The organ culture and grafting of lamprey cartilage and teeth.
Cartilage from larval (ammocoetes) and adult (prespawning upstream migrant) lamprey was successfully maintained both when cultured in vitro or grafted in vivo (on the chorioallantoic membrane (CAM) of host chick embryos). In addition teeth from adult lamprey were successfully cultured in vitro. Cartilages were cultured in supplemented Lebovitz's l15 medium at 15 and 20 degrees C for periods of up to 56 d and in supplemented BGJb medium at 37 degrees C for periods of up to 14 d. Cartilages were also grafted onto the CAM for up to 16 d. Both the cultured and grafted cartilages retained their structural and cellular integrity as verified histologically. The viability of the cartilage, even after extended culture periods, was demonstrated ultrastructurally by the presence of chondrocytes displaying abundant rough endoplasmic reticulum, mitochondria, and Golgi apparatii with associated vesicles. In addition the cartilages were shown to be metabolically active in vitro by the incorporation of radioactive sulfur into the matrix. Some cell outgrowth from other tissues, such as connective tissue, muscle, and gill when left adjacent to the cartilage, occurred over time in cultures. No cell outgrowth was observed in CAM-grafted tissue nor was there any invasion of the agnathan tissue by chorioallantoic blood vessels. Teeth cultured in L15-supplemented media for up to 14 d at either 15 or 20 degrees C retained their structural and cellular integrity as observed histologically, with no apparent cell outgrowth. With the successful culture of these tissues, their development, biochemistry, and physiology, potentially of great importance in understanding early vertebrate evolution, can be better understood.


Having cancer does not change wanting a baby: healthy adolescent girls' perceptions of cancer-related infertility.
The goal of this study was to determine healthy adolescents' perceptions of cancer and fertility. A secondary goal of the study was to test items related to the development of a health-related quality-of-life tool with healthy control subjects to determine whether the participants shared a common understanding of the items and response options and to confirm face and content validity. Four focus groups of two age-groups were held with healthy female adolescents: 12-14 years (N = 11) and 15-18 years (N = 14). Adolescents in both age-groups expressed significant concerns regarding potential infertility from cancer treatment, hereditary transmission, and the impact it would have on their future. Differences emerged in language preferences among older adolescents who preferred more open-ended statements. Fertility concerns and desires for future motherhood can be accurately assessed using the 10 statements tested, and clinicians should be made aware of the differences between younger and older adolescents to facilitate effective communication. This research suggests adolescents have predetermined expectations for becoming future parents, and their concerns about fertility and childbearing are present before becoming a patient.


Inadvertent overinfusion of norepinephrine using infusion pump loading dose.
Programming infusion pumps has been recognised as a high-risk step and a source of adverse events (Nuckols et al., 2008; Hyman, 2010). Literature describing infusion pump loading dose errors and NORepinephrine complications is scarce (Girard et al., 2010). This case study presents the first ever report of an inadvertent overinfusion of NORepinephrine due to the loading dose option on the infusion pump, and resulting cardiac arrest of the patient. A patient was admitted to the emergency room and started on a NORepinephrine infusion inadvertently as a loading dose rather than a primary infusion. Historical values for the loading dose volume to be infused (VTBI) and primary rate were not adjusted during the setup. Eight hours and 58minutes later, the loading dose VTBI reached 0mL and the pump reverted to the historical primary rate of 999mL/hour. The event log showed that 37.1mL of NORepinephrine was infused resulting in an equivalent calculated bolus dose of 1.8mg administered in two minutes. The patient suffered a cardiac arrest and the infusion was stopped. No faults were found with the pump. Herein, we discuss our analysis of the pump event logs and propose further safety strategies and interventions.


Rearrangement-Driven Molecular Diversity: Synthesis of Functionalized Pyrones, Orthoesters, and Xanthones from Spiroketals.
The reaction of tricyclic 5,5-benzannulated spiroketals with trifluoroacetic acid (TFA) and AlCl3 furnished benzopyranobenzopyrans, benzofuro-orthoesters, and benzofuroxanthones. Whereas the reaction of tricyclic 5,5-benzannulated spiroketals with TFA produced the pyrones, the reaction with AlCl3 furnished densely functionalized orthoesters and xanthones. The formation of these products was rationalized by fascinating mechanistic pathways involving semipinacol/α-ketol molecular rearrangements.


Digoxin removal from an anephric patient by hemoperfusion over XAD-4.
Removal of digoxin by hemoperfusion over Amberlite XAD-4 was determined in a functionally anephric patient. During four hours of hemoperfusion, 50.45 microgram of digoxin were removed by the column and serum digoxin concentrations decreased by 0.2 ng/ml after the post-hemoperfusion reequilibration was complete.


Toxoplasmosis and the acquired immune deficiency syndrome.
The literature on toxoplasmosis in the acquired immune deficiency syndrome is reviewed with reference to more than 140 cases from various centres. The incidence, pathogenesis, clinical features, diagnosis, treatment and prognosis are considered.


Dual action effects of morphine on the electrical activity of the dorsal tegmentum.
The midbrain tegmentum has been identified as an important locus for development of negative reinforcement with electrical stimulation of the brain. It also plays a central role in the motivational-affective component of pain, and is a site of the analgesic action of morphine. The present study reports the effects of morphine on the electrical activity of areas of the dorsal tegmentum of rats that were also tested for the aversive effects of brain stimulation. The results of spectral analysis of the EEG indicated that IP injections of 16 mg/kg of morphine significantly depressed intensity of EEG, while 8 mg/kg of morphine tended to increase intensity. The results were interpreted in terms of the dual action hypothesis of morphine action and Winters' model of drug effects on electrical activity of the brain. It was concluded that morphine may produce complementary inhibitory and excitatory effects on the negative and positive reinforcement systems of the brain respectively.


Circulating free triiodothyronine concentration is positively associated with β-cell function in euthyroid patients with obesity and type 2 diabetes.
To investigate the relationship between thyroid hormone concentrations and β-cell function in euthyroid patients with obesity and type 2 diabetes. We performed a single-center cross-sectional study of 254 patients with type 2 diabetes mellitus aged ≥40 years. The participants were allocated to an obesity group or non-obesity group on the basis of their body mass index (BMI). Their β-cell function was assessed by measuring C-peptide concentration during a 75-g oral glucose tolerance test (OGTT); and their serum free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone concentrations were measured. The serum FT3 concentration and the C-peptide concentrations at five time points of the OGTT were significantly higher in the obesity group than in the non-obesity group. FT3 was positively associated with the β-cell function of the obesity group, but not that of the non-obesity group, in multiple linear regression analysis, after adjustment for potential confounding factors. Serum FT3 concentration was also significantly associated with indices of obesity (BMI, waist circumference, body fat percentage, fat mass, fat mass/height2 and visceral fat area). Obesity-associated high serum FT3 concentrations might affect β-cell function in euthyroid patients with obesity and type 2 diabetes.


Functional analyses of a highly thermostable hexokinase from Pyrobaculum calidifontis.
The gene encoding a repressor open reading frame sugar kinase (ROK) family protein from hyperthermophilic crenarchaeon Pyrobaculum calidifontis, Pcal-HK, was cloned and expressed in Escherichia coli. The recombinant protein was produced in soluble and highly active form. Purified Pcal-HK was highly thermostable and existed in a monomeric form in solution. The enzyme was specific to ATP as phosphoryl donor but showed broad specificity to phosphoryl acceptors. It catalyzed the phosphorylation of a number of hexoses, including glucose, glucosamine, N-acetyl glucosamine, fructose and mannose, at nearly the same rate and similar affinity. The enzyme was metal ion dependent exhibiting highest activity at 90-95 °C and pH 8.5. Mg2+ was most effective metal ion, which could be partially replaced by Mn2+, Ni2+ or Zn2+. Kinetic parameters were determined at 90 °C and the enzyme showed almost similar catalytic efficiency (kcat/Km) towards the above mentioned hexoses. To the best of our knowledge, Pcal-HK is the most active thermostable ROK family hexokinase characterized to date which catalyzes the phosphorylation of various hexoses with nearly similar affinity.


Chaotic-Like Transfers of Energy in Hamiltonian PDEs.
We consider the nonlinear cubic Wave, the Hartree and the nonlinear cubic Beam equations on T 2 and we prove the existence of different types of solutions which exchange energy between Fourier modes in certain time scales. This exchange can be considered "chaotic-like" since either the choice of activated modes or the time spent in each transfer can be chosen randomly. The key point of the construction of those orbits is the existence of heteroclinic connections between invariant objects and the construction of symbolic dynamics (a Smale horseshoe) for the Birkhoff Normal Form truncation of those equations.


Radiologic Outcomes According to Varus Deformity in Minimally Invasive Surgery Total Knee Arthroplasty.
To identify the accuracy of postoperative implant alignment in minimally invasive surgery total knee arthroplasty (MIS-TKA), based on the degree of varus deformity. The research examined 627 cases of MIS-TKA from November 2005 to December 2007. The cases were categorized according to the preoperative degree of varus deformity in the knee joint in order to compare the postoperative alignment of the implant: less than 5° varus (Group 1, 351 cases), 5° to less than 10° varus (Group 2, 189 cases), 10° to less than 15° varus (Group 3, 59 cases), and 15° varus or more (Group 4, 28 cases). On average, the alignment of the tibial implant was 0.2±1.4°, 0.1±1.3°, 0.1±1.6°, and 0.3±1.7° varus, and the tibiofemoral alignment was 5.2±1.9degrees, 4.7±1.9°, 4.9±1.9°, and 5.1±2.0° valgus for Groups 1, 2, 3, and 4, respectively, in the preoperative stage, indicating no difference between the groups (p>0.05). With respect to the accuracy of the tibial implant alignment, 98.1%, 97.6%, 87.5%, and 86.7% of Groups 1, 2, 3, and 4, respectively, had 0±3° varus angulation, demonstrating a reduced level of accuracy in Groups 3 and 4 (p<0.0001). There was no difference in terms of tibiofemoral alignment, with 83.9%, 82.9%, 85.4%, and 86.7% of each group, respectively, showing 6±3° valgus angulation (p>0.05). Satisfactory component alignment was achieved in minimally invasive surgery in total knee arthroplasty, regardless of the degree of varus deformity.


Clinically important body weight gain following total hip arthroplasty: a cohort study with 5-year follow-up.
Literature examining the effects of total hip arthroplasty (THA) on subsequent body weight gain is inconclusive. Determining the extent to which clinically relevant weight gain occurs following THA has important public health implications. We used multi-variable logistic regression to compare data from one of the largest US-based THA registries to a population-based control sample from the same geographic region. We also identified factors that increased risk of clinically important weight gain specifically among persons undergoing THA. The outcome measure of interest was weight gain of ≥5% of body weight up to 5 years following surgery. The multi-variable adjusted [age, sex, body mass index (BMI), education, comorbidity and pre-surgical weight change] odds ratio for important weight gain was 1.7 [95% confidence interval (CI), 1.06, 2.6] for a person with THA as compared to the control sample. Additional arthroplasty procedures during the 5-year follow-up further increased odds for important weight gain (OR = 2.0, 95% CI, 1.4, 2.7) relative to the control sample. A patient with THA had increased risk of important post-surgical weight gain of 12% (OR = 1.12, 95% CI, 1.08, 1.16) for every kilogram of pre-operative weight loss. While findings should be interpreted with caution because of missing follow-up weight data, patients with THA appear to be at increased risk of clinically important weight gain following surgery as compared to peers. Patients less than 60 years and who have lost a substantial amount of weight prior to surgery appear to be at particularly high risk of important post-surgical weight gain.


The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues.
Dendritic cell (DC) development begins in the bone marrow but is not completed until after immature progenitors reach their sites of residence in lymphoid organs. The hematopoietic growth factors regulating these processes are poorly understood. Here we examined the effects of signaling by the receptor tyrosine kinase Flt3 on macrophage DC progenitors in the bone marrow and on peripheral DCs. We found that the macrophage DC progenitor compartment was responsive to superphysiological amounts of Flt3 ligand but was not dependent on Flt3 for its homeostatic maintenance in vivo. In contrast, Flt3 was essential to the regulation of homeostatic DC development in the spleen, where it was needed to maintain normal numbers of DCs by controlling their division in the periphery.


Metabolic profiling of hypoxia/reoxygenation injury in H9c2 cells reveals the accumulation of phytosphingosine and the vital role of Dan-Shen in Xin-Ke-Shu.
Xin-Ke-Shu (XKS), a patent medicine consisting of five commonly used traditional Chinese herbs, is used for the treatment of coronary heart diseases. A previous study showed that XKS has protective effects for ameliorating myocardial ischemia/reperfusion (I/R) injury. This study was aimed to deeply understand the mechanisms and compatible principle of XKS against hypoxia/reoxygenation (H/R) injury and the contribution of each single herb to the efficacy of XKS. An H/R model in H9c2 cardiomyocytes was applied to mimic I/R injury observed in vivo. The cell viability, the levels of LDH, MDA, SOD, and apoptosis were determined to evaluate the cardioprotection of XKS and its subtracted formula (knocked out one herb) in H/R injury. Cell metabolomics, combined with western blot analysis, was performed to uncover the inert molecular mechanism of XKS against H/R injury. Significant protective effects of XKS against oxidative stress and apoptosis induced by H/R injury were found in the pharmacodynamic evaluation. Moreover, the metabolic profile deviation of the H/R group from the control group was mainly ascribed to thirteen metabolites involved in four aberrant pathways, in which sphingolipid metabolism was revealed as the most relevant pathway involved in H/R injury (impact > 0.1). Notably, the accumulation of phytosphingosine (VIP = 5.84) was considered the most likely characteristic in H/R injury, which is well known to promote the opening of the mitochondrial permeability transition pore (mPTP) and activate cell apoptosis. Furthermore, XKS ameliorated all the abnormalities of the metabolic network in response to H/R injury. In agreement with this, a western blot analysis showed that XKS markedly regulated the over-expression of CaMK II and cleaved caspase-3. However, the subtracted formula showed no significant difference in comparison with the XKS group on protecting H/R injury except for QDS (subtracted Dan-Shen from XKS). The roots of Salvia miltiorrhiza Bge. (Dan-Shen) play an important role in the regulation of Ca2+ overloading, oxidative stress and apoptosis in H/R injury. Our study enabled information from holistic cell metabolomics to be used for mechanism and compatibility rule elucidations of TCMs.


Comparative Analysis of Radiographic Hip Joint Geometry Using Measurement Tools on Picture Archiving and Communication System: A Prospective Study of 100 Pelvic Radiographs of Koreans.
A contralateral normal hip joint has been often used as a reference standard in preoperative planning and intraoperative assessment of hip arthroplasty, with the assumption that bilateral hip joint geometries have no significant differences. However, one previous study using analog measurements on hardcopy films reported significant bilateral variation in hip joint geometry. We therefore investigated the level of agreement between the right and left hips for each measurement and determined index values and the range of normal bilateral variations. We assessed 100 standard anteroposterior radiographs of the pelvis in this study. Two independent observers measured the actual value of femoral head diameter, location of the femoral head center, acetabular offset, femoral offset, hip offset, greater trochanteric height, neck-shaft angle, medullary canal diameter, and proximal femoral diameter. Intraclass correlation coefficients (ICCs) and values of mean difference were calculated for each measurement. The results demonstrated perfect agreement (ICC >0.8) between the right and left hips for most parameters and substantial agreement for greater trochanteric height (ICC = 0.735) and femoral offset (ICC = 0.773). The mean difference and standard deviation in the measurement between the right and left hips for the location of the femoral head center and the acetabular offset were 0.60 ± 0.48 mm and 0.42 ± 0.30 mm, respectively. Hip joint geometry is not influenced by side. In hip arthroplasty, a contralateral normal hip can be reliably used as a guide for preoperative planning using measurement tools on a picture archiving and communication system.


¹H-MAS-NMR chemical shifts in hydrogen-bonded complexes of chlorophenols (pentachlorophenol, 2,4,6-trichlorophenol, 2,6-dichlorophenol, 3,5-dichlorophenol, and p-chlorophenol) and amine, and H/D isotope effects on ¹H-MAS-NMR spectra.
Chemical shifts (CS) of the ¹H nucleus in N···H···O type hydrogen bonds (H-bond) were observed in some complexes between chlorophenols [pentachlorophenol (PCP), 2,4,6-tricholorophenol (TCP), 2,6-dichlorophenol (26DCP), 3,5-dichlorophenol (35DCP), and p-chlorophenol (pCP)] and nitrogen-base (N-Base) by solid-state high-resolution ¹H-NMR with the magic-angle-spinning (MAS) method. Employing N-Bases with a wide range of pKa values (0.65-10.75), ¹H-MAS-NMR CS values of bridging H atoms in H-bonds were obtained as a function of the N-Base's pKa. The result showed that the CS values were increased with increasing pKa values in a range of DpKa < 0 [DpKa = pKa(N-Base)-pKa(chlorophenols)] and decreased when DpKa > 2: The maximum CS values was recorded in the PCP (pKa = 5.26)-4-methylpyridine (6.03), TCP (6.59)-imidazole (6.99), 26DCP (7.02)-2-amino-4-methylpyridine (7.38), 35DCP (8.04)-4-dimethylaminopyridine (9.61), and pCP (9.47)-4-dimethylaminopyridine (9.61) complexes. The largest CS value of 18.6 ppm was recorded in TCP-imidazole crystals. In addition, H/D isotope effects on ¹H-MAS-NMR spectra were observed in PCP-2-amino-3-methylpyridine. Based on the results of CS simulation using a B3LYP/6-311+G** function, it can be explained that a little changes of the N-H length in H-bond contribute to the H/D isotope shift of the ¹H-MAS-NMR peaks.


Lower academic performance and dropout rates among University students with children: a prospective cohort study of nursing students in Bogotá, Colombia.
To determine the association between parenthood and academic performance and dropout among professional Nursing degree program students. A prospective cohort was conducted. 310 students were included, 26 parents (exposed) and 284 nonparents (unexposed), who were followed up during 16 weeks. At the end of this follow-up, student records were reviewed. Academic performance in the exposed and unexposed groups was 3.51/5.0 and 3.64/5.0 respectively. Although it was higher in the latter group, i.e., with a difference of 0.13, the values were not statistically significant (p=0.058). After adjusting for confounding variables, a difference of -0.165 point was seen (p=0.037). The risk of students dropping out of college is 34 % less for exposed compared to those who are unexposed (RR: 0.66; CI: 0.075-5.78; p=0.708). The results suggest that parenthood has a modest impact on the academic performance, and has no impact on the risk of dropping out.


Mutations in the RAS and PI3K pathways are associated with metastatic location in colorectal cancers.
Identification of mutations in the downstream epidermal growth factor receptor (EGFR) signaling pathway could provide important insights of EGFR-targeted therapies in colorectal cancers. We analyzed the mutation spectra of the PI3K/PTEN/AKT and RAS/RAF/MAPK pathways in colorectal cancers and the associations of these mutations with sites of metastases or recurrence. The study population comprised 1,492 retrospectively collected stages I-IV colorectal cancer specimens. Tissue was obtained between 2000 and 2010 at a single hospital. We analyzed 61 hot spots using MALDI-TOF mass spectrometry for nucleic acid analysis. Mutations were found in the RAS pathway in 47.3% of patients and in the PI3K pathway in 14.3% of patients, with 9.2% of patients carrying mutations in both pathways. Both the RAS and PI3K pathway mutations were significantly associated with proximal tumors, mucinous tumors, and microsatellite instability. Tumors carrying a RAS pathway mutation exhibited a higher frequency of lung and peritoneal metastasis than did tumors with a wild-type gene (P = 0.025 and 0.009, respectively). NRAS gene mutation was significantly associated with lung metastasis (P = 0.001). Somatic mutations in the RAS pathway of the primary tumor in colorectal cancer can influence patterns of metastasis and recurrence.


Cycling without CDK2?
Cyclin-dependent kinase 2 (CDK2) regulates diverse aspects of the mammalian cell cycle. Most cancer cells contain mutations in the pathways that control CDK2, and CDK2 activity has received much attention as a target for cancer therapy. However, a recent report demonstrating that some cancer cells can proliferate without CDK2 activity questions the essential role of CDK2 in cell-cycle control, as well as its suitability as a therapeutic target.


Who uses over-the-counter psychotropics? Characteristics, functioning, and (mental) health profile.
As part of a population study on the prevalence of psychopathology, users of "Over-The-Counter" Psychotropics (OTC-Ps) were studied. First, their mental health profile was examined by a number of subjective and objective assessments. Second, the medical consumption of the users was studied with special attention to the psychotropic drugs prescribed. The prevalence of psychological problems and symptoms of psychological distress was higher among OTC-P users than among non-users. Somatic problems and symptoms were comparable in the two groups; social support was better in the OTC-P users. Half of the users were known to have mental health problems by their Primary Care Physician (PCP). The DSM IV Axis I disorders were mostly mood and anxiety disorders. A benzodiazepine had been prescribed to one-third of the OTC-P users. No other psychotropic drugs had been prescribed, and the medical consumption was comparable in the two groups. PCPs should be aware of concomitant OTC-Ps use.


Administration of mycophenolic acid is not associated with malformations in descendants from kidney transplanted males.
In pregnant women, the use of Mycophenolic acid (MPA) is associated with teratogenicity. Recently, the European Medicines Agency (EMEA) and the Spanish Agency of Medicine and Sanitary Products (AEMPS) warned about the potential teratogenic effects of MPA. These adverse events may occur even in children from males on treatment with MPA. However, evidence of malformations in offsprings of male kidney transplanted patients (KT) exposed to MPA is limited. Thus, the present study aimed to evaluate the incidence of offspring malformations in children of renal transplanted males under MPA. We conducted a retrospective study in which we evaluated the incidence of malformations in descendants from male recipients that were exposed or not to MPA before and at the time of conception. Two groups of patients were evaluated. Those exposed to MPA (MPA group, n = 20) and the non-MPA group (n = 13) that included patients that did not receive AZA (n = 5) and eight that did receive AZA (n = 8) at the time of conception. A total of forty-nine post-transplant conceptions were identified from 33 different renal transplanted males. MPA was used as the immunosuppressant in 28 of the conceptions. Males from the non-MPA group fathered the other 21 children. Median time from grafting to conception was 6.1 (IQR 2.4-11.1) years, and it was similar between groups. There were eight miscarriage episodes, 2 in the non-MPA group and 6 in the MPA group although differences were not reached. After that, all patients had children without problems. No malformations were detected in any of the 49 regardless whether they were exposed or not to MPA. No evidence of MPA-associated malformations was observed in descendants of kidney transplanted males on treatment with MPA. Further research is warranted to confirm our findings to properly advice transplanted males keen to procreate.


Role of pentose phosphate pathway-derived NADPH in hypoxic pulmonary vasoconstriction.
We have previously shown that pentose phosphate pathway (PPP) inhibitors, 6-aminonicotinamide (6-AN) and epiandrosterone (EPI), markedly reduce hypoxic pulmonary vasoconstriction (HPV). Although it has been suggested that changes in the NADPH/NADP+ ratio and redox status are involved in the mechanism of HPV, the role of PPP-derived NADPH in this phenomenon is not known. The aim of this study, therefore, was to investigate the role of PPP-derived NADPH in HPV using isolated rat pulmonary arteries (PA) and perfused rat lungs. The NADPH/NADP+ ratio and NADPH levels in PA and lungs exposed to hypoxia increased 2-fold and 7-fold, respectively, compared to time-matched normoxic controls. Both hypoxia-induced increases in lung NADPH levels and lung perfusion pressure were inhibited by 6-AN (500 microM) or EPI (300 microM). The chemical inhibitors of PPP and hypoxia similarly decreased lung tissue NOx levels by approximately 50%. In contrast, hypoxia increased the lung soluble guanylate cyclase (sGC) activity (from 22.9+/-6.3 to 57.1+/-7.6 pmol/min/g), which was prevented by PPP inhibitors. ODQ, a sGC inhibitor, potentiated HPV. These results suggest that while PPP-derived NADPH may play a significant role in HPV, it may also moderate the magnitude of HPV through activation of the NO-sGC-cGMP vasodilation pathway.


Updating the Cost Effectiveness of Oral Anticoagulants for Patients with Atrial Fibrillation Based on Varying Stroke and Bleed Risk Profiles.
Previous investigations into the cost effectiveness of direct oral anticoagulants only considered individual stroke risk but not bleed risk even though bleeding is an important and potentially fatal side effect for anticoagulated patients. This study aimed to evaluate the cost effectiveness of dabigatran, rivaroxaban, apixaban, and edoxaban vs warfarin in patients with atrial fibrillation with varying stroke/bleed risk profiles over a lifetime horizon. A Markov micro-simulation was adapted to examine the lifetime costs and quality-adjusted survival of five anticoagulants from a US private payer's perspective. The study hypothetical cohort consisted of 10,000 patients with atrial fibrillation with age, CHA2DS2-VASc, and HAS-BLED scores similar to a commercially insured patient with atrial fibrillation cohort. Model input parameters including the efficacy and safety of each strategy, utilities, and cost were estimated from public sources, published literature, and analysis conducted in the IBM MarketScan database. Lifetime cost, quality-adjusted life-years, and incremental cost-effectiveness ratios were assessed for each treatment strategy. Subgroup analyses stratified by age, stroke risk score alone, bleed risk score alone and both were performed. Uncertainty was assessed by a deterministic sensitivity analysis and a probabilistic sensitivity analysis. The base-case analysis suggested dabigatran was the optimal treatment with an incremental cost-effectiveness ratio of $35,055 per quality-adjusted life-year relative to warfarin. Subgroup analyses stratified by age, stroke risk score, and bleed risk score alone were largely consistent with the base-case analysis. Subgroup analyses stratified by both stroke and bleed risk score showed edoxaban was the preferred treatment in patients with a low stroke and a low or medium bleed risk, and patients with a high stroke and low bleed risk. Apixaban was the preferred treatment in patients with a medium stroke and high bleed risk. Results of the deterministic sensitivity analysis indicate the model results were most sensitive to the drug cost and hazard ratio for stroke and bleeding event. Results of the probability sensitivity analysis showed dabigatran is cost effective vs. other treatments in 32.8% and 42.4% of iterations at a willingness to pay of $50,000/quality-adjusted life-year and a willingness to pay of $100,000/quality-adjusted life year, respectively. From a US private payer's perspective, dabigatran appears cost effective compared with other anticoagulants. This study indicated risk stratification especially considering both stroke and bleed risk simultaneously is important not only in clinical practice but also in health technology assessment exercises among patients with atrial fibrillation.


Are there two classes of classically-conditioned responses?
It is proposed that two response classes interact during classical conditioning: (1) a specific effect which directs responding towards or away from the CS, depending upon whether a positive or negative outcome is signaled, and (2) a general, emotional effect which interferes with responding. The interaction between these two response classes can account for the varied results obtained under CER and autoshaping procedures, and must be considered in any analysis which attempts to account for the complex nature of the conditioned response.


Occipital and external acoustic meatus to axis angle as a predictor of the oropharyngeal space in healthy volunteers: a novel parameter for craniocervical junction alignment.
The occipito-C2 angle (O-C2a) influences the oropharyngeal space. However, O-C2a has several limitations. There is no normal value of O-C2a because of the wide individual variations, and O-C2a does not reflect translation of the cranium to the axis, another factor influencing the oropharyngeal space in patients with atlantoaxial subluxation. The objective of this study was to propose a novel parameter that accounts for craniocervical junction alignment (CJA) and the oropharyngeal space. This is a post hoc analysis of craniocervical radiological parameters from another study. Forty healthy volunteers were included in the study. Craniocervical measurement parameters included the occipital and external acoustic meatus to axis angle (O-EAa), the C2 tilting angle (C2Ta), O-C2a, and the anterior-posterior distance of the narrowest oropharyngeal airway space (nPAS). We collected 40 healthy volunteers' lateral cervical radiographs in neutral, flexion, extension, protrusion, and retraction positions. We measured O-C2a, C2Ta (formed by the inferior end plate of C2 and a line connecting the external acoustic meatus and the midpoint of the inferior end plate of C2 [EA-line]), O-EAa (formed by the McGregor line and the EA-line), and nPAS. We evaluated the inter-rater and intrarater reliability of O-EAa and C2Ta, and the associations between each of the measured parameters. The inter-rater and intrarater reliabilities of measuring O-EAa and C2Ta were excellent. The neutral position O-EAa values remained in a narrower range (mean±standard deviation, 90.0°±5.0°) than O-C2a (15.6°±6.7°) (Levene test of equality of variances, p=.044). In the linear mixed-effects models, sex, O-C2a, C2Ta, and O-EAa were significantly associated with nPAS. The marginal R2 values for the mixed-effect models, which express the variance explained by fixed effects, were 0.605 and 0.632 for the O-C2a and O-EAa models, respectively. In all models, the subaxial alignment (C2-C6a) had no significant association with nPAS. The O-EAa may be a useful parameter of CJA with several advantages over O-C2a, including less individual variation, easier visual recognition during surgery, and improved prediction of postoperative nPAS after occipitocervical fusion.


Invasive ductal breast cancer: preoperative predict Ki-67 index based on radiomics of ADC maps.
The purpose of this study is to develop a radiomics model for predicting the Ki-67 proliferation index in patients with invasive ductal breast cancer through magnetic resonance imaging (MRI) preoperatively. A total of 128 patients who were clinicopathologically diagnosed with invasive ductal breast cancer were recruited. This cohort included 32 negative Ki67 expression (Ki67 proliferation index < 14%) and 96 cases with positive Ki67 expression (Ki67 proliferation index ≥ 14%). All patients had undergone diffusion-weighted imaging (DWI) MRI before surgery on a 3.0T MRI scanner. Radiomics features were extracted from apparent diffusion coefficient (ADC) maps which were obtained by DWI-MRI from patients with invasive ductal breast cancer. 80% of the patients were divided into training set to build radiomics model, and the rest into test set to evaluate its performance. The least absolute shrinkage and selection operator (LASSO) was used to select radiomics features, and then, the logistic regression (LR) model was established using fivefold cross-validation to predict the Ki-67 index. The performance was evaluated by receiver-operating characteristic (ROC) analysis, accuracy, sensitivity and specificity. Quantitative imaging features (n = 1029) were extracted from ADC maps, and 11 features were selected to construct the LR model. Good identification ability was exhibited by the ADC-based radiomics model, with areas under the ROC (AUC) values of 0.75 ± 0.08, accuracy of 0.71 in training set and 0.72, 0.70 in test set. The ADC-based radiomics model is a feasible predictor for the Ki-67 index in patients with invasive ductal breast cancer. Therefore, we proposed that three-dimensional imaging features from ADC maps could be used as candidate biomarker for preoperative prediction the Ki-67 index noninvasively.


Atypical fibroxanthoma and pleomorphic dermal sarcoma: Local recurrence and metastasis in a nationwide population-based cohort of 1118 patients.
The prognosis of patients with atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) remains uncertain and no standardized follow-up programs have been established. To recommend a standardized follow-up program of patients with AFX and PDS based on nationwide long-term estimates of local recurrence and metastasis. All patients with AFX and PDS in Denmark between 2002 and 2022 were included. Danish National Registries were used to estimate the risks of local recurrence and metastasis for AFX and PDS. The 5-year risk of local recurrence was 10% for AFX and 17% for PDS. The 5-year risk of metastasis was 0.8% for AFX and 16% for PDS. PDS metastasized within 3 years in >90% of the patients with the lungs as the primary metastasis site (50%). Invasion beyond the subcutis, perineural/intravascular infiltration, and increasing age significantly increased the risk of PDS relapse. Risk of misclassification and lack of detailed surgical information. The follow-up of patients with AFX can be limited to clinical visits for 4 years. Patients with PDS should be followed with clinical visits and PET/CT twice a year for the first 3 years and once a year for a minimum of 1 year.


A case of chronic total occlusion in popliteal artery recanalized by double snare piercing technique.
Although majority of cases with chronic total occlusion (CTO) in femoro-popliteal lesion were treated with antegrade approach only, some lesions require alternative approach due to its complexity. Bi-directional approach is useful on endovascular therapy (EVT) for CTO; however guidewire passage through the lesion is impossible in some challenging cases. The present case shows a successful re-entry technique utilizing two snare catheters from an antegrade and retrograde access site (double snare piecing technique). A 79-year-old woman with right leg intermittent claudication (Rutherford category IV), who had undergone unsuccessful EVT for popliteal CTO, required another EVT for the worsening symptom. Following the failed conventional crossing technique (wire knuckle technique, intravascular-ultrasound-guided wiring, and controlled antegrade and retrograde subintimal tracking technique), two snare catheters were placed and the snare loops were pierced by a puncture needle percutaneously. After an 0.014 wire was inserted into the needle, the needle was withdrawn. The wire was pulled from the retrograde side and was externalized. Then, the antegrade snare catheter was pulled and externalized, to make the wire across the lesion. After that, a microcatheter was advanced along the externalized wire from the retrograde side and cross the lesion. The wire was replaced with a new wire, which completely created pull-through system. After the hemostasis by balloon inflation and lesion preparation, this procedure was completed with an endoluminal-covered stent and two inter-woven stents. The re-entry site was covered by the inter-woven stent. Her symptoms improved after the procedure, and the lesion has not developed restenosis at 2-years follow-up. This re-entry technique of puncturing two snare loops (double snare piercing technique) might be effective for achieving successful passage through challenging femoropopliteal CTO cases.


Phase II trial of weekly ixabepilone in men with metastatic castrate-resistant prostate cancer (E3803): a trial of the Eastern Cooperative Oncology Group.
Ixabepilone is an epothilone B analogue with activity in a variety of solid malignancies, including prostate cancer. The main dose-limiting toxicity of ixabepilone is myelosuppression when administered by using an every 3-week schedule. Here we evaluate the activity of a weekly ixabepilone in men with metastatic castrate-resistant prostate cancer to minimize hematologic toxicity. BMS-247550 (ixabepilone) is an epothilone B analogue with activity in taxane-resistant cancer cell lines. Here we report the activity and toxicity of ixabepilone, administered by using a weekly schedule, in men with metastatic castrate-resistant prostate cancer (CRPC). Patients with metastatic CRPC received ixabepilone at 20 mg/m(2) intravenous weekly x 3, in 4-week cycles. This noncomparative study stratified patients to either a chemotherapy naive (CN), prior taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm. The primary endpoint was prostate-specific antigen response by using PCWG (Prostate Cancer Working Group) 1 criteria. Secondary endpoints included radiographic response when using RECIST (Response Evaluation Criteria In Solid Tumors). In total, 124 patients were enrolled, of whom, 109 were eligible (35 CN, 42 Tax, and 32 TCx) for the primary response determination in this study. Prostate-specific antigen responses were seen in 12 (34.3%) of 35, 12 (28.6%) of 42, and 7 (21.9%) of 32 patients with the partial objective response in 5 (22.7%) of 22, 2 (8.0%) of 25, and 0 (0.0%) of 24 patients for the CN, Tax, and TCx arms, respectively. Significant (grade 3/4) neutropenia was seen in 6 (15.4%), 7 (14.6%), and 9 (25.0%); and grade 3/4 sensory neuropathy was seen in 8 (20.5%), 12 (25.0%), and 12 (33.3%) for CN, Tax, and TCx, respectively. Grade 3/4 thrombocytopenia was infrequent and seen in only one patient on the CN and the TCx arm. Ixabepilone was found to have an acceptable toxicity profile when administered by using a weekly schedule with less myelosuppression compared with prior studies when using the every 3-week schedule. Single-agent activity was observed and met prespecified activity levels for the Tax treated arm.


Neuroimaging studies of mood disorder effects on the brain.
Studies of early-onset recurrent depression, late life depression associated with neurologic disorders, and bipolar illness have revealed structural brain changes within a neuroanatomical circuit. This circuit, originally described by, has been termed the limbic-cortical-striatal-pallidal-thalamic tract and is comprised of structures which are extensively interconnected. In three-dimensional magnetic resonance imaging studies of affective illness, many of the structures that comprise this tract have been found to have volume loss or structural abnormalities. Mechanisms proposed to explain volume loss in depression include glucocorticoid neurotoxicity, decreased brain-derived growth factor, decreased neurogenesis, and loss of plasticity.


Functional outcomes of a criterion-based rehabilitation protocol for anterior cruciate ligament reconstruction in amateur athletes: A randomised clinical trial.
Although current rehabilitation protocols following anterior cruciate ligament reconstruction (ACLR) are based on the graft remodeling process, there is uncertainty about its time schedule. Moreover, there are individual differences in neuromotor learning and flexibility after ACLR. The current study was conducted to investigate the functional outcomes of the criterion-based rehabilitation protocol in amateur athletes following ACLR. Fifty amateur male athletes who had ACLR were assigned randomly into two equal groups. The experimental group received a criterion-based rehabilitation protocol. The control group received a conventional physical therapy program. Both groups had five treatment sessions per week for six months. The primary outcome was pain intensity measured by VAS. Secondary outcomes included functional assessments measured by the limb symmetry index (LSI) of the hop test battery, knee effusion, and the Knee injury and Osteoarthritis Outcome Score (KOOS). Mixed-design-MANOVA indicated significant treatment, time, and treatment × time interaction. The interaction was significant for all outcome measures in favor of subjects who received a criterion-based rehabilitation protocol. Within-group analysis revealed a significant reduction in pain in both groups and improvements in all variables related to the KOOS or LSI of the hop test battery. Knee effusion was significantly reduced post-treatment in patients who received a criterion-based protocol when compared to their controls. Although application of a criterion-based rehabilitation protocol for 6 months after ACLR is more effective than a conventional program, its duration should be expanded beyond this period to allow patients to reach their return to play goals.


Nuclear androgen receptors of human prostatic tissue--a quantitative histological study.
The objective of this study was to determine the nuclear dihydrotestosterone (DHT) nuclear receptors content in tissues of normal prostate, benign prostatic hypertrophy (BPH), and prostatic cancer. We also attempted to correlate this with the histological pattern of these tissues. Specimens were obtained from five normal subjects, 24 BPH, and 19 prostatic cancer patients. Nuclear receptors content was determined. All histological sections were reviewed by three independent pathologists. The criteria for the quantitative analysis were the degree of cellularity and the stromal content. The mean receptor content was not significantly different between neoplastic tissue (52.6 fmol/mg protein) and hyperplastic tissue (38.9 fmol/mg protein). The number of binding sites in normal prostatic tissue was 8.5 fmol/mg protein. The correlation between the degree of cellularity and DHT receptors showed no significant difference for both BPH, as well as prostatic cancer. Similar results were obtained when stromal content was compared.


Target-binding proteins based on the 10th human fibronectin type III domain (¹⁰Fn3).
We describe concepts and methods for generating a family of engineered target-binding proteins designed on the scaffold of the 10th human fibronectin type III domain ((10)Fn3), an extremely stable, single-domain protein with an immunoglobulin-like fold but lacking disulfide bonds. Large libraries of possible target-binding proteins can be constructed on the (10)Fn3 scaffold by diversifying the sequence and length of its surface loops, which are structurally analogous to antibody complementarity-determining regions. Target-binding proteins with high affinity and specificity are selected from (10)Fn3-based libraries using in vitro evolution technologies such as phage display, mRNA display, or yeast-surface display. (10)Fn3-based target-binding proteins have binding properties comparable to those of antibodies, but they are smaller, simpler in architecture, and more user-friendly; as a consequence, these proteins are excellent building blocks for the construction of multidomain, multifunctional chains. The ease of engineering and robust properties of (10)Fn3-based target-binding proteins have been validated by multiple independent academic and industrial groups. In addition to performing well as specific in vitro detection reagents and research tools, (10)Fn3-based binding proteins are being developed as therapeutics, with the most advanced candidate currently in Phase II clinical trials.


Allelotype analysis of uterine leiomyoma: localization of a potential tumor suppressor gene to a 4-cM region of chromosome 7q.
Uterine leiomyoma is a benign smooth muscle tumor of the myometrium and is the most commonly encountered neoplasm in women of reproductive age. As for most benign tumors, the pathogenesis of leiomyoma remains obscure, especially at the molecular genetic level. The purpose of this study was to perform a genome-wide allelotype analysis to identify potential sites of tumor suppressor gene inactivation. Fifty-two cases of uterine leiomyoma were subjected to allelotype analysis by using matched pairs of tumor and blood DNA. Loss of heterozygosity (LOH) was assessed at 61 microsatellite markers distributed throughout the genome and representing all 41 chromosome arms. In general, LOH was very rare except on chromosome 7q, where LOH was observed in 34% of all informative tumors. Fine-deletion mapping with 25 microsatellite markers from the 7q22 region revealed a minimal deletion unit of approximately 4 cM, bounded by the markers D7S2453 proximally and D7S496 distally, that probably harbors a novel tumor suppressor gene involved in the etiology of this tumor.


Comparison of analytical performance of i-Smart 300 and pHOx ultra for the accurate determination of pleural fluid pH.
Pleural fluid pH is an essential test for diagnosing complicated parapneumonic effusion. We evaluated the performance of two blood gas analyzers in measuring pleural fluid pH. The i-STAT G3+ (Abbott) was used as a reference analyzer to evaluate the pH values obtained from other methods: the i-Smart 300 (i-SENS), the pHOx Ultra (Nova Biomedical), using a clot catcher to filter off microclot, and pH indicator paper. Within-device precision was performed using quality control materials. We compared pleural fluid pH (n = 86) by the above methods and analyzed the concordance rate at the level of the medical decision point, pH 7.2. The within-device coefficient of variations of pH were below 0.1% for all blood gas analyzers tested. The slopes of the regression equations for the i-Smart 300, pHOx Ultra, and pH indicator paper against the reference analyzer were 0.850 (95% confidence interval, CI, 0.800-0.896), 0.714 (95% CI, 0.671-0.766), and 1.105 (95% CI, 0.781-1.581), respectively. The kappa values for the i-Smart 300, pHOx Ultra, and pH indicator paper against the reference analyzer were 0.883 (95% CI, 0.656-1.110), 0.739 (95% CI, 0.393-1.084), and 0.464 (95% CI, 0.102-0.826), respectively. The i-Smart 300 and pHOx Ultra demonstrated good analytical performance and diagnostic accuracy when determining pleural fluid pH compared with that by the i-STAT G3+, whereas the pH indicator paper showed unsatisfactory results.


Sym-(CH2X)5-corannulenes: molecular pentapods displaying functional group and bioconjugate appendages.
Pentapodal ω-functional derivatives of corannulene have been synthesized from sym-pentachlorocorannulene by iron-catalyzed aryl-alkyl cross coupling reactions. Click chemistry gives access to pentapods with bioconjugate appendages.


The Relationship Between Length of Surgery and the Incidence of Pressure Ulcers in Cardiovascular Surgical Patients: A Retrospective Study.
The aim of this study was to investigate the relationship between the length of surgery and the incidence of pressure ulcers (PrUs) in cardiovascular surgical patients. A retrospective analysis was performed among consecutive patients with cardiac surgery in 2012. Propensity score matching was used to control differences in the baseline characteristics between with and without surgery-related pressure ulcer (SRPU) groups. A total of 286 patients with cardiac surgery were included in the study: 47 patients developed 57 SRPUs, with incidence of 16.4% (95% confidence interval, 12.3%-21.2%); 97.9% of SRPUs were Stage I, and the other 2.1% were Stage II. After propensity score matching, statistically significant difference of the length of surgery between the 2 groups was found (195 minutes [30-330 minutes] vs 240 minutes [125-675 minutes], P = .003). However, the length of cardiopulmonary bypass was found to be not statistically significantly different between the 2 groups (37 minutes [15-144 minutes] vs 44 minutes [16-107 minutes], P = .830). The curve fitting showed the SRPU incidence increased gradually with the extension of length of surgery. The authors' retrospective analysis showed the length of surgery was an important risk factor for PrUs in cardiovascular surgical patients, but not the length of cardiopulmonary bypass. The incidence of SRPUs increased gradually with the extension of length of surgery.


Measurement of cytoplasmic calcium concentration in cell suspensions: correction for extracellular Fura-2 through use of Mn2+ and probenecid.
1321N1 astrocytoma cells loaded with Fura-2 were found to continuously transport Fura-2 to the extracellular medium. To correct for extracellular Fura-2 fluorescence a protocol was developed in which Mn2+ was added to duplicate cuvettes of cells to quench extracellular Fura-2 at the beginning and end of the experimental time course. Since the export of Fura-2 was linear with time, two separate quench determinations allowed the amount of fluorescence from extracellular Fura-2 fluorescence to be estimated at every point in the time course and subtracted from the data. The uncorrected and Mn2+-corrected basal cytoplasmic calcium concentrations averaged 153 nM and 72 nM, respectively. The peak intracellular calcium concentrations following muscarinic stimulation with 300 microM carbachol averaged 1159 nM (uncorrected) and 889 nM (Mn2+-corrected). Probenecid (2.5 mM) was found to block the export of Fura-2 from these cells and did not change the basal calcium concentration or the muscarinic calcium response.


Assessment, diagnosis, and investigation of erectile dysfunction.
Diagnosis of erectile dysfunction (ED) now largely rests on the medical, sexual, and psychosocial history of the patient, ideally involving the man's partner. The medical history is crucial because ED is associated with so many common disorders and their treatment. A range of validated questionnaires may be used in taking the history. They can provide an objective and systematic record. The history helps identify whether the ED is largely physical or psychogenic. In particular, gradual onset suggests a physical cause, and sudden onset suggests a psychogenic cause. Physical examinations are not usually necessary. Taking blood pressure and physical examination of the genitals for signs of Peyronie's disease and hypogonadism may be helpful. Laboratory tests that identify diabetes (glycosylated haemoglobin), hyperlipidaemia (lipids), and hypogonadism (testosterone) may identify causes of ED. A range of specialized investigations, such as ultrasound and nocturnal penile tumescence and rigidity assessment, is also available, but is not used routinely in most patients with ED.


Oral 5-aminolevulinic acid induced Photodynamic Diagnostic Ureterorenoscopy--does the blood pressure require monitoring?
Photodynamic Diagnosis has been proven to improve detection of superficial bladder cancer and improve visualisation of resection margins. The use of 5-aminolevulinic acid as the photosensitising agent has been associated with side effects, specifically hypotension. We aimed to evaluate the effect of oral 5-ALA on the blood pressure in a group of patient who underwent Photodynamic Diagnostic Ureterorenoscopy. We carried out an observational study on all patients who underwent PDD-Ureterorenoscopy with oral 5-ALA between July 2009 and September 2011. Pre-administration, hourly post-administration and hourly post-operative blood pressures were noted. Mean arterial blood pressure and the threshold for cerebral ischaemia were calculated as well. The study includes thirty-eight procedures which involved twenty-four patients with a mean age of 74 (SD±16.95). Hypotension was defined as <80% of the systolic or diastolic baseline blood pressure. Twenty patients were hypotensive pre-operatively after the ingestion of 5-ALA while 21 patients were hypotensive post-operatively. Three patients crossed their MAP threshold pre-operatively and were symptomatic. Fast infusion of intravenous fluids improved their symptoms. Hypotension is a common occurrence after the ingestion of 5-ALA. Patients undergoing PDD Ureterorenoscopy should have their blood pressure monitored closely after the ingestion of 5-ALA.


The role of gender and biological sex in irritable bowel syndrome.
Irritable bowel syndrome (IBS), which is characterized by abdominal pain or discomfort that is associated with altered bowel function (diarrhea, constipation, or alteration between the two), is one of several gastrointestinal motility disorders. IBS affects up to one in five North Americans, mostly women. The reason(s) this disorder is reported more often by women than men, and the role of gender and biological sex in the prevalence, pathophysiology, symptom presentation, impact on quality of life, diagnosis, and response to treatment, are poorly understood. The purpose of this article is to review the evidence surrounding the roles of gender and biological sex in IBS.


Evaluation of Tl-201 SPECT for monitoring the treatment of pulmonary and mediastinal tumors.
Tl-201 single photon emission computed tomography (SPECT) was performed in 88 patients with pulmonary or mediastinal tumors in order to evaluate its usefulness for the detection of disease and for the assessment of the effect of treatment. We also examined mediastinal and hilar lymph node metastasis from lung cancer. Tl-201 SPECT showed abnormal accumulation on delayed images in all lung cancer patients with tumor diameters more than 12 mm. In the 14 operated lung cancer patients, mediastinal and hilar lymph node metastases with diameters of more than 15 mm were imaged, but one with a diameter of 9 mm was missed. The retention index (RI) was 27.52 +/- 31.58 in malignant tumors and -13.67 +/- 8.15 in benign tumors (p < 0.05). The RI was significantly lower after treatment than before treatment. The interval until tumor recurrence or reactivation tended to be longer in patients who showed a significant decrease in the RI after therapy. These findings suggest the usefulness of the RI as an index of therapeutic efficacy.


In vivo myocardial gene transfer: optimization and evaluation of intracoronary gene delivery in vivo.
Clinical reports suggest that intracoronary delivery of adenoviruses encoding angiogenic growth factors, or their transactivators, has a therapeutic benefit. However there has not been a systematic assessment of the transfection efficiency of this technique in vivo. In rabbits we investigated the efficiency of myocardial gene transfer following intracoronary infusion of 1 x 10(-10) -1 x 10(12) p.f.u. of adenovirus in combination with interventions to enhance transfection. In five standard short axis sections, we were barely able to detect reporter gene expression following unmodified intracoronary infusion. Efficiency was not enhanced by the exclusion of blood and the increase of intracoronary dwell time through occlusive engagement of the left coronary ostium enabled by oxygenated perfluorocarbon emulsion as viral diluent. Of the interventions and pretreatments designed to increase vascular permeability, VEGF, calcium-free viral diluent and adenosine, only the latter tended to increase efficiency. However an intervention designed to increase the myocardial transcapillary gradient, by increasing venular pressure with pulmonary artery occlusion and arteriolar pressure with occlusion of the aorta above the coronary ostia, increased transfection efficiency by two orders of magnitude. Unfortunately the clinical utility of this technique may be limited by accompanying cardiac dilation and marked elevations in intracardiac pressure.


Asparagine-linked sugar chains of plasma membrane glycoproteins from healthy and common variable immunodeficiency B lymphoblastoid cell lines.
Asparagine-linked sugar chains of plasma membrane glycoproteins, which are formed by glycosylation during B cell maturation, were examined with B lymphoblastoid cell lines (LCLs) transformed by Epstein-Barr virus derived from healthy controls and patients with common variable immunodeficiency (CVI). Both two patients with CVI showed hypogammaglobulinemia and impaired B cell functions. LCLs from healthy controls and the patients showed CD19+ and HLA/DR+ in the cell surface and secreted IgM. In both healthy controls and the patients, the main oligosaccharide in asparagine-linked sugar chains of the membrane glycoproteins of LCLs was biantennary sugar chain with bisected GlcNAc (Gal2-GlcNAc2-Man3-GlcNAc-GlcNAc-Fuc-GlcNAcOT). Biantennary sugar chain with an alpha-fucosyl residue linked at the proximal GlcNAc was seen but biantennary sugar chain without an alpha-fucosyl residue at the proximal GlcNAc was little detected in each LCL. There was no difference in quality and quantity of asparagine-linked sugar chains between healthy controls and the patients. These results suggest that glycosylation during B cell maturation may not be impaired in patients with CVI.


Maternal folate depletion and high-fat feeding from weaning affects DNA methylation and DNA repair in brain of adult offspring.
The mechanisms through which environmental and dietary factors modulate DNA repair are still unclear but may include dysregulation of gene expression due to altered epigenetic markings. In a mouse model, we investigated the effect of maternal folate depletion during pregnancy and lactation, and high-fat feeding from weaning, on base excision repair (BER) and DNA methylation and expression of selected BER-related genes in the brain of adult offspring. While folate depletion did not affect BER activity of the mothers, BER increased in the offspring at weaning (P=0.052). In the long term, as observed in 6-mo-old offspring, the double insult, i.e., maternal low-folate supply and high-fat feeding from weaning, decreased BER activity significantly in the cortex, cerebellum, hippocampus, and subcortical regions (P≤0.017). This fall in BER activity was associated with small changes in methylation or expression of BER-related genes. Maternal folate depletion led to slightly increased oxidative DNA damage levels in subcortical regions of adult offspring, which may increase sensitivity to oxidative stress and predispose to neurological disorders. In summary, our data suggest that low-folate supply during early life may leave an epigenetic mark that can predispose the offspring to further dietary insults, causing adverse effects during adult life.


Metalliferous Biosignatures for Deep Subsurface Microbial Activity.
The interaction of microbes and metals is widely assumed to have occurred in surface or very shallow subsurface environments. However new evidence suggests that much microbial activity occurs in the deep subsurface. Fluvial, lacustrine and aeolian 'red beds' contain widespread centimetre-scale reduction spheroids in which a pale reduced spheroid in otherwise red rocks contains a metalliferous core. Most of the reduction of Fe (III) in sediments is caused by Fe (III) reducing bacteria. They have the potential to reduce a range of metals and metalloids, including V, Cu, Mo, U and Se, by substituting them for Fe (III) as electron acceptors, which are all elements common in reduction spheroids. The spheroidal morphology indicates that they were formed at depth, after compaction, which is consistent with a microbial formation. Given that the consequences of Fe (III) reduction have a visual expression, they are potential biosignatures during exploration of the terrestrial and extraterrestrial geological record. There is debate about the energy available from Fe (III) reduction on Mars, but the abundance of iron in Martian soils makes it one of the most valuable prospects for life there. Entrapment of the microbes themselves as fossils is possible, but a more realistic target during the exploration of Mars would be the colour contrasts reflecting selective reduction or oxidation. This can be achieved by analysing quartz grains across a reduction spheroid using Raman spectroscopy, which demonstrates its suitability for life detection in subsurface environments. Microbial action is the most suitable explanation for the formation of reduction spheroids and may act as metalliferous biosignatures for deep subsurface microbial activity.


Cerebroventricular size and cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy volunteers.
Computed tomography (CT) measures and cerebrospinal fluid (CSF) levels of the monoamine metabolites homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were determined in 43 healthy volunteers and in 26 patients with an acute psychosis of the schizophrenic type. There were no differences in the mean CSF levels of monoamine metabolites between the two groups. However, the patients had significantly wider lateral and third ventricles as compared to the volunteers. In the volunteers there were no significant correlations between ventricular sizes and monoamine metabolite levels, whereas in the patients a significant negative correlation was obtained between the size of the lateral ventricles and the levels of HVA and 5-HIAA in the CSF. These results may indicate that the enlargements of the brain ventricles found in a subgroup of schizophrenic patients may be associated with deficiencies in central monoamine transmission mechanisms.


The utility of electrodiagnostic tests for the assessment of medically unexplained weakness and sensory deficit.
Patients with suspected medically unexplained symptoms or psychogenic disorders are frequently requested to undergo an EMG exam. However, the suspected diagnosis is not always told to the electromyography practitioner, who must be able to recognize such a condition to avoid false positive diagnosis without dismissing the possibility to uncover any true dysfunction. There are many clinical manoeuvers to assess the consistency of the patients' reported weakness or sensory deficit. The electrodiagnostic practitioner should be aware of those clinical tricks and interpret the electrodiagnostic findings in the clinical context. There are many electrodiagnostic tests that the practitioner can use for the assessment of motor and sensory functions but these tests have also important drawbacks and limitations. Only after a good clinical evaluation would the practitioner be able to give his/her opinion on the clinical relevance of the electrodiagnostic findings. Here we review some of the tests that can help the practitioner to define the electrophysiological characteristics of a suspected functional disorder presenting with weakness or sensory deficit.


Determination of Cu/Zn and Fe in human serum of patients with sickle cell anemia using radiation synchrotron.
In this work we analyzed serum samples from patients with Sickle Cell Anemia (SCA) using Total Reflection X-Ray Fluorescence using Synchrotron Radiation (SRTXRF). The SRTXRF measurements were performed at the X-Ray Fluorescence Beamline at the Brazilian National Synchrotron Light Laboratory (LNLS). We studied forty-three patients aged 18-50 suffering from SCA and sixty healthy volunteers aged 18-60. It was possible to determine the concentrations of the following elements: P, S, Cl, K, Ca, Fe, Cu, Zn, Br and Rb. Moreover, there are evidences of an association among Fe, Cu, Zn and Cu/Zn in the SCA pathogenesis process. The concentrations of Fe and Cu in the serum samples of patients with SCA were larger, 120% and 20%, respectively, when compared with the CG. The serum level Cu/Zn ratio was significantly higher (60%) in the serum samples from patients suffering from SCA than from the CG. Therefore, the Cu/Zn ratio can be used as an adjuvant index in enhancement for diagnosis of SCA.


Snapshot of a social movement: Mental health and protest classes in Hong Kong.
Popular protests have broken out worldwide, particularly in the last few years. In 2019, numerous demonstrations against an extradition bill occurred in Hong Kong until pandemic restrictions were imposed. The policing response relied heavily on methods such as batons, tear gas and rubber bullets. Given the relevance for other geographical contexts, the current study investigated the mental health impacts on protest participants and spillover to community members. Surveys were disseminated on social media in August and October 2019 to collect demographics, political views, protest participation, exposure to (protest-related) potentially traumatic events (PTEs) and mental health symptoms. A latent class analysis (LCA) was conducted using demographic data and inter-class differences in PTEs and mental health symptoms were examined. There were 37,541 (59.8% female) and 40,703 (50.0% female) responses in August and October. Respondents, even those with low participation, reported significant levels of depression, anxiety, and symptoms of traumatic stress (STS). The LCA suggested a 5-class solution (youth, allies, supporters, sympathizers, and frontliners). Mental health symptoms and PTEs varied with class membership, with 50.8% of frontliners reporting severe STS. The non-random sampling and self-reported measures may over-estimate the prevalence of mental distress in the wider population. Large numbers of pro-democracy supporters in Hong Kong reported high rates of depression, anxiety and STS during mass protests. Younger and more heavily involved respondents faced the highest mental health risks, however elevated rates were also observed for respondents with low participation.


Epidemiologic survey of Kawasaki disease in Jilin from 1999 through 2008.
The epidemiologic pictures of Kawasaki disease (KD) in Jilin Province of China is still not clear. We sent a questionnaire form and diagnostic guidelines for KD to the province's 32 hospitals above the county and city level with pediatric in-patients. All patients with KD diagnosed during January 1999 through December 2008 were recruited in this survey. The incidence of KD was 1.39 to 11.07 (5.26 ± 3.97) per 100,000 children under the age of 5 years between 1999 and 2008. The ratio of male to female was 1.96 to 1. Ages at onset ranged from 58 days to 14 years. Patients under 5 years of age accounted of 88.73%. The disease occurred throughout the year, but it occurred more frequently in May to July and November. The most common cardiac abnormality was coronary artery dilatation (49.5%). Age at onset and hypoalbuminemia (<30 g/l) were selected for multivariate logistic regression equation. In conclusion, incidences of KD increased in Jilin Province. Age and gender distribution shared similarities with previous reports, and the seasonal distribution was different. Age and lower serum albumin were the most important risk factors of coronary arterial lesions (CAL) in KD. In addition, patients treated with steroids also had a possible heightened risk of contracting CAL.


[The use of a mathematical method in evaluating the severity of the condition of patients with pyopneumothorax].
The course of pyopneumothorax in 427 patients, among whom 310 were subjected to temporary occlusion of the bronchus, was appraised by means of the severity index based on consideration of deviations of the values of hemodynamics, external respiration, blood, and acid-base equilibrium from the normal level. In a favourable course of pyopneumothorax the severity index was found to be within the ranges of the confidential interval. The method makes it possible to appraise the compensatory properties of the organism and prognosticate the course of the disease.


Kugel herniorrhaphy: clinical results of 124 consecutive operations.
Due to its recent clinical application, the results of Kugel herniorrhaphy have not yet been well documented. We analyzed our experience in performing 124 consecutive Kugel herniorrhaphies at a single institute. Since the first introduction of Kugel herniorrhaphy in Japan in September 2001, a total of 117 patients (124 hernias) have undergone this procedure at our institute. The operative technique of Kugel herniorrhaphy was directly obtained through two hands-on training courses that were given by Dr. Kugel. The clinical results of the 124 hernias were analyzed, and to understand the feasibility of performing Kugel herniorrhaphy for various types of hernias, the operation time and the necessity for dividing the hernia sac were compared among each type based on the Nyhus classification. The operation times in types 2, 3A, 3B, 3C, and 4 were 48.5 +/- 19.5, 45.9 +/- 19.9, 54.2 +/- 24.8, 52.5 +/- 10.6, and 64.4 +/- 56.7 min, respectively, and the differences between each group were not statistically significant. In type 3A, no patient required a division of the hernia sac (0%), in contrast to 43% in type 3B. Peritoneal injury during operation and local hematoma/seroma were the most common complications (8.1% and 8.9%, respectively). Postoperatively the patients' quality of life factors, such as the analgesics needed, number of days before a return to normal activity, number of days before a return to work, and the recurrence rate of 0.9%, were comparable with other tension-free herniorrhaphy findings reported in the past. Our results suggest that Kugel herniorrhaphy is equally feasible for all types of Nyhus classifications, including femoral and recurrent hernias.


Microtiter cell-based assay for detection of agents that alter cellular levels of Her2 and EGFR.
Overexpression of the transmembrane tyrosine kinases Her2 and EGFR is associated with aggressive malignancies, and several therapeutic strategies targeting the two receptors are now in various stages of clinical development. Most of the known agents block the activation or inhibit the activity of the kinases; however, a more significant therapeutic outcome may result from degrading these oncoproteins. Here, we report the development of a microtiter cell-based assay that sensitively detects cellular levels of Her2 and EGFR. The assay is useful in identifying small molecules that alter cellular levels of these kinases and in quantifying their effect. The method gives results comparable to Western blot, but it is faster, less labor intensive, and amenable to high throughput.


Conserved allosteric inhibitory site on the respiratory syncytial virus and human metapneumovirus RNA-dependent RNA polymerases.
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are related RNA viruses responsible for severe respiratory infections and resulting disease in infants, elderly, and immunocompromised adults1-3. Therapeutic small molecule inhibitors that bind to the RSV polymerase and inhibit viral replication are being developed, but their binding sites and molecular mechanisms of action remain largely unknown4. Here we report a conserved allosteric inhibitory site identified on the L polymerase proteins of RSV and HMPV that can be targeted by a dual-specificity, non-nucleoside inhibitor, termed MRK-1. Cryo-EM structures of the inhibitor in complexes with truncated RSV and full-length HMPV polymerase proteins provide a structural understanding of how MRK-1 is active against both viruses. Functional analyses indicate that MRK-1 inhibits conformational changes necessary for the polymerase to engage in RNA synthesis initiation and to transition into an elongation mode. Competition studies reveal that the MRK-1 binding pocket is distinct from that of a capping inhibitor with an overlapping resistance profile, suggesting that the polymerase conformation bound by MRK-1 may be distinct from that involved in mRNA capping. These findings should facilitate optimization of dual RSV and HMPV replication inhibitors and provide insights into the molecular mechanisms underlying their polymerase activities.


Organ dose in CT: Comparison between measurements and computational methods.
This study aims to compare two methods for the organ dose evaluation in computed tomography (CT) in the head- and thorax regions: an experimental method, using radiochromic films, and a computational one, using a commercial software. Gafchromic® XR-QA2 and EBT-3 were characterized in terms of energetic, angular, and irradiation configurations dependence. Two free-in-air irradiation calibration configurations were employed using a CT scanner: with the sensitive surface of the film orthogonal (OC) and parallel (PC) to the beam axis. Different dose-response curves were obtained by varying the irradiation configurations and the beam quality (BQ). Subsequently, films were irradiated within an anthropomorphic phantom using CT-thorax and -head protocols, and the organ dose values obtained were compared with those provided by the commercial software. At different configurations, an unchanged dose response was achieved with EBT-3, while a dose response of 15% was obtained with XR-QA2. By varying BQ, XR-QA2 showed a different response below 10%, while EBT-3 showed a variation below 5% for dose values >20 mGy. For films irradiation angle equal to 90°, the normalized to 0° relative response was 41% for the XR-QA2 model and 83% for the EBT-3 one. Organ dose values obtained with EBT-3 for both configurations and with XR-QA2 for OC were in agreement with the DW values, showing percentage discrepancies of less than 25%. The obtained results showed the potential of EBT-3 in CT patient dosimetry since the lower angular dependence, compared to XR-QA2, compensates for low sensitivity in the diagnostic dose range.


alpha-Methyl-p-tyrosine inhibits the production of free arachidonic acid and diacylglycerols in brain after a single electroconvulsive shock.
A single electroconvulsive shock (ECS) significantly enlarged the free fatty acid (FFA) pool of the mouse brain, arachidonic acid being the most actively released FFA (48% over controls). In animals pretreated with alpha-methyl-p-tyrosine (alpha-MT), the endogenous levels of FFA (25 sec after decapitation) were decreased and the effect of ECS was completely abolished. The most pronounced inhibition took place in free arachidonic acid (42% and 52% under controls in nonstimulated and ECS-stimulated mice, respectively). A similar tendency, although lower and less specific than the one taking place in FFA, was observed in mouse brain diacylglycerols (DG). In contrast to ECS, alpha-MT treatment did not effect the marked release of FFA and DG taking place 3 min after decapitation. Taking into account the specific inhibitory action of alpha-MT on tyrosine hydroxylase activity, the present findings provide experimental in vivo evidence about the relationship between biogenic amines and membrane lipid breakdown during electrical stimulation and suggest an involvement of FFA and DG in neurotransmission.


Environment friendly green synthesis method based natural bioactive functional "catechin and gingerol" loaded nanomedicine for the management of obesity.
Obesity is one of the major health problems across the world and the leading cause of death. Natural bioactive functional compounds (catechin, Cat and gingerol, Gin) have been reported to control obesity. The application of a nanoparticulate (NPs) delivery system has shown greater efficacy in the treatment of different diseases. The present study was designed to prepare the Cat-Gin silver nanoparticles (AgNPs) using the microwave method. The prepared Cat-Gin-AgNPs were characterized for particle size, zeta potential, encapsulation efficiency and drug release. Further, it was evaluated for anti-obesity activity (body weight, total abdominal fat, lipid profile and liver profile) using a high-fed diet (HFD) induced obesity model. The formulated Cat-Gin-AGNPs showed nano-metric size (110 ± 4.65 nm), polydispersity index (PDI) of 0.27 ± 0.03, and surface charge (-17.6 ± 2.6 mV) with a spherical shape. It also depicted high encapsulation efficiency (<80 %) with prolonged drug release behaviour (Cat - 84.34 ± 4.12 % and Gin - 72.33 ± 3.87 %). The in vivo study parameters revealed a significant (p ≤ 0.001) reduction in body weight, food intake and total abdominal fat. The biochemical results displayed a reversal in altered biochemical parameters to the normal range (Group 4) as compared to HFD control (Group 2). It also helps restored the liver enzymes in obese rats. The results of the study highlighted the applicability of Cat-Gin-AGNPs as a novel delivery system in the treatment of obesity.


Open traumatic avulsion of the flexor pollicis longus tendon from the musculotendinous area: a case report.
A traumatic avulsion of the flexor tendon at the musculotendinous junction in nonamputated digits is a very rare injury. We present a 14-year-old girl who sustained a longitudinal, tensile, injurious force directly to the flexor pollicis longus tendon after an open thenar injury resulting in its avulsion at the musculotendinous junction. In an effort to minimize soft-tissue damage and preserve the transverse ligament of the carpus the tendon was retrieved through a separate forearm incision. Direct repair was made by encapsulation of the tendon into the muscle belly. The functional result 30 months after surgery was satisfactory.


Effects of Performance Versus Game-Based Mobile Applications on Response to Exercise.
Given the popularity of mobile applications (apps) designed to increase exercise participation, it is important to understand their effects on psychological predictors of exercise behavior. This study tested a performance feedback-based app compared to a game-based app to examine their effects on aspects of immediate response to an exercise bout. Twenty-eight participants completed a 30-min treadmill run while using one of two randomly assigned mobile running apps: Nike + Running, a performance-monitoring app which theoretically induces an associative, goal-driven state, or Zombies Run!, an app which turns the experience of running into a virtual reality game, theoretically inducing dissociation from primary exercise goals. The two conditions did not differ on primary motivational state outcomes; however, participants reported more associative attentional focus in the performance-monitoring app condition compared to more dissociative focus in the game-based app condition. Game-based and performance-tracking running apps may not have differential effects on goal motivation during exercise. However, game-based apps may help recreational exercisers dissociate from exercise more readily. Increasing the enjoyment of an exercise bout through the development of new and innovative mobile technologies is an important avenue for future research.


Augmented early aged neutrophil infiltration contributes to late remodeling post myocardial infarction.
Neutrophils oscillate in number and phenotype after being released from bone marrow. Myocardial infarction (MI) outcome is associated with the time-of-day of ischemia onset. However, the underlying contributive factors of neutrophils to cardiac remodeling post MI remain unknown. We examined neutrophil infiltration into the heart and cardiac function and remodeling in C57BL/6J MI model created by permanent coronary ligation at different zeitgeber times (ZT). We found that cell surface markers (CD62L, CXCR2, CXCR4) of neutrophils in peripheral blood lost diurnal oscillation 24 h post MI. Meanwhile, circadian gene Bmal1, Nr1d1, and Clock mRNA expression displayed disrupted diurnal patterns. Flow cytometry showed augmented aged neutrophil (CD11b+Ly6G+CD62Llow) infiltration into the heart along with increased circulating aged neutrophils in MI groups with more infiltration at ZT5 (p < 0.05), but no difference for aged neutrophil infiltration at different ZT points in late stage. Infiltrated neutrophils had significantly higher CXCL2 and CXCR2 but lower CXCR4 gene expression (p < 0.05). Mice that underwent ligation at ZT5 had high mortality rate and large infarct size. Echocardiography showed that those mice had significantly larger end diastolic and systolic volume and lower ejection fraction (p < 0.05). Immunohistology revealed that those mice displayed more fibrosis, cardiomyocyte hypertrophy, and less angiogenesis compared to ZT13 or ZT21 group (p < 0.05). However, treatment with anti-CXCL2 antibody significantly reduced LV dilatation, fibrosis, hypertrophy and improved cardiac function. These results indicate greater aged neutrophil infiltration into the heart contributes to cardiac hypertrophy, fibrosis, and dysfunction which suggests that blocking neutrophil aging may be a therapeutic alternative following acute myocardial infarction.


The evaluation of a mupirocin-based selective medium for the enumeration of bifidobacteria from probiotic animal feed.
In this study, MRS medium supplemented with cysteine hydrochloride and mupirocin, termed Bifidobacterium selective medium (BSM) was found to be elective for bifidobacteria but inhibitory to a wide range of non-bifidobacteria strains commonly included in probiotic animal feed. Bacilli, lactobacilli, lactococci and streptococci failed to form colonies on BSM and enterococci, pediococci and propionibacteria formed colonies <0.5 mm in diameter. Bifidobacteria formed colonies >1 mm in size and could be readily distinguished. The addition of nystatin to BSM further inhibited Saccharomyces cerevisiae. BSM was successfully used to enumerate the bifidobacteria components, confirmed through fructose-6-phophate-phosphoketolase detection, present in two commercial probiotic feeds. The medium is recommended for the enumeration of bifidobacteria from animal feeds especially when not a numerically dominant component.


Interactions between reproductive biology and microbiomes in wild animal species.
Many parts of the animal body harbor microbial communities, known as animal-associated microbiomes, that affect the regulation of physiological functions. Studies in human and animal models have demonstrated that the reproductive biology and such microbiomes also interact. However, this concept is poorly studied in wild animal species and little is known about the implications to fertility, parental/offspring health, and survival in natural habitats. The objective of this review is to (1) specify the interactions between animals' reproductive biology, including reproductive signaling, pregnancy, and offspring development, and their microbiomes, with an emphasis on wild species and (2) identify important research gaps as well as areas for further studies. While microbiomes present in the reproductive tract play the most direct role, other bodily microbiomes may also contribute to facilitating reproduction. In fish, amphibians, reptiles, birds, and mammals, endogenous processes related to the host physiology and behavior (visual and olfactory reproductive signals, copulation) can both influence and be influenced by the structure and function of microbial communities. In addition, exposures to maternal microbiomes in mammals (through vagina, skin, and milk) shape the offspring microbiomes, which, in turn, affects health later in life. Importantly, for all wild animal species, host-associated microbiomes are also influenced by environmental variations. There is still limited literature on wild animals compared to the large body of research on model species and humans. However, the few studies in wild species clearly highlight the necessity of increased research in rare and endangered animals to optimize conservation efforts in situ and ex situ. Thus, the link between microbiomes and reproduction is an emerging and critical component in wild animal conservation.


Student-teacher relationship quality and prosocial behaviour: The mediating role of academic achievement and a positive attitude towards school.
The current research investigated the association between teacher-student relationship (both teacher-perceived and student-perceived relationship quality) and students' prosocial behaviours, as well as the mediating roles of students' attitudes towards school and perceived academic competence in this association. Four hundred and fifty-nine Italian primary students (aged 4-9, Mage = 7.05, SDage = 1.37) and 47 teachers (aged 26-60, Mage = 48.35, SDage = 8.13) participated and finished all the questionnaires and scales. Multiple regression analyses and bootstrapping analyses were employed to test the direct and the mediating effects between the teacher/student-perceived relationship and students' prosocial behaviours. Results indicated that (1) teacher-student relationship was positively associated with students' prosocial behaviour; and (2) students' attitudes towards school could significantly mediate the association between teacher/student-perceived relationship and students' prosocial behaviours. Our understanding of how teacher-student relationship helps to enhance students' prosocial behaviours, as well as the intervention programmes that aim to enhance students' prosocial behaviours, may benefit from these findings.


Beta-cell replacement strategies for diabetes.
Diabetes is characterized by elevated levels of blood glucose as a result of insufficient production of insulin from loss or dysfunction of pancreatic islet β-cells. Here, we review several approaches to replacing β-cells that were recently discussed at a symposium held in Kyoto, Japan. Transplant of donor human islets can effectively treat diabetes and eliminate the need for insulin injections, supporting research aimed at identifying abundant supplies of cells. Studies showing the feasibility of producing mouse islets in rats support the concept of generating pigs with human pancreas that can serve as donors of human islets, although scientific and ethical challenges remain. Alternatively, in vitro differentiation of both human embryonic stem cells and induced pluripotent stem cells is being actively pursued as an islet cell source, and embryonic stem cell-derived pancreatic progenitor cells are now in clinical trials in North America in patients with diabetes. Macro-encapsulation devices are being used to contain and protect the cells from immune attack, and alternate strategies of immune-isolation are being pursued, such as islets contained within long microfibers. Recent advancements in genetic engineering tools offer exciting opportunities to broaden therapeutic strategies and to probe the genetic involvement in β-cell failure that contributes to diabetes. Personalized medicine might eventually become a possibility with genetically edited patient-induced pluripotent stem cells, and the development of simplified robust differentiation protocols that ideally become standardized and automated. Additional efforts to develop a safe and effective β-cell replacement strategy to treat diabetes are warranted.


Radiation chronotherapy-clinical impact of treatment time-of-day: a systematic review.
Many brain tumor patients suffer from radiation-induced toxicities. Chronotherapy is a treatment modality that utilizes circadian rhythms to optimize the effect on tumor while minimizing negative outcomes on healthy tissue. This review aims to systematically examine the literature on the application of a radiation chronotherapeutic for all cancers and determine the possible advantages of incorporating a circadian-based fixed time-of-day for radiotherapy into CNS cancers. A systematic review of the literature was conducted in two electronic databases from inception to February 1, 2019. Primary research manuscripts were screened for those related to adult human subjects exposed to ionizing radiation using the chronotherapy technique. Nine manuscripts were included in the review from 79 eligible articles. Three were prospective randomized trails and 6 were retrospective reviews. This survey revealed that overall survival and tumor control do not have consistent effects with only 60% and 55.5% of paper which included the variables having some significance, respectively. Treatment symptoms were the primary endpoint for both the prospective trials and were examined in 3 of the retrospective reviews; effects were observed in sensitive tissue for all 5 studies including mucosal linings and skin basal layer. Existing literature suggests that the application of radiation chronotherapy may reduce negative symptom outcome within highly proliferative tissues. Further examination of radiation chronotherapy in well-designed prospective trials and studies in brain tumor patients are merited.


Alport syndrome and pregnancy: Good obstetric and nephrological outcomes in a pregnant woman with homozygous autosomal recessive Alport syndrome.
We describe the course of pregnancy in a 27-year-old woman with homozygous autosomal recessive Alport syndrome. Genetic analysis revealed a homozygous COL4A4 mutation in exon 36 (c.3307G > A) with p.G1102R inherited from her parents (who were parallel cousins) 1 year before conception. Before pregnancy, the patient's renal function and blood pressure were normal, and her urinary protein excretion was below 2 g/day. The pregnancy course was uneventful in the first and second trimesters. She was detected to have nephrotic-range proteinuria during the third trimester, but was observed closely on an outpatient basis without any medications, as her general condition was good, her renal function and blood pressure remained stable, and the fetal well-being was maintained. At 39(+0) weeks of pregnancy, she vaginally gave birth to an appropriate-birthweight infant and her urinary protein excretion returned to pre-pregnancy level. This is the first report of pregnancy in a patient with autosomal recessive Alport syndrome with good obstetric and nephrological outcomes in the absence of any treatment or hospitalization.


Assessment of vergence facility in a sample of older adults with presbyopia.
The aim of this study was to establish whether assessment of vergence facility is clinically useful in older adults with presbyopia and to determine pilot normative data for this age range. Vergence facility was measured in a sample of 50 asymptomatic subjects with a mean age of 58.7 years using 8delta base-in (BI) and 12delta base-out (BO) prisms mounted in clinical flipper frames. Testing was performed for 1 min on four separate occasions over the course of a few weeks. Of the 42 subjects that completed the study, vergence facility could be satisfactorily measured on only 21 subjects. The mean vergence facility for this group was approximately 7 cycles per minute (cpm), commensurate with previous results in younger subjects using a similar paradigm. There were no differences in vergence facility between the first and second 30-s periods of testing, nor were there any differences in average vergence facility over the 4 test occasions. Test-retest repeatability, however, was poor. The BI prism phase took longer, on average, to fuse than the BO prism phase (BI 5.2 s and BO 3.7 s). Our results show a high degree of variability in vergence facility in older subjects with presbyopia. More research is required before deciding whether measurements of vergence facility are of use in investigating binocular vision of older patients with presbyopia.


Prognostic Impact of Histologic Grade for Papillary Thyroid Carcinoma.
While numerous factors affect prognosis in papillary thyroid carcinoma (PTC), the comparative impact of histologic grade has not been well described. Moreover, indications for external beam radiation therapy (EBRT) remain imprecise. We evaluate clinicopathologic characteristics and outcomes for PTC stratified by grade. We profiled histologic grade for PTC (well differentiated, moderately differentiated, poorly differentiated) via hospital (National Cancer Database) and population-based (Surveillance, Epidemiology, and End Results) registries. Cox regression was used to adjust for clinicopathologic covariates. Statistical interactions between subtypes and the effect of EBRT on survival were assessed. Collectively, worsening clinicopathologic factors (age, tumor size, extrathyroidal extension, nodal spread, M1 disease) and outcomes (disease-free survival, overall survival) correlated with less differentiated state, across all histologic grades (p < 0.001). Multivariable analysis showed escalating hazard with loss of differentiation relative to well-differentiated PTC (moderately differentiated hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.04-1.41, p = 0.02; poorly differentiated HR 2.62, 95% CI 2.23-3.08, p < 0.001). Correspondingly, greater survival benefit was associated with EBRT for poorly differentiated cases (HR 0.36, 95% CI 0.18-0.72, p = 0.004). This finding was upheld after landmark analysis to address potential immortal time bias (HR 0.37, 95% CI 0.17-0.80, p = 0.01). Worsening histologic grade in PTC is independently associated with parallel escalation in mortality risk, on a scale approximating or surpassing established thyroid cancer risk factors. On preliminary analysis, EBRT was associated with improved survival in the most aggressive or least differentiated subvariants. Further investigation is warranted to examine the efficacy of EBRT for select poorly differentiated thyroid carcinomas.


The management of cardiac surgical patients in a general surgical recovery ward.
A suitable combination of anaesthetic and surgical techniques has allowed the safe management of post-operative cardiac surgical patients to be conducted in a surgical recovery area rather than in the intensive care ward. The results of the first 103 patients so managed (aged 49 +/- 10.7 years) are presented. Coronary artery bypass grafts were performed on 98 patients, 4 patients underwent repair of atrial septal defect and on 1 patient a pulmonary valvotomy was performed. The complications and their management are described.


[The Road to Discovery of the Pulmonary Gas Exchange - From the "Phlogiston-" to the "Oxygen Theory"].
The discovery of oxygen and pulmonary gas exchange was a major advancement in our understanding of breathing. For centuries it was believed that the lungs were primarily necessary to cool the heart or to "refine" the blood. Richard Lower (1631-1691) observed that the blood had a different colour before and after passage through the lung. His assumption was that breathing must have been added a special substance to the blood. Georg Ernst Stahl (1660-1734) formulated a fire substance "phlogiston" (phlox = flame) with his phlogiston theory. He postulated that phlogiston is contained in all combustible substances and escapes when burned. John Mayow (1641-1679) recognised that about one fifth of the breathing gas is important for the breathing process. He called the gas "spiritus nitro aerius". Oxygen was first discovered in the early 1770 s by the Swedish-German pharmacist Carl Wilhelm Scheele (1742-1786) and the English chemist Joseph Priestley (1733-1804) - independently of each other. Antoine-Laurent Lavoisier (1743-1794) recognised oxygen as element and for the first time described the oxidation process accurately.


The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus.
GTPases of the Rho family are transducers of extracellular signals and control cellular processes such as organization of the actin cytoskeleton, motility, adhesion and gene regulation. The Rho signalling pathway is activated, for example, by bioactive sphingolipids such as sphingosine-1-phosphate (SPP) or by overexpression of Rho family members in tumorigenesis and metastases. Here, we show that stimulation of the Rho signalling pathway induces translocation of the transcriptional LIM-only coactivator FHL2 to the nucleus and subsequent activation of FHL2- and androgen receptor-dependent genes. Interestingly, prostate tumours overexpress Rho GTPases and display altered cellular localization of FHL2 concomitant with tumour dedifferentiation. SPP-induced FHL2 activation is mediated by Rho GTPases, but not by the GTPases Cdc42, Rac1 or Ras, and depends on Rho-kinase. In addition, Rho signalling influences other transcriptional coactivators, thus pointing to a general regulatory role for Rho GTPases in cofactor function. In summary, our data propose a yet undescribed signalling pathway in which the coactivator FHL2 acts as a novel molecular transmitter of the Rho signalling pathway, thereby integrating extracellular cues into altered gene expression.