Plasma clearance of intravenous fat emulsion in acute bacterial infections.
A variety of abnormalities in lipid metabolism during infection have been reported and it has been questioned whether intravenous fat emulsion should be given in septic states. This study was designed to investigate the removal of a fat emulsion from plasma during septicaemia. An intravenous fat tolerance test (0.1 g of fat in the form of Intralipid 10% per kg b.w.) was performed in 28 adult patients who had been admitted for suspected septicaemia. All patients were febrile (mean body temperature 38.9 +/- 0.1 degrees C SEM), the majority had leucocytosis (mean value 10.5 +/- 1.0 10 (9)1 ) and all were haemodynamically stable. On the basis of bacterial cultures taken from various locations, the patients were classified as septic (n = 12; gram-negative sepsis, n = 8; gram-positive sepsis, n = 4), infected but without septicaemia (n = 9) or febrile of unknown cause (all cultures negative, n = 7). Plasma fractional removal rates of intravenous fat were similar in the different groups. The mean plasma clearance rate of intravenous fat was 6.6 +/- 0.5 (% minute), which does not differ from that reported for healthy controls. All patients with proven septicaemia and 5 non-septic patients were studied two weeks later when their infection had been treated and they were off antibiotic medication. The plasma clearance rate of i.v. fat was significantly lower in the recovery phase than during the acute febrile state (5.9 +/- 0.5 vs 4.2 +/- 0.4 %/min, n = 17; p < 0.05). It is concluded that clearance of intravenous fat emulsions from plasma is unimpaired in haemodynamically stable patients with septicaemia or other acute infections.


Cobalt molybdate hollow spheres decorated graphitic carbon nitride sheets for electrochemical sensing of dimetridazole.
In the present work, a cobalt molybdate (CoMoO4) hollow spheres-incorporated graphitic carbon nitride (g-CN) composite is prepared for the electrochemical detection of dimetridazole (DZ). The synergistic effect between the hollow-structured CoMoO4 and g-CN nanosheets facilitates the transportation of electrons through kinetic barriers, thereby providing a high electrical conductivity with increased electroactive sites. The proposed CoMoO4@g-CN-modified electrode displayed a wide linear range (0.001-492.77 μM) and a lower detection limit (LOD: 0.4 nM) for the determination of DZ through the amperometry (i-t) method. In addition, the CoMoO4@g-CN-modified electrode achieved good operational stability, anti-interfering ability (five-fold excess amount of co-interfering compounds) and reproducibility. These results demonstrate the increased electrocatalytic activity of CoMoO4@g-CN modified glassy carbon electrode (GCE) towards the detection of DZ in food samples with satisfactory recovery ranges.


Metformin versus insulin for gestational diabetes: Adiposity variables and adipocytokines in offspring at age of 9 years.
To compare body composition, visceral adiposity, adipocytokines, and low-grade inflammation markers in prepubertal offspring of mothers who were treated with metformin or insulin for gestational diabetes mellitus (GDM). 172 offspring of 311 mothers randomized to receive metformin (n = 82) or insulin (n = 90) for GDMwere studied at 9 years of age (follow-up rate 55%). Measurements included anthropometrics, adipocytokines, markers of the low-grade inflammation, abdominal magnetic resonance imaging (MRI), magnetic liver spectrometry (MRS), and whole body dual-energy X-ray absorptiometry (DXA). Serum markers of low-grade inflammation, visceral adipose tissue volume, total fat percentage, and liver fat percentage were similar between the study groups. Serum adiponectin concentration was higher in children in the metformin group compared to insulin group (median 10.37 vs 9.50 µg/ml, p = 0.016). This difference between groups was observed in boys only (median 12.13 vs 7.50 µg/ml, p < 0.001). Leptin/adiponectin-ratio was lower in boys in the metformin group than in the insulin group (median 0.30 vs 0.75; p = 0.016). Maternal metformin treatment for GDM had no effects on adiposity, body composition, liver fat, or inflammation markers in prepubertal offspring compared to maternal insulin treatment but was associated with higher adiponectin concentration and lower leptin/adiponectin-ratio in boys.


Survival of glochidial larvae of the freshwater pearl mussel, Margaritifera laevis (Bivalvia: Unionoida), at different temperatures: a comparison between two populations with and without recruitment.
The viability of free-living glochidia of the freshwater pearl mussel (Margaritifera laevis) was studied in the laboratory at water temperatures of 10 degrees C, 15 degrees C and 20 degrees C. To obtain glochidia, gravid female mussels were collected from the Chitose River, inhabited by adult and juvenile mussels, and from the Abira River, where only adult mussels were found. Daily survival rates of glochidia from each population at various water temperatures were significantly different, and survival time was longest at the lowest temperature in each population. Maintenance of some field mussel populations might become difficult at higher water temperatures due to the short survival time of glochidia and expected low density of host fish. Daily survival rates of glochidia were compared between the Abira population at 15 degrees C and the Chitose population at 20 degrees C, since these temperatures were close to the mean water temperature during the period of glochidial release in the respective rivers. Daily mean survival rates were significantly different between the Abira population at 15 degrees C and the Chitose population at 20 degrees C. Mean glochidial survival rate for the Chitose population changed from 85.3% to 66.2% from 9 to 13 h, whereas that for the Abira population dropped suddenly from 80.4% to 34.2% from 10 to 14 h after the initiation of experiment. Absence of juveniles in the Abira River might have been caused by the low glochidial viability. Survival times of free-living glochidia in Margaritiferidae tend to be shorter than in other families in Unionoida. A trade-off is suggested between high fertility and low glochidial survival rate in Margaritiferidae.


Living donor liver transplantation in children: should the adult donor be operated on by an adult or pediatric surgeon? Experience of a single pediatric center.
Living donor liver transplantation has become a cornerstone for the treatment of children with end-stage hepatic dysfunction, especially within populations or countries with low rates of organ utilization from deceased donors. The objective is to report our experience with 185 living donors operated on by a team pediatric surgeons in a tertiary center for pediatric liver transplantation. Retrospective analysis of medical records of donors of hepatic grafts for transplant undergoing surgery between June 1998 and March 2013. Over the last 14 years, 185 liver transplants were performed in pediatric recipients of grafts from living donors. Among the donors, 166 left lateral segments (89.7%), 18 left lobes without the caudate lobe (9.7%) and 1 right lobe (0.5%) were harvested. The donor age ranged from 16 to 53 years, and the weight ranged from 47 to 106 kg. In 10 donors, an additional graft of the donor inferior mesenteric vein was harvested to substitute for a hypoplastic recipient portal vein. The transfusion of blood products was required in 15 donors (8.1%). The mean hospital stay was 5 days. No deaths occurred, but complications were identified in 23 patients (12.4%): 9 patients experienced abdominal pain and severe gastrointestinal symptoms and 3 patients required reoperations. Eight donors presented with minor bile leaks that were treated conservatively, and 3 patients developed extra-peritoneal infections (1 wound collection, 1 phlebitis and 1 pneumonia). Eight grafts (4.3%) showed primary dysfunction resulting in recipient death (3 cases of fulminant hepatitis, 1 patient with metabolic disease, 1 patient with Alagille syndrome and 3 cases of biliary atresia in infants under 1 year old). There was no relation between donor complications and primary graft dysfunction (P=0.6). Living donor transplantation is safe for the donor and presents a low morbidity. The donor surgery may be performed by a team of trained pediatric surgeons.


Energy generation from anaerobic co-digestion of food waste, cow dung and piggery dung.
The study investigated bioenergy generation from anaerobic co-digestion of food wastes (FW), cow dung (CD) and piggery dung (PD). The physicochemical parameters of the substrates were determined before and after digestion following standard procedures after mechanical pretreatment. Throughout the study, pH remained slightly alkaline while temperature varied between 26 and 32 °C. The highest cumulative biogas yield of 0.0488 L was recorded from the digestion of FW + CD + PD on the ninth day. After analyses, the highest methane content of 64.6 was obtained from the digestion of FW + PD while the lowest (54.0%) was from the digestion of FW only. Overall, cumulative biogas production for the four digestion regimes followed the order: FW + CD + PD, FW + PD, FW + CD and FW only respectively. Accumulation of VFAs was recorded at a slow rate during the digestions.


(Chlorido/bromido)[(1,2,5,6-η)-cyclo-octa-1,5-diene](4-isopropyl-1-methyl-1,2,4-triazol-5-yl-idene)rhodium(I).
A new triazole-based neutral RhI complex, [Rh(Cl0.846Br0.154)(C6H11N3)(C8H12)], has been synthesized and structurally characterized. The RhI atom has a distorted square-planar coordination environment, formed by a bidentate cyclo-octa-1,5-diene (COD) ligand, an N-heterocyclic carbene and a halide ligand that shows substitutional disorder (Cl:Br = 0.846:0.154). No significant inter-molecular inter-actions other than van der Waals forces are found in the crystal structure. Diffraction data indicated a two-component inversion twin with a ratio of 0.95 (5):0.05 (5).


Rorschach ratings in depressed and suicidal patients with low levels of 5-hydroxyindoleacetic acid in cerebrospinal fluid.
In order to explore the psychodynamics of a previously observed association between a low concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and an increased tendency to suicidal behavior, blind ratings of Rorschach variables were compared between depressed and/or suicidal patients with low (less than 80 nanomoles/l) and normal (greater than 80 nanomoles/l) CSF 5-HIAA. In 14 patient pairs matched for sex, age, body height, and interview-based ratings of severity of depression, the low 5-HIAA subjects had significantly more anxiety and more hostility in the Rorschach ratings. Their anxiety tolerance was lower, and they were significantly less efficient in their handling of conflict. The results support the hypothesis that biochemical variables may be of importance for certain psychodynamic mechanisms suggested to be relevant for psychopathology, including suicidal behavior.


Carnitine content of blood and amniotic fluid.
Free carnitine levels were determined in amniotic fluids between the 10th and 40th week of gestation. They were found to decrease significantly with gestational age. Blood levels of carnitine were lower in pregnant than in nonpregnant women. Levels were found to be higher in cord blood than in maternal blood and usually were higher in the umbilical artery than vein. Intra-arterial injection of L-carnitine into a pregnant ewe did not cause a rise in the fetal blood level of carnitine, which, in contrast to human fetal blood, contained less than half the level of carnitine in maternal blood.


Effect of the pilates method on pain and quality of life in pregnancy: A systematic review and meta-analysis.
More than two-thirds of pregnant women experience low back pain during pregnancy. This condition increases with advancing pregnancy, interfering with work, daily activities and sleep. To assess the efficacy of the Pilates method in comparison to prenatal care on the control of lower back pain in pregnant women. Electronic searches were carried out with no language or year of publication restriction in the databases Medline via Pubmed, Embase, CINAHL, LILACS, PEDro, and SPORTDiscus on 20 March 2021. The keywords "Pilates" and "Pregnancy" were applied and the search strategies, adapted to each databank. Randomized clinical trials with pregnant women with muscle pain symptoms and Pilates as an intervention method in comparison to conventional prenatal care were considered. two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The critical evaluation was done using the Risk of Bias tool assess the quality and GRADE to assess the certainty of evidence. We conducted a meta-analysis for the main outcome "pain". through our searches, 687 papers were identified, but only two fulfilled the inclusion criteria and were included in this review. Only two studies compared Pilates with a control group without physical exercise for pain in the short term. In the meta-analysis, there was a significant difference for pain in the comparison between the Pilates group and the control group without exercise; the mean difference (MD) was -23.09 (95% CI), from -31.07 to -15.10, p = 0.001, for 65 individuals (33 in the Pilates group and 32 in the conventional group). Limitation found was the lack of blinding of therapists and participants and the small sample size of individual studies. In addition, no adverse effects were reported. There is moderate-quality evidence that Pilates exercise may reduce pregnancy-related low-back pain more than usual prenatal or no exercise. Prospero registration number CRD42021223243.


Psychometric properties of an established heart disease specific health-related quality of life questionnaire for pacemaker patients.
Little is known about the HRQL of pacemaker patients due to the limited availability of disease-specific instruments. The aim of the Pacemaker Patients Quality of Life (PAPQoL) study was to determine the psychometric properties for the MacNew Heart Disease Health-related Quality of Life Questionnaire (MacNew) in patients before and after pacemaker implantation. Patients with a given indication for pacemaker therapy (N = 68) completed two self-administered HRQL instruments, the SF-36, a well-known and psychometrically sound health survey, and the MacNew, a reliable and valid heart-disease-specific HRQL instrument, before and one, three and six months after pacemaker implantation. We assessed disease severity with the New York Heart Association (NYHA) classification. Test-retest reliability, intra-class correlation, Cronbach's alpha, validity coefficients, sensitivity analyses (effect sizes) and confirmatory factor analysis were carried out. The MacNew demonstrated adequate reliability (Cronbach's alpha and ICCs > 0.80 on all scales), validity (correlations between similar SF-36 and MacNew subscales > 0.80), and responsiveness (all effect sizes > or = 0.67) in pacemaker patients. The MacNew demonstrates adequate psychometric properties for evaluating HRQL in patients before and after pacemaker implantation.


Representation of Women as Authors of Rheumatology Research Articles.
In academic medicine, journal article authorship is central to career advancement and promotion. This study aimed to examine the contemporary representation of women as first and senior authors of rheumatology original research articles. The gender of the first and senior author, disease category, research design, and funding source were extracted from rheumatology original research articles published in high-impact rheumatology and general medical journals between 2015 and 2019. The analysis included 7,651 original research articles. In total, 51.5% of the articles had women first authors (95% confidence interval [95% CI] 50.4-52.6%) and 35.3% had women senior authors (95% CI 34.2-36.4%). Women were significantly less likely to be first and senior authors of articles reporting randomized controlled trials compared with other clinical research designs (P < 0.001), and of articles reporting industry-funded/industry-initiated studies compared with studies not funded by industry (P ≤ 0.01). Of the articles reporting industry-funded/industry-initiated randomized controlled trials, women were first authors in 18.5% (95% CI 13.8-24.0%) and senior authors in 23.9% (95% CI 18.6-29.8%). In rheumatology research articles, there is gender parity for first authorship, but women are underrepresented in senior authorship positions. Underrepresentation of women in authorship is particularly apparent in articles reporting randomized controlled trials, and especially those that are initiated by industry.


Profound Non-Randomness in Dinucleotide Arrangements within Ultra-Conserved Non-Coding Elements and the Human Genome.
Long human ultra-conserved non-coding elements (UCNEs) do not have any sequence similarity to each other or other characteristics that make them unalterable during vertebrate evolution. We hypothesized that UCNEs have unique dinucleotide (DN) composition and arrangements compared to the rest of the genome. A total of 4272 human UCNE sequences were analyzed computationally and compared with the whole genomes of human, chicken, zebrafish, and fly. Statistical analysis was performed to assess the non-randomness in DN spacing arrangements within the entire human genome and within UCNEs. Significant non-randomness in DN spacing arrangements was observed in the entire human genome. Additionally, UCNEs exhibited distinct patterns in DN arrangements compared to the rest of the genome. Approximately 83% of all DN pairs within UCNEs showed significant (>10%) non-random genomic arrangements at short distances (2-6 nucleotides) relative to each other. At the extremes, non-randomness in DN spacing distances deviated up to 40% from expected values and were frequently associated with GpC, CpG, ApT, and GpG/CpC dinucleotides. The described peculiarities in DN arrangements have persisted for hundreds of millions of years in vertebrates. These distinctive patterns may suggest that UCNEs have specific DNA conformations.


Hydranencephaly: prenatal and neonatal ultrasonographic appearance.
The prenatal diagnosis and postpartum confirmation of hydranencephaly is discussed. The need for an adequate knowledge of fetal cranial anatomy when performing obstetric sonography is stressed.


Covalent binding of 15-deoxy-delta12,14-prostaglandin J2 to PPARgamma.
Since 15-deoxy-delta(12,14)-prostaglandin J(2) (15dPGJ(2)) has been identified as an endogenous ligand of PPARgamma thus inducing adipogenesis, it has been reported to play active parts in numerous cellular regulatory mechanisms. As 15dPGJ(2) has been shown to covalently bind several peptides and proteins, we investigated whether it also covalently binds PPARgamma. We first observed that after incubation of 15dPGJ(2) with recombinant PPARgamma, the quantity of free 15dPGJ(2) measured was always lower than the initial amount. We then measured the ability of the labeled agonist rosiglitazone to displace the complex PPARgamma(2)/15dPGJ(2) obtained after pre-incubation. We observed that the binding of rosiglitazone was dependent on the initial concentration of 15dPGJ(2). Finally using MALDI-TOF mass spectrometry analysis, after trypsinolysis of an incubate of the PPARgamma(2) ligand binding domain (GST-LBD) with 15dPGJ2, we found a fragment (m/z = 1314.699) corresponding to the addition of 15dPGJ(2) (m/z = 316.203) to the GST-LBD peptide (m/z = 998.481). All these observations demonstrate the existence of a covalent binding of 15dPGJ(2) to PPARgamma, which opens up new perspectives to study the molecular basis for selective activities of PPARs.


Pharmacokinetics and leukocyte responses of recombinant human interleukin-10.
To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single s.c. and i.v. dosing. A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 microg/kg s.c. and i.v. doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-alpha and IL-1beta) by LPS-treated peripheral blood cells were measured over 96 hr. A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (s.c. and i.v.). The i.v. dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for s.c. dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-alpha and IL-1beta production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both i.v. and s.c. doses. The IC50 values were about 0.03 ng/ml and Imax values were about 0.85 for both TNF-alpha and IL-1beta suppression. The degree of change as well as the duration of leukocyte response was greater after s.c. administration than after i.v. administration. rHuIL-10 shows favorable PKPD characteristics especially by the s.c. route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.


Usefulness of [111In-DTPA0] octreotide scintigraphy in a family with von Hippel-Lindau disease.
The identification of patients with von Hippel-Lindau (VHL) disease dictates accurate genetic counseling of family members, whereas screening for early detection of visceral and neurological involvement is usually performed by a combination of radiological and nuclear medicine techniques such as ultrasonography or contrast-enhanced computed tomography of the upper abdomen, magnetic resonance imaging of the central nervous system and 131I-metaiodobenzylguanidine-scintigraphy. The role of 111-indium-diethylenetriaminepentaacetic acid [111In-DTPA0] octreotide scintigraphy in this clinical context has never been investigated. Here, we report imaging findings in a VHL patient and in 3 consecutive family members undergoing clinical and radiological screening that included [111In-DTPA0] octreotide scintigraphy in addition to the above-mentioned procedures. Somatostatin receptor expression was investigated in vitro by immunohistochemistry in pancreatic tumor sections. On the basis of in vivo and in vitro findings, octreotide long-acting release treatment followed by 90Y-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA0)-Tyr3-octreotide led to a lack of progression in this patient although this result is a possibility which needs to be proved by further investigation and longer follow-up. The results of this study suggest that [111In-DTPA0] octreotide scintigraphy may be helpful in the routine work-up of VHL patients for diagnostic and therapeutic purposes.


Ovoinhibitor introns specify functional domains as in the related and linked ovomucoid gene.
We have isolated cDNA clones and determined the gene structure of chicken ovoinhibitor, a seven domain Kazal serine proteinase inhibitor. Using RNA blot hybridization analysis, the gene was identified initially as a region 9-23 kilobases upstream of the gene for the related inhibitor ovomucoid. Ovoinhibitor RNA appears in oviduct and liver. cDNA clones were identified by screening an oviduct cDNA library with a nick-translated DNA restriction fragment which contained an exon of the gene. The mature protein sequence derived from a cDNa clone is in excellent agreement with that which we obtained from direct sequencing of purified ovoinhibitor. The protein-sequencing strategy is reported. The P1 amino acids of the Kazal domains are consistent with the known broad inhibitory specificity of ovoinhibitor. The gene is about 10.3 kilobases in length and consists of 16 exons. Each Kazal domain is encoded by two exons. Like ovomucoid, introns fall between the coding sequences of the ovoinhibitor domains, an arrangement which may have facilitated domain duplication. The intradomain intron occurs in an identical position in all of the ovoinhibitor and ovomucoid Kazal domains, suggesting that this intron was present in the primordial inhibitor gene. We discuss the location of the intradomain intron in relation to the known structure of four Kazal inhibitors and suggest a scheme for the evolution of the ovoinhibitor gene.


Neuroanatomy of auditory verbal hallucinations in schizophrenia: a quantitative meta-analysis of voxel-based morphometry studies.
Voxel-based morphometry (VBM) studies demonstrate grey matter volume (GMV) deficits in schizophrenia. This method is also applied for detecting associations between specific psychotic symptoms and brain structure, such as auditory verbal hallucinations (AVHs). However, due to differing methodological approaches, the available findings are inconsistent and difficult to integrate. We used a novel voxel-based meta-analytical method to provide a robust quantitative review of neuroanatomical abnormalities specifically associated with the hallucinatory phenomenon in the schizophrenic brain. We reviewed all VBM studies of AVHs in schizophrenia published until July 2011 (n = 9). A total of 438 patients with a diagnosis of schizophrenia were included (307 with AVHs). Using a random-effects parametric voxel-based meta-analysis, coordinates of 83 foci reported as significant in the source studies were extracted and computed to estimate the brain locations most consistently associated with AVHs. Severity of AVHs was significantly associated with GMV reductions in the left (p = .022) and marginally with the right (p = .062) superior temporal gyri (STGs, including Heschl's gyri) across studies examining correlations with AVHs severity in patients (n = 8). Analysis of studies categorically comparing patients with and without AVHs did not reveal any significant findings, possibly due to the small number of studies using this approach (n = 3). This meta-analysis implicates bilateral STG (including Heschl's gyri) as key areas of structural pathology in AVHs in schizophrenia. These findings support a model postulating that aberrations within neural systems involved at different levels of language processing are critical to AVHs in schizophrenia.


Respiratory symptoms and pulmonary function as predictors of 10-year mortality from respiratory disease, cardiovascular disease, and all causes in the Whitehall Study.
Relationships between various measures of respiratory impairment and 10-year mortality from chronic respiratory diseases, cardiovascular disease and all causes have been investigated in 17,717 male London civil servants aged 40-64 years. Controlling for age and smoking habits, chronic phlegm production was significantly associated with all-causes and respiratory disease mortality. These associations did not persist after controlling for breathlessness or FEV1 percent predicted. Breathlessness was significantly associated with mortality from respiratory and cardiovascular diseases, and all causes. The associations persisted after controlling for age, smoking habits, employment grade, blood pressure, antihypertensive medication, plasma cholesterol level, diabetes, ECG changes, myocardial ischemia, and FEV1 percent predicted. Anti-hypertensive medication, myocardial ischemia and breathlessness showed the strongest associations with cardiovascular disease mortality. FEV1 less than 65% predicted was significantly associated with mortality from respiratory and cardiovascular diseases, and all causes; for the latter two, the rate ratios were not as high as those for breathlessness.


Halothane anaesthesia and suxamethonium III. Atropine 30 s before a second dose of suxamethonium during inhalation anaesthesia: effects and side-effects.
The protection against bradycardia afforded by atropine given intravenously just prior to a second dose of suxamethonium during halothane inhalation anaesthesia was studied in 100 healthy, adult patients randomly allocated to one of five groups characterized by dosage of atropine. ECG monitoring was continuous, and regular determinations were made of serum potassium, PaCO2, PaO2 and blood pressure. Slowing of the heart rate was seen in more than 50% of patients in each group, but bradycardia (heart rate less than 60 beats/min) was seen only in patients receiving the lowest dose of atropine--0.0075 mg/kg. In the other four groups (atropine 0.01 mg/kg-0.02 mg/kg), bradycardia prophylaxis was effective, but at the cost of serious ventricular arrhythmias in 15% of the patients. The incidence of these arrhythmias seemed to increase with increasing atropine dosage. Marked tachycardia was also seen. Because of the incidence of side effects in this and other studies, no absolute recommendation can be made about suxamethonium bradycardia prophylaxis during halothane inhalation anaesthesia, but our present experience suggests that atropine in a dose not exceeding 0.01 mg/kg, given 30 s prior to a second dose of suxamethonium is best.


Predominant localization of phosphoenolpyruvate carboxykinase mRNA in the periportal zone of rat liver parenchyma demonstrated by in situ hybridization.
In rat liver parenchyma, expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene was studied by Northern blot analysis with a biotinylated cRNA probe and the zonal localization of PEPCK mRNA was demonstrated by in situ hybridization with a radiolabelled cRNA probe. During the feeding period at night, overall PEPCK mRNA levels were low and PEPCK mRNA was detected only in small areas of the periportal zone. At the beginning of the light period (7 am) the overall PEPCK mRNA level began increasing and the periportal areas containing PEPCK mRNA broadened. The maximum of the total abundance and of the area with high levels of PEPCK mRNA was reached at noon. Fasting for 24-72 h did not cause further significant alterations in the level or localization of PEPCK mRNA. The present data are in line with previous findings of the predominant localization of PEPCK activity and enzyme protein in periportal hepatocytes. They suggest that the heterogeneous expression of the PEPCK gene in rat liver is regulated at the pretranslational level.


Evaluation of a new method for the carotid pulse check in cardiopulmonary resuscitation.
The ability to determine the presence or absence of a central pulse remains a key skill in cardiopulmonary resuscitation (CPR) for healthcare providers, despite studies showing that they perform this poorly. The aim of this study was to evaluate a modified technique for palpation of the carotid pulse. Sixty seven undergraduate dental students were taught the standard method of carotid pulse detection during a basic life support session and were also taught a modified method. Each student was asked to palpate the carotid pulse of a volunteer in two positions (neck neutral and neck extended) with the volunteer on the floor and on a trolley. The time taken to identify the pulse was measured and the scenarios compared. The time to detect the carotid pulse was reduced in three of the four scenarios (floor, neck extended P=0.0053, trolley neck neutral P=0.0070, trolley neck extended P=0.0024). The final scenario (floor, neck neutral) showed no improvement (P=0.36). The new method of carotid pulse palpation results in a more rapid determination of the carotid pulse when it is present in all positions except with the neck neutral on the floor. This will only be clinically significant if trauma is suspected.


Pyrolysis of waste surgical masks into liquid fuel and its life-cycle assessment.
Pyrolysis of the middle layer of a surgical mask (MLM) and inner and outer layers of a surgical mask (IOM) was performed to assess their potential valorization as waste-to-energy feedstocks, and the characteristics of the resulting products were investigated. Pyrolysis of the main organics in waste surgical masks occurred at a very narrow temperature range of 456-466 °C. The main product was carbon-rich and oxygen-deficient liquid oil with a high heating value (HHV) of 43.5 MJ/kg. From the life-cycle perspective, environmental benefits and advantages of this upcycling approach were verified compared with conventional waste management approaches. This study advocated the potential application of waste surgical masks as feedstocks for fuels and energy, which is beneficial to mitigate plastic pollution and achieve sustainable plastic waste-to-energy upcycling, simultaneously.


Advances and challenges in using nirmatrelvir and its derivatives against SARS-CoV-2 infection.
On December 22, 2021, the United States Food and Drug Administration approved the first main protease inhibitor, i.e., oral antiviral nirmatrelvir (PF-07321332)/ritonavir (Paxlovid), for the treatment of early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Nirmatrelvir inhibits SARS-CoV-2 infection, but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression. The chiral structure of nirmatrelvir plays a key role in its antiviral activity. Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P450 3A4 expression and occupying the plasma protein binding sites. Multidrug resistance protein 1 inhibitors may increase the efficacy of nirmatrelvir. However, Paxlovid has many contraindications. Some patients treated with Paxlovid experience a second round of coronavirus disease 2019 (COVID-19) symptoms soon after recovery. Interestingly, the antiviral activity of nirmatrelvir metabolites, such as compounds 12-18, is similar to or higher than that of nirmatrelvir. Herein, we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge for drug developers and physicians in the fight against COVID-19.


Detection of antagonist activity for narcotic analgesics in mouse hot-plate test.
On the assumption that by the use of the hot-plate procedure the antagonist properties of narcotic analgesics could be detected, the effect of morphine, pentazocine, nalorphine and naloxone were investigated. The latency of paw-licking and jumping-off were determined and compared. The agonist, morphine, at doses of 0.025, 0.05 and 0.1 mmole/kg injected IP significantly increased paw-lick and jump-off latency above that seen in saline controls. The mixed agonist-antagonist, pentazocine, at doses of 0.048, 0.096 and 0.192 mmole/kg and nalorphine, an antagonist with some agonist activity, at doses of 0.032, 0.064 and 0.128 mmole/kg significantly increased the latency of paw-licking, but did not significantly change the jump-off latency. At a dose of 0.016 mmole/kg naloxone treated mice jumped from the hot-plate significantly sooner than controls but no effects of naloxone on paw-licking latency were observed. These results suggest that agonist properties are involved in the paw-lick response and that antagonistic properties determine jumping-off behavior.


CCA (disodium 4-chloro-2,2'-iminodibenzoate) inhibits progression of human T cell proliferation triggered by PHA.
The effect of the anti-rheumatic drug CCA (disodium 4-chloro-2,2'-iminodibenzoate) on the proliferation of T cells activated by PHA was examined. Cell cycle analysis showed that CCA blocked the transition of the cells from G1 to S (progression), but had little effect on the G0----G1 transition (initiation). CCA had no significant effect on IL-2 receptor expression, an early G1 event, but did inhibit transferrin receptor expression, a late G1 event. CCA did not inhibit IL-2 production by PHA-activated T cells, but did block IFN-gamma production at 72 hr after the stimulation. CCA failed to inhibit c-myc mRNA induction, but did delay the decrease in c-myc mRNA levels that normally occurs with the onset of DNA synthesis. These results indicate that CCA inhibits the progression, but not initiation, of human T cell proliferation.


Analysis of age-at-death estimation through the use of pubic symphyseal data.
The question of whether age parameters derived from an American population will reliably estimate age-at-death for East European skeletal populations is important since the ability to accurately estimate an individual's age-at-death hinges on what standard is used. A reference sample of identified individuals with known ages-at-death from the regions of the Former Yugoslavia (n = 861) is used to determine the age structure of victims and serves as the prior in the Bayesian analysis. Pubic symphyseal data in the manners of Todd (Am J Phys Anthropol, 3 [1920], 285; Am J Phys Anthropol, 4 [1921], 1) and Suchey-Brooks (Am J Phys Anthropol, 80 [1986], 167) were collected for n = 296 Balkan males and females and for n = 2078 American males and females. An analysis of deviance is calculated using an improvement chi-square to test for population variation in the aging processes of American and East European populations using proportional odds probit regression. When males and females are treated separately, there is a significant association among females and the population (df = 1, chi-square likelihood ratio = 15.071, p = 0.001). New age estimates for Balkan populations are provided and are based on the calculated age distribution from the Gompertz-Makeham hazard analysis and the ages-of-transition. To estimate the age-at-death for an individual, the highest posterior density regions for each symphyseal phase are provided.


Dr. Lupattelli et al. Reply.
We thank Dr. Shaligram, author of this Letter to the Editor, for the interest in our recent article reporting time-dependent effects of prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) on behavioral, emotional, and social development in offspring at age 5 years.1 Dr. Shaligram raises interesting points of consideration for interpretation of the study results, and poses methodological questions about our window of exposure classification.2.


Salt elicitation to enhance phytochemicals in durum wheat seedlings.
Salt has been identified as an elicitor that can increase the accumulation of phytochemicals in seedlings during the germination process. However, the salinity level required to maximize the yield of phytochemicals, particularly phenolic compounds, needs further investigation for several plant species. To address this issue, we imposed increasing levels of salinity (NaCl solutions) on the sprouting substrate of Triticum durum (var. Platone) grains, at concentrations of 0, 50, 100, 150, 200, 250, and 300 mM (0_S, 50_S, 100_S, 150_S, 200_S, 250_S, and 300_S, respectively). The highest NaCl doses (250_S and 300_S) significantly impacted germination performance and were excluded from further analysis. The seedlings harvested at 8 days after sowing exhibited different growth stages depending on the salinity level: wheatgrass for 0_S, early wheatgrass for 50_S, intermediate between sprout and wheatgrass for 100_S, sprout for 150_S, and very early sprout for 200_S. Furthermore, salinity induced the concentration of phenolic compounds (PhCs) in the seedlings' tissues (i.e., both roots and shoots) in a salinity-dependent manner. The highest values were observed at 200_S, with an increase of 187% of the total investigated PhCs in comparison with 0_S, averaged over shoots and roots. In particular, in 200_S, the accumulation of phenolic acids was up to fourfold higher in roots, and that of flavonoids was up to twofold higher in shoots. Our findings suggest that the use of 200 mM NaCl applied to the sprouting substrate is excessive for producing edible sprouts but may be suitable for phytochemical extraction purposes. © 2023 Society of Chemical Industry.


Impact of quality of life on future frailty status of rural Japanese community-dwelling older adults.
We aimed to clarify the factors that contribute to the improvement or progression of frailty in rural Japanese community-dwelling older adults. Of the 840 participants in the cohort study of independent older adults aged 65 years and older living in the Tamba-Sasayama area of Hyogo Prefecture (FESTA study) from September 2016 to December 2017, 551 participated in the 2-year follow-up survey from September 2018 to December 2019. We evaluated clinical background, physical and cognitive function, total physical activity, daily protein intake, quality of life (QOL) using the WHOQOL-BREF (WHOQOL-26), and frailty status diagnosed using the Japanese version of the Cardiovascular Health Study. We compared the frailty status at the initial and follow-up examinations and classified the participants into three groups: improvement, unchanged, and worsening. Each parameter was compared among the three groups and the factors contributing to the improvement or worsening of frailty status were analyzed using a modified Poisson regression analysis. The median age at the first survey was 72 years (range: 68-76); 190 men and 361 women were enrolled. The improvement group consisted of individuals with a change in status from frail to prefrail/robust and from prefrail to robust (n = 114); the worsening group consisted of individuals with a change in status from robust to prefrail/frail and from prefrail to frail (n = 92). The physical domain of QOL was significantly associated with an improvement in frailty status independent of the frailty status at baseline. Contrastingly, any domains of QOL were not significantly associated with a worsening frailty status. This study demonstrated for the first time that QOL has a significant impact on the future improvement and progression of frailty status and that QOL conditions and frailty status affect older adults bidirectionally.


The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy.
The variety of factors and events involved in neurodegeneration renders the subject a major challenge. Neurodegenerative disorders include a number of different pathological conditions, which share similar critical metabolic processes, such as protein aggregation and oxidative stress, both of which are associated with the involvement of metal ions. In this review, Alzheimer's disease, Parkinson's disease and prion disease are discussed, with the aim of identifying common trends underlying these devastating neurological conditions. Chelation therapy could be a valuable therapeutic approach, since metals are considered to be a pharmacological target for the rationale design of new therapeutic agents directed towards the treatment of neurodegeneration.


Clinical relevance of comorbidity in obsessive compulsive disorder: the Netherlands OCD Association study.
This study describes lifetime and current rates of comorbidity, its onset and its consequences in a large clinical sample of patients with obsessive compulsive disorder (OCD). A wide range of risk factors and clinical characteristics were also examined to determine whether pure OCD is different from OCD with current comorbidity. Finally, the temporal sequencing of the disorders was examined. Data were obtained from the Netherlands Obsessive Compulsive Disorder Association (NOCDA) study. A sample of 382 participants with current OCD (during the past month) was evaluated. Current comorbidity occurred in 55% of patients with OCD, while 78% suffered from lifetime comorbidity. Comorbidity is associated with more severe OCD, anxiety and depressive symptoms and more negative consequences on daily life. Multiple comorbid disorders often precede OCD and influence both its course and severity. Childhood trauma and neuroticism are vulnerability factors for the development of multiple comorbid disorders in OCD. It should be noted that causal inferences about the association between risk factors and OCD are precluded since our results were based on cross-sectional data. (Multiple) comorbidity in OCD is clinically relevant since it is associated with a specific pattern of vulnerability, with greater chronicity, with more severe OCD and more negative consequences on daily life. This indicates that the diagnosis and treatment of all comorbid disorders is clinically relevant, and clinicians should be especially aware of multiple disorders in cases of childhood trauma and high levels of neuroticism. Primary OCD has a different developmental and comorbidity pattern compared to secondary OCD.


Cardiac magnetic resonance T1 mapping for evaluating myocardial fibrosis in patients with type 2 diabetes mellitus: correlation with left ventricular longitudinal diastolic dysfunction.
We aimed to evaluate myocardial fibrosis using cardiac magnetic resonance (CMR) T1 mapping in type 2 diabetes mellitus (T2DM) patients and investigate the association between left ventricular (LV) subclinical myocardial dysfunction and myocardial fibrosis. The study included 37 short-term (≤ 5 years) and 44 longer-term (> 5 years) T2DM patients and 41 healthy controls. The LV global strain parameters and T1 mapping parameters were compared between the abovementioned three groups. The association of T1 mapping parameters with diabetes duration, in addition to other risk factors, was determined using multivariate linear regression analysis. The correlation between LV strain parameters and T1 mapping parameters was evaluated using Pearson's correlation. The peak diastolic strain rates (PDSRs) were significantly lower in longer-term T2DM patients compared to those in healthy subjects and short-term T2DM patients (p < 0.05). The longitudinal peak systolic strain rate and peak strain were significantly lower in the longer-term T2DM compared with the short-term T2DM group (p < 0.05). The extracellular volumes (ECVs) were higher in both subgroups of T2DM patients compared with control subjects (all p < 0.05). Multivariate linear regression analysis showed that diabetes duration was independently associated with ECV (β = 0.413, p < 0.001) by taking covariates into account. Pearson's analysis showed that ECV was associated with longitudinal PDSR (r = - 0.441, p < 0.001). T1 mapping could detect abnormal myocardial fibrosis early in patients with T2DM, which can cause a decline in the LV diastolic function. • CMR T1 mapping could detect abnormal myocardial fibrosis early in patients with T2DM. • The diabetes duration was independently associated with ECV. • Myocardial fibrosis can cause a decline in the LV diastolic function in T2DM patients.


Evaluation of the value of re-wetting prior to resin infiltration of post-orthodontic caries lesions.
Assessment of the influence of colour changes during the re-wetting process as a possible predictor for the final result after resin infiltration to mask post-orthodontic white spot lesions. Resin infiltration (ICON; DMG, Hamburg, Germany) was performed according to the manufacturer's recommendation with the exception of repeated, at maximum three etching procedures based on the subjective decision of the dentist during a so called re-wetting process using ethanol. The masking effect by ethanol as well as after resin infiltration was evaluated by digital images taken before, for nine seconds during re-wetting and one week after treatment using CIE L*a*b* colour space. Twenty-nine patients (16 female) with a total of 221 lesions (ICDAS 2) were included (mean age 16 years). Mean time after debonding the orthodontic appliances was ten weeks. Colour changes during re-wetting, evaluated in the first ten patients (71 lesions) showed a significant correlation between the minimum ΔE observed during re-wetting and the final ΔE after resin infiltration (r = 0.65, p < 0.001; Spearman correlation). The main drop in ΔE becomes visible after three seconds when performing the re-wetting process. Regarding the 221 lesions, resin infiltration significantly reduced the colour difference between sound and lesion areas from a baseline ΔE (25th/75th percentiles) of 10.9 (8.2/13.2) to a ΔE of 4 (2.1/5.8) after one week (p < 0.001). The number of etching procedures correlated significantly with baseline ΔE (p < 0.05). The minimum ΔE observed during the re-wetting process seems to be a useful predictor for the final result of resin infiltration of post-orthodontic caries lesions. More prominent lesions with higher ΔE at baseline seem to require more erosion of the surface layer. In general, a significant and considerable clinical reduction of ΔE could be observed. We corroborate that resin infiltration technique is a very useful method to mask caries lesions having developed during treatment with fixed orthodontic appliances. Colour changes while re-wetting the lesions with ethanol seem to be a valuable indicator for the number of required etching procedures.


Co-doped triel-pnicogen graphene as metal-free catalyst for CO oxidation: Role of multi-center covalency.
Third and fifth group atoms, named triel and pnicogen, respectively, were used for graphene doping. AlP and AlN structures were selected as co-doped graphene-based catalysts. The electronic structure and catalytic properties of binary AlN, AlP co-doped graphene were investigated through density functional theory (DFT). Results show that the AlP co-doped graphene strictly enhances the oxygen reactivity compared to AlN one. The CO oxidation on AlP and AlN co-doped graphene sheets is mainly done through Eley-Rideal mechanism as follows: CO + O2➔CO2 + Oads and CO + Oads➔ CO2. The CO oxidation reaction paths over the AlN and AlP-co-doped graphene have revealed that they can be regarded as the competent catalyst for CO oxidation in the presence of O2. Mechanistically, both AlP and AlN co-doped graphene catalysts are appropriately active in the first step while the second step is too hard to do regarding the multi-center covalency character between O2 and AlP co-doped graphene and hence its catalytic efficiency is significantly lower compared to AlN co-doped graphene sheet. Thus, the substitution of a C-C bond with Al-N is an effective way to design the graphene-based catalysts for CO oxidation.


Impact of adverse childhood experiences on life expectancy with depression in the U.K. population: The mitigating role of educational attainment.
Adverse childhood experiences (ACEs) are associated with depression in later life. This study aimed to measure the impact of ACEs on life expectancy with depression (DLE) and to assess how educational attainment affected expectations. The study used data on 5597 participants from the English Longitudinal Study of Aging (2006-2013). Depression was assessed through the eight-item short version of the Centre for Epidemiologic Studies Depression. We used discrete-multistate life table models to estimate total life expectancy and life expectancy with depression. Older adults with ACEs had longer DLE and a higher proportion of remaining life with depression compared with those without ACEs. For example, men aged 60 years with ACEs could expect to live 5.2 (95 % confidence interval (CI): 4.2, 6.2) years with depression compared with 2.8 (95 % CI: 2.3, 3.3) years for men without ACEs. Women aged 60 years who reported ACEs could expect to live 9.4 (95 % CI: 7.6, 11.1) years with depression compared with 6.0 (95 % CI: 5.1, 7.0) years for women without ACEs. With a high level of educational attainment, older adults from younger cohorts with ACEs lived fewer depression years and spent a higher proportion of their life being free of depression than adults with ACEs and had a low level of educational attainment. Our results indicated that ACEs may increase years of life with depression among U.K. adults. Meanwhile, high educational attainment could mitigate the mental health burden associated with ACEs.


Suspect the donor with potential infection in the adult deceased donor liver transplantation.
Liver transplantation is the treatment of choice for end-stage liver disease. However, the shortage of donors is still the major problem in most Asian countries. Using extended donor criteria may maximize the deceased donor pool, but some high-risk donors may show adverse recipient outcomes due to preexisting infection. This study included deceased donor liver transplant patients from June 2002 through June 2007. We retrospectively reviewed the clinical manifestations of donors and recipients. The donors showed no definite infection at the time the organs were matched to the recipients. Routine sputum, urine, blood, and bile cultures were obtained from the donor during the perioperative period. According to the final reports of the cultures, the recipients divided into two groups: donor infection (DI) and no donor infection (NDI). This study included 59 donor and 72 recipients, including 34 who received a graft from a donor with a positive culture (47.2%) finally, defined as the DI groups, and 38 recipients (52.8%) as the NDI group. Most of them had positive sputum cultures, followed by urine cultures. Staphylococcus aureus was the most common pathogen. Using a stepwise logistical regression model to analyze the significant donor characteristics, donor admission to the intensive care unit (ICU) for 7 days or longer (P < or = .0001), previous cardiopulmonary cerebral resuscitation (CPCR) (P = .036), and inotropic agents (P = .022) were the only three independent factors to predict donor infection. To compare the outcomes between DI and NDI groups, the days of recipient ICU or hospital admission, the 1-week or 1-month mortality rate, and the overall survival showed no significant difference between both groups. However, the hospital mortality rate was mildly higher in the DI group (P = .050). Donors with prolonged ICU admissions, rescue by CPCR, and use of inotropic agents carried an high risk of potential infections. Our data did not show a significant increase in adverse outcomes if the recipient received a graft from a potentially infected donor. However, there may be an increased risk of hospital mortality. We should be careful in using these potentially infected donors in selective recipients.


Pharmacokinetics of the soman simulant 1,2,2-trimethylpropyl dimethylphosphinate (PDP) in rats.
The soman simulant 1,2,2-trimethylpropyl dimethylphosphinate (PDP) antagonizes the therapeutic complications due to persistence of the nerve agent 1,2,2-trimethylpropyl methylphosphonofluoridate (soman) in rats. Using [13D]PDP or 1,2-dimethylpropyl dimethylphosphinate as an internal standard, we developed a gas chromatographic procedure for the analysis of PDP in aqueous solution and in blood samples. This procedure was used to investigate the pharmacokinetics of PDP in anaesthetized rats at intravenous doses of 2.0 and 0.6 mg/kg. The blood concentrations measured over a 420-min period can be described by a two-compartment open model with a rapid distribution phase (t 1/2 = 4.3 min) and a rather slow elimination phase (t 1/2 ss = 2-3 h). The kinetics are approximately linear with dose. Under "steady state conditions", PDP distributes evenly over the central and peripheral compartment (Vdss = 1.1-1.5 1.kg-1). At most 0.7% of intact PDP is renally excreted, which indicates that it is extensively metabolized. Since the partition coefficients (20 degrees C) over n-octanol and water of PDP and soman are in the same range, i.e., 12 and 60, respectively, the much more rapid decrease in blood levels of C(+/-)P(-)-soman compared to PDP must be due to metabolic pathways of soman which are not available for PDP. At comparable doses, the blood level of PDP is initially 1 order of magnitude higher than that of C(+/-)P(-)-soman. This ratio increases in the course of 420 min to 4 orders of magnitude.(ABSTRACT TRUNCATED AT 250 WORDS)


Untreated posttraumatic stress among persons with severe mental illness despite marked trauma and symptomatology.
The study examined the degree to which trauma was addressed among clients being treated for a severe mental illness and a substance use disorder at a community mental health center. Participants (N=74) were a randomly selected sample of clients who were enrolled for at least two years in an outpatient clinic and who had at least one clinic visit in the month preceding the study's start. The primary diagnoses were schizophrenia or schizoaffective disorder (53%), bipolar disorder (24%), and major depression (23%), and all participants had a current or past substance use disorder. A majority had a history of trauma, including sexual trauma, physical assault, the loss of a family member, or having witnessed someone being killed or seriously injured. Clients were asked about past sexual or physical assault history by a median of zero providers, and 59% said a history of assault was not addressed during treatment. Severity of posttraumatic stress disorder and the range of traumas experienced by the client were not predictors of the degree to which trauma and its consequences were a part of treatment. Clients' desire to discuss trauma during treatment and feeling upset while discussing trauma were both predictors of whether trauma was a focus of treatment. Clinicians may not adequately address trauma during treatment of severe mental illness. Future research is required to examine more effective methods to screen and treat trauma among individuals with severe mental illnesses.


A Phase Ib Study of NUC-1031 in Combination with Cisplatin for the First-Line Treatment of Patients with Advanced Biliary Tract Cancer (ABC-08).
Cisplatin/gemcitabine is standard first-line treatment for patients with advanced biliary tract cancer (ABC). NUC-1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites. Patients with untreated ABC, Eastern Cooperative Oncology Group performance status 0-1 received NUC-1031 (625 or 725 mg/m2 ) and cisplatin (25 mg/m2 ) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression-free survival (PFS), and overall survival (OS). Twenty-one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC-1031 625 mg/m2 (n = 8 and expansion n = 7; median six cycles) or 725 mg/m2 (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment-emergent grade 3-4 adverse events occurring in more than one patient with 625 mg/m2 NUC-1031 were increased gamma-glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m2 , increased GGT, 67%, and fatigue, 33%. NUC-1031 725 mg/m2 was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3-10.1), and median OS was 9.6 months (95% CI, 6.7-13.1). The median estimates of area under the plasma concentration-time curve from time 0 to last measurable time and maximum concentration were highest for NUC-1031 (218-324 μg•h/mL and 309-889 μg/mL, respectively) and lowest for di-fluoro-deoxycytidine (0.47-1.56 μg•h/mL and 0.284-0.522 μg/mL, respectively). This is the first study reporting on the combination of NUC-1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m2 NUC-1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: NCT02351765; EudraCT ID: 2015-000100-26). The prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first-line treatment for patients with ABC. NUC-1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC-08) demonstrated a favorable safety profile of NUC-1031 in combination with cisplatin for the first-line treatment of patients with ABC, and 725 mg/m2 NUC-1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling.


Time-space clustering of Vibrio cholerae 01 in Matlab, Bangladesh, 1970-1982.
Growing evidence for the existence of an aquatic reservoir of Vibrio cholerae has led some observers to postulate the existence of two distinct modes of disease transmission: primary and secondary. In primary transmission vibrios pass from the aquatic reservoir to humans via edible aquatic flora or fauna, or drinking water. Secondary transmission consists of faecal-oral transmission from person-to-person and may spawn epidemics. Cholera outbreaks are particularly well documented for the Matlab area of Bangladesh, where a field station has been run since 1963, at which patients from a study population of nearly 200,000 are treated for diarrhoeal diseases and monitored in a longitudinal demographic surveillance system. This paper seeks to illuminate the process of secondary transmission by presenting preliminary results of an analysis of the time-space distribution of cholera cases in Matlab for the period 1970-1982. It is argued that the detection of time-space clusters of cases resulting from secondary transmission requires locational data below the level of the village, that is at the level of the bari, or patrilineally-related household group because this is where inter-personal contact is greatest. The mapping of the study area at the bari level is described briefly and it is argued that the proportion of all asymptomatic infections and cases which can be mapped is great enough to enable inferences about transmission processes to be drawn. Results of the analysis of time-space interaction using the Knox method are presented and provide some support for within-bari clustering of cases resulting from secondary transmission.(ABSTRACT TRUNCATED AT 250 WORDS)


[Characteristics of recombination of heterosis hybrids of Drosophila melanogaster in high temperature conditions].
Spontaneous and high temperature-induced crossing over in regions b-cn and cn-vg of chromosome 2 was studied in Drosophila stocks and hybrids differing in fertility level and heat resistance. No essential distinction in recombination frequency was revealed in variants studied under the temperature 21-22 degrees C. The effect of temperature on 1- and 10-days imago during 4 or 7 h under 35 degrees C leads to increase in exchange frequency in the region b-cn. The hybrids show weaker reaction to this influence.


Characterization and comparative analysis of the Escherichia marmotae M-12 isolate from bank vole (Myodes glareolus).
The Escherichia marmotae is a bacterium of the Enterobacterales order, which was first isolated from the Himalayan marmot (Marmota himalayana). Recently E. marmotae has been shown to cause severe infections in humans. Wild animals were suggested to be a natural reservoir of this bacterium. The present study describes the first case of E. marmotae isolation from an apparently healthy wild bank vole (Myodes glareolus). Phenotype, as well as genotype-based techniques, were applied to characterize E. marmotae M-12 isolate. E. marmotae M-12 had the capsule-positive phenotype, high adhesion to human erythrocytes and HEp-2 cells as well as a low invasion into HEp-2 cells. E. marmotae M-12 was avirulent in mice. The phylogenomic analyses of E. marmotae showed dispersed phylogenetic structure among isolates of different origins. Virulome analysis of M-12 isolate revealed the presence of the following factors: siderophores, heme uptake systems, capsule synthesis, curli and type I fimbriae, flagella proteins, OmpA porin, etc. Comparative virulome analysis among available E. marmotae genomes revealed the presence of capsule K1 genes mostly in pathogenic isolates and OmpA porin presence among all strains. We assume that the K1 capsule and OmpA porin play a key role in the virulence of E. marmotae. Pathogenesis of the latter might be similar to extraintestinal pathogenic E. coli.


Pharmaceutical Lozenges: Recent Trends and Developments with an Update on Research and Patents.
Pharmaceutical oral dosage forms are tremendously preferred by both consumers as well as pharmaceutical manufacturers owing to the plethora of benefits they offer. Lozenges (LZs) are one of the dosage forms that provide a palatable means of drug administration and have great importance with respect to their pharmaceutical applications. LZs offer additional benefits to pediatric and geriatric patients, along with people having problems associated with the gastro-intestinal tract. Dysphagia is a common problem faced by all age groups, which gives rise to the need for LZs. Moreover, the foremost merit presented by the medicated LZs includes its augmented retention time in the oral cavity that results in an enhanced bioavailability for buccal or upper gastro-intestinal disorders. Further, LZs can also be used to bypass the first-pass effect. The present review covers various aspects of LZs such as formulation, manufacturing techniques, evaluation parameters, marketed products, patents, and a compilation of research work that has been done on lozenges as a delivery system.


Prosthetic tricuspid valve dysfunction assessed by three-dimensional transthoracic and transesophageal echocardiography.
A 39-year-old male who had undergone tricuspid valve replacement for severe tricuspid regurgitation was admitted with palpitation and general edema. Two-dimensional (2D) echocardiography showed tricuspid prosthetic valve dysfunction. Additional three-dimensional (3D) transthoracic and transesophageal echocardiography (TEE) could clearly demonstrate the disabilities of the mechanical tricuspid valve. Particularly, 3D TEE demonstrated a mass located on the right ventricular side of the tricuspid prosthesis, which may have caused the stuck disk. This observation was confirmed by intra-operative findings.


Cost-Utility Analysis of Prostatic Artery Embolization for Treatment of Lower Urinary Tract Symptoms.
To perform a post hoc cost-utility analysis of a randomized controlled clinical trial comparing prostatic artery embolization (PAE) and transurethral resection of the prostate (TURP) in patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia. We conducted a cost-utility analysis over a 5-year period to compare PAE versus TURP from a Spanish National Health System perspective. Data were collected from a randomized clinical trial performed at a single institution. Effectiveness was measured as quality-adjusted life years (QALYs), and an incremental cost-effectiveness ratio (ICER) was derived from the cost and QALY values associated with these treatments. Further sensitivity analysis was performed to account for the impact of reintervention on the cost-effectiveness of both procedures. At the 1-year follow-up, PAE resulted in mean cost per patient of €2904.68 and outcome of 0.975 QALYs per treatment. In comparison, TURP had cost €3846.72 per patient and its outcome was 0.953 QALYs per treatment. At 5 years, the cost for PAE and TURP were €4117.13 and €4297.58, and the mean QALY outcome was 4.572 and 4.487, respectively. Analysis revealed an ICER of €2121.15 saved per QALY gained when comparing PAE to TURP at long-term follow-up. Reintervention rate for PAE and TURP was 12% and 0%, respectively. Compared to TURP, in short term, PAE could be considered a cost-effective strategy within the Spanish healthcare system for patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia. However, in long term, the superiority is less apparent due to higher reintervention rates.


Transvaginal endoscopic appendectomy in humans: a unique approach to NOTES--world's first report.
Natural orifice translumenal endoscopic surgery (NOTES) is the newest technique emerging in the field of surgery. There are several techniques described in the literature; however there is no standardization yet. We describe the transvaginal approach for endoscopic appendectomy in humans, probably the world's first report. Pneumoperitoneum was achieved via a Veress needle in the umbilicus. Routine 12-mm endoscope and routine instruments were used. Peritoneal access was gained via a transvaginal approach through the posterior fornix. Out of a total of six patients, a totally endoscopic transvaginal appendectomy was successfully performed for one patient. The other five patients were either converted to conventional laparoscopy or aided by a laparoscope. The average age of the patients was 29.5 years. The mean operating time was 103.5 min. Hospital stay was 1-2 days. The follow-ups were scheduled at 7 days, 30 days, 90 days, and 6 months. The vaginal wound was examined by the gynecologist and found to have completely healed during the first and second follow-up. So far in humans, transgastric appendectomy and cholecystectomy, and transvaginal cholecystectomy have been reported. A transvaginal endoscopic appendectomy in humans has not been reported yet. The transvaginal approach provided a normal image of the target organ, unlike the inverted image of a transgastric approach caused by the inability to manipulate the scope outside the mouth. The technical ease of the procedure and early outcome seem satisfactory, although comparative studies are needed to confirm this.


Menu labeling influence on purchase behaviors: Applying the theory of planned behavior and health consciousness.
Mixed findings have been reported in the literature on the effectiveness of menu labeling in assisting consumers to make informed purchase decisions when eating out. Therefore, this study examined factors that influenced consumers' intentions to use menu labeling and whether these intentions influenced caloric purchases relative to actual caloric needs. While other researchers have assessed impacts of menu labeling on total calories purchased, our study assessed the impact relative to caloric needs, therein recognizing that each consumer has different caloric needs. An extended theory of planned behavior (TPB) incorporating health consciousness served as the theoretical underpinning. The TPB addresses reasons why an individual takes action on a certain behavior; in the case of this research, that behavior was purchasing food. Food purchases were further operationalized using the calorie content of foods and comparing that number of calories to caloric needs. Two-step structural equation modeling was used to analyze 316 surveys from restaurant consumers. Results indicated that attitudes, subjective norms, and health consciousness positively influenced intentions to use menu labeling. Intentions to use menu labeling also significantly influenced actual purchase behaviors (measured as the difference between caloric purchases and caloric needs). Overall, the current research findings provide novel insights for researchers to further explore the role of menu labeling on purchase behavior by using the TPB model with integration of health consciousness.


Interactions of sugars with membranes.
Water profoundly affects the stability of biological membranes, and its removal leads to destructive events including fusion and liquid crystalline to gel phase transitions. In heterogeneous mixtures such as those found in biological membranes the phase transitions can lead to increases in permeability and lateral phase separations that often are irreparable. Certain sugars are capable of preventing these deleterious events by inhibiting fusion during drying and by maintaining the lipid in a fluid state in the absence of water. As a result, the increased permeability and lateral phase separations that accompany dehydration are absent. The weight of the evidence suggests strongly that there is a direct interaction between the sugars and lipids in the dry state. Although the evidence is less clear about whether these sugars can interact directly with hydrated bilayers, there are strong suggestions in the literature that sugars free in solution or covalently linked to membrane constituents can also affect the physical properties and presumably the stability of bilayers. Finally, we have far less evidence concerning the mechanism by which they do so, but the same sugars are also capable of preserving the structure and function of both membrane-bound and soluble proteins in the absence of water. We believe these effects may be important in the survival of intact cells and organisms such as seeds in the absence of water. Furthermore, in view of the practical importance of preserving biological structures we suspect that the results described here will ultimately have important applications in biology and medicine.


Two-step pyrolysis biochar derived from agro-waste for antibiotics removal: Mechanisms and stability.
This study used acetone washing biochar (BCA) and nitric-acid washing biochar (BCN) derived from bagasse to remove sulfamethoxazole (SMX) and tetracycline (TC) in water. Higher specific surface area (1119.53 m2 g-1) and graphitization degree can significantly improve decontamination efficacy, of which BCN has the highest SMX and TC sorption capacities (274.63 mg g-1 and 353.85 mg g-1). The kinetics, isotherms and characterization analysis indicated O-containing functional group complexation and π-π interaction were dominant mechanisms in the adsorption process. Adsorption stability experiment showed that BCA has better stability with the coexistence of anions and cations. Besides, the enhancement and competitive adsorption from the interaction between soluble organic matter and TC could facilitate TC decontamination. Therefore, bagasse biochar derived from agro-waste has a promising potential for antibiotic contaminants removal from multi-interference conditions and promotes the recycling of waste, thereby achieving harmony between materials and the ecological environment.


[The enlargement of the meatal entrance in canal-wall-down operations].
The canal-wall-down operation may narrow the meatal entrance. By means of excision of skin from the cavum conchae and conchal cartilage an adequate-sized meatus can be created. 17 children were treated in case of cholesteatoma with canal-wall-down operation and metoplasty. The meatal entrance was sufficiently enlarged in all patients. The presented metoplasty supplies good functional and cosmetic results.


Weyl Fermions and broken symmetry phases of laterally confined3He films.
Broken symmetries in topological condensed matter systems have implications for the spectrum of Fermionic excitations confined on surfaces or topological defects. The Fermionic spectrum of confined (quasi-2D)3He-A consists of branches of chiral edge states. The negative energy states are related to the ground-state angular momentum,Lz=(N/2)ℏ, forN/2Cooper pairs. The power law suppression of the angular momentum,Lz(T)≃(N/2)ℏ[1-23(πT/Δ)2]for0⩽T≪Tc, in the fully gapped 2D chiral A-phase reflects the thermal excitation of the chiral edge Fermions. We discuss the effects of wave function overlap, and hybridization between edge states confined near opposing edge boundaries on the edge currents, ground-state angular momentum and ground-state order parameter of superfluid3He thin films. Under strong lateral confinement, the chiral A phase undergoes a sequence of phase transitions, first to a pair density wave (PDW) phase with broken translational symmetry atDc2∼16ξ0. The PDW phase is described by a periodic array of chiral domains with alternating chirality, separated by domain walls. The period of PDW phase diverges as the confinement lengthD→Dc2. The PDW phase breaks time-reversal symmetry, translation invariance, but is invariant under the combination of time-reversal and translation by a one-half period of the PDW. The mass current distribution of the PDW phase reflects this combined symmetry, and originates from the spectra of edge Fermions and the chiral branches bound to the domain walls. Under sufficiently strong confinement a second-order transition occurs to the non-chiral 'polar phase' atDc1∼9ξ0, in which a single p-wave orbital state of Cooper pairs is aligned along the channel.


Isolation and characterization of a cDNA encoding mouse 3alpha-hydroxysteroid dehydrogenase: an androgen-inactivating enzyme selectively expressed in female tissues.
3alpha-Hydroxysteroid dehydrogenase catalyzes the transformation of 3-ketosteroids into 3alpha-hydroxysteroids, thus playing an important role in androgen and progesterone metabolism. So far, mouse cDNA and gene encoding 3alpha-HSD has not been reported. In this report, we describe the isolation of a mouse 3alpha-HSD cDNA and the characterization of its substrate specificity and tissue distribution. Sequence analysis indicates that m3alpha-HSD shares 87% amino acid identity with rat 3alpha-HSD. Cells stably transfected with this enzyme catalyze the transformation of dihydrotestosterone (DHT), 5alpha-androstanedione (5alpha-dione) and dihydroprogesterone (DHP) into 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), androsterone (ADT) and 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone), respectively. Quantification of mRNA expression levels of this enzyme was determined in male and female mouse sex-specific tissues using quantitative Realtime PCR. We show that this enzyme is mainly expressed in female-specific tissues while being almost absent from male-specific tissues. In the liver, the same expression level is seen in both male and female, while there is 6-fold higher expression level in female pituitary than in male. These results strongly suggest that m3alpha-HSD could play an important role in the female mouse physiology similar to that of type 1 5alpha-reductase with which it works in tandem. This role could be related to the inactivation of excess of androgen and progesterone that are more severely regulated than in man.


3 T: the good, the bad and the ugly.
It is around 20 years since the first commercial 3 T MRI systems became available. The theoretical promise of twice the signal-to-noise ratio of a 1.5 T system together with a greater sensitivity to magnetic susceptibility-related contrast mechanisms, such as the blood oxygen level dependent effect that is the basis for functional MRI, drove the initial market in neuroradiology. However, the limitations of the increased field strength soon became apparent, including the increased radiofrequency power deposition, tissue-dependent changes in relaxation times, increased artifacts, and greater safety concerns. Many of these issues are dependent upon MR physics and workarounds have had to be developed to try and mitigate their effects. This article reviews the underlying principles of the good, the bad and the ugly aspects of 3 T, discusses some of the methods used to improve image quality and explains the remaining challenges and concerns.


[Role of intestinal flora in insulin resistance and obesity].
Intestinal flora can be modified by diet in both humans and rodents. Excess caloric intake in obese humans and rodents promotes proliferation of the bacterial phylum Firmicutes. Bacteria of the Firmicutes phylum permit more efficient intestinal extraction of nutrients. Oral transplantation of Firmicutes flora into axenic mice is sufficient to make them obese. The translocation towards the general circulation of the lipopolysaccharides released by lysis of Gram-negative intestinal bacilli promotes systemic inflammation. This inflammation plays a role in the genesis of insulin resistance and hepatic steatosis in rodents. Pharmacological or dietary manipulation of intestinal flora may be a new strategy for treatment of overweight and its complications.


Individualising therapy. The right dose, dosage form, frequency and duration.
Having chosen which drug to prescribe, the prescription now needs to be individualised for the patient in front of you. This article discusses the factors that have to be considered when individualising drug therapy for each patient. Before considering writing a prescription it is important to develop a personalised approach for the individual patient. The prescription should also then be individualised as to the route of administration, dosage, dosage form, frequency, and duration of the medication being prescribed.


Considerations on structure and function of the "Central-Amazonian inundation forest ecosystem" with particular emphasis on selected soil animals.
Studies were carried out in Central-Amazonian inundation forests having seasonal inundations during the emersion phase (e.p.) and the submersion phase (s.p.). Two várzea forests (white water areas), one in the Amazon valley on Ilha de Curarí and one at Lago Janauarí, and an igapó (black water area) situated in the Rio Negro valley at Rio Tarumã Mirím were investigated. A community analysis consisting of the species diversity and species similarity of the aquatic and terrestrial soil fauna was executed in these forests. Each forest is differentiated into an inner, middle, and outer part. The annual development of the soil invertebrates is dictated by the periodic changes in water level. Data on species diversity indicate an alternate occurrence of the soil- and trunk-dwelling carabids and staphylinids (Coleoptera). Low species diversity is obtained for the aquatic soil fauna during the high water period. This is correlated with both oxygen concentration and relative abundance of a few specialized species.A function model approach was tried. Investigations showed that both the phytophages and the saprophages consumed about 9.4% and 13% respectively of the yearly litter fall. Litter decomposition is retarded during the inundation period (170 g·m-2·s.p.-1 is decomposed) but is accelerated during the emersion phase (420 g·m-2·e.p.-1 is decomposed). Nearly 14% of the yearly litter fall is presumed to be exported by the current from the inundation forest during the inundation phase, probably into the surrounding rivers and lakes. A rough estimation of a nutrient budget containing some selected elements was given. The estimation allowed us to suppose, that in the igapó the loss of some elements cannot be compensated for by the input from the river water and the precipitation. Unlike the igapó, the várzea forest may compensate for this loss of litter through input of nutrients from the inflowing white water. The igapó may thus be considered as a source of nutrients while the várzea forest is a nutrient sink.


Secreted frizzled-related proteins: A promising therapeutic target for cancer therapy through Wnt signaling inhibition.
The Wnt signaling system is a critical pathway that regulates embryonic development and adult homeostasis. Secreted frizzled-related proteins (SFRPs) are extracellular inhibitors of Wnt signaling that act by binding directly to Wnt ligands or Frizzled receptors. SFRPs can act as anti-Wnt agents and suppress cancer growth by blocking the action of Wnt ligands. However, SFRPs are often silenced by promoter methylation in cancer cells, resulting in hyperactivation of the Wnt pathway. Epigenetic modifiers can reverse this silencing and restore SFRPs expression. Despite the potential of SFRPs as a therapeutic target, the effects of SFRPs on tumor development remain unclear. Therefore, a review of the expression of various members of the SFRPs family in different cancers and their potential as therapeutic targets is warranted. This review aims to summarize the current knowledge of SFRPs in cancer, focusing on their expression patterns and their potential as novel therapeutic targets.


Deregulating iron-erythropoiesis regulation: transferrin receptor 2 as potential target for treating anemia in CKD.
Both insufficient kidney production of erythropoietin and inflammation-mediated reduction of transferrin-bound iron are major factors in anemia of chronic kidney disease. Improved therapies for anemia in chronic kidney disease may involve modifying regulators of erythropoiesis and iron availability. Olivari et al. show in a mouse model of chronic kidney disease that transferrin receptor 2 in hepatocytes, where it is required for hepcidin production, and in erythroid cells, where it downregulates erythropoietin receptor activity, is a potential therapeutic target.


Loss of a single chlorophyll in CP29 triggers re-organization of the Photosystem II supramolecular assembly.
In land plants, both efficient light capture and photoprotective dissipation of chlorophyll excited states in excess require proper assembly of Photosystem II supercomplexes PSII-LHCs. These include a dimeric core moiety and a peripheral antenna system made of trimeric LHCII proteins connected to the core through monomeric LHC subunits. Regulation of light harvesting involves re-organization of the PSII supercomplex, including dissociation of its LHCII-CP24-CP29 domain under excess light. The Chl a603-a609-a616 chromophore cluster within CP29 was recently identified as responsible for the fast component of Non-Photochemical Quenching of chlorophyll fluorescence. Here, we pinpointed a chlorophyll-protein domain of CP29 involved in the macro-organization of PSII-LHCs. By complementing an Arabidopsis knock-out mutant with CP29 sequences deleted in the residue binding chlorophyll b614/b3-binding, we found that the site is promiscuous for chlorophyll a and b. By plotting NPQ amplitude vs. CP29 content we observed that quenching activity was significantly reduced in mutants compared to the wild type. Analysis of pigment-binding supercomplexes showed that the missing Chl did hamper the assembly of PSII-LHCs supercomplexes, while observation by electron microscopy of grana membranes highlighted the PSII particles were organized in two-dimensional arrays in mutant grana partitions. As an effect of such array formation electron transport rate between QA and QB reduced, likely due to restricted plastoquinone diffusion. We conclude that chlorophyll b614, rather being part of pigment cluster responsible for quenching, is needed to maintain full rate of electron flow in the thylakoids by controlling protein-protein interactions between PSII units in grana partitions.


Bipodal dyes with bichromic triphenylamine architectures for use in dye-sensitized solar cell applications.
A family of four bipodal triphenylamine-based dyes, three of which incorporate two triphenylamine (TPA) units, have been studied to understand their potential in light-harvesting applications. Compared to previously reported TPA-based dyes, these exhibit improved device performance. Theoretical calculations correlate excited state dipole moments to device efficiency.


Enterostomy-related complications in Hirschsprung's disease in a single cohort.
Hirschsprung's disease (HSCR) is a frequent cause of intestinal obstruction in children and may require an enterostomy. The study aimed to describe the most common enterostomy-related complications in a series of patients treated in a single center. A series of consecutive HSCR patients treated or followed-up at our institution between January 1993 and December 2016 were included. Data about HSCR type, enterostomy site, duration and complications of the stoma were recorded. Three hundred one patients with HSCR were followed-up. Sixty-one had ultralong forms (TCSA/TIA), 21 had long forms (L-HSCR) and 219 had classic short forms (S-HSCR). One hundred thirty-seven patients required a stoma (100% of patients with TCSA/TIA, 66.7% with L-HSCR and 28.3% with S-HSCR). We observed 64 stoma-related complications: 36 major complications and 28 minor complications. Major complications occurred more often in long forms (P=0.037). The presence of an ileostomy was statistically associated with an increased rate of complications compared to colostomy. The longer the stoma was in site, the higher the complication rate was. Long and ultra-long forms are associated with a longer duration of the stoma and to a major risk of stoma-related complications.


Persistent spectral theory-guided protein engineering.
While protein engineering, which iteratively optimizes protein fitness by screening the gigantic mutational space, is constrained by experimental capacity, various machine learning models have substantially expedited protein engineering. Three-dimensional protein structures promise further advantages, but their intricate geometric complexity hinders their applications in deep mutational screening. Persistent homology, an established algebraic topology tool for protein structural complexity reduction, fails to capture the homotopic shape evolution during the filtration of a given data. This work introduces a Topology-offered protein Fitness (TopFit) framework to complement protein sequence and structure embeddings. Equipped with an ensemble regression strategy, TopFit integrates the persistent spectral theory, a new topological Laplacian, and two auxiliary sequence embeddings to capture mutation-induced topological invariant, shape evolution, and sequence disparity in the protein fitness landscape. The performance of TopFit is assessed by 34 benchmark datasets with 128,634 variants, involving a vast variety of protein structure acquisition modalities and training set size variations.


Secondhand smoke exposure in outdoor children's playgrounds in 11 European countries.
Tobacco presence in outdoor children's playgrounds is concerning not only because it leads to secondhand smoke (SHS) exposure, but also cigarette butt pollution and tobacco normalization. This study aimed to assess SHS exposure in children's playgrounds, according to area-level socioeconomic status (SES), smoke-free regulations, national smoking prevalence, and SHS exposure prevalence in playgrounds (2017-2018). We monitored vapor-phase nicotine concentration and tobacco-related variables in 20 different playgrounds in 11 European countries (n = 220 measurements) from March 2017 to April 2018. Playgrounds were selected according to area-level SES. Data on the number of people smoking, and cigarette butts inside the playground and on playground surroundings (<1 m away) were recorded. Playground smoking bans, the Tobacco Control Scale (TCS) score, national smoking prevalence and SHS exposure prevalence in playgrounds were used to group countries. To determine nicotine presence, we dichotomized concentrations using the limit of quantification as a cut-off point (0.06 μg/m3). Nicotine median concentrations were compared using non-parametric tests, and nicotine presence and tobacco-related observational variables using the Chi-squared test. Airborne nicotine presence was found in 40.6% of the playgrounds. Median nicotine concentration was <0.06 μg/m3 (Interquartile range: <0.06-0.125) and higher median concentrations were found in more deprived neighborhoods, non-regulated playgrounds, in countries with lower overall TCS scores, higher national smoking prevalence and higher SHS exposure prevalence in playgrounds. Overall, people were smoking in 19.6% of the playgrounds. More than half of playgrounds had cigarette butts visible inside (56.6%) and in the immediate vicinity (74.4%). Presence of butts inside playgrounds was higher in sites from a low area-level SES, in countries with low TCS scores, and greater smoking prevalence and SHS exposure prevalence (p<0.05). There is evidence of SHS exposure in children's playgrounds across Europe. These findings confirm the need for smoking bans in playgrounds and better enforcement in those countries with smoking bans in playgrounds.


Autophagy reduces neuronal damage and promotes locomotor recovery via inhibition of apoptosis after spinal cord injury in rats.
Autophagy is an intracellular catabolic mechanism that maintains the balance of proteins, lipids and aging organelles. 3-Methyladenine (3-MA) is a selective inhibitor of autophagy, whereas rapamycin, an antifungal agent, is a specific inducer of autophagy, inhibiting the protein mammalian target of rapamycin. In the present study, we examined the role of autophagy, inhibited by 3-MA and enhanced by rapamycin, in a model of acute spinal cord injury in rats. We found that rapamycin could significantly increase the expression of microtubule-associated protein 1 light chain 3 (LC3) and Beclin1 at the injury site. At the same time, the number of neurons and astrocytes with LC3 positive in the spinal cord was upregulated with time. In addition, administration of rapamycin produced an increase in the Basso, Beattie and Bresnahan scores of injured rats, indicating high recovery of locomotor function. Furthermore, expression of the proteins Bcl-2 and Bax was upregulated and downregulated, respectively. By contrast, the results for rats treated with 3-MA, which inhibits autophagy, were the opposite of those seen with the rapamycin-treated rats. These results show that induction of autophagy can produce neuroprotective effects in acute spinal cord injury in rats via inhibition of apoptosis.


ADHD and ADHD-related neural networks in benign epilepsy with centrotemporal spikes: A systematic review.
Attention-deficit/hyperactivity disorder (ADHD) and benign epilepsy with centrotemporal spikes (BECTS or rolandic epilepsy) present with a very high level of comorbidity. We aimed to review the existing literature focusing on two aspects: the possible role of epileptic activity in the damage of ADHD-related neural networks and the clinical approach to patients presenting with both conditions. A systematic review was performed using Sapienza Library System and PubMed. The following search terms have been considered: attention networks, ADHD, attention systems, rolandic epilepsy, benign epilepsy with centrotemporal spikes, centrotemporal spikes epilepsy, and focal epilepsy in children. The target population consisted of patients under 18 years of age diagnosed with either BECTS and ADHD or healthy controls. Nine case-control and cohort studies have been selected. The reported prevalence of ADHD in patients with BECTS was around 60%. No clinical correlation was found between the medical records and the presence of ADHD in patients with BECTS, if not due to febrile convulsion (FC). One study showed higher levels of bilateral discharges in patients with severe ADHD. The negative influence of the age at onset of seizures was demonstrated on attention but not on intelligence quotient (IQ). Moreover, the frequency of seizures and the occurrence of discharges during nonrapid eye movement (NREM) sleep were correlated to attention impairment. From a neurobiological point of view, functional connectivity in patients with BECTS and ADHD appears to be disrupted. Two studies reported a specific impairment in selective visual attention, while one study underlined a decreased activation of the dorsal attention network (DAN). Two different studies found that patients with BECTS and comorbid ADHD presented with altered thickness in their magnetic resonance imaging (MRI) scans in the cortical and subcortical regions (including the frontal lobes, lingual-fusiform cortex, cuneus and precuneus, limbic area and pericalcarine cortex among others). This might explain the cognitive and behavioral symptoms such as poor selective visual attention, speech disturbance, and impulsivity. Despite BECTS being considered to have a relative benign course, many studies have documented cognitive and/or behavioral problems in patients diagnosed with this type of epilepsy. In particular, children affected by rolandic epilepsy should receive a complete neuropsychological evaluation at seizure onset considering the high rate of comorbidity with ADHD. A further investigation of the common pathogenic substrate is desirable to better orientate the clinical and therapeutic interventions applied.


Zinc iodide-osmium staining of membrane-coating granules in keratinized and non-keratinized mammalian oral epithelium.
Specimens of keratinized and non-keratinized oral epithelium were examined in the electron microscope after being stained with zinc iodide-osmium. In both types of tissue, reaction was seen in unmyelinated nerves, in the specific granules of epithelial Langerhans cells and within lysosome-like organelles and small vesicles associated with Golgi systems. In keratinized epithelia, the reaction was also present in the membrane-coating granules and between the deepest cells of the keratinized layer. In contrast, the membrane-coating granules of non-keratinized epithelia lacked Zn iodide-osmium staining despite the presence of reaction in adjacent Golgi systems. It is suggested that Zn iodide-osmium stains glycolipid or glycoprotein material in the cell. This material is elaborated in the Golgi systems from which lysosomes and the membrane-coating granules of keratinized tissues are probably derived.


Changes induced by Ehrlich ascites carcinoma in hepatic fumarase and aconitase activities.
Ehrlich ascites carcinoma induced significant changes in liver fumarase (activation) and aconitase (inhibition). A significant increase in hepatic fumarase specific activity was also observed in mice inoculated with Ehrlich ascites fluid after centrifugation of cells (EAF). Hepatic aconitase was not significantly influenced by EAF.


Degradation of adenosine by extracellular adenosine deaminase in the rat duodenum.
1. Extracellular degradation of adenosine by adenosine deaminase was studied in the rat duodenum using high performance liquid chromatography (HPLC) and pharmacological techniques. 2. Relaxant responses to adenosine (1-10 microM) were potentiated in a concentration-dependent manner by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and deoxycoformycin, both of which are inhibitors of adenosine deaminase. 3. Breakdown of adenosine, determined by HPLC, due to incubation with segments of rat duodenum was inhibited by both EHNA and deoxycoformycin. Cytosolic sources of adenosine deaminase were excluded. 4. Relaxant responses to adenosine were also potentiated by the adenosine transport inhibitor dilazep, which did not inhibit adenosine deaminase activity. 5. The extracellular adenosine deaminase activity (4 units/g tissue) was high compared with activity previously determined in other organs.