Long-Read Metagenomics and CAZyme Discovery.
Microorganisms play a primary role in regulating biogeochemical cycles and are a valuable source of enzymes that have biotechnological applications, such as carbohydrate-active enzymes (CAZymes). However, the inability to culture the majority of microorganisms that exist in natural ecosystems restricts access to potentially novel bacteria and beneficial CAZymes. While commonplace molecular-based culture-independent methods such as metagenomics enable researchers to study microbial communities directly from environmental samples, recent progress in long-read sequencing technologies are advancing the field. We outline key methodological stages that are required as well as describe specific protocols that are currently used for long-read metagenomic projects dedicated to CAZyme discovery.


Effects of undernutrition on glial maturation.
Rats of Wistar strain were conceived and breast-fed until the 25th day by mothers maintained on a low protein (5%) and low caloric (21 calories/day) diet, producing a severe deficiency in weight body growth (more than 50% at the 10th day) and of the weight of the central nervous system (40% on the 15th day) both in the cerebral hemispheres and the spinal cord. Histological and biochemical analysis of the central nervous system shows: (1) Glial proliferation is insufficient and delayed, the number of glial cells is reduced by 50% on the 10th day in the cuneatus and gracilis tracts and the density of the glial cells is reduced by 50% in the corpus callosum at the 19th day. (2) Maturation of the glial cells is greatly retarded, especially in the corpus callosum a structure which matures late. On the 19th day, the majority of the cells in this structure still have a glioblastic appearence, whereas in the normal rat, at this age the majority of the glial cells are oligodendrocytes. (3) These abnormalities of glial maturation agree well with the delay of the increase of DNA, RNA and protein measured in the spinal cord and cerebral hemispheres. (4) There is a defect in myelination assessed by estimation of the density of the myelin fibres, and a definitive reduction in the caliber of the spinal tracts.


Prevalence and correlates of prostatitis in the health professionals follow-up study cohort.
Prostatitis is an ill-defined condition whose symptoms overlap with benign prostatic hyperplasia (BPH). Little is known about the prevalence and correlates of prostatitis, or factors that distinguish prostatitis from BPH. We examined these issues in a large, nationwide sample of healthy men. In 1992, 31,681 United States health professionals without prostate cancer provided information on urological diagnoses, lower urinary tract symptoms, and demographic, clinical and lifestyle factors. We calculated age adjusted odds ratios and 95% confidence intervals for these correlates predicting a history of prostatitis. We also compared characteristics of men with prostatitis to those with BPH. The prevalence of a self-reported history of prostatitis was 16%. Men reporting a history of BPH had 7.7-fold greater odds of a history of prostatitis, those with moderate or severe lower urinary tract symptoms had 1.8 and 2.8-fold greater odds, respectively, those with a history of sexually transmitted disease had 1.8-fold greater odds and those reporting stress at home or work had 1.5- and 1.2-fold greater odds, respectively. The 2,163 men with prostatitis alone were younger and had less severe urinary tract symptoms (but a similar pattern of symptoms) than the 4,575 men with BPH alone. Self-reported prostatitis was common among healthy men of all ages but there was considerable overlap with self-reported BPH. Prostatitis had several identifiable correlates that may aid in its recognition.


The Impact of the COVID-19 Pandemic on Psychological Distress, Physical Activity, and Symptom Severity in Parkinson's Disease.
The ongoing COVID-19 pandemic has many consequences for people with Parkinson's disease (PD). Social distancing measures complicate regular care and result in lifestyle changes, which may indirectly cause psychological stress and worsening of PD symptoms. To assess whether the COVID-19 pandemic was associated with increased psychological distress and decreased physical activity in PD, how these changes related to PD motor and non-motor symptom severity, and what frequency and burden of COVID-related stressors were. We sent an online survey to the Personalized Parkinson Project (PPP) cohort (n = 498 PD patients) in the Netherlands. In the survey, we distinguished between COVID-related stressor load, psychological distress, PD symptom severity, and physical activity. We related inter-individual differences to personality factors and clinical factors collected before the pandemic occurred. 358 PD patients completed the survey between April 21 and May 25, 2020 (response rate 71.9%). Patients with higher COVID-related stressor load experienced more PD symptoms, and this effect was mediated by the degree of psychological distress. 46.6% of PD patients were less physically active since the COVID-19 pandemic, and reduced physical activity correlated with worse PD symptoms. Symptoms that worsened most were rigidity, fatigue, tremor, pain and concentration. Presence of neuropsychiatric symptoms (anxiety, depression) before the pandemic, as well as cognitive dysfunction and several personality traits predicted increased psychological distress during the COVID-19 pandemic. Our findings show how an external stressor (the COVID-19 pandemic) leads to a worsening of PD symptoms by evoking psychological distress as well as lifestyle changes (reduced physical activity).


Identification and quantification of electrochemically generated metabolites of thyroxine by means of liquid chromatography/electrospray-mass spectrometry and countergradient liquid chromatography/inductively coupled plasma-mass spectrometry.
Thyroxine (T4) is one of the major thyroid hormones, which regulates cellular metabolism, central nervous system development, body temperature, reproduction and growth. The simulation of oxidation reactions of T4 may provide further information about the fate of T4 in cells without using laborious in vitro and susceptible in vivo tests. In this study, oxidation products of T4, generated inside an electrochemical (EC) cell, were separated and identified by on-line EC/liquid chromatography/electrospray ionization-mass spectrometry (EC/LC/ESI-MS). In another experimental setup, the electrogenerated metabolites were separated by LC, subsequently mixed with a compensating countergradient (cg), and finally introduced into an inductively coupled plasma-mass spectrometer (ICP-MS). The gradient compensation was achieved by an additional pump module which generated a reversed gradient to the analytical gradient used for the separation. This setup enabled a constant composition of the LC eluent flowing into the plasma so that stable plasma conditions and a uniform response over the complete elution time could be achieved. Combined with identification information from online-coupled EC/LC/ESI-MS, robust and reliable quantification of T4 and its oxidation products was accomplished by on-line coupled EC/cgLC/ICP-MS, with LOD of 33nM of iodine.


Induced resistance in mountain birch: defence against leaf-chewing insect guild and herbivore competition.
The effect of leaf damage simulating the feeding of early season insect herbivore species, e.g. Epirrita autumnata, to mountain birch, Betula pubescens ssp. tortuosa, on the performance of insect larvae was studied with eleven leaf-chewing sawfly species. I found variation in the results that was due to short- and long-term inducible responses and to the phenology of herbivore species. In general, early and mid-season species were more strongly affected by induced reactions than late-season species. This finding is in accordance with earlier results but I could show that the persistance of induced reactions rather than the influence of timing of damage is responsible for the result. The growth of the larvae of mid-season sawfly species was affected by both short- and long-term induced reactions. This result shows that early season species may escape short-term induced reactions of mountain birch in current year but may not avoid long-term effects. It is supposed that seasonal deterioration of leaf quality either masks the effects of induced defences or late-season species are better adapted to low-quality leaves. Some species show variation in their response to induced defence in different years. This may be due to yearly differences in induced reactions as well as to species-specific responses. Induced defence reactions may play a role in competitive interactions between herbivore species in leaf-chewing guild of mountain birch.


Assessment of the Validity of Administrative Data for Gestational Diabetes Ascertainment.
Administrative data, including International Classification of Diseases codes and birth certificate records, are often used for retrospective gestational diabetes research investigations to describe associations of gestational diabetes with perinatal complications and long-term outcomes, and to determine gestational diabetes prevalence. Research investigating the validity of using International Classification of Diseases codes and birth certificates for gestational diabetes ascertainment shows varying degrees of reliability. This study aimed to evaluate the accuracy of both International Classification of Diseases codes and birth certificate diagnosis for gestational diabetes ascertainment in a large hospital-based cohort of pregnant individuals, using laboratory criteria for gestational diabetes mellitus as the reference. We studied individuals who received prenatal care at an academic hospital and affiliated community health centers between 1998 and 2016. In the setting of universal 2-step screening for gestational diabetes, pregnant individuals were classified as having gestational diabetes if ≥2 oral glucose tolerance test values met or exceeded National Diabetes Data Group thresholds. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value for International Classification of Diseases code and birth certificate ascertainment of gestational diabetes, and their exact binomial 95% confidence intervals. In a cohort of 51,059 pregnancies with complete glucose screening, 1303 (2.6%) met National Diabetes Data Group laboratory criteria for gestational diabetes. Gestational diabetes International Classification of Diseases codes had moderate sensitivity of 70.5% (95% confidence interval, 67.9-72.9), high specificity of 99.3% (95% confidence interval, 99.3-99.4), a positive predictive value of 73.3% (95% confidence interval, 70.8-75.8), and a negative predictive value of 99.2% (95% confidence interval, 99.1-99.3). In the 46,512 pregnancies linked to birth certificate data, birth certificate diagnosis had moderate sensitivity (66.3% [95% confidence interval, 63.6-69.0]), high specificity (98.9% [95% confidence interval, 98.8-99.0]), moderate positive predictive value (62.1% [95% confidence interval, 59.8-64.4]), and high negative predictive value (99.1% [95% confidence interval, 99.0-99.2]). Ascertainment of gestational diabetes using administrative data, including International Classification of Diseases codes or birth certificates, has moderate sensitivity, moderate positive predictive value, high specificity, and high negative predictive value. Our findings provide context for interpreting the validity of studies that depend on administrative data for ascertainment of gestational diabetes and comparing them with prospective studies that use laboratory-based gestational diabetes criteria.


Medical research in New South Wales 1993-1996 assessed by Medline publication capture.
To assess medical research publication output in New South Wales (NSW). Analysis of publication information from the Medline indexing database, 1993-1996 inclusive. Teaching hospitals and affiliated universities and medical research institutes within NSW, the major sites for NSW medical science publications. Cumulative number and location of Medline-identified publications; journal citation indices (impact factor and immediacy index). 8860 published articles were captured for the analysis period. Universities and hospitals accounted for most of the publications (n = 7755). A mean of 73.1% (range, 36%-100%) of all articles were published in overseas journals, and the rest in Australian journals. This average trend applied to most universities and teaching hospitals, whereas research institutes published almost exclusively in overseas journals. Average publication impact factor values for most universities and teaching hospitals were around the average value for all NSW publications (2.203). The range for teaching hospital publications was 1.000-2.823, but for the overseas-publishing medical research institutes it tended to be higher (2.480-5.423). Immediacy index data yielded similar findings. The universities and teaching hospitals account for most of the medical publications arising from NSW, and also those appearing in Australian journals. Thus, these sites provide the bulk of Australian medical practice end-user information. In contrast, the medical institutes concentrate on publishing in overseas journals with higher and quicker citation rates (higher impact factor and immediacy index).


[Comparison of descriptive expressions between ILO U/C international classification of radiographs of pneumoconiosis 1971 and Japanese classification of pneumoconiosis law in Japan 1960 in pulmonary asbestosis (author's transl)].
In the explanatory text of the ILO U/C International classification of Radiographs of Pneumoconiosis (1971) sent to Japan in 1973, items of its expression on pulmonary asbestosis were analyzed by the author. On the other hand, items of Japanese Asbestosis Classification of Pneumoconiosis Law were also analyzed. The ILO U/C International Classification of Radiographs of Pneumoconiosis (1971) have some confused words. As to pulmonary asbestosis, an expression of irregular opacities is used, but the fundamental X-ray opacities such as linear opacities are forgot in the description. The X-ray findings of the pulmonary asbestosis are divided into 3 types as s, t and u. It is, however, difficult in practice to divide X-ray findings of the pulmonary asbestosis into such types. The classification of X-ray findings of the pulmonary asbestosis in the Japanese Pneumoconiosis Law is based on the classification worked out by many investigators i; the past, providing for simplicity and ease of handling.


Correlation of subpulse structure in a sequence of pulses from pulsar PSR 1919+21.
The fluctuation power spectrum of a sequence of momentary pulse energies formed using an integration gate narrower than the pulse width displays features not visible with a wider gate. The analysis indicates that the class two period is a function of phase within the pulse profile. The statistical constitution of the mean pulse is discussed.


Biological CNP removal from meat-processing wastewater in an innovative high rate up-flow A2O bioreactor.
A high rate up-flow anaerobic, anoxic and oxic (A2O) bioreactor was designed and operated for meat-processing wastewater (MPW) treatment as a single cost-effective system with the aim of simultaneous CNP removal. The influence of three essential factors, HRT, COD/TN ratio and aerated volume fraction on the reactor performance was assessed using response surface methodology (RSM). The required HRT to reach 98.5% COD removal was achieved at 7.5 h. Simultaneous CNP removal under denitrification rate of 199.4 mg/l.d gave high nitrate to nitrogen gas conversion of 74.6 mg/l. An HRT, COD/TN ratio and aerated volume fraction of 10 h, 100:20 and 60%, respectively, was a favored condition for an efficient nitrogen removal with effluent total Kjeldahl nitrogen (TKN) less than 70 mg/l. Under optimum condition, an HRT, COD/TN and aerated volume fraction of 8 h, 100:14 and 65%, respectively, resulted an effluent phosphorus of 43 mg/l, but 93.97 mg/l phosphorus was released in an anaerobic condition at 6 h. An effluent with a low turbidity of about 1.5 NTU and a sludge volume index (SVI) of 75.9 ml/g was achieved using at HRT of 12.5 h, COD/TN ratio of 100: 8 and aerated volume fraction of 50%. Under these conditions, the removal efficiencies for COD, TKN, nitrate-nitrogen (NO3--N), total nitrogen (TN) and phosphorus (PO43--P) were obtained to be 98.33, 92.06, 91.97, 90.48 and 83.48%, respectively. As a result, the application of the up-flow A2O bioreactor is a promising configuration to get hygienic water from wastewater.


Cholera outbreak caused by drug resistant Vibrio cholerae serogroup O1 biotype ElTor serotype Ogawa in Nepal; a cross-sectional study.
Cholera is a major cause of mortality and morbidity in underdeveloped countries including Nepal. Recently drug resistance in Vibrio cholerae has become a serious problem mainly in developing countries. The main objectives of our study were to investigate the occurrence of Vibrio cholerae in stool samples from patients with watery diarrhea and to determine the antimicrobial susceptibility patterns of V. cholerae isolates. A total of 116 stool samples from patients suffering from watery diarrhea during July to December 2012 were obtained from outbreak areas from all over Nepal. Alkaline peptone water and thiosulphate citrate bile salt sucrose agar (TCBS) were used to isolate the Vibrio cholerae. The isolates were identified with the help of colony morphology, Gram's staining, conventional biochemical testing, serotyping and biotyping. Antimicrobial susceptibility testing was performed by determining the minimum inhibitory concentration (MIC) by agar dilution method. Vibrio cholerae was isolated from 26.72 % of total samples. All isolated Vibrio cholerae were confirmed to be Vibrio cholerae serogoup O1 biotype El Tor and serotype Ogawa. All isolates were resistant to ampicillin and cotrimoxazole. Twenty nine isolates were resistant toward two different classes of antibiotics, one strain was resistant to three different classes of antibiotics and one strain was resistant to four different classes of antibiotics. According to the definition of the multidrug resistant bacteria; 6.45 % of the strains of Vibrio cholerae were found to be multidrug resistant. Cholera due to multidrug resistant Vibrio cholerae is also possible in Nepal. According to the antimicrobial susceptibility pattern of Vibrio cholerae in our study we recommend to use any antibiotics among tetracycline, doxycycline, levofloxacin, azithromycin, chloramphenicol and ciprofloxacin for preliminary treatment of cholera in Nepal.


Genetic Effects of ITPK1 Polymorphisms on the Risk of Neural Tube Defects: a Population-Based Study.
Inositol is closely related to the occurrence of neural tube defects (NTDs). Inositol 1, 3, 4-trisphosphate 5/6-kinase (ITPK1) gene encoded an essential regulatory enzyme ITPK1, which is involved in inositol metabolism and has a critical role in the development of neural tube and axial mesoderm. It had been reported that some polymorphisms of critical genes in inositol pathways, including ITPK1, were associated with NTDs in Chinese pregnant women; however, the association between fetus ITPK1 polymorphisms and NTDs had not been reported. In a high incidence of NTDs region of China, a case-control study was performed to evaluate the association between fetal ITPK1 polymorphisms and NTDs. The ITPK1 polymorphisms were genotyped by iPLEX® Gold assay. Inositol levels in fetus brain tissues were analyzed. Three genetic polymorphisms of fetus ITPK1's, including rs3818175, rs2295394, and rs4586354, were statistically associated with spina bifida (NTD subtypes). A higher risk of spina bifida was associated with genotype GG of rs3818175, genotype CC of rs4586354, and genotype TT of rs2295394 (OR = 2.66, 95% CI [1.17-6.05], P = 0.017; OR = 2.22, 95% CI [1.02-4.80], P = 0.041; and OR = 2.33, 95% CI [1.00-5.48], P = 0.047), when compared with the other wild-type genotypes CC, TT, and CC, respectively. Decreased brain inositol level was found in NTDs fetuses, compared to normal controls. Inositol levels were found to significantly decrease with rs2295394 (CC genotype), rs4586354 (TT genotype), and rs3818175 (GC genotype) (P < 0.05). The polymorphisms of fetus ITPK1 were associated with the incidence of NTDs and might be a genetic risk factor for spina bifida.


The normal immune response and what can go wrong. A classification of immunologic disorders.
It is difficult to summarize any discussion of a subject when its vitality and growth increases and changes almost daily. It has been clearly demonstrated that the immune response is important in all organ systems of the body. Although we have learned a great deal about cellular recognition and the regulatory aspects of immunity, we are literally only scratching the surface of its complexity and applicability. A totally comprehensive review of the immune response is impossible in this short space. We do hope, however, that we have set the stage for the following in-depth reviews of the immunologic disorders in adults.


Results of a Phase II trial of gemcitabine, mitoxantrone, and rituximab in relapsed or refractory mantle cell lymphoma.
Gemcitabine (G) has shown activity in mantle cell lymphoma (MCL) as a single agent. The combination of mitoxantrone (M) and rituximab (R) is also active in MCL. The primary objective of this study was to determine the efficacy of G+M+R in relapsed or refractory MCL. Sixteen patients were enrolled between April 2005 and January 2007, 88% had Stage IV MCL, Median patient age was 74 years. Patients received gemcitabine 900 mg/m(2) IV (30-60 min infusion) on Days 1 and 8, mitoxantrone 10 mg/m(2) IV (5-10 min infusion) on day 1, and rituximab 375 mg/m(2) IV on Day 1 (max 400 mg/hour) of the 21-day cycle. Patients received a median of 6 cycles (range, 1-8). Best responses were CR 20% (95%CI, 0, 40.2), PR 27% (95%CI, 4.3, 49.1), SD 40% (95%CI, 15.2, 64.8), and PD 13% (95%CI, 0, 30.5). Median survival and PFS have not been reached with a median follow-up of 10.7 months. The most common Grade 3-4 toxicities were neutropenia (100%), thrombocytopenia (67%), leukopenia (53%), and anemia (33%). The study was closed early due to slow accrual owing to an alternative treatment which became available at the time. The combination of G+M+R in MCL was well-tolerated with manageable toxicity using growth factors to minimize neutropenia; further studies are warranted.


The use of macroarrays for the identification of MDR Mycobacterium tuberculosis.
The emergence of Mycobacterium tuberculosis (Mtb), resistant to both isoniazid (INH) and rifampicin (RIF) (MDR-TB), is an increasing threat to tuberculosis control programs. Susceptibility testing of Mtb complex isolates by phenotypic methods requires a minimum of 14 days from a primary specimen. This can be reduced significantly if molecular analysis is used. Low density oligonucleotide arrays (macroarrays) have been used successfully for the detection of RIF resistance in Mtb. We describe the use of macroarray technology to identify Mtb complex isolates resistant to INH and/or RIF. The macroarray MDR-Mtb screen has been designed to detect mutations in the RIF resistance determining region (RRDR) of Mtb rpoB and loci in katG and mabA-inhA associated with INH resistance. A panel of Mtb isolates containing 38 different RRDR genotypes, 4 different genotypes within codon 315 of katG and 2 genotypes at mabA-inhA was used to validate the macroarray. The wild type (WT) genotype was correctly identified at all three loci. Of the 37 mutant rpoB genotypes, 36 were correctly detected; the single mutant not detected contained a 9 base insertion. All mutations within katG and mabA-inhA were correctly identified. We conclude that this low cost, rapid system can usefully detect the mutations associated with the vast majority of MDR-Mtb.


Examining a window of vulnerability for affective symptoms in the mid-luteal phase of the menstrual cycle.
Particular phases of the menstrual cycle may exacerbate affective symptoms for females with a diagnosed mental health disorder. However, there are mixed findings regarding whether affective symptoms change across the menstrual cycle in females without a clinical diagnosis. The window of vulnerability model proposes that natural increases in ovarian hormones in the mid-luteal phase of the menstrual cycle lead to systematic changes in brain networks associated with affective processing. Consequently, the model posits that females may experience stress more intensely and remember negative events more readily in the mid-luteal phase, increasing their risk for higher affective symptoms. Using a 35-day longitudinal study design, we tested the window of vulnerability model in a non-clinical sample. We tracked naturally cycling females' daily stress and three types of affective symptoms: anxious apprehension, anxious arousal, and anhedonic depression. Using multilevel modeling, we simultaneously modeled within- and between-person associations among stress and menstrual phase for each affective symptom. We found increased anhedonic depression in the mid-luteal phase but not anxious apprehension or anxious arousal. Moreover, we detected a positive association between within- and between-person stress and anxious apprehension and anhedonic depression, but not anxious arousal. These associations were not stronger in the mid-luteal phase. Overall, we provide weak evidence for a window of vulnerability for affective symptoms in the mid-luteal phase of the menstrual cycle. Our findings suggest that stress is a better predictor of fluctuations in affective symptoms than the menstrual cycle. Moreover, our findings highlight the importance of measuring multiple negative affective symptoms because they may be differentially related to stress and the menstrual cycle.


Calcium transients in human platelets monitored by aequorin, fura-2 and quin-2: effects of protein kinase C activation and inhibition.
Tumour-promoting phorbol esters and 1,2-dioctanoyl-sn-glycerol both induce calcium transients in platelets. However, these can only be detected in platelets loaded with aequorin, but not in those loaded with the fluorescent probes quin-2 and fura-2 presumably because of intracellular calcium buffering. Several effects induced by phorbol esters and diacylglycerols, including the rise in (Ca2+)i, the stimulation of Na+/H+ transporter and the inhibition of the effects of thrombin alone on (Ca2+)i are potently antagonised by staurosporine, a compound known to inhibit protein kinase C. Higher concentrations of staurosporine themselves inhibit the thrombin-induced calcium transient. Staurosporine inhibits the effects of phorbol esters and dioctanoyl glycerol with equal potency although the latter does not cause enzyme translocation of cytosolic protein kinase C to membranes. These results therefore suggest that some, if not all, the effects of protein kinase C activation can occur without translocation of the enzyme.


Estimating the social value of nature-based solutions in European cities.
By implementing nature-based solutions (NBS), cities generate value for their residents, such as health and wellbeing. We estimate the aggregate social value to urban residents of 85 NBS projects implemented across Europe and find that the majority yield attractive social returns on investment. We offer a new metric to support investments for NBS by public and private actors for whom social value creation to residents is a core objective.


Yorkshire's influence on the understanding and treatment of mental diseases in Victorian Britain: The golden triad of York, Wakefield, and Leeds.
In the late-eighteenth and nineteenth centuries, a more humane approach to the care of the insane in Britain was catalyzed in part by the illness of King George III. The Reform Movement envisaged "moral" treatment in asylums in pleasant rural environments, but these aspirations were overwhelmed by industrialization, urbanization, and the scale of the need, such that most asylums became gigantic institutions for chronic insanity. Three institutions in Yorkshire remained beacons of enlightenment in the general gloom of Victorian alienism: the Retreat in York founded and developed by the Quaker Tuke family; the West Riding Lunatic Asylum in Wakefield led by Sir James Crichton-Browne, which initiated research into brain and mental diseases; and the Leeds Medical School and Wakefield axis associated with Sir Thomas Clifford Allbutt, which pioneered teaching of mental diseases and, later, the first Chair of Psychiatry. Three other Yorkshiremen who greatly influenced nineteenth-century "neuropsychiatry" in Britain and abroad were Thomas Laycock in York and Edinburgh, and Henry Maudsley and John Hughlings Jackson in London.


Alkaline extracellular reduction: isolation and characterization of an alkaliphilic and halotolerant bacterium, Bacillus pseudofirmus MC02.
To isolate an alkaliphilic bacterium and to investigate its ability of extracellular reduction. An alkaliphilic and halotolerant humus-reducing anaerobe, Bacillus pseudofirmus MC02, was successfully isolated from a pH 10·0 microbial fuel cell. To examine its ability of extracellular reduction, AQDS (anthraquinone-2, 6-disulfonae), humic acids (HA) and Fe(III) oxides were chosen as representative electron acceptors. All the experiments were conducted in a pH 9·5 carbonate buffer. The results are as follows: (i) Sucrose, lactate, glucose and glycerol were the favourable electron donors for AQDS reduction by the strain MC02; (ii) The strain had the ability of reducing HA in the presence of sucrose; (iii) It could effectively reduce Fe(III) oxides coupled with sucrose fermentation when AQDS was added as electron shuttle and its Fe(III) reducing capacity ranked as: lepidocrocite (γ-FeOOH) > goethite (α-FeOOH) > haematite(α-Fe(2) O(3) ); (iv) The strain could decolourize azo dye Orange I. Bacillus pseudofirmus MC02 was capable of extracellular reduction in AQDS, HA and Fe(III) oxides, and it can be used for decolourizing azo dye (Orange I) in alkaline conditions. This is the first report of an alkaliphlic strain of B. pseudofirmus capable of extracellular reduction in AQDS, HA, Fe(III) oxides and decolourization of Orange I. This study could provide valuable information on alkaline biotransformation in the printing and dyeing wastewater and saline-alkali soil.


The stroke patient and assessment of caregiver needs.
Currently, morbidity and mortality rates after stroke are declining as a result of advances in medical care and technology. Despite this decline, the physical, emotional, and psychologic effects of stroke remain devastating. Continuous requirements and long-term commitment with limited resources are a reality for many caregivers. Common problems include role changes, stress, social isolation, and financial burden. A supportive and encouraging atmosphere by the caregiver and an understanding of the emotional and physical challenges that are faced by the person who has had a stroke are essential determinants of a successful rehabilitation.


Modulating antibody effector functions by Fc glycoengineering.
Antibody based drugs, including IgG monoclonal antibodies, are an expanding class of therapeutics widely employed to treat cancer, autoimmune and infectious diseases. IgG antibodies have a conserved N-glycosylation site at Asn297 that bears complex type N-glycans which, along with other less conserved N- and O-glycosylation sites, fine-tune effector functions, complement activation, and half-life of antibodies. Fucosylation, galactosylation, sialylation, bisection and mannosylation all generate glycoforms that interact in a specific manner with different cellular antibody receptors and are linked to a distinct functional profile. Antibodies, including those employed in clinical settings, are generated with a mixture of glycoforms attached to them, which has an impact on their efficacy, stability and effector functions. It is therefore of great interest to produce antibodies containing only tailored glycoforms with specific effects associated with them. To this end, several antibody engineering strategies have been developed, including the usage of engineered mammalian cell lines, in vitro and in vivo glycoengineering.


Atrial fibrillation: a geriatric perspective on the 2020 ESC guidelines.
The Task Force for the diagnosis and management of atrial fibrillation (AF) of the European Society of Cardiology (ESC) published in 2020 the updated Guidelines for the Diagnosis and Management of Atrial Fibrillation with the contribution of the European Heart Rhythm Association (EHRA) of the ESC and the European Association for Cardiothoracic Surgery (EACTS). In this narrative viewpoint, we approach AF from the perspective of aging medicine and try to provide the readers with information usually neglected in clinical routine, mainly due to the fact that while the large majority of AF patients in real life are older, frail and cognitively impaired, these are mostly excluded from clinical trials, and physicians' attitudes often prevail over standardized algorithms. On the basis of existing evidence, (1) opportunistic AF screening by pulse palpation or ECG rhythm strip is cost-effective, and (2) whereas advanced chronological age by itself is not a contraindication to AF treatment, a Comprehensive Geriatric Assessment (CGA) including frailty, cognitive impairment, falls and bleeding risk may assist in clinical decision making to provide the best individualized treatment.


Monitoring failure rates of commercial implant brands; substantial equivalence in question?
The aim of this study was to report on the failure rates of two distinct dental implant systems in a clinical practice setting. Date of implant placement and loss were entered prospectively in a data registry system. Failure rates of two commercially pure titanium implants, one with a porous oxydized surface (POS) and the other with a chemically altered surface (CAS), were assessed using a quality control chart and survival analyses. A total of 860 POS and 759 CAS implants were placed. A warning of an increased failure rate of the CAS implant was identified by means of the quality control chart. Survival analyses indicated that the CAS implant failure rate was twice that of the POS implant (Hazard Ratio: 2.08; 95% CI: 1.33-3.28, P-value < 0.0012). After adjusting for alternative explanations, the CAS implant remained associated with a 95% increased failure rate (95% CI: 1.14-3.35; P-value = 0.0146). Abandoning the CAS implant and returning to a POS implant was associated with a non-significant 64% drop in the implant failure rate within less than a year (HR: 0.36; 95% CI: 0.12-1.14; P-value < 0.0826). The difference between a 4% failure rate with the POS implant and an 8% failure with the CAS implant appears inconsistent with the assumption of substantial equivalence.


Removal of chloramphenicol antibiotics in natural and engineered water systems: Review of reaction mechanisms and product toxicity.
Chloramphenicol antibiotics are widely applied in human and veterinary medicine. They experience natural attenuation and/or chemical degradation during oxidative water treatment. However, the environmental risks posed by the transformation products of such organic contaminants remain largely unknown from the literature. As such, this review aims to summarize and analyze the elimination efficiency, reaction mechanisms, and resulting product risks of three typical chloramphenicol antibiotics (chloramphenicol, thiamphenicol, and florfenicol) from these transformation processes. The obtained results suggest that limited attenuation of these micropollutants is observed during hydrolysis, biodegradation, and photolysis. Comparatively, prominent abatement of these compounds is accomplished using advanced oxidation processes; however, efficient mineralization is still difficult given the formation of recalcitrant products. The in silico prediction on the multi-endpoint toxicity and biodegradability of different products is systematically performed. Most of the transformation products are estimated with acute and chronic aquatic toxicity, genotoxicity, and developmental toxicity. Furthermore, the overall reaction mechanisms of these contaminants induced by multiple oxidizing species are revealed. Overall, this review unveils the non-overlooked and serious secondary risks and biodegradability recalcitrance of the degradation products of chloramphenicol antibiotics using a combined experimental and theoretical method. Strategic improvements of current treatment technologies are strongly recommended for complete water decontamination.


The patellotrochlear index: a new index for assessing patellar height.
The radiological methods to determine patellar height described in the literature are variable, not reliable and depend on the chosen ratio. The purpose of this paper is to describe another method of measuring patellar height on sagittal MRI using the true articular cartilage patellotrochlear relationship. An analysis of magnetic resonance (MR) examinations of 66 consecutive patients was performed. The most common diagnoses were meniscal or anterior cruciate ligament pathologies. No patient suffered from patellofemoral complaints. Measurements on sagittal MR images included different parameters using the articular cartilage of the patella and the trochlea. The ratio patella : trochlea of the cartilage baselines was measured in percentages and described as patellotrochlear index. The measurements were assessed at two different times by three raters under blinded conditions. The mean patellotrochlear index was 31.7% (CI: 12.5-50.0; range -5.0 to 61.1%; SD +/-11.6). The intraobserver variability showed only in the "second observer" a difference of the mean values of the two different measurements (t=2.189; P=0.032). The interobserver correlation was high and significant (0.663-0.893; P=0.000). Our results indicate that the patellotrochlear index is a reliable and precise method to determine the exact articular correlation of the patellofemoral joint and the patellar height. The results represent the average patellotrochlear index in the normal population without patellofemoral complaints. Measurements of the articular cartilage congruence can be helpful to define an underlying pathology of patellar height, such as patella alta or infera.


Optimization of membrane bioreactors by the addition of powdered activated carbon.
It was found that with replenishment, powdered activated carbon (PAC) in the membrane bioreactor (MBR) would develop biologically activated carbon (BAC) which could enhance filtration performance of a conventional MBR. This paper addresses two issues (i) effect of PAC size on MBR (BAC) performance; and (ii) effect of sludge retention time (SRT) on the MBR performance with and without PAC. To interpret the trends, particle/floc size, concentration of mixed liquor suspended solid (MLSS), total organic carbon (TOC), short-term filtration properties and transmembrane pressure (TMP) versus time are measured. The results showed improved fouling control with fine, rather than coarse, PAC provided the flux did not exceed the deposition flux for the fine PAC. Without PAC, the longer SRT operation gave lower fouling at modest fluxes. With PAC addition, the shorter SRT gave better fouling control, possibly due to greater replenishment of the fresh PAC.


Comparison of methods for the analysis of 226Ra in water samples.
226Ra is one of the key nuclides among the natural radionuclides from the point of view of radiation protection. For monitoring the radiation exposure risk along the water pathway it has to be measured routinely with low detection limits. Because of the properties of 226Ra and its progenies, a number of quite different methods are possible for this purpose. This paper presents a comparison of routine techniques for the determination of 226Ra in water samples as applied by the authors.


The voice of the child in parental divorce: implications for clinical practice and mental health practitioners.
Research on parental divorce suggests that the nature of the divorce process, as experienced by the child, is the most important factor in his or her post-divorce adjustment. Research regarding children's experiences of the divorce process has been limited and the adult perspective has dominated the discourse on divorce; only recently has research started to consider children's viewpoint. This article describes a narrative inquiry into the experiences and perceptions of parental divorce, of 9- to 10-year-old children. Its aim is to use children's stories of parental divorce to inform the practice of professionals working with such children. The research adopted a narrative paradigm. Unstructured interviews were conducted with five children whose parents were divorced. Data were analysed thematically. Seven themes were identified. The first theme explored children's endeavours to describe and explain parental divorce. An additional six themes were developed around the types of stories children told of the divorce process. The seven themes were: (i) What is a divorcement; (ii) Stories of loss; (iii) Stories of gain; (iv) Stories of change; (v) Stories of stability; (vi) Healing stories; and (vii) Complicating stories. On the basis of the narratives elicited from children on parental divorce, this article proposes several guidelines for professionals such as psychologists, registered counsellors, social workers, and teachers as well as parents in their possible interventions with children. Some guidelines may also be of use to family and maintenance courts, and the government departments of health and education.


Optimal Delivery Route of Mesenchymal Stem Cells for Cardiac Repair: The Path to Good Clinical Practice.
Research has shown that mesenchymal stem cells (MSCs) could be a promising therapy for treating progressive heart disease. However, translation into clinics efficiently and successfully has proven to be much more complicated. Many questions remain for optimizing treatment. Application method influences destiny of MSCs and afterwards impacts results of procedure, yet there is no general agreement about most suitable method of MSC delivery in the clinical setting. Herein, we explain principle of most-frequent MSCs delivery techniques in cardiology. This chapter summarizes crucial translational obstacles of clinical employment of MSCs for cardiac repair when analysed trough a prism of latest research centred on different techniques of MSCs application.


[The control of radiation protection in the field of radiotherapy by the French Nuclear Safety Authority (ASN)].
During the last months, several incidents at radiotherapy services occurred in France; one of these accidents led to the death of several patients or required further heavy surgical acts. In this context, ASN (Autorité de sûreté nucléaire) issued an experimental guide for the notification of radiation protection events and achieved, in dialogue with professional organisations, a new scale intended to facilitate public information on radiotherapy incidents. ASN is also fully involved in the preparation of the action plan managed by the Health ministry in order to improve the safety of treatment in radiotherapy.


Higher mortality rates for large- and medium-sized mammals on plantation roads compared to highways in Peninsular Malaysia.
The fragmentation of forests by agricultural expansion, urbanization, and road networks is an ongoing global biodiversity crisis. In Southeast Asia and other tropical regions, wildlife populations are being isolated into pockets of natural habitat surrounded by road networks and monoculture plantations. Mortality from wildlife-vehicle collisions (WVCs) is contributing to a decline in many species of conservation priority in human-modified landscapes. This study is the first in Malaysia to investigate factors affecting the occurrence of WVCs. We assessed roadkill data gathered by the Department of Wildlife and National Parks on small-, medium-, and large-sized mammals in Peninsular Malaysia. We examined the relationship between wildlife road accidents and several environmental factors. We found a total of 605 roadkill animals, involving 21 species, which included three species classified as Endangered. Road type (plantation road or highway), year, and distance of the road from continuous and fragmented forests were significant in determining mammal mortality. Unexpectedly, the majority of road mortality occurred on palm oil plantation roads compared to highways. Mortality of small- and medium-sized mammals was greater at locations further from continuous forest than those closer to fragmented forests. Segmentation of continuous forest by roads should be avoided wherever possible to reduce the threat of roads on crossing wildlife.


Catalytic, oxidative condensation of CH4 to CH3COOH in one step via CH activation.
Acetic acid is an important petrochemical that is currently produced from methane (or coal) in a three-step process based on carbonylation of methanol. We report a direct, selective, oxidative condensation of two methane molecules to acetic acid at 180 degrees C in liquid sulfuric acid. Carbon-13 isotopic labeling studies show that both carbons of acetic acid originate from methane. The reaction is catalyzed by palladium, and the results are consistent with the reaction occurring by tandem catalysis, involving methane C-H activation to generate Pd-CH3 species, followed by efficient oxidative carbonylation with methanol, generated in situ from methane, to produce acetic acid.


Higher morning to evening ratio in total dose of twice-daily biphasic insulin analog might be effective in achieving glucose control in patients with poorly controlled type 2 diabetes.
The aims of this study are to investigate not only the glucose-lowering effectiveness of twice-daily premixed insulin lispro 25 (Humalog(®) Mix25(™), Eli Lilly and Co., Indianapolis, IN), but also the optimal divided ratio of total Mix25 dose in Korean patients with poorly controlled type 2 diabetes. In this retrospective study, we retrieved data for subjects who were on intensive insulin therapy with twice-daily Mix25 regimen for at least 24 weeks. Changes of hemoglobin A1c (HbA(1c)) and other clinical and laboratory parameters were evaluated. Two groups were defined according to dose ratio of pre-breakfast to pre-dinner insulin at 24 weeks: Group I, pre-breakfast:pre-dinner insulin dose ratio=50:50; Group II, ratio=53:47-75:25. In total, 143 subjects were ultimately analyzed in this study. Twice-daily Mix25 significantly improved HbA(1c) levels from 10.1% to 7.7%, and 34% of patients had reached the target glycemic goal (HbA(1c)<7%) after 24 weeks. Compared with Group I, a significant reduction in HbA(1c) (Group I vs. Group II, -1.9±0.3% vs. -2.8±0.3%, P=0.02) and a larger proportion of subjects with HbA(1c)<7% (23.2% vs. 46.7%, P=0.01) were observed in subjects in Group II. Among clinical and laboratory factors, duration of diabetes (odd ratios [OR]=0.93, 95% confidence interval [CI] 0.86-0.99, P=0.04) and history of sulfonylurea use (OR=0.27, 95% CI 0.10-0.72, P=0.01) were independently associated with achieving target HbA(1c) levels less than 7%. Twice-daily Mix25 is an effective option for Korean subjects with type 2 diabetes having uncontrolled hyperglycemia. A higher pre-breakfast/pre-dinner dose ratio (53:47-75:25) might be taken into consideration as an initial protocol to accomplish better glycemic control in twice-daily Mix25.


Association of Cumulative Blood Pressure With Cognitive Decline, Dementia, and Mortality.
Elevated blood pressure (BP) has been linked to impaired cognition and dementia in older adults. However, few studies have accounted for long-term cumulative BP exposure. The aim of this study was to test whether long-term cumulative BP was independently associated with subsequent cognitive decline, incident dementia, and all-cause mortality among cognitively healthy adults. This study used data from the HRS (Health and Retirement Study) and ELSA (English Longitudinal Study of Ageing). Cumulative BP was calculated as the area under the curve using measurements from wave 0 (1998-1999) to wave 4 (2008-2009) in ELSA and wave 8 (2006-2007) to wave 10 (2010-2011) in the HRS. Outcomes included cognitive decline, incident dementia, and all-cause mortality. A total of 7,566 and 9,294 participants from ELSA and the HRS were included (44.8% and 40.2% men and median age 62.0 years [IQR: 55.0-70.0 years] and 65.0 years [IQR: 58.0-72.0 years], respectively). The median follow-up duration was 8.0 years (IQR: 4.0-8.0 years) and 8.0 years (IQR: 6.0-8.0 years), respectively. Elevated cumulative systolic BP and pulse pressure were independently associated with accelerated cognitive decline (P < 0.001 for both), elevated dementia risk (P < 0.001 for both), and all-cause mortality (P < 0.001 for both), while a significant inverse association was observed for diastolic BP. Strong dose-response relationships were identified, with similar results for the 2 cohorts. Long-term cumulative BP was associated with subsequent cognitive decline, dementia risk, and all-cause mortality in cognitively healthy adults aged ≥50 years. Efforts are required to control long-term systolic BP and pulse pressure and to maintain adequate diastolic BP.


Occupational identity development, school performance, and social support in adolescence: findings of a Dutch study.
Three hundred adolescents completed a Dutch version of the Dellas Identity Status Inventory-Occupation (DISI-O). Reliability of the five subscales ranged from "sufficient" to "very good," and the four identity status classifications accommodated about 90% of the respondents. As expected, achievement and social support by friends in the educational setting stimulated development of occupational identity.


Tarlov cyst-a rare lesion in children: case report.
Perineural cysts, also known as Tarlov cysts, are benign lesions increasingly found in patients undergoing neuroimaging studies. These cysts can very rarely be identified in children and even then, they are not so likely to be responsible for some neurological deficit. It seems to be of scientific and clinical importance to present a pediatric case with Tarlov cyst. We report a case of a patient, a 7-year-old boy, previously treated for nocturnal enuresis (bedwetting), who later developed signs and symptoms of classic urinary incontinence. Magnetic resonance imaging (MRI) showed a relatively large extradural cyst at the level of S2. The cyst was approached by laminectomy of L5 to S2, excised, and completely removed from the belonging nerve root. The patient has established normal sphincter control without even a single episode of involuntary discharge of urine. A surgery is a powerful, safe, and efficacious option for treatment in pediatric patients with sacral Tarlov cysts.


Role of macrophage cytokines in mucosal adjuvanticity.
Delivery of protein antigens to the GALT can result in immunity or oral tolerance depending on the circumstances of the encounter. One mechanism by which mucosal adjuvants can affect these circumstances is by the induction of macrophage cytokines, including IL-1 and IL-12. These cytokines can directly affect the immune response by their effects on antigen-specific T cells and by the induction of IFN-gamma by T cells or NK cells. This IFN-gamma also activates macrophages to up-regulate MHC or costimulatory molecules and by further inducing IL-1 and IL-12. In effect, mucosal adjuvants function both directly and indirectly as activators of antigen presenting cells, resulting in stimulation of the immune response to coincidental antigens. Our studies in swine have shown CT is a potent mucosal adjuvant for CT-B. CT also increased IL-1 and IL-12 mRNA in cultured macrophages, especially after activation with IFN-gamma. The effect of CT on the secretion of bioactive IL-12 protein is currently being investigated. While the mucosal adjuvanticity of CT involves a variety of mechanisms, these findings suggest a role for the induction of the macrophage cytokines IL-1 and IL-12.


Association between remnant cholesterol level and severity of chronic kidney disease in patients with type 2 diabetes.
Studies on whether remnant cholesterol (RC) affects the progression of chronic kidney disease (CKD) remain insufficient. This study aimed to determine whether RC level was associated with the severity of CKD in patients with type 2 diabetes mellitus (T2DM). In total, 3383 individuals diagnosed with T2DM were enrolled in this cross-sectional study from China. The severity of CKD was defined as no, moderate, severe, and very severe CKD based on the urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. Because RC was non-normally distributed, it was log-transformed and categorized into quantiles. Multivariate logistic regression and multivariate ordinal logistic regression analysis were performed to investigate whether RC was independently associated with CKD and its severity. The median RC level was 25.9 mg/dL. The number of patients with no, moderate, severe, and very severe CKD was 2587 (76.5 %), 520 (15.4 %), 189 (5.6 %), and 87 (2.5 %), respectively. After adjusting for confounding factors, the prevalence of CKD increased 1.67-fold when the log-transformed RC level was elevated by one unit (OR [95 % CI], 1.67 [1.43-1.95]). The likelihood of CKD severity increasing by one degree was 1.76-fold for each one-unit increase in log-transformed RC level (OR [95 % CI], 1.76 [1.52-2.05]). When RC was incorporated as a categorical variable, it still correlated with CKD severity compared with quantile 1 (Q1) (Q2, 1.30 [1.01-1.68]; Q3, 1.60 [1.23-2.07]; Q4, 2.39 [1.86-3.09]). The association remained regardless of whether the patient's traditional lipid profiles achieved the target range. RC level was associated with CKD severity even when traditional lipid profiles were within the target range in patients with T2DM.


Evidence for a direct peripheral effect of clonidine on the norepinephrine release in vivo in pithed rats.
To study the in vivo peripheral effects of clonidine on sympathetic neuronal function we measured, after different doses of clonidine, plasma norepinephrine (NE) and blood pressure (BP) responses during electric stimulation of sympathetic outflow in pithed male Sprague-Dawley rats. In this preparation, clonidine produced dose-dependent inhibition of the sympathetic stimulation-induced pressor and plasma NE responses. The dose of clonidine inhibiting the NE response by 50% (ID50) was 14.2 +/- 0.3 micrograms/kg i.v., while ID50 for the diastolic pressor response was 22.0 +/- 0.2 micrograms/kg i.v. Since clonidine did not alter the relationship between NE released into the plasma and the pressor responses, the entire effect of clonidine in decreasing the pressor response to sympathetic stimulation may be attributed to its presynaptic alpha 2-adrenoceptor-mediated inhibition of NE release.


Topological methods for genomics: present and future directions.
Topological methods are emerging as a new set of tools for the analysis of large genomic datasets. They are mathematically grounded methods that extract information from the geometric structure of data. In the last few years, applications to evolutionary biology, cancer genomics, and the analysis of complex diseases have uncovered significant biological results, highlighting their utility for fulfilling some of the current analytic needs of genomics. In this review, the state of the art in the application of topological methods to genomics is summarized, and some of the present limitations and possible future developments are reviewed.


Alterations of coronary vascular responses to noradrenaline, acetylcholine and isoprenaline during acute myocardial ischaemia in dogs.
1. The reactivity of coronary arteries to noradrenaline (NA), acetylcholine (ACh) and isoprenaline (Iso) during acute myocardial ischaemia was studied in anaesthetized, open-chest dogs. 2. The left anterior descending coronary artery (LAD) was cannulated and perfused via an extracorporal circuit at constant flow. Ischaemia was produced by decreasing the perfusion blood flow of the LAD to 50% (moderate ischaemia) and 27% (severe ischemia) of normal. A dose of each agent which had no significant myocardial effects was chosen. Heart rate was held constant by ventricular pacing during ACh administration. 3. Under normal conditions, the infusion of NA, ACh and Iso into the LAD produced significant decreases in coronary vascular resistance (P less than 0.01). However, under either moderate or severe ischaemic conditions intracoronary NA resulted in a marked increase in coronary vascular resistance (P less than 0.01), which was completely blocked by phentolamine, an alpha-adrenoceptor blocker; intracoronary ACh and Iso did not have a significant effect on coronary vascular resistance (P greater than 0.05). 4. These results indicate that coronary arterial responsiveness to some intrinsic vasoactive substances, such as NA and ACh, is altered during acute myocardial ischaemia. This may be important in the pathophysiology of myocardial ischaemia.


Alternative prostate cancer grading systems incorporating percent pattern 4/5 (IQ-Gleason) and cribriform architecture (cGrade) improve prediction of outcome after radical prostatectomy.
Percentage Gleason pattern 4, invasive cribriform and/or intraductal carcinoma (IC/IDC) and minor pattern 5 are recognized as independent parameters for prostate cancer outcome, but are not incorporated in current grade groups (GGs). Two proof-of-principle studies have proposed alternative grading schemes based on percentage Gleason pattern 4/5 (integrated quantitative Gleason score; IQ-Gleason) and IC/IDC presence (cribriform grade; cGrade). Our objective was to compare the performance of GG, IQ-Gleason and cGrade for predicting biochemical recurrence and metastasis after radical prostatectomy (RP). RP specimens of 1064 patients were pathologically reviewed and graded according to the three schemes. Discriminative power for prediction of biochemical recurrence-free (BCRFS) and metastasis-free (MFS) survival was compared using Harrell's c-index. The GG distribution at RP was 207 (19.4%) GG1, 472 (44.4%) GG2, 126 (11.8%) GG3, 140 (13.2%) GG4 and 119 (11.2%) GG5. Grading according to 5-tier IQ-Gleason and cGrade systems led to categorical shifts in 49.8% and 29.7% of cases, respectively. Continuous IQ-Gleason had the best performance for predicting BCRFS (c-index 0.743, 95% confidence interval (CI) 0.715-0.771), followed by cGrade (c-index 0.738, 95%CI 0.712-0.759), 5-tier categorical IQ-Gleason (c-index 0.723, 95%CI 0.695-0.750) and GG (c-index 0.718, 95%CI 0.691-0.744). Continuous IQ-Gleason (c-index 0.834, 95%CI 0.802-0.863) and cGrade (c-index 0.834, 95%CI 0.808-0.866) both had better predictive value for MFS than categorical IQ-Gleason (c-index 0.823, 95%CI 0.788-0.857) and GG (c-index 0.806, 95%CI 0.777-0.839). In conclusion, the performance of prostate cancer grading can be improved by alternative grading schemes incorporating percent Gleason pattern 4/5 and IC/IDC.


A clinical correlation between hypozincemia and tinnitus.
We examined a group of 115 patients suffering from tinnitus and have attempted to find a statistically significant correlation between the tinnitus experienced and low blood zinc levels (hypozincemia). No particular correlation could be made between the nature of the tinnitus experienced and hypozincemia except for the continuation of head noises, these being more frequently associated with hypozincemia when they are intermittent. Two hypotheses of pathogenesis are proposed to explain this phenomenon and are based on the importance of zinc to the syntheses of enzymes and proteins.


Spring water quality and usability in the Mount Cameroon area revealed by hydrogeochemistry.
Groundwater is the only reliable water resource for drinking, domestic, and agricultural purposes for the people living in the Mount Cameroon area. Hydrogeochemical and R-mode factor analysis were used to identify hydrogeochemical processes controlling spring water quality and assess its usability for the above uses. Main water types in the study area are Ca-Mg-HCO(3) and Na-HCO(3). This study reveals that three processes are controlling the spring water quality. CO(2)-driven silicate weathering and reverse cation exchange are the most important processes affecting the hydrochemistry of the spring waters. While tropical oceanic monsoon chloride-rich/sulfate-rich rainwater seems to affect spring water chemistry at low-altitude areas, strong correlations exist between major ions, dissolved silica and the altitude of springs. In general, the spring waters are suitable for drinking and domestic uses. Total hardness (TH) values indicate a general softness of the waters, which is linked to the development of cardiovascular diseases. Based on Na %, residual sodium carbonate, sodium adsorption ratio, and the USSL classification, the spring waters are considered suitable for irrigation. Though there is wide spread use of chemical fertilizers and intense urban settlements at the lower flanks of the volcano, anthropogenic activities for now seem to have little impact on the spring water quality.


The classification and management of skin and soft tissue infections.
Skin and soft tissue infections (SSTIs) are a common problem in patients presenting to the emergency department, varying from mild local inflammation to necrotizing fasciitis. SSTI were the 2nd most common indication for antibiotic use in Europe in 2006. Currently, the National Institute of Clinical Excellence (a UK based independent organization responsible for providing national guidance on the promotion of good health and the prevention and treatment of ill health) has not published any guidelines for the classification and management of these patients. This is a review of the evidence around attempts at developing classification systems for SSTI and their management. It also considers the financial implications for both the patient and the healthcare system and the personal ramifications for patients.


Effect of therapy for thyroid dysfunction on musculoskeletal symptoms.
Our purpose was to assess the long-term effect of treatment for thyroid dysfunction on musculoskeletal symptoms. Forty-six patients (37 with hypothyroidism, 9 with hyperthyroidism), who visited the outpatient clinic of rheumatology and had abnormal thyroid function tests on their first visit, cooperated in the study. They were interviewed with a structured questionnaire about their past and current musculoskeletal complaints. Thyroid dysfunction was considered the only explanation for the original musculoskeletal symptoms in 24 patients (Group I); in 19 patients an additional (rheumatological) diagnosis was made (Group II), and in 3 patients no apparent relation between musculoskeletal complaints and thyroid dysfunction was found. After treatment for thyroid dysfunction, the original complaints decreased in 52% and 47% of the patients in Group I and II, respectively. At the time of the follow-up study (mean follow-up duration 67 months) 91% of the patients had musculoskeletal symptoms, 80% of the patients said their present complaints were similar to their original symptoms. Treatment for thyroid dysfunction resulted in a temporary effect on musculoskeletal symptoms.


Activation of GABAB receptors results in excitatory modulation of calyx terminals in rat semicircular canal cristae.
Previous studies have found GABA in vestibular end organs. However, existence of GABA receptors or possible GABAergic effects on vestibular nerve afferents has not been investigated. The current study was conducted to determine whether activation of GABAB receptors affects calyx afferent terminals in the central region of the cristae of semicircular canals. We used patch-clamp recording in postnatal day 13-18 (P13-P18) Sprague-Dawley rats of either sex. Application of GABAB receptor agonist baclofen inhibited voltage-sensitive potassium currents. This effect was blocked by selective GABAB receptor antagonist CGP 35348. Application of antagonists of small (SK)- and large-conductance potassium (BK) channels almost completely blocked the effects of baclofen. The remaining baclofen effect was blocked by cadmium chloride, suggesting that it could be due to inhibition of voltage-gated calcium channels. Furthermore, baclofen had no effect in the absence of calcium in the extracellular fluid. Inhibition of potassium currents by GABAB activation resulted in an excitatory effect on calyx terminal action potential firing. While in the control condition calyces could only fire a single action potential during step depolarizations, in the presence of baclofen they fired continuously during steps and a few even showed repetitive discharge. We also found a decrease in threshold for action potential generation and a decrease in first-spike latency during step depolarization. These results provide the first evidence for the presence of GABAB receptors on calyx terminals, showing that their activation results in an excitatory effect and that GABA inputs could be used to modulate calyx response properties.NEW & NOTEWORTHY Using in vitro whole cell patch-clamp recordings from calyx terminals in the vestibular end organs, we show that activation of GABAB receptors result in an excitatory effect, with decreased spike-frequency adaptation and shortened first-spike latencies. Our results suggest that these effects are mediated through inhibition of calcium-sensitive potassium channels.


Sonographic findings of tuberculous thyroiditis in a patient with Behçet's syndrome.
We report a case of tuberculous thyroiditis in a woman with Behçet's syndrome. The initial physical examination in May 1998 revealed multiple soft, nontender, mobile lymph nodes, each measuring less than 1 cm, in the left lower internal jugular chain. Sonography performed in February 2000 showed multiple small (< 1 cm), oval lymph nodes, each with an intact fatty hilum, in the left lower internal jugular chain; the thyroid gland appeared normal. Follow-up sonography 6 months later showed multifocal, heterogeneous, hypoechoic lesions with ill-defined margins in both lobes of the thyroid and several small, oval lymph nodes, each with an intact fatty hilum, in the left lower internal jugular chain. Fine-needle aspiration was performed on the largest thyroid lesion, and cytologic analysis of the aspirate revealed a small number of epithelioid histiocytes in a necrotic background, which was suggestive of tuberculosis. Follow-up sonography after 3 months of antituberculosis chemotherapy showed that the thyroid lesions had resolved.


Comment on Suresh et al. The Short-Term Effects and Tolerability of Low-Viscosity Soluble Fibre on Gastroparesis Patients: A Pilot Clinical Intervention Study. Nutrients 2021, 13, 4298.
Zhou and colleagues are commended for their innovative research on the tolerability of "low-viscosity" fibre supplements in symptomatic diabetic gastroparesis patients [...].


Inhibition of adriamycin-induced micronuclei by desferrioxamine in Swiss albino mice.
Swiss albino male mice, 6-8 weeks old, were treated i.p. with different doses of desferrioxamine dissolved in water for 7 days. Some of the mice in each group were injected i.p. with adriamycin (15 mg/kg) and killed after 30 or 24, 48 and 72 h. The femoral cells of mice in different groups were collected and studied. Desferrioxamine treatment failed to affect the incidence of micronuclei at doses of 125-250 mg/kg/day. Pretreatment with desferrioxamine was found to provide significant protection against adriamycin-induced micronuclei without interfering with its cytotoxic potential.


[Laser coagulation in the endoscopic management of fourth branchial pouch sinus].
To describe a new method of treatment of the fourth branchial pouch sinuses by laser endoscopic coagulation of the fistula. Retrospective study of two children aged 3 and 12 years with fourth branchial pouch sinuses. Both children presented recurrent cervical abscesses. The diagnosis was established on results of ultrasound, barium study, CT scan and pharyngoscopy. After recovering from infection, the definitive treatment was a laser diode cauterization of the fistulous route and its pharyngeal opening. Outcome was rapidly favorable in both children without complications or recurrence. These two cases and other reports in the literature confirm the role of endoscopic management for the treatment of the fourth branchial pouch sinus. Laser treatment is especially useful because of its convenience, its harmlessness and its reliability. Fourth branchial pouch sinuses are rare. Surgery, which can be difficult and not without risks, is the generally accepted treatment. This new laser method combines ease of treatment and efficacy.


Cytomegalovirus in juvenile iridocyclitis.
We cultured cytomegalovirus from lens material aspirated from the eye of a 4-year-old boy who had a severe bilateral iridocyclitis and secondary cataracts. There were neither systemic manifestations of congenital disease nor chorioretinitis.


A chemoenzymatic approach to the synthesis of enantiomerically pure (S)-3-hydroxy-gamma-butyrolactone.
Optically pure (S)-3-hydroxy-gamma-butyrolactone, an important chiral building block in the pharmaceutical industry, was synthesized from L: -malic acid by combining a selective hydrogenation and a lipase-catalyzed hydrolysis. Lipase from Candida rugosa was found to be the most efficient enzyme for the hydrolysis of (S)-beta-benzoyloxy-gamma-butyrolactone. The use of organic solvent-aqueous two-phase system was employed to extract benzoic acid generated from enzymatic hydrolysis of the substrate. Tert-butyl methyl ether as an organic solvent was effective to extract the reaction product, benzoic acid, and stably maintained the enzyme activity of Lipase OF immobilized on polymeric supports Amberlite XAD-7. The immobilization made the recovery of the product simpler and prevented the formation of the emulsion. The pH adjustment was unnecessary with the immobilized Lipase OF. The scale-up of the enzymatic hydrolysis of S-BBL at 1,850-kg scale was carried out without problems to give 728.5 kg of S-HGB at 80% isolated yield. The scale-up results are similar to those of bench scale reactions. Racemic (R,S)-beta-benzoyloxy-gamma-butyrolactone was prepared from D-, L: -malic acid and was found to be hydrolyzed nonselectively by the enzyme.


Tremor and Movement Slowness Are Two Unrelated Adverse Effects Induced by Valproate Intake.
To date, only a few clinical and neurophysiological studies have assessed the features of valproate-induced tremor (VIT), and whether valproate (VPA) affects voluntary movements is underinvestigated. To better characterize the clinical and neurophysiological features of VIT in patients with epilepsy and the effect of VPA on the execution of voluntary movement. We tested 29 patients with VIT (13 taking VPA alone and 16 taking VPA plus other antiepileptics). Patients underwent a neurological examination, video recordings and kinematic assessments of postural, kinetic, and resting upper limb tremor using a motion analysis system. Movement execution was tested by kinematic assessment of finger tapping. Data of patients with VIT were compared with those of 13 patients with epilepsy taking VPA but without tremor, 13 patients with epilepsy who were not on VPA treatment, 20 patients with Parkinson's disease (PD), and 20 healthy controls (HCs). Clinical and kinematic evaluations showed that tremor in patients taking VPA alone was less severe than tremor in patients taking VPA plus other antiepileptics. All patients taking VPA, regardless of the presence of tremor, performed slower finger tapping compared with HCs, similar to what was observed in PD, although with no sequence effect. Patients with epilepsy without VPA showed a normal motor performance. Tremor and movement slowness are motor signs induced by VPA. VIT severity is exacerbated when VPA is taken in combination with other antiepileptics. VPA-induced slowness occurs regardless of tremor, may precede tremor development, and is not attributed to epilepsy.


An internal model for canceling self-generated sensory input in freely behaving electric fish.
Internal models that predict the sensory consequences of motor actions are vital for sensory, motor, and cognitive functions. However, the relationship between motor action and sensory input is complex, often varying from one moment to another depending on the state of the animal and the environment. The neural mechanisms for generating predictions under such challenging, real-world conditions remain largely unknown. Using novel methods for underwater neural recording, a quantitative analysis of unconstrained behavior, and computational modeling, we provide evidence for an unexpectedly sophisticated internal model at the first stage of active electrosensory processing in mormyrid fish. Closed-loop manipulations reveal that electrosensory lobe neurons are capable of simultaneously learning and storing multiple predictions of the sensory consequences of motor commands specific to different sensory states. These results provide mechanistic insights into how internal motor signals and information about the sensory environment are combined within a cerebellum-like circuitry to predict the sensory consequences of natural behavior.


Selective screening for lysosomal storage diseases with dried blood spots collected on filter paper in 4,700 high-risk colombian subjects.
Lysosomal storage disorders (LSDs) are a very heterogeneous group of hereditary disorders. The diagnostic process usually involves complex sampling, processing, testing, and validation procedures, performed by specialized laboratories only, which causes great limitations in reaching a diagnosis for patients affected by these diseases.There are few studies about LSDs in Colombia. The diagnostic limitations often make medical practitioners disregard the possibility of these disorders while diagnosing their patients. The current study documents the results of a 7-year screening in high-risk patients, aimed to detect LSDs using dried blood spots (DBS) collected on filter paper, with a micromethodology that facilitates diagnosis even with a large number of samples.The activities of α-galactosidase A, α glucosidase, α-L-iduronidase, arylsulfatase B, β-galactosidase, β-glucosidase, total hexosaminidase, iduronate sulfatase, and chitotriosidase were analyzed in high-risk patients for lysosomal disease. The catalytic activity was evaluated with fluorometric micromethods using artificial substrates marked with 4-methylumbelliferone.The reference values for a control population were established for the enzymes listed above, and 242 patients were found to have an enzyme deficiency, guiding to the following diagnoses: Fabry disease (n = 31), Pompe disease (n = 16), Hurler Syndrome (n = 15), Maroteaux-Lamy Syndrome (n = 34), GM1 Gangliosidosis (n = 10), Morquio B (n = 1), Gaucher disease (n = 101), Sandhoff disease (n = 1), Mucolipidosis (n = 2), and Hunter Syndrome (n = 31). In conclusion, this protocol provides a comprehensive diagnostic approach which could be carried out in Colombia and made it available to medical services spread around the country, enabling the identification of a large number of patients affected by LSDs, which could potentially benefit from the therapeutic tools already available for many of these diseases.


Current status and development trends of morbidity and mortality in gastric cancer patients in Xining, 2009-2016.
The incidence of gastric cancer is declining in parts of Asia including China. This study was designed to investigate the incidence and mortality trend of gastric cancer in different regions and ethnic groups in Xining of Qinghai-Tibet Plateau. Data of gastric cancer from January 2009 to December 2016 were collected from Disease Control Center in Xining for repeated cross-sectional study. Gastric cancer. Xining resident population with pathological diagnosis of gastric cancer. Age, gender composition ratio, morbidity, mortality and trends. There were 4822 new cases of gastric cancer from 2009 to 2016, including 3583 males and 1239 females; 2290 cases were in villages and 2532 in towns. Male incidence rate (38.37/100,000) was higher than female (13.35/100,000). The incidence in rural areas (39.29/100,000) was higher than in urban areas (20.59/100,000). During 2009-2016, there were 2109 gastric cancer deaths in Xining, 1543 in males and 566 in females. There were 1185 cases in villages and 924 in cities. Male mortality (16.64/100,000) was higher than female (6.42/100,000). The mortality rate in rural areas (20.40/100,000) was higher than in urban areas (7.62/100,000). Overall morbidity and mortality rates of gastric cancer are on the rise in Xining. Male morbidity and mortality rates are higher than female ones, and rural areas are higher than urban areas.


PAS-Port: a new implantable vascular access device for arm placement: experiences from the first two years.
To evaluate the performance of a new subcutaneous infusion port for placement in the arm. Retrospective study. Karolinska Hospital, Stockholm, Sweden. 85 of 90 consecutive patients referred for implantation of a subcutaneous infusion port. Five records were missing. Implantation was successful in 81 cases (95%). Implantation of a PAS-Port (Kabi Pharmacia Deltec) subcutaneously on the forearm. Vascular access was obtained by cut-down. Success rate, complications and reliability in routine use. After a follow-up time of 1-24 months (median 5), 42 ports were still in use, 21 patients had died with functioning ports, two ports had been removed at the end of treatment, 11 had been removed because of complications and because they malfunctioned; and 3 patients were lost to follow-up. The overall infection rate was 0.08/100 catheter days. PAS-Port is a safe alternative to chest-placed port systems where there is a need for long term vascular access in adult patients.


Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype.
Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor; in addition to being a low-density lipoprotein (LDL)-like particle, it contains highly heterogeneous apolipoprotein(a) [apo(a)]. No prior studies have evaluated extended-release (ER) niacin effect on Lp(a) level depending on apo(a) phenotype. For this 24-week, prospective, open-label clinical trial we recruited 30 men (mean age 46.2 ± 7.5 years) with Lp(a) levels >20 mg/dL. No participant had previously received lipid lowering therapy, and started ER niacin 500 mg with stepwise dose increasing up to 1.5-2.0 g. Subjects were evaluated for Lp(a), lipids, high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 (Lp-PLA2), and fibrinolytic markers (plasminogen activator inhibitor-1, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasmin-antiplasmin complex). Patients were divided into two groups with major low- (LMW) or high-molecular weight (HMW) apo(a) isoforms determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of plasma under reducing conditions followed by immunoblotting. At baseline, groups were comparable in age, lipid, inflammatory and fibrinolytic biomarkers levels. There was a significant difference in baseline Lp(a) concentrations: 92 ± 29 mg/dL versus 54 ± 46 mg/dL in LMW and HMW apo(a) groups, respectively, p < 0.01. During the course of niacin treatment Lp(a) decreased by 28% (p < 0.003), Lp-PLA2 by 22% (p < 0.001), C-reactive protein by 24% (p = 0.07) in LMW apo(a) group, whereas no changes in Lp(a) and biomarkers levels were obtained in HMW apo(a) group. High-dose ER niacin declines elevated Lp(a) level in male subjects with low- but not high-molecular weight apo(a) phenotype.


Workers at long-term care facilities and their risk for severe COVID-19 illness.
Given the high concentration of COVID-19 cases in long-term care (LTC) facilities in the United States, individuals working in these facilities are at heightened risk of SARS-CoV-2 exposure. Using data from the nationally-representative 2017 and 2018 National Health Interview Surveys on adults who reported working in LTC facilities, this study examines the extent to which LTC workers are also at increased risk or potentially at increased risk for severe illness from COVID-19 including hospitalization, intubation, or death. We used the Centers for Disease Control and Prevention's list of conditions placing individuals in these risk categories to the extent possible. We also examined the sociodemographic characteristics of LTC workers by occupation and COVID-19 illness severity risk status. One percent (552 out of 52,159) of the weighted NHIS sample worked in LTC facilities. Workers in LTC facilities were disproportionately Black, female, and low income. Half of LTC workers (50%) were at increased risk of severe illness from COVID-19 and another 19.6% were potentially at increased risk. There were few significant differences in demographic characteristics between risk groups, though those at increased risk had lower educational attainment and recent trouble affording prescription medications. Despite the high degree of vulnerability of both LTC residents and workers to severe illness from COVID-19, many LTC facilities still have inadequate supplies of personal protective equipment and COVID-19 tests. Given that state budget deficits due to the COVID-19 pandemic limit the potential for state actions, enhanced federal efforts are needed to protect LTC residents and staff from COVID-19.


Novel cyclohexane monooxygenase from Acidovorax sp. CHX100.
Acidovorax sp. CHX100 has a remarkable ability for growth on short cycloalkanes (C5-C8) as a sole source of carbon and energy under aerobic conditions via an uncharacterized mechanism. Transposon mutagenesis of Acidovorax sp. CHX100 revealed a novel cytochrome P450 monooxygenase (CYP450chx) which catalyzed the transformation of cyclohexane to cyclohexanol. Primer walking methods categorized CYP450chx as cytochrome P450 class I taking into account its operon structure: monooxygenase, FAD oxidoreductase, and ferredoxin. CYP450chx was successfully cloned and expressed in Escherichia coli JM109. The activity of CYP450chx was demonstrated by means of the indole co-oxidation. Biotransformation capability of CYP450chx was confirmed through the catalysis of cycloalkanes (C5-C8) to their respective cyclic alcohols.


Reversed palmaris longus muscle on MRI: report of four cases.
Muscle anomalies around the wrist, in particular the palmaris longus muscle, may cause effort-related median nerve compression. A search of the medical records at our university hospital between 1994 and 1999 revealed four patients with an effort-related median nerve compression due to a reversed palmaris longus muscle. Magnetic resonance imaging was used in the patient work-up and showed an anomalous muscle in each case that had been missed initially. All four patients were free of pain after simple excision of the anomalous muscle. Awareness of muscle anomalies at the wrist on MR imaging is essential in evaluating patients with nerve compressions at the wrist. The purpose of this article is to heighten this awareness in radiologists.


Integrative transcriptomic and proteomic analysis reveals CD9/ITGA4/PI3K-Akt axis mediates trabecular meshwork cell apoptosis in human glaucoma.
Glaucoma has been the leading cause of irreversible blindness worldwide. High intraocular pressure (IOP) is a high-risk factor of glaucoma, repression of which has been the important treatment of glaucoma in clinic. Trabecular meshwork is crucial for maintaining IOP in aqueous humour out-flow system. It is urgent to reveal the molecular mechanism of trabecular meshwork in glaucoma. Previous studies found that some pathways were related to glaucoma, such as extracellular matrix (ECM)-receptor interaction, phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) and apoptosis. To identify novel molecules in glaucoma, we performed high-throughput transcriptome and proteome analysis to immortal human trabecular meshwork cells (iHTM) and glaucomatous human trabecular meshwork cells (GTM3 ), respectively. Twenty-six up-regulated genes/proteins and 59 down-regulated genes/proteins were identified as the high-risk factors based on differential analysis, including some known factors of glaucoma. Furthermore, a glaucoma-related protein-protein interaction (PPI) network was constructed for investigating the function roles of risk factors. Some genes were identified as potential regulator in the pathogenesis of glaucoma based on the topology analysis and module analysis to the network. Importantly, we identified and demonstrated that CD9 played key roles in glaucoma by biological experiment. CD9 is down-regulated in glaucoma, overexpression of CD9 can active integrin α4 (ITGA4), PI3K and Akt, which lead to the decreased apoptosis and attenuate glaucoma. All these results provide a novel molecular therapy of glaucoma.


Short communication: prevalence of antibodies against Coxiella burnetii (Q fever) in children in The Gambia, West Africa.
To estimate the prevalence of antibodies against Coxiella burnetii (Q fever) among children in eight villages in The Gambia, West Africa. Sera of 796 children aged 1-15 years were tested for presence of antibodies against phase II of C. burnetii by ELISA. IgG and/or IgM phase II antibodies against C. burnetii were detectable in 8.3% (66/796) of all serum samples analysed with significant differences in seroprevalence between villages. Highest prevalence was found in the age group 1-4 years. Exposure to C. burnetii is considerable in the early years of life in The Gambia, and further studies are warranted to estimate the role of Q fever in acute febrile illness in The Gambia and elsewhere in Africa.


Nicardipine: When high dose nitrates fail in treating heart failure.
Sympathetic Crashing Acute Pulmonary Edema (SCAPE) describes patients who present with acute hypertensive cardiogenic pulmonary edema. These patients present in respiratory distress, and requiring immediate medical and airway management. The treatment of SCAPE includes non-invasive positive pressure ventilation (NIPPV) to maintain oxygenation, and high dose nitrates to lower blood pressure and reduce afterload. We present a case report of a patient with refractory hypertension to high dose nitrates likely due to nitroglycerin resistance or an attenuated response. The addition of nicardipine led to marked clinical improvement, normalized blood pressure and spared the patient from endotracheal intubation and admission to the intensive care unit.


Spontaneous urinary bladder and ureter tumors in the Brown Norway rat.
Cell lines have been developed in Brown Norway rats from 3 primary uroepithelial tumors and from 2 in vivo transplanted uroepithelial tumors. After sc injection, cells of all cell lines gave rise to progressively growing tumors that eventually kill the host.


microRNA classifiers are powerful diagnostic/prognostic tools in ALK-, EGFR-, and KRAS-driven lung cancers.
microRNAs (miRNAs) can act as oncosuppressors or oncogenes, induce chemoresistance or chemosensitivity, and are major posttranscriptional gene regulators. Anaplastic lymphoma kinase (ALK), EGF receptor (EGFR), and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are major drivers of non-small cell lung cancer (NSCLC). The aim of this study was to assess the miRNA profiles of NSCLCs driven by translocated ALK, mutant EGFR, or mutant KRAS to find driver-specific diagnostic and prognostic miRNA signatures. A total of 85 formalin-fixed, paraffin-embedded samples were considered: 67 primary NSCLCs and 18 matched normal lung tissues. Of the 67 primary NSCLCs, 17 were echinoderm microtubule-associated protein-like 4-ALK translocated (ALK(+)) lung cancers; the remaining 50 were not (ALK(-)). Of the 50 ALK(-) primary NSCLCs, 24 were EGFR and KRAS mutation-negative (i.e., WT; triple negative); 11 were mutant EGFR (EGFR(+)), and 15 were mutant KRAS (KRAS(+)). We developed a diagnostic classifier that shows how miR-1253, miR-504, and miR-26a-5p expression levels can classify NSCLCs as ALK-translocated, mutant EGFR, or mutant KRAS versus mutation-free. We also generated a prognostic classifier based on miR-769-5p and Let-7d-5p expression levels that can predict overall survival. This classifier showed better performance than the commonly used classifiers based on mutational status. Although it has several limitations, this study shows that miRNA signatures and classifiers have great potential as powerful, cost-effective next-generation tools to improve and complement current genetic tests. Further studies of these miRNAs can help define their roles in NSCLC biology and in identifying best-performing chemotherapy regimens.


Jab1/CSN5, a component of the COP9 signalosome, regulates transforming growth factor beta signaling by binding to Smad7 and promoting its degradation.
Smad7 inhibits responses mediated by transforming growth factor beta (TGF-beta) and acts in a negative-feedback loop to regulate the intensity or duration of the TGF-beta signal. However, the aberrant expression and continued presence of Smad7 may cause TGF-beta resistance. Here we report that Jab1/CSN5, which is a component of the COP9 signalosome complex, associates constitutively with Smad7 and that overexpression of Jab1/CSN5 causes the translocation of Smad7 from the nucleus to the cytoplasm, promoting its degradation. Overexpression of Jab1/CSN5 increases Smad2 phosphorylation and enhances TGF-beta-induced transcriptional activity. The inhibition of endogenous Jab1/CSN5 expression by small interfering RNA (siRNA) induces Smad7 expression. This study thus defines Jab1/CSN5 as an adapter that targets Smad7 for degradation, thus releasing Smad7-mediated suppression of TGF-beta signaling.


Inhibition of hepatic neoglucogenesis and glucose-6-phosphatase by quercetin 3-O-alpha(2''-galloyl)rhamnoside isolated from Bauhinia megalandra leaves.
In intact microsomes, quercetin 3-O-alpha-(2''-galloyl)rhamnoside (QGR) inhibits glucose-6-phosphatase (G-6-Pase) in a concentration-dependent manner. QGR increased the G-6-Pase K(m) for glucose-6-phosphate without change in the V(max). The flavonol did not change the kinetic parameters of disrupted microsomal G-6-Pase or intact or disrupted microsomal G-6-Pase pyrophosphatase (PPase) activity. This result allowed the conclusion that QGR competitively inhibits the glucose-6-phosphate (G-6-P) transporter (T1) without affecting the catalytic subunit or the phosphate/pyrophosphate transporter (T2) of the G-6-Pase system.QGR strongly inhibits the neoglucogenic capacity of rat liver slices incubated in a Krebs-Ringer bicarbonate buffer, supplemented with lactate and oleate saturated albumin. The QGR G-6-Pase inhibition might explain the decrease in the liver slice neoglucogenic capacity and, in turn, could reduce glucose levels in diabetic patients.


Preliminary study on magnetic tracking-based planar shape sensing and navigation for flexible surgical robots in transoral surgery: methods and phantom experiments.
Flexible surgical robot can work in confined and complex environments, which makes it a good option for minimally invasive surgery. In order to utilize flexible manipulators in complicated and constrained surgical environments, it is of great significance to monitor the position and shape of the curvilinear manipulator in real time during the procedures. In this paper, we propose a magnetic tracking-based planar shape sensing and navigation system for flexible surgical robots in the transoral surgery. The system can provide the real-time tip position and shape information of the robot during the operation. We use wire-driven flexible robot to serve as the manipulator. It has three degrees of freedom. A permanent magnet is mounted at the distal end of the robot. Its magnetic field can be sensed with a magnetic sensor array. Therefore, position and orientation of the tip can be estimated utilizing a tracking method. A shape sensing algorithm is then carried out to estimate the real-time shape based on the tip pose. With the tip pose and shape display in the 3D reconstructed CT model, navigation can be achieved. Using the proposed system, we carried out planar navigation experiments on a skull phantom to touch three different target positions under the navigation of the skull display interface. During the experiments, the real-time shape has been well monitored and distance errors between the robot tip and the targets in the skull have been recorded. The mean navigation error is [Formula: see text] mm, while the maximum error is 3.2 mm. The proposed method provides the advantages that no sensors are needed to mount on the robot and no line-of-sight problem. Experimental results verified the feasibility of the proposed method.


Ionanofluid flow through a triangular grooved microchannel heat sink: Thermal heightening.
With recent technological advances, thermal transport from different electronic and electrical devices is the most vital concern. The microchannel heat sink (MCHS) of liquid cooling is a useful device to remove over thermal load. Ionanofluid is a brand new and super potential cooling fluid for its ionic conductivity, non-flammability, negligible volatility, and high-level heat stability. In this research, the ionanofluid's velocity and thermal field characteristics through a triangular grooved MCHS are investigated using numerical tools. The combination of ionic liquid (IL) 1-Butyl-3-methylimidazolium Bis(trifluoromethanesulfonyl)imide [C4mim]NTf2 and propylene glycol (PG) is used as base fluid whereas graphene (G) and single-walled carbon nanotube (SWCNT) are chosen as hybrid nanoparticles to make the working ionanofluid. The governing equations of nonlinear partial differential equations describing the physical phenomena along with proper border settings are resolved by applying the finite element method (FEM). Different ratios of hybrid nanoparticles (G: SWCNT) like (1: 0, 1/3: 2/3, 1/2: 1/2, 2/3: 1/3, 0: 1) are suspended in the base fluid mixture. In addition, the base fluid mixture is assumed in different combinations of (IL: PG) as (100: 0, 50: 50, 0: 100). The numerical results are displayed in the forms of streamlines, isothermal lines, and rate of thermal transfer for the pertinent parameters namely forced convection (Re = 100-900) and solid concentration (φ = 0.001-0.05). Also, pressure drop, field synergy number, relative fanning friction feature, relative Nusselt number, and temperature enhancement efficiency are calculated. The results indicate that a higher heat transport rate is found using the IL-based ionanofluid with the highest solid concentration. Moreover, the higher forced convection enhances the thermal efficiency of MCHS. Two linear regression equations along with very good correlation coefficients have been derived from the numerical results.


Plasma anti-inflammatory cytokines and monocyte human leucocyte antigen-DR expression in patients with acute pancreatitis.
Immune suppression plays a role in the pathogenesis of acute pancreatitis. The purpose was to describe plasma anti-inflammatory cytokines and blood monocyte human leucocyte antigen (HLA)-DR expression, a cellular marker of immune suppression, in relation to clinical outcome in acute pancreatitis. We studied 74 patients with acute pancreatitis admitted within 72 h after symptom onset; 27 had mild disease and 47 severe disease, of whom 20 developed organ failure. Plasma cytokine concentrations and monocyte HLA-DR density were determined at admission and 1, 2, 3, 7, 14 and 21 days later. The levels of interleukin-1 receptor antagonist, interleukin-6 and interleukin-10 correlated inversely to monocyte HLA-DR expression; each marker correlated with disease severity. Interleukin-4, -11 and -13 levels were low. Organ failure occurred at median 36 h (range 8 to 158) after admission and was predicted at admission by the combination of interleukin-6 and interleukin-10 with sensitivity of 95%, specificity of 88% and positive likelihood ratio of 7.6 (95% confidence interval 3.3 to 17). Patients with secondary infections had a lower proportion of HLA-DR positive monocytes than did controls at day 14 (median: 32% versus 65%; n = 7) and at day 21 (median: 49% versus 83%; n = 6), P < 0.05 each. In the organ failure group, HLA-DR expression did not differ between survivors and non-survivors. Determining the severity of anti-inflammatory reaction at admission and monitoring the course of immune suppression provide a means for predicting clinical outcome in acute pancreatitis.


Microgravity influences circadian clock oscillation in human keratinocytes.
Microgravity and sudden changes of gravitational forces exert numerous effects on tissues, organs and apparatus. Responses to these forces variably applied to cells indicate the existence of mechanotransduction pathways able to modulate transcription. Oscillation of circadian clocks similarly influences many cellular and metabolic processes. Here we hypothesized that signals derived from changes of gravitational forces applied to epidermal cells might influence their physiology in harmony with the oscillation of the molecular clock. In this study, we describe amplified oscillations of Bmal1 circadian clock gene in human keratinocytes exposed to short simulated microgravity and to rapid variation of gravitational forces. We found that exposure to microgravity enhances the amplitude of the Bmal1 feedback loop sustained by an apparently lower variability of Rev-erbα transcription, while recovery from microgravity is characterized by increased amplitude of Bmal1 expression and elongation of the oscillatory periods of Bmal1 and Rev-erbα. These data highlight the existence of integrated signaling network connecting mechanosensitive pathways to circadian gene regulation.