Comparison between central corneal thickness and IOP in patients with macrodiscs with physiologic macrocup and normal-sized vital discs.
Macrodiscs with physiologic macrocups and elevated intraocular pressure (IOP) are frequently suspicious for glaucoma. Patients with an elevated c/d ratio and an IOP of more than 21 mmHg are often treated for glaucoma. We investigated a possible relationship between macrodiscs, IOP and central corneal thickness. Using the Erlangen glaucoma registry, 341 out of 1,096 consecutive patients with unremarkable and repeated visual field (Octopus 500, G1-3, MD<2.1) were selected. Most of these patients had been sent as glaucoma suspects. The following data were collected: corneal ultrasound pachymetry (Tomey, AL-2000), IOP profile, visual acuity and central corneal power. The morphometric analysis was performed by planimetry using the Littmann formula. Optic nerve heads with a disc area of more than 3.1 mm(2) were defined as macrodiscs. Patients were subdivided into the following groups: group A: healthy macrodiscs, IOP <22 mmHg (87 patients); group B: healthy macrodiscs, IOP >21 mmHg (66 patients); group C: normal-sized healthy discs, IOP <22 mmHg (93 patients); group D: normal-sized healthy discs, IOP >21 mmHg (95 patients). Mean corneal thickness was: group A: 575+/-36 microm, group B: 596+/-37 microm, group C: 557+/-31 microm and group D: 585+/-38 microm ( P=0.003). Mean central corneal power measured: group A: 41.7+/-1.3 D, group B: 42.4+/-1.3 D, group C: 43.0+/-1.2 D and group D: 42.8+/-1.2 D ( P<0.05). The maximum of IOP was: group A: 17.6+/-3.1, group B: 26.2+/-4.1, group C: 17.2+/-3.4 and group D: 29.7+/-5.5 mmHg. Optic disc size measurements were: group A: 3.91+/-0.66, group B: 3.65+/-0.6, group C: 2.56+/-0.30 mm(2) and group D: 2.39+/-0.39 microm, respectively. Macrodiscs with elevated IOP have a higher corneal curvature (mean: +0.7 D) and a thicker central cornea (mean: +21 microm) compared to macrodiscs without elevated IOP. An exact evaluation of optic disc morphology in combination with pachymetric and keratometric measurements in relation to IOP could avoid an overtreatment in patients with suspect primary open-angle glaucoma.


Baseline bony erosions and time-averaged DAS28 predict discontinuation of TNF inhibitors in rheumatoid arthritis.
The present study evaluated the predictive role of baseline radiographic change and disease activity on drug retention and clinical response in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor inhibitor (TNFi). Korean Observational Study Network for Arthritis (KORONA) registry was evaluated to identify RA patients treated with a TNFi. Disease activity score-28 (DAS28) was evaluated at baseline and 1 year after TNFi initiation or at termination of TNFi due to inefficacy (within 1 year). The retention rate of TNFi was compared in patients with and without bony erosions. The hazard ratio (HR) for drug retention was evaluated by Cox regression analysis, as was the odds ratio (OR) for achieving remission (DAS28 < 2.6). This study included 109 RA patients, including 97 (89%) women and 30 (27.5%) with erosions, who were treated with a TNFi. Higher baseline DAS28 was negatively associated with achievement of remission (OR = 0.56, 95% CI 0.35-0.88). The TNFi retention rate was significantly lower in RA patients with than in those without erosions (p = 0.04). Factors significantly associated with drug discontinuation included the presence of erosions (HR = 2.45, 95% CI 1.08-5.51) and higher time-averaged DAS28 (HR = 2.17, 95% CI 1.47-3.20), whereas concomitant methotrexate was associated with lack of drug discontinuation (HR = 0.40, 95% CI 0.17-0.95). The presence of erosions and high time-averaged disease activity could predict poor retention of TNFi by RA patients. Higher baseline DAS28 was associated with a reduced clinical response in patients with RA.Trial registration Clinical Research Information Service of South Korea https://cris.nih.go.kr : KCT0000086, registered May 26, 2009.


Relocation of antigens to the cell surface membrane can enhance immune stimulation and protection.
The major outer capsid glycoprotein of rotaviruses, VP7, is normally synthesized and directed to the ER, where it is required for virus assembly. By substituting a foreign signal sequence for the VP7 signal peptide, a secreted form of VP7 with an authentic amino terminus was produced. Secreted VP7 was further modified by the addition of a transmembrane anchor and cytoplasmic domain to its C-terminus. When the novel chimeric protein was expressed in transfected cells it became anchored in the cell surface membrane. The antigenicity of the chimeric protein was compared with that of the intracellular form of VP7 using recombinant vaccinia viruses to deliver the antigens in vivo. The novel antigen produced enhanced stimulation of both B and T lymphocytes of the immune system, and in mice it was able to induce protection against rotavirus-induced diarrhoeal disease. Other secreted and intracellular antigens show a similar improved level of antigenicity as a result of their relocation to the cell surface. Surface localization may therefore have general utility in the development of recombinant subunit vaccines.


Verreaux's eagles (Aquila verreauxi) as potential predators of hamadryas baboons (Papio hamadryas hamadryas) in Eritrea.
In this paper we describe for the first time encounters of Verreaux's eagle (Aquila verreauxi) with hamadryas baboons (Papio hamadryas hamadryas) in the central highlands of Eritrea (15 degrees 22' N, 38 degrees 58' E, 2300 m). During 12 h of observation on 4 days, we observed four encounters of Verreaux's eagles with baboons, of which three can be classified as possible attacks. The baboons always responded with alarm calls. In three cases some immatures rushed to adult group members and clung to them, particularly to the adult male. Adult males threatened the eagle, and the whole group did not flee. The response of baboons towards smaller raptors like tawny eagles (Aquila rapax) and black kites (Milvus migrans) was very different. The adult baboons gave no alarm barks but scanned the raptors. The permanent presence of a pair of Verreaux's eagles in the home range of the baboons may represent a considerable predation pressure, at least for immature baboons.


Vitamin D and Bone Mineral Density in HIV Newly Diagnosed Therapy-Naive Patients Without Any Secondary Causes of Osteoporosis.
Bone loss and vitamin D deficiency are common in HIV patients. However, bone health status in newly diagnosed HIV patients has not been thoroughly described. Our aim was to assess the bone mineral density (BMD), bone resorption and vitamin D status in newly diagnosed HIV patients. A prospective observational study in HIV newly diagnosed therapy-naive persons. Patients with secondary causes of osteoporosis were excluded. Bone densitometry (DXA), a bone resorption marker (CTx), 25-hydroxyvitamin D (25OHD), CD4 count and HIV viral load (VL) were done in 70 patients. Vitamin D results were compared with a group of healthy volunteers. All patients were men, mean age 31 years (19-50). Low BMD (Z score ≤ 2.0) was found in 13%, all of them in lumbar spine, and in only one patient also in femoral neck. Bone resorption was high in 16%. One out of four participants had low BMD or high bone resorption. Vitamin D deficiency (25OHD < 20 ng/mL) was found in 66%. Mean 25OHD in patients was significantly lower than in healthy volunteers (p = 0.04). No associations were found between BMD, CTx, 25OHD and VL or CD4 count. We hypothesize that HIV infection negatively affects bone health based on the results we found among newly diagnosed, therapy-naive, HIV-infected patients, without any known secondary causes of osteoporosis. Low BMD or high bone resorption, are significantly prevalent in these patients. HIV-infected patients had a higher prevalence of vitamin D deficiency than controls, which was not correlated with CD4 count or VL.


Transitional cell carcinoma in patients with spinal cord injury: a high risk malignancy?
To study bladder cancer incidence in patients with spinal cord injury (SCI) in Germany, Switzerland, and Austria. SCI is associated with neurogenic bladder dysfunction. These patients are at an increased risk of developing bladder malignancies. A questionnaire was mailed to all SCI centers in these countries. The number of patients with SCI treated between 1995 and 1999, and the data of all patients with SCI with bladder cancer were recorded. The charts of 43,561 patients were reviewed. Of these, 48 patients (0.11%) developed bladder cancer. The data of 8 female and 29 male patients were fully available. The mean age was 53.3 years. Bladder management was reflex voiding in 18 patients, intermittent catheterization in 12 patients, and an indwelling catheter in 7 patients. Twelve patients were smokers. The mean time between SCI and the first bladder cancer diagnosis was 22.6 years. Thirty-two percent had superficial cancers, 8% had carcinoma in situ, and 60% presented with muscle-infiltrating tumors; 81% had urothelial cancer and 19% squamous cell cancer. Thirteen patients rarely had urinary tract infections (UTIs), 9 had more than 10 UTIs annually, and 15 had chronic UTIs. The bladder cancer incidence in patients with SCI and in the general population is comparable. More than 60% of the patients with SCI, however, initially presented with muscle-infiltrating bladder cancer. Indwelling catheters and chronic UTIs were common in patients with bladder cancer. Immunologic pathologic mechanisms and a prolonged exposure to carcinogens may be involved in bladder cancer carcinogenesis in patients with SCI.


Predictive factors of seizure frequency and duration of antiepileptic treatment in rolandic epilepsy: a retrospective study.
Factors useful to predict seizure frequency and duration of antiepileptic treatment of children with benign partial epilepsy and rolandic spikes were retrospectively evaluated in 72 patients seizure-free for at least 5 years and off antiepileptic drugs for at least 2 years. Three groups were considered: Group I, 11 patients (15%) with a single seizure: Group II, 40 patients (56%) with 2 to 6 seizures; Group III, 21 patients (29%) with over 6 seizures. Significant predictors of rare seizure frequency were: presence of convulsive generalized seizures as the sole ictal manifestation, found in 17 patients of Group II and in one patient of Group III (p less than 0.001), and longer average interval between first and second seizure in Group II than in Group III (7.8 months versus 3.5 months, p less than 0.0001). Although the average duration of the disease was significantly shorter in Group II than in Group III (1.5 years versus 4.5 years, p less than 0.00001), the duration of the antiepileptic treatment was similar in both groups. Of the 8 untreated patients, 5 had a single seizure and one had 2 seizures. Therefore, it is suggested that antiepileptic treatment be delayed without risk until the third seizure occurrence and restricted to patients with no predictor of rare seizure recurrence.


Effects of Sodium Arsenite and Arsenate in Testicular Histomorphometry and Antioxidants Enzymes Activities in Rats.
The main source of environmental arsenic exposure in most countries of the world is drinking water in which inorganic forms of arsenic predominate. The present study was aimed to test the impact of two different compounds of inorganic arsenic in histomorphometric and enzymatic parameters in the testes by oral exposition. Adult Wistar male rats were exposed to sodium arsenite and arsenate in drinking water, testing for each chemical form the concentrations of 0.01 and 10 mg/L per 56 days. The animals intoxicated with arsenic, mainly sodium arsenite, showed reduction in the percentage of seminiferous epithelium and in proportion and volume of Leydig cells. Moreover, there was an increase in the percentage of tunica propria, lumen, lymphatic space, blood vessels, and macrophages. The activity of superoxide dismutase (SOD) did not change among the groups. However, the activity of catalase (CAT) decreased in animals exposed to both arsenic compounds. In addition, the higher concentration of arsenic, mainly as sodium arsenite, caused vacuolization in the seminiferous epithelium. The body and testes weight as well as testosterone concentration remained unchanged among the groups. In conclusion, exposition to arsenic, mainly as sodium arsenite, caused alteration in histomorphometric parameters and antioxidant defense system in the testes.


Impact of Rapid Susceptibility Testing and Antibiotic Selection Strategy on the Emergence and Spread of Antibiotic Resistance in Gonorrhea.
Increasing antibiotic resistance limits treatment options for gonorrhea. We examined the impact of a hypothetical point-of-care (POC) test reporting antibiotic susceptibility profiles on slowing resistance spread. A mathematical model describing gonorrhea transmission incorporated resistance emergence probabilities and fitness costs associated with resistance based on characteristics of ciprofloxacin (A), azithromycin (B), and ceftriaxone (C). We evaluated time to 1% and 5% prevalence of resistant strains among all isolates with the following: (1) empiric treatment (B and C), and treatment guided by POC tests determining susceptibility to (2) A only and (3) all 3 antibiotics. Continued empiric treatment without POC testing was projected to result in >5% of isolates being resistant to both B and C within 15 years. Use of either POC test in 10% of identified cases delayed this by 5 years. The 3 antibiotic POC test delayed the time to reach 1% prevalence of triply-resistant strains by 6 years, whereas the A-only test resulted in no delay. Results were less sensitive to assumptions about fitness costs and test characteristics with increasing test uptake. Rapid diagnostics reporting antibiotic susceptibility may extend the usefulness of existing antibiotics for gonorrhea treatment, but ongoing monitoring of resistance patterns will be critical.


Hypersialyloligosacchariduria in mucolipidoses: a method for diagnosis.
A method is described for the detection of abnormal oligosaccharides in a small (5 ml) volume of urine, employing filtration on a Bio Gel P-6 column, determination of neutral sugar and bound sialic acid, and determination of creatinine content. With this method increased urinary excretion of sialic acid-rich oligosaccharides has been detected in nine patients with mucolipidoses (five cases of mucolipidosis II and four patients of mucolipidosis, with beta-galactosidase deficiency). The filtration patterns of oligosaccharides in mucolipidoses were clearly distinguishable from those in other inborn errors of metabolism. Total excreted oligosaccharides were increased 5--30-fold in these patients; mucolipidosis II, 640--1350 microgram neutral sugar/mg creatinine; control 54 +/- 20 microgram neutral sugar/mg creatinine. The oligosaccharides consisted of three sialic acid-rich fractions and were common in both types of mucolipidosis. Our data indicate that hypersialyoligosacchariduria is the main biochemical feature of both types of mucolipidosis.


Sustainable groundwater treatment technologies for underserved rural communities in emerging economies.
Worldwide, about one out of two people depend on groundwater resources to satisfy their drinking water needs. While groundwater typically is of higher quality than surface water, pollution and geologic conditions may require treating groundwater to meet safe water quality criteria. Herein, a critical overview is presented of water treatment technologies for rural and underserved communities in emerging economies that depend on groundwater. Given that small to medium sized rural communities in emerging economies often lack the financial resources to support technologically complex and expensive centralized public water treatment systems, the focus is on proven technologies that are sustainable and acceptable by the rural population. After an overview of the underlying treatment mechanisms and the principal groundwater contaminants targeted by the traditional, advanced, and experimental water treatment technologies, we identify the groundwater quality parameters that may impact or interfere with the technology performance. We also introduce enabling environmental factors that might govern the implementation of water treatment technologies in the target communities and a brief discussion of safe storage of water after treatment to underline the importance of protecting the water from re-contamination. Our overview is further supported by tabulated summaries of the principal (dis)advantages of each technology covered herein, including cost considerations and social acceptance. Overall, our review suggests that underserved rural communities have sustainable and affordable options for cases where the quality of local groundwater resources requires treatment.


Therapeutic application of regeneration-associated cells: a novel source of regenerative medicine.
Chronic diseases with comorbidities or associated risk factors may impair the function of regenerative cells and the regenerative microenvironment. Following this consideration, the vasculogenic conditioning culture (VCC) method was developed to boost the regenerative microenvironment to achieve regeneration-associated cells (RACs), which contain vasculogenic endothelial progenitor cells (EPCs) and anti-inflammatory/anti-immunity cells. Preclinical and clinical studies demonstrate that RAC transplantation is a safe and convenient cell population for promoting ischemic tissue recovery based on its strong vasculogenicity and functionality. The outputs of the scientific reports reviewed in the present study shed light on the fact that RAC transplantation is efficient in curing various diseases. Here, we compactly highlight the universal features of RACs and the latest progress in their translation toward clinics.


A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia.
Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.


The performance of blood pressure-to-height ratio as a screening measure for identifying children and adolescents with hypertension: a meta-analysis.
The blood pressure-to-height ratio (BPHR) has been shown to be an accurate index for screening hypertension in children and adolescents. The aim of the present study was to perform a meta-analysis to assess the performance of BPHR for the assessment of hypertension. Electronic and manual searches were performed to identify studies of the BPHR. After methodological quality assessment and data extraction, pooled estimates of the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, area under the receiver operating characteristic curve and summary receiver operating characteristics were assessed systematically. The extent of heterogeneity for it was assessed. Six studies were identified for analysis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio values of BPHR, for assessment of hypertension, were 96% [95% confidence interval (CI)=0.95-0.97], 90% (95% CI=0.90-0.91), 10.68 (95% CI=8.03-14.21), 0.04 (95% CI=0.03-0.07) and 247.82 (95% CI=114.50-536.34), respectively. The area under the receiver operating characteristic curve was 0.9472. The BPHR had higher diagnostic accuracies for identifying hypertension in children and adolescents.


In vivo 31P NMR in crustacean muscles: fatigue and recovery in the tail musculature from the prawn Palaemon elegans.
31P NMR has been used to observe the in vivo phosphometabolite concentrations in the tail musculature from the prawn Palaemon elegans, at rest and after escape swimming and subsequent recovery. Muscular fatigue corresponds to a 60% breakdown of phosphoarginine, and a 45% increase of sugar phosphates. The pHi fell from 7.10 to 6.86. During recovery, the sugar phosphates and arginine phosphate are replenished after 20 minutes. The ATP concentration did not change throughout the experiment. The pHi was restored within 20 minutes.


Diagnostic Challenges in Sepsis.
Sepsis is a leading cause of death worldwide. Groundbreaking international collaborative efforts have culminated in the widely accepted surviving sepsis guidelines, with iterative improvements in management strategies and definitions providing important advances in care for patients. Key to the diagnosis of sepsis is identification of infection, and whilst the diagnostic criteria for sepsis is now clear, the diagnosis of infection remains a challenge and there is often discordance between clinician assessments for infection. We review the utility of common biochemical, microbiological and radiological tools employed by clinicians to diagnose infection and explore the difficulty of making a diagnosis of infection in severe inflammatory states through illustrative case reports. Finally, we discuss some of the novel and emerging approaches in diagnosis of infection and sepsis. While prompt diagnosis and treatment of sepsis is essential to improve outcomes in sepsis, there remains no single tool to reliably identify or exclude infection. This contributes to unnecessary antimicrobial use that is harmful to individuals and populations. There is therefore a pressing need for novel solutions. Machine learning approaches using multiple diagnostic and clinical inputs may offer a potential solution but as yet these approaches remain experimental.


Methylations in human hemoglobin.
Levels of N-Methylvaline (MeVal) and N tau-methylhistidine (MeHis) were measured in male smokers and non-smokers in a program aimed at mapping background alkylations of hemoglobin (Hb) as potential indicators of doses of exogenous and endogenous genotoxic agents. MeVal was also determined in Hb from rats, Syrian golden hamsters, mice and chickens. MeVal was found to occur at levels around 0.5 nmole/g Hb, with relatively little variation between individuals and species. MeVal was not significantly affected by smoking. This result contrasts with elevated levels of N-hydroxyethylvaline (HOEtVal) measured in the same persons (Törnqvist et al., 1986b). Levels of S-methylcysteine (MeCys) (Bailey et al., 1981) and MeHis were much higher than those of MeVal. The high levels of MeCys and MeHis may be due partly to misincorporation during protein synthesis and to artifacts. S-Adenosylmethionine and formaldehyde are possible endogenous sources of MeVal. One individual (smoker) out of 21 selected for measurement of MeVal was an outlier, with raised levels of both MeVal and HOEtVal, as would be expected in case of a defective detoxification system.


Association of treatment-achieved HbA1c with incidence of coronary artery disease and severe eye disease in diabetes patients.
To examine the association between treatment-achieved HbA1c values and incidence of both coronary artery disease (CAD) and severe eye disease with different diabetes treatments. Associations of treatment-achieved HbA1c were investigated in various treatment groups [diet only; insulin; sulphonylurea (SU) alone; SU with glinides; and antihyperglycaemic agents other than glinides, SU or insulin] taken from a nationwide claims database of 14,633 Japanese diabetes patients. Cox's regression analysis examined risks over a 5.1-year follow-up. A significant linear trend was associated with HbA1c levels and CAD events in the diet-only group, and CAD risks were significantly higher in insulin and SU groups with HbA1c ≤ 7.0% and > 8.0% than in the diet-only group with HbA1c ≤ 7.0%. In contrast to CAD, a linear association was observed regardless of treatment modality between achieved HbA1c levels and risk of severe diabetic eye disease, but with no significant difference in eye disease risk between groups with HbA1c ≤ 7.0% and 7.1-8.0% in those treated with either SU alone, SU with glinides, or insulin. These findings suggest that the relationship between treatment-achieved HbA1c and incidence of both CAD and severe diabetic eye disease differed according to treatment, based on a large-scale real-life database. More research is now needed to confirm these findings and to further investigate the underlying mechanisms.


A rare case presentation of a symptomatic omphalomesenteric cyst in an adult, 24-year-old patient, treated with laparoscopic resection.
A persistent omphalomesenteric duct remnant is a rare finding, which typically presents in the pediatric population. Most commonly, it is encountered in the form of a Meckel's diverticulum. In rare instances, omphalomesenteric cysts have been reported in the pediatric population. We present a case of a symptomatic omphalomesenteric cyst in an adult male and our management of this entity.


Subjective time is predicted by local and early visual processing.
Time is as pervasive as it is elusive to study, and how the brain keeps track of millisecond time is still unclear. Here we addressed the mechanisms underlying duration perception by looking for a neural signature of subjective time distortion induced by motion adaptation. We recorded electroencephalographic signals in human participants while they were asked to discriminate the duration of visual stimuli after different types of translational motion adaptation. Our results show that perceived duration can be predicted by the amplitude of the N200 event-related potential evoked by the adapted stimulus. Moreover, we show that the distortion of subjective time can be predicted by the activity in the Beta band frequency spectrum, at the offset of the adaptor and during the presentation of the subsequent adapted stimulus. Both effects were observed from posterior electrodes contralateral to the adapted stimulus. Overall, our findings suggest that local and low-level perceptual processes are involved in generating a subjective sense of time.


Measurement of clofibric acid (CPIB) metabolites in plasma of patients on clofibrate therapy.
1. The metabolites of clofibric acid [CPIB;2-(chlorophenoxy)-2-methylpropionic acid] are present in the plasma of patients on clofibrate therapy. The highest plasma concentrations of CPIB in metabolite form (up to 51 micrograms/ml) were generally found in patients with renal disease. Negligible concentrations (less than or equal to 2 micrograms/ml) were found in only seven patients out of thirty-six studied. 2. The two conjugates of CPIB found in urine were present in plasma. 3. When measuring conjugated CPIB in plasma it is essential to take care in the handling and storage of specimens, and to select an assay method known to be specific for unmetabolized CPIB.


Expanding the phenotype of PURA-related neurodevelopmental disorder: a close differential diagnosis of infantile hypotonia with psychomotor retardation and characteristic facies.
Purine-rich element-binding protein A (PURA) encodes Pur-alpha, a transcriptional activator protein is crucial for normal brain development. Pathogenic variants in PURA are known to cause mental retardation, autosomal dominant 31, characterized by psychomotor delay, absent or poor speech, hypotonia, feeding difficulties, seizures or 'seizure-like' movements, and dysmorphism. PURA-related neurodevelopmental disorder (PURA-related NDD) result either from heterozygous pathogenic sequence variants in PURA or microdeletions spanning PURA. Singleton whole-exome sequencing (WES) was performed for the proband after a clinical diagnosis of infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) was made. The pathogenic variant was validated by Sanger sequencing in the proband and parents. Comparison of PURA-related NDD and IHPRF was carried out. WES identified a novel, de-novo stop-gain variant c.178G>T in PURA. In addition to typical phenotype, subject also had hypersensitivity to various stimuli which was not reported in PURA-related NDD. Significant phenotypic overlap was observed in subjects with PURA-related NDD and IHPRF especially with IHPRF2, caused by biallelic pathogenic variants in UNC80. This study expands the phenotypic and mutational spectrum of PURA-related NDD. We propose PURA-related NDD to be considered as a close differential diagnosis of IHPRF.


Hemodynamic effects of L-threo-3,4-dihydroxyphenylserine (Droxidopa) in hypotensive individuals with spinal cord injury.
To determine the effect of an escalating dose of droxidopa (100, 200, and 400 mg) compared with placebo on seated blood pressure (BP) in hypotensive individuals with spinal cord injury (SCI). Secondarily, we aimed to determine the effect of droxidopa on (1) supine BP and heart rate, (2) the change in BP and heart rate when these individuals were transferred from the supine to the seated position, and (3) adverse event (AE) reporting. Open-label dose titration trial. A Veterans Administration Medical Center. Participants with SCI (C3-T12) (N=10) were studied during 4 laboratory visits. Subjects visited the laboratory for about 5 hours on each visit, which incorporated a 30-minute seated baseline, a 30- to 60-minute supine, and a 4-hour seated postdrug observation. Placebo on visit 1, droxidopa 100 mg on visit 2, droxidopa 200 mg on visit 3, and droxidopa 400 mg on visit 4. BP and heart rate changes from baseline to the postdrug period, orthostatic heart rate and BP responses, and subjective AE reporting. Seated BP was significantly elevated with 400 mg droxidopa compared with placebo and 100 mg droxidopa for 3 hours and was elevated for 2 hours compared with 200 mg droxidopa. Increase in supine BP was not worsened following droxidopa, and the expected fall in BP when transferred to the seated position was prevented with droxidopa 200 and 400 mg. There were no significant differences in the heart rate response or AE reporting among the study visits. Our preliminary findings suggest that droxidopa, at the doses tested, does not cause excessive increases in supine BP and the 400-mg dose appears to be effective at increasing seated BP for up to 3 hours in persons with SCI.


[Primary cutaneous cribriform apocrine carcinoma : An underdiagnosed entity?].
Primary cutaneous cribriform apocrine carcinoma is a distinctive but little known variant of cutaneous apocrine carcinoma with indolent biological behaviour. It should not be mistaken for a cutaneous metastasis of a visceral carcinoma, an adenoid cystic basal cell carcinoma or a primary cutaneous adenoid cystic carcinoma.


Transcranial Doppler assessment of cerebral collateral during carotid endarterectomy.
Sixteen patients (mean age 59 +/- 9 years) who were to undergo carotid endarterectomy were examined pre- and peroperatively using pulsed Doppler-shifted ultrasound; blood velocities in the middle cerebral artery were measured before and during common carotid compression in the conscious patient, and before and during measurement of carotid stump pressures at surgery in the anaesthetized patient. Measurements at endarterectomy showed a significant difference in middle cerebral artery blood velocities from patients with stump pressures of greater and less than 50 mmHg (t = 4.0, P less than 0.005). A threshold of 10 cm s-1 distinguished between stump pressures of greater and less than 50 mmHg in 15 of the 16 patients. Pre-operative blood velocity measurements during carotid compression did not correlate with those taken peroperatively at carotid clamping.


Lipidomics as a principal tool for advancing biomedical research.
Lipidomics, which targets at the construction of a comprehensive map of lipidome comprising the entire lipid pool within a cell or tissue, is currently emerging as an independent discipline at the interface of lipid biology, technology and medicine. The diversity and complexity of the biological lipidomes call for technical innovation and improvement to meet the needs of various biomedical studies. The recent wave of expansion in the field of lipidomic research is mainly attributed to advances in analytical technologies, in particular, the development of new mass spectrometric and chromatographic tools for the characterization and quantification of the wide array of diverse lipid species in the cellular lipidome. Here, we review some of the key technical advances in lipidome analysis and put forth the applications of lipidomics in addressing the biological roles of lipids in numerous disease models including the metabolic syndrome, neurodegenerative diseases and infectious diseases, as well as the increasing urgency to construct the lipidome inventory for various mammalian/organism models useful for biomedical research.


Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia.
Behavioural Variant Frontotemporal Dementia (bvFTD) is a rapidly progressing neurodegenerative proteinopathy. Perivascular spaces (PVS) form a part of the brain's glymphatic clearance system. When enlarged due to poor glymphatic clearance of toxic proteins, PVS become larger and more conspicuous on MRI. Therefore, enlarged PVS may be a useful biomarker of disease severity and progression in neurodegenerative proteinopathies such as bvFTD. This study aimed to determine the utility of PVS as a biomarker of disease progression in patients with bvFTD. Serial baseline and week 52 MRIs acquired from ten patients with bvFTD prospectively recruited and followed in a Phase 1b open label trial of sodium selenate for bvFTD were used in this study. An automated algorithm quantified PVS on MRI, which was visually inspected and validated by a member of the study team. The number and volume of PVS were extracted and mixed models used to assess the relationship between PVS burden and other measures of disease (cognition, carer burden scale, protein biomarkers). Additional exploratory analysis investigated PVS burden in patients who appeared to not progress over the 12 months of selenate treatment (i.e., "non-progressors"). Overall, PVS cluster number (ß = -3.27, CI [-7.80 - 1.27], p = 0.267) and PVS volume (ß = -36.8, CI [-84.9 - 11.3], p = 0.171) did not change over the paired MRI scans 12 months apart. There was association between cognition total composite scores and the PVS burden (PVS cluster ß = -0.802e-3, CI [9.45e - 3 - -6.60e - 3, p ≤ 0.001; PVS volume ß = -1.30e - 3, CI [-1.55e - 3 - -1.05e - 3], p ≤ 0.001), as well as between the change in the cognition total composite score and the change in PVS volume (ß = 4.36e - 3, CI [1.33e - 3 - 7.40e - 3], p = 0.046) over the trial period. There was a significant association between CSF t-tau and the number of PVS clusters (ß = 2.845, CI [0.630 - 5.06], p = 0.036). Additionally, there was a significant relationship between the change in CSF t-tau and the change in the number of PVS (ß = 1.54, CI [0.918 - 2.16], p < 0.001) and PVS volume (ß = 13.8, CI [6.37 - 21.1], p = 0.003) over the trial period. An association was found between the change in NfL and the change in PVS volume (ß = 1.40, CI [0.272 - 2.52], p = 0.045) over time. Within the "non-progressor" group (n = 7), there was a significant relationship between the change in the CSF total-tau (t-tau) levels and the change in the PVS burden (PVS cluster (ß = 1.46, CI [0.577 - 2.34], p = 0.014; PVS volume ß = 14.6, CI [3.86 - 25.4], p = 0.032) over the trial period. Additionally, there was evidence of a significant relationship between the change in NfL levels and the change in the PVS burden over time (PVS cluster ß = 0.296, CI [0.229 - 0.361], p ≤ 0.001; PVS volume ß = 3.67, CI [2.42 - 4.92], p = 0.002). Analysis of serial MRI scans 12 months apart in patients with bvFTD demonstrated a relationship between PVS burden and disease severity as measured by the total cognitive composite score and CSF t-tau. Further studies are needed to confirm PVS as a robust marker of neurodegeneration in proteinopathies.


Glucose and amino acid metabolism in aging man: differential effects of insulin.
Insulin is a major regulator of glucose and body protein homeostasis, both of which demonstrate age-related changes. To clarify insulin's role in these age-related changes and to compare age-related glucose and protein homeostatic responses, insulin-mediated aspects of glucose and amino acid metabolism were simultaneously examined in healthy postabsorptive young (n = 5, mean age, 25 years) and elderly (n = 5, mean age, 76 years) men. Primed constant infusions of L-[1-13C]leucine and L-[15N]alanine were administered during a basal period (0 to 180 minutes) and during four separate single rate euglycemic insulin infusions (180 to 360 minutes). Steady state insulin concentrations were 16 +/- 1, 29 +/- 3, 75 +/- 5, and 2407 +/- 56 microU/mL in the young and 23 +/- 4, 37 +/- 8, 96 +/- 11 and 3,357 +/- 249 microU/mL in the elderly at the different insulin infusion rates of 6, 10, 30, and 400 mU mU.m-2.min-1, respectively. For the 6 and 10 mU insulin infusion rates, a primed, constant infusion of [6,6 - 2H2]glucose permitted quantitation of hepatic glucose production. Glucose disposal rates adjusted for lean body mass (LBM) were lower in the elderly than in the young at the 6, 10, and 30 mU insulin infusion rates and similar in the two age groups in the 400 mU studies. Insulin dose-dependent reductions occurred in eight of ten plasma amino acids and were not influenced by age. There was an insulin dose-dependent reduction in plasma leucine flux which was similar in both age groups.(ABSTRACT TRUNCATED AT 250 WORDS)


A highly sensitive hybrid organic-inorganic sensor for continuous monitoring of hemoglobin.
Microelectronic-based sensors are ideal for real-time continuous monitoring of health states due to their low cost of production, small size, portability, and ease of integration into electronic systems. However, typically semiconductor-based devices cannot be operated in aqueous solutions, especially in solutions with a low pH. However, in this work we overcame this difficulty and demonstrated the feasibility of a hemoglobin sensing array based on hybrid organic GaAs-based devices, which can remain in biological solutions for more than 24h. This was achieved by coating devices with a nanometer-thick polymer protective layer with subsequent adsorption of antibodies on its surface. The device is capable of functioning even in harsh physiological fluids, such as urine and bile juice. The surface modification allows a change in electrical potential, created by the interaction, to be efficiently transferred to the surface of the semiconductor device. By utilizing an array configuration, it is possible to obtain high sensitivity and selectivity.


Disposition of perfluorinated acid isomers in Sprague-Dawley rats; part 2: subchronic dose.
Two major industrial synthetic pathways have been used to produce perfluorinated acids (PFAs) or their precursors: Telomerization and electrochemical fluorination (ECF). Products of telomer and ECF origin can be distinguished by structural isomer profiles. A mixture of linear and branched perfluoroalkyl isomers is associated with ECF. Telomer products characteristically consist of a single perfluoroalkyl geometry, typically linear. In biota, it is unclear if the isomer profile is conserved relative to the exposure medium and hence whether PFA isomer profiles in organisms are useful for distinguishing environmental PFA sources. A companion study suggested isomer-specific disposition following a single oral gavage exposure to rats. To confirm these findings under a more realistic subchronic feeding scenario, male and female rats were administered PFA isomers by diet for 12 weeks, followed by a 12-week depuration period. The diet contained 500 ng/g each of ECF perfluorooctanoate (PFOA, approximately 80% n-PFOA), ECF perfluorooctane sulfonate (PFOS, approximately 70% n-PFOS), and linear and isopropyl perfluorononanoate (n- and iso-PFNA). Blood sampling during the exposure phase revealed preferential accumulation of n-PFOA and n-PFNA compared to most branched isomers. Female rats depurated all isomers faster than males. Both sexes eliminated most branched perfluorocarboxylate isomers more rapidly than the n-isomer. Elimination rates of the major branched PFOS isomers were not statistically different from n-PFOS. Two minor isomers of ECF PFOA and one branched PFOS isomer had longer elimination half-lives than the n-isomers. Although extrapolation of these pharmacokinetics trends in rats to humans and wildlife requires careful consideration of dosage level and species-specific physiology, cumulative evidence suggests that perfluorocarboxylate isomer profiles in biota may not be suitable for quantifying the relative contributions of telomer and ECF sources.


Airway clearance services (ACSs) in Australia for adults with chronic lung conditions: scoping review of publicly available web-based information.
Consumers frequently access the internet looking for health information. With the growing burden of chronic disease internationally, strategies are focussing on self-management interventions in community and ambulatory settings. The objective of this scoping review was to describe publicly available information on Australian airway clearance services. Publicly funded health services network webpages and Google were systematically searched between July and November 2018 using relevant keywords. We identified the number, location and currency of contact information of services; and described the services that were in operation and/or identifiable on the internet. Where specific airway clearance services were not identifiable via searching methods, webpages were navigated for associated physiotherapy services. All identified services were contacted via the listed phone or email to confirm web-based findings. Searching 131 publicly funded health service pages and 191 keyword hits identified four publicly funded airway clearance services (two of which were in operation when confirmed by direct contact) and six private services, all in metropolitan areas of capital cities. Webpages described who their services were for (9/10 services), how to gain referral (4/10) and types of airway clearance techniques available (5/10). A further 286 public physiotherapy services were identified, of which 24 (8%) included descriptors of service provision for respiratory patients on their webpage. In contrast, on direct telephone enquiry airway clearance intervention of some kind was confirmed as being available at 174/286 (61%) sites and unavailable at 69/286 (24%) sites. This scoping review demonstrated inconsistencies between airway clearance service information available on the internet and the reported provision of services confirmed by direct phone contact. Services that are available need to make information visible to consumers on the internet and include details such as referral pathways, interventions and current contact details, to support people with airway clearance problems to access appropriate care in the community.


Neutralization of MMP-2 and TNFR1 Regulates the Severity of S. aureus-Induced Septic Arthritis by Differential Alteration of Local and Systemic Proinflammatory Cytokines in Mice.
Despite advancement in the field of antibiotics septic arthritis remains a serious concern till date. Staphylococcus aureus is the most common bacterium that causes septic arthritis. Severity of this disease is directly correlated with chronic inflammation induced by proinflammatory cytokines like TNF-α, interleukin (IL)-1β, IL-6, and induction of matrix metalloproteinases (MMPs) including MMP-2. The objective of our study was to evaluate the role of MMP-2 and tumor necrosis factor receptor 1 (TNFR1) in the pathogenesis of S. aureus infection-induced septic arthritis. Mice were infected with live S. aureus (5 × 106 cells/ml) followed by administration of MMP-2 inhibitor and TNFR1 antibody. Arthritis index showed highest reduction in severity of arthritis in mice treated with both MMP-2 inhibitor and TNFR1 antibody after infection. Combined neutralization of MMP-2 and TNFR1 led to marked diminution in bacterial count in the combined group. Lowest levels of pro inflammatory cytokines like TNF-α, IL-1β, IL-6, and IFN-γ were observed in both serum and synovial tissues indicating maximum protection in S. aureus arthritis during combination treatment. Increment in the level of IL-10 in the combination group could be positively correlated with the recovery of arthritis. Similarly, expressions of COX-2 and iNOS, markers of acute inflammation were also significantly reduced in the combination group due to resolution of inflammation. Levels of O2.- and NO also showed a significant fall in case of the group treated with MMP-2 inhibitor and TNFR1 antibody both. Neutralization of both MMP-2 and TNFR1 caused rapid decline in recruitment of neutrophil and macrophages in the synovial tissues as evident from reduced MPO and MCP-1 levels, respectively, compared to other groups. Overall, it can be suggested that administration of MMP-2 inhibitor and TNFR1 antibody in combination is protective against the severity of inflammation and cartilage destruction associated with S. aureus infection-induced septic arthritis by altering the levels of cytokines.


Encoding biological recognition in a bicomponent cell-membrane mimic.
Self-assembling dendrimers have facilitated the discovery of periodic and quasiperiodic arrays of supramolecular architectures and the diverse functions derived from them. Examples are liquid quasicrystals and their approximants plus helical columns and spheres, including some that disregard chirality. The same periodic and quasiperiodic arrays were subsequently found in block copolymers, surfactants, lipids, glycolipids, and other complex molecules. Here we report the discovery of lamellar and hexagonal periodic arrays on the surface of vesicles generated from sequence-defined bicomponent monodisperse oligomers containing lipid and glycolipid mimics. These vesicles, known as glycodendrimersomes, act as cell-membrane mimics with hierarchical morphologies resembling bicomponent rafts. These nanosegregated morphologies diminish sugar-sugar interactions enabling stronger binding to sugar-binding proteins than densely packed arrangements of sugars. Importantly, this provides a mechanism to encode the reactivity of sugars via their interaction with sugar-binding proteins. The observed sugar phase-separated hierarchical arrays with lamellar and hexagonal morphologies that encode biological recognition are among the most complex architectures yet discovered in soft matter. The enhanced reactivity of the sugar displays likely has applications in material science and nanomedicine, with potential to evolve into related technologies.


Cisplatin-induced acute renal failure in mice is mediated by chymase-activated angiotensin-aldosterone system and interleukin-18.
Mechanism(s) of cisplatin-induced acute renal failure, as manifested by increases in blood urea nitrogen and creatinine, was evaluated in relation to production and activation of endogenous mediator(s) in mice. In interleukin (IL)-18-deficient (IL-18KO) mice, cisplatin failed to induce acute renal failure. Administration of recombinant IL-18 prior to cisplatin restored acute renal failure in IL-18KO mice. Accumulation of cisplatin in the kidney was not different in IL-18KO and wild-type (WT) mice, but, clearance of cisplatin was more rapid in IL-18KO mice than in WT mice. Cisplatin increased serum levels of aldosterone and angiotensin II in WT mice, but only angiotensin II levels in IL-18 KO mice. Administration of IL-18 augmented plasma levels of aldosterone and angiotensin II in WT mice. Eplerenone, an aldosterone receptor blocker, TY-51469, a chymase inhibitor and PD123319, a selective angiotensin II type 2 (AT2) receptor antagonist, but not benazepril, an angiotensin-converting enzyme inhibitor, and candesartan, a selective angiotensin II type 1 (AT1) receptor antagonist improved acute renal failure caused by cisplatin, confirming involvement of IL-18, aldosterone and angiotensin II in cisplatin-induced, chymase-dependent acute renal failure in mice. These results show that IL-18, aldosterone and angiotensin II synergistically act to prolong the accumulation of cisplatin in the kidney, leading to acute renal failure. Combined therapy with inhibitors for chymase and aldosterone receptors or AT2 receptors might reduce acute renal failure induced by cisplatin.


Exacerbation of the inflammatory response to Mycobacterium tuberculosis after antiretroviral therapy.
A patient with HIV infection was successfully treated for pulmonary tuberculosis, but pulmonary inflammation and lymphadenitis worsened dramatically after subsequent combination antiretroviral therapy. As this relapse coincided with development of a strong delayed-type hypersensitivity response to tuberculin and improved after treatment with the anti-inflammatory agent oxpentifylline, it was probably caused by restoration of pathogen-specific cellular immunity.


Carbon, iron and sulfur metabolism in acidophilic micro-organisms.
Acidophilic micro-organisms are those (mostly prokaryotes) that grow optimally at pH <3 (extreme acidophiles) or at pH 3-5 (moderate acidophiles). Although once considered to comprise relatively few species of bacteria and archaea, the biodiversity of extreme acidophiles is now recognized as being extensive, both in terms of their physiologies and phylogenetic affiliations. Chemolithotrophy (the ability to use inorganic chemicals as electron donors) is widespread among extreme acidophiles, as ferrous iron and sulfur represent two major available energy sources in many natural and man-made extremely acidic environments. Dissimilatory reduction of iron and sulfur (as a consequence of their use as electron acceptors in oxygen-limited and anoxic environments) are also a major biogeochemical processes in low-pH environments. Acidophiles display considerable diversity in how they assimilate carbon; some are obligate autotrophs, others obligate heterotrophs, while a large number use either organic or inorganic carbon, depending on the availability of the former. This review describes the intricate relationships between carbon, iron and sulfur transformations by acidophilic micro-organisms, and how these are significant in both industrial and environmental contexts.


Association of GH polymorphisms with growth traits in buffaloes.
Members of the somatotrophic axis, especially GH and IGF1, are essential for growth. The association between GH polymorphisms and growth traits was numerously studied in cattle; however, no data are available for such association studies in buffalo. Therefore, this study was conducted to screen for polymorphisms in the GH gene and to study their putative association with growth traits in 200 Egyptian buffaloes. Polymerase chain reaction single-strand conformation polymorphism and sequencing were applied to look for polymorphisms in 3 loci spanning all exons and introns of buffalo GH. The C (MspI+) >T (MspI-) SNP in intron3, which is well known in cattle, was not detected in the examined buffaloes. However, 2 missense mutations were detected in exon5: one previously detected p.Leu153Val SNP, with very low frequencies for the mutant (Val) allele and one novel p.Asn174His SNP. At weaning age, the p.Leu153Val SNP was significantly associated with weaning body weight and gain with the positive effect of the wild allele (Leu) and higher GH serum, mRNA, and protein levels in animals with Leu/Asn and Leu/His haplotypes. At yearling age, the 2 SNPs associated with yearling weight and gain with positive effect for the mutant (Val and His) alleles with increased GH, and IGF1 serum, mRNA, and protein and GHR mRNA and protein levels in animals with Val/Asn haplotype. Therefore, the selection of Egyptian buffaloes with the Val/Asn haplotype could improve the growth traits of Egyptian buffaloes at yearling age which is the target age for perfect growing.


Iterative reconstruction vs deep learning image reconstruction: comparison of image quality and diagnostic accuracy of arterial stenosis in low-dose lower extremity CT angiography.
To compare image quality and diagnostic accuracy of arterial stenosis in low-dose lower-extremity CT angiography (CTA) between adaptive statistical iterative reconstruction-V (ASIR-V) and deep learning image reconstruction (DLIR) algorithms. 46 patients undergoing low-dose lower-extremity CTA were enrolled. Images were reconstructed using ASIR-V (blending factor of 50% (AV-50) and 100% (AV-100)) and DLIR (medium (DL-M), and high (DL-H)). CT values and standard deviation of the aorta, psoas, popliteal artery, popliteal and ankle muscles were measured. The edge-rise distance and edge-rise slope were calculated. The degrees of granularity and edge blurring were assessed using a 5-point scale. The stenosis degrees were measured on the four reconstructions, and their mean square errors against that of digital subtraction angiography were calculated and compared. For both ASIR-V and DLIR, higher reconstruction intensity generated lower noise and higher signal-to-noise ratio and contrast-to-noise ratio values. The standard deviation values in AV-100 images were significantly lower than other reconstructions. The two DLIR image groups had higher edge-rise slope and lower edge-rise distance (DL-M:1.79 ± 0.37 mm and DL-H:1.82 ± 0.38 mm vs AV-50:1.96 ± 0.39 mm and AV-100:2.01 ± 0.36 mm, p = 0.014) than ASIR-V images. The overall image quality of DLIR was rated higher than ASIR-V (DL-M:0.83 ± 0.61, DL-H:0.41 ± 0.62, AV-50:1.85 ± 0.60 and AV-100:2.37 ± 0.77, p < 0.001), with DL-H having the highest overall image quality score. For stenosis measurement, DL-H had the lowest mean-square-errors compared to digital subtraction angiography among all reconstruction groups. DLIR images had higher image quality ratings with lower image noise and sharper vessel walls in low-dose lower-extremity CTA, and DL-H provides the best overall image quality and highest accuracy in diagnosing artery stenoses. DLIR provides high-quality images with sharper edges compared to ASIR-V during low-dose CTA of lower extremity arteries, and DLIR (high) provides the best overall image quality and highest accuracy in diagnosing artery stenoses among all reconstruction algorithms (ASIR-V and DLIR). ASIR-V with blending factor of 100% has the strongest noise reduction ability among all reconstruction algorithms (ASIR-V and DLIR); however, it generates the most blurred images.


Optimization of endotracheal tube cuff filling by continuous upper airway carbon dioxide monitoring.
Inappropriate cuff filling is responsible for various complications related to the use of an endotracheal tube (ETT). In this study, we evaluated an objective, noninvasive method for continuous assessment of leak around the ETT cuff by monitoring carbon dioxide pressure (P(CO2) in the upper airway. P(CO2) levels were measured by capnography simultaneously between the ETT cuff and the vocal cords, at the oropharynx, and in the nares of the nose. Cuff filling was regulated by an electronic controller to achieve the minimal pressure needed to prevent CO2 leak. Feasibility of the method was assessed in a human simulator and in a porcine model. Clinical function was evaluated in 60 patients undergoing surgery, comparing the method to the standard anesthesiologist evaluation. Linear correlations were observed between the ETT cuff pressure and P(CO2) level in the human simulator (R2 = 0.954, P < 0.0001) and in the porcine model (R2 > 0.98, P < 0.0001). Iodine leak around the ETT cuff, in the porcine model, occurred only when P(CO2) levels were >2 mm Hg. In the surgery patients, the mean ETT cuff pressure determined clinically by the anesthesiologist was significantly higher than the optimal cuff pressure assessed by P(CO2) (25.2 +/- 3.6 versus 18.2 +/- 7.8 mm Hg, respectively; P < 0.001). According to these findings, optimal ETT cuff filling pressure can be identified by monitoring P(CO2) at the nares or the oropharynx. A new, objective, noninvasive method for optimizing endotracheal tube cuff filling based on monitoring carbon dioxide levels in the upper airways can be used to identify the minimal cuff pressure necessary to eliminate leak and prevent aspiration.


A randomized controlled trial of reflexology effect after abdominal surgery on patient satisfaction, pain and vital signs.
In our study, we investigated the effect of reflexology on patient satisfaction, pain and vital signs after abdominal surgery. This study was conducted as a randomized controlled trial with the participation of 156 abdominal surgery patients hospitalized in the general surgery unit of a training and research hospital. Personal Information Form, Visual Analogue Scale and Newcastle Nursing Care Satisfaction Scale were used in data collection. We performed the data analysis with One-way analysis of variance, Chi-squared test, paired samples t-test, and independent samples t-test. When the pain, vital signs and satisfaction levels of the experimental and control groups were compared, the pain intensity of the experimental group was found to be lower and the level of satisfaction was higher after reflexology (p<0.01). After reflexology, the blood pressure was closer to 120/80 in the experimental group, the respiratory rate was between 16-22 (number/minute), the difference between the experimental and control groups were statistically significant (p<0.01). There was no statistically significant difference between the pulce oximetry values between the experimental and control groups. Surgical pain and non-optimal vital signs that are not well managed after surgery causes various complications and decrease patient satisfaction. The results of our study emphasize the power of reflexology in effective surgical pain management and normalizing vital signs and increasing patient satisfaction. We suggest that reflexology be performed to patients following abdominal surgery.


Relaxation with biofeedback-assisted guided imagery: the importance of breathing rate as an index of hypoarousal.
Fifteen men and 35 women, suffering from a number of psychological and somatic disorders, were taught to relax by biofeedback-assisted deep-diaphragmatic breathing together with guided mental imagery. No instructions were given about rate. Breathing rate and pattern, PETCO2, and EEG were monitored before training and after the first three 2-minute training trials (session 1). In 27 subjects (54%), breathing patterns and rate were noted to resemble those reported by meditation practitioners (3 to 5 b/min). The PETCO2 and EEG changes support a hypothesis of metabolic hypoarousal. Four subjects spontaneously reported experiencing altered awareness. A centrally mediated hypoarousal response is tentatively implicated.


Associations between meat type consumption pattern and incident cardiovascular disease: The ATTICA epidemiological cohort study (2002-2022).
Meat consumption has shown from detrimental to beneficial effects against cardiovascular disease (CVD) incidence, mainly depending on the type of meat studied (i.e., red/white, processed/unprocessed) and quantity consumed. To examine the associations between meat type consumption patterns and incident CVD among apparently healthy adults. ATTICA study was conducted in the greater metropolitan Athens area, Greece, during 2001-2002 studying adults free-of-CVD at baseline. Twenty-year follow-up was performed in n = 1988 participants (n = 718 incident cases). Meat consumption during the follow-up period was categorized as: never/rare meat consumption (i.e., <1 time/week), mostly red meat (i.e., compared to other types of meat or processed meat), mostly white meat, and mostly processed meat products (e.g., bacon, sausage). Approximately 38% of the participants reported rare or no consumption of any type of meat, 31% consumed mostly red meat, 19% mostly white meat and the remainder 12% mostly processed meat. In multivariate analysis, compared to never/rarely consuming any type of meat, consuming mostly processed meat [HR: 2.89, 95%CI: 1.05, 7.89], but not red meat [HR: 1.22, 95%CI: 0.81, 1.82], was positively associated with incident CVD during 20 years of follow-up, while consuming mostly white meat was inversely associated with incident CVD [HR: 0.35, 95%CI: 0.17, 0.71]. The findings of this study suggest that the type of meat, irrespective of the frequency of consumption, plays a role in the risk of developing CVD. In clinical practice, emphasis should be placed on avoiding processed meat and replacing it with white unprocessed meat.


Anticoagulation for atrial fibrillation: should warfarin be temporarily stopped or continued after acute cardioembolic stroke?
Despite anticoagulation for atrial fibrillation, some patients still suffer an ischaemic stroke. The issue of whether to stop or continue warfarin, or possibly to reverse the anticoagulation is an area of uncertainty. Continued anticoagulation may, however, increase haemorrhagic transformation of the infarct. In this article we review the published evidence in an attempt to quantify the risks and benefits of each treatment strategy and identify areas for further research.


The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction.
The brain-specific synaptic guanosine triphosphatase (GTPase)-activating protein (SynGAP) is important in synaptic plasticity. It shows dual specificity for the small guanine nucleotide-binding proteins Rap and Ras. Here, we show that RapGAP activity of SynGAP requires its C2 domain. In contrast to the isolated GAP domain, which does not show any detectable RapGAP activity, a fragment comprising the C2 and GAP domains (C2-GAP) stimulates the intrinsic GTPase reaction of Rap by approximately 1 x 10(4). The C2-GAP crystal structure, complemented by modelling and biochemical analyses, favours a concerted movement of the C2 domain towards the switch II region of Rap to assist in GTPase stimulation. Our data support a catalytic mechanism similar to that of canonical RasGAPs and distinct from the canonical RapGAPs. SynGAP presents the first example, to our knowledge, of a GAP that uses a second domain for catalytic activity, thus pointing to a new function of C2 domains.


Prominin-1 Modulates Rho/ROCK-Mediated Membrane Morphology and Calcium-Dependent Intracellular Chloride Flux.
Membrane morphology is an important structural determinant as it reflects cellular functions. The pentaspan membrane protein Prominin-1 (Prom1/CD133) is known to be localised to protrusions and plays a pivotal role in migration and the determination of cellular morphology; however, the underlying mechanism of its action have been elusive. Here, we performed molecular characterisation of Prom1, focussing primarily on its effects on cell morphology. Overexpression of Prom1 in RPE-1 cells triggers multiple, long, cholesterol-enriched fibres, independently of actin and microtubule polymerisation. A five amino acid stretch located at the carboxyl cytosolic region is essential for fibre formation. The small GTPase Rho and its downstream Rho-associated coiled-coil-containing protein kinase (ROCK) are also essential for this process, and active Rho colocalises with Prom1 at the site of initialisation of fibre formation. In mouse embryonic fibroblast (MEF) cells we show that Prom1 is required for chloride ion efflux induced by calcium ion uptake, and demonstrate that fibre formation is closely associated with chloride efflux activity. Collectively, these findings suggest that Prom1 affects cell morphology and contributes to chloride conductance.


Structures of the sugar chains of mouse immunoglobulin G.
The asparagine-linked sugar chains of mouse immunoglobulin G (IgG) were quantitatively liberated as radioactive oligosaccharides from the polypeptide portions by hydrazinolysis followed by N-acetylation, and NaB3H4 reduction. After fractionation by paper electrophoresis, lectin (RCA120) affinity high-performance liquid chromatography, and gel filtration, their structures were studied by sequential exoglycosidase digestion in combination with methylation analysis. Mouse IgG was shown to contain the biantennary complex type sugar chains. Eight neutral oligosaccharide structures, viz, +/- Gal beta 1----4GlcNAc beta 1----2Man alpha 1----6(+/- Gal beta 1---- 4GlcNAc beta 1----2Man alpha 1----3)Man beta 1----4GlcNAc beta 1----4(+/- Fuc alpha 1----6)GlcNAc, were found after the sialidase treatment. The molar ratio of the sugar chains with 2,1, and 0 galactose residues was 2:5:3. The galactose residue in the monogalactosylated sugar chains was distributed on Man alpha 1----3 and Man alpha 1----6 sides in the ratio of 1:3. The oligosaccharides were almost wholly fucosylated and contained no bisecting N-acetylglucosamine which is present in human, rabbit, and bovine IgGs.


The nutritional sensitivity of the diurnal cycling of body protein enables protein deposition to be measured in subjects at nitrogen equilibrium.
In adults in overall protein balance on intakes of protein equal to or greater than minimum requirements, the diurnal pattern of feeding and fasting results in cycling of body protein, with fasted losses and fed state gains of increasing amplitude with increasing habitual protein intake. Measurement of the slope of the fed state gain-intake relationship enables investigation of the ability of various patient groups to utilise dietary protein, without the need to impose negative nitrogen balance due to sub-maintenance protein intakes.


Understanding the relationship between co-occurring PTSD and MDD: symptom severity and affect.
How to best understand theoretically the nature of the relationship between co-occurring PTSD and MDD (PTSD+MDD) is unclear. In a sample of 173 individuals with chronic PTSD, we examined whether the data were more consistent with current co-occurring MDD as a separate construct or as a marker of posttraumatic stress severity, and whether the relationship between PTSD and MDD is a function of shared symptom clusters and affect components. Results showed that the more severe depressive symptoms found in PTSD+MDD as compared to PTSD remained after controlling for PTSD symptom severity. Additionally, depressive symptom severity significantly predicted co-occurring MDD even when controlling for PTSD severity. In comparison to PTSD, PTSD+MDD had elevated dysphoria and re-experiencing - but not avoidance and hyperarousal - PTSD symptom cluster scores, higher levels of negative affect, and lower levels of positive affect. These findings provide support for PTSD and MDD as two distinct constructs with overlapping distress components.


Probucol and other antioxidants prevent the inhibition of endothelium-dependent relaxation by low density lipoproteins.
Hypercholesterolaemia and atherosclerosis impair responses to endothelium-derived nitric oxide (EDRF) in human and animal coronary arteries, a dysfunction that correlates with elevated low density lipoproteins (LDL). Previous studies show that native LDL immediately and reversibly inhibit acetylcholine-evoked EDRF responses in rabbit aortic ring precontracted with noradrenaline or serotonin whereas Cu(2+)-oxidised LDL (oxLDL) inhibit relaxations after 30 min with a potency that varies with the donor. We now show that antioxidants, probucol (10 microM) and ascorbic acid (100 microM) in vitro, prevent the inhibition by native LDL, indicating that this effect involves free radicals. As expected, the antioxidants had no influence on the inhibition by oxLDL. Superoxide dismutase appeared to have no effect on the inhibition by native or oxLDL. The oral administration of probucol to selected volunteers also prevented the inhibition of relaxation by their native LDL. These preparations showed a diminished susceptibility to oxidation and their oxLDL caused a markedly reduced and always reversible inhibition of relaxation compared to the potent and sometimes irreversible inhibition prior to administration of the drug. We conclude that antioxidants such as probucol reduce the formation of free radicals and the oxidative modification of LDL that lead to the impairment of EDRF responses and may prevent this same dysfunction in hypercholesterolaemia and atherosclerosis.


Real-Time PCR Analysis of Chimerism in T Cell Subsets as an Early Predictor of Graft-Versus-Host Disease Following Allogeneic Stem Cell Transplantation.
Graft-versus-host-disease (GvHD) is the major cause of morbidity and mortality after stem cell transplantation. The development of early prediction methods is therefore of importance. Our aim was to analyze the usefulness of early donor chimerism monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in T cells and in CD4+ and CD8+ (lineage chimerism) for GvHD prediction. Chimerism was analyzed in 76 consecutive adult patients using RQ-PCR TaqMan technology on DNA extracted from Pan T, CD4+, and CD8+ cell subsets on Day 5, 10, 15 and 30 after allo-HSCT. The threshold of chimerism predictive for GvHD was the same for all tested cell subsets. In acute myeloid leukemia (AML) patients treated with myeloablative conditioning (MAC), the threshold predictive for acute graft versus host disease was 95% and 99% for Day 10 and Day 15, respectively. In patients treated with reduced intensity conditioning (RIC), the threshold predictive for chronic graft versus host disease was 98% on Day 10. The differences were statistically significant. Chimerism analysis in T cell subsets by RQ-PCR on Day 10 and Day 15 after transplantation is useful for prediction of aGvHD (AML patients after MAC) and cGvHD (patients after RIC). However, there was no difference in the results between chimerism in the T cell subsets. Our RQ-PCR protocol was highly sensitive and proved effective for analysis of lineage chimerism.


Influence of ATOMS implant on the voiding phase of patients with post-prostatectomy urinary incontinence.
To assess changes in voiding phase, especially urethral resistance after post-prostatectomy urinary incontinence (PPI) treatment with the Adjustable TransObturator Male System (ATOMS). A longitudinal prospective study was performed on 45 men treated with ATOMS for PPI, with the intention to evaluate the changes produced by the implant on the voiding phase. Patients with preoperative urodynamic study were offered postoperative urodynamic evaluation, and both studies were compared. The following urodynamic date were evaluated: maximum voiding detrusor pressure, detrusor pressure at maximum flow rate, maximum flow rate (Qmax), voiding volume, post-void residue, bladder outlet obstruction index (BOOI), urethral resistance factor (URA), and bladder contractility index (BCI). The statistical analysis used were the mean comparison test for dependent groups (Student's t test) for parametric variables and the Wilcoxon test for non-parametric variables. The signification level was set at 95% bilateral. A total of 37 patients (82.2%) used zero pads/day at the time of urodynamic postoperative evaluation and pad-test evolved from 592 ± 289 ml baseline to 25 ± 40 ml (p = 0.0001). Significant differences were observed in Qmax (15 ± 8.3 before and 11 ± 8.3 after surgery; p = 0.008), voiding volume (282 ± 130.7 before and 184 ± 99.92 after surgery). BOOI (-12 ± 23.9 before and -2 ± 21.4 after surgery; p = 0.025) and BCI (93 ± 46.4 before and 76 ± 46.0 after surgery; p = 0.044). In no case did we observe postoperative bladder outlet obstruction, according to URA parameter below 29 cm H2 O in all cases. There was not a significant variation either in post-void urinary residual volume (15 ± 47.4 before and 14 ± 24.2 after surgery, p = 0.867). The ATOMS implant induces a decrease of Qmax, voided volume, and bladder contractility and an increase of BOOI. However, our findings suggest that ATOMS device does not cause bladder outlet obstruction.


Altered macrophage activity and tumor necrosis factor: tumor necrosis and host cachexia.
Tumor necrosis factor (TNF) may be a mediator of cancer cachexia. This study evaluates the activity of macrophages from non-tumor-bearing (NTB) and tumor-bearing (TB) rats by measuring TNF production in response to endotoxin (LPS), both in vitro and in vivo, and correlates macrophage activity with tumor burden and parameters of host cachexia. Isolated macrophages from rats with small tumors, normal food intake, and weight gain secreted more TNF in response to 10 micrograms/ml LPS than macrophages from control NTB rats and behaved similar to activated macrophages from rats previously treated with thioglycollate. Heightened macrophage activity (increased production of TNF in response to LPS) in TB rats increased further as tumor burden increased (r = 0.889, P less than 0.001). Tumor resection reversed the heightened macrophage activity as LPS-induced levels of TNF secreted by macrophages from resected TB rats were not different from those of sham-operated NTB control rats. TB rats had serum levels of TNF activity following an iv bolus of 10 mg/kg LPS greater than those of NTB rats (P less than 0.05). In addition, peak serum TNF activity levels following iv LPS increased directly as tumor burden increased (r = 0.91, P less than 0.001). Supernatants from tissue cultures of the tumor (MCA sarcoma) failed to have any detectable TNF activity. However, large tumors in vivo had increased amounts of necrosis (78 +/- 8%), increased numbers of infiltrating macrophages, and increased levels of TNF (480 +/- 68 U/ml) compared to small tumors.(ABSTRACT TRUNCATED AT 250 WORDS)


Variety classification of coated maize seeds based on Raman hyperspectral imaging.
As an essential factor in quality assessment of maize seeds, variety purity profoundly impacts final yield and farmers' economic benefits. In this study, a novel method based on Raman hyperspectral imaging system was applied to achieve variety classification of coated maize seeds. A total of 760 maize seeds including 4 different varieties were evaluated. Raman spectral data of 400-1800 cm-1 were extracted and preprocessed. Variable selection methods involved were modified competitive adaptive reweighted sampling (MCARS), successive projections algorithm (SPA), and their combination. In addition, MCARS was proposed for the first time in this paper as a stable search technology. The performance of support vector machine (SVM) models optimized by genetic algorithm (GA) was analyzed and compared with models based on random forest (RF) and back-propagation neural network (BPNN). Same models based on Vis-NIR spectral data were also established for comparison. Results showed that the MCARS-GA-SVM model based on Raman spectral data obtained the best performance with calibration accuracy of 99.29% and prediction accuracy of 100%, which were stable and easily replicated. In addition, the accuracy on the independent validation set was 96.88%, which proved that the model can be applied in practice. A more simplified MCARS-SPA-GA-SVM model, which contained only 3 variables, had more than 95% accuracy on each data set. This procedure can help to develop a real-time detection system to classify coated seed varieties with high accuracy, which is of great significance for assessing variety purity and increasing crop yield.


Successful intraoperative retrieval of dislocated femoral trial head during total hip arthroplasty.
Since the advent of modular hip prostheses in the early 1970s, dissociation of the femoral trial head and migration into the deep tissue space of the pelvis are rarely reported complications of total hip arthroplasty. Several case reports have described this complication, but the actual incidence is unknown and likely underreported. Two cases are presented here using a new technique to retrieve a trial femoral head from within the pelvis without use of an extensile approach, laparoscopic retrieval, or secondary incisions.


Arthroscopic acetabular labrum suture.
It is essential to be aware of the anatomy and biomechanics of the acetabular labrum in order to understand why it should be conserved. Vascularization comes from the capsule and also from the bone. The joint side contains numerous nerve endings, which explains why labral lesions are painful. It is involved in joint stabilization by maintaining a negative pressure inside the joint able to resist distraction. It acts as a seal. There are two main suture techniques: trans- and peri-labral. Translabral suture is better suited to a wide and solid labrum free of degenerative lesions. Both techniques should be known, and may be associated. Results are comparable. It is essential to manage the underlying pathology responsible for the labral lesion. Joint degeneration is associated with poor prognosis. It needs to be recognized and discussed with the patient, to avoid unrealistic expectations.


Presence and characteristics of medical home and health services utilization among children with asthma.
Having a medical home is advocated by the National Association of Pediatric Nurse Practitioners and others, yet there is limited research that documents desired health benefits. We examine the presence of medical home characteristics and describe relationships between medical home and health services utilization in a national sample that includes children with asthma. Medical home is represented by: (a) the presence of a usual source of care (USC), (b) identification of a named person as USC, and (c) a 10-item index of other medical home characteristics. Health services utilization over a calendar year is measured by (a) emergency department visits for asthma, (b) wellness examination, and (c) rescue bronchodilator fill/refill. Analyses include chi-square and logistic regression. A USC was reported for 95% of participants. Children with a USC were more likely to have a wellness examination (odds ratio, 2.10; 95% confidence interval, 1.15-3.81). Overall, 51% reported the USC to be a facility versus a named person. Identifying a person as the USC was related to higher scores on the 10-item medical home index but not to other outcomes. Most parents were satisfied with the USC. Benefits of having a USC, but not necessarily a named person, appear in preventive actions.


Organ-sparing treatment of penile cancer with interstitial pulsed-dose-rate brachytherapy.
To assess the efficacy and toxicity profile of protocol-based interstitial pulsed-dose-rate (PDR) brachytherapy for penile carcinoma. From August 2002 to February 2014, 13 men with penile cancer were treated by interstitial brachytherapy. The tumor stage was T1 for eight patients, T2 for four patients, and T3 for one patient. The tumor grade was well differentiated for five patients and moderately differentiated for seven patients, while it was unknown for one patient. Lymph node staging was positive for three of 13 patients. All patients were treated using interstitial PDR brachytherapy with dose specifications according to the Paris system. For data collection of erectile dysfunction, the International Index of Erectile Function questionnaire was used, supplemented by the follow-up data. The median follow-up was 54.0 months (range, 13-155 months). Only one patient (1/13, 7.7 %) with local failure was documented. At 5 and 10 years, the local cumulative recurrence rate, disease-free survival, and the cancer-specific survival rates were 12.5 % (95 % CI, 80.4-119.6), 80.8 % (95 % CI, 75.2-124.8), and 77.9 % (95 % CI, 74.3-125.7), respectively. At the time of analysis, nine of 13 men were alive; two of 13 men died of distant metastases from the tumor and two for other reasons with no sign of cancer disease. Serious late side effects such as soft tissue necrosis occurred in four of 13 patients (30 %) and all were successfully treated with medication. Mutilating salvage surgery was not necessary in any of the cases. Urethral stenosis was documented for two of 13 (15.4 %) and dysuria occurred in four of 13 patients (30.8 %). Eight of 11 men (72.7 %) never or only sometimes had erectile dysfunction. In selected patients, interstitial PDR brachytherapy of penile cancer is effective as an organ-sparing treatment. It yields satisfactory results for the conservation of sexual function.


Usefulness of prognostic indices in upper gastrointestinal bleeding.
Upper gastrointestinal haemorrhage remains a significant cause of hospital admission, with mortality rates up to 14%. In order to standardise and improve care, various scoring systems (e.g. Rockall, Blatchford and Baylor) have been developed to identify those individuals at high risk of requiring treatment (transfusion, endoscopic or surgical intervention) or of re-bleeding or death. There is also increasing interest in the utilisation of scoring systems to identify individuals at low risk of complications, as these may be discharged early, possibly with outpatient endoscopy. Most scoring systems are developed to predict outcomes in non-variceal bleeding. However, several indices are used to predict the outcome of advanced liver disease, including Child-Pugh and the Model of End-Stage Liver Disease (MELD). This chapter reviews all these aspects of the various scoring systems.


Association of Fibroblast Growth Factor-23 Levels and Angiotensin-Converting Enzyme Inhibition in Chronic Systolic Heart Failure.
The aim of this study was to evaluate the association of fibroblast growth factor (FGF)-23 with clinical and laboratory findings, the prognostic value of FGF-23, and the relationship between angiotensin-converting enzyme inhibitor (ACEi) therapy, FGF-23 levels, and outcomes in patients with chronic systolic heart failure (HF). FGF-23 is a bone-derived hormone regulating mineral metabolism. Higher FGF-23 levels are associated with an increased risk of cardiovascular mortality or HF development. Mechanisms leading to increased FGF-23 and its prognostic value have not been thoroughly studied in HF. FGF-23 was measured in 369 patients (mean age 59 ± 11 years, 84% male) with systolic HF. Patients were followed for adverse events (e.g., death, urgent heart transplantation, ventricular assist device implantation). Tricuspid regurgitation severity, chronic kidney disease (CKD), alkaline phosphatase concentrations, inferior vena cava dilation, and absence of ACEi therapy were independently associated with FGF-23. FGF-23 was independently associated with outcomes in patients without CKD (hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.14 to 1.78), but not in CKD patients (HR: 1.12, 95% CI: 0.87 to 1.45). In patients without CKD and with FGF-23 in the highest tertile, ACEi therapy was associated with a lower risk of adverse events (HR: 0.42, 95% CI: 0.21 to 0.81), whereas no association was seen in the remaining patients (HR: 1.18, 95% CI: 0.52 to 2.70). In systolic HF, elevated FGF-23 is an independent predictor of adverse events, particularly in patients with preserved renal function. The association of FGF-23 with adverse events likely reflects early alterations of renal hemodynamics and renin-angiotensin system activation. Increased FGF-23 may identify a subset of HF patients benefiting from ACEi therapy.


An empirical comparison of time-to-event models to analyse a composite outcome in the presence of death as a competing risk.
Competing risks arise when subjects are exposed to multiple mutually exclusive failure events, and the occurrence of one failure hinders the occurrence of other failure events. In the presence of competing risks, it is important to use methods accounting for competing events because failure to account for these events might result in misleading inferences. Using data from a multisite retrospective observational longitudinal study done in Ethiopia, we performed sensitivity analyses using Fine-Gray model, Cause-specific Cox (Cox-CSH) model, Cause-specific Accelerated Failure Time (CS-AFT) model, accounting for death as a competing risk to determine baseline covariates that are associated with a composite of unfavourable retention in care outcomes in people living with Human Immune Virus who were on both Isoniazid preventive therapy (IPT) and antiretroviral therapy (ART). Non-cause specific (non-CSH) model that does not account for competing risk was also performed. The composite outcome comprises of loss to follow-up, stopped treatment and death. Age, World Health Organisation (WHO) stage, gender, and CD4 count were the considered baseline covariates. We included 3578 patients in our analysis. WHO stage III-or-IV was significantly associated with the composite of unfavourable outcomes, Sub-hazard ratio (SHR) = 1.31, 95% confidence interval (CI):1.04-1.65 for the sub-distribution hazard model, hazard ratio [HR] = 1.31, 95% CI:1.05-1.65, for the Cox-CSH model, and HR = 0.81, 95% CI:0.69-0.96, for the CS-AFT model. Gender and WHO stage were found to be significantly associated with the composite of unfavourable outcomes, HR = 1.56, 95% CI:1.27-1.90, HR = 1.28, 95% CI: 1.06-1.55 for males and WHO stage III-or-IV, respectively for the non-CSH model. Results show that WHO stage III-or-IV is significantly associated with unfavourable outcomes. The results from competing risk models were consistent. However, results obtained from the non-CSH model were inconsistent with those obtained from competing risk analysis models.


Antimicrobial efficacy and mechanical properties of BAC-modified hard and soft denture liners.
This study investigated the antimicrobial efficacy and mechanical strength of hard and soft denture liners modified with benzalkonium chloride (BAC). The specimens (1 mm thickness, 8 mm diameter) were prepared by mixing 0.5, 1, 2 and 5 wt% BAC with soft (Sofreliner Medium, Tokuyama) and hard (Rebase II, Tokuyama) denture liners (n = 5/group). BAC was not added to the controls. Candida albicans ATCC 28366 (A 550 = 0.5) and Streptococcus mutans Ingbritt suspensions (A 550 = 0.35) were pipetted onto the specimens, and incubated for 4 h. The viable cells were collected, and determined by plate-culturing (CFU). The tests were repeated after the specimens were soaked in distilled water for 7 days. The mechanical strengths were evaluated by tear and 4-point flexural strength tests for soft and hard liners, respectively. The data were analyzed with ANOVA and Tukey's HSD tests at p = 0.05. C. albicans viability was lost in all groups of BAC-modified soft liners (p < 0.001), and S. mutans viability was reduced (p < 0.01), except of soaked BAC 0.5 wt% group (p > 0.05). For the hard liner, BAC 5 wt% killed the C. albicans and S. mutans cells both before and after soaked in water (p < 0.001). BAC 2 wt% showed comparable tear strength with the soft liner control (p > 0.05). BAC did not reduce the flexural strength of the hard liner (p > 0.05), except of BAC 5 wt% group (p < 0.01). BAC can be a promising agent reducing the C. albicans and S. mutans viability on the soft and hard denture liner surfaces.


Small-cell lung cancer (human): potentiation of endocytic membrane activity by voltage-gated Na(+) channel expression in vitro.
The possible functional role of voltage-gated Na(+) channel (VGSC) expression in controlling endocytic membrane activity in human small-cell lung cancer (SCLC) cell lines (H69, H209, H510) was studied using uptake of horseradish peroxidase (HRP). The normal human airway epithelial (16HBE14o) cell line was used in a comparative approach. Uptake of HRP was vesicular, strongly temperature-sensitive and suppressed by cytoskeletal poisons (cytochalasin D and colchicine), consistent with endocytosis. Compared with the normal cells, HRP uptake into SCLC cells was kinetically more efficient, resulting in more than four-fold higher uptake under optimized conditions. Importantly, HRP uptake into SCLC cells was inhibited significantly by the specific VGSC blocker tetrodotoxin, as well as lidocaine and phenytoin. These effects were dose-dependent. None of these drugs had any effect on the uptake into the 16HBE14o cells. Uptake of HRP into SCLC cells was reduced by approximately 66% in Na(+)-free medium and was partially ( approximately 30%) dependent on extracellular Ca(2+). The possibility that the endocytic activity in the H510 SCLC cells involved an endogenous cholinergic system was investigated by testing the effects of carbachol (a cholinergic receptor agonist) and eserine (an inhibitor of acetylcholinesterase). Both drugs inhibited HRP uptake, thereby suggesting that basal cholinergic activity occurred. It is concluded that VGSC upregulation could enhance metastatic cell behavior in SCLC by enhancing endocytic membrane activity.


Ultra-trace electrochemical impedance determination of bovine serum albumin by a two dimensional silica network citrate-capped gold nanoparticles modified gold electrode.
In this work, a gold electrode (GE) was modified by coating with two dimensional silica network/citrate capped gold nanoparticles-poly(diallyldimethylammonium chloride) (GE-TDSN-CGNP-PDDA) for ultra-sensitive determination of Bovine Serum Albumin (BSA). After covalently binding of a silica network (in two-dimensional form) on the surface of a gold electrode, via twice in situ hydrolysis of 3-mercaptopropyl-tri-ethoxysilane, citrate capped gold nanoparticles (CGNP) were chemically adsorbed on the silica cage. Subsequently, PDDA was bonded to CGNP via electrostatic interaction of positively charged polymer and negatively charged stabilizer of CGNP. Analytical properties of GE-TDSN-CGNP-PDDA were studied by Electrochemical Impedance Spectroscopy (EIS). The detection limit for measured BSA was found to be 8.4×10(-13) mol L(-1) and the measuring linear concentration range of the proposed sensor was 9.9×10(-12)-1.6×10(-10) mol L(-1) of BSA. In addition, GE-TDSN-CGNP-PDDA exhibited good stability with high selectivity and was applied for determination of BSA in some samples with satisfactory results.


Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas.
Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the "genomic recipe" for beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.


Occurrence of polybrominated diphenyl ethers, polychlorinated biphenyls, and phthalates in freshwater fish from the Orge river (Ile-de France).
Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and phthalates were investigated from July 2009 to April 2010 in three fish species from the Orge river, which flows in a densely populated area of Ile-de-France. In two Cyprinidae (roach and chub) and one Percidae (perch), muscle contents in increasing order ranged as follows: 12-18 ng g(-1) dw for PBDEs (Σtri-hepta), 120-170 ng g(-1) dw for PCBs (Σ7), and 2,250-5,125 ng g(-1) dw for phthalates (Σ7). No variation was observed between contaminant contents and lipid levels. No biomagnification was found according to the trophic level for PBDEs and PCBs, whereas for phthalates the highest contents were found in perch. Seasonal variations were observed with the lowest PBDE and PCB contents occurring in July after spawning in roach and perch (p < 0.001). PBDE content followed a decreasing trend-gonad > liver > muscle-whatever the period. For PCBs, gonad and liver contents remained greater than that of muscle (p < 0.05). Our results indicate a preferential accumulation of halogenated compounds in gonad and liver outside the reproduction period. Bioaccumulation factors for PCBs in muscle were significantly correlated to their chlorination degree in perch (p < 0.01) and roach (p < 0.01). In roach, that correlation slope was by decreasing importance order as follows: gonad > liver > muscle. The biota-sediment accumulation factors varied from 0.1 to 29.2, from 1.6 to 4.8, and from 1 to 123.5 for PBDEs, PCBs, and phthalates, respectively. These results contribute to document the use of freshwater fish as bioindicators of river quality.


Real-world histopathological approach to malignancy of undefined primary origin (MUO) to diagnose cancers of unknown primary (CUPs).
The aim of this study is to envisage a streamlined pathological workup to rule out CUPs in patients presenting with MUOs. Sixty-four MUOs were classified using standard histopathology. Clinical data, immunocytochemical markers, and results of molecular analysis were recorded. MUOs were histologically subdivided in clear-cut carcinomas (40 adenocarcinomas, 11 squamous, and 3 neuroendocrine carcinomas) and unclear-carcinoma features (5 undifferentiated and 5 sarcomatoid tumors). Cytohistology of 7/40 adenocarcinomas suggested an early metastatic cancer per se. In 33/40 adenocarcinomas, CK7/CK20 expression pattern, gender, and metastasis sites influenced tissue-specific marker selection. In 23/40 adenocarcinomas, a "putative-immunophenotype" of tissue of origin addressed clinical-diagnostic examinations, identifying 9 early metastatic cancers. Cell lineage markers were used to confirm squamous and neuroendocrine differentiation. Pan-cytokeratins were used to confirm the epithelial nature of poorly differentiated tumors, followed by tissue and cell lineage markers, which identified one melanoma. In total, 47/64 MUOs (73.4%) were confirmed CUP. Molecular analysis, feasible in 37/47 CUPs (78.7%), had no diagnostic impact. Twenty CUP patients, mainly with squamous carcinomas and adenocarcinomas with putative-gynecologic-immunophenotypes, presented with only lymph node metastases and had longer median time to progression and overall survival (< 0.001), compared with patients with other metastatic patterns. We propose a simplified histology-driven workup which could efficiently rule out CUPs and identify early metastatic cancer.


Development of a Competency-Based Radiology Clerkship Using Categorical and Statistical Analysis of Assessment.
The purpose was to create and analyze a competency-based model of educating medical students in a radiology clerkship that can be used to guide curricular reform. During the 2019 to 2020 academic year, 326 fourth-year medical students were enrolled in a 2-week required clerkship. An online testing platform, ExamSoft (Dallas, Texas), was used to test pre- and postinstruction knowledge on "must see" diagnoses, as outlined in the National Medical Student Curriculum in Radiology. Assessment analysis was used to compare the frequency with which the correct diagnosis was identified on the pretest to that on the posttest. At the end of the academic year, in addition to statistical analysis, categorical analysis was used to classify the degree of this change to uncover topics that students found most challenging. For 23 of the 27 topics (85%), there was a significant improvement in diagnostic accuracy after instruction in the test curriculum. Categorical analysis further demonstrated that the clerkship had a high impact in teaching 13 of the 27 topics (48%), had a lower impact for 6 topics (22%), and identified the remaining 8 topics (30%) as gaps in teaching and learning. For medical students, our instructional program significantly increased competency for most critical radiologic diagnoses. Categorical analysis adds value beyond statistical analysis and allows dynamic tailoring of teaching to address gaps in student learning.