Distinct Aβ pathology in the olfactory bulb and olfactory deficits in a mouse model of Aβ and α-syn co-pathology.
Several degenerative brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the simultaneous appearance of amyloid-β (Aβ) and α-synuclein (α-syn) pathologies and symptoms that are similar, making it difficult to differentiate between these diseases. Until now, an accurate diagnosis can only be made by postmortem analysis. Furthermore, the role of α-syn in Aβ aggregation and the arising characteristic olfactory impairments observed during the progression of these diseases is still not well understood. Therefore, we assessed Aβ load in olfactory bulbs of APP-transgenic mice expressing APP695KM670/671NL and PSEN1L166P under the control of the neuron-specific Thy-1 promoter (referred to here as APPPS1) and APPPS1 mice co-expressing SNCAA30P (referred to here as APPPS1 × [A30P]aSYN). Furthermore, the olfactory capacity of these mice was evaluated in the buried food and olfactory avoidance test. Our results demonstrate an age-dependent increase in Aβ load in the olfactory bulb of APP-transgenic mice that go along with exacerbated olfactory performance. Our study provides clear evidence that the presence of α-syn significantly diminished the endogenous and seed-induced Aβ deposits and significantly ameliorated olfactory dysfunction in APPPS1 × [A30P]aSYN mice.


Molecular imaging, part 1: apertures into the landscape of genomic medicine.
Conventional imaging paradigms rely on the detection of anatomical changes in disease that are preceded by molecular genetic changes that go otherwise undetected. With the advent of molecular imaging, it will be possible to detect these changes prior to the manifestation of disease. Molecular imaging is the amalgamation of molecular biology and imaging technology that was spawned by parallel advances in the two fields. Fundamental to this technique is the ability to directly image biological processes that precede the anatomical changes detected by conventional imaging techniques. The two main strategies for imaging of biologic processes are direct and indirect imaging techniques. Direct techniques use molecules that have specific affinities for targets of interest that can be radiolabeled or otherwise detected on imaging. Indirect imaging uses reporter genes that are coexpressed with therapeutic proteins or other proteins of interest to image vector-transfected cells. Optical imaging and nanotechnology paradigms will also prove to be important additions to the imaging armamentarium. The first installment of this two-part series on molecular imaging seeks to demonstrate basic principles and illustrative examples for the uninitiated neophyte to this field.


Evaluation of performance and validity limits of gas chromatography electron ionisation with Orbitrap detection for fatty acid methyl ester analyses.
While the GC-Orbitrap, marketed in 2015, represents a technological breakthrough in terms of sensitivity, resolution and mass stability, many studies have reported ion ratio modification in mass spectra using the standard 70 eV electron ionisation. We studied the influence of the acquisition and sample parameters leading to these modifications on fatty acid methyl esters (FAMEs). FAMEs showed that these variations in relative intensities of ions were related to the acquisition parameters such as the mass range and the offset values of the C-TRAP, but also directly related to the column concentration of the sample, and especially that it was molecule-dependent. Advantageously, it is possible to use this feature to promote the molecular ions of FAMEs sometimes not present in a spectrum under electron ionisation at 70 eV. The 70 eV electron ionisation mass spectra from the GC-Orbitrap were clearly molecule-dependent and could be due to metastable ions during storage states in the C-TRAP.


Correlation of Body Mass Index with Epidermal Biophysical Properties Varies with Gender in Chinese.
Epidermal function is associated with diabetes and renal disease. Whether obesity can reflect the changes in epidermal function is not clear yet. We assessed here the correlation of epidermal functions with body mass index (BMI) in a large Chinese cohort. A total of 1,405 Chinese aged 21-98 years old were enrolled in this study. Epidermal functions, including transepidermal water loss (TEWL), stratum corneum hydration, and skin surface pH, were measured on the flexor forearm and the shin. Subjects' height and body weight were also measured. Age positively correlated with both TEWL and skin surface pH, while it negatively correlated with stratum corneum hydration on both the forearm and the shin of females. Similarly, age positively correlated with skin surface pH, while negatively correlating with stratum corneum hydration on both the forearm and the shin of males. In females, BMI positively correlated with skin surface pH, while it negatively correlated with stratum corneum hydration on both the forearm and the shin. However, BMI correlated neither with skin surface pH on both the forearm and the shin nor with stratum corneum hydration on the shin of males. These results demonstrate that correlations of BMI with age and epidermal functions vary with gender.


Effect of Melilotus officinalis extract on the apoptosis of brain tissues by altering cerebral thrombosis and inflammatory mediators in acute cerebral ischemia.
Present investigation evaluates the protective effect of Melilotus officinalis (MO) extract on the brain tissues in acute cerebral ischemia. Acute cerebral ischemia was induced by occlusion of carotid artery and rats with cerebral ischemia were treated with MO (100, 250 & 500mg/kg) for the duration of three days. Cerebral ischemia was confirmed by estimating infract volume and neurological deficit score. Moreover biochemical parameters in plasma such as 6-keto-PGF1α and TXB2 and concentration of cytokine, oxidative stress, apoptosis ratio and protein expressions of Bcl2 & Bax were estimated in the brain tissues. It was observed that treatment with MO significantly (p<0.01) decreases the infract volume and neurological deficit score than negative control group. There was significant decrease (p<0.01) in the oxidative stress and cytokine in the brain tissues and increase in the plasma concentration of 6-keto-PGF1α in MO treated group of rats compared to negative control group. Plasma concentration of TXB 2 was significantly enhanced in MO treated group compared to negative control group of rats. It was also found that treatment with MO ameliorates the apoptosis induced by cerebral ischemia. Present study concludes that MO ameliorates apoptosis of brain tissues in cerebral ischemic rats by decreasing cerebral thrombosis, oxidative stress and inflammatory mediators.


Inhibition of simian immunodeficiency virus by foamy virus vectors expressing siRNAs.
Viral vectors available for gene therapy are either inefficient or suffer from safety concerns for human applications. Foamy viruses are non-pathogenic retroviruses that offer several unique opportunities for gene transfer in various cell types from different species. In this report, we describe the use of simian foamy virus type 1 (SFV-1) vector to examine the efficacy of therapeutic genes. Hairpin short-interfering RNA (siRNA) that targets the simian immunodeficiency virus (SIV) rev/env was placed under the control of the PolIII U6 snRNA promoter for expression and screened for silencing target genes using cognate target-reporter fusions. We have identified an effective siRNA (designated R2) which reduces the rev and env gene expression by 89% and 95%, respectively. Using the simian foamy virus type 1 (SFV-1) based vector, we delivered the PolIII expressed R2 siRNA into cultured cells and challenged with SIV. The results show that the R2 siRNA is a potent inhibitor of SIV replication as determined by p27 expression and reverse transcriptase assays. Vectors based on a non-pathogenic SFV-1 vector may provide a safe and efficient alternative to currently available vectors, and the SIV model will help devise protocols for effective anti-HIV gene therapy.


Left or right temporal lesion might induce aggression or escape during awake surgery, respectively: role of the amygdala.
Some patients with temporal lobe brain tumours show aggressive or escape behaviour during awake surgery. As the amygdala plays a critical role in coping with stress, we evaluated whether the left or right amygdala was involved in aggressive or escape behaviour in six patients undergoing awake surgery for temporal lobe brain tumours. Brain tumours were located in the left temporal lobe in cases 1-3 and in the right temporal lobe in cases 4-6. In cases 1, 2, 4 and 5, the tumours invaded the amygdala. In case 1, the patient showed aggressive behaviour before partial removal of the left amygdala during awake surgery; just after partial removal of left amygdala, the patient was calm and cooperative. In case 2, the patient showed aggressive behaviour when the tumour near the left amygdala was removed. In case 3, the patient showed aggressive behaviour when awakening during awake surgery. In case 4, the patient showed escape behaviour when removal of the tumour near the right amygdala was initiated. In cases 5 and 6, patients showed escape behaviour upon awakening and upon initiation of tumour removal from the temporal lobe. In conclusion, these results suggest that left or right temporal lesions might induce aggressive or escape behaviour during awake surgery, respectively, and that the amygdala on the respective side may play a role in these behaviours.


Increasing Awareness on Substance Use Disorder.
There is a lack of substance use disorder (SUD) providers in the micropolitan Midwestern state. Individuals who live in rural areas with SUD may have a gap in treatment for their addiction. The objective of this quality improvement project was to increase the engagement, participation, and awareness of rural primary care providers in treatment of individuals with SUD. This is a quality improvement project that utilized a skip-logic standardized survey to evaluate participants who attended Project ECHO (Extension for Community Healthcare Outcomes) Addiction educational sessions. Findings included 176 participants over 14 sessions, while reaching primary care providers in 62 clinics over a 7-month period. However, it was found that only half of those participants completed the survey. A variety of topics surrounding SUD were offered. In addition, each session included a case study with feedback provided by the team. Seventy participants (79%) rated "strongly agree" and "agree" to "I will make changes to my practice." Participants provided feedback as to how they would change their practice after an educational session; responses included adapting how naltrexone is prescribed based on the recommendations made during the presentation, update treatment guidelines, screen for adverse childhood experiences, utilize motivational interviewing, feeling more confident in providing medication-assisted treatment for patients, and finally, better able to manage pain in those with SUD. Project ECHO Addiction is an evidence-based translational quality improvement project that reaches rural primary care providers to help increase awareness, engagement, and networking in treatment of patients with SUD, which in turn improves patient outcomes as they receive treatment in a timely fashion.


Novel and efficient synthesis of N,N-dialkylaminoand O-alkylphenyl-2-(1-alkyl/phenyl-2-oxopropylidene) phosphonohydrazido oximes--potential marine fish toxin analogues. Part 2.
A novel and efficient method for the synthesis of N,N-dialkylamino/O-alkyl phenyl-2-(1-alkyl/phenyl-2-oxopropylidene) phosphonohydrazido oximes 4 using activated silica has been developed. The reaction involves the condensation of substituted alpha-ketooxime and N,N-dialkylaminophenylphosphonohydrazides or O-alkylphenylphosphonohydrazides and gave the corresponding phosphonohydrazido oximes in excellent yields under mild conditions.


Bronchodilator effect of infused B-type natriuretic peptide in asthma.
To determine the bronchodilator effect of recombinant human B-type natriuretic peptide (BNP; nesiritide) on patients with asthma. A prospective, open-label study. Outpatient setting. Eight adult patients with asthma confirmed by > 12% and > 200 mL increase in FEV1 after bronchodilator inhalation. An IV nesiritide bolus, 2 microg/kg, followed by continuous infusion for a total of 3 h at escalating doses of 0.01, 0.02, and 0.03 microg/kg/min for 1 h each as tolerated. Spirometry and forced oscillation technique (FOT) measurements were both obtained at baseline and every 30 min during the infusion. Two doses of albuterol, 90 microg, inhalation via metered-dose inhaler were then administered at the end of nesiritide infusion, followed by repeat spirometry and FOT measurements after 30 min. Primary end points were FEV1 and FVC changes after the nesiritide infusion for 3 h. Wilcoxon signed-ranks tests were used to compare the effects of nesiritide and albuterol. Baseline measurements (mean +/- SD) were as follows: FEV1, 1.89 +/- 0.87 L; FVC, 3.02 +/- 0.99 L; respiratory resistance at 5 Hz (Rrs5), 10.3 +/- 3.85 cm H2O . s/L; and mean respiratory resistance at 5 to 20 Hz, 7.56 +/- 1.92 cm H2O/L/s. Mean baseline serum BNP level was 27 +/- 27 pg/mL. After 180 min of nesiritide infusion, the following measurements showed significant changes: FEV1 increased to 2.41 +/- 0.78 L (mean increase, 520 mL), p = 0.012; FVC increased to 3.65 +/- 1.05 L (mean increase, 630 mL), p = 0.017; and Rrs5 decreased to 8.24 +/- 4.02 cm H2O/L/s, p = 0.017. After albuterol, there were no further significant changes in these measurements. IV nesiritide is an effective bronchodilator in patients with asthma.


alpha1-syntrophin gene disruption results in the absence of neuronal-type nitric-oxide synthase at the sarcolemma but does not induce muscle degeneration.
alpha1-Syntrophin is a member of the family of dystrophin-associated proteins and is strongly expressed in the sarcolemma and the neuromuscular junctions. All three syntrophin isoforms have a PDZ domain that appears to participate in protein-protein interactions at the plasma membrane. alpha1-Syntrophin has additionally been shown to associate with neuronal nitric-oxide synthase (nNOS) through PDZ domains in vitro. These observations suggest that alpha1-syntrophin may work as a modular adaptor protein that can link nNOS or other signaling enzyme to the sarcolemmal dystrophin complex. In the sarcolemma, nNOS regulates the homeostasis of reactive free radical species and may contribute to the oxidative damage to muscle protein in muscle disease such as Duchenne muscular dystrophy. In this study, we generated alpha1-syntrophin knock-out mice to clarify the interaction between alpha1-syntrophin and nNOS in the skeletal muscle. We observed that nNOS, normally expressed in the sarcolemma, was largely absent from the sarcolemma, but considerably remained in the cytosol of the knock-out mice. Even though the distribution of nNOS was altered, the knock-out mice displayed no gross histological changes in the skeletal muscle. We also discovered that muscle contractile properties have not been influenced in the knock-out mice.


Macrophage polarization in atherosclerosis.
Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.


Novel Cardiac Imaging Risk Score for Mortality Prediction in Duchenne Muscular Dystrophy.
Cardiovascular disease is the leading cause of death in patients with Duchenne Muscular Dystrophy (DMD), but there is significant cardiomyopathy phenotypic variability. Some patients demonstrate rapidly progressive disease and die at a young age while others survive into the fourth decade. Criteria to identify DMD subjects at greatest risk for early mortality could allow for increased monitoring and more intensive therapy. A risk score was created describing the onset and progression of left ventricular dysfunction and late gadolinium enhancement in subjects with DMD. DMD subjects prospectively enrolled in ongoing observational studies (which included cardiac magnetic resonance [CMR]) were used to validate the risk score. A total of 69 subjects had calculable scores. During the study period, 12 (17%) died from complications of DMD. The median risk score was 3 (IQR [2,5]; range [0,9]). The overall risk score applied at the most recent imaging age was associated with mortality at a median age of 17 years (IQR [16,20]) (HR 2.028, p < 0.001). There were no deaths in subjects with a score of less than two. Scores were stable over time. An imaging-based risk score allows risk stratification of subjects with DMD. This can be quickly calculated during a clinic visit to identify subjects at greatest risk of early death.


Transfer of IgE-mediated hypersensitivity with autologous stem cell transplantation.
In this paper, the transfer of IgE-mediated food allergy by means of autologous stem cell transplantation in a 24-years old male patient is reported.


The WHO histological classification of urinary bladder tumours.
The WHO histological classification of urinary bladder tumours was formulated to promote better international communication and more reliable statistical comparisons. The axes of classification concern histological type, grade of anaplasia and growth pattern.


Primary malignant melanoma of the oral cavity: a case report.
A rare case of a primary malignant melanoma of the upper alveolus with rapid spread to the cervical lymph nodes and brain in a 47-year-old man is described.


Population history of Manihot esculenta (Euphorbiaceae) inferred from nuclear DNA sequences.
The nature of gene flow in plants -- including the propensity for interspecific introgression -- makes them interesting candidates for phylogeographical analysis. Plant phylogeography studies have been limited, however, by the availability of suitable intraspecific variation. In this study, DNA sequence variation from a nuclear gene [Glyceraldehyde 3-phosphate dehydrogenase; (G3pdh)] was used to examine the population history of Manihot esculenta ssp. flabellifolia and a potentially hybridizing species, M. pruinosa. These species occur in the rainforest-savanna ecotone adjoining the Amazon basin, a region believed to have undergone major habitat shifts since the Pleistocene. Geographical distributions of the G3pdh haplotypes indicate genetic isolation-by-distance across the range of M. esculenta ssp. flabellifolia. However, there is greater genetic similarity between northeastern and western populations than would be expected given the present species distribution. A nested clade analysis suggests that northeastern and western populations were connected by gene flow until relatively recently, when they became fragmented. This inferred fragmentation event is consistent with post-Pleistocene habitat shifts proposed for the Amazon basin. At the interspecific level, haplotype sharing with M. pruinosa may reflect either recent interspecific introgression or incomplete lineage sorting between these closely related species.


Appendico-cutaneous fistula in cystic fibrosis.
Appendico-cutaneous fistulae are rare. We describe a 12-year-old girl with cystic fibrosis (CF) and a chronically draining sinus in the right iliac fossa, found to be a primary appendico-cutaneous fistula. Misdiagnosis of right iliac fossa pain in patients with CF and the preponderance of complicated disease frequently lead to manifestations of appendicitis rarely seen in usual clinical practice.


A case report of a successful alternative regiment therapy for toxoplasma encephalitis in AIDS patients.
AIDS patients are more susceptible to opportunistic diseases, such as toxoplasma encephalitis, because of weakened immune systems. Toxoplasma encephalitis manifests as a severe neurological crisis in HIV patients. The standard initial treatments are sulfadiazine and pyrimethamine. This case presents an HIV patient treated with an alternative regimen for toxoplasma encephalitis. A young Acehnese man, 32 years old, arrived at the emergency unit after complaining of a general seizure 2 hours before arrival. He has a history of a two-week fever and white patches on his tongue and oral cavity. The result of the HIV test was positive, and after a thorough examination, he was diagnosed with toxoplasma encephalitis. The patient was given cotrimoxazole 960 mg twice daily and clindamycin 600 mg four times daily as an alternative treatment. Clinical improvement was reported after six weeks of therapy. A case of toxoplasma encephalitis was reported. The first-line treatment for toxoplasma encephalitis is pyrimethamine and sulfadiazine; however, the patient was treated with cotrimoxazole and clindamycin as an alternative treatment. Clinical improvement was used to assess the success of therapy. Cotrimoxazole and clindamycin can be utilized as alternative regiment therapy if the first-line treatment option is unavailable.


The evolution of treatment for Wilms tumor.
The prognosis for children with Wilms tumor (WT) has improved dramatically as the result of advances in surgical techniques, anesthesia, and supportive care. During the last three decades, the National Wilms Tumor Study Group (NWTSG), the International Society of Pediatric Oncology (SIOP), and the United Kingdom Children's Cancer Study Group (UKCCSG) conducted sequential studies of treatments for children with WT. The National Wilms Study Group demonstrated that radiation therapy is not necessary for those with Stage I and II, favorable histology Wilms tumor, and that the dose necessary for local control for those with local Stage III disease is 1050 to 1080 cGy. Administration of actinomycin D and doxorubicin using a single dose rather than divided dose schedule produced less myelosuppression and equivalent outcomes. Loss of heterozygosity for chromosomes 1p and 16q was associated with an inferior outcome. Areas for future investigation include the role of whole lung irradiation in the treatment of those with pulmonary metastases, the use of parenchymal sparing surgical techniques for removal of Wilms tumors, and identification of minimal necessary therapy.


Opiate tolerance and dependence: receptors, G-proteins, and antiopiates.
Despite the existence of a large body of information on the subject, the mechanisms of opiate tolerance and dependence are not yet fully understood. Although the traditional mechanisms of receptor down-regulation and desensitization seem to play a role, they cannot entirely explain the phenomena of tolerance and dependence. Therefore, other mechanisms, such as the presence of antiopiate systems and the coupling of opiate receptors to alternative G-proteins, should be considered. A further complication of studies of opiate tolerance and dependence is the multiplicity of endogenous opiate receptors and peptides. This review will focus on the endogenous opioid system--peptides, receptors, and coupling of receptors to intracellular signaling via G-proteins--in the context of their roles in tolerance and dependence. Opioid peptides include the recently discovered endomorphins and those encoded by three known genes--pro-opiomelanocortin, pro-enkephalin, and pro-dynorphin. They bind to three types of receptors--mu, delta, and kappa. Each of the receptor types is further divided into multiple subtypes. These receptors are widely known to be coupled to G-proteins of the Gi and Go subtypes, but an increasing body of results suggests coupling to other G-proteins, such as Gs. The coupling of opiate receptors to Gs, in particular, has implications for tolerance and dependence. Alterations at the receptor and transduction level have been the focus of many studies of opiate tolerance and dependence. In these studies, both receptor down-regulation and desensitization have been demonstrated in vivo and in vitro. Receptor down-regulation has been more easily observed in vitro, especially in response to morphine, a phenomenon which suggests that some factor which is missing in vitro prevents receptors from down-regulating in vivo and may play a critical role in tolerance and dependence. We suggest that antiopiate peptides may operate in vivo in this capacity, and we outline the evidence for the antiopiate properties of three peptides: neuropeptide FF, orphanin FQ/nociceptin, and Tyr-W-MIF-1. In addition, we provide new results suggesting that Tyr-W-MIF-1 may act as an antiopiate at the cellular level by inhibiting basal G-protein activation, in contrast to the activation of G-proteins by opiate agonists.


Pericardial heterograft valves: an assessment of leaflet stresses and their implications for heart valve design.
Bovine pericardium, stabilized with glutaraldehyde, is used widely in the construction of heart valve substitutes, but the design and construction of valve substitutes from this material are empirically based. Collagenous tissue can support tension, but experimental evidence indicates that flexure-induced compressive stresses can lead to fatigue failure. This study uses experimental results obtained from cyclic uniaxial load tests to predict the type and magnitude of operational stresses which occur in pericardial heterograft leaflets. Both Young's modulus and Poisson's ratio varied with uniaxial loading in pericardium, chemically modified free of tension. Leaflet stresses were analysed in using effective incremental representations of these parameters. In leaflets with unrestricted rotation at the point of attachment to the stent, the mid-plane tensions always exceeded the bending stresses, and no zones of leaflet compression were predicted. In contrast, with totally restricted leaflet rotation induced by clamping (possibly between a male and female frame) the bending stresses were greater than the mid-plane tensions at the hinge line and significant compressive stresses were predicted at this site. If elastic boundary conditions were introduced at the stent (possibly by wrapping the stent in pericardium) then the compressive stresses were reduced as the degree of elasticity was increased. Glutaraldehyde fixation of the pericardium under load produced a stiffer material; higher compressive stresses at the stent and significant increases in total stress were predicted for this tissue. The application of elevated pressure loading also increased the compressive and total stresses in the leaflet. Finally, it was shown that bicuspid leaflets were likely to experience higher stresses than tricuspid leaflets. This simple stress analysis should help valve designers of pericardial heterografts to identify those conditions which lead to tissue compression, high total stress, and ultimately material fatigue.


Cross-sectional evaluation of the association between greenness and cognitive performance in Mexican pre-pubertal boys.
Evidence shows that greenspace exposure benefits children's health and cognitive development. However, evidence assessing this association in young children in low- and middle-income economies is scarce. To assess the association between exposure to greenness and cognitive performance in pre-pubertal boys living in Mexico City. Cross-sectional study using data from 144 boys aged 6-11 years living in Mexico City in 2017 and enrolled in the "MetCog" study. Cognitive performance was evaluated through selected Wechsler Scale for Intelligence in Children Fourth Edition (WISC-IV) and Neuropsychological Assessment of Children (Evaluación Neuropsicológica Infantil, ENI) tests. Exposure to greenness was assessed through Normalised Difference Vegetation Index (NDVI) at 300, 500, 1500, 2000, and 3000 m buffer zones from children's residences. Multiple linear regression analysis was undertaken to assess associations between cognitive performance and greenness (aβ) with 95% confidence intervals (CI) and adjusted for potential confounding variables. Significance was set at q < 0.05 after False Discovery Rate (FDR) correction. A positive association was found between the NDVI Interquartile Range (IQR) at 2000 m and the WISC-IV block design test score (aβ 2000 = 1.18, 95% CI = 0.31, 2.06; q < 0.05), which assesses perceptual reasoning. Positive associations were found with NDVI IQR at 1500 m and WISC-IV block design (aβ1500 = 1.00, 95% CI = 0.14, 1.86) and matrix reasoning (aβ1500 = 0.83, 95% CI = 0.06, 1.61) scores, but neither survived FDR correction. No significant associations were found between NDVI IQR at any buffer size with other WISC-IV and ENI task scores. Greater exposure to greenness was associated with higher perceptual reasoning skills in 144 pre-pubertal boys living in Mexico City. Thus, urban planning should consider increasing vegetation in megacities, especially in neighbourhoods with high percentages of young children.


Interpreting the trail making test following traumatic brain injury: comparison of traditional time scores and derived indices.
The purpose of this study was to examine the clinical application of traditional time scores and various derived indices from the Trail Making Test (TMT) in a sample of 571 patients with acute traumatic brain injury (TBI). Participants were classified into four injury severity groups. A clear linear relation between injury severity and TMT performance was demonstrated, with the more severely brain injured patients performing more poorly on most measures. Hierarchical logistic regression analysis of TMT time scores across binary extreme groups based on injury severity resulted in high classification rates for patients with very mild TBI (93.0% correctly classified) and low classification rates for patients with moderate to severe TBI (50.0% correctly classified). However, TMT derived indices did not provide a unique contribution to test interpretation beyond what is already available from Part A and B separately.


Epidemiology of early onset dementia and its clinical presentations in the province of Modena, Italy.
Patients with early onset dementia (EOD), defined as dementia with symptom onset at age <65, frequently present with atypical syndromes. However, the epidemiology of different EOD presentations, including variants of Alzheimer's disease (AD) and frontotemporal dementia (FTD), has never been investigated all together in a population-based study. Epidemiologic data of all-cause EOD are also scarce. We investigated EOD epidemiology by identifying patients with EOD seen in the extended network of dementia services of the Modena province, Northern Italy (≈700,000 inhabitants) from 2006 to 2019. In the population age 30 to 64, incidence was 13.2 per 100,000/year, based on 160 new cases from January 2016 to June 2019, and prevalence 74.3 per 100,000 on June 30, 2019. The most frequent phenotypes were the amnestic variant of AD and behavioral variant of FTD. EOD affects a significant number of people. Amnestic AD is the most frequent clinical presentation in this understudied segment of the dementia population.


Utility of ultrasound in the diagnosis of chronic worsened gout.
Ultrasound (US) may be used to diagnose chronic worsened gout. US confirmed the clinical evidence of tophaceous deposits in the left elbow of a 75-year-old man; it also identified crystalline materials on the cartilage surface of the second metacarpophalangeal joint of the left hand. US may be helpful to detect signs of deposition of monosodium urate crystals in periarticular and intra-articular joints of patients with clinically suspected chronic worsened gout.


Intraoperative portal vein stenting through umbilical vein approach: An innovative salvage procedure for portal vein thrombosis in pediatric liver transplant.
IPVS is considered a last resort or a salvage procedure in the event of recurrent PV thrombosis despite multiple attempts at redo PV anastomosis. We employed the opened umbilical vein approach to place the stent in the PV and deliver anticoagulation through a catheter. From Jan 2017 to Feb 2022, 150 patients underwent pediatric transplantation at department of liver transplant and hepatobiliary surgery unit, Indraprastha Apollo hospitals, New Delhi. Age, weight, PELD Score, diagnosis, portal vein diameter on preoperative CT, Portal flow after stenting, decrease in spleen size after stenting in follow-up CT were collected from a prospectively maintained data base and reviewed. Eight patients underwent IPVS following LDLT (mean age-10.6 ± 2.2 months, mean weight 8.1 ± 1.6, mean PELD score 32.7 ± 7.3). The mean PV diameter on preoperative CT scan was 3.6 mm (range 2.7-5.6 mm). The mean portal flow following stenting was 718.75 cc/min. Percentage reduction in size of the spleen was 26.35% beyond 2nd post-operative week. No patient had recurrent PV thrombosis following IPVS and all maintained an adequate portal flow throughout the immediate postoperative period. Two patients had in-hospital mortality secondary to septic complications. Umbilical vein approach is technically feasible, easy to manipulate the stent and catheter placement after stenting helps to deliver anticoagulants locally.


Electrogenic transport of 5-oxoproline in rabbit renal brush-border membrane vesicles. Effect of intravesicular potassium.
The Na+-dependent transport of 5-oxoproline into rabbit renal brush-border vesicles was stimulated by a K+ diffusion potential (interior-negative) induced by valinomycin. Na+ salts of two anions of different epithelial permeabilities also affected 5-oxoproline transport. These results show that the Na+-dependent 5-oxoproline transport in renal brush-border vesicles is an electrogenic process which results in a net transfer of positive charge. Maximum transport of 5-oxoproline occurred at an extravesicular pH of 6.0 to 8.0 and over that pH range, 5-oxoproline exists completely as an anion with a negative charge. The simplest stoichiometry consistent with this process is, therefore, the cotransport of one 5-oxoproline anion with two sodium ions. The presence of K+ inside the vesicles stimulated the Na+-dependent transport of 5-oxoproline. This stimulatory effect was specific for K+ and required the presence of Na+. The presence of Na+ gradient was not mandatory for the K+ action. The stimulation by the intravesicular K+ was seen in the presence as well as in the absence of a K+ gradient. Therefore, the increased influx of 5-oxoproline was not coupled to the simultaneous efflux of K+. The presence of K+ in the extravesicular medium alone did not affect the Na+-dependent transport of 5-oxoproline, showing that the site of K+ action was intravesicular. Glutamate did not interact with the Na+-dependent 5-oxoproline transport even in the presence of an outward K+ gradient.


Effect of vitamin E on stroke-associated pneumonia.
To study the role of vitamin E in stroke-associated pneumonia. We selected 183 patients with stroke-related pneumonia who were divided into different nutrition groups according to the Mini Nutritional Assessment score. Patients were then administered different doses of vitamin E. CD55 and CD47 levels in patients taking vitamin E across different nutrition score groups were better than those in patients who did not use vitamin E. The levels of CD55 and CD47 and the duration of hospitalization were better in the high-dose vitamin E group than in the low-dose vitamin E group. Vitamin E may have an auxiliary therapeutic effect in patients with stroke-associated pneumonia.


The L-arginine/NO pathway in end-stage liver disease and during orthotopic liver and kidney transplantation: biological and analytical ramifications.
The L-arginine/nitric oxide (L-Arg/NO) pathway is altered in liver and kidney diseases. However, the status of the L-Arg/NO pathway during and after orthotopic transplantation is insufficiently investigated and findings are uncertain because of analytical shortcomings. Also, most human studies have focused on individual members of the L-Arg/NO pathway such as nitrate or asymmetric dimethylarginine (ADMA). In the present article we report on a pilot study investigating extensively the status of the L-Arg/NO pathway before and during orthotopic liver transplantation (OLT). By using fully validated, highly sensitive and specific GC-MS and GC-MS/MS methods nitrite, nitrate, ADMA and its hydrolysis product dimethylamine (DMA), L-arginine and L-ornithine were measured in blood and urine. Our study gives strong evidence of the exceptional importance of hepatic dimethylarginine dimethylaminohydrolase (DDAH) activity for the elimination of systemic ADMA. In end-stage liver disease the synthesis of NO and ADMA as well as the DDAH activity are elevated. However, increase in DDAH activity is insufficient to efficiently eliminate overproduced ADMA. The transplanted liver graft is capable of clearing ADMA in a rapid and sufficient manner. In contrast to studies from other groups, our study shows that in OLT as well as in living donor kidney transplantation, the second study reported here, reperfusion of the graft does not cause drastic alterations to the L-Arg/NO pathway with regard to NO synthesis. In the OLT study the concentration of circulating L-arginine fell temporally dramatically, while L-ornithine levels increased diametrically, most likely due to elevation of arginase activity. However, the relatively long-lasting decrease in plasmatic L-arginine in OLT seems not to have affected NO synthesis after reperfusion. Our OLT study suggests that liver reperfusion is associated with greatly elevated activity of proteolytic and hydrolytic enzymes including DDAH and arginase. Suppression of proteolytic and hydrolytic activity in transplantation could be a useful measure to improve outcome and remains to be investigated in further studies on larger patient collectives. The importance of analytical chemistry in this area of research is also discussed in this article.


Selective inhibition by minoxidil of prostacyclin production by cells in culture.
The effect of minoxidil on arachidonic acid metabolism by cells in culture was studied. In bovine aorta endothelial cells, treatment with minoxidil in the presence of various stimulators of arachidonic acid metabolism was accompanied by a dose-dependent inhibition of prostacyclin production (measured as 6-keto-prostaglandin F1 alpha). Synthesis of the other cyclooxygenase products (prostaglandins E2, F2 alpha and thromboxane) was not inhibited. When the bovine aorta endothelial cells were stimulated by the Ca2+ ionophore A-23187, the inhibition was seen as early as 2 min. Minoxidil also inhibited prostacyclin production by a second cell line of bovine aorta endothelial cells (the established CPAE cell line), bovine aorta smooth muscle cells, porcine aorta endothelial cells, and rat liver cells (the C-9 cell line)--the latter, less effectively. Again, formation of all the other cyclooxygenase products studied was not inhibited. Minoxidil did not affect significantly prostaglandin E2 and F2 alpha production by newborn rat keratinocytes (the NBR cell line)--a cell that does not produce PGI2. The clinical, biochemical, and pharmacologic implications are discussed.


NRG-1 Stimulates Serum DJ-1 Increase in Breast Cancers.
To explore the relationship between the expression of DJ-1/HER3 and tumor grade in breast cancer, and investigate the effect of HER3 on NRG-1-mediated serum DJ-1 level in vivo. We analyze the expression level of DJ-1 and HER3 in 68 patients with different grades of breast cancer by immunostaining the tissue microarray. Besides, we investigated the serum DJ-1 level by ELISA. We found that the detectable DJ-1 protein expression is decreased, and the HER3 expression is increased in tumor tissue with the progression of breast cancer. There is a significant rise of DJ-1 in serum in vivo with the stimulation of NRG-1. Meanwhile, we found that HER3 knockdown abolishes NRG-1-induced serum DJ-1 increase and HER3 overexpress improves NRG-1-induced serum DJ-1 increase. This study provides a serum biomarker for breast cancer. The results showed that DJ-1 was associated with clinical stage of breast cancer, and NRG-1 increased the dissociation of HER3 and DJ-1, with promoting the level of DJ-1 in peripheral blood. It is suggested that the level of DJ-1 in peripheral blood may be conducive to assess the prognosis of patients with breast cancer and serum DJ-1 levels can serve as an indicator of therapeutic effectiveness for the development of HER3 targeting breast cancer antibody therapies.


MicroRNA-223-3p modulates dendritic cell function and ameliorates experimental autoimmune myocarditis by targeting the NLRP3 inflammasome.
Autoimmune myocarditis is a cause of dilated cardiomyopathy and heart failure. MicroRNAs regulate many immune processes, but their role in aberrant inflammation during autoimmune myocarditis remains unclear. In this study, we investigated the role of miR-223-3p in experimental autoimmune myocarditis (EAM). We found that miR-223-3p expression was significantly lower in EAM mice than that in normal mice. miR-223-3p inhibited NLRP3 inflammasome expression, promoting the polarization of dendritic cells (DCs) towards a tolerogenic DC phenotype. miR-223-3p effectively induced regulatory T cell (Treg) generation by inhibiting the function of antigen-presenting DCs. Transfer of miR-223-3p-overexpressing DCs protected mice against the development of EAM. Our findings suggest that miR-223-3p is involved in the induction of the tolerogenic DC phenotype and regulates tolerance in autoimmune myocarditis.


Reduction of the ST6 β-galactosamide α-2,6-sialyltransferase 1 (ST6GAL1)-catalyzed sialylation of nectin-like molecule 2/cell adhesion molecule 1 and enhancement of ErbB2/ErbB3 signaling by microRNA-199a.
Nectin-like molecule 2 (Necl-2)/cell adhesion molecule 1 (CADM1) is shown to be down-regulated by the promoter hypermethylation and/or loss of heterozygosity at chromosome 11q23.2 in many types of cancers, including lung and breast cancers, and is proposed to serve as a tumor suppressor. However, the incidence of these epigenetic and genetic abnormalities of Necl-2 is 30-60% in these cancers, and other mechanisms for the suppression of Necl-2 are presumed to be present. We previously showed that Necl-2 interacts in cis with ErbB3 and suppresses the heregulin (HRG)-induced ErbB2/ErbB3 signaling for cell movement and death. We studied here the relationship between Necl-2 and microRNA-199a (miR-199a) that is up-regulated or down-regulated in a variety of cancers. miR-199a did not directly target the Necl-2 mRNA or affect its mRNA level in human lung cancer A549 cells and human embryonic kidney HEK293 cells. Necl-2 was at least sialylated by the sialyltransferase ST6 β-galactosamide α-2,6-sialyltransferase 1 (ST6GAL1). miR-199a targeted ST6GAL1 and reduced both the sialylation and the protein level of Necl-2. In addition, miR-199a enhanced the HRG-induced ErbB2/ErbB3 signaling. These results indicate that the suppressive role of Necl-2 in the HRG-induced ErbB2/ErbB3 signaling is regulated by miR-199a at least through the reduction of the ST6GAL1-catalyzed sialylation of Necl-2 and/or through the reduction of the protein level of Necl-2 presumably by the protein degradation.


Noninvasive Cerebral Perfusion and Oxygenation Monitoring Augment Prolonged Field Care in a Non-Human Primate Model of Decompensated Hemorrhage and Resuscitation.
Decompensated hemorrhagic shock (DHS) is the leading cause of preventable death in combat casualties. "Golden hour" resuscitation effects on cerebral blood flow and perfusion following DHS in prolonged field care (PFC) are not well investigated. Using an established non-human primate model of DHS, we hypothesized noninvasive regional tissue oxygenation (rSO2) and Transcranial Doppler (TCD) would correlate to the invasive measurement of partial pressure of oxygen (PtO2) and mean arterial pressure (MAP) in guiding hypotensive resuscitation in a PFC setting. Ten rhesus macaques underwent DHS followed by a 2 h PFC phase (T0-T120), and subsequent 4 h hospital resuscitation phase (T120-T360). Invasive monitoring (PtO2, MAP) was compared against noninvasive monitoring systems (rSO2, TCD). Results were analyzed using t tests and one-way repeated measures ANOVA. Linear correlation was determined via Pearson r. Significance = P < 0.05. MAP, PtO2, rSO2, and mean flow velocity (MFV) significantly decreased from baseline at T0. MAP and PtO2 were restored to baseline by T15, while rSO2 was delayed through T30. At T120, MFV returned to baseline, while the Pulsatility Index significantly elevated by T120 (1.50 ± 0.31). PtO2 versus rSO2 (R2 = 0.2099) and MAP versus MFV (R2 = 0.2891) shared very weak effect sizes, MAP versus rSO2 (R2 = 0.4636) displayed a low effect size, and PtO2 versus MFV displayed a moderate effect size (R2 = 0.5540). Though noninvasive monitoring methods assessed here did not correlate strongly enough against invasive methods to warrant a surrogate in the field, they do effectively augment and direct resuscitation, while potentially serving as a substitute in the absence of invasive capabilities.


Comparative Characteristics of the Spleen White Pulp in Experimental Models of Sepsis Caused by Different Strains of Pseudomonas aeruginosa.
We describe reactive changes in the spleen white pulp in male C57BL/6 mice with experimental sepsis induced by intraperitoneal administration of Pseudomonas aeruginosa 1840 (Pa1840) with exotoxin U gene or Pseudomonas aeruginosa 1623 (Pa1623) with exotoxin S gene. Histological analysis and morphometry revealed hypoplasia of the spleen white pulp in mice with sepsis induced by Pa1840, while sepsis caused by Pa1623 was associated with its hyperplasia; with apoptosis of white pulp cells was observed in both cases. The results attest to ambiguous nature of the reactive changes in the white pulp of the spleen in experimental sepsis models initiated by Pa1840 and Pa1623 stains.


Power-Doppler perfusion phenotype in RA patients is dependent on anti-citrullinated peptide antibody status, not on rheumatoid factor.
It is not known whether there are any consistent non-serological differences between seropositive and seronegative rheumatoid arthritis, and if any, whether they depend upon rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), or both. In a pilot study, we showed that the two forms could be differentiated using power-Doppler sonography (PDS), and that the difference is ACPA dependent. This extended study explored whether the previous findings could be confirmed. 103 patients 51 ACPA positive (ACPA +), 52 ACPA negative (ACPA -) with active wrist arthritis were examined using PDS. By means of a temporal image series, pulsatility was evaluated over a 3-5-s period, maximum and minimum perfusion signal were determined using a computer program counting the number of coloured pixels for each frame. Maxima (Pmax) and minima (Pmin) were determined, and the standardized peak-to-peak amplitude sA was calculated (sA = (Pmax - Pmin)/Pmax). This parameter was then compared for ACPA + and ACPA- patients. In addition, a multivariate regression was performed, to determine which factors influence sA. sA differed significantly between ACPA + and ACPA- patients [20% (13-26) vs. 41% (32-57), p < 0. 0001]. In the multivariate analysis, age (t = 2.5, p = 0.02) and ACPA status (t = - 4.8, p < 0.0001) were independent predictors of sA. PDS perfusion patterns are different in seropositive and seronegative RA. The difference appears to be ACPA, not RF dependent. This suggests that the underlying pathophysiological process is different in ACPA-positive and ACPA-negative RA.


An Alcian blue (pH 2.5)-PAS-keratin immunoperoxidase method for the simultaneous demonstration of keratin and neutral and acidic mucosubstances.
A method is proposed for the simultaneous staining of neutral and acidic, periodate reactive and nonperiodate reactive mucosubstances, glycogen and keratin in paraffin sections. Briefly, sections are stained by the Alcian blue (pH 2.5)-PAS method, followed by a peroxidase-antiperoxidase immunohistochemical stain for keratin. The proposed method modifies an existing method, and expands the range of polysaccharides and mucosubstances which may be demonstrated. The proposed method is easily performed within a single working day and promises to be of value in surgical pathology as well as in studies of bronchial carcinogenesis.


Immune responses in BALB/c mice following immunization with aromatic compound or purine-dependent Salmonella typhimurium strains.
Two near isogenic strains of Salmonella typhimurium HWSH, stably mutated in either the aroA gene affecting the biosynthesis of aromatic compounds, or the purA gene affecting the biosynthesis of purines, were administered intravenously as live attenuated vaccines to BALB/c mice. HWSH aroA-immunized mice were well protected against intravenous (i.v.) challenge with wild-type virulent HWSH for at least 10 weeks, whereas HWSH purA-immunized mice were unprotected. Furthermore, HWSH aroA-immunized mice could also control a heterologous challenge with virulent Listeria monocytogenes at 7 and 14 days post-immunization, whereas mice receiving a similar dose of HWSH purA could not. Increasing the i.v. dose of HWSH purA compared to HWSH aroA induced some resistance to L. monocytogenes. Induction of early anti-S. typhimurium resistance by HWSH aroA immunization appeared slightly later than the anti-L. monocytogenes resistance. Mice immunized with either vaccine were able to mount S. typhimurium-specific T-cell proliferative responses and produced anti-S. typhimurium humoral antibodies in their serum. The antibody titre was greater in those mice immunized with the aroA mutant.


Excitation energy flow control in {Ru(2,2'-bipyridine)2}-{pyridylporphyrin}2 systems.
The direction of excitation energy migration is reversed in a system composed of {Ru(bpy)(2)}-{pyridylporphyrin}(2) by the addition of a Zn(2+) ion. The Zn(2+) system shows an excitation-wavelength dependent emission.


Lung CD4+ resident memory T cells remodel epithelial responses to accelerate neutrophil recruitment during pneumonia.
Previous pneumococcal experience establishes lung-resident IL-17A-producing CD4+ memory TRM cells that accelerate neutrophil recruitment against heterotypic pneumococci. Herein, we unravel a novel crosstalk between CD4+ TRM cells and lung epithelial cells underlying this protective immunity. Depletion of CD4+ cells in pneumococcus-experienced mice diminished CXCL5 (but not CXCL1 or CXCL2) and downstream neutrophil accumulation in the lungs. Epithelial cells from experienced lungs exhibited elevated mRNA for CXCL5 but not other epithelial products such as GM-CSF or CCL20, suggesting a skewing by CD4+ TRM cells. Genome-wide expression analyses revealed a significant remodeling of the epithelial transcriptome of infected lungs due to infection history, ~80% of which was CD4+ cell-dependent. The CD4+ TRM cell product IL-17A stabilized CXCL5 but not GM-CSF or CCL20 mRNA in cultured lung epithelial cells, implicating posttranscriptional regulation as a mechanism for altered epithelial responses. These results suggest that epithelial cells in experienced lungs are effectively different, owing to their communication with TRM cells. Our study highlights the role of tissue-resident adaptive immune cells in fine-tuning epithelial functions to hasten innate immune responses and optimize defense in experienced lungs, a concept that may apply broadly to mucosal immunology.


Nitrogen Removal and N₂O Emission in Biochar-Sludge Subsurface Wastewater Infiltration Systems.
Nitrogen removal and N2O emission of biochar-sludge amended subsurface wastewater infiltration systems (SWISs) with/without intermittent aeration under different organic surface loading rates (OSLRs) were investigated. Under OSLR, between 8.5 and 54.6 g COD/(m2 d), average chemical oxygen demand (COD), <inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="00800-ilm01.gif"/>, and total nitrogen (TN) removal rates decreased with OSLR increasing in non-aerated SWISs amended with/without biochar-sludge; increasing OSLR hardly affected COD and <inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="00800-ilm12.gif"/> removal in biochar-sludge amended SWIS with intermittent aeration; N2O emission rate decreased with influent OSLR increasing in the SWISs. Biochar-sludge amended SWIS with intermittent aeration obtained higher removal rates for COD (94.9 to 95.5%), <inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="00800-ilm23.gif"/> (90.5 to 93.7%), TN (86.5 to 89.9%) and lower N2O emission rates [13.4 to 14.7 mg/(m2 d)] under high influent OSLR of 36.2 and 54.6 g COD/(m2 d) were compared with non-aerated SWISs with/without biochar-sludge. Furthermore, the abundances of amoA, nxrA, napA, narG, nirS, nirK, qnorB, and nosZ genes involved in nitrogen removal were enhanced under high influent OSLR in biochar-sludge amended SWIS with intermittent aeration.


Sustained effect of continuous positive airway pressure on baroreflex sensitivity in congestive heart failure patients with obstructive sleep apnea.
Patients with either heart failure or obstructive sleep apnea have a reduced baroreflex sensitivity for heart rate, a sign of poor prognosis. We previously demonstrated that nocturnal application of continuous positive airway pressure to heart failure patients with obstructive sleep apnea increased baroreflex sensitivity acutely, but it is not known whether these effects persist into wakefulness. To determine whether treating obstructive sleep apnea in heart failure patients with continuous positive airway pressure improves baroreflex sensitivity during wakefulness. Spontaneous baroreflex sensitivity was assessed during wakefulness in 33 heart failure patients (left ventricular ejection fraction < or = 45%) with obstructive sleep apnea (apnea-hypopnea index > or = 20). Subsequently, baroreflex sensitivity was reassessed 1 month after patients were randomly allocated to nocturnal continuous positive airway pressure treatment or no treatment (control). Compared with the 14 control patients, the 19 continuous positive airway pressure-treated patients experienced a greater increase in baroreflex sensitivity [median, (25%, 75%)] [from 5.4 (2.2, 8.3) to 7.9 (4.4, 9.4) ms/mmHg; P = 0.01] and left ventricular ejection fraction (P < 0.001). In addition, daytime systolic blood pressure and heart rate decreased more in the continuous positive airway pressure group (from 122 +/- 15 to 113 +/- 12 mmHg; P = 0.02, and from 66 +/- 8 to 62 +/- 8 bpm; P < 0.001, respectively) than in the control group. Treatment of coexisting obstructive sleep apnea by continuous positive airway pressure in heart failure patients improves baroreflex sensitivity during wakefulness in addition to improving left ventricular ejection fraction and lowering blood pressure and heart rate. These data indicate that the improved autonomic regulation of heart rate in heart failure patients treated for obstructive sleep apnea during sleep persists into wakefulness.


Determinants of dental care use in patients with rare diseases: a qualitative exploration.
Oral health is an inherent part of overall health as an important physiological crossroad of functions such as mastication, swallowing or phonation; and plays a central role in the life of relationships facilitating social and emotional expression.Our hypothesis was that in patients with rare diseases, access to dental care could be difficult because of the lack of professionals who know the diseases and accept to treat the patients, but also because some patients with cognitive and intellectual disabilities could not find adequate infrastructure to assist in managing their oral health. This study employed a qualitative descriptive design including semi-structured interviews using guiding themes. The transcripts were reviewed to identify key themes and interviews were performed until the data were saturated and no further themes emerged. Twenty-nine patients from 7 to 24 years old were included in the study of which 15 patients had an intellectual delay. The results show that access to care is complicated more by aspects concerning intellectual disability than by the fact that the disease is rare. Oral disorders are also an obstacle to the maintenance of their oral health. The oral health of patients with rare diseases, can be greatly enhanced by a pooling of knowledge between health professionals in the various sectors around the patient's care. It is essential that this becomes a focus of national public health action that promotes transdisciplinary care for the benefit of these patients.


Regional Injury Classification and Treatment of Open Pelvic Fractures.
To propose the regional injury classification of open pelvic fracture and summarize the characteristics of its treatment. Clinical data for 67 open pelvic fractures treated from January 2001 to December 2017 were retrospectively analyzed. There were 48 male and 19 female patients. The patients were aged from 12 to 68 years old, and their pelvic fractures were categorized according to Tile classification (type A: 23 cases; type B: 19 cases; type C: 25 cases). Main injury distribution: pubic perineum, 29 cases; ilioinguinal, 20 cases; and sacroiliac, 7 cases. There were 5 cases of ilioinguinal-perineum and 6 cases of sacroiliac-perineum injury. Based on the region of the injury, the mortality and combined injury of each group were observed. The relationship between regional injury groups and death was examined. Following active treatment, 28 patients died. The mortality rate was 41.8% (28/67), with 39 patients surviving. The average follow-up time was 6 months (3 months to 1 year after discharge). Majeed pelvic fracture score: the score was excellent in 12 cases, good in 14 cases, fair in 9 cases, and poor in 4 cases; there was an excellent and good rate of 66.7%. Open pelvic fracture regional injury classification includes: the perineal type (type I); the ilioinguinal type (type II); the sacroiliac type (type III); and the composite type (type IV). All types were independent of each other, and the mortality of open pelvic fractures was positively correlated with this classification, with a correlation coefficient of 0.620 (P = 0.001 < 0.05; the difference was statistically significant). In this study, cystourethral injury, anorectal injury, and infection were the main combined injuries of type I. The type II and III injuries were mainly iliac vascular injuries. The main combined injuries of type IV were infection, injury of ilium vessels and its branches. There was a statistical difference among the combined injuries of each subtype (P = 0.001 < 0.05). The criteria for regional classification were clear, the mortality of the four subtypes increased gradually, and the incidence of combined injury of each subtype varied. Each subtype had different therapeutic characteristics.


Novel role of TGF-beta in differential astrocyte-TIMP-1 regulation: implications for HIV-1-dementia and neuroinflammation.
Astrocyte production of tissue inhibitor of metalloproteinase (TIMP)-1 is important in central nervous system (CNS) homeostasis and inflammatory diseases such as HIV-1-associated dementia (HAD). TIMPs and matrix metalloproteinases (MMPs) regulate the remodeling of the extracellular matrix. An imbalance between TIMPs and MMPs is associated with many pathologic conditions. Our recently published studies uniquely demonstrate that HAD patients have reduced levels of TIMP-1 in the brain. Astrocyte-TIMP-1 expression is differentially regulated in acute and chronic inflammatory conditions. In this and the adjoining report (Gardner et al., 2006), we investigate the mechanisms that may be involved in differential TIMP-1 regulation. One mechanism for TIMP-1 downregulation is the production of anti-inflammatory molecules, which can activate signaling pathways during chronic inflammation. We investigated the contribution of transforming growth factor (TGF)-signaling in astrocyte-MMP/TIMP-1-astrocyte regulation. TGF-beta1 and beta2 levels were upregulated in HAD brain tissues. Co-stimulation of astrocytes with IL-1beta and TGF-beta mimicked the TIMP-1 downregulation observed with IL-1beta chronic activation. Measurement of astrocyte-MMP protein levels showed that TGF-beta combined with IL-1beta increased MMP-2 and decreased proMMP-1 expression compared to IL-1beta alone. We propose that one of the mechanisms involved in TIMP-1 downregulation may be through TGF-signaling in chronic immune activation. These studies show a novel extracellular regulatory loop in astrocyte-TIMP-1 regulation.


Supplemental effects and metabolic fate of crystalline arginine in juvenile shrimp Marsupenaeus japonicus.
Feeding experiments with juvenile kuruma shrimp (Marsupenaeus japonicus) were conducted to understand the effects of supplemental levels of crystalline arginine hydrochloride on the growth and assimilation of arginine. In experiment 1 the juvenile shrimp were maintained on diets with and without arginine supplements. The addition of 3.0% arginine to a casein-based diet was slightly effective in improving the growth of the juveniles. In experiment 2, tracer experiments using [14C] arginine were conducted to clarify the ingestion and assimilation of arginine, 9 and 24 h after feeding, at different levels of supplemental arginine. Tracer experiments showed that the leaching rate of arginine 1 h after feeding ranged from 16 to 26% in the diets with different levels (0, 0.1, 1.5, 3.0 and 6.0%) of supplemental arginine; that is, 74-84% of the given arginine was actually ingested by the shrimp fed the diets. However, with increasing levels of supplemental arginine the incorporation rate of arginine into the whole body decreased and the utilization of absorbed arginine for body protein synthesis was reduced, whereas the excretion of absorbed arginine was increased. Thus, the absorbed arginine was not effectively utilized for body protein synthesis when large amounts of arginine were supplemented to the diets.


A device to perform percutaneous cervical pharyngostomy (PCP) for enteral nutrition.
Percutaneous Cervical Pharyngostomy (PCP) is a technique of proven usefulness in Enteral Nutrition and has been used for over 20 years. The procedure has been modified to make it less traumatic and easier to perform. To further improve the technique we have developed a special device, with which it can be performed with minimum trauma under local anaesthesia, and with a smaller number of manoeuvres when compared with previous techniques. In addition, it gives rise to less occupation of the pharyngostomic passage by the nutritional tube (8 Fr.). We have successfully utilised this device on 37 patients, in whom the procedure took no more than 15 minutes. We had no technical complications. Based on our experience, we think that the use of this device makes the application of PCP easier in Enteral Nutrition.


Nasal obstruction in the neonate secondary to nasolacrimal duct cysts.
The neonate is an obligate nasal breather and any form of nasal obstruction causes respiratory distress during feeding and sleeping. We report two patients with unusual causes of respiratory distress secondary to nasolacrimal duct cysts. The failure of the lacrimal duct to perforate at the distal end results in dacryocystitis and cyst formation. Removal of the nasal wall of the cyst resolves the obstruction and the dacryocystitis. The nasolacrimal duct cyst is an unusual, but readily treated, cause of neonatal respiratory distress.


Drosophila TRPA channel modulates sugar-stimulated neural excitation, avoidance and social response.
Drosophila melanogaster postfeeding larvae show food-averse migration toward food-free habitats before metamorphosis. This developmental switching from food attraction to aversion is regulated by a neuropeptide Y (NPY)-related brain signaling peptide. We used the fly larva model to delineate the neurobiological basis of age-restricted response to environmental stimuli. Here we provide evidence for a fructose-responsive chemosensory pathway that modulates food-averse migratory and social behaviors. We found that fructose potently elicited larval food-averse behaviors, and painless (pain), a transient receptor potential channel that is responsive to noxious stimuli, was required for the fructose response. A subset of pain-expressing sensory neurons have been identified that show pain-dependent excitation by fructose. Although evolutionarily conserved avoidance mechanisms are widely appreciated for their roles in stress coping and survival, their biological importance in animal physiology and development remains unknown. Our findings demonstrate how an avoidance mechanism is recruited to facilitate animal development.


Calcitonin inhibits the growth of human gastric carcinoma cell line KATO III.
Calcitonin has a wide variety of actions on gastrointestinal function. In this study, we investigated the effects of calcitonin on the growth of human gastric carcinoma cell line KATO III in comparison with those of calcitonin gene-related peptide (CGRP). Calcitonin, but not CGRP, significantly and dose-dependently inhibited the growth of KATO III cells. This inhibition of cell growth was accompanied by an increase in cyclic AMP production. The proliferation of KATO III cells was also inhibited by forskolin and dibutyryl cyclic AMP, although agents which do not stimulate cyclic AMP production had no effect. Furthermore, in the presence of GTP, calcitonin stimulated adenylate cyclase activity in KATO III cell membranes, and this increase was reduced in the absence of GTP. On the other had, neither calcitonin nor CGRP enhanced the turnover of inositolphospholipid or the intracellular Ca2+ level. In addition, 125I-labeled human calcitonin was specifically bound to KATO III cell membranes, and this binding was dose-dependently displaced by unlabeled calcitonin but not CGRP. Furthermore, the specific binding of 125I-labeled human calcitonin to KATO III cell membranes was significantly reduced by addition of GTP but not ATP. These results suggest that calcitonin inhibits the growth of human gastric carcinoma cell line KATO III by stimulating cyclic AMP production via a GTP-dependent process coupled to specific calcitonin receptors.


Juniors' voice at the ERS International Congress, Amsterdam 2015: Juniors' Voice.
Junior member activities at the ERS International Congress 2015 http://ow.ly/R2oIn.


Using radial pulse wave as hemodynamic measurements to quantify effects of acupuncture therapy for patients with traumatic brain injury and ischemia stroke.
Traumatic Brain Injury (TBI) and stroke are major sources of death and disability worldwide. Acupuncture has been used as a supplemental therapy for patients with TBI and stroke. This study was aimed to evaluate the effects of acupuncture therapy for patients with TBI and stroke by radial pulse spectrum. 22 patients (6 TBI and 16 stroke) were enrolled and underwent radial pressure wave measurement before and after acupuncture treatment at Dubi (ST-35), Zusanli (ST-36) and Jiexi (ST-41). The harmonic analysis of the radial pressure wave was calculated and transformed into Fourier series coefficients Cn, Pn and the variation coefficient CnCV. After acupuncture, systolic blood pressure, heart rate, and Glasgow Coma Scale changed very slightly. The harmonic index C4, C7, C9, C10, C3CV and C5CV had significant increases. (P < 0.05) After 3-week course acupuncture treatment, systolic blood pressure, C7, C8, C9, C10 and P10 had significant increases. (P < 0.05). Harmonic analysis of radial pulse waves may detect earlier circulatory system changes of acupuncture treatment before they were evident with other hemodynamic readings or scale.


Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2.
Fibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, small heterodimer partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP-seq analysis. The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels. This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF19.


Inhibitory effect of acupuncture on the finger flexion reflex induced by finger tip vibration.
The effect of acupuncture on finger flexion reflex, caused by mechanical vibration applied to the finger tip, was studied by using the cross-correlation function. A stainless steel acupuncture needle was inserted into the acupuncture point called "Wai-Kuan" for 10 min. Acupuncture inhibited the reflex and suppressed the two modes seen in the cross-correlogram between unitary EMG activity of the muscle flexor digitorum superficialis and finger tip vibration with random frequency. The recovery of the primary mode, which may be via the spinal monosynaptic reflex loop, was significantly earlier than the recovery of the secondary mode, which may be via the supraspinal reflex long loop. This suggests that the distinct inhibitory effect of acupuncture takes place on the reflex at spinal and supraspinal levels.


Pharmacology of GABA receptor Cl- channels in rat retinal bipolar cells.
gamma-Aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian nervous system, is known to operate bicuculline-sensitive Cl- channels through GABAA receptors and bicuculline-insensitive cation channels through GABAB receptors. Recent observations indicate that the retina may contain GABA receptors with unusual pharmacological properties. Here we report that GABA gates bicuculline-insensitive Cl- channels in rod bipolar cells of the rat retina, which were not modulated by flunitrazepam, pentobarbital and alphaxalone and were only slightly blocked by picrotoxinin. Moreover, the GABAB receptor agonist baclofen, and the antagonist 2-hydroxysaclofen had no effect. The underlying single-channel conductance was 7 pS and the open time 150 ms. These values are clearly different from those obtained for GABAA receptor channels recorded in other neurons of the same preparation, and in other parts of the brain. The bicuculline- and baclofen-insensitive GABA receptors were activated selectively by the GABA analogue cis-4-aminocrotonic acid (CACA). Hence they may be similar to those receptors termed GABAC receptors.


Osteoarthritis Was Associated With a Faster Decline in Hippocampal Volumes in Cognitively Normal Older People.
To examine whether osteoarthritis (OA) is associated with a change in adjusted hippocampal volumes (HpVR: hippocampal/intracranial volume × 103) over time among cognitively normal older people. We examined the cross-sectional and longitudinal associations of OA with HpVR among individuals with normal cognition (NC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. At baseline, a total of 372 individuals with NC were included. In the cross-sectional analyses of baseline data, we did not find a significant relationship between OA and HpVR among individuals with NC. However, in the longitudinal analyses, OA was significantly associated with change in HpVR over time among individuals with NC. Specifically, compared with individuals without OA, those with OA showed a faster decline in HpVR over time when controlling for other potential confounders, including age, educational attainment, gender, and APOE4 genotype. OA status was significantly associated with a change in HpVR over time among individuals with NC.


Estradiol and progesterone receptors content and response to norethisterone treatment in advanced breast cancer.
Twenty-six patients with advanced breast cancer and progressive disease were treated by norethisterone. Estradiol and progesterone receptors were measured before starting treatment, and in three cases after 2 to 4.75 months of therapy. Partial remissions (greater than 50% decrease of all lesions) or objective improvements (decrease of 20-50%) were obtained in 7 patients, with a mean duration of 6.7 months. Stabilization of the lesions (no change or decrease of less than 20% in the size of the target lesion) was observed in 7 patients. No clear-cut correlation was found between clinical response and presence in biopsies of estradiol and progesterone receptors. However, absence of response occurred more frequently if tumors did not contain progesterone receptors.


The North/South Ireland Food Consumption Survey: the dietary fibre intake of Irish adults.
Mean daily intakes of dietary fibre (DF, Southgate) and non-starch polysaccharide (NSP, Englyst) are estimated in a representative sample of adults aged 18-64 years in Ireland. The contribution of food groups to DF and NSP intake is reported and fibre intakes are compared with dietary recommendations and with intakes in some European countries. Food consumption was estimated using 7-day food diaries for a representative sample (n=1379); 662 men, 717 women) of 18-64 year old adults in the Republic of Ireland and Northern Ireland selected from the electoral register. DF and NSP intakes were estimated from tables of food composition. The mean daily intake of DF in the total sample was 20.2 g (standard deviation (SD) 7.8) [23.2 g (SD 8.5) in men, 17.4 g (SD 5.9) in women] or 2.24 g MJ(-1) (SD 0.7) [2.16 g MJ(-1) (SD 0.7) in men, 2.33 g MJ(-1) (SD 0.7) in women]. Mean daily intake of NSP was 14.8 g (SD 6.2) [16.7 g (SD 6.8) in men, 13.0 g (SD 5.0) in women] or 1.65 g MJ(-1) (SD 0.6) [1.56 g MJ(-1) (SD 0.6) in men, 1.74 g MJ(-1) (SD 0.6) in women]. The main food groups that contributed to mean daily intake of DF (NSP) in the sample were breads 31% (23%), potatoes 19% (23%), and vegetables 17% (19%). Absolute intakes of DF and NSP were higher (P<0.001) in men than women; however, women overall consumed more (P<0.001) fibre-dense diets than men. Women aged 18-35 years consumed less (P<0.01) DF and NSP (g) than women aged 36-64 years. Both men and women aged 18-35 years consumed less (P<0.01) fibre-dense diets than men and women aged 36-64 years. The NSP intake was below the nutritional goal of 18 g day(-1) in 77% of adults and below the minimum of the recommended range (12 g day(-1) in 37% of the total sample. Compliance (i.e. the maximum number of individuals whose collective mean daily intake corresponded to the population goal) with the (UK) population goal for an average intake of 18 g day(-1) NSP was achieved by a greater proportion of the population (63%) than compliance with the (German) dietary fibre recommendation of 30 g day(-1) (27%) or the (Nordic) recommendation of 3 g MJ(-1) day(-1) (33%). DF (NSP) intakes were lower than dietary recommendations in a substantial proportion of the population. This is likely to contribute to impaired bowel function and constipation, which in turn may contribute to increased risk of chronic gastrointestinal disease.


[Benign tumor of duodenum: report of 8 cases].
To investigate the problems of diagnosis and treatment in patients with benign tumor of duodenum. Clinico pathological data of 8 patients with benign tumors of duodenum treated surgically in our department from 1989 to 2000 were analyzed retrospectively. Of the 8 patients, 3 had a Brunner's grand adenoma, 2 leiomyoma, 2 mesenchymoma, and 1 lipoma. In general, the patients were asymptomatic and the lesions were discovered incidentally. Gastrointestinal bleeding might be the main symptom even if it was nonspecific. Bleeding might be melena or hematemesis and the patients might develop signs of anemia. Upper gastrointestinal tract examination and gastroduodenoscopy was performed before operation in 7 patients. The tumor was removed through longitudinal incision during duodenotomy. Gastrointestinal bleeding is common in patients with benign tumor of duodenum. The upper gastrointestinal tract examination and gastroduodenoscopy are major methods for diagnosis. The best treatment of choice is local resection.


Albumin magnetic microspheres: a novel carrier for myelin basic protein.
Myelin basic protein (MBP) of guinea pig origin was incorporated into magnetically responsive albumin microspheres. Protein-protein bonding and stabilization of the GPMBP microspheres by heating at 120 degrees C did not adversely influence their capacity to bind anti-MBP antibodies or demonstrably alter the encephalitogenic activity of the incorporated GPMBP. The magnetic properties of the particles and the fact that immunodeterminants of some of the incorporated MBP fortuitously were distributed on the exterior surfaces of the microspheres allowed a number of experiments to be carried out in Lewis rats for the first time: (a) selective capture and deletion of that particular subpopulation of lymphoid cells responsible for transfer of experimental allergic encephalomyelitis (EAE) represented within the lymph node cells (LNC) of donor animals sensitized to neutral antigen, (b) enhancement of in vivo uptake of MBP by macrophages (M phi s) contained in oil-induced peritoneal cell exudates and exposed briefly to MBP microspheres, and (c) preparation of cell suspensions specifically enriched with respect to MBP-containing M phi s.


Neuroendocrine Tumors of the Stomach.
Gastric neuroendocrine tumors (NETs) are classified into three types. Type I gastric NETs are associated with chronic atrophic gastritis. They have a good prognosis and endoscopic resection is the mainstay of treatment. Type II gastric NETs are caused by hypergastrinemia. They have a poorer prognosis, and resection is required to control the disease. Endoscopic versus surgical resection is recommended for the gastric lesion. Type III gastric NETs are sporadic and not associated with any specific condition. They have the worst prognosis with the highest rate of metastatic disease, and oncologic resection is recommended. Medical therapies have some role.


Reparative operations for interrupted aortic arch with ventricular septal defect.
From January, 1975, through September, 1982, 24 infants underwent primary or staged repair of interrupted aortic arch (IAA) with ventricular septal defect (VSD). Seven patients had IAA type A and 17 patients had type B. Eleven of the patients, median age 5 days, underwent staged operations and 13 infants, median age 6 days, underwent primary repair. Palliation was by tube graft interposition (six), subclavian-aortic anastomosis (three), left carotid-aortic anastomosis (one), or end-to-side aortic anastomosis (one) combined with pulmonary artery banding (eight) or early VSD closure. With palliation, there were three (27%) early deaths among the eleven patients and one (13%) late death among the eight remaining. Delayed repair at 5 days to 14 months (median 7 months) in seven patients incurred three (43%) early and no late deaths. Primary repair in 13 patients consisted of VSD closure combined with graft interposition (12) or end-to-side aortic anastomosis (one), with three (23%) early and no late deaths. Nine of 14 survivors had hemodynamic evaluation by catheterization 1 to 3 years following repair. None had a significant residual VSD or pressure gradients between the ascending and thoracic aorta. Six had subaortic stenosis, two mild (gradient less than 20 mm Hg) and four severe (gradient greater than 50 mm Hg), necessitating operation. Results of operations in neonates with IAA continue to improve. Essential in management is an awareness that subaortic stenosis and hypocalcemia may be accompaniments of this anomaly. Based on these data, we prefer primary repair for IAA with VSD.


Tumor volume changes during stereotactic ablative radiotherapy for adrenal gland metastases under MRI guidance.
Gross tumor volume (GTV) changes during stereotactic ablative radiotherapy (SABR) for adrenal tumors are not well characterized. We studied treatment-induced GTV changes during, and after, 5-fraction MR-guided SABR on a 0.35 T unit. Details of patients treated for adrenal metastases using 5-fraction adaptive MR-SABR were accessed. GTV changes between simulation and first fraction (ΔSF1) and all fractions were recorded. Wilcoxon paired tests were used for intrapatient comparisons. Logistic and linear regression models were used for features associated with dichotomous and continuous variables, respectively. Once-daily fractions of 8 Gy or 10 Gy were delivered to 70 adrenal metastases. Median simulation-F1 interval was 13 days; F1-F5 interval was 13 days. Median baseline GTVs at simulation and F1 were 26.6 and 27.2 cc, respectively (p < 0.001). Mean ΔSF1 was + 9.1% (2.9 cc) relative to simulation; 47% of GTVs decreased in volume at F5 versus F1. GTV variations of ≥ 20% occurred in 59% treatments at some point between simulation to end SABR, and these did not correlate with baseline tumor characteristics. At a median follow-up of 20.3 months, a radiological complete response (CR) was seen in 23% of 64 evaluable patients. CR was associated with baseline GTV (p = 0.03) and ΔF1F5 (p = 0.03). Local relapses were seen in 6%. Frequent changes in adrenal GTVs during 5-fraction SABR delivery support the use of on-couch adaptive replanning. The likelihood of a radiological CR correlates with the baseline GTV and intra-treatment GTV decline.


Visualization and Quantification of Phagocytosis by Neutrophils.
Phagocytosis by phagocytes such as neutrophils is a crucial part of the host innate immune response against invading pathogens. Phagocytosis is a complex process that initiates with the binding of the particles on the cell surface of the phagocytes through the interaction of pattern recognition receptors with ligands on the surface of the pathogens. During this process, phagocytes undergo extensive membrane reorganization and cytoskeleton rearrangement at their cell surface. To gain better insight about the molecular mechanisms of this dynamic cellular process, visualization and quantification in a high-throughput manner is essential. Here, we describe a microscope-based method to visualize and quantify phagocytic uptake of pathogens (such as bacteria and fungi) and model particulates that are larger than 0.5 μm (such as Zymosan A and IgG-coated beads).


Derivation of epidermal colony-forming progenitors from embryonic stem cell cultures.
In our two-step culturing system, epidermal progenitor cells derived from differentiating embryonic stem cells in vitro are plated on either a basement membrane matrix or in coculture. On plating on basement membrane, differentiation along the epidermal lineage is evident and reproducible, with several markers of epidermal differentiation observed in a pattern reminiscent of their in vivo expression. However, when epidermal progenitor cells are plated in a co-culture environment with mature epidermal cells at low density, colony formation, and differentiation along the epidermal pathway is enhanced with a high frequency of K14-positive cells. Thus, the in vitro co-culture model system described here is useful in dissecting the process of commitment and differentiation of epithelial progenitors that occurs during epidermogenesis as well as for the investigation of the molecular mechanisms underlying these processes.


Mechanisms and pharmacotherapy of hypertension associated with type 2 diabetes.
Type 2 diabetes is often complicated with hypertension, such that 73.6 % of patients ≥ 18 years with type 2 diabetes also have hypertension. With increasing age, the risk of developing these conditions rises significantly. Co-existence of type 2 diabetes and hypertension suggests that there are overlapping genetic, physiologic, and environmental factors at play. Research has shown several overlying metabolic abnormalities including sympathetic nervous system overactivation, insulin resistance, inflammatory and endothelial dysfunction, deleterious expression of microRNAs, and obstructive sleep apnea. Though diet and physical activity are the mainstays of treatment early in the disease course, they are generally not a viable long-term strategy. Treatment with novel hypoglycemic and anti-hypertensive medications can greatly assist in preventing long-term complications of these chronic conditions. Recognition of the common causes and consequences of type 2 diabetes and comorbid hypertension allows for a robust response towards being proactive regarding prevention and treatment of this unique patient population. Thus, the purpose of this current review is four-part: to (1) review the latest discoveries into the mechanisms of hypertension in the setting of type 2 diabetes, (2) discuss the latest treatments of hypertension with a brief discussion about novel hypoglycemic agents in patients with type 2 diabetes, (3) summarize blood pressure targets and (4) to address evidence gaps in treating patients with diabetes and resistant hypertension, and elderly individuals with both hypertension and diabetes.


The human cystatin C gene (CST3) is a member of the cystatin gene family which is localized on chromosome 20.
The fourth gene from the human cystatin gene family of salivary-type cysteine-proteinase inhibitors has been isolated and partially characterized by DNA analysis. The gene, which we name CST3, codes for human cystatin C, and has the same organization as the CST1 gene for cystatin SN and the CST2 gene for cystatin SA. Southern analysis of EcoR I digested DNAs from 32 independent somatic cell hybrid clones hybridized to a probe from CST1 demonstrated that all members of the cystatin gene family segregate with human chromosome 20. These results indicate that the genes for salivary-type cystatins and cystatin C are members of a multigene family--the cystatin gene family.


Lignans and terpenoids from the stem of Ephedra equisetina Bunge.
Seven undescribed lignans, equiselignan A-F, and six undescribed terpenoids, equiseterpenoid A-E (including two pairs of enantiomers, (+/-)-equiselignan A and (+/-)-equiseterpenoid E), were isolated from the stems of Ephedra equisetina Bunge. Their structures were elucidated by spectroscopic methods, and the absolute configurations of the undescribed compounds were determined by interpretation of their electronic circular dichroic (ECD) and optical rotation data. In β-hexosaminidase (β-Hex) release assay, anti-asthmatic activities of all of the compounds were evaluated by releasing β-Hex in C48/80-induced RBL-2H3 cells. The β-Hex release rates of equiselignan B and equiseterpenoid B were 0.86 ± 0.094 and 0.86 ± 0.012 by comparing with model group, whereupon equiselignan B and equiseterpenoid B exhibited significant anti-asthmatic activities.


Developmental trajectories of physical activity during elementary school physical education.
Physical education (PE) during school provides an opportunity for children to be physically active. Few empirical studies have investigated developmental trajectories and determinants of objective moderate to vigorous physical activity (MVPA) during PE classes. The purpose of this study was to examine the developmental trajectories and determinants of MVPA during PE lessons in young children (8-12years of age) in primary schools. Students in grades 5-7 (n=1202; 51.2% girls) were recruited from 17 elementary schools from the Geneva canton in 2012-2013. The percentage of time spent in accelerometer-assessed MVPA during regular PE lessons was used as a dependent variable. Linear mixed-model analyses revealed (a) that boys had a higher percentage of MVPA than girls, but none of the children reached the recommended activity levels (i.e., 50% of the PE class time spent in MVPA), (b) a linear decrease in the percentage of MVPA with age, (c) that higher perceived competence predicted a higher percentage of MVPA, and (d) that higher perceived competence reduced the negative linear effect of age among boys, but not among girls. The percentage of PE time spent in MVPA did not reach recommendations made by Centers for Disease Control and Prevention and decreased from 8 to 12years old both for boys and girls. Perceived competence appears crucial to reduce MVPA decline for boys, but not for girls.


Estradiol-induced changes in rabbit luteal cell progestin production and cholesterol and cholesterol ester content.
Estradiol deprivation in vivo causes accumulation of cholesterol and cholesterol ester in the corpora lutea of pseudo-pregnant rabbits within 24 hours. These accumulations occur concomitantly with an abrupt cessation of progestin production. Retreatment with estradiol restores progestin production and can block further increases in cholesterol accumulation (per mg total tissue protein). Ample quantities of precursor cholesterol ester and cholesterol substrate are present in corpora lutea when progestin falls because of estradiol deprivation. We conclude therefore that the gonadotropic action of estradiol is, in part, because of its stimulation of cholesterol conversion to progestins.


A comparative and pooled analysis of the safety and tolerability of the contraceptive patch (Ortho Evra/Evra).
To review the safety and tolerability of the contraceptive patch (Ortho Evra/Evra) versus a standard oral contraceptive (Triphasil) and to present the pooled safety and tolerability of the patch across three pivotal studies. Three open-label, contraceptive studies of up to 13 treatment cycles. 183 centers. Comparative study (812 patch, 605 oral contraceptive); pooled analysis (3,330 patch). The patch regimen was three consecutive 7-day patches (21 days) followed by 1 patch-free week per cycle; the oral contraceptive was dosed according to the U.S. physician package insert. Adverse events, laboratory tests, vital signs, and body weight. The incidence of most events was similar between the patch and oral contraceptive groups, with the exception of a higher incidence of application site reactions, breast discomfort (cycles 1 and 2 only), and dysmenorrhea in the patch group. Pooled analysis demonstrated that most application site reactions (92%) and breast symptoms (86%) were mild or moderate in severity, and <2% of participants discontinued the patch because of either event. Only 7 (0.2%) participants experienced a serious adverse event classified as possibly, probably, or likely related to the patch. The mean change in body weight from baseline to the end of treatment was an increase of 0.3 kg. Overall, the contraceptive patch is well tolerated and has a side effect profile similar to an established oral contraceptive.


Utilization of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale for evaluation of quality of life among cancer patients treated with chemotherapy: A hospital-based observational study.
In this new era of cancer management, the quality of life (QOL) is given more importance than the quantity of life. QOL evaluation studies are widely used in oncology to assess the patient's performance in different cancer types and treatment modalities. To evaluate cancer patients' QOL after various chemotherapy cycles. An observational study was performed on cancer patients receiving chemotherapy in the daycare setting of a South Indian Tertiary Care Hospital for 6 months. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire was employed to study the QOL. Precisely, 102 patients participated in the study, out of which the majority were in the 51 to 60 age group (24%). Female participants (65%) were more. Functional scale domains especially physical ability (P = 0.004), role (P = 0.033), and emotional functioning (P = 0.01) were significantly decreased in patients treated with 4 to 6 chemotherapy cycles. Cognitive ability (P = 0.043) significantly improved in patients treated with more than 6 chemotherapy cycles. Dyspnea (P = 0.036) was significantly increased in patients treated with 4 to 6 chemotherapy cycles and decreased significantly with the further addition of chemotherapy cycles. Dyspnea is a commonly observed symptom among cancer patients and is often neglected by physicians. Chronic dyspnea can negatively impact a patient's functional ability. Cancer symptoms such as dyspnea should also be given priority and need appropriate treatment. Based on the findings, further interventions can be made to improve the functional ability of cancer patients. Also, studies can be conducted to correlate with cancer rehabilitation programs to improve functional ability and complete the entire chemotherapy cycle.


PM2.5 concentration modeling and prediction by using temperature-based deep belief network.
Air quality prediction is a global hot issue, and PM2.5 is an important factor affecting air quality. Due to complicated causes of formation, PM2.5 prediction is a thorny and challenging task. In this paper, a novel deep learning model named temperature-based deep belief networks (TDBN) is proposed to predict the daily concentrations of PM2.5 for the next day. Firstly, the location of PM2.5 concentration prediction is Chaoyang Park in Beijing of China from January 1, 2018 to October 27, 2018. The auxiliary variables are selected as input variables of TDBN by Partial Least Square (PLS), and the corresponding data is divided into three independent sections: training samples, validating samples and testing samples. Secondly, the TDBN is composed of temperature-based restricted Boltzmann machine (RBM), where temperature is considered as an effective physical parameter in energy balance of training RBM. The structural parameters of TDBN are determined by minimizing the error in the training process, including hidden layers number, hidden neurons and value of temperature. Finally, the testing samples are used to test the performance of the proposed TDBN on PM2.5 prediction, and the other similar models are tested by the same testing samples for convenience of comparison with TDBN. The experimental results demonstrate that TDBN performs better than its peers in root mean square error (RMSE), mean absolute error (MAE) and coefficient of determination (R2).


Omics insights into spermatozoa activation induced by Fetal bovine serum in viviparous black rockfish (Sebastes schlegelii).
Black rockfish (Sebastes schlegelii) is an economically important marine species with the characteristics of viviparity. The spermatozoa were transferred into the ovary by mating and stored for several months until fertilization. Little is known about spermatozoa activation and its mechanism in black rockfish. In this study, the suitable medium for spermatozoa activation in vitro was explored, and the underlying mechanism was studied by omics analysis. Fetal bovine serum (FBS) could significantly enhance spermatozoa motility in vitro. Omics analysis showed 559 differentially expressed genes (DEGs) and 1311 differentially methylated genes (DMGs) were identified after FBS treatment. Transcriptome analysis revealed that FBS-induced spermatozoa motility activation is associated with spermatozoa capacitation regulated by the cAMP-SRC-PKA, cGMP-PKG and phospholipase D signaling pathway. Spermatozoa capacitation-related gene hsp90aa1 and chemotaxis-related gene cxcr4 were two of the important DMGs. Methylome analysis further revealed that FBS-induced epigenetic modifications are involved in spermatozoa capacitation and chemotaxis. 36 overlaps were identified between DMGs and DEGs, of which five genes were demonstrated to play a role in spermatozoa physiology, required for flagellum stability and spermatozoa motility. The results could provide new clues for understanding spermatozoa activation's molecular mechanism and help establish activation and/or immobilizing media for improving either artificial fertilization or cryopreservation in black rockfish.


Direct Two-Minute Unassisted Breathing Evaluation (DTUBE) Is an Attractive Alternative to Longer Spontaneous Breathing Trials: A Prospective Observational Study.
We sought to identify a simple bedside method to predict successful extubation outcomes that might be used during rounds. We hypothesized that a direct 2-minute unassisted breathing evaluation (DTUBE) could replace a longer spontaneous breathing trial (SBT). Data were prospectively collected on all patients endotracheally intubated for >48 hours nearing extubation in a tertiary center's mixed trauma/surgical intensive care unit from August 2012 to August 2013. The SBT was performed for at least 30 minutes at 40 per cent FiO2, PEEP 5, and PS 8. DTUBE was performed by physically disconnecting the intubated patient from the ventilator circuit for a 2-minute period of direct observation on room air. Successful extubation was defined freedom from ventilator for greater than 72 hours. Both SBT and DTUBE were performed 128 times, resulting in 90 extubations. The DTUBE correctly predicted success in 75/79 (94.9%) extubations versus 82/89 (92.1%) via SBT. No adverse effects were directly attributed to the DTUBE. The DTUBE is a rapid method of evaluating patients for extubation with prediction accuracy similar to the SBT.