Predicting Life Expectancy for Pirfenidone in Idiopathic Pulmonary Fibrosis.
Conducting an adequately powered survival study in idiopathic pulmonary fibrosis (IPF) is challenging due to the rare nature of the disease and the need for extended follow-up. Consequently, registration trials of IPF treatments have not been designed to estimate long-term survival. To predict life expectancy for patients with IPF receiving pirfenidone versus best supportive care (BSC) in a population that met the inclusion criteria of patients enrolled in the ASCEND and CAPACITY trials. Kaplan-Meier survival data for pirfenidone and BSC were obtained from randomized controlled clinical studies (CAPACITY, ASCEND), an open-label extension study (RECAP), and the Inova Fairfax Hospital database. Data from the Inova registry were matched to the inclusion criteria of the CAPACITY and ASCEND trials. Life expectancy was estimated by the area under the curve of parametric survival distributions fit to the Kaplan-Meier data. Mean (95% confidence interval) life expectancy was calculated as 8.72 (7.65-10.15) years with pirfenidone and 6.24 (5.38-7.18) years with BSC. Therefore, pirfenidone improved life expectancy by 2.47 (1.26-4.17) years compared with BSC. In addition, treatment with pirfenidone recuperated 25% of the expected years of life lost due to IPF. Sensitivity analyses found that results were sensitive to the choice of parametric survival distribution, and alternative piecewise and parametric approaches. This analysis suggests that this population of patients with IPF has an improved life expectancy if treated with pirfenidone compared with BSC. This study was funded by InterMune International AG, a wholly owned Roche subsidiary since 2014. Fisher was previously employed by InterMune UK, a wholly owned Roche subsidiary, until July 2015. He is currently employed by FIECON, which has received funding from F. Hoffmann-La Roche for consulting services. Nathan has received consulting fees from Roche-Genentech and Boehringer Ingelheim. He is also on the speakers' bureau for Roche-Genentech and Boehringer Ingelheim and has received research funding from both companies. Hill was previously employed by InterMune UK until October 2014. Hill and Marshall are employees of MAP BioPharma, which has received funding from F. Hoffmann-La Roche for consulting services. Dejonckheere and Thuresson are employees of F. Hoffmann-La Roche. Maher has received grants, consulting fees, and speaker fees from GlaxoSmithKline and UCB, and grants from Novartis. He has also received consulting fees and speaker fees from AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, Lanthio, InterMune International AG, F. Hoffmann-La Roche, Sanofi-Aventis, and Takeda. Maher is supported by a National Institute for Health Research Clinician Scientist Fellowship (NIHR Ref: CS: -2013-13-017). Study concept and design were contributed by Fisher, Hill, Marshall, and Dejonckheere. Fisher, Nathan, and Thuresson collected the data, along with Hill and Marshall. Data interpretation was performed by Fisher, Maher, Nathan, and Dejonckheere. The manuscript was written primarily by Fisher, along with Maher and Dejonckheere, and revised by Fisher and Maher, along with the other authors.


[Recurrent abdominal pain caused by nodular focal hyperplasia of the liver. A case report].
A case of focal nodular hyperplasia of the liver in childhood (FNH or NRC) is reported; a conservative approach is usually preferred in this disease when the diagnosis is surely identified, and a follow-up for some years is recommended. Despite the increased accuracy of modern imaging methods none of them, singly or together, is able to differentiate a malignant lesion with certainty and histological confirmation is mandatory. In the case described a laparotomy frozen section was performed but it was not possible to make a diagnosis and the liver mass was removed. The patient had a complete relief of symptoms with no evidence of recurrence in the follow-up. A review of the literature has been made, trying to point out this disease and its treatment.


Polymorphism in a kappa I primary (AL) amyloid protein (BAN).
In an attempt to understand the relationship of amino acid sequence to the formation of primary or multiple myeloma-related amyloid (AL amyloid), we have determined the complete amino acid sequence of amyloid protein BAN. This protein belongs to the kappa I immunoglobulin light chain subgroup and has a polypeptide chain length of 126 amino acids. It encompasses the entire variable region, the joining segment and the first tryptic peptide of the constant region. This protein has two unique features. First, the molecule is glycosylated. At position 61 the usual arginine residue has been replaced by an asparagine with the generation of the signal sequence Asn-Phe-Thr, to which a glucosamine-containing carbohydrate unit is attached. Secondly, the protein is not monoclonal but consists of two chains which have the same variable region but different J-segments. Comparison of the BAN sequence with other amyloid and nonamyloid kappa I proteins reveals a systematic difference between the two groups. In the amyloid proteins, several hydrophilic framework residues have been replaced by hydrophobic residues. These substitutions may provide the nucleation sites for self-aggregation and fibril formation.


Foetal-associated material: its expression in long-term cultured human skin.
Using immunofluorescence and electron microscopy, we have demonstrated the presence of "foetal substances" (antigens) in skin kept in tissue culture medium for periods of time ranging from 9 days-18 weeks. This is a specific reaction demonstrated with an anti-human foetal serum raised in New Zealand white rabbits. It is suggested that the expression of foetal substances by cells in the skin under these abnormal conditions might lead to the masking or modification of the normal histo-compatible antigens, enabling such skins to survive transplantation without rejection.


What dentists should know about sickle cell disease.
The medical history should be a communication between the patient and the dentist. A good history will reveal a patient's medical problems,concerns, ideas, and expectations. Understanding medical conditions on a patient's medical history is of up most importance in providing the patient with the best possible standard of care. Sickle cell disease is an inherited blood disorder that affects red blood cells. Normal red blood cells contain hemoglobin A. People with sickle cell disease have red blood cells containing mostly hemoglobin S, an abnormal type of hemoglobin. These mutated sickle cells do not have the smooth motion needed for oxygenation and deoxygenation. One of the main concerns in sickle cell disease is the reversible extreme pain episodes called "sickle cell crisis."Pain episodes occur when sickle cells clog small vessels, depriving the body of adequate blood and oxygen. Treatment of the sickle cell patient should be a team approach between dentist,patient, and physician. Dental treatments should be conservative and stress free for the patient.Prevention of dental disease and infections are of the up most importance to the sickle cell patient.If your patient has sickle cell disease, know about it and talk to your patient about the disease.Maintaining excellent oral health to decrease the possibility of oral infections will ensure the best care for these patients.Key words: communication, sickle cell disease (SCD), sickle cell anemia (SCA), blood inherited disorder, sickle cell trait, crisis, African Americans, deoxygenation, hemoglobin,supporting dentist, prophylactic antibiotics, and infection.


Pharmacokinetic-pharmacodynamic integration and modelling of oxytetracycline for the calf pathogens Mannheimia haemolytica and Pasteurella multocida.
A calf tissue cage model was used to study the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytetracycline in serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids. After intramuscular administration, the PK was characterized by a long mean residence time of 28.3 hr. Based on minimum inhibitory concentrations (MICs) for six isolates each of Mannheimia haemolytica and Pasteurella multocida, measured in serum, integration of in vivo PK and in vitro PD data established area under serum concentration-time curve (AUC0-∞ )/MIC ratios of 30.0 and 24.3 hr for M. haemolytica and P. multocida, respectively. Corresponding AUC0-∞ /MIC ratios based on MICs in broth were 656 and 745 hr, respectively. PK-PD modelling of in vitro bacterial time-kill curves for oxytetracycline in serum established mean AUC0-24 hr /MIC ratios for 3log10 decrease in bacterial count of 27.5 hr (M. haemolytica) and 60.9 hr (P. multocida). Monte Carlo simulations predicted target attainment rate (TAR) dosages. Based on the potency of oxytetracycline in serum, the predicted 50% TAR single doses required to achieve a bacteriostatic action covering 48-hr periods were 197 mg/kg (M. haemolytica) and 314 mg/kg (P. multocida), respectively, against susceptible populations. Dosages based on the potency of oxytetracycline in broth were 25- and 27-fold lower (7.8 and 11.5 mg/kg) for M. haemolytica and P. multocida, respectively.


Beta 2-microglobulin restriction of antigen presentation.
Antigens are generally thought to be recognized by cytotoxic T lymphocytes as peptides in the context of class I major histocompatibility proteins complex, which are heterodimers of heavy chains noncovalently associated with beta 2-microglobulin (beta 2m). The highly polymorphic nature of the heavy chains and their resulting ability to present different sets of peptides has presumably evolved to allow potent immune responses against most pathogens. By contrast, the polymorphism of beta 2m is limited; seven alleles are known in the mouse and only one has been identified in humans. beta 2-Microglobulin was consequently thought to have only structural functions: namely, to ensure correct folding of class I molecules and their transport to the cell surface. Although beta 2m is not implicated directly in the formation of the peptide binding site, we report here that it participates in the selection of MHC class I molecule-associated peptides.


A hybrid approach to simulation of electron transfer in complex molecular systems.
Electron transfer (ET) reactions in biomolecular systems represent an important class of processes at the interface of physics, chemistry and biology. The theoretical description of these reactions constitutes a huge challenge because extensive systems require a quantum-mechanical treatment and a broad range of time scales are involved. Thus, only small model systems may be investigated with the modern density functional theory techniques combined with non-adiabatic dynamics algorithms. On the other hand, model calculations based on Marcus's seminal theory describe the ET involving several assumptions that may not always be met. We review a multi-scale method that combines a non-adiabatic propagation scheme and a linear scaling quantum-chemical method with a molecular mechanics force field in such a way that an unbiased description of the dynamics of excess electron is achieved and the number of degrees of freedom is reduced effectively at the same time. ET reactions taking nanoseconds in systems with hundreds of quantum atoms can be simulated, bridging the gap between non-adiabatic ab initio simulations and model approaches such as the Marcus theory. A major recent application is hole transfer in DNA, which represents an archetypal ET reaction in a polarizable medium. Ongoing work focuses on hole transfer in proteins, peptides and organic semi-conductors.


A case of acute bilateral retrocochlear hearing loss as an initial symptom of unilateral thalamic hemorrhage.
A speech discrimination test is a test using a list of 25 phonetically balanced monosyllables. It is often overlooked but significant enough for pure tone audiometry. Many physicians have performed pure tone audiometry but without a speech discrimination test. A 73-year-old woman visited our clinic complaining of sudden bilateral hearing loss. Pure tone audiometry showed only bilateral high frequency loss. However, speech discrimination had decreased markedly. We decided to follow-up after 1 week of Ginexin-F® (ginkgo leaf extract) and Nafril® (nafronyl oxalate). She felt a gait disturbance within 2 days. Magnetic resonance imaging revealed a left thalamic hemorrhage. After a 1 month hospitalization, the hematoma subsided, and speech discrimination recovered 3 months later. Acute hearing loss due to thalamic hemorrhage that recovered has never been reported. We report the first case of retrocochlear hearing loss that occurred with a thalamic hemorrhage in a patient who recovered.


Improving the GaN Growth Rate by Optimizing the Nutrient Basket Geometry in an Ammonothermal System Based on Numerical Simulation.
The low growth rate of bulk gallium nitride (GaN) when using the ammonothermal method is improved herein by optimizing the nutrient geometry. A numerical model considering the dissolution and crystallization process is developed. Heater powers are employed as thermal boundary conditions to match the real ammonothermal system. The flow field, thermal field, and mass concentration field in the autoclave are calculated with or without a central hole in the nutrient basket. Numerical results show that the mass transfer efficiency and supersaturation on the seed crystal surface can be improved with a hole in the nutrient basket in the center in spite of its diverse effect on the heat transfer, which can be overcome by adjusting the heater powers. As a result, the growth rate of the GaN crystal can be obviously increased.


Sunghyangjungisan protects PC12 cells against neurotoxicity elicited by withdrawal of trophic support via CRE activation.
Sunghyangjungisan (SHJS) is a commonly prescribed drug for cerebrovascular diseases in Oriental medicine. The water extract of SHJS was found to be protective against neurotoxicity elicited by deprivation of tropic factors. SHJS inhibited the activation of caspase 3-like protease and nucleosome-sized DNA fragmentation in serum-deprived PC12 Pheochromocytoma cells. Interestingly, pretreatment with an inhibitor of protein kinase A, KT5720 inhibited the neuroprotective effects of SHJS via inhibition of capase 3-like protease activation. When PC12 cells were treated with SHJS, Ser133 phosphorylation of cAMP-responsive elements binding protein (CREB), a transcription factor, was also increased in a time- and dose-dependent manner. In addition, CRE DNA binding activity of CREB was also increased in a time-dependent manner. SHJS-induced CRE binding activity was blocked by KT5720. Taken together, we suggest the possibility that SHJS may provide a neuroprotective effects on serum-deprived apoptosis of PC12 cells in a CREB- and CRE-dependent manner.


Maternal diet supplemented with methyl-donors protects against atherosclerosis in F1 ApoE(-/-) mice.
Atherosclerosis is an inflammatory condition of the arterial wall mediated by cells of both innate and adaptive immunity. T lymphocytes play an important role in orchestrating the pathogenic immune response involved in the acceleration of atherosclerosis. Previously, we have shown that a prenatal methyl-donor supplementation diet (MS), when fed to dams during pregnancy and lactation, decreased the T cell-mediated pro-inflammatory cytokine and chemokine response in F1 mice. In the current study, we report feeding Apolipoprotein E (ApoE(-/-)) deficient dams with the MS diet during pregnancy reduces atherosclerotic plaques in F1 mice that were fed high fat diet (HFD) after weaning. F1 mice from dams on the MS diet exhibited increased global T cell DNA methylation. T-cell chemokines and their receptors (in particular CCR2, CCR5, and CXCR3) play important roles in the inflammatory cell recruitment to vascular lesions. MS diet significantly reduced Ccr2 mRNA and protein expression in CD3+ T cells but not in CD11b+ monocytes in MS F1 mice relative to controls. F1 litter size, HFD consumption, body weight, and body fat were similar between control and MS diet groups. Moreover, serum thiol metabolite levels were similar between the two groups. However, MS diet is associated with significantly higher serum HDL and lower LDL+VLDL levels in comparison to F1 mice from dams on the control diet. Inflammatory cytokines (IL-17, TNF-α, IL-6) were also lower in MS F1 mice serum and conditioned media from T-cell culture. Altogether, these data suggest that the MS diet ameliorates development of atherosclerosis by inhibiting the T-cell Ccr2 expression, reducing inflammatory cytokines production and increasing serum HDL:LDL ratio.


In vitro neutralization of the scorpion, Buthus tamulus venom toxicity.
Scorpion (Buthus tamulus) venom was subjected to neutralization by treating the venom with various chemicals such as hydrochloric acid, sodium hydroxide, thiourea, formaldehyde, zinc sulphate, acetic acid and trichloroacetic acid. The venom was also subjected to heat treatment. The levels of total protein, free amino acids and protease activity in neutralized venom decreased significantly. The decrease in venom protein and free amino acids was in proportion to the duration of the heat treatment and the concentration of chemicals used except zinc sulphate, sodium hydroxide and thiourea. Protease activity of neutralized venom samples also showed a decrease except with zinc sulphate which enhanced the enzyme activity. Intramuscular injection of formaldehyde, trichlcroacetic acid and heat treated venoms into albino rats produced low mortality while thiourea and zinc sulphate were not effective in reducing the mortality. Hydrochloric acid and acetic acid treated venoms reduced the mortality by 50% with a decrease in the symptoms of envenomation. The changes were attributed to the denaturing of venom protein by chemical and heat treatments.


[Colorectal pathology: an analysis and comparison between patients of different ages].
The increasing incidence of large bowel diseases observed in the last years is age-related. The authors have analyzed 366 patients who underwent surgery for colorectal pathology, divided in two groups (> or < 65 years) considering sex, diagnosis, type of clinical presentation, incidence and type of associated pathology, and post-operative complications. The analysis of the series revealed that type of clinical presentation, surgical patterns, post-operative infections were the same in the two groups, as reported in the literature. The substantial differences were only due to the different incidence of colo-rectal pathology, associated pathology and cardiovascular complications, factors that become characteristic of the elderly patients.


An outbreak of human rhinovirus species C infections in a neonatal intensive care unit.
We describe an outbreak of human rhinovirus type C infection in 7 infants in our neonatal/pediatric intensive care unit. Five infants had clinically significant apneic episodes and 5 required increased oxygen or ventilatory support. Infants shed virus detectable by polymerase chain reaction for a median of 4 weeks.


Role of Artificial Intelligence in Drug Discovery and Target Identification in Cancer.
Drug discovery and development (DDD) is a highly complex process that necessitates precise monitoring and extensive data analysis at each stage. Furthermore, the DDD process is both time-consuming and costly. To tackle these concerns, artificial intelligence (AI) technology can be used, which facilitates rapid and precise analysis of extensive datasets within a limited timeframe. The pathophysiology of cancer disease is complicated and requires extensive research for novel drug discovery and development. The first stage in the process of drug discovery and development involves identifying targets. Cell structure and molecular functioning are complex due to the vast number of molecules that function constantly, performing various roles. Furthermore, scientists are continually discovering novel cellular mechanisms and molecules, expanding the range of potential targets. Accurately identifying the correct target is a crucial step in the preparation of a treatment strategy. Various forms of AI, such as machine learning, neural-based learning, deep learning, and network-based learning, are currently being utilised in applications, online services, and databases. These technologies facilitate the identification and validation of targets, ultimately contributing to the success of projects. This review focuses on the different types and subcategories of AI databases utilised in the field of drug discovery and target identification for cancer.


Quantity of remaining double bonds of propanal-containing resins.
Improved mechanical properties of resin composites have been reported to be a consequence of the addition of aldehyde to the resins. The objective of the present study was to examine whether this improvement could be attributed to an increased degree of conversion of double bonds. For this purpose, propanal was added to monomer mixtures, which were then made light-curing. The monomer mixtures were varied with respect to monomer composition and content of propanal. The quantity of remaining double bonds was determined by means of transmission infrared spectra of the resins recorded before and after wet or dry storage for one week. The addition of propanal resulted in a decrease in the quantity of remaining double bonds by as much as 89% as compared with the mixtures without propanal. Negative correlations of statistical significance were found between the content of propanal and quantity of remaining double bonds in BISGMA:TEGDMA-based as well as in UEDMA:HEMA-based resins for both modes of storage. Significant negative correlations were found between the quantity of remaining double bonds and the previously determined mechanical properties.


Quality of life in arthritis patients using nonsteroidal anti-inflammatory drugs.
Arthritis is a painful and disabling condition. To suppress the pain and the inflammatory process, patients are often chronic nonsteroidal anti-inflammatory drug (NSAID) users. Chronic use of NSAIDs may induce peptic ulcer, dyspeptic problems and heartburn. Therefore, these patients are often provided with treatment to relieve and/or protect against gastrointestinal problems. Rheumatic disorders also affect a range of health-related quality of life domains. In one study, patients with NSAID-associated gastroduodenal lesions complained about lack of energy, sleep disturbances, emotional distress and social isolation in addition to pain and mobility limitations. The degree of distress and dysfunction differed markedly from scores in an unselected population. Clinical trial data suggest that acid-suppressing therapy with omeprazole is superior to therapy with misoprostol and ranitidine in healing gastroduodenal lesions and preventing abdominal pain, heartburn and indigestion symptoms during continued NSAID treatment. Because arthritic patients are severely incapacitated by their condition regarding most aspects of health-related quality of life, it is important to offer a treatment that is effective in healing and preventing NSAID-induced ulcers and gastrointestinal symptoms during continued NSAID treatment without further compromising the patients' quality of life. Treatment with omeprazole once daily has been shown to be superior to that with ranitidine and misoprostol in this respect.


INTERSPECIFIC HYBRIDS OF DROSOPHILA HETERONEURA AND D. SILVESTRIS I. COURTSHIP SUCCESS.
Drosophila heteroneura and D. silvestris are well-defined, sympatric species of the planitibia subgroup of Hawaiian Drosophila. D. silvestris can be subdivided into two allopatric morphotypes that differ in the number of bristle rows on the front tibia (two rows versus three rows). We measured courtship success of intraspecific and interspecific hybrids as the proportion of females inseminated during a two-week period with a single sib male. Proportions were arcsin-transformed so that the values were asymptotically normal in distribution, and tests of homogeneity and of mean differences were performed. Of key importance is the discovery of genetic variation for the proportion of inseminated females within both D. heteroneura and D. silvestris. The interspecific crosses and the D. silvestris intraspecific crosses also provide evidence for a coadapted gene complex with some dominance or heterosis. This coadapted gene complex correlates with the morphotypes of these flies, rather than with the D. heteroneura/D. silvestris contrasts per se. This observation stresses the importance of recognizing both behavioral and morphological components of the mate-recognition system. The incompatible coadaptation that separates the two-row from the three-row forms also supports recent molecular studies which indicate that the three-row form split from the two-row form prior to the split between D. heteroneura and two-row D. silvestris. The observations of intraspecific variability and coadaptation support the predictions of a genetic-transilience model which explains the origin of a new mate-recognition system in terms of sexual selection in the context of a founder-flush event.


Adrenaline-induced digital ischaemia reversed with phentolamine.
Adrenaline autoinjectors are widely prescribed for self-treatment of anaphylactic syndromes. Accidental misfire into digits can cause prolonged significant ischaemia with serious outcomes. Phentolamine is a readily available treatment, which is easily and safely given in the emergency setting.


Factors Affecting Leave out of General Practitioners from Rural Family Physician Program: A Case of Kerman, Iran.
Rural family physician program as the new reform in the Iranian health system has been implemented since 2005. Its success depends much on physicians' retention. The present study aimed to identify influential factors on physicians' willingness to leave out this program in Kerman province. The present cross-sectional study was performed in Kerman province in 2011. All family physicians working in this program (n = 271) were studied using a questionnaire. Data analysis was carried out using descriptive statistics and logistic regression through SPSS version 18.0. Twenty-six percent (70) of the physicians had left out the program in the past. In addition, 77.3% (208) intended to leave out in the near future. Opportunity for continuing education, inappropriate and long working hours, unsuitable requirements of salary, irregular payments, lack of job security and high working responsibility were regarded as the most important reasons for leaving out the program in the past and intention to leave out in future orderly. According to univariate logistic regression, younger physicians (odds ratio [OR] =2.479; 95% confidence interval [CI]: 1.261-4.872) and physicians who had older children (OR = 4.743; 95% CI: 1.441-15.607) were more willing to leave out the plan in the near future, however it was not significant in multivariate logistic regression. Physician retention in family physician program is faced with serious doubts due to different reasons. The success of the program is endangered because of the pivotal role of human resources. Hence, the revision of human resources policies of the program seems necessary in order to reduce physicians leave out and improving its effectiveness.


Risk factors leading to hospital admission in Iranian asthmatic children.
Asthma is one of the most common chronic diseases in the world, leading to an increased rate of hospitalization. We performed this study to better understand the factors leading to admission among asthmatic children. We performed a study among asthmatic children in a referral hospital for asthma and allergy in Tehran. Sixty-three cases were selected from asthmatic children admitted to the emergency room (ER) who still had an indication for ward or intensive care unit admission after primary treatment. Our control group was the asthmatic children discharged after primary treatment and patients who were referred to the asthma and allergy clinic (63 patients). Data were obtained by structured questionnaires filled out during clinical interviews. There was a significant difference in mean age (5 years for cases vs. 6 years for controls; p = 0.049), personal and familial allergic history (69.8 and 57.1% for cases vs. 34.9 and 36.5% for controls; p < 0.01 and p = 0.02, respectively), history of recent respiratory infections (79.4% for cases vs. 49.2% for controls; p < 0.01), hospitalization history due to asthma (57.1% for cases vs. 23.8% for controls; p < 0.01) and regular use of inhaled corticosteroid (66.7% for cases vs. 33.3% for controls; p < 0.01). Our findings confirm most previous observations, suggesting that recent respiratory infections, hospitalization, personal or familial allergy, disease severity and lower ages are important factors leading to hospitalization. We also found that regular clinical follow-up, regular use of inhaled corticosteroids, higher IgE levels and O2 saturation may lower the probability of hospitalization during asthmatic attacks.


Evidence for a physiological role of NH4+ transport on the secretory Na(+)-K(+)-2Cl- cotransporter.
The secretory Na(+)-K(+)-2Cl- cotransporter in salivary acinar cells is responsible for driving the transepithelial Cl- fluxes that give rise to fluid secretion. We demonstrate that the application of the muscarinic agonist carbachol to rat parotid acini results in an intracellular acid load that can be blocked by bumetanide, a specific inhibitor of the cotransporter. One component of this bumetanide-sensitive acid load is ouabain-sensitive while a second is dependent on the presence of sub-millimolar concentrations of NH4+ in our media. Our data indicate that this latter effect arises from NH4+ entry on the cotransporter operating in a Na(+)-NH4(+)-2Cl- cotransport mode and that at physiological NH4+ levels in the rat (approximately 0.1 mM), 10-15% of the acinar Cl- entry occurs via this route. We suggest that Na(+)-NH4(+)-2Cl- cotransport may also play a significant physiological role in other cell types and that this mode of operation of the secretory Na(+)-K(+)-2Cl- cotransporter could account for the currently unexplained presence of this protein in a number of tissues.


Clinical efficacy of avatrombopag and recombinant human thrombopoietin in the treatment of chronic liver disease-associated severe thrombocytopenia: A real-world study.
Purpose: To investigate the clinical efficacy of avatrombopag, an oral thrombopoietin receptor agonist, versus subcutaneous recombinant human thrombopoietin (rh-TPO) in the treatment of severe thrombocytopenia (TCP) associated with chronic liver disease (CLD). Methods: Clinical data of 250 patients with severe TCP associated with CLD were collected in a single hospital from January 2019 to January 2022. The main parameters measured were the therapeutic response rate, changes in platelets (PLTs), and adverse events. Propensity score matching (PSM) was used to avoid possible selection bias. Results: After PSM, a total of 154 patients were enrolled in the study: 77 in the avatrombopag group and 77 in the rh-TPO group. There was no statistically significant difference between the two groups in the effect of increasing the PLT count (Waldχ 2 = 1.659, p = 0.198; Waldχ 2 = 0.220, p = 0.639). In addition, no interaction between time and different medications was found (Waldχ 2 = 0.540, p = 0.910; Waldχ 2 = 1.273, p = 0.736). Interestingly, in the subgroup analysis, both before and after PSM, avatrombopag showed better clinical efficacy than rh-TPO in the treatment of TCP associated with CLD in Child‒Pugh Class A (88.89% vs. 63.41%, p =0.003; 81.33% vs. 61.76%, p = 0.043). Fewer patients reported dizziness in the avatrombopag group than in the rh-TPO group both before and after PSM (7.8% vs. 25.0%; 7.8% vs. 24.7%, p < 0.05). Conclusion: Both before and after PSM, avatrombopag showed better clinical efficacy than rh-TPO in the treatment of TCP associated with CLD in Child‒Pugh Class A and showed a lower incidence of dizziness in all patients.


Alcohol-related injury among Greek-letter college students: defining a target population for secondary prevention.
Members of Greek-letter societies are the heaviest drinkers on college campuses, and experience more alcohol-related problems than their peers. This study reports the results of a web-based survey administered to stratified random samples of college students from 10 North Carolina universities. Greek-letter status was a significant independent risk factor for increased injury (both experienced and caused to others), even after adjusting for drinking behaviors. Prevention, screening, and intervention strategies are discussed in the context of these results.


Morphometric studies of the juxtaglomerular apparatus in perimembranous glomerulonephritis.
In 23 cases of perimembranous glomerulonephritis (PGN, membranous nephropathy), the juxtaglomerular cell complex (JGC-complex) in early postmortal (2 cases) and bioptically obtained specimens (21 cases) was investigated quantitatively by planimetry. The results were correlated with the stage of the PGN and the clinical findings. A statistically significant increase in mean size of the JGC-complex was found in perimembranous glomerulonephritis compared with the control group (p smaller than 0.005). Comparing the different morphological stages of PGN, the size of the JGC-complex was increased and the serum creatinine level raised in stages 3 and 4. In hypertensive patients with perimembranous glomerulonephritis, the serum creatinine levels were significantly raised as compared with the normotensive group.


(-)-menthol increases excitatory transmission by activating both TRPM8 and TRPA1 channels in mouse spinal lamina II layer.
(-)-menthol, a major form of menthol, is one of the most commonly used chemicals. Many studies have demonstrated that (-)-menthol produces analgesic action through peripheral mechanisms which are mainly mediated by activation of TRPM8. Moreover, intrathecal injection of menthol induces analgesia as well. However, the central actions and mechanisms of (-)-menthol remain unclear. Here, we have investigated the action of (-)-menthol on excitatory synaptic transmission in spinal lamina II layer which plays a pivotal role in modulating nociceptive transmission from the periphery by using patch-clamp technique in mice spinal cord. We found that (-)-menthol increased miniature excitatory postsynaptic current frequency. The frequency increases which (-)-menthol induced were in a dose-dependent manner (EC50: 0.1079 mM). However, neither genetic knockout nor pharmacological inhibition of TRPM8 could block (-)-menthol-induced effects entirely. Furthermore, this increase was also impaired by TRPA1 antagonist HC030031, but abolished utterly by co-application of TRPM8 and TRPA1 antagonist. Our results indicate that (-)-menthol increases the excitatory synaptic transmission by activating either TRPA1 or TRPM8 channels in spinal lamina II layer.


Healthcare Professional Experiences of Clinical Incident in Hong Kong: A Qualitative Study.
Studies showed that adverse events within health care settings can lead to two victims. The first victim is the patient and family and the second victim is the involved healthcare professionals. However, there is a lack of research studying the experiences of healthcare professionals encountering clinical incidents in Hong Kong. This paper reports a qualitative study in exploring the healthcare professional experiences of clinical incident, their impacts and needs. This study is the second part of the mixed research method with two studies conducted in a cluster of hospitals in Hong Kong. Study 1 was a quantitative questionnaire survey and Study 2 was a qualitative In-Depth Interview. In study 2, a semi-interview guide was used. Results showed that symptoms experienced after the clinical incident were mostly from psychological, physical, then social and lastly spiritual aspects which were consistent with those found in study 1 and other studies. Using content analysis for analyzing the impacts, four themes were identified. Concerning the impacts immediately from the clinical incident, two themes emerged were 1) facing emotion distress and 2) maintaining rationality. Regarding the impacts after the clinical incident, another two themes were 3) managing further emotional distress 4) restoring personal wellness. With regard to the needs after clinical incidents, three themes emerged were 1) self-recovery; 2) senior good mentoring and 3) positive organization climate with emphasis on enhancement of training and development of a positive practice culture. Great impacts are found with healthcare professionals encountering clinical incidents from a holistic perspective. They need time for self-recovery with support from good supervisors, peers and a caring environment. Some recommendations based on the findings of the study are made.


Clonal hematopoiesis in patients with acquired aplastic anemia.
To determine whether patients with acquired asplastic anemia (AA) exhibit clonal hematopoiesis, we used restriction fragment length polymorphisms of the X-linked genes phosphoglycerate kinase (PGK1) and hypoxanthine phosphoribosyltransferase (HPRT) and the X-linked probe M27 beta. Of the 19 female patients studied, 18 (95%) patients were informative for at least one marker. Of these, eight patients (42%) were heterozygous for PGK1, two (11%) for HPRT, and 16 (84%) for M27 beta. In 13 (72%) patients, a monoclonal pattern was found. Analysis of purified cell suspensions of four of these patients showed that both myeloid and lymphoid cells were of monoclonal origin, indicating the involvement of an early stem cell. The four patients who were studied at presentation all showed a monoclonal pattern. One of these patients showed a spontaneous recovery despite persistent clonal hematopoiesis. The presence of either clonal or polyclonal hematopoiesis did not show a correlation with the response to antithymocyte globulin (ATG) treatment. A relapse after ATG was also seen in a patient exhibiting polyclonal hematopoiesis. Conversely, a monoclonal pattern did not preclude the occurrence of a partial or complete response to ATG. Other potential markers to study clonality, including cytogenetic abnormalities or point mutations of the N-ras protooncogene, were not found in any of the patients. It is concluded that patients with AA may exhibit clonal hematopoiesis. The significance with respect to evolution to disorders with clonal hematopoiesis like paroxysmal nocturnal hemoglobinuria, myelodysplasia, and acute leukemia remains to be determined.


Tall fescue (Festuca arundinacea Schreb.).
Tall fescue (Festuca arundinacea Schreb.) is the predominant cool-season perennial grass in the United States. It is widely used for both forage and turf purposes. This chapter describes a protocol that allows for the generation of a large number of transgenic tall fescue plants by Agrobacterium tumefaciens-mediated transformation. Embryogenic calli induced from caryopsis are used as explants for inoculation with A. tumefaciens. The Agrobacterium strain used is EHA105. Hygromycin phosphotransferase gene (hph) is used as the selectable marker, and hygromycin is used as the selection agent. Calli resistant to hygromycin are obtained after 4-6 weeks of selection. Soil-grown tall fescue plants can be regenerated 4-5 months after Agrobacterium tumefaciens-mediated transformation.


Studying bacterial metabolic states using Raman spectroscopy.
Natural metabolic variability expected during characteristic growth phases in batch cultures of Escherichia coli and Staphylococcus epidermidis were studied by Raman spectroscopy. Spectral changes induced by metabolic changes found in the growth phases (i.e., lag, exponential, stationary, and decay) were identified. Maximum intensity of bands assigned to DNA and RNA bases are seen at the beginning of the exponential phase, when cells are metabolically active, and minimum intensities are seen when cells are decaying. High agreement in spectral variation due to growth phases was seen for all the trials that were performed, four growth cycles for E. coli and two for S. epidermidis. Batch cultures were monitored by standard plate counts to identify all growth phases, including decay. Spectral data were analyzed by principal component analysis (PCA) and discriminant analysis to identify similarities and differences and to estimate a classification performance based on growth phases. For the species evaluated, spectra during decay are grouped closer to each other and separated from lag, exponential, and stationary cells. These results suggest that Raman spectroscopy can be used to study metabolic states in bacteria and in particular cell viability.


The impact of stereoscopic imagery and motion on anatomical structure recognition and visual attention performance.
Gross anatomy is located in a three-dimensional space. Visualizing aspects of structures in gross anatomy education should aim to provide information that best resembles their original spatial proportions. Stereoscopic three-dimensional imagery might offer possibilities to implement this aim, though some research has revealed potential impairments that may result from observing stereoscopic visualizations, such as discomfort. However, possible impairments of working memory such as decreased visual attention performance due to applying this technology in gross anatomy education have not yet been investigated. Similarly, in gross anatomy education the impact of stereoscopic imagery on learners' recognition of anatomical-spatial relationships and the impact of different presentation formats have only been investigated in a small number of studies. In this study, the performance of 171 teacher trainees working on the anatomy of hearing was examined, either with non-stereoscopic or stereoscopic imagery. Static and dynamic picture presentations were applied. Overall, benefits for stereoscopic imagery on estimating anatomical-spatial relations were found. The performance on a visual attention test indicates that the impact of stereoscopic visualizations on the human cognitive system varies more from person to person compared to non-stereoscopic visualizations. In addition, combinations of temporarily moving pictures and stereoscopic imagery lead to decreased visual attention performance compared to combinations of moving pictures and non-stereoscopic imagery. Anat Sci Educ 11: 15-24. © 2017 American Association of Anatomists.


Photorefractoriness in turkey breeder hens is affected by age and season.
Experiments were conducted to determine if the incidence or temporal characteristics of photorefractoriness (PR) in turkey hens were influenced by age or season. Age effects on PR were determined by comparing characteristics of PR in the same hens through two consecutive lay periods. Seasonal influences on PR were evaluated by comparing characteristics of PR in hens photostimulated into lay at different seasons of the year. The onset of PR was evaluated by the spontaneous cessation of lay. Data were collected from daily egg production records for time to onset of PR, time to spontaneous termination of PR, and time required for the transition from photosensitive to the PR state. Percentage incidence, repeatability between consecutive cycles, and persistence (duration) of PR were calculated. Age did not influence the mean time to onset of PR following photostimulation but did affect percentage incidence. All second-year hens (recycled) expressed PR, whereas 89% of the first-year hens did so. Time to onset of PR was not correlated between first- and second-year (recycled) hens. Most, but not all, first-year (84.4%) and recycled (92%) hens were transiently PR and spontaneously terminated PR after 20 to 21 wk of unchanged photoperiod. Hens photostimulated in the winter (December) had delayed mean time to onset of PR from that observed with hens photostimulated in spring (May) by about 7.7 wk. Percentage incidence of PR and duration of PR were similar in both seasons of the year. It was concluded that age and season could affect PR.


Revisiting the Integration Hypothesis: Correlational and Longitudinal Meta-Analyses Demonstrate the Limited Role of Acculturation for Cross-Cultural Adaptation.
When moving to a new country or living in that country as ethnic-minority-group members, individuals have to relate to different cultural spheres. Scholars and practitioners commonly agree that how people acculturate influences their psychological and sociocultural adaptation. Integration (or biculturalism), which involves engagement in both one's heritage culture and the dominant mainstream culture, is considered the most beneficial acculturation strategy. But how robust is the evidence for the role of acculturation in adaptation? Here, we present a reanalysis of a previous meta-analysis of mostly correlational studies (k = 83, N = 23,197) and a new meta-analysis of exclusively longitudinal studies (k = 19, N = 6,791). Results show that the correlational link between acculturation and adaptation is much weaker than previously assumed and that longitudinal evidence is minuscule at best. Our findings suggest that empirical support is still lacking for the most basic premises of acculturation theory.


Methacrylate Copolymers with Liquid Crystalline Side Chains for Organic Gate Dielectric Applications.
Polymers for all-organic field-effect transistors are under development to cope with the increasing demand for novel materials for organic electronics. Besides the semiconductor, the dielectric layer determines the efficiency of the final device. Poly(methyl methacrylate) (PMMA) is a frequently used dielectric. In this work, the chemical structure of this material was stepwise altered by incorporation of cross-linkable and/or self-organizing comonomers to improve the chemical stability and the dielectric properties. Different types of cross-linking methods were used to prevent dissolution, swelling or intermixing of the dielectric e.g. during formation processes of top electrodes or semiconducting layers. Self-organizing comonomers were expected to influence the dielectric/semiconductor interface, and moreover, to enhance the chemical resistance of the dielectric. Random copolymers were obtained by free radical and reversible addition-fragmentation chain transfer (RAFT) polymerization. With 6-[4-(4'-cyanophenyl)phenoxy]alkyl side chains having hexyl or octyl spacer, thermotropic liquid crystalline (LC) behavior and nanophase separation into smectic layers was observed, while copolymerization with methyl methacrylate induced molecular disorder. In addition to chemical, thermal and structural properties, electrical characteristics like breakdown field strength (EBD) and relative permittivity (k) were determined. The dielectric films were studied in metal-insulator-metal setups. EBD appeared to be strongly dependent on the type of electrode used and especially the ink formulation. Cross-linking of PMMA yielded an increase in EBD up to 4.0 MV/cm with Ag and 5.7 MV/cm with PSS electrodes because of the increased solvent resistance. The LC side chains reduce the ability for cross-linking resulting in decreased breakdown field strengths.


Chemoenzymatic one-pot reaction from carboxylic acid to nitrile via oxime.
We report a new chemoenzymatic cascade starting with aldehyde synthesis by carboxylic acid reductase (CAR) followed by chemical in situ oxime formation. The final step to the nitrile is catalyzed by aldoxime dehydratase (Oxd). Full conversions of phenylacetic acid and hexanoic acid were achieved in a two-phase mode.


Multifunction vitreous forceps (maculorrhexis forceps).
We developed novel multifunction vitreous forceps to decrease the frequency of forceps insertion and enable the removal of the internal limiting membrane and other intravitreal membranes for better surgical results. The basic forceps were conventional continuous curvelinear capsulorrhexis (CCC) forceps. The size of the shaft is 23G and its pointed end measures 500 microm in diameter. Additionally, there is a platform in its tip. The pointed end with platform helps to hold the membrane because the outer sheath can be moved while the tip of the forceps is fixed in position, and its pen hold type grip helps to reduce hand movement. The most advantageous thing is that the sharp point enables us to make an initial flap easily and the desired area of internal limiting membrane can be peeled off by firmly holding the platform.


Can a plantar pressure-based tongue-placed electrotactile biofeedback improve postural control under altered vestibular and neck proprioceptive conditions?
We investigated the effects of a plantar pressure-based tongue-placed electrotactile biofeedback on postural control during quiet standing under normal and altered vestibular and neck proprioceptive conditions. To achieve this goal, 14 young healthy adults were asked to stand upright as immobile as possible with their eyes closed in two Neutral and Extended head postures and two conditions of No-biofeedback and Biofeedback. The underlying principle of the biofeedback consisted of providing supplementary information related to foot sole pressure distribution through a wireless embedded tongue-placed tactile output device. Center of foot pressure (CoP) displacements were recorded using a plantar pressure data acquisition system. Results showed that (1) the Extended head posture yielded increased CoP displacements relative to the Neutral head posture in the No-biofeedback condition, with a greater effect along the anteroposterior than mediolateral axis, whereas (2) no significant difference between the two Neutral and Extended head postures was observed in the Biofeedback condition. The present findings suggested that the availability of the plantar pressure-based tongue-placed electrotactile biofeedback allowed the subjects to suppress the destabilizing effect induced by the disruption of vestibular and neck proprioceptive inputs associated with the head extended posture. These results are discussed according to the sensory re-weighting hypothesis, whereby the CNS would dynamically and selectively adjust the relative contributions of sensory inputs (i.e. the sensory weights) to maintain upright stance depending on the sensory contexts and the neuromuscular constraints acting on the subject.


Inhibitory effects of 3α-hydroxy-lup-20(29)-en-23, 28-dioic acid on lipopolysaccharide-induced TNF-α, IL-1β, and the high mobility group box 1 release in macrophages.
We investigated the anti-inflammatory effects of 3α-hydroxy-lup-20(29)-en-23, 28-dioic acid (HLEDA)-a lupane-type triterpene isolated from leaves of Acanthopanax gracilistylus W. W.Smith (AGS), as well as the underlying molecular mechanisms in lipopolysaccharide (LPS)-induced RAW264.7 cells. Our results demonstrated that HLEDA concentration-dependently reduced the production of nitric oxide (NO), significantly suppressed LPS-induced expression of TNF-α and IL-1β at the mRNA and protein levels in RAW264.7 cells. Further analysis revealed that HLEDA could reduce the secretion of High Mobility Group Box 1 (HMGB1). Additionally, the results showed that HLEDA efficiently decreased nuclear factor-kappaB (NF-κB) activation by inhibiting the degradation and phosphorylation of IκBα. These results suggest that HLEDA exerts anti-inflammatory properties in LPS-induced macrophages, possibly through inhibition of the NF-κB signaling pathway, which mediates the expression of pro-inflammatory cytokines. These results warrant further studies that would concern candidate therapy for diseases, such as fulminant hepatitis and rheumatology of triterpenoids in AGS.


Evaluation of a Digital Companion for Older Adults with Mild Cognitive Impairment.
Study Objective: The purpose of this study was to examine the feasibility of a digital companion system used by older adults with mild cognitive impairment (MCI). We utilized a commercially available system that is comprehensive in its functionalities (including conversation ability, use of pictures and other media, and reminders) to explore the system's impact on older adults ' social interactions, anxiety, depressive symptoms, and acceptance of the system. Study Design: We conducted a three-month mixed methods evaluation study of the digital companion. Results: Ten female community-dwelling older adults (average age 78.3 years) participated in the study. Overall, participants utilized the tool regularly and appreciated its presence and their interactions. Participants scored higher at the end of the study in cognition and social support scales, and lower in presence of depressive symptoms. Conclusion: Findings indicate the feasibility of a digital companion for people with MCI and inform the need for additional research.


Empowerment and turnover of nurse managers before and after a major health care reform in Cyprus: A cross sectional study.
This study aimed to investigate the perceived empowerment and turnover intention of middle nurse managers before and after the implementation of a major reform of the health care system in Cyprus, which also includes the transition of public hospitals towards administrative and financial autonomy. The empowerment of nurse managers is important since previous studies have shown that it is associated with performance at work and may have an impact on their turnover intention. A repeated cross-sectional study was conducted in March 2019 (first phase) and was repeated in March 2020 (second phase), after the introduction of major changes. The target population was all nurse managers of the public hospitals. The final sample consisted of 175 (RR 94%) participants in the first phase and 178 (RR 95.6%) in the second. Measurements at both time points revealed moderate levels of perceived empowerment among Cyprus nurse managers. Empowerment score (17.95) appeared slightly lower at the repeat measurement compared to the first empowerment score (18), but the observed difference was not statistically significant (p = 0.184). Among the categories of empowerment opportunities was presenting statistically significant differences between the two phases. At the second phase, mean scores of empowerment were consistently lower among those who stated YES compared to those who stated NO in relation to (a) the intention to change department, (b) the intention to change profession and (c) the intention to change organization/hospital. This study demonstrated lower levels of empowerment among nurse managers with turnover intentions. It is therefore needed to be investigated further whether lower empowerment levels are the main reason for turnover intentions. It also suggests the need for senior management to create opportunities and to develop and implement interventions which aim to maintain and further improve the empowerment of the nurse managers and assess their effectiveness in terms of turnover intention in the organization. The senior management of the hospitals needs to adopt retention strategies by establishing an empowered positive working environment for nurse managers. Nurse managers need to collaborate with the senior management and seek more access to opportunities, information, support and resources which will enable them to perform their duties with efficiency and be more effective.


[An intercept survey on the status of driving after alcohol drinking among motor vehicle drivers in 6 counties of Zhejiang, China].
To investigate the status of driving after drinking alcohol among motor vehicle drivers and to provide evidence for the development of specific interventions. A 7-day intercept survey on driving after alcohol drinking, having drinking habit or driving after getting drunk, among motor vehicle drivers, was conducted in 6 counties of Zhejiang province, 2010. 16 467 motor vehicle drivers were included in the survey. Rates of driving after drinking alcohol [blood alcohol concentration (BAC) > 0 mg/100 ml], having habit of drinking alcohol (20 mg/100 ml ≤ BAC < 80 mg/100 ml) and driving after being drunk (BAC ≥ 80 mg/100 ml), were 1.82%, 1.03% and 0.27% respectively. Rates of driving after drinking alcohol, having habit of drink alcohol and driving and drunk-driving among the drivers from urban areas were significantly higher than those of drivers from rural areas, and those rates of male drivers were significantly higher than female drivers as well. 60.20% of drivers after drinking alcohol, were 35 to 49 year-olds, and the three above said rates all increased along with age. The highest above said three rates were observed at 23:00 PM and 1:00 AM. Compared with other motor vehicle drivers, motorcyclists possessed the highest rates of the three items, as 9.27%, 5.01% and 1.57% respectively. Driving after drinking alcohol among motor vehicle drivers still prevailed in Zhejiang, especially between 23:00 PM and 1:00 AM. Drivers from the cities, being male or motorcyclists were among the high-risk populations that called for special attention to be paid in the future, including law enforcement and health promotion to fight against the problem.


Hippocampal gene expression meta-analysis identifies aging and age-associated spatial learning impairment (ASLI) genes and pathways.
A number of gene expression microarray studies have been carried out in the past, which studied aging and age-associated spatial learning impairment (ASLI) in the hippocampus in animal models, with varying results. Data from such studies were never integrated to identify the most significant ASLI genes and to understand their effect. In this study we integrated these data involving rats using meta-analysis. Our results show that proper removal of batch effects from microarray data generated from different laboratories is necessary before integrating them for meta-analysis. Our meta-analysis has identified a number of significant differentially expressed genes across age or across ASLI. These genes affect many key functions in the aged compared to the young rats, which include viability of neurons, cell-to-cell signalling and interaction, migration of cells, neuronal growth, and synaptic plasticity. These functional changes due to the altered gene expression may manifest into various neurodegenerative diseases and disorders, some of which leading into syndromic memory impairments. While other aging related molecular changes can result into altered synaptic plasticity simply causing normal aging related non-syndromic learning or spatial learning impairments such as ASLI.


Reduced Circulating Levels of miR-433 and miR-133b Are Potential Biomarkers for Parkinson's Disease.
Aberrant expression of microRNA (miRNA) in tissues may lead to altered level in circulation. Considerable evidence has suggested that miRNA deregulation is involved in the pathogenesis of Parkinson's disease (PD). In this study, we screened a set of PD-associated miRNAs and aimed to identify differentially expressed miRNAs in plasma of PD patients and to evaluate their potentiality to serve as PD biomarkers. A total of 95 subjects consisting of 46 sporadic PD cases and 49 controls were recruited. Plasma levels of six miRNAs including miR-433, miR-133b, miR-34b, miR-34c, miR-153, and miR-7 were evaluated using reverse transcribed quantitative PCR, among which we found that miR-34c and miR-7 were below detection limit under our condition. The results showed that levels of circulating miR-433 (P = 0.003) and miR-133b (P = 0.006), but not miR-34b and miR-153, were reduced in PD patients. miR-433 and miR-133b were strongly correlated in both control and PD groups (rs = 0.87 and 0.85, respectively). The correlation between miR-34b and miR-153 expressions was significantly reduced (P < 0.05) in the PD group. Although miR-433 and miR-133b were likely to be functionally complimentary as suggested by Pathway and Gene Ontology analyses, these two miRNAs per se might not be sufficient to predict PD. No correlation was observed between the four miRNAs and age or severity of disease. Collectively, our results demonstrate that circulating miR-433 and miR-133b are significantly altered in PD and may serve as PD biomarkers.


Continuing evolution of regionalized perinatal care: community hospital neonatal convalescent care.
We describe the convalescent care of 169 back-transported (to community hospitals) and 285 eligible but not back-transported very low birth weight (VLBW) infants. Eligible infants who were not back transported to a level I or II community hospital were transferred to a level II nursery within the Medical University of South Carolina (MUSC) for convalescent care. Study infants were admitted to the neonatal intensive care unit (NICU) at MUSC from July 1985 through June 1989. They were admitted after maternal transport to MUSC for imminent delivery (N = 159), out-born community delivery (N = 55), or in-born MUSC delivery (N = 240). The mean +/- SD birth weight and gestational age and the NICU admission diagnoses for the back-transported and non-back-transported neonates were similar. The mean +/- SD weight of neonates at the time they were back transported was significantly greater than the weight of neonates at the time of intrahospital transfer. In contrast, the discharge weight to home and total days hospitalized were significantly less in the back-transported infants. Five back-transported neonates (3%) and 12 non-back-transported neonates (4%) were readmitted to the NICU. The back-transported infants used more than 3,800 bed days at community hospitals that would otherwise have been spent in the regional center, thus facilitating increased parental and primary physician involvement in their care.


A simple accurate method of alignment of beamline optics with the use of EUV multilayer polarizers.
A simple alignment method is proposed, which enables the alignment of beamline optics of a bending section accurately, relying on the linear state of polarization of synchrotron orbital radiation rather than the beam intensity. The method utilizes extreme UV (EUV) multilayers as a compact polarization monitor detecting unwanted vertical polarization components. The proposed method was found to be far more sensitive than that relying on the maximum intensity. Another advantage is the insensitivity to surface contamination, such as an irradiation mark on the mirror degrading reflectance. A design example is presented for use around a photon energy of 370 eV along with an experimental example at a photon energy of 97 eV.


Biochemical speciation of enterococci causing human infections.
As Enterococci are now coming up as important nosocomial pathogens, their speciation and antibiotic sensitivity testing is important. 120 isolates of Enterococci from various clinical samples were physiologically and biologically characterised. Speciation on the basis of recommended methods revealed 114(95%) as E. faecalis and 6(5%) as E. faecium. Antibiogram of the 120 isolates showed that 100(83.3%) were sensitive to Ampicillin. Combination of Penicillin and Gentamicin was more effective. E. faecium was more drug resistant.


Mechanisms and therapeutic challenges in autism spectrum disorders: insights from Rett syndrome.
A major challenge for understanding neurodevelopmental disorders, including autism spectrum disorders (ASDs), is to advance the findings from gene discovery to an exposition of neurobiological mechanisms that underlie these disorders and subsequently translate this knowledge into mechanism-based therapeutics. A promising way to proceed is revealed by the recent studies of rare subsets of ASDs. In this review, we summarize the latest advances in the mechanisms and emerging therapeutics for a rare single-gene ASD, Rett syndrome. Rett syndrome is caused by mutations in the gene coding for methyl CpG-binding protein 2 (MeCP2). Although MeCP2 has diverse functions, examination of MeCP2 mutant mice suggests the hypothesis that MeCP2 deficiency leads to aberrant maturation and maintenance of synapses and circuits in multiple brain systems. Some of the deficits arise from alterations in specific intracellular pathways such as the PI3K/Akt signaling pathway. These abnormalities can be at least partially rescued in MeCP2 mutant mice by treatment with therapeutic agents. Mechanism-based therapeutics are emerging for single-gene neurodevelopmental disorders such as Rett syndrome. Given the complexity of MeCP2 function, future directions include combination therapeutics that target multiple molecules and pathways. Such approaches will likely be applicable to other ASDs as well.


Spectral counterstaining in luminescence-enhanced biological Raman microscopy.
Cell imaging heavily depends on fluorescent labels typically incompatible with Raman microscopy. The europium(iii) complex based on dipicolinic acid (DPA) presented here is an exception from this rule. Although its luminescence bands are very narrow, their intensity is comparable to the background Raman bands. This makes it complementary to less luminous compounds referred to as Raman tags. Through several examples we show that the complex provides a morphological context in otherwise unstained cells, thus acting as a spectral-counterstaining agent.


Switching of the nonallelic forms of fetal hemoglobin during late gestation.
The gamma chains of human fetal hemoglobin occur in two nonallelic forms, designated G gamma and A gamma, which differ from one another in having either glycine or alanine as their 136th residue respectively. In newborns, G gamma comprises about 75% of the total gamma chains, while in adults, G gamma comprises about 40% of the total gamma chains. The timing of the switching events that lead to the alteration of the rates of production of G gamma and A gamma are still unknown. Umbilical cord red blood cells from term infants were separated by density gradient fractionation into four age-dependent fractions. Red blood cell size and reticulocyte content decreased and the percent fetal hemoglobin increased with increasing gradient densities, confirming age-dependent density separation. The percent G gamma was determined by two methods on fractionated cord red blood cells to determine if the switch in the production ratio of the nonallelic forms of gamma chains began during late gestation. The G gamma content of fetal hemoglobin was found to decrease with decreasing red blood cell age, demonstrating that the switch from predominately glycine-containing gamma chains to predominately alanine-containing gamma chains begins during late gestation.


[Development of a computer program to assess nutritional status of infants and preschool children].
A computer program named INFANDIET has been designed with a Window's application (ToolBook software vs. 1.53), based upon object-oriented programming, and devised to assess the nutritional status of infants by using compatible computers PC. Additionally, it is a useful tool to elaborate personalized diets. This program has been developed to assist health professionals and students in the evaluation of the infant nutritional status by a) creating and managing clinical histories with anthropometrical, immunological and clinical data; b) showing infant dietary guidelines, with the ability to update the nutritional and food composition database of the program; c) giving information about infant nutrition; d) and presenting a complete list of references.


Can Coenzyme Q10 supplementation protect the ovarian reserve against oxidative damage?
We investigated antioxidant effects of CoQ10 supplementation on the prevention of OS-induced ovarian damage and to evaluate the protective effect of such supplementation against OS-related DNA damage. Twenty-four adult female Sprague-Dawley rats were randomly divided into three groups (8 rats per group): group 1 (control): saline, ip, and orally; group 2 (cisplatin group): cisplatin, 4.5 mg/kg ip, two times with an interval of 7 days; and group 3 (cisplatin + CoQ10 group): cisplatin, 4.5 mg/kg ip, two times with an interval of 7 days, and 24 h before cisplatin, 150 mg/kg/day orally in 1 mL of saline daily for 14 days. Serum concentrations of anti-Mullerian hormone (AMH), number of AMH-positive follicles, the assessment of the intensity of 8'OHdG immunoreactivity, the primordial, antral and atretic follicle counts in the ovary were assessed. The mean serum AMH concentrations were 1.3 ± 0.19, 0.16 ± 0.03, and 0.27 ± 0.20 ng/mL in groups 1, 2, and 3, respectively (p < 0.01). Serum AMH levels were significantly higher in group 1 compared to groups 2 and 3 (p < 0.01 and p = 0.01, respectively). There was a statistically significant difference in AMH-positive follicle count between the groups (p < 0.01). Group 1 showed higher numbers of AMH-positive granulosa cells compared to group 2 (p = 0.01). A significant difference was found in the primordial, the atretic, and antral follicle counts between the three groups (p < 0.01, p < 0.01, and p < 0.01, respectively). The atretic follicle count was significantly lower in the cisplatin plus CoQ10 group compared to the cisplatin group (p < 0.01). The antral follicle counts were significantly higher in the cisplatin plus CoQ10 group compared with the cisplatin group (p < 0.01). There was a statistically significant difference in the intensity of staining of the follicles that were positive for anti-8'OHdG between the groups (p = 0.02). Group 1 showed a significant lower intensity of staining of the follicles positive for anti-8'OHdG compared with group 2 (p = 0.03). CoQ10 supplementation may protect ovarian reserve by counteracting both mitochondrial ovarian ageing and physiological programmed ovarian ageing although the certain effect of OS in female infertility is not clearly known.


American Thyroid Association Scientific Statement on the Use of Potassium Iodide Ingestion in a Nuclear Emergency.
This document serves to summarize the issues and the American Thyroid Association (ATA) position regarding the use of potassium iodide as a thyroid blocking agent in the event of a nuclear accident. The purpose is to provide a review and updated position statement regarding the advanced distribution, stockpiling, and availability of potassium iodide in the event of nuclear radiation emergencies in the United States.


Regio- and Chemoselective Kumada-Tamao-Corriu Reaction of Aryl Alkyl Ethers Catalyzed by Chromium Under Mild Conditions.
Acting as an environmentally benign synthetic tool, the cross-coupling reactions with aryl ethers via C-O bond activation have attracted broad interest. However, the functionalizations of C-O bonds are mainly limited to nickel catalysis, and selectivity has long been a prominent challenge when several C-O bonds are present in the one molecule. We report here the first chromium-catalyzed selective cross-coupling reactions of aryl ethers with Grignard reagents by the cleavage of C-O(alkyl) bonds. Diverse transformations were achieved using simple, inexpensive chromium(II) precatalyst combining imino auxiliary at room temperature. It offers a new avenue for buildup functionalized aromatic aldehydes with high efficiency and selectivity.


Elucidating the landscape of aberrant DNA methylation in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common cancers and frequently presents with an advanced disease at diagnosis. There is only limited knowledge of genome-scale methylation changes in HCC. We performed genome-wide methylation profiling in a total of 47 samples including 27 HCC and 20 adjacent normal liver tissues using the Illumina HumanMethylation450 BeadChip. We focused on differential methylation patterns in the promoter CpG islands as well as in various less studied genomic regions such as those surrounding the CpG islands, i.e. shores and shelves. Of the 485,577 loci studied, significant differential methylation (DM) was observed between HCC and adjacent normal tissues at 62,692 loci or 13% (p<1.03e-07). Of them, 61,058 loci (97%) were hypomethylated and most of these loci were located in the intergenic regions (43%) or gene bodies (33%). Our analysis also identified 10,775 differentially methylated (DM) loci (17% out of 62,692 loci) located in or surrounding the gene promoters, 4% of which reside in known Differentially Methylated Regions (DMRs) including reprogramming specific DMRs and cancer specific DMRs, while the rest (10,315) involving 4,106 genes could be potential new HCC DMR loci. Interestingly, the promoter-related DM loci occurred twice as frequently in the shores than in the actual CpG islands. We further characterized 982 DM loci in the promoter CpG islands to evaluate their potential biological function and found that the methylation changes could have effect on the signaling networks of Cellular development, Gene expression and Cell death (p=1.0e-38), with BMP4, CDKN2A, GSTP1, and NFATC1 on the top of the gene list. Substantial changes of DNA methylation at a genome-wide level were observed in HCC. Understanding epigenetic changes in HCC will help to elucidate the pathogenesis and may eventually lead to identification of molecular markers for liver cancer diagnosis, treatment and prognosis.


Tilted implantation technique for edentulous patients.
The tilted implantation technique is characterized by placing the implant at an angle of more than 15° and less than 45° from the horizontal plane. This technique can avoid damaging the maxillary sinus, inferior alveolar nerve, nasal base, and other anatomical structures when the height of the upper and lower jaw available bone is insufficient, to maximize the use of available bone and avoid a large range of bone increment. The tilted implantation technique can reduce the trauma of the surgery, increase the possibility of immediate restoration and shorten the treatment cycle, which has been widely used clinically. In this review, the scope of application, design elements, design scheme and complications of the tilted implantation technique for edentulous patients will be described.


Isolation and identification of renal cell carcinoma-derived peptides associated with GP96.
We determined the possible associated determinants and analyzed whether gp96-_associated antigenic peptides can be found in renal cell carcinoma (RCC). The gp96-peptide complexes were chromatographically purified from resected tumor tissue of RCC patients. SDS-PAGE and Western blot analysis confirmed gp96 using the gp96 monoclonal antibody, and its concentration was measured using BCA. Approximately 20 to 50 μg gp96-peptide complexes was obtained from 1 g RCC tissue. The mass spectrometry (MS) analysis of the eluted peptides included the initial profiling using matrix-assisted laser desorption/ionization time-of-flight MS. Quadrupole time-of-flight MS combined with the Mascot search engine was used to identify the peptides and find proteins from primary sequence databases. MS analysis results demonstrated that the mass range of peptide associated with gp96 was from 1046.48 to 3501.56 Da. Further research confirmed the sequences of two gp96-associated peptides, namely, LVPLEGWGGNVM and PPVYYVPYVVL. However, the original protein of the two peptides could not be found. The results demonstrated that the gp96-associated peptides are small molecular peptides, and the two peptides are deduced to be RCC-associated peptides. The identified peptides were confirmed to be associated with gp96 using the protocols described above. However, the specificity and relevance of the association to the immunogenicity of gp96 remains to be examined. Further analysis must be accomplished before the findings can be applied in peptide vaccine.


In vitro effect of T-2 mycotoxin on the immune response of mice.
The in vitro biologic effects of T-2 mycotoxin on the immune response of mice was undertaken. Twenty nanograms of toxin abrogated the immune response to the T-dependent antigen sheep RBC, whereas a partial response was observed when 2 ng was used. Analysis of cell culture viabilities indicated that cell death occurred with toxin doses that coincided with the diminished immune responses. A similar decreased response was observed against the T-independent antigen, TNP-lipopolysaccharide, indicating toxic effects on both B and T lymphocyte populations. Delay of toxin administration as much as 116 hours of the 120-hour incubation period still resulted in a substantially diminished immune response, indicating the toxin acts on both the afferent and efferent immune systems. Equal effects were observed for mice of the b, d, and k haplotype, indicating no apparent strain variability in sensitivity to T-2 mycotoxin effects. These results indicated that T-2 mycotoxin can modulate the immune response, and that this modulation is attributable to direct toxic effects on the cells of the immune system.


Association Between Fatigue and Motor Exertion in Patients With Multiple Sclerosis-a Prospective Study.
Background: Fatigue in multiple sclerosis (MS) is conceived as a multidimensional construct. Objectives: This study aims to describe the changes of balance and gait parameters after 6 min of walking (6 MW) as potential quantitative markers for perceptions of state fatigue and trait fatigue in MS. Methods: A total of 19 patients with MS (17 with fatigue) and 24 healthy subjects underwent static posturography, gait analysis, and ratings of perceived exertion before and after 6 MW. Results: 6 MW was perceived as exhaustive, but both groups featured more dynamic comfortable speed walking after 6 MW. Shorter stride length at maximum speed and increased postural sway after 6 MW indicated fatigability of balance and gait in MS group only. While most changes were related to higher levels of perceived exertion after 6 MW (state fatigue), higher fatigue ratings (trait fatigue) were only associated with less increase in arm swing at comfortable speed. Further analysis revealed different associations of trait fatigue and performance fatigability with disability and motor functions. Performance fatigability was most closely related to the Expanded Disability Status Scale, while for trait fatigue, the strongest correlations were seen with balance function and handgrip strength. Conclusions: Fatigability of performance was closely related to perceptions of exertion after 6 MW (state fatigue) and disability in MS but distinct from fatigue ratings, conceived as trait fatigue. Our study identified postural sway, arm swing during gait, and hand grip strength as unexpected potential motor indicators of fatigue ratings in MS.


Is AGC beneficial in hearing aids?
Three different functions of Automatic Gain Control (AGC) circuits in hearing aids are distinguished and the evidence for their benefits is considered. The value of AGC's function as a relatively distortion-free means of limiting output has been well established. With regard to compression, the benefit of short-term or 'syllabic' compression has not been demonstrated convincingly. Most evaluations of this type of AGC have looked for increase in speech intelligibility, but theoretical predictions of its effect do not appear to take account of the acoustic cues to consonant contrasts actually used by hearing impaired people, and empirical studies have often used listening conditions which do not give a realistic test of benefit. Relatively little attention has been paid to long-term compression, or to the effect of AGC on comfort rather than intelligibility. Listening tests carried out at the RNID and reported here have shown that AGC can benefit hearing aid users by allowing them to listen to a wider range of sound levels without either strain or discomfort, and, if time constants are well chosen, without adverse effects on speech intelligibility in quiet or in noise.


In vitro activity of ceftobiprole and comparator antibiotics against contemporary European isolates (2016-19).
To evaluate the susceptibility to ceftobiprole of clinical bacterial isolates obtained from hospitalized patients in Europe. A total of 20 000 non-duplicate bacterial isolates were collected in 2016-19 from patients with documented infections at medical centres located in 17 countries in Europe. Bacterial identification was confirmed and susceptibility to ceftobiprole and comparator agents was tested using the EUCAST broth microdilution methodology and interpretive criteria by a central microbiology laboratory. Of the 20 000 isolates, 10 007 (50.0%) were Gram-positive and 9993 (50.0%) were Gram-negative. The most common species was Staphylococcus aureus (35.0%), followed by Streptococcus pneumoniae (15.0%), Klebsiella pneumoniae (11.1%), Pseudomonas aeruginosa (11.0%), Escherichia coli (9.7%) and Haemophilus influenzae (3.0%). Overall, 99.7% (6981/7000) of S. aureus, including 99.5% (3483/3502) of MRSA, 97.8% (2941/3007) of S. pneumoniae, 100% (605/605) of H. influenzae and 76.3% (5492/7197) of Enterobacterales isolates were susceptible to ceftobiprole. Susceptibility to ceftobiprole was higher for isolates from northern and western Europe as compared with eastern and southern Europe. Ceftobiprole continues to exhibit potent and broad-spectrum activity against Gram-positive and Gram-negative clinical isolates from Europe, and as expected, with a slight north-to-south and west-to-east susceptibility gradient.


Effects of ethacrynic acid on the alpha-adrenergic control ov hepatic glycogenolysis.
Ethacrynic acid (ECA) was used to study the relationship between ion transport and alpha-adrenergic activation of glycogenolysis in perfused rat livers. ECA alone enhanced glycogenolysis and produced a massive loss of K+ from the liver. These effects were partially blocked by dithioerythritol. ECA suppressed the metabolic responses to phenylephrine and the alpha-adrenergic redistribution of ions. Ouabain-sensitive and ouabain-insensitive ATPase of isolated liver plasma membranes were inhibited and binding of [3H]epinephrine to alpha-adrenergic sites was decreased by ECA. It is concluded that in liver ECA acts at three different sites by blocking SH groups: active ion transport across the plasma membrane, alpha-adrenoreceptors, and phosphorylase phosphatase.


Influence of ground blocking on the acoustic phase variance in a turbulent atmosphere.
Sound propagation through atmospheric turbulence is important in many applications such as localization of low flying aircraft, sonic boom disturbances, and auralization of aircraft during takeoff and landing. This article extends an isotropic turbulence model in the atmospheric boundary layer to account for ground blocking of buoyancy-produced velocity fluctuations. The extended, anisotropic turbulence model is needed to correctly predict the effect of the largest velocity eddies on the statistical characteristics of sound signals. This model and geometrical acoustics are then employed to derive a closed-form expression for the variance of the phase fluctuations of a spherical sound wave for vertical and slanted propagation, without the use of the Markov approximation. A numerical analysis of this expression indicates significant anisotropy of the phase variance due to the buoyancy-produced velocity fluctuations with ground blocking such that it decreases in the vertical direction and increases in the near-horizontal directions. The newly formulated phase variance is compared with data from an outdoor experiment on vertical and slanted sound propagation. By accounting for ground blocking, much better agreement is obtained between the theoretical predictions and experimental data.


The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite 'scavenger'?
Hydrogen sulfide (H2S) is a well-known cytotoxic gas. Recently it has been shown to stimulate N-methyl-D-aspartate (NMDA) receptors to enhance long-term potentiation suggesting a novel neuromodulatory role in vivo. Endogenous levels of H2S in the brain are reported to range between 10 and 160 microm. Considerably lower H2S levels are reported in the brains of Alzheimer's disease (AD) patients, where levels of brain protein nitration (probably mediated by peroxynitrite) are markedly increased. Activation of NMDA receptors leads to intracellular tyrosine nitration by peroxynitrite. Because H2S and peroxynitrite are important mediators in brain function and disease, we investigated the effects of the H2S 'donor', sodium hydrogen sulfide (NaSH) on peroxynitrite-mediated damage to biomolecules and to cultured human SH-SY5Y cells. H2S significantly inhibited peroxynitrite-mediated tyrosine nitration and inactivation of alpha1-antiproteinase to a similar extent to reduced glutathione at each concentration tested (30-250 microm). H2S also inhibited peroxynitrite-induced cytotoxicity, intracellular protein nitration and protein oxidation in human neuroblastoma SH-SY5Y cells. These data suggest that H2S has the potential to act as an inhibitor of peroxynitrite-mediated processes in vivo and that the potential antioxidant action of H2S deserves further study, given that extracellular GSH levels in the brain are very low.


Chronological and reproductive aging-associated changes in resistance to oxidative stress in post-reproductive female mice.
Effort toward reproduction is often thought to negatively influence health and survival. Reproduction has been shown to influence metabolism, but the pathways and mechanisms have yet to be thoroughly elucidated. In the current experiments, our aim was to dissect the role of young and old ovarian tissues in the response to oxidative stress, through changes in liver oxidative stress response proteins. Liver proteins were analyzed in control mice at 4, 13, and 27 months of age and compared to 23-month-old mice which received young ovarian tissue transplants (intact or follicle-depleted) at 13 months of age. In control mice, of the 29 oxidative stress response proteins measured, 31% of the proteins decreased, 52% increased, and 17% were unchanged from 13 to 27 months. The greatest changes were seen during the period of reproductive failure, from 4 to 13 months of age. In transplanted mice, far more proteins were decreased from 13 to 23 months (93% in follicle-containing young ovary recipients; 62% in follicle-depleted young ovary recipients). Neither transplant group reflected changes seen in control mice between 13 and 27 months. Estradiol levels in transplant recipient mice were not increased compared with age-matched control mice. The current results suggest the presence of a germ cell- and estradiol-independent ovarian influence on aging-associated changes in the response to oxidative stress, which is manifest differently in reproductive-aged adults and post-reproductive-aged mice. The results presented here separate chronological and ovarian aging and the influence of estradiol in the response to aging-associated oxidative stress and support a novel, estradiol-independent role for the ovary in female health and survival.


Lupus mastitis: a mimicker of breast carcinoma.
The authors present a case of lupus mastitis which was initially diagnosed following an incisional biopsy of a breast lump, with similar pathology found 2 years later after an ultrasound guided biopsy of the same lump. The woman had been diagnosed 7 years before with systemic lupus erythematosus. The radiological and pathological features are presented in this report with discussion of similar cases in the literature.


Blocking the QB-binding site of photosystem II by tenuazonic acid, a non-host-specific toxin of Alternaria alternata, activates singlet oxygen-mediated and EXECUTER-dependent signalling in Arabidopsis.
Necrotrophic fungal pathogens produce toxic compounds that induce cell death in infected plants. Often, the primary targets of these toxins and the way a plant responds to them are not known. In the present work, the effect of tenuazonic acid (TeA), a non-host-specific toxin of Alternaria alternata, on Arabidopsis thaliana has been analysed. TeA blocks the QB -binding site at the acceptor side of photosystem II (PSII). As a result, charge recombination at the reaction centre (RC) of PSII is expected to enhance the formation of the excited triplet state of the RC chlorophyll that promotes generation of singlet oxygen ((1)O₂). (1)O₂ activates a signalling pathway that depends on the two EXECUTER (EX) proteins EX1 and EX2 and triggers a programmed cell death response. In seedlings treated with TeA at half-inhibition concentration (1)O₂-mediated and EX-dependent signalling is activated as indicated by the rapid and transient up-regulation of (1)O₂-responsive genes in wild type, and its suppression in ex1/ex2 mutants. Lesion formation occurs when seedlings are exposed to higher concentrations of TeA for a longer period of time. Under these conditions, the programmed cell death response triggered by (1)O₂-mediated and EX-dependent signalling is superimposed by other events that also contribute to lesion formation.


The Hypoxia-Adenosine Link during Intestinal Inflammation.
Intestinal inflammation is a key element in inflammatory bowel disease and is related to a combination of factors, including genetics, mucosal barrier dysfunction, bacteria translocation, deleterious host-microbe interactions, and dysregulated immune responses. Over the past decade, it has been appreciated that these inflammatory lesions are associated with profound tissue hypoxia. Interestingly, an endogenous adaptive response under the control of hypoxia signaling is enhancement in adenosine signaling, which impacts these different endpoints, including promoting barrier function and encouraging anti-inflammatory activity. In this review, we discuss the hypoxia-adenosine link in inflammatory bowel disease, intestinal ischemia/reperfusion injury, and colon cancer. In addition, we provide a summary of clinical implications of hypoxia and adenosine signaling in intestinal inflammation and disease.


Is there a final common pathway in mitochondrial encephalomyopathies? Considerations based on an autopsy case of Kearns-Sayre syndrome.
A case of Kearns-Sayre syndrome (KSS) diagnosed 18 years prior to death due to stroke and heart failure with postnatal onset was followed over 15 years and confirmed by postmortem examination. Within the brain, an old cystic infarction of the left hemisphere was found. Other features included white matter gliosis and cerebellar atrophy. Equal or similar features were observed in other conditions thought to be due to failure of mitochondrial metabolism, therefore, a common evolution of neuropathological changes must be discussed.


Best Practices to Maximize the Use and Reuse of Quantitative and Systems Pharmacology Models: Recommendations From the United Kingdom Quantitative and Systems Pharmacology Network.
The lack of standardization in the way that quantitative and systems pharmacology (QSP) models are developed, tested, and documented hinders their reproducibility, reusability, and expansion or reduction to alternative contexts. This in turn undermines the potential impact of QSP in academic, industrial, and regulatory frameworks. This article presents a minimum set of recommendations from the UK Quantitative and Systems Pharmacology Network (UK QSP Network) to guide QSP practitioners seeking to maximize their impact, and stakeholders considering the use of QSP models in their environment.


Maternal, neonatal, pregnancy outcome characteristics of pregnant women with high plasma cell-free DNA concentration in non-invasive prenatal screening: a retrospective analysis.
Cell-free DNA (cfDNA) is a useful biomarker in various clinical contexts. Herein, we aimed to identify maternal characteristics and pregnancy outcomes associated with a failed NIPS test due to high cfDNA concentrations. A retrospective study of cases with high plasma cfDNA concentration in pregnant women in which NIPS test was performed (from 174,318 cases). We reported the detection of 126 cases (118 with complete clinical information) in which the high amount of cfDNA did not allow the performance of NIPS and study the possible causes of this result. 622 (0.35%) of 174,318 pregnant women had failed the NIPS test, including 126 (20.3%) cases with high plasma cfDNA concentrations. The failed NIPS due to high plasma cfDNA concentrations was associated with maternal diseases and treatment with low-molecular-weight heparin (LMWH). Further follow-up of the 118 pregnant women in the case group revealed that the pregnancy outcomes included 31 premature deliveries, 21 abortions. The cfDNA concentrations of pregnant women with preterm deliveries were 1.15 (0.89, 1.84), which differed significantly from those who had full-term deliveries. Among pregnant women with high cfDNA concentrations, systemic autoimmune diseases, pregnancy complications and LMWH were associated with increased incidence of failed NIPS test. High maternal cfDNA concentrations may not be associated with chromosomal abnormalities in the fetus. However, they should be alerted to the possibility of preterm births and stillbirths. Further clinical studies on pregnant women with high cfDNA concentrations are required.


Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate.
Dietary NO3- (nitrate) and NO2- (nitrite) support ˙NO (nitric oxide) generation and downstream vascular signaling responses. These nitrogen oxides also generate secondary nitrosating and nitrating species that react with low molecular weight thiols, heme centers, proteins, and unsaturated fatty acids. To explore the kinetics of NO3-and NO2-metabolism and the impact of dietary lipid on nitrogen oxide metabolism and cardiovascular responses, the stable isotopes Na15NO3 and Na15NO2 were orally administered in the presence or absence of conjugated linoleic acid (cLA). The reduction of 15NO2- to 15NO was indicated by electron paramagnetic resonance spectroscopy detection of hyperfine splitting patterns reflecting 15NO-deoxyhemoglobin complexes. This formation of 15NO also translated to decreased systolic and mean arterial blood pressures and inhibition of platelet function. Upon concurrent administration of cLA, there was a significant increase in plasma cLA nitration products 9- and 12-15NO2-cLA. Coadministration of cLA with 15NO2- also impacted the pharmacokinetics and physiological effects of 15NO2-, with cLA administration suppressing plasma NO3-and NO2-levels, decreasing 15NO-deoxyhemoglobin formation, NO2-inhibition of platelet activation, and the vasodilatory actions of NO2-, while enhancing the formation of 9- and 12-15NO2-cLA. These results indicate that the biochemical reactions and physiological responses to oral 15NO3-and 15NO2-are significantly impacted by dietary constituents, such as unsaturated lipids. This can explain the variable responses to NO3-and NO2-supplementation in clinical trials and reveals dietary strategies for promoting the generation of pleiotropic nitrogen oxide-derived lipid signaling mediators. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT01681836.


A review of the Elachista subula Parenti species complex (Lepidoptera, Elachistidae), with descriptions of nine new Palearctic species.
Taxonomy of the here established Elachista subula species complex is reviewed. This species complex is subordinate to the E. dispilella group sensu Kaila et al. (2015), in subgenus Aphelosetia. The E. subula species complex is exclusively Palearctic. Most of the currently recognized species occur in dry areas in Central Asia where they appear to form a significant part of the Elachista diversity. The constituent species are characterized by a phallus with bent and sharp-tipped apex, and the vesica with one weakly sclerotized plate-like cornutus that usually bears one blunt or spine-like tooth. Fourteen species are recognized, of which the following 9 are described as new: E. ameteria Kaila, sp. nov. (Type locality country Kazakhstan), E. cisoria Kaila, sp. nov. (Spain), E. cultella Kaila, sp. nov. (Mongolia), E. drepanella Kaila, sp. nov. (Russia: Tuva), E. marusiki Kaila, sp. nov. (Mongolia), E. perona Kaila, sp. nov. (Kyrgyzstan), E. platamodes Kaila, sp. nov. (Croatia), E. scalpra Kaila, sp. nov. (Turkey) and E. spinipyra Kaila, sp. nov. (Turkmenistan). Redescriptions are given to E. mus Parenti¸ E. bimaculata Parenti, E. semnani Parenti, E. subula Parenti and E. acutella Kaila.


siRNA-induced silencing of hypoxia-inducible factor 3α (HIF3α) increases endurance capacity in rats.
Molecular mechanisms of adaptation to exercise despite a large number of studies remain unclear. One of the crucial factors in this process is hypoxia inducible factor (HIF) that regulates transcription of many target genes encoding proteins that are implicated in molecular adaptation to hypoxia. Experiments were conducted on 24 adult male Fisher rats. Real-time PCR analysis was performed for quantitative evaluation of Hif3α, Igf1, Glut-4 and Pdk-1 in m. gastrocnemius, m. soleus, in lung and heart tissues. Mitochondrial respiratory function and electron microscopy were performed. Knockdown of Hif3α using siRNA increases time of swimming to exhaustion by 1.5 times. Level of mitochondrial NAD- and FAD-dependent oxidative pathways is decreased, however efficiency of phosphorylation is increased after Hif3α siRNA treatment. Expression of HIF target genes in muscles was not changed significantly, except for increasing of Pdk-1 expression in m. soleus by 2.1 times. More prominent changes were estimated in lung and heart: Igf1 gene expression was increased by 32.5 and 37.5 times correspondingly. Glut4 gene expression in lungs was increased from undetected level till 0.3 rel. units and by 84.2 times in heart. Level of Pdk1 gene expression was increased by 249.2 in lungs and by 35.1 times in hearts, correspondingly. Some destructive changes in muscle tissue were detected in animals with siRNA-inducing silencing of Hif3α.