Initially untreated fasting hyperglycaemia in early pregnancy: prognosis according to occurrence of gestational diabetes mellitus after 22 weeks' gestation: a case-control study.
To evaluate the percentage of women with untreated fasting hyperglycaemia in early pregnancy who develop gestational diabetes mellitus after 22 weeks' gestation, the determinants of gestational diabetes development in such women and the prognosis of early fasting hyperglycaemia according to whether the women go on to develop gestational diabetes. From a large cohort of women who delivered in our hospital between 2012 and 2016, we retrospectively selected all those who had untreated early fasting hyperglycaemia and separated them into a 'gestational diabetes' and a 'no-gestational diabetes' group according to oral glucose tolerance test results after 22 weeks' gestation. We compared the incidence of a predefined composite outcome (preeclampsia or large-for-gestational-age infant or shoulder dystocia or neonatal hypoglycaemia) in both groups. A total of 268 women (mean fasting plasma glucose 5.3 ± 0.3 mmol/l at a mean ± sd of 10.2 ± 4.2 weeks' gestation) were included. Gestational diabetes developed in 134 women and was independently associated with early fasting plasma glucose ≥ 5.5 mmol/l [odds ratio 3.16 (95% CI 1.57, 6.33)], age ≥ 30 years [odds ratio 2.78 (95% CI 1.46, 5.31)], preconception obesity [odds ratio 2.12 (95% CI 1.11, 4.02)], family history of diabetes [odds ratio 1.87 (95% CI 1.00, 3.50)] and current employment [odds ratio 0.46 (95% CI 0.26, 0.83)]. Despite treatment, gestational diabetes induced a significant increase in the composite outcome as compared to no gestational diabetes (odds ratio 2.16 [95% CI 1.08, 4.34]). The association disappeared after adjustment for risk factors. Only half of the women with early fasting hyperglycaemia and no specific care subsequently developed gestational diabetes, and these women had a poor prognosis despite gestational diabetes treatment. Poor prognosis was mostly attributable to risk factors. Our results suggest that only women with certain risk factors should be screened for early fasting hyperglycaemia.


SWI/SNF- and RSC-catalyzed nucleosome mobilization requires internal DNA loop translocation within nucleosomes.
The multisubunit SWI/SNF and RSC complexes utilize energy derived from ATP hydrolysis to mobilize nucleosomes and render the DNA accessible for various nuclear processes. Here we test the idea that remodeling involves intermediates with mobile DNA bulges or loops within the nucleosome by cross-linking the H2A N- or C-terminal tails together to generate protein "loops" that constrict separation of the DNA from the histone surface. Analyses indicate that this intranucleosomal cross-linking causes little or no change in remodeling-dependent exposure of DNA sequences within the nucleosome to restriction enzymes. However, cross-linking inhibits nucleosome mobilization and blocks complete movement of nucleosomes to extreme end positions on the DNA fragments. These results are consistent with evidence that nucleosome remodeling involves intermediates with DNA loops on the nucleosome surface but indicate that such loops do not freely diffuse about the surface of the histone octamer. We propose a threading model for movement of DNA loops around the perimeter of the nucleosome core.


Expression analysis of PIN family genes in Chinese hickory reveals their potential roles during grafting and salt stress.
Grafting is an effective way to improve Chinese hickory while salt stress has caused great damage to the Chinese hickory industry. Grafting and salt stress have been regarded as the main abiotic stress types for Chinese hickory. However, how Chinese hickory responds to grafting and salt stress is less studied. Auxin has been proved to play an essential role in the stress response through its re-distribution regulation mediated by polar auxin transporters, including PIN-formed (PIN) proteins. In this study, the PIN gene family in Chinese hickory (CcPINs) was identified and structurally characterized for the first time. The expression profiles of the genes in response to grafting and salt stress were determined. A total of 11 CcPINs with the open reading frames (ORFs) of 1,026-1,983 bp were identified. Transient transformation in tobacco leaves demonstrated that CcPIN1a, CcPIN3, and CcPIN4 were localized in the plasma membrane. There were varying phylogenetic relationships between CcPINs and homologous genes in different species, but the closest relationships were with those in Carya illinoinensis and Juglans regia. Conserved N- and C-terminal transmembrane regions as well as sites controlling the functions of CcPINs were detected in CcPINs. Five types of cis-acting elements, including hormone- and stress-responsive elements, were detected on the promoters of CcPINs. CcPINs exhibited different expression profiles in different tissues, indicating their varied roles during growth and development. The 11 CcPINs responded differently to grafting and salt stress treatment. CcPIN1a might be involved in the regulation of the grafting process, while CcPIN1a and CcPIN8a were related to the regulation of salt stress in Chinese hickory. Our results will lay the foundation for understanding the potential regulatory functions of CcPIN genes during grafting and under salt stress treatment in Chinese hickory.


Bile cast nephropathy due to cholestatic jaundice after using stanozolol in 2 amateur bodybuilders.
Elevated level of bile can cause bile cast nephropathy, which can be seen in patients with severe cholestatic liver disease. Stanozolol is a C17α-alkylation steroid derived from dihydrotestosterone and its major adverse effect is cholestatic jaundice. We report 2 bodybuilders who received stanozolol for 6 weeks and developed icterus. Serum total bilirubin was around 50 mg/dL. Liver biopsy showed intrahepatic cholestasis. In spite of fluid and albumin therapy, serum creatinine increased and the patients experienced oliguria. Urine sediment showed granular cast and normal erythrocyte count. Protein excretion in 24-hour urine was less than 1000 mg in both patients. Hemodialysis was started on and renal biopsy revealed acute tubular epithelial cell damage along with bile pigment (cast) deposition, compatible with bile cast-related nephropathy. Serum bilirubin decreased gradually and urine output increased. Serum creatinine was around 1.5 mg/dL in both of the patients 2 months after discharge.


Concomitant trocar-guided transvaginal mesh surgery with a midurethral sling in treating advanced pelvic organ prolapse associated with stress or occult stress urinary incontinence.
The purpose of this study was to evaluate the efficacy and feasibility of concomitant trocar-guided transvaginal mesh (TVM) surgery with a midurethral sling (MUS) for treating women with advanced pelvic organ prolapse (POP) and stress urinary incontinence (SUI) or occult SUI (OSUI). Eighty-nine women with advanced POP and SUI or OSUI were retrospectively enrolled. The Total Prolift and Tension-free Vaginal Tape-Obturator Systems were used for trocar-guided TVM surgery and MUS. Patients received regular follow-up at 1 week, and 1 month, 3 months, 6 months, and 12 months postoperatively, and then annually thereafter. The endpoints were the success rate for POP, and perioperative and postoperative complications. Functional outcomes were the presence of voiding difficulty, persistent or de novo overactive bladder symptoms, postoperative SUI, and paresthesia. The median follow-up period was 35 months (range, 12-50 months). Within the follow-up period, 84 patients (94.4%) were objectively cured, five patients (5.6%) had vaginal apical mesh exposure, 29 individuals (32.6%) had persistent or de novo overactive bladder symptoms, six individuals (22.5%) had de novo SUI (two were found by urodynamics), and nine individuals (10.1%) had voiding difficulties (two were found by urodynamics). In addition, the vaginal hysterectomy group had greater blood loss, longer operation times, and a higher mesh erosion rate compared to the uterine suspension group. Concomitant trocar-guided TVM surgery and MUS with the use of total Prolift and Tension-free Vaginal Tape-Obturator offer good efficacy in treating women with advanced POP and SUI or OSUI. The vaginal hysterectomy group had more perioperative complications.


Three brain sodium channel alpha-subunit genes are clustered on the proximal segment of mouse chromosome 2.
We have used long-range physical mapping and restriction fragment length polymorphisms between two mouse species to determine the chromosomal organization and location of the genes encoding three distinct isoforms of the alpha-subunit of the brain sodium channel. Physical mapping by pulsed-field gel electrophoresis has established that Scn2a and Scn3a (genes encoding type II and type III sodium channel alpha-subunit isoforms) are physically linked and are separated by a maximum distance of 600 kb. The segregation of restriction fragment length variations in backcross progeny of a Mus musculus and Mus spretus mating indicates that Scn 1 a (gene encoding the type I sodium channel alpha subunit) and Scn2a are tightly linked and are separated by a distance of 0.7 cM. Linkage analysis in backcross and recombinant inbred (BXD and AKXD) strains of mice localized the three sodium channel genes to the proximal segment of mouse chromosome 2 and suggested the probable gene order centromere-Hc-Neb-Pmv7-Scn2a/Scn3a-Scn1a-Mpmv 14. These results indicate that the three isoforms of the brain sodium channel alpha-subunit are encoded by three distinct genes that share a common ancestral origin.


The +276 polymorphism of the APM1 gene, plasma adiponectin concentration, and cardiovascular risk in diabetic men.
Recently, the genetic variability at adiponectin locus (APM1) was associated with cardiovascular risk in patients with type 2 diabetes. We sought to examine the associations of five variants of APM1 gene (C-11365G, A-4034C, A-3964G, T45G, and G276T) with the risk of cardiovascular diseases (CVDs) in a larger cohort of diabetic patients. Of 879 diabetic men from the Health Professionals Follow-up Study, 239 participants developed coronary heart disease or stroke during 14 years of follow-up and 640 CVD-negative subjects were used as control subjects. The risk of CVD was significantly lower in TT homozygotes at locus +276 than in other genotypes under a recessive inheritance model after adjusting for age, BMI, smoking, alcohol consumption, physical activity, aspirin use, HbA1c, and history of hypertension or hypercholesterolemia (odds ratio 0.38 [95% CI 0.18-0.79]; P = 0.009). In the CVD-negative control subjects, the allele 276T was associated with significantly higher plasma adiponectin levels in a dose-dependent pattern (GG 14.8, GT 16.2, and TT 18.8 microg/ml) after adjusting for age, BMI, and other variables (P for trend = 0.0019). In conclusion, our study showed significant associations between APM1 G276T and decreased CVD risk and increased plasma adiponectin levels in diabetic men.


Enhanced perioperative management of children with autism: a pilot study.
When children with autism spectrum disorder (ASD) are in hospital, difficulties with socialization, communication, and behaviour can be exacerbated. The purpose of this study was to establish feasibility of an enhanced perioperative care pathway. Utilizing parental and provider feedback, a protocol including environment modification, anxiolysis plans, specialized order sets, and child life specialist (CLS) support was developed over a nine-month period. Autism severity scores (ASS), communication styles, triggers, and previous experiences were used to create individualized care plans in the preoperative clinic. Emotion and sedation scores in the same day surgery unit, at anesthesia induction, and in the postanesthesia care unit were recorded. Acceptance was obtained from nurses, anesthesiologists, and parents. Feasibility criteria included the recruitment rate, adherence to protocol, data collection, and patient follow-up. Eighteen patients were enrolled in this pilot study. All feasibility criteria including recruitment, adherence to study protocol (97%), and follow-up (94%) were met. Fifteen (83%) patients were nonverbal and minimally interactive (ASS = 3). Common triggers were loud noises (78%), crowds (78%), and bright lights (56%). After implementation of the protocol, 15 (83%) of the anesthetic inductions were described as excellent. Ten different premedication plans were used. Parents described the personalized plan, anxiolysis medication, and CLS support as advantageous. All (100%) nurses, anesthesiologists, and parents felt the program should continue. We showed that a multidisciplinary perioperative care plan for children with severe ASD was feasible and 100% accepted at our institution. The individual nature of anxiolysis plans was considered a strength of the protocol.


Androgen receptor expression in circulating tumour cells from castration-resistant prostate cancer patients treated with novel endocrine agents.
Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated nuclear AR expression in CTCs in patients treated with enzalutamide and abiraterone. CTCs were captured and characterised using the CellSearch system. An automated algorithm to identify CTCs and quantify AR expression was employed. The primary aim was to evaluate the association between CTC AR expression and prior treatment with abiraterone or enzalutamide. AR expression in CTCs was evaluated in 94 samples from 48 metastatic CRPC patients. We observed large intra-patient heterogeneity of AR expression in CTCs. Prior exposure to abiraterone or enzalutamide was not associated with a change in CTCs AR expression (median intensity and distribution of AR-positive classes). In support of this, we also confirmed maintained nuclear AR expression in tissue samples collected after progression on abiraterone. AR staining also identified additional AR-positive CD45-negative circulating cells that were CK-negative/weak and therefore missed using standard protocols. The number of these events correlated with traditional CTCs and was associated with worse outcome on univariate analysis. We developed a non-invasive method to monitor AR nuclear expression in CTCs. Our studies confirm nuclear AR expression in CRPC patients progressing on novel endocrine treatments. Owing to the significant heterogeneity of AR expression in CTCs, studies in larger cohorts of patients are required to identify associations with outcome.


Deficiency of cytomegalovirus (CMV)-specific CD8+ T cells in patients presenting with late-onset CMV disease several years after transplantation.
Cytomegalovirus (CMV) is a major cause of morbidity and mortality among transplant recipients. The routine use of anti-CMV prophylaxis has modified the epidemiology of post-transplant CMV infection by delaying the onset of clinical disease. While the majority of delayed-onset CMV disease still occurs during the first year after transplant, reports of late-onset CMV disease presenting many years after transplantation are increasing. Here, we describe 2 CMV-seropositive transplant recipients who presented with late-onset CMV disease at 8 and 11 years after transplantation. To determine whether CMV disease occurring at a very late period after transplantation is related to immune competence, we assessed global and CMV-specific cellular immunity by evaluating the activation capability of CD8+ T cells to a mitogenic stimulus and by quantitative and functional analysis (as assessed by intracellular cytokine production and degranulation) of CMV-specific CD8+ T cells. In both patients, we demonstrated the absence or marked deficiency of CMV-specific T-cell immunity despite CMV seropositivity, and in one patient, a partial defect in the immune response to phorbol myristate acetate and ionomycin suggesting impaired global immune competence. Hence, our data suggest that late-onset CMV disease occurring many years after transplantation remains related to defects in the immune competence of patients. Measurement of CMV-specific cellular immune competence may therefore provide an additional tool to screen for patients at high risk of developing late-onset CMV disease. The clinical utility of this assay, however, will need to be evaluated in larger prospective studies.


Parental loss in childhood: relationship to adult psychiatric impairment and contact with psychiatric services.
Both parental death in childhood and parent-child separations (from causes other than death) were assessed in a community survey of psychiatric disorder and in an equivalent sample of psychiatric outpatients from the same community. Symptomatic disorder (psychiatric caseness) and psychiatric illness behavior (patient status) were examined. Symptomatic disorder was defined by comparing community (unreferred) cases with noncases. Illness behavior was specified by comparing the psychiatric outpatients with the community cases. Parental death in childhood bore no relation to either symptomatic disorder in the community sample (psychiatric caseness) or to psychiatric illness behavior (patient status) in adult life. Parent-child separations similarly had no relation to adult symptomatic disorder but were significantly associated with psychiatric illness behavior.


Participation of the Halogens in Photochemical Reactions in Natural and Treated Waters.
Halide ions are ubiquitous in natural waters and wastewaters. Halogens play an important and complex role in environmental photochemical processes and in reactions taking place during photochemical water treatment. While inert to solar wavelengths, halides can be converted into radical and non-radical reactive halogen species (RHS) by sensitized photolysis and by reactions with secondary reactive oxygen species (ROS) produced through sunlight-initiated reactions in water and atmospheric aerosols, such as hydroxyl radical, ozone, and nitrate radical. In photochemical advanced oxidation processes for water treatment, RHS can be generated by UV photolysis and by reactions of halides with hydroxyl radicals, sulfate radicals, ozone, and other ROS. RHS are reactive toward organic compounds, and some reactions lead to incorporation of halogen into byproducts. Recent studies indicate that halides, or the RHS derived from them, affect the concentrations of photogenerated reactive oxygen species (ROS) and other reactive species; influence the photobleaching of dissolved natural organic matter (DOM); alter the rates and products of pollutant transformations; lead to covalent incorporation of halogen into small natural molecules, DOM, and pollutants; and give rise to certain halogen oxides of concern as water contaminants. The complex and colorful chemistry of halogen in waters will be summarized in detail and the implications of this chemistry for global biogeochemical cycling of halogen, contaminant fate in natural waters, and water purification technologies will be discussed.


Neurocognitive outcome and ventricular volume in children with myelomeningocele treated for hydrocephalus in Uganda.
Despite lower failure and infection rates compared with shunt placement, it has not been known whether endoscopic third ventriculostomy/choroid plexus cauterization (ETV/CPC) might be inferior in regard to neurocognitive development. This study is the first to describe neurocognitive outcome and ventricle volume in infants with hydrocephalus due to myelomeningocele that was treated primarily by ETV/CPC. The modified Bayley Scales of Infant Development (BSID-III) test was administered to 93 children with spina bifida who were 5-52 months of age. Fifty-five of these children had been treated by ETV/CPC, 19 received ventriculoperitoneal (VP) shunts, and 19 had required no treatment for hydrocephalus. Raw scores were converted to scaled scores for comparison with age-corrected norms. Ventricular volume was assessed by frontal/occipital horn ratio (FOR) calculated from late postoperative CT scans. The mean values between and among groups of patients were compared using independent samples t-test and ANOVA. The comparison of mean values to population normal means was performed using the single-sample t-test. Linear regression analyses were performed using BSID scores as the dependent variables, with treatment group and ventricular size (FOR) as the independent variables. Probability values < 0.05 were considered significant. There was no significant difference in mean age at assessment among groups (p = 0.8). The mean scale scores for untreated patients were no different from normal (all p > 0.27) in all portions of the BSID (excluding gross motor), and were generally significantly better than those for both VP shunt-treated and ETV/CPC groups. The ETV/ CPC-treated patients had nonsignificantly better mean scores than patients treated with VP shunts in all portions of the BSID (all p > 0.06), except receptive communication, which was significantly better for the ETV/CPC group (p = 0.02). The mean FOR was similar among groups, with no significant difference between the untreated group and either the VP shunt or ETV/CPC groups. The FOR did not correlate with performance. The ETV/CPC and VP shunt groups had similar neurocognitive outcomes. Neurocognitive outcomes for infants not requiring treatment for hydrocephalus were normal and significantly better than in those requiring treatment. The mean ventricular volume was similar among all 3 groups, and significantly larger than normal. There was no association between FOR and performance. Stable mild-to-moderate ventriculomegaly alone should not trigger intervention in asymptomatic infants with spina bifida.


Extent of ossification at the amputation plane is correlated with the decline of blastema formation and regeneration in Xenopus laevis hindlimbs.
Xenopus laevis larvae gradually lose the ability to regenerate lost hindlimb structures as they progress through metamorphosis. Previous studies have suggested that this loss of regenerative capacity occurs in a proximal-to-distal fashion. We assessed the quality of overall regeneration and early bud blastema formation in order to evaluate previous explanations for this loss of regenerative ability in Xenopus. We further examined the extent to which epidermis, basement membrane, dermis, cartilage, bone, periosteum, and accumulated mesenchyme within the blastema are involved in the decline of regenerative abilities during mid-metamorphic stages of development. Each tissue was scored based on its contributions to the regeneration blastema, in accordance with previously reported blastemal descriptions. Tadpoles amputated at the ankle and tarsal-metatarsal joints scored objectively higher within the overall regeneration and blastema quality rating systems. Both joint sites met more criteria associated with regeneration-capable blastemas than tadpoles amputated through the middle of the tarsus, especially at later stages of metamorphosis. The three amputation sites studied began to vary in their ability to regenerate skeletal elements and to generate productive blastemas during the same stages at which we initially observed ossification of the tarsus. These results suggest that the decline of Xenopus hindlimb regeneration does not occur in a strictly proximal-to-distal fashion but rather is dependent at later stages on the state of ossification of the structure through which amputation occurs. Our morphological and cellular observations reveal specific times and places during Xenopus hindlimb development at which further investigations into tissue-specific molecular events during early regeneration should be focused.


Cl-/HCO-3 antiporter in red cell ghosts: a kinetic assessment with fluorescent probes.
The pH sensitive fluorescent probe acridine orange and membrane potential-sensitive fluorescent probe acridine orange and membrane potential-sensitive fluorescent probe 3,3'-dipropylthiadicarbocyanine iodide were used to evaluate the Cl-/HCO-3 antiporter and proton and potassium conductances, respectively, in human red blood cell ghosts. Acidic, chloride-loaded ghosts alkalinized rapidly in pH 8.5 chloride-free media. Alkalinization could not be ascribed to conductive proton efflux with either depolarizing potassium influx or chloride efflux. Alkalinization was consequent to flux on the Cl-/HCO-3 antiporter: this process displayed saturation kinetics, competitive inhibition by external chloride, and inhibition by 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid. The mean Kms for internal chloride, external bicarbonate, and external chloride were 2.19, 0.24, and 0.44 mM, respectively. These studies confirm both the asymmetry of this carrier and the high affinity for external HCO-3; however, the affinities for internal and external chloride are significantly greater than prior estimates. The Km for internal chloride (2.19 mM) was considerably lower than levels previously reported (20-65 mM) unless external (trans) chloride was raised above 2 mM. The present studies thus demonstrate and emphasize the critical importance of trans substrate concentration in assessing the kinetics of a carrier whose mobility is faster in the loaded than in the unloaded state.


Adaptive clinical trial design.
In recent years, the use of adaptive design methods in clinical trials based on accumulated data at interim has received much attention because of its flexibility and efficiency in pharmaceutical/clinical development. In practice, adaptive design may provide the investigators a second chance to modify or redesign the trial while the study is still ongoing. However, it is a concern that a shift in target patient population may occur after significant adaptations are made. In addition, the overall type I error rate may not be preserved. Moreover, the results may not be reliable and hence are difficult to interpret. As indicated by the US Food and Drug Administration draft guidance on adaptive design clinical trials, the adaptive design has to be a prospectively planned opportunity and should be based on information collected within the study, with or without formal statistical hypothesis testing. This article reviews the relative advantages, limitations, and feasibility of commonly considered adaptive designs in clinical trials. Statistical concerns when implementing adaptive designs are also discussed.


The Expression of Epac2 and GluA3 in an Alzheimer's Disease Experimental Model and Postmortem Patient Samples.
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by amyloid beta (Aβ) and hyperphosphorylated tau accumulation in the brain. Recent studies indicated that memory retrieval, rather than memory formation, was impaired in the early stage of AD. Our previous study reported that pharmacological activation of hippocampal Epac2 promoted memory retrieval in C57BL/6J mice. A recent study suggested that pharmacological inhibition of Epac2 prevented synaptic potentiation mediated by GluA3-containing AMPARs. In this study, we aimed to investigate proteins associated with Epac2-mediated memory in hippocampal postmortem samples of AD patients and healthy controls compared with the experimental AD model J20 and wild-type mice. Epac2 and phospho-Akt were downregulated in AD patients and J20 mice, while Epac1 and phospho-ERK1/2 were not altered. GluA3 was reduced in J20 mice and tended to decrease in AD patients. PSD95 tended to decrease in AD patients and J20. Interestingly, AKAP5 was increased in AD patients but not in J20 mice, implicating its role in tau phosphorylation. Our study points to the downregulation of hippocampal expression of proteins associated with Epac2 in AD.


Hyperintense basal ganglia on T1-weighted MR images in a patient with central nervous system lupus and chorea.
We describe a patient with central nervous system lupus and choreatic movements in whom both basal ganglia showed high signal intensity on T1-weighted MR images, while the signal on T2-weighted images remained low. Within 8 months after onset, the choreatic movements had disappeared, with a corresponding decrease in the hyperintense T1 signal. The emergence of the choreatic movement disorder in this patient might have been related to the T1 hyperintensity of the basal ganglia, which, in turn, might have resulted from a vascular insult associated with central nervous system lupus.


ACE inhibitor angioedema: characterization and treatment versus non-ACE angioedema in acute hospitalized patients.
Background: ACE angioedema has not been characterized in comparison with angioedema from other causes in acute hospitalized patients. Methods: We retrospectively compared ACE-angioedema and non-ACE angioedema patients from January 2013 to May 2017. Results: Of 855 cases screened, 575 met the inclusion criteria of angioedema diagnosis and an electronic medical record. Of these, 297 (51.7%) had ACE angioedema and 278 had angioedema from other causes, of these 31 who were taking an ACE inhibitor that was not considered to be the cause of angioedema (ACE other cause). At least 80% of cases in all groups were African American. Epinephrine was prescribed in 21% of ACE angioedema cases. One-third of patients in all groups were admitted to the ICU, and about 25% required intubation. Previous history of ACE inhibitor-induced angioedema was found in 63 of 278 non-ACE cause angioedema patients (23%) and in 23 (8%) in the ACE cause group. Conclusion: ACE angioedema was the cause of half of angioedema admissions over a 4.5-year period. Mortality, morbidity, and treatment did not differ between the groups. Patients on ACE inhibitors were often treated with medications known not to be effective for ACE angioedema. Over one-fourth of patients not taking an ACE inhibitor had a previous history of ACE angioedema, and 31 patients taking ACE inhibitors were diagnosed with non-ACE angioedema. Regardless of the etiology of angioedema, 25% of patients required airway protection in the form of intubation.


Depression and the older medical patient--when and how to intervene.
Depression in the elderly, particularly those with chronic physical health problems, is a common, but complex problem. In this paper we review the research literature on both the epidemiology and management of depression in the older medical patient. After a general overview of depression in the elderly, we discuss some of the particular issues relevant to depression and co-morbid physical illness amongst elderly patients. Depression can be difficult to diagnose in medically unwell older adults, particularly when there is substantial overlap in symptomatology. The epidemiology and evidence base for the treatment of depression in a number of chronic health problems common in an older adults population are then discussed, specifically cardiac disease, cerebrovascular disease, cancer, chronic kidney disease, chronic obstructive pulmonary disease, and Parkinson's disease. For many of these conditions there is emerging evidence that treatments can be effective in reducing depressive symptoms. However, these potential benefits need to be balanced against the often-increased risk of adverse events or interactions with medical treatments. Although co-morbid depression is consistently associated with poorer medical outcomes, there is limited evidence that standard anti-depressive therapy has additional benefits in terms of physical health outcomes. Collaborative care models appear particularly well suited to medically unwell older adult patients, and may provide more generalised benefits across both mental and physical health measures.


Nutritional models of the developmental programming of adult health and disease.
The ability to not only replicate but also extend the findings from both historical epidemiological studies and contemporary cohorts of the developmental programming of later disease are critical if the mechanisms by which early diet impacts on later disease are to be fully understood. To date, a plethora of models have been established, with the range including global changes in dietary input, imbalanced diets and diets deficient in single nutrients. Key factors in translating these findings to the human situation are the pronounced differences in the relative growth and development between large and small mammals from the time of conception through pregnancy, lactation and weaning. This disparity is reflected in the very different nutritional requirements between species and the substantial divergence between rodents and large animals in the ontogeny of many of the organ systems that are nutritionally regulated. For example, hypothalamic circuitry is much more developed in species with a long gestation and offspring are born with a mature hypothalamic-pituitary axis in sheep and man compared with mice and rats. Similarly, nephron number is established towards the end of gestation in large mammals compared with the lactational period in rats. These types of differences will impact on the ability of individual and combined nutritional interventions to reset developmental processes, and may be further compounded by the gender of a fetus. The challenge for future work in this exciting and dynamic area of research is to utilise these marked comparative differences to generate imaginative nutritional interventions in order to improve the viability, health and well-being of the offspring.


Short-term heart rate variability in a population-based sample of 10-year-old children.
Heart rate variability (HRV) is a non-invasive quantitative marker of cardiac autonomic function derived from continuous electrocardiogram (ECG) recordings. Normative HRV values and development factors have not been established in pediatric populations. The objective was to derive referent time- and frequency-domain HRV values for a population-based sample of children. Children aged 9-11 years (N = 1,036) participated in the Québec Longitudinal Study of Child Development cohort cardiovascular health screening. Registered nurses measured anthropometrics (height, weight) and children wore an ambulatory Holter monitor to continuously record an ECG signal. HRV variables included time (SDNN, pNN50, RMSSD, SDANN) and frequency (HF, LF, LF/HF ratio) domain variables. Normative HRV values, stratified by age, sex, and heart rate, are presented. Greater heart rate (β avg = -0.60, R avg (2) = 0.39), pubertal maturation (β avg = -0.11, R avg (2) = 0.01), later ECG recording times (β avg = -0.19, R avg (2) = 0.07), and higher diastolic blood pressure (β avg = -0.11, R avg (2) = 0.01) were significantly associated with reduced HRV in 10-year-old children. The normative HRV values permit clinicians to monitor, describe, and establish pediatric nosologies in primary care and research settings, which may improve treatment of diseases associated with HRV in children. By better understanding existing values, the practical applicability of HRV among clinicians will be enhanced. Lastly, developmental (e.g., puberty) and procedural (e.g., recording time) factors were identified that will improve recording procedures and interpretation of results.


The ABA392/pET30a protein of Pasteurella multocida provoked mucosal immunity against HS disease in a rat model.
Haemorrhagic septicaemia (HS) is a well-known high fatality septicaemic disease happening among bovines. The disease is caused by the Pasteurella multocida serotype B:2 bacteria. P. multocida B:2 has high mortality and morbidity rates and is spread through the intranasal and oral routes in bovines. In this study, our aim was to investigate the efficacy of the recombinant protein vaccine, ABA392/pET30a via intranasal inoculation by targeting the mucosal immunity. The constructed recombinant protein vaccine ABA392/pET30a was subjected to an animal study using Sprague Dawley rats. The study was divided into two parts: active and passive immunization studies. Both studies were carried out through the determination of immunogenicity (using Total White Blood Cell (TWBC) Count with Indirect ELISA) and histopathogenicity, analyzing (Bronchus Associated Lymphoid Tissue (BALT) formation) in lungs. As a result, the IgA and IgG development of both tested groups: group 1 (50μg/mL protein vaccine) and group 2 (100μg/mL protein vaccine) showed equivalent with the positive control group 4 (formalin-killed P. multocida B:2). However, there was a significant difference when compared with the negative control group 3 (normal saline). These results demonstrate that both the protein vaccine at the concentration 50μg/mL and 100μg/mL have the same efficacy as the commercially available positive control vaccine. From the studies, higher concentration of protein vaccine at 100μg/mL showed higher development of both IgA and IgG compared to 50μg/mL protein vaccine. Higher and rapid development of IgA compared to IgG showed that mucosal immunity has been induced through the intranasal administration of the protein vaccine. In addition, leucocytosis was observed at each dose of vaccination showed that the protein vaccine is capable to induce the immune responses of the host. Histopathogenicity studies of the vaccinated groups showed more BALT formation and no severe lesions after challenge compared to the negative control group. Besides, no inflammatory onsite or anaphylactic responses were observed after the intranasal inoculation which proved to be safer and provided longer lasting immunity. Therefore, recombinant protein vaccine ABA392/pET30a could be a potential candidate for intranasal administration which can provoke mucosal immunity against HS disease.


Long-term antidepressant efficacy and safety of olanzapine/fluoxetine combination: a 76-week open-label study.
The olanzapine/fluoxetine combination has demonstrated effectiveness in treatment-resistant depression (TRD). Although this combination is being used by prescribers, this is the first study to examine long-term use. Long-term efficacy and safety were therefore investigated in a group of patients with major depressive disorder (MDD) with and without TRD. 560 patients who met DSM-IV diagnostic criteria for MDD were enrolled in this 76-week, open-label study (Feb. 2000-July 2002). The Montgomery-Asberg Depression Rating Scale (MADRS) total score was the primary efficacy measure. Safety was assessed via adverse events, vital signs, laboratory analytes, electrocardiography, and extrapyramidal symptom measures. MADRS mean total scores decreased 7 points from baseline (31.6 [N = 552]) at 1/2 week of treatment, 11 points at 1 week of treatment, and 18 points at 8 weeks of treatment. This effect was maintained to endpoint with a mean decrease of 22 points at 76 weeks. Response and remission rates for the total sample were high (62% and 56%, respectively), and the relapse rate was low (15%). Response, remission, and relapse rates for TRD patients (N = 145) were 53%, 44%, and 25%, respectively. The most frequently reported adverse events were somnolence, weight gain, dry mouth, increased appetite, and headache. At endpoint, there were no clinically meaningful changes in vital signs, laboratory analytes, or electrocardiography. There were no significant increases on any measure of extrapyramidal symptoms. The olanzapine/fluoxetine combination showed rapid, robust, and sustained improvement in depressive symptoms in patients with MDD, including patients with TRD. The long-term safety profile of the combination was similar to that of its component monotherapies.


Astigmatism and myopia in Tohono O'odham Native American children.
To describe change in spherical equivalent (M) in a longitudinal sample of Tohono O'odham students ages 3 to 18 years and to test the hypothesis that astigmatism creates complex cues to emmetropization, resulting in increased change in M in the direction of increasing myopia and increased occurrence of myopia. Subjects were 777 Tohono O'odham Native American children on whom cycloplegic right eye autorefraction was measured on at least two study encounters between ages 3 and 18 years (first encounter prior to age 5.5 years, final encounter ≥3 years later). Regression lines were fit to individual subjects' longitudinal M data to estimate rate of change in M (regression slope, D/yr). Regression was also used to predict if a subject would be myopic (≤-0.75 D M) by age 18 years. Analysis of covariance was used to assess the relation between M slope and magnitude of baseline M and astigmatism. Chi-square analyses were used to assess the relation between predicted myopia onset and magnitude of baseline M and astigmatism. Mean M slope was significantly more negative for hyperopes (M ≥ +2.00) than for myopes (M ≤ -0.75) or for subjects neither hyperopic nor myopic (NHM, M > -0.75 and < +2.00), but there was no significant difference between the myopic and NHM groups. Chi-square analysis indicated that final myopia status varied across level of baseline astigmatism. Subjects with high astigmatism were more likely to be predicted to have significant myopia by age 18 years. The association between greater shift in M towards myopia with age in subjects who were hyperopic at baseline is consistent with continued emmetropization in the school years. Results regarding predicted myopia development imply that degradation of image quality due to refractive astigmatism creates complex cues to emmetropization, resulting in increased occurrence of myopia.


A spliced leader is present on a subset of mRNAs from the human parasite Schistosoma mansoni.
We present evidence that a subset of mRNAs in the human parasitic trematode Schistosoma mansoni contain an identical 36-nucleotide spliced leader (SL) sequence at their 5' termini. The SL is derived from a 90-nucleotide nonpolyadenylylated RNA (SL RNA), presumably by trans-splicing. Neither the SL nor the SL RNA share significant sequence identity with previously described trans-spliced leaders and SL RNAs in trypanosomatid protozoans or nematodes. However, several features, such as predicted secondary structure, trimethylguanosine cap, and potential Sm binding site, suggest similarities among SL RNAs in widely divergent organisms. Our evidence also indicates that the exon 3 acceptor site of the 3-hydroxy-3-methylglutaryl-CoA reductase gene can be spliced either to the SL by trans-splicing or to an upstream exon, 2, by cis-splicing. The presence of a SL sequence in S. mansoni, a member of the phylum Platyhelminthes, suggests that transplicing may be a common feature of other lower invertebrates.


Hospital nurses' perceptions of respect and organizational justice.
To test an exploratory model of the antecedents and consequences of nurses' perceptions of respect in hospitals. Although nurses in hospital settings often state that they do not receive the respect they deserve for their contribution to patient care, there is little empirical research on this phenomenon. Interactional organizational justice theory framed the analysis. A random sample of 285 staff nurses from Ontario teaching hospitals completed measures of interactional justice, structural empowerment, perceived respect, work pressures, emotional exhaustion, and work effectiveness. More than half of the nurses felt that managers did not show concern or deal with them in a sensitive and truthful manner regarding decisions affecting their jobs. The strongest predictors of perceptions of respect were interactional organizational justice, followed by structural empowerment and job stress resulting from lack of recognition, poor interpersonal relationships and heavy workload. Consequences of nurses' feelings of respect included greater job satisfaction, trust in management, and lower emotional exhaustion, as well as higher nurse ratings of quality of care and perceived staffing adequacy. A positive organizational environment increases nurses' perceptions of respect, resulting in positive outcomes for both the nurse and the organization.


Cell-replacement and gene-therapy strategies for Parkinson's and Alzheimer's disease.
Parkinson's disease and Alzheimer's disease are the most common neurodegenerative diseases in the elderly population. Given that age is the most important risk factor in these diseases, the number of patients is expected to rise dramatically in the coming years. Therefore, an effective therapy for these diseases is highly sought. Current treatment brings only temporary symptomatic relief and does not result in halting the progression of these diseases. The increasing knowledge on the molecular mechanisms that underlie these diseases enables the design of novel therapies, targeted at degenerating neurons by creating an optimal regenerative cellular environment. Here, we review the progress made in the field of cell-replacement and gene-therapy strategies. New developments in the application of embryonic stem cells and adult neuronal progenitors are discussed. We also discuss the use of genetically engineered cells in neuronal rescuing strategies that have recently advanced into the clinic. The first trials for the treatment of Alzheimer's disease and Parkinson's disease with this approach are ongoing.


Estimation of the Structural and Geomechanical Anisotropy in Fault Gouges Using 3D Micro-Computed Tomography (μ-CT).
Fault gouges play an important role in the shear deformation of fault zones, by causing weakness and frictional instability in structures. Previous studies have investigated the evolution of shear deformation of fault zones by observing experiments using remolded and synthetic gouge specimens at a micro-scale. However, how the spatial configuration of the rock constituents accounts for the 3D anisotropy of intact structures of fault gouges, particularly at the core-scale, is not well understood. We obtained 3D μ-CT images of directionally cored gouge specimens and performed statistical analysis to quantify the major orientation of the internal structures. Direct shear tests were conducted to investigate the relationship between the distribution of the internal structures and geomechanical behavior. The results show that the undisturbed fault gouge has a clear anisotropy parallel to the fault plane even at the core-scale. Moreover, the direct shear test results show that the frictional resistance of a fault gouge has anisotropy related to the fault plane. The simple, yet robust method proposed in this study confirms that the core-scale structural anisotropy is correlated to the anisotropic shear resistance.


Advocate cultivation of academic ethics: why is it necessary?
We teach and practice ethical behavior with all clinical and research activities. Notably, we are well educated to treat the subjects participating in research studies with high ethical standards. However, the ethics of interacting with colleagues, or with junior faculty members, are neither well defined nor taught. Dealing with junior faculty has parallels to dealing with vulnerable research subjects such as children, mentally or physically challenged groups, prison inmates or army recruits. Like any other vulnerable population, lower-ranking faculty members are often at the mercy of department chairs or other higher-ranked faculty members. Herein we present some potentially unethical or unfair examples related to academic research. Our goal is to educate the academic community of conceptual paths and to prevent similar untoward occurrences from happening in the future. Unethical behaviors related to sexual misconduct have already been described elsewhere and are not included in this manuscript.


Efficacy of an HIV prevention program among African American female adolescents reporting high depressive symptomatology.
We examined the efficacy of an HIV prevention intervention among African American adolescent females reporting at or above threshold depressive symptomatology. In this analysis, a subgroup of participants (n = 245) reporting at or above threshold depressive symptoms involved in a randomized controlled trial were assessed at 6-month and 12-month follow-ups on condom use and psychosocial mediators associated with HIV prevention behaviors. The intervention emphasized HIV knowledge, condom attitudes, communication self-efficacy, and condom use skills. Relative to the comparison condition, participants randomized to the intervention reported using condoms more consistently, engaged in a greater proportion of condom protected intercourse acts, had fewer episodes of unprotected vaginal sex, were more likely to use a condom at last sex, and had higher HIV knowledge, favorable attitudes toward condoms, condom use self-efficacy, and condom use skills. Overall, the pattern of effects found strengthen our confidence in the efficacy of the HIV intervention assessed for a broad range of young women, including those with high levels of depressive symptoms. Although young women with high depressive symptoms benefited from this HIV intervention, future studies employing interventions that specifically address the affective needs of this population might be even more effective in terms of sexual risk reduction and amelioration of depressive symptoms.


Colposcopic evaluation of cervical neoplasia in pregnancy.
The need for histologic examination of the cervix during pregnancy is not uncommon. Classically, the cone biopsy has been the diagnostic procedure of choice, but this procedure is attended by a significant and excessive complication rate. The cumulative data strongly supports the conclusion that the combination of cytology and colposcopically directed biopsy can be relied upon to provide an accurate diagnosis in a high percentage of patients. Colposcopy should be a routine diagnostic procedure in the evaluation of patients with abnormal Pap smears or grossly abnormal cervices.


[Characteristic features of the ranks genus and subgenus, and an intercalary rank "species complex" in ixodid ticks (Acari: Ixodidae)].
The work was carries our from the standpoint of the morphological conception of species. Vast collections of the Zoological Institute of the Russian Academy of Science testify to the existence of hiatuses in both genera and subgenera of Palearctic ixodids at all active phases of their ontogenesis. The fact that the subgenera of Palearctic genera have been well studies is notes, and composition of the subgenera is presented. The question of a taxonomic intercalary rank "species complex" is considered in detail in the context of the coevolution between some complexes of closely related species of ixodid ticks and some closely related species (genospecies, strains) of pathogens. The question of the taxonomic rank "species complex" in ixodid ticks as a phyletic species association is postulated on the basis of comparative ontogenetic data. Nomenclature status of the intercalary association "species complex" is specified in conformity with the fourth edition of the International Code of Zoological Nomenclature. Species composition of most studied complexes is presented. Some variants of morphological differentiation between species complexes within subgenus are considered. Significance of the taxonomic concept "species complex" for zoological. parasitological, and medical aspects of the ixodid ticks study was evaluated. Prognostic significance of the rank "species complex" for the study of the relationships between ixodid ticks and pathogens is discussed.


Multiphoton excitation spectra in biological samples.
Multiphoton microscopy is becoming a popular mode of live and fixed cell imaging. This mode of imaging offers several advantages due to the fact that fluorochrome excitation is a nonlinear event resulting in excitation only at the plane of focus. Multiphoton excitation is enhanced by the use of ultrafast lasers emitting in the near IR, offering better depth penetration coupled with efficient excitation. Because these lasers, such as titanium:sapphire lasers, offer tunable output it is possible to use them to collect multiphoton excitation spectra. We use the software-tunable Coherent Chameleon laser coupled to the Zeiss LSM 510 META NLO to acquire x-y images of biological samples at multiple excitation wavelengths, creating excitation lambda stacks. The mean intensity of pixels within the image plotted versus excitation wavelength reveals the excitation spectra. Excitation lambda stacks can be separated into individual images corresponding to the signal from different dyes using linear unmixing algorithms in much the same way that emission fingerprinting can be used to generate crosstalk free channels from emission lambda stacks using the META detector. We show how this technique can be used to eliminate autofluorescence and to produce crosstalk-free images of dyes with very close overlap in their emission spectra that cannot be separated using emission fingerprinting. Moreover, excitation finger- printing can be performed using nondescanned detectors (NDDs), offering more flexibility for eliminating autofluorescence or crosstalk between fluorochromes when imaging deep within the sample. Thus, excitation fingerprinting complements and extends the functions offered by the META detector and emission fingerprinting. We correct biases in the laser and microscope transmission to acquire realistic multiphoton excitation spectra for fluorochromes within cells using the microscope, which enables the optimization of the excitation wavelength for single and multilabel experiments and provides a means for studying the influence of the biological environment on nonlinear excitation.


Evaluation of seasonal and monthly variation and location of deep vein thrombosis.
Deep vein thrombosis of the lower extremities is associated with a significant burden of comorbidities. In this study, our objective was to investigate the presence of seasonal variation in deep vein thrombosis (DVT) and assess the location of the thrombus. Out of 8177 patients admitted to two university hospitals and referred to outpatient clinics, we included a total of 611 consecutive patients (316 females, 295 males) diagnosed with acute deep vein thrombosis in this retrospective study. The mean age of the patients was 59.35±18.49 years, ranging from 1 to 96 years. Patients were categorized into four groups by age. DVT was found to be more frequent in the summer (n = 190 or 31%, p = 0.003) and specifically in August (n = 65 or 10.6%, p = 0.014), while it was least frequent in the spring (n = 128 or 20.9%) and in May (n = 40 or 6.5%). However, when comparing seasons, no significant differences were observed in terms of seasonal variation (p = 0.062) or monthly variation (p = 0.143). Contrary to previous studies, this study demonstrated a higher occurrence of DVT during the summer, particularly in August. However, it did not reveal a clear seasonal pattern. One plausible explanation for these findings could be the adverse winter conditions and transportation challenges within the province, which may result in fewer DVT patients being able to reach hospitals for timely treatment.


MDR1 transcript levels as an indication of resistant disease in acute myelogenous leukaemia.
The expression of the MDR1 gene was studied by Northern blot analysis in leukaemic cell specimens obtained from 74 patients with acute myelogenous leukaemia (AML). No relationship was found between MDR1 RNA levels and FAB type of leukaemia or patient age. Transcript levels tended to be highest in the leukaemic cells of patients with a history of toxic exposure or preleukaemia compared with 'standard risk' patients at diagnosis but the differences were not significant (P = 0.07). Patients whose leukaemic cells contained high MDR1 transcript levels were difficult to induce into remission and, if remission was induced, the remissions were short. Hence high levels of MDR1 expression may explain, at least in part, the ineffectiveness of anthracycline antibiotic containing treatment regimens in some patients with AML.


Age- and activity-related changes in three proteinase enzymes of rat skeletal muscle.
The specific activities of three proteinases, cathepsins B, D and H, were measured in two skeletal-muscle types as a function of age (i.e. from large foetal life to old age), and in muscles immobilized at various lengths for 3 days. The activities of the lysosomal endopeptidases B and D, but not H, consistently changed in parallel with previously determined rates of protein breakdown, indicating a good and potentially useful correlation between the two.


A critical review and update of modelling of treated water discharging from Fukushima Daiichi NPP.
Since the accident at the Fukushima Daiichi nuclear power plant (FDNPP) in March 2011 seawater is still needed to cool the reactor cores. This water, contaminated with radionuclides, has been collected in tanks and treated on the site of the FDNPP. In 2021, the Japanese government decided to gradually discharge treated water into the ocean, which started on the 24th of August 2023 and will continue for the next 30 years. This paper provides a critical analysis of the models that were used in the different radiological impact studies. Based on the analysis, a hydrodynamic and a compartment models with a harmonized setup were used to estimate the impact of the discharge on humans and biota. Doses obtained with these two models were within one order of magnitude for humans (<0.1 μSv/year) and for biota (<10-6 mGy/d) indicating that harmonization of the model parameters improved the reliability of the simulation results.


Diagnosing Invasive Pulmonary Aspergillosis in Hematology Patients: a Retrospective Multicenter Evaluation of a Novel Lateral Flow Device.
Invasive pulmonary aspergillosis (IPA) is a potentially lethal infection in patients with hematological diseases or following allogeneic stem cell transplantation. Early diagnosis is essential, as delayed treatment results in increased mortality. Recently, a lateral flow device (LFD) for the diagnosis of IPA was CE marked and made commercially available by OLM Diagnostics. We retrospectively analyzed bronchoalveolar lavage fluid (BALf) collected from adult hematology patients from 4 centers in The Netherlands and Belgium. Galactomannan was retested in all samples. All samples were applied to an LFD and read out visually by two independent researchers blinded to the diagnosis of the patient. All samples were also read out using a digital reader. We included 11 patients with proven IPA, 68 patients with probable IPA, 44 patients with possible IPA, and 124 patients with no signs of IPA (controls). In cases of proven IPA versus controls, sensitivity and specificity were 0.82 and 0.86 for visual readout and 0.82 and 0.96 for digital readout, respectively. When comparing patients with proven and probable IPA as cases versus controls, sensitivity and specificity were found to be 0.71 and 0.86, respectively. When excluding serum and BALf galactomannan as mycological criteria from the 2008 European Organization for Research and Treatment of Cancer Invasive Fungal Infections Cooperative Group (EORTC)/Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (MSG) consensus definitions, the LFD was less specific than galactomannan when comparing subjects with proven and probable IPA to controls (0.86 versus 0.96; P = 0.005) but had similar sensitivity (0.76 versus 0.85; P = 0.18). In conclusions, in this large study of the CE-marked LFD in BALf from hematology patients, the LFD had a good performance for the diagnosis of IPA.


Critical elements of the crisis intervention team model of jail diversion: an expert survey.
The Crisis Intervention Team (CIT) model of jail diversion is a promising approach to addressing the over-involvement of people with mental illness with the criminal justice system. Despite its popularity and promising empirical support, the literature has yet to clarify CIT's critical elements. The aim of this study was to assess the degree to which experts agreement on the importance and perceived implementation of the critical elements of CIT. Study 1 used a literature review to cull potential elements. Three experts familiar with the CIT model reviewed these elements. Study 2 utilized an online survey of 55 CIT co-ordinators/officers and published experts to assess agreement regarding importance and degree the element is implemented. A preliminary list of 36 elements was identified with a high level of expert agreement on their importance regarding importance and implementation. This study developed a preliminary list of elements of the CIT's program. Further research should develop consensus, explore elements' association with outcomes, and differentiate elements from those common to all jail diversion programs.


Hyperthermia sensitizes Rhizopus oryzae to posaconazole and itraconazole action through apoptosis.
The high mortality rate of mucormycosis with currently available monotherapy has created interest in studying novel strategies for antifungal agents. With the exception of amphotericin B (AMB), the triazoles (posaconazole [PCZ] and itraconazole [ICZ]) are fungistatic in vitro against Rhizopus oryzae . We hypothesized that growth at a high temperature (42°C) results in fungicidal activity of PCZ and ICZ that is mediated through apoptosis. R. oryzae had high MIC values for PCZ and ICZ (16 to 64 μg/ml) at 25°C; in contrast, the MICs for PCZ and ICZ were significantly lower at 37°C (8 to 16 μg/ml) and 42°C (0.25 to 1 μg/ml). Furthermore, PCZ and ICZ dose-dependent inhibition of germination was more pronounced at 42°C than at 37°C. In addition, intracellular reactive oxygen species (ROS) increased significantly when fungi were exposed to antifungals at 42°C. Characteristic cellular changes of apoptosis in R. oryzae were induced by the accumulation of intracellular reactive oxygen species. Cells treated with PCZ or ICZ in combination with hyperthermia (42°C) exhibited characteristic markers of early apoptosis: phosphatidylserine externalization visualized by annexin V staining, membrane depolarization visualized by bis-[1,3-dibutylbarbituric acid] trimethine oxonol (DiBAC) staining, and increased metacaspase activity. Moreover, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and DAPI (4',6-diamidino-2-phenylindole) staining demonstrated DNA fragmentation and condensation, respectively. The addition of N-acetylcysteine increased fungal survival, prevented apoptosis, reduced ROS accumulation, and decreased metacaspase activation. We concluded that hyperthermia, either alone or in the presence of PCZ or ICZ, induces apoptosis in R. oryzae. Local thermal delivery could be a therapeutically useful adjunct strategy for these refractory infections.


Total complement hemolytic activity of colostral whey and sera from dairy cows.
Two methods were used to clarify bovine colostrum for quantitation of total complement (C') hemolytic activity in the whey. The renin precipitation method produced whey which tended to have higher C' hemolytic activity (5.0 +/- 3.4 CH50 units) than did whey prepared by ultracentrifugation (2.5 +/- 2.6 CH50 units) although this difference was not significant. No correlation was found between levels of complement in the sera of cows at parturition and in the colostral whey from the same animal. Total complement activity was not detected in milk taken a 96 hours or one month after parturition. This is apparently the first report of quantitation of total C' hemolytic activity in bovine colostrum.


A case of acute traumatic aortic injury of a right-sided aortic arch with rupture of an aberrant left subclavian artery.
Acute traumatic aortic injury is a potentially lethal condition with most patients die at the scene of the accidents. Rapid deceleration due to motor vehicle accidents is the commonest mechanism of injury. These injuries can be successfully repaired in the few patients who survive the initial trauma if proper diagnosis and rapid treatment are provided. The occurrence of acute traumatic aortic injury in patients with congenital abnormality of the aortic arch has been rarely reported; however, it renders the diagnosis and treatment more difficult. In this paper, we describe an extremely rare case of aortic injury in a young patient who had a right sided aortic arch with rupture of an aberrant left subclavian artery. The patient was suspected to have a Kommerell's diverticulum in the aberrant subclavian artery origin. This injury resulted in an unusually huge pseudoaneurysm involving part of the mediastinum and extending into the neck. Unfortunately; patient succumbed in spite of surgical intervention.


Intramuscular compared with subcutaneous transposition for surgery in cubital tunnel syndrome.
Background There is no consensus on the most effective surgical technique in the treatment of cubital tunnel syndrome. Anterior subcutaneous transposition (AST) and anterior intramuscular transposition (AIT) are common surgical treatments in this regard. The aim of this study was to compare the clinical outcomes of these two surgeries for cubital tunnel syndrome. Methods In a retrospective study, we compared surgical outcomes (pain, sensation, motor recovery, atrophy, and total satisfaction) in 40 patients undergoing AIT and 43 undergoing AST of the ulnar nerve. Results The patients undergoing AIT showed a significant improvement in all the outcomes after the surgery (P = 0); however, those undergoing AST only experienced an improvement in pain and sensation after the surgery (P = 0). Comparing the two surgeries, we found that there was a high total satisfaction with AIT compared with AST (P = 0). When we independently compared each outcome in the two groups, we found that the muscle force recovery was significantly improved in the AIT group compared with the AST group (P = 0). Conclusions AIT is preferable to AST for the surgical treatment of cubital tunnel syndrome. In particular, AIT achieves a better motor recovery of the ulnar nerve compared with AST.


Collagen gel contraction as a measure of fibroblast function in carpal tunnel syndrome.
Noninflammatory subsynovial connective tissue (SSCT) fibrosis with nerve compression is a prominent feature of carpal tunnel syndrome (CTS). Studies have shown that SSCT matrix synthesis and material property changes in CTS are associated with increased activity of transforming growth factor (TGF)-β1. The aim of this study were to (1) investigate the ability of SSCT fibroblasts from CTS patients and unaffected individuals to contract a collagen gel ring and (2) determine how the addition of TGF-β1 affects this ability. SSCT fibroblasts from three normal cadavers and three age-matched female patients who had undergone surgery for CTS were used. Results showed patient cell-seeded gels had a significantly higher contraction rate (p < 0.001) than control cells, and fully contracted gel rings possessed a significantly higher tensile strength (p = 0.003) and stiffness (p < 0.001). Furthermore, TGF-β1 significantly intensified contraction rate (p < 0.001), tensile strength (p < 0.001), and stiffness (p < 0.001). In conclusion, SSCT cells from normal donors and CTS patients contract collagen gel rings differently, and this ability is affected by TGF-β1 treatment. This cell-seeded collagen gel model may be useful for developing new methods of stopping or eliminating the effect of TGF-β1 on the SSCT fibroblasts and surrounding matrix, which might aid in the identification of medical treatment for CTS.


Prospective assessment of inter-rater reliability of a neonatal adverse event severity scale.
Introduction: To ensure the quality of clinical trial safety data, universal data standards are required. In 2019 the International Neonatal Consortium (INC) published a neonatal adverse event severity scale (NAESS) to standardize the reporting of adverse event (AE) severity. In this study the reliability of AE severity grading with INC NAESS was prospectively assessed in a real-world setting. Methods: Severity of AEs was assessed by two independent observers at each of four centers across the world. In each center two series of 30 neonatal adverse events were assessed by both observers: in a first phase with a generic (Common Terminology Criteria for Adverse Events, CTCAE) severity scale not specific to neonates, and in a second phase with INC NAESS (after a structured training). Intraclass correlation coefficients (ICC) were calculated to express inter-rater agreement in both phases, and bootstrap sampling was used to compare them. Results: 120 AEs were included in each of both phases. The ICC with the use of INC NAESS in phase 2 was 0.69. This represents a significant but modest improvement in comparison to the initial ICC of 0.66 in phase 1 (confidence interval of ratio of ICC in phase 2 to phase 1 = 1.005-1.146; excludes 1). The ICC was higher for those AEs for which a diagnosis specific AE severity table was available in INC NAESS (ICC 0.80). Discussion: Good inter-rater reliability of the INC NAESS was demonstrated in four neonatal intensive care units (NICUs) across the globe. The ICC is comparable to what is reported for scales with similar purposes in different populations. There is a modest, but significant, improvement in inter-rater agreement in comparison to the naïve phase without INC NAESS. The better performance when reviewers use AE-specific NAESS tables highlights the need to expand the number of AEs that are covered by specific criteria in the current version of INC NAESS.


Predicting loop-helix tertiary structural contacts in RNA pseudoknots.
Tertiary interactions between loops and helical stems play critical roles in the biological function of many RNA pseudoknots. However, quantitative predictions for RNA tertiary interactions remain elusive. Here we report a statistical mechanical model for the prediction of noncanonical loop-stem base-pairing interactions in RNA pseudoknots. Central to the model is the evaluation of the conformational entropy for the pseudoknotted folds with defined loop-stem tertiary structural contacts. We develop an RNA virtual bond-based conformational model (Vfold model), which permits a rigorous computation of the conformational entropy for a given fold that contains loop-stem tertiary contacts. With the entropy parameters predicted from the Vfold model and the energy parameters for the tertiary contacts as inserted parameters, we can then predict the RNA folding thermodynamics, from which we can extract the tertiary contact thermodynamic parameters from theory-experimental comparisons. These comparisons reveal a contact enthalpy (DeltaH) of -14 kcal/mol and a contact entropy (DeltaS) of -38 cal/mol/K for a protonated C(+)*(G-C) base triple at pH 7.0, and (DeltaH = -7 kcal/mol, DeltaS = -19 cal/mol/K) for an unprotonated base triple. Tests of the model for a series of pseudoknots show good theory-experiment agreement. Based on the extracted energy parameters for the tertiary structural contacts, the model enables predictions for the structure, stability, and folding pathways for RNA pseudoknots with known or postulated loop-stem tertiary contacts from the nucleotide sequence alone.


An automated system for performing continuous viscosity versus temperature measurements of fluids using an Ostwald viscometer.
An automated system was developed to measure the viscosity of fluids as a function of temperature using image analysis tracking software. An Ostwald viscometer was placed in a three-wall dewar in which ethylene glycol was circulated using a thermal bath. The system collected continuous measurements during both heating and cooling cycles exhibiting no hysteresis. The use of video tracking analysis software greatly reduced the measurement errors associated with measuring the time required for the meniscus to pass through the markings on the viscometer. The stability of the system was assessed by performing 38 consecutive measurements of water at 42.50 ± 0.05 °C giving an average flow time of 87.7 ± 0.3 s. A device was also implemented to repeatedly deliver a constant volume of liquid of 11.00 ± 0.03 ml leading to an average error in the viscosity of 0.04%. As an application, the system was used to measure the viscosity of two Li-ion battery electrolyte solvents from approximately 10 to 40 °C with results showing excellent agreement with viscosity values calculated using Gering's Advanced Electrolyte Model (AEM).


Perfusion scintigraphy versus 256-slice CT angiography in pregnant patients suspected of pulmonary embolism: comparison of radiation risks.
One aim of the current study was to determine normalized dose data for maternal radiosensitive organs and embryo/fetus from 256-slice CT pulmonary angiography (CTPA) performed on pregnant patients suspected of having pulmonary embolism. A second aim was to provide reliable maternal and fetal doses and associated radiation cancer risk estimates from 256-slice CTPA and lung perfusion scintigraphy (LPS) for comparison. Mathematic anthropomorphic phantoms were generated to simulate the average woman at early pregnancy and at the third, sixth, and ninth months of gestation. In each phantom, 0-3 additional 1.5-cm-thick fat tissue layers were added to derive 4 phantoms representing pregnant women with different body sizes. Monte Carlo methods were used to simulate low-dose 256-slice CTPA exposures on each of the 16 generated phantoms. Normalized organ and embryo/fetal dose data were derived for exposures at 80, 100, and 120 kV. Maternal effective dose and embryo/fetal dose from 256-slice CTPA and associated lifetime attributable risks of radiation cancer were determined for different body sizes and gestational stages and compared with corresponding data from LPS. For an average-sized pregnant patient at the first trimester, the 256-slice CTPA exposure resulted in a maternal effective dose of 1 mSv and an embryo/fetal dose of 0.05 mGy. However, maternal effective dose considerably increased with body size, whereas embryo/fetal dose increased with both body size and gestational stage. Compared with LPS, low-dose CTPA to an average-sized pregnant patient resulted in a 30% higher maternal effective dose but a 3.4-6 times lower embryo/fetal dose. Nevertheless, LPS was associated with less aggregated radiation risk for an average-sized pregnant patient, with the difference from CTPA being increased further for larger patients. Compared with CTPA performed with a modern wide-area CT scanner, LPS remains comparatively more dose-efficient.


Patient satisfaction after anterior cervical discectomy and fusion is primarily driven by relieving pain.
A prospective follow-up study of patients with anterior cervical discectomy and fusion (ACDF) for single-level cervical disc disease was conducted to determine the extent of impact of pain, sensory function, motor function, and range of motion (ROM) of the neck on patient satisfaction after ACDF. A total of 67 ACDF patients were monitored by clinical examination (pain, motor function, sensory function, and ROM in the neck) preoperatively and at follow-up (mean, 217 d after surgery; range, 198 to 232 d) and by a satisfactory questionnaire (SQ) at follow-up only. According to the SQs, 4 patient groups were characterized. Inside each patient group for each examination parameter, the percentage of patients who showed improved, unchanged, or worsened clinical results was analyzed. Patient satisfaction was found to depend primarily on the improvement in pain (P=0.001). The development of motor function (P=0.056), sensory function (P=0.225), and ROM of the neck (P=0.565) did not demonstrate significant correlation with patient satisfaction. The Numerical Rating Scale score decreased from 6.2 before surgery to 2.1 on follow-up, whereas the level of analgesic use (World Health Organization scheme) decreased from 1.9 to 0.3. Improvement in pain seemed to be most important aspect in ACDF patients regarding the subjective SQ. Therefore, we strongly recommend focusing on pain-reducing therapies when choosing treatment for these patients during the postoperative period.


Human Mesenchymal Stem Cells Prevent Neurological Complications of Radiotherapy.
Radiotherapy is a highly effective tool for the treatment of brain cancer. However, radiation also causes detrimental effects in the healthy tissue, leading to neurocognitive sequelae that compromise the quality of life of brain cancer patients. Despite the recognition of this serious complication, no satisfactory solutions exist at present. Here we investigated the effects of intranasal administration of human mesenchymal stem cells (hMSCs) as a neuroprotective strategy for cranial radiation in mice. Our results demonstrated that intranasally delivered hMSCs promote radiation-induced brain injury repair, improving neurological function. This intervention confers protection against inflammation, oxidative stress, and neuronal loss. hMSC administration reduces persistent activation of damage-induced c-AMP response element-binding signaling in irradiated brains. Furthermore, hMSC treatment did not compromise the survival of glioma-bearing mice. Our findings encourage the therapeutic use of hMSCs as a non-invasive approach to prevent neurological complications of radiotherapy, improving the quality of life of brain tumor patients.


Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer.
Genetic and epigenetic alterations are essential for the initiation and progression of human cancer. We previously reported that primary human medulloblastomas showed extensive cancer-specific CpG island DNA hypermethylation in critical developmental pathways. To determine whether genetically engineered mouse models (GEMMs) of medulloblastoma have comparable epigenetic changes, we assessed genome-wide DNA methylation in three mouse models of medulloblastoma. In contrast to human samples, very few loci with cancer-specific DNA hypermethylation were detected, and in almost all cases the degree of methylation was relatively modest compared with the dense hypermethylation in the human cancers. To determine if this finding was common to other GEMMs, we examined a Burkitt lymphoma and breast cancer model and did not detect promoter CpG island DNA hypermethylation, suggesting that human cancers and at least some GEMMs are fundamentally different with respect to this epigenetic modification. These findings provide an opportunity to both better understand the mechanism of aberrant DNA methylation in human cancer and construct better GEMMs to serve as preclinical platforms for therapy development.


Oocyte Competence Biomarkers Associated With Oocyte Maturation: A Review.
Oocyte developmental competence is one of the determining factors that influence the outcomes of an IVF cycle regarding the ability of a female gamete to reach maturation, be fertilized, and uphold an embryonic development up until the blastocyst stage. The current approach of assessing the competency of an oocyte is confined to an ambiguous and subjective oocyte morphological evaluation. Over the years, a myriad of biomarkers in the cumulus-oocyte-complex has been identified that could potentially function as molecular predictors for IVF program prognosis. This review aims to describe the predictive significance of several cumulus-oocyte complex (COC) biomarkers in evaluating oocyte developmental competence. A total of eight acclaimed cumulus biomarkers are examined in the study. RT-PCR and microarray analysis were extensively used to assess the significance of these biomarkers in foreseeing oocyte developmental competence. Notably, these biomarkers regulate vital processes associated with oocyte maturation and were found to be differentially expressed in COC encapsulating oocytes of different maturity. The biomarkers were reviewed according to the respective oocyte maturation events namely: nuclear maturation, apoptosis, and extracellular matrix remodeling, and steroid metabolism. Although substantial in vitro evidence was presented to justify the potential use of cumulus biomarkers in predicting oocyte competency and IVF outcomes, the feasibility of assessing these biomarkers as an add-on prognostic procedure in IVF is still restricted due to study challenges.


Influence of body temperature on bacterial growth rates in experimental pneumococcal meningitis in rabbits.
We examined the role of fever as a host defense in experimental pneumococcal meningitis in rabbits. Twelve hours after intracisternal inoculation of an encapsulated type 3 Streptococcus pneumoniae strain, body temperature was manipulated by using two different anesthetic drugs: pentobarbital, which did not affect temperature, and urethane, which mitigated the febrile response to infection. Growth rates of pneumococci in cerebrospinal fluid were dramatically influenced by modification of the febrile response. Rabbits whose fever was not suppressed had mean bacterial doubling times of 2.76 +/- 1.43 h. Animals with a blunted febrile response had a significantly faster mean bacterial growth rate (doubling time = 1.10 +/- 0.27 h; P less than 0.02). When the antipyretic effect of urethane was counteracted by raising the ambient temperature, animals also showed a marked reduction in pneumococcal growth rates. In vitro, the pneumococci grew well at 37 degrees C in Trypticase soy broth (doubling time = 0.61 +/- 0.05 h) and in pooled rabbit cerebrospinal fluid (doubling time = 0.85 +/- 0.07 h). However, at 41 degrees C neither medium supported growth. Thus, body temperature appears to be a critical determinant of pneumococcal growth rates in experimental meningitis, and fever could be a host defense in this disease.


A key problem and challenge for hepatology: Obesity-related metabolic liver diseases.
With the arrival of the new millennium, gastroenterologists have been faced with the problem of metabolic liver diseases associated with obesity. The active role of the liver in metabolism and inflammation make it a key organ in the war against the rapidly-spreading world-wide epidemic of obesity. Many lives and much money could be saved if the work of hepatologists led to the development of effective diagnostic and therapeutic strategies against this growing leader of cirrhosis.


[Percutaneous nephrolithotomy after extracorporeal lithotripsy for the treatment of complex renal lithiasis. Technical details and results].
The new therapeutic approach combining percutaneous nephrolithotomy (PNL) and extracorporeal shock wave lithotripsy (ESWL) has become widely used instead of conventional surgery. The use of this combined treatment modality has been extended to complex renal calculi. In our view, the need to achieve complete removal of struvite stone fragments to cure infection and prevent subsequent stone formation has led to a change in our therapeutic approach. The present study describes several maneuvers to facilitate PNL and compares two treatment modalities: PNL to reduce stone volume + ESWL (an approach utilized by many) and ESWL + PNL for remaining stone fragments (our therapeutic approach). Our approach (ESWL followed by PNL) has enhanced our results in the treatment of complex renal calculi: 68.4% of the renal units were completely stone-free at the time of discharge from the hospital. Good results were achieved in 89.5%, if we include the renal units with stone fragments that could be spontaneously passed.


The sperm-specific form of lactate dehydrogenase is required for fertility and is an attractive target for male contraception (a review).
There has been a recent upsurge in the interest about contraceptive development, evidenced by the Contraceptive Special Issue of Biology of Reproduction [1], with research funding from the Male Contraceptive Initiative and the Bill and Melinda Gates Foundation. Support from the Contraceptive Research Branch of the Eunice Kennedy Shriver National Institutes of Child Health and Human Development continues with a marked change in focus in the funding announcements. This has motivated me to reflect on research, mostly from my laboratory starting in the 1960s to the present, on the development of a male contraceptive based on the sperm-specific glycolytic enzyme, lactate dehydrogenase C (LDHC4). This review considers the rationale behind this research, the development paths pursued, obstacles encountered, and the renewed interest in going forward toward development of a male contraceptive mediated by the inhibition of the sperm-specific form of LDHC. I will address how some papers published many years ago are relevant to the present goals of non-hormonal contraception and will mention about innovative technology now available that can advance this project. This review presumably will serve as an instructive guide for a research program with a focused program related to contraception. As an aside, many of the citations in this review are to most of the 26 publications in Biology of Reproduction co-authored by this investigator and collaborators from 1974 through 2020 not long after the first issue of BOR which was published in April 1969.


The herpes simplex virus DNA polymerase: analysis of the functional domains.
The structural and functional organization of the herpes simplex virus type I (HSV-1) DNA polymerase enzyme of strain ANG was studied by a combination of sequence and immunobiochemical analyses. Comparison of the HSV-1 ANG DNA polymerase sequence with those of pro- and eukaryotic DNA polymerases resulted in the allocation of eleven conserved regions within the HSV-1 DNA polymerase. From the analysis of all currently identified mutations of temperature-sensitive and drug-resistant HSV-1 DNA polymerase mutants as well as from the degree of conservancy observed, it could be deduced that the amino-acid residues 597-961, comprising the homologous sequence regions IV-IX, constitute the major structural components of the catalytic domain of the enzyme which should accommodate the sites for polymerizing and 3'-to-5' exonucleolytic functions. Further insight into the structural organization was gained by the use of polyclonal antibodies responding specifically to the N-terminal, central and C-terminal polypeptide domains of the ANG polymerase. Each of the antisera was able to immunostain as well as to immunoprecipitate a viral polypeptide of 132 +/- 5 kDa that corresponded well to the molecular mass of 136 kDa predicted from the coding sequences. Enzyme-binding and neutralization studies confirmed that both functions, polymerase and 3'-to-5' exonuclease, are intimately related to each other, and revealed that, in addition to the sequences of the proposed catalytic domain, the very C-terminal sequences, except for amino-acid residues 1072-1146, are important for the catalytic functions of the enzyme, most likely effecting the binding to DNA.


Hand-held turbine spirometer: agreement with the conventional spirometer at baseline and after exercise.
Portable hand-held spirometers are widely used in outpatient clinics and in field surveys when examining children for asthma. However, the validity of the results obtained from the hand-held spirometers has not been assessed in population-based studies. We evaluated the agreement between the forced expiratory volume (FEV1) values got by the conventional flow volume spirometer (FVS) and the pocket-sized turbine spirometer (TS) at baseline and after exercise, among the 212 children screened for asthma and asthma-like symptoms from a population of 1633 school-aged children. The comparison was made between and within three diagnostic groups: clinical asthma (n = 34), possible asthma (n = 31), and controls (n = 147). In general, the differences in FEV1 between the FVS and the TS were small. For all children, the mean difference in FEV1 and the limits of agreement (difference +/-2 s.d.) was 0.05 l (0.23 to -0.13) at baseline and 0.06 l (0.24 to -0.12) after exercise. No significant differences were observed in the agreement between the diagnostic groups. In conclusion, although FEV1 results obtained by the hand-held spirometer are not interchangeable with those by the conventional spirometer, they are in reasonable agreement. The agreement is similar both at baseline and after exercise, and is not influenced by the presence of asthma.


Next generation sequencing: an application in forensic sciences?
Over the last few decades, advances in sequencing have improved greatly. One of the most important achievements of Next Generation Sequencing (NGS) is to produce millions of sequence reads in a short period of time, and to produce large sequences of DNA in fragments of any size. Libraries can be generated from whole genomes or any DNA or RNA region of interest without the need to know its sequence beforehand. This allows for looking for variations and facilitating genetic identification. A deep analysis of current NGS technologies and their application, especially in forensics, including a discussion about the pros and cons of these technologies in genetic identification. A systematic literature search in PubMed, Science Direct and Scopus electronic databases was performed for the period of December 2012 to June 2015. In the forensic field, one of the main problems is the limited amount of sample available, as well as its degraded state. If the amount of DNA input required for preparing NGS libraries continues to decrease, nearly any sample could be sequenced; therefore, the maximum information from any biological remains could be obtained. Additionally, microbiome typification could be an interesting application to study for crime scene characterisation. NGS technologies are going to be crucial for DNA human typing in cases like mass disasters or other events where forensic specimens and samples are compromised and degraded. With the use of NGS it will be possible to achieve the simultaneous analysis of the standard autosomal DNA (STRs and SNPs), mitochondrial DNA, and X and Y chromosomal markers.


Improvements in cognition following hospital discharge of community dwelling seniors.
Seniors frequently struggle during the transition home following an acute hospitalization resulting in frequent rehospitalizations. Studies consistently show a lack of comprehension of discharge instructions. To determine the frequency of low cognition at hospital discharge among community dwelling seniors and the changes in cognition that occur one month following hospitalization. Face-to-face surveys were performed at hospital discharge and one month later in the home of the subject. The Mini-Mental Status Examination (MMSE), Backward Digit Span, and 15 Word Immediate and Delayed Recall Tests were used to evaluate cognition. Low cognition was determined to be a score of less than 25 on the MMSE for subjects with high school education and less than 18 for subjects with less than high school education. Two hundred community-dwelling seniors ≥ 70 years, admitted to acute medicine services >24 hours, consenting to their own procedures, not having previously documented cognitive loss, and not admitted for cognitive changes. Upon hospital discharge, 31.5% of subjects had previously unrecognized low cognition. One month later, 58% of these patients no longer had low cognition (p < 0.001). Of those subjects with low cognition, the MMSE improved by an average of 4 points one month post-discharge. Within the MMSE, subjects experienced significant improvements in the areas of orientation, registration, repetition, comprehension, naming, reading, writing, and calculation. Low cognition at discharge is common among elderly patients without dementia, and cognition often improves one month post-hospitalization. Seniors may not comprehend discharge instructions, and patient self-management may be better taught as an outpatient following discharge rather than at the time of hospital discharge. Discharge interventions should incorporate screening of seniors for low cognition prior to hospital discharge to provide optimal transitional care.


How we are shaped: the biomechanics of gastrulation.
Although it is rarely considered so in modern developmental biology, morphogenesis is fundamentally a biomechanical process, and this is especially true of one of the first major morphogenic transformations in development, gastrulation. Cells bring about changes in embryonic form by generating patterned forces and by differentiating the tissue mechanical properties that harness these forces in specific ways. Therefore, biomechanics lies at the core of connecting the genetic and molecular basis of cell activities to the macroscopic tissue deformations that shape the embryo. Here we discuss what is known of the biomechanics of gastrulation, primarily in amphibians but also comparing similar morphogenic processes in teleost fish and amniotes, and selected events in several species invertebrates. Our goal is to review what is known and identify problems for further research.


[Folate determination in spinach. Influence of cultivation, harvest and cooking methods].
The aim of this work was to determine vitamin contents in spinach produced by different cultivation type (organic and traditional), harvesting period and after cooking in water. The determination was carried out by High Performance Liquid Chromatography. There was no significant difference in folate contents between spinach cultivated by traditional and organic method and there was also no significant difference between the values obtained at different periods of the year. Folate levels determined as 5-methylTHF and 5-formylTHF varied from 226 to 527 microg/100 g and 4.6 to 10 microg/100 g, respectively. Cooking in water resulted in approximately 74% of losses of 5-methylTHF and 56% of 5-formylTHF. The mainly losses occurred by leaching.


Restricted trivariate polycube splines for volumetric data modeling.
This paper presents a volumetric modeling framework to construct a novel spline scheme called restricted trivariate polycube splines (RTP-splines). The RTP-spline aims to generalize both trivariate T-splines and tensor-product B-splines; it uses solid polycube structure as underlying parametric domains and strictly bounds blending functions within such domains. We construct volumetric RTP-splines in a top-down fashion in four steps: 1) Extending the polycube domain to its bounding volume via space filling; 2) building the B-spline volume over the extended domain with restricted boundaries; 3) inserting duplicate knots by adding anchor points and performing local refinement; and 4) removing exterior cells and anchors. Besides local refinement inherited from general T-splines, the RTP-splines have a few attractive properties as follows: 1) They naturally model solid objects with complicated topologies/bifurcations using a one-piece continuous representation without domain trimming/patching/merging. 2) They have guaranteed semistandardness so that the functions and derivatives evaluation is very efficient. 3) Their restricted support regions of blending functions prevent control points from influencing other nearby domain regions that stay opposite to the immediate boundaries. These features are highly desirable for certain applications such as isogeometric analysis. We conduct extensive experiments on converting complicated solid models into RTP-splines, and demonstrate the proposed spline to be a powerful and promising tool for volumetric modeling and other scientific/engineering applications where data sets with multiattributes are prevalent.


Molecular genetics of androgen-dependent and -independent expression of mouse sex-limited protein.
Genes of the mouse S locus encoding C4 (the fourth component complement) and Slp (sex-limited protein) show extensive homology but are distinct in their function and regulation. In some mouse strains, such as B10.D2, Slp is androgen regulated, whereas in others, such as B10.W7R, expression of Slp is constitutive. We have previously shown that the B10.W7R strain has multiple Slp genes. In this report, we present the structure of the single C4 and four Slp genes of the B10.W7R S locus and compare the upstream flanking regions by partial sequence analysis and function in transfection assays. Of the four Slp genes, three (Slpw7.A, Slpw7.B, and Slpw7.C) have upstream and promoter regions very similar to those of C4. The fourth Slp gene (Slpw7.D) is instead virtually identical to the androgen-regulated allele (Slpd from the B10.D2 mouse) in upstream regions. In particular, far-upstream sequences from both Slpd and Slpw7.D render the bacterial chloramphenicol acetyltransferase gene hormonally responsive upon transfection into mammary carcinoma cell lines. The upstream sequences between 2 to 3 kilobases of the Slp promoter initiate transcription from multiple sites when fused proximal to the chloramphenicol acetyltransferase gene, and these transcripts are threefold more abundant in the presence of androgen. This behavior is similar for Slpd and Slpw7.D, which suggests that Slpw7.D may be androgen regulated but that this is masked in vivo by constitutive expression of the other Slp genes. Nonhomologous recombination is implicated not only in expanding the copy number of C4 and Slp genes in the B10.W7R mouse but also in creating hybrid genes with regulatory features of C4 and structural features of Slp.


An update on PPAR activation by cannabinoids.
Some cannabinoids activate the different isoforms of PPARs (α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies. Activation of all isoforms, but primarily PPARα and γ, mediates some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumour, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel. PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins. The aims of this review are to update the evidence supporting PPAR activation by cannabinoids and to review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation.