections confirmed by polymerase chain reaction. Logistic multivariate regression models adjusted for age and sex were constructed to analyse independent predictive factors associated with death, ICU admission and hospitalization. We included 322 patients (mean age 56.7 years, 50% female, 115 (35.7%) aged ≥ 65 years): 123 (38.2) were health workers (doctors, nurses, auxiliaries). Predictors of ICU admission or death were greater age (OR = 1.05; 95%CI = 1.03 to 1.07), male sex (OR = 2.94; 95%CI = 1.55 to 5.82), autoimmune disease (OR = 2.82; 95%CI = 1.00 to 7.84), bilateral pulmonary infiltrates (OR = 2.86; 95%CI = 1.41 to 6.13), elevated lactate-dehydrogenase (OR = 2.85; 95%CI = 1.28 to 6.90), elevated D-dimer (OR = 2.85; 95%CI = 1.22 to 6.98) and elevated C-reactive protein (OR = 2.38; 95%CI = 1.22 to 4.68). Myalgia or arthralgia (OR = 0.31; 95%CI = 0.12 to 0.70) was protective factor against ICU admission and death. Predictors of hospitalization were chills (OR = 5.66; 95%CI = 1.68 to 23.49), fever (OR = 3.33; 95%CI = 1.89 to 5.96), dyspnoea (OR = 2.92; 95%CI = 1.62 to 5.42), depression (OR = 6.06; 95%CI = 1.54 to 40.42), lymphopenia (OR = 3.48; 95%CI = 1.67 to 7.40) and elevated C-reactive protein (OR = 3.27; 95%CI = 1.59 to 7.18). Anosmia (OR = 0.42; 95%CI = 0.19 to 0.90) was the only significant protective factor for hospitalization after adjusting for age and sex. Determining the clinical, biological and radiological characteristics of patients with suspected COVID-19 infection will be key to early treatment and isolation and the tracing of contacts.


Current status and future perspectives of prosthetic valve selection for aortic valve replacement.
Aortic valve abnormality is the most frequent form of valvular heart disease. Notably, aortic stenosis in the elderly population has been increasingly common. Aortic valve replacement (AVR) using prosthetic valve has been still believed as a gold standard surgical intervention for various types of diseased aortic valve. The numerous reports and studies evaluating the clinical outcomes and durability of prosthesis were revealed, however, prosthesis selection for AVR is still debated. In twenty-first century, paradigm shift of prosthesis preference might be emerged from mechanical valves to bioprosthesis due to the development of the technology. Moreover, transcatheter aortic valve implantation accelerated among the worldwide trends. It could be developed having the potential to reduce the mortality and morbidity associated with high-risk traditional AVR. After the current guidelines for the management of patients with valvular heart disease, we should consider the valve choice in various patients' profile setting. This review summarizes the current status of prosthesis selection and future perspectives of ideal aortic valve intervention, including minimal invasive care.


Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists.
Type 2 diabetes mellitus (T2DM) results from compromised pancreatic β-cell function, reduced insulin production, and lowered insulin sensitivity in target organs resulting in hyperglycemia. The GLP-1 hormone has two biologically active forms, GLP-1-(7-37) and GLP-1-(7-36)amide, which are equipotent at the glucagon-like peptide-1 receptor (GLP-1R). These peptides are central both to normal glucose metabolism and dysregulation in T2DM. Several structurally modified GLP-1 analogues are now approved drugs, and a number of other analogues are in clinical trials. None of these compounds is orally bioavailable and all require parenteral delivery. Recently, a number of smaller peptidomimetics containing 11-12 natural and unnatural amino acids have been identified that have similar insulin regulating profiles as GLP-1. The α-conotoxins are a class of disulfide rich peptide venoms isolated from cone snails, and are known for their highly constrained structures and resistance to enzymatic degradation. In this study, we examined whether 11-residue peptidomimetics incorporated into α-conotoxin scaffolds, forming monocyclic or bicyclic compounds constrained by disulfide bonds and/or backbone cyclization, could activate the GLP-1 receptor (GLP-1R). Several compounds showed potent (nanomolar) agonist activity at GLP-1R, as evaluated via cAMP signaling. In addition, HPLC retention times and in silico calculations suggested that mono- and bicyclic compounds had more favorable n-octanol/water partition coefficients according to the virtual partition coefficient model (vLogP), while maintaining a smaller radius of gyration compared to corresponding uncyclized peptidomimetics. Our findings suggest that cyclic peptidomimetics provide a potential avenue for future design of potent, compact ligands targeting GLP-1R and possessing improved physicochemical properties.


Ab initio multireference study of Hetero-Diels-Alder reaction of buta-1,3-diene with alkyl glyoxylates.
Hetero-Diels-Alder (HDA) reaction of methyl glyoxylate with buta-1,3-diene has been investigated using multireference methods (complete active space SCF and multi-reference perturbation theory) and compared with several single-reference methods (including DFT) often used in calculations of catalysed [4+2] cycloadditions. Concerted and stepwise mechanisms, found in the literature, are compared. It is shown, that the stepwise mechanism may be a result of choosing unbalanced active space. Such choice leads to very close singlet and triplet states in the intermediate geometry - an artificial effect, that disappears if properly balanced active space is used (here, we use active space of 12 orbitals and 12 electrons). Conclusions concerning the mechanism and usefulness of the applied methodology are drawn, which might be important for theoretical investigation of stereoselectivity and specificity of catalysts for the HDA reaction.


Antibiotic Stewardship: A Decade of Progress.
Antibiotic stewardship has seen transformative change over the past decade. Antibiotic stewardship infrastructure has grown significantly across the spectrum of health care in hospitals, nursing homes, and ambulatory settings, and issues related to improving antibiotic use have become central to high-level policy discussions, regulations, and legislation. Herein we review important events and developments in stewardship across the spectrum of care with a focus on (1) infrastructure and implementation, (2) requirement and regulation, and (3) measurement of antibiotic use and other outcomes.


High dose of tranexamic acid for treatment of severe menorrhagia in patients with von Willebrand disease.
Menorrhagia is one of the most important and frequent complications in women with congenital von Willebrand disease (vWD). Three cases of menorrhagia with vWD (type 1; 1 case, type 2A; 2 cases) were successfully treated with tranexamic acid at dose of 3 grams daily in four divided doses for the first 5 days of the menstrual cycle. All patients had severe menorrhagia lasted for more than 10 days with iron deficiency anemia of hemoglobin levels of 6.5-8.4 g/dl. Common dosage of tranexamic acid of 1 gram daily in 4 divided doses on days 1-5 of their menstrual cycles did not correct their menorrhagia. The treatment was then changed to the daily dose of 3 grams in 4 divided doses on days 1-5 of their menstrual cycles. Thereafter, their menorrhagia became well-controlled with improvement of their anemia up to hemoglobin of 11.5-12.4 g/dl. High dose of tranexamic acid has been administered safely in all patients for 3-5 years without significant complications. Oral high-dose administration of tranexamic acid is very convenient and useful for treatment of menorrhagia in the patients with vWD.


The cytotoxic properties and preferential toxicity to tumour cells displayed by some 2,4-bis(benzylidene)-8-methyl-8-azabicyclo[3.2.1] octan-3-ones and 3,5-bis(benzylidene)-1-methyl-4-piperidones.
This study demonstrated that replacement of the axial protons on the C2 and C6 atoms of various 1-methyl-3,5-bis(benzylidene)-4-piperidones 3 by a dimethylene bridge leading to series 2 lowered cytotoxic potencies. Four compounds 2a and 3a-c emerged as lead molecules based on their toxicity towards different neoplasms and their selective toxicity for malignant rather than normal cells. Some possible reasons for the disparity between the IC(50) values in the two series of compounds are presented based on molecular modeling, logP values and respiration in rat liver mitochondria.


Acute severe functional mitral regurgitation secondary to cocaine-mediated anterior myocardial infarction.
We report a case of acute severe functional mitral regurgitation in a patient with cocaine-related anterior myocardial infarction. Transesophageal echocardiography played a pivotal role in excluding a mechanical complication, and determining the presence, severity, and mechanism of this life-threatening complication.


Correction to: Post-migration Social-Environmental Factors Associated with Mental Health Problems among Asylum Seekers: A Systematic Review.
The original version of the article unfortunately contained an error in Table 1 and the text under Result section.


Use of monoclonal antibody in a blocking ELISA to detect group specific antibodies to bluetongue virus.
An enzyme-linked immunosorbent assay (ELISA) in the form of a blocking test is described for the detection of group specific antibodies to bluetongue virus (BTV). The test relies upon interruption of the reaction between BTV antigen and a group specific murine monoclonal antibody against BTV by addition of serial dilutions of bovine or ovine test sera containing specific antibodies to BTV which inhibit binding of the monoclonal antibody to the BTV antigen. This is detected as a reduction in the optical density (O.D.) reading obtained with the monoclonal antibody alone. The test is capable of specific detection of antibodies to all 22 serotypes of BTV but, unlike the agar gel precipitin (AGP) test, does not show cross-reactions with antibodies to epizootic haemorrhagic disease of deer (EHD) viruses. Furthermore, antibodies to cellular proteins which complicate interpretation of the AGP test and the indirect ELISA are not detected in the blocking ELISA. The high sensitivity and specificity of the blocking ELISA make it an ideal alternative to the AGP test. The use of a monoclonal antibody would facilitate standardisation of diagnostic testing between laboratories.


First Structure-Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme.
17β-HSD14 belongs to the SDR family and oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD+ as cofactor. The goal of this study was to identify and optimize 17β-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17β-HSD1 and 17β-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17β-HSD14 inhibition. The most interesting hit was taken as starting point for chemical modification applying a ligand-based approach. The designed compounds were synthesized and tested for 17β-HSD14 inhibitory activity. The two best inhibitors identified in this study have a very high affinity to the enzyme with a Ki equal to 7 nM. The strong affinity of these inhibitors to the enzyme active site could be explained by crystallographic structure analysis, which highlighted the role of an extended H-bonding network in the stabilization process. The selectivity of the most potent compounds with respect to 17β-HSD1 and 17β-HSD2 is also addressed.


Altered physical pain processing in different psychiatric conditions.
Several reports indicate either increased or decreased pain sensitivity associated with psychiatric disorders. Chronic pain is highly prevalent in many of these conditions. We reviewed the literature regarding experimental pain sensitivity in patients with major depression, bipolar disorder, posttraumatic stress disorder (PTSD), generalized anxiety disorder, panic disorder, obsessive-compulsive disorder and schizophrenia. Electronic searches were performed to identify studies comparing experimental pain in patients with these conditions and controls. Across 31 depression studies, reduced pain threshold was noted except for ischemic stimuli, where increased pain tolerance and elevated sensitivity to ischemic pain was observed. A more pervasive pattern of low pain sensitivity was found across 20 schizophrenia studies. The majority of PTSD studies (n = 20) showed no significant differences compared with controls. The limited number of bipolar disorder (n = 4) and anxiety (n = 9) studies precluded identification of clear trends. Wide data variability was observed. Awareness of psychiatric patients' pain perception abnormalities is needed for active screening and addressing physical comorbidities, in order to enhance quality of life, life expectancy and mental health.


CD59 homologue regulates complement-dependent cytolysis of rat Schwann cells.
Antibody (Ab) sensitized sciatic nerve Schwann cells (SchC) of 2-day-old rats (SchC/2d) were significantly more susceptible to cytolysis by both heterologous, guinea pig (GP), and homologous rat serum complement (40 +/- 3.8% and 21.2 +/- 3.1%, respectively) than SchC of 6-day-old rats (SchC/6d) (7.9 +/- 5.9% and 2.6 +/- 3.1%, respectively). To determine if resistance to complement (C)-mediated cytolysis correlated with expression of membrane proteins which regulate C activation, we used Western blot and FACS analysis. Binding of specific polyclonal Ab demonstrated similar concentrations of Crry, a regulator of C3 convertase formation, on plasma membranes of SchC 2d and 6d. During C activation, both C3b deposition and iC3b formation were greater on SchC/6d than on SchC/2d and the C3b deposition did not correlate with enhanced cytolysis. In contrast, 2.1-fold more rat CD59, a regulator of C8 and C9 incorporation into C5b-9, detected with Western blot on SchC/6d compared with SchC/2d was confirmed by FACS. Further, both rat and GP C8/C9 lysed SchC/2d expressing human C5b-7 (20.1 +/- 3.7 and 21.6 +/- 4.7%, respectively), while only GP C8/C9 caused cytolysis of 10.7 +/- 4.3% SchC/6d expressing hu C5b-7 and rat C8/C9 did not (0.5 +/- 0.5%). Preincubation of SchC/6d with an F(ab)2 fragment of an mAb to rCD59 with blocking capacity, increased cytolysis mediated by rat serum C more than 6-fold to 16.7 +/- 3.0% but only 1.7-fold (maximum cytolysis 37.4 +/- 11.2%) in SchC/2d. Our data suggest that expression of rat CD59 on SchC increased almost two-fold between postnatal days 2 and 6, and this increased expression on more terminally differentiated SchC is a significant factor in regulating terminal complement complex formation and limiting cytolysis of rat SchC by homologous serum complement.


Classification of Pharynx from MRI Using a Visual Analysis Tool to Study Obstructive Sleep Apnea.
Obstructive sleep apnea (OSA) is a chronic sleeping disorder. The analysis of the pharynx and its surrounding tissues can play a vital role in understanding the pathogenesis of OSA. Classification of the pharynx is a crucial step in the analysis of OSA. A visual analysis-based classifier is developed to classify the pharynx from MRI datasets. The classification pipeline consists of different stages, including pre-processing to select the initial candidates, extraction of categorical and numerical features to form a multidimensional features space, and a supervised classifier trained by using visual analytics and silhouette coefficient to classify the pharynx. The pharynx is classified automatically and gives an approximately 86% Jaccard coefficient by evaluating the classifier on different MRI datasets. The expert's knowledge can be utilized to select the optimal features and their corresponding weights during the training phase of the classifier. The proposed classifier is accurate and more efficient in terms of computational cost. It provides additional insight to better understand the influence of different features individually and collectively. It finds its applications in epidemiological studies where large datasets need to be analyzed.


Enhancement of biocontrol efficacy of Kluyveromyces marxianus induced by N-acetylglucosamine against Penicillium expansum.
This research aimed to investigate the effect of N-acetylglucosamine (GlcNAc) on the biocontrol activity of Kluyveromyces marxianus and involved possible mechanisms. The results indicated that 0.5% GlcNAc significantly improved the antagonistic efficacy of K. marxianus against Penicillium expansum. GlcNAc supplementation led to increases of biocontrol-related enzymes and stress-resistant substances in K. marxianus including chitinase, β-1,3-glucanase, trehalose and proline, being beneficial for yeasts vigor maintenance under adverse circumstances. The antioxidative-related enzyme activities in K. marxianus, such as superoxide dismutase (SOD), catalase (CAT) and others, were increased by GlcNAc along with more quickly excess reactive oxygen species (ROS) scavenging. GlcNAc resulted in an enhancement of proliferative capacity in K. marxianus according to the transcriptomic analysis. Consequently, GlcNAc contributed to improvements of K. marxianus in the environmental adaptability and stress resistance. Our study demonstrated that both GlcNAc and K. marxianus could be regarded as potential candidates for postharvest technology application.


Isolation and characterization of cellulose nanofibers from Agave gigantea by chemical-mechanical treatment.
Nanocellulose is a renewable and biocompatible nanomaterial that evokes much interest because of its versatility in various applications. This study reports the production of nanocellulose from Agave gigantea (AG) fiber using the chemical-ultrafine grinding treatment. Chemical treatment (alkalization and bleaching) removed non-cellulose components (hemicellulose and lignin), while ultrafine grinding reduced the size of cellulose microfibrils into nanocellulose. From the observation of Transmission Electron Microscopy, the average diameter of nanocellulose was 4.07 nm. The effect of chemical-ultrafine grinding on the morphology and properties of AG fiber was identified using chemical composition, Scanning Electron Microscopy, X-ray Diffraction, Fourier Transform Infrared, and Thermogravimetric Analysis. The bleaching treatment increased the crystal index by 48.3% compared to raw AG fiber, along with an increase in the cellulose content of 20.4%. The ultrafine grinding process caused a decrease in the crystal content of the AG fiber. The crystal index affected the thermal stability of the AG fiber. The TGA results showed that AG fiber treated with bleaching showed the highest thermal stability compared to AG fiber without treatment. The FTIR analysis showed that the presence of CH vibrations from the ether in the fiber. After chemical treatment, the peaks at 1605 and 1243 cm-1 disappeared, indicating the loss of lignin and hemicellulose functional groups in AG fiber. As a result, nanocellulose derived from AG fiber can be applied as reinforcement in environmentally friendly polymer biocomposites.


Lymphangiogenesis and angiogenesis in oral cavity and lower lip squamous cell carcinoma.
Tumors of the lip and oral cavity differ in various aspects; therefore a clarification of the distinctions among these sites may help to better understand the biologic behavior of neoplasms occurring in these locations. Considering that angiogenesis and lymphangiogenesis are two major elements that can influence various aspects of tumor biology, we aimed to compare these factors between squamous cell carcinoma of the lower lip and oral cavity. A total of 84 primary squamous cell carcinomas including 45 oral and 39 lower lip tumors were selected and immunohistochemically stained with monoclonal antibody against D2-40 and CD105. Mean microvessel density was assessed in tumoral tissue, while lymphatic vessel density was calculated in both neoplastic tissue and invasion front. Data were statistically analyzed using t-test and p-values of <0.05 were considered significant. We found a mean microvessel density±standard deviation of 31.94±18.9 in oral cavity and 27.54±20.8 in lower lip squamous cell carcinomas, with no significant difference (p=0.32). Mean lymphatic vessel density±standard deviation was 13.05±8.2 and 16.57±10.79 in of oral cavity and lower lip neoplastic tissue, respectively. The corresponding values were 9.94±5.59 and 12.50±7.8 in the invasive front. Significant differences were not observed in either of the lymphatic vessel density variables between the two sites. According to our results, it seems that the search for additional factors other than those related to the vasculature should continue, to help clarify the differences in biologic behavior between lower lip and oral cavity squamous cell carcinomas.


Pedicel development in Arabidopsis thaliana: contribution of vascular positioning and the role of the BREVIPEDICELLUS and ERECTA genes.
Although the regulation of Arabidopsis floral meristem patterning and determinacy has been studied in detail, very little is known about the genetic mechanisms directing development of the pedicel, the short stem linking the flower to the inflorescence axis. Here, we provide evidence that the pedicel consists of a proximal portion derived from the young flower primordium, and a bulged distal region that emerges from tissue at the bases of sepals in the floral bud. Distal pedicel growth is controlled by the KNOTTED1-like homeobox gene BREVIPEDICELLUS (BP), as 35S::BP plants show excessive proliferation of pedicel tissue, while loss of BP conditions a radial constriction around the distal pedicel circumference. Mutant radial constrictions project proximally along abaxial and lateral sides of pedicels, leading to occasional downward bending at the distal pedicel. This effect is severely enhanced in a loss-of-function erecta (er) background, resulting in radially constricted tissue along the entire abaxial side of pedicels and downward-oriented flowers and fruit. Analysis of pedicel vascular patterns revealed biasing of vasculature towards the abaxial side, consistent with a role for BP and ER in regulating a vascular-borne growth inhibitory signal. BP expression in a reporter line marked boundaries between the inflorescence stem and lateral organs and the receptacle and floral organs. This boundary expression appears to be important to prevent homeotic displacement of node and lateral organ fates into underlying stem tissue. To investigate interactions between pedicel and flower development, we crossed bp er into various floral mutant backgrounds. Formation of laterally-oriented bends in bp lfy er pedicels paralleled phyllotaxy changes, consistent with a model where the architecture of mutant stems is controlled by both organ positioning and vasculature patterns. Collectively, our results indicate that the BP gene acts in Arabidopsis stems to confer a growth-competent state that counteracts lateral-organ associated asymmetries and effectively radializes internode and pedicel growth and differentiation patterns.


The correlation between pretreatment serum hormone levels and treatment outcome for patients with prostatic cancer and bony metastasis.
To evaluate whether pretreatment serum hormone levels are a prognostic factor for prostatic cancer with bony metastasis under hormonal treatment. Between 1980 and 1994, 96 patients with prostate cancer and bony metastasis were included for an evaluation by a retrospective review of their charts. All 96 had received hormonal treatment after a diagnosis of metastatic prostatic carcinoma. Serum testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin were assessed before treatment. The patients were divided into two groups according to their response during the follow-up. Group 1 (good response) had no change or resolution of metastatic lesion(s) on the bone scan and a declining prostate-specific antigen (PSA) level. Group 2 had increased PSA or progression of metastatic lesion(s) on the bone scan. Tumours were graded as low (2-4), intermediate (5-7) and high (8-10) using the Gleason score. There were 43 patients in group 1 and 53 in group 2; the overall mean (sd) age was 72.5 (6.8) years and the follow-up 29.5 (0.5) months. The respective mean (sd) levels of testosterone, LH, FSH and prolactin before treatment were 4.6 (1.6) ng/mL, 20.2 (13.3) mIU/mL, 19.6 (18.6) mIU/mL and 20.7 (12.1) ng/mL in group 1, and 2.6 (1.0) ng/mL, 27.3 (11.0) mIU/mL, 27.1 (9.8) mIU/mL and 41.3 (28.4) ng/mL in group 2. The level of testosterone was significantly higher in group 1 than in group 2, while LH, FSH and prolactin were significantly lower in group 1 than in group 2. When stratified by tumour grade, patients in group 1 still had significantly higher pretreatment testosterone and lower LH, FSH and prolactin than those in group 2. Higher testosterone and lower LH, FSH and prolactin levels were good prognostic factors for patients with metastatic prostatic cancer under hormonal treatment, irrespective of tumour grading.


High mobility group protein 1 interacts specifically with the core domain of human TATA box-binding protein and interferes with transcription factor IIB within the pre-initiation complex.
The high mobility group (HMG) box domain has defined a family of proteins, mostly transcription factors, that specifically interacts with DNA on the minor groove and sharply bends it. The founding member of the family, HMG1, does not specifically recognize regular B-DNA but is recruited to DNA by interaction with other transcription factors and TATA box-binding protein (TBP). However, conflicting effects of HMG1 on transcription have been reported. We show that the interaction between HMG1 and TBP is species-specific. This interaction in turn affects the interaction of TBP with transcription factor (TF) IIB and is competed by TFIIA. A primary binding site was mapped to the H2' alpha-helix in the highly conserved core domain of human TBP. On HMG1, the primary binding site was only in the HMG box A, and HMG box A was also sufficient to interact with native TFIID. Both HMG boxes efficiently repressed transcription in vitro as fusions to the Gal4-DNA binding domain. Additionally, HMG box B showed a weak level of activation at very low amounts. These results suggest a general involvement of HMG1 at the early stages of polymerase II transcription that may result in subtle activation or repression of individual genes.


West Midlands Care Home Dental Survey 2011: part 1. Results of questionnaire to care home managers.
To provide baseline data on dental issues affecting residents from the perspective of care home managers to inform oral health local needs assessments and commissioning decisions. A pre-piloted postal questionnaire was sent to all identified managers of adult care homes (1,832) in the West Midlands between February and April 2011. Quantitative analysis was complemented by seeking the views of care home managers regarding training and experience of, and access to, dental services. The response rate to the study was 63.9% (1,170/1,832). There were 194 responding care homes who reported that residents had problems accessing dental services. Nearly double the proportion of nursing care homes and care homes with residents with elderly mental impairment (EMI) reported problems accessing dental services compared with care homes without nursing care and non-EMI care homes. Issues raised included patient safety concerns, reservations regarding expertise of dental staff, difficulties with transporting residents and waiting times for treatment. The survey provided a snapshot of dental issues as reported by care home managers, these results should help inform both the dental profession and those who commission services about issues affecting the oral health of patients living in care homes.


Critical appraisal of the expression of cytochrome P450 enzymes in human lung and evaluation of the possibility that such expression provides evidence of potential styrene tumorigenicity in humans.
Styrene is widely used with significant human exposure, particularly in the reinforced plastics industry. In mice it is both hepatotoxic and pneumotoxic, and this toxicity is generally thought to be associated with its metabolism to styrene oxide. Styrene causes lung tumors in mice but not in rats. The question is how the tumorigenic effect in mouse lung may relate to the human. This review examines the comparison of the metabolic activation rates (1) between the liver and lung and (2) for the lung, between the rodent and human. Emphasis is placed on the specific cytochromes P450 present in the lungs of humans and what role they might play in the bioactivation of styrene and other compounds. In general, pulmonary metabolism is very slow compared to hepatic metabolism. Furthermore, metabolic rates in humans are slow compared to those in rats and mice. There is a wide difference in what specific cytochromes P450 investigators have reported as being present in human lung which makes comparisons, both inter-species and inter-organ, difficult. The general low activity for cytochrome P450 activity in the lung, especially for CYP2F1, the human homolog for CYP2F2 which has been identified in mice as being primarily responsible for styrene metabolism, argues against the hypothesis that human lung would produce enough styrene oxide to damage pulmonary epithelial cells leading to cell death, increased cell replication and ultimately tumorigenicity, the presumed mode of action for styrene in the production of the mouse lung tumors.


Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease?
MicroRNAs (miRNAs) are endogenous 19-25 nucleotide RNAs that have recently emerged as a novel class of important gene-regulatory molecules involved in many critical developmental and cellular functions. miRNAs have been implicated in the pathogenesis of several human diseases, such as neurodegenerative disorders, cancer, and more recently in viral and metabolic diseases. Unraveling the roles of miRNAs in cellular processes linked to human diseases will lead to novel opportunities for the regulation of protein function and will help to evaluate their potential for therapeutic intervention. Approaches to interfere with miRNA function in vitro and in vivo based on synthetic anti-miRNA oligonucleotides (AMOs) are discussed in this review.


Clinical outcomes of ventricular assist device support by HIV infection status: An STS-INTERMACS analysis.
Cardiovascular disease remains the leading cause of mortality in human immunodeficiency virus-infected (HIV-positive) patients. Ventricular assist device therapy is rarely offered to these patients and data on outcomes are sparse. We investigated outcomes following ventricular assist device implants for HIV-positive as compared to non-HIV-infected (HIV-negative) patients. We analyzed 22,065 patients from the Interagency Registry for Mechanically Assisted Circulatory Support registry for outcomes by HIV status. A propensity-matched analysis adjusting for 21 preimplant risk factors was also conducted. Compared with 21,980 HIV-negative device recipients, the 85 HIV-positive recipients were younger (median age 58 years vs 59 years, p = 0.02), had lower body mass index (26 kg/m2 vs 29 kg/m2, p = 0.001), and had higher rates of prior stroke (8% vs 4%, p = 0.02). In the matched HIV-positive and HIV-negative cohorts, there was significantly higher mortality in HIV-positive patients in earlier implant years, however, this association was not seen in later implant years (2018-2020). In both unmatched and matched cohorts, no significant differences in postimplantation stroke, major bleeding, or major infection were noted. With recent advancements in mechanical circulatory support and HIV treatment, ventricular assist device therapy is a viable therapeutic option for HIV-positive patients with end-stage heart failure.


Altered plasma antioxidant status in subjects with Alzheimer's disease and vascular dementia.
Oxygen-free radicals and lipid hydroperoxides may have an aetiological role in the development of lesions in the central nervous system in patients with Alzheimer's disease and in those with vascular dementia. This study aimed to make a cross-sectional comparison of blood markers of oxidative stress in two groups of patients with these disorders and a control group. Cross-sectional comparative study. Established memory clinics in Cardiff organized by a University Department of Geriatric Medicine within an acute care NHS Trust. Following a dietary assessment, postprandial venous blood samples were obtained from the following: 25 subjects with probable Alzheimer's disease (AD) (mean age 74.3; 10 F, 15 M); 17 subjects with probable vascular dementia (VD) (mean age 75.5; 5 F, 12 M); and 41 controls (mean age 73.4; 24 F, 17 M) for measurement of circulating lipid peroxides (LP), total antioxidant capacity (TAC), vitamin C (VitC), vitamin E (VitE) and beta-carotene (BC). Plasma levels of VitC were significantly lower in subjects with vascular dementia compared with controls (VD, 6.5 (4.8, 8.2); controls, 10.0 (8.38, 11.6); VD vs controls, p = 0.015), but no significant difference was seen between controls and patients with Alzheimer's disease (AD, mean 8.3 (6.2, 10.4)). VitE levels were significantly lower in subjects with AD compared with controls (31.1 (28.2, 34.0) vs 36.0 (32.8, 39.2), p = 0.035). BC levels were similar in subjects with AD and controls, but significantly elevated in those with VD (AD, 0.28 (0.2, 0.34); VD, 0.40, (0.27, 0.53); controls, 0.28 (0.22, 0.34); VD vs controls, p = 0.046). There were no significant differences in LP or TAC between the three groups. Subjects with dementia attributed to Alzheimer's disease or to vascular disease have a degree of disturbance in antioxidant balance which may predispose to increased oxidative stress. This may be a potential therapeutic area for antioxidant supplementation.


Lung transplantation for lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease, associated with respiratory symptoms of dyspnea and spontaneous pneumothorax, along with various extra-thoracic manifestations. Often a progressive disease, albeit slowly, patients can develop chronic and severe respiratory failure and require supplemental oxygen. Lung transplantation (LTX) can offer improved duration and quality of life for patients with end-stage lung disease due to LAM. There are several unique considerations for LTX in LAM patients, and disease-specific complications of LAM prior to LTX can affect management decisions. Furthermore, there are several possible post-transplant issues specific to LAM. In this review, we discuss evaluation and management, disease-specific complications (both pre- and post-transplant), and outcomes for LAM patients undergoing lung transplantation.


The Auckland City Hospital Device Point Prevalence Survey 2005: utilisation and infectious complications of intravascular and urinary devices.
In November 2005 a point prevalence survey of all inpatients at Auckland City Hospital was conducted to define the utilisation of intravascular and urinary devices; to measure the prevalence of infectious complications from these devices; and to provide quality assurance information about the use of these devices. All 830 inpatients admitted on a single day under paediatric; adult medical; adult surgical, and women's health were visited by a member of the survey team and data regarding devices in situ was collected. Intravenous (IV) devices were present in 376/830 patients (45%; 95%CI 42-49), and 25/830 (3%; CI 2-4) had either confirmed infection or showed signs of infection. 33/830 patients (4%; CI 3-6) had intravascular devices in situ that were not required. Urinary devices were present in 93/830 patients (11%; CI 9-13), and 13/91 (14%; CI 8-23) had bacteriuria. A large proportion of urinary devices (19/91, 21%; CI 13-31) were found to have been inserted for inappropriate reasons. This study provides information on the current utilisation of devices in our hospital that can be extrapolated to other public hospitals in New Zealand. Healthcare workers require ongoing education to ensure prompt removal of devices that are not required for patient care.


Transfer of (85)Sr and (134)Cs from diet to reindeer foetuses and milk.
Sr-85 and (134)Cs in aqueous solution of the chlorides were administered daily to four pregnant reindeer during the last part of gestation. Radionuclide concentrations were determined in calves sacrificed at birth, and secretion of the nuclides was measured in milk. Although the gastrointestinal absorption of (85)Sr was low, an apparently higher transfer of the absorbed fraction of (85)Sr than (134)Cs from the mother to the foetus led to similar accumulation of (85)Sr and (134)Cs in foetuses. At birth 1.4-1.6 and 1.5-2.5% of the total administered activities of (85)Sr and (134)Cs, respectively, were present in the calves' bodies. Transfer coefficients (F (m)) for (85)Sr and (134)Cs from feed to milk were estimated at 0.0218+/-0.0026 and 0.185+/-0.025 day kg(-1), respectively, and the observed ratio (OR(milk-diet)) for (85)Sr was 0.124+/-0.037. Transfer of radiostrontium to reindeer milk was in agreement with previously reported relationships between Ca intake and radiostrontium transfer in ruminants. These relationships suggest that the transfer of radiostrontium to foetuses and milk of free-ranging reindeer can be 3-4 times higher than observed in this experiment (due to lower Ca intake with natural forage), but the transfer to milk will not be as high as that of ionic (134)Cs. The concentrations of (85)Sr in milk suggested that the does mobilized skeletal stores of Ca and (85)Sr for milk production, although the diet appeared to satisfy the Ca requirements. In reindeer with radiostrontium intake during the whole year, radiostrontium concentrations in milk will therefore be higher than indicated by the F (m) value observed in our study. No differences in half-times for (85)Sr and (134)Cs secretion in milk were detected. Both nuclides were secreted with short- and long-term half-times of 1-2 and 12-19 days, respectively. For (85)Sr, 80-90% of the activity was excreted with the short half-time, whereas the corresponding value for (134)Cs was 30-50%.


Physical dimensions and torsional properties of rotary endodontic instruments. 1. Gates Glidden drills.
A laboratory study was performed on Gates Glidden drills to determine their physical dimensions and torsional properties. Five samples of sizes #1 to #6 drills from two brands distributed in the United States were measured for physical dimensions. Five samples of the most commonly used sizes #1, #2, and #3 drills from these two brands were tested at failure in both the clockwise and counterclockwise directions using an analog torque meter. The values for the bur head dimensions of both brands correspond closely to those established by the ISO. The mean values for torque at failure for both the clockwise and counterclockwise directions showed no statistically significant difference for each brand-size combination. However, some instrument groups had separation or fracture sites near the bur head, while other groups underwent failure near the hand-piece end. This study is the first part of a continuing investigation to establish standards for rotary endodontic instruments.


Development of piperidinyl dipyrrrolopyridine-based dual inhibitors of Janus kinase and Bruton's tyrosine kinase: a potential therapeutic probability to deal with rheumatoid arthritis.
Rheumatoid arthritis is an autoimmune disorder causing joint deformity and work disability. Several drugs are available to deal with the disease including conventional drugs; biological drugs such as TNFα inhibitors, B cell-targeted drugs, T cell co-stimulation inhibitors, interleukin-6 inhibitors, and interleukin-1 inhibitors; and kinase inhibitory drugs. In spite of the broad spectrum of drugs available, the disease remains uncontrolled in a number of patients and there is a need for new drugs with better efficacy and universal response rate. The failure of the available drugs to control the disease can be owed to the complex pathogenesis with complementary pathways of disease progression. The blockade of one pathway cannot supersede pathogenesis through other complementary pathways. Janus kinase (JAK) and Bruton's tyrosine kinase (BTK) are the two important mediators of disease which control a number of signaling pathways involved in rheumatoid arthritis pathogenesis. In this study, using the computer-aided drug designing techniques (virtual screening, molecular docking, and molecular dynamics studies), we have designed piperidinyl dipyrrolopyridine-based dual inhibitors of Janus kinase and Bruton's tyrosine kinase. Dual JAK and BTK inhibitors seem promising to fight the complex pathogenesis of the disease at multiple fronts and can be the future drug for patients unresponsive to current remedies.


Depicting and defining sleep disturbed breathing associated with vagal nerve stimulation.
Vagal nerve stimulators (VNS), which have been approved for management of refractory epilepsy and depression, induce unique disturbances of breathing during sleep (SDBVNS) that are not captured well using standard criteria. The primary purpose of this retrospective study was to compare AASM definitions with alternative criteria to more accurately measure SDBVNS We also sought to assess outcome variables that may be clinically relevant and response to positive airway pressure therapy. We analyzed the electronic medical records and comprehensive polysomnography results of all adult subjects with active VNS for epilepsy who were referred to the sleep center for suspected sleep apnea (2015-2020). We compared standard AASM criteria for defining apneas/hypopnea index (AHIAASM) with three novel scoring criteria for hypopnea according to degree of oxygen desaturation associated with VNS events: AHIVNS0 (none required); AHIVNS2 (2% required); and AHIVNS3 (3% required). Twenty-six subjects were included in the final analysis with 35 PSGs (14 females/12 males). The mean age was 33.6 years and mean body mass index (BMI) of 32.2 kg/m2. AHIAASM measured ≥ 15/hour in 7 (26.9%) subjects versus 21 (80.8%) by AHIVNS0; 15 (70.0%) by AHIVNS2; and 5 (19.2%) by AHIVNS3. Clinically significant hypoxemia was not present. The mean time SpO2<89% was 7 (20.8) minutes. Oximetry tracings often showed a desaturation pattern that resembled a sawfish rather than sawtooth. Arousals specifically linked to VNS activation were not elevated (2.9/hour). The baseline AHIVNS0 was 27.7/hour with a lowest AHIVNS0 on PAP of 27.9/hr. AASM scoring criteria significantly underestimated the degree of VNS induced respiratory disturbances. VNS events were not associated with increased arousals or significant hypoxemia. PAP therapy was an ineffective treatment in this population. This study adds to the increasing body of evidence of sleep disordered breathing related to VNS and questions the clinical significance of this finding.


Evolution and mortality risk factors in children with continuous renal replacement therapy after cardiac surgery.
To study the clinical course of children requiring continuous renal replacement therapy after cardiac surgery and to analyze factors associated with mortality. A prospective observational study was performed that included children requiring continuous renal replacement therapy after cardiac surgery. Univariate and multivariate analyses were performed to determine the influence of each factor on mortality. We compared these patients with other critically ill children requiring continuous renal replacement therapy. Of 1650 children undergoing cardiac surgery, 81 (4.9%) required continuous renal replacement therapy, 65 of whom (80.2%) presented multiple organ failure. The children who started continuous renal replacement therapy after cardiac surgery had lower mean arterial pressure, lower urea and creatinine levels, and higher mortality (43%) than the other children on continuous renal replacement therapy (29%) (P=.05). Factors associated with mortality in the univariate analysis were age less than 12 months, weight under 10 kg, higher pediatric risk of mortality score, hypotension, lower urea and creatinine levels when starting continuous renal replacement therapy, and the use of hemofiltration. In the multivariate analysis, hypotension when starting continuous renal replacement therapy, pediatric risk of mortality scores equal to or greater than 21, and hemofiltration were associated with mortality. Although only a small percentage of children undergoing cardiac surgery required continuous renal replacement therapy, mortality among these patients was high. Hypotension and severity of illness when starting the technique and hemofiltration were factors associated with higher mortality.


Inhibition of two human tumor cell lines by antimetabolites of coenzyme Q10.
5-Chloro-2,3-dimethyoxy-6-octylmercapto-1,4-benzoquinone (NSC 252188) and 2,3-dimethoxy-5-hydroxy-6-phytyl-1,4-benzoquinone (NSC 277818) inhibited the human cell lines 4265 and K 562c, and the experimental animal tumor line W256; they also showed antitumor activity against Walker carcinosarcoma 256 in rats with cures; they also inhibited the mitochondrial coenzyme Q10-enzymes, succinoxidase and NADH-oxidase. 5-Chloro-2,3-dimethoxy-6-n-dodecylmercapto-1,4-benzoquinone (NSC 220334) and 5-chloro-6-omega-cyclohexylhexylmercapto-2,3-dimethoxy-1,4-benzoquinone (NSC 238136) were also active against the K 562c cell line and showed cures against the Walker carcinosarcoma 256 in rats.


Higher serum concentrations of dietary antioxidants are associated with lower levels of inflammatory biomarkers during the year after hip fracture.
Chronic inflammation impairs recovery among the 1.6 million people who suffer from hip fracture annually. Vitamin E and the carotenoids are two classes of dietary antioxidants with profound anti-inflammatory effects, and the goal of this study was to assess whether higher post-fracture concentrations of these antioxidants were associated with lower levels of interleukin 6 (IL-6) and the soluble receptor for tumor necrosis factor-alpha (sTNF-αR1), two common markers of inflammation. Serum concentrations of the dietary antioxidants and inflammatory markers were assessed at baseline and 2, 6, and 12 month follow-up visits among 148 hip fracture patients from The Baltimore Hip Studies. Generalized estimating equations modeled the relationship between baseline and time-varying antioxidant concentrations and inflammatory markers. Higher post-fracture concentrations of vitamin E and the carotenoids were associated with lower levels of inflammatory markers. Associations were strongest at baseline, particularly between the α-tocopherol form of vitamin E and sTNF-αR1 (p = 0.05) and total carotenoids and both sTNF-αR1(p = 0.01) and IL-6 (p = 0.05). Higher baseline and time-varying α-carotene and time-varying lutein concentrations were also associated with lower sTNF-αR1 at all post-fracture visits (p ≤ 0.05). These findings suggest that a clinical trial increasing post-fracture intake of vitamin E and the carotenoids may be warranted.


Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus.
Resistance to the biological action of insulin in its target tissues is a cardinal feature of non-insulin-dependent diabetes mellitus. Protein-tyrosine phosphatases (PTPases) have been postulated to play a key role in the regulation of the insulin action pathway, especially in skeletal muscle, the major site of insulin-mediated glucose disposal in vivo. To evaluate whether changes in the activity and/or abundance of candidate skeletal muscle PTPases is associated with severe resistance to insulin in an animal model, we measured PTPase enzyme activity and PTPase protein level by immunoblotting in subcellular fractions of skeletal muscle in lean (+/?), insulin-resistant obese (fa/fa), and diabetic (ZDF/Drt-fa/fa) Zucker rats. Using a phosphotyrosylmyelin basic protein substrate, the solubilized-particulate fraction PTPase activity was increased by 65% and 74% (P < .05) and in vitro dephosphorylation of a recombinant rat insulin receptor kinase domain was increased by 104% and 114% in obese and diabetic animals, respectively (P < .01). These changes in PTPase activity were associated with an increase in specific immunoreactivity of leukocyte common antigen-related PTPase ([LAR] by 42% and 50%), PTPase 1B (by 61% and 69%), and the SHZ domain containing PTPase (SH-PTP2) (by 44% and 48%) in the solubilized-particulate fraction of obese and diabetic animals, respectively (P < .05). In diabetic muscle, increased SH-PTP2 abundance was also associated with a shift of SH-PTP2 to a plasma membrane component, which may have important consequences for the activation of this enzyme in the insulin-resistant state. These results provide evidence that specific PTPases play a role in the insulin resistance of this genetic model of obesity and non-insulin-dependent diabetes.


Efficacy and safety of abrocitinib and upadacitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: A systematic review and meta-analysis.
The sparsity of head-to-head trials for medications used as in atopic dermatitis (AD) treatment makes therapy options difficult. To better compare the efficacy and safety of abrocitinib and upadacitinib with dupilumab in patients with moderate-to-severe AD. We systematically searched MEDLINE, EMBASE, and the Cochrane Library database for head-to-head trials. Three studies with 2256 patients were included. The analysis revealed that improvement of EASI-75 was rapidly registered with abrocitinib/upadacitinib as compared to the dupilumab, even as early as week 2 of treatment. The proportions of patients who reached the endpoint of EASI-75 at week 12 and end of therapy were also higher in the abrocitinib/upadacitinib group. Significant improvement in EASI-90 scores was demonstrated with abrocitinib/upadacitinib at week 2 and at all subsequent time points. The administration of abrocitinib/upadacitinib provided a faster onset of IGA response at week 2. The differences in IGA response remained significant at week 12 and end of therapy. Compared with dupilumab, a larger proportion of patients treated with abrocitinib/upadacitinib achieved early itch relief at 2 weeks. Better results were found later during treatment, in between the 12 weeks to the end of study in abrocitinib/upadacitinib group. The only observed significant result of adverse events were severe adverse events between the abrocitinib/upadacitinib group (n = 40) and the dupilumab group (n = 24) (p = 0.043). TEAEs of any causality that led to treatment discontinuation and serious adverse events have not shown special risks in the patients treated with abrocitinib/upadacitinib. This study demonstrated that anti-JAK therapy, particularly abrocitinib and upadacitinib, exhibited superiority over dupilumab in achieving fast relief of disease signs with an acceptable safety profile in patients with moderate-to-severe atopic dermatitis.