Pyrylium-based dye and charge tagging in proteomics.
The pyrylium group is a selective reagent for ε-amino groups in proteins. In particular, for fluorescence labeling, a number of advantages over traditional N-hydroxysuccinimidyl ester chemistry were recognized such as the rapid prestaining procedure. Here, we have investigated the labeling reaction for the fluorogenic pyrylium dye Py-1 using liquid chromatography coupled to MS with the aim of determining its specificity and possible side products. Peptides containing no, one, and two lysine residue and a choice of no or one cysteine residue were labeled with Py-1 at yields > 30%. Gas phase fragmentation proved both labeling of lysine residues as well as that of the N-terminus also in peptides that contained a lysine residue. Evidence for cysteine labeling was not found, but several other products were detected such as the results of rearrangements with adjacent acidic amino acids. Apart from the use as a fluorogenic label, Py-1 recommends itself for N-terminal charge tagging as alternative to the commonly used quaternary ammonium salts. Predominantly a- and b-type ion series were observed for N-terminally labeled peptides. Further applications include chromophore tagging since the labeled product is not only fluorescent but also colored red.


Khat chewing and smoking effect on oral mucosa: a clinical study.
Khat (Catha Edulis Forskal) is widely cultivated in Yemen and East of Africa. The habit of chewing tender leaves and twigs of khat is deep-rooted in Yemen. Our study investigates the chronic khat chewing and smoking effect on oral mucosa. The sample (n=79) consists of two main groups, khat chewers (n=54) and control groups (n=25). Khat chewers group is divided into 4 subgroups according to duration of khat chewing and smoking habit. The control group is divided into 2 subgroups according to smoking habit. Whitening with mild corrugation, frictional keratosis and frictional keratosis with mild or sever corrugation were the clinical findings. One hundred percent of clinical findings were present on buccal mucosa of chewing side of both smokers and non-smokers whatever the duration of khat chewing period. On the vestibular and mucobuccal fold mucosa, (100 % and 73.3 %) and (60 % and 43.7 %) of the khat chewers group had clinical findings on chewing side of smokers and non-smokers according to khat chewing duration respectively. There was clinical relationship between these lesions and khat chewing, but not smoking. Khat chewing causes oral white lesions on the chewing side and it is found that smoking, clinically, does not exacerbate such lesions.


What happened to the stem cells?
Five partly successive and partly overlapping framings have dominated the public debate about human embryonic stem cells since they first were "derived" a decade ago. Geron Corporation staged the initial framings as 1) basic research and 2) medical hope, but these two were immediately refuted and opposed by 3) bioethical concerns, voiced by influential politicians and leaders of opinion. Thereafter, the research community presented adult stem cells and therapeutic cloning as 4) techno-fix solutions supposed to bypass these ethical concerns. And in recent years, 5) institutional limitations to and hurdles within the university-industrial complex (such as patentability, misconduct and fraud) have attracted more attention. The article purifies the arguments and points out the interests and institutions behind the five framings. It also discusses their interplay and finally addresses the question of what happened to the stem cells?


Malondialdehyde as an indicator of oxidative stress during abdominal aortic aneurysm repair.
Ischemia-reperfusion injury significantly contributes to abdominal aortic aneurysm (AAA)- related mortality and morbidity; therefore, we measured oxidative stress during open AAA repair and investigated any potential associations with intraoperative or perioperative events (aortic clamping time, blood loss, and the need to transfer to the intensive care unit). Blood samples were collected at specific time points from 53 patients undergoing open AAA repair: (1) before induction of anesthesia; (2) 15, 30, 60, and 120 minutes after aortic clamping; (3) 15 and 60 minutes after clamp removal; and (4) 24 hours postoperatively. Malondialdehyde (MDA) levels were measured by a spectrophotometric method. Baseline MDA values in patients with AAA were significantly higher than in controls (P < .0001). A positive correlation was found between preoperative MDA levels and the size of AAAs (Pearson correlation = 0.578, P < .001). No difference was observed in MDA levels between ruptured and nonruptured AAAs; however, when all symptomatic patients (ruptured and elective symptomatic AAAs, n = 18) were considered, there was a significant elevation in MDA levels (P < .001). There was also a significant increase in MDA values in patients transferred postoperatively to the intensive care unit (P < .001). Finally, a positive association was found between the duration of aortic clamping with MDA values at 15 and 60 minutes after declamping, but not after 24 hours (Pearson correlation = 0.467, P < .001). MDA levels may predict the postoperative course of elective and ruptured AAAs.


In vitro antioxidant of a water-soluble polysaccharide from Dendrobium fimhriatum Hook.var.oculatum Hook.
A water-soluble crude polysaccharide (DFHP) obtained from the aqueous extracts of the stem of Dendrobium fimhriatum Hook.var.oculatum Hook through hot water extraction followed by ethanol precipitation, was found to have an average molecular weight (Mw) of about 209.3 kDa. Monosaccharide analysis revealed that DFHP was composed of mannose, glucose and galactose in a content ratio of 37.52%; 43.16%; 19.32%. The investigation of antioxidant activity in vitro showed that DFHP is a potential antioxidant.


Humic acid-oxidizing, nitrate-reducing bacteria in agricultural soils.
This study demonstrates the prevalence, phylogenetic diversity, and physiology of nitrate-reducing microorganisms capable of utilizing reduced humic acids (HA) as electron donors in agricultural soils. Most probable number (MPN) enumeration of agricultural soils revealed large populations (10(4) to 10(6) cells g(-1) soil) of microorganisms capable of reducing nitrate while oxidizing the reduced HA analog 2,6-anthrahydroquinone disulfonate (AH(2)DS) to its corresponding quinone. Nitrate-dependent HA-oxidizing organisms isolated from agricultural soils were phylogenetically diverse and included members of the Alphaproteobacteria, Betaproteobacteria, and Gammaproteobacteria. Advective up-flow columns inoculated with corn plot soil and amended with reduced HA and nitrate supported both HA oxidation and enhanced nitrate reduction relative to no-donor or oxidized HA controls. The additional electron donating capacity of reduced HA could reasonably be attributed to the oxidation of reduced functional groups. Subsequent 16S rRNA gene-based high-density oligonucleotide microarray (PhyloChip) indicated that reduced HA columns supported the development of a bacterial community enriched with members of the Acidobacteria, Firmicutes, and Betaproteobacteria relative to the no-donor control and initial inoculum. This study identifies a previously unrecognized role for HA in stimulating denitrification processes in saturated soil systems. Furthermore, this study indicates that reduced humic acids impact soil geochemistry and the indigenous bacterial community composition. This study identifies a new metabolic capacity in soil microbial communities that may be responsible for the mediation of significant nitrogen losses from soil systems. Nitrate-dependent humic acid (HA)-oxidizing organisms isolated from agricultural soils were phylogenetically diverse and included members of Alphaproteobacteria, Betaproteobacteria, and Gammaproteobacteria. Advective up-flow columns inoculated with corn plot soil and amended with reduced HA and nitrate supported both HA oxidation and enhanced nitrate reduction relative to no-donor or oxidized HA controls. The additional electron donating capacity of reduced HA could reasonably be attributed to the oxidation of reduced functional groups.


New predictive equations for estimation of basal metabolic rates of adolescents: tropics versus temperate.
The energy and nutritional requirements of adolescents are influenced primarily by the growth spurt that occurs at puberty, and also by the need to maintain adequate levels of physical activity. Predictions of BMR have gained attention since the publication of the FAO/WHO/UNU (1985) expert consultation report, which adopted the principle of relying on energy expenditure rather than energy intake to derive requirement of individuals. While the report predicts BMR accurately in many individuals from temperate climate, they are said to be less accurate in predicting BMR in populations living in the tropics. The collation of worldwide data on basal metabolism indicated that, relative to adults, there was a paucity of data in other age groups including the adolescents. Although several BMR studies among children had been reported in the 90's, the data in normal weight children are almost exclusively from small control groups in obesity studies. Furthermore, we know little as to whether BMR of children differs in differing climatic conditions. This paper presents predictive equations for estimating BMR from a two-centre study, Bangi (Malaysia) and Oxford (UK) and to compare the results with the currently used predictive equations.


Factors influencing the Sharp score of 1057 patients with rheumatoid arthritis and anemia: a retrospective study.
This study examined the relationship of the Sharp score with demographic factors and clinical immune-inflammatory markers in patients with anemia in rheumatoid arthritis (RA). The clinical data of 1057 patients with RA and anemia and 1006 patients with RA without anemia were retrospectively analyzed. Spearman's correlation coefficient analysis, association rule analysis, and logistic regression were used to study the relationships between the Sharp score and influencing factors in patients with RA and anemia. The incidence of anemia was 51.24% (1057/2063), and mild anemia accounted for 81.93% (866/1057) of cases. Spearman's correlation coefficient and association rule analyses revealed that the Sharp score of patients with RA and anemia was correlated with immune-inflammatory response and anemia. Logistic regression analysis illustrated that advanced age (>60 years), female, low serum iron levels, C-reactive protein positivity, and immunoglobulin A positivity were risk factors for a high Sharp score (>28.25) in patients with RA and anemia. The Sharp score is closely related to clinical disease activity and anemia, and it should be considered in the treatment strategy of patients with RA and anemia.


Allergic angina and allergic myocardial infarction: a new twist on an old syndrome.
A series of eight patients admitted to a single-centre coronary care unit over a two-year period is described. All of the patients presented with an acute coronary syndrome within less than 48 h from the onset of an allergic reaction (six patients), or during an acute asthmatic paroxysm (two patients). None of the patients had any history of cardiac diseases, yet two had risk factors and two were former smokers. Four patients developed subendocardial myocardial infarction, three developed transmural myocardial infarction and one had unstable angina with no elevation in cardiac enzyme levels. Coronary angiograms were performed in seven of the eight patients; hemodynamically significant stenosis (greater than 70%) of one or more coronary arteries was detected in all patients. All seven patients underwent successful revascularization and recovered without complications. The present observational report hypothesizes that atopic people expressing an amplified mast cell degranulation may be more vulnerable to plaque rupture.


[The measurement of total blood cell volume in newborns with respiratory distress].
The total blood cell volume was measured with 51Cr labelled red blood cells in 52 premature newborns, divided into 3 groups, with similar gestational ages and birth weigths: 15 controls, 11 children with transitory respiratory distress and 26 with hyaline membrane disease. The total red blood cell volumes were significantly different (p less than 0.001) in newborns with hyaline membrane disease (32.12 ml/kg +/- 8.75). No hypothesis explaining these results was satisfactory. However, early blood transfusion in children with hyaline membrane disease may be proposed as a practical application.


Development of a fast method for quantitative measurement of hyperpolarized 129Xe dynamics in mouse brain.
A fast method has been established for the precise measurement and quantification of the dynamics of hyperpolarized (HP) xenon-129 ((129)Xe) in the mouse brain. The key technique is based on repeatedly applying radio frequency (RF) pulses and measuring the decrease of HP (129)Xe magnetization after the brain Xe concentration has reached a steady state due to continuous HP (129)Xe ventilation. The signal decrease of the (129)Xe nuclear magnetic resonance (NMR) signal was well described by a simple theoretical model. The technique made it possible to rapidly evaluate the rate constant α, which is composed of cerebral blood flow (CBF), the partition coefficient of Xe between the tissue and blood (λ(i)), and the longitudinal relaxation time (T(1i)) of HP (129)Xe in the brain tissue, without any effect of depolarization by RF pulses and the dynamics in the lung. The technique enabled the precise determination of α as 0.103 ± 0.018 s(-1) (± SD, n = 5) on healthy mice. To investigate the potential of this method for detecting physiological changes in the brain of a kainic acid (KA) -induced mouse model of epilepsy, an attempt was made to follow the time course of α after KA injection. It was found that the α value changes characteristically with time, reflecting the change in the physiological state of the brain induced by KA injection. By measuring CBF using (1)H MRI and (129)Xe dynamics simultaneously and comparing these results, it was suggested that the reduction of T(1i), in addition to the increase of CBF due to KA-induced epilepsy, are possible causes of the change in (129)Xe dynamics. Thus, the present method would be useful to detect a pathophysiological state in the brain and provide a novel tool for future brain study.


Delineation of immunologically and biochemically distinct HLA-A2 antigens.
Cytotoxic T cell (CTL) recognition of influenza virus in conjunction with HLA-A2 was examined in a population study. Virus-infected target cells from three unrelated A2-positive donors were not lysed by virus-immune CTL from any donor matched only for A2. The A2 antigens of these three donors were indistinguishable from the A2 antigens of other A2-positive donors as assessed by extensive serologic analyses; however, isoelectric focusing (IEF) of A2 molecules from these three donors demonstrated that their A2 heavy polypeptide chains are structurally distinct from those of "normal" A2-positive donors. To date 11% of all A2-positive donors tested exhibited a "variant" A2-associated CTL restriction antigen, and IEF of A2 heavy chains from all "variant" A2-positive cells revealed structural differences in each of these polypeptides. These results suggest there may be considerably greater polymorphism of HLA-A gene products than has been revealed by current serologic techniques.


ABC (Atrial fibrillation Better Care) Pathway and Healthcare Costs in Atrial Fibrillation: The ATHERO-AF Study.
The Atrial fibrillation Better Care (ABC) pathway has been proposed to streamline patient management in an integrated, holistic manner. Compliance to ABC resulted in lower incidence of cardiovascular events, but its impact on health-related costs has not been evaluated. Exploratory analysis of costs related to cardiovascular events in the ATHERO-AF prospective cohort study including atrial fibrillation patients on vitamin K antagonists. A Diagnosis-Related Group code provided by the Italian Ministry of Health was assigned to each event to estimate the relative cost. The analysis was performed by dividing patients according to ABC pathway components. Overall, 118 cardiovascular events incurred a cost of 1,017,354 euros (1,149,610 USD). The mean total costs were 13,050 (14,747 USD) and 11,218 euros (12,676 USD) for a non-fatal cardiac event or ischaemic stroke, respectively. The cost-saving was 719 euros (813 USD) per patient-year for patients in group A vs non-A, 703 euros (794 USD) for B vs non-B, 480 euros (542 USD) for C vs non-C and 2776 euros (3,137 USD) for ABC vs non-ABC. The cost per event increased with the number of uncontrolled ABC components: 507 euros (573 USD) for 1, 965 euros (1,091 USD) for 2 and 3,431 euros (3,877 USD) for patients not having any of the three components of the ABC. Management of atrial fibrillation patients according to the ABC pathway was associated with significantly lower health-related costs. Application of the ABC pathway may help reduce healthcare costs related to cardiovascular events in this high-risk patient population.


[Intracellular recovery--basis of hyperfractionation].
The radiobiological basis of a hyperfractionated radiation therapy versus conventional fractionation with respect to therapeutic gain, i.e., improved normal tissue sparing for the same level of tumour cell inactivation, will be presented. Data on the recovery potential of various tissues as well as the kinetics of repair will be given. The problem of incomplete repair with short irradiation intervals will be discussed.


Triplet and higher-order births: what is the optimal delivery route?
Data concerning 16 triplet and higher-order deliveries (resulting in a total of 56 infants) are reviewed. The vaginal delivery rate was 81%. Maternal morbidity was more serious after abdominal delivery. Prematurity (less than 36 weeks gestation) rate amounted to 68%. Overall perinatal and neonatal mortalities for infants born after 28 weeks gestation and weighing at least 1000 g were 7% and 3%, respectively. We doubt that neonatal outcome could have been markedly improved by performing more cesareans. The importance of antenatal care is stressed.


Do the Five Combinations of Suicidal Ideation in the FDA 2012 Draft Guidance Document and the C-SSRS Adequately Cover All Suicidal Ideation Combinations in Practice? A Case Study.
The United States Food and Drug Administration's newest classification system for suicidality assessment anchors suicidal ideation to various combinations of passive suicidal ideation, active suicidal ideation, method, intent, and plan. This is based upon the suicidal ideation categories in the Columbia-Suicide Severity Rating Scale. Although there are 32 possible combinations of these suicidal ideation phenomena, the Food and Drug Administration's 2012 system and the Columbia-Suicide Severity Rating Scale accommodate six combinations. We use a case study to explore the impact of possible type II errors on suicidality classification posed by not including remaining 26 possible categories. A suicidal subject kept detailed daily records of her experience of suicidality over two separate intervals of eight-months' and nine-months' duration. These records permitted classification of individual events into each of the possible 32 suicidal ideation combinations. Although only a small percentage of all events of suicidality from either collection period fell outside of the Food and Drug Administration's classification system and the Columbia -Suicide Severity Rating Scale categories, those that were not so categorized constituted a large percentage of the time this subject experienced suicidality. When these two timeframes were aggregated, more than half of the subject's time spent experiencing suicidality fell into the suicidal ideation combinations not captured by the Food and Drug Administration's classification system and the Columbia-Suicide Severity Rating Scale categories. This case study suggests that type II errors in the Food and Drug Administration's classification system and in the Columbia-Suicide Severity Rating Scale categories for suicidal ideation may represent important omissions.


Ectopic Molar Removal from the Ramus/Condyle Unit: A Minimally Invasive Approach.
Ectopic molars within the mandibular ramus/condyle unit, although rare, present a unique challenge to the surgeon. Multiple approaches have been described in the literature for their removal. A review of the English literature on the subject of mandibular ectopic molars and their epidemiology, etiology, indications for removal, and surgical techniques was completed. In addition, a case report is presented of an ectopic mandibular molar in the mid-ramus region which was removed via a minimally invasive, intraoral, technique combining the use of endoscopy and piezoelectric surgery. The authors advocate this technique as it offers the following advantages: avoidance of injury to branches of the facial nerve, unaesthetic scars, and sialocele formation; maximization of surgical field visualization with limited dissection; ability for safe sectioning of the tooth with minimal risks to adjacent structures; and precise bone removal, reducing the risk of iatrogenic or postoperative mandible fracture.


Clinical application of perioperative evidence-based practice.
Practitioners today are seeing changes in our health care system, economic pressures related to decreased reimbursement, and the growth of managed care that are producing major adjustments in health professions' education, patient care, and research. Evidence-based practice (EBP) is considered by many to be the way of the future. This article describes factors affecting implementation of EBP in the clinical arena. It also gives some practical applications found when implementing EBP at one hospital.


Early detection of regional myocardial ischemia in ex vivo piglet hearts: MR imaging with magnetization transfer.
The effects of regional myocardial ischemia and reperfusion on magnetization transfer (MT) contrast were investigated in an ex vivo perfused piglet heart model. The extent of the ischemic area was defined with perfusion magnetic resonance (MR) studies performed with use of extracellular contrast agents. Relative MT contrast was calculated for a total of 106 regions of interest in nine hearts. In the areas defined as being severely ischemic in the perfusion studies, a small but significant increase in the MT contrast of 18% +/- 9 (standard deviation) (n = 35) was found as early as 10 minutes after the start of ischemia. This contrast difference was reduced to 11% +/- 10 after 2 hours of total occlusion. The contrast between normal and ischemic tissue can be explained in part by the effect of inflowing blood, which leads to changes in both equilibrium magnetization and the apparent T1 of the perfused tissue. However, theoretical estimation suggests that these flow-related changes would produce a maximal relative change in MT contrast of approximately 4%. The most likely explanation for the rest of the observed changes is alteration in the distribution of cellular water related to the so-called intracellular edema that is known to be associated with the acute phase of myocardial ischemia.


The downside of right ventricular apical pacing.
The right ventricular (RV) apex has been the standard pacing site since the development of implantable pacemaker technology. Although RV pacing was initially only utilized for the treatment of severe bradyarrhythmias usually due to complete heart block, today the indications for and implantation of RV pacing devices is dramatically larger. Recently, the adverse effects of chronic RV apical pacing have been described including an increased risk of heart failure and death. This review details the detrimental effects of RV apical pacing and their shared hemodynamic pathophysiology. In particular, the role of RV apical pacing induced ventricular dyssynchrony is highlighted with a specific focus on differential outcome based upon QRS morphology at implant.


Supersensitive detection of explosives by recyclable AIE luminogen-functionalized mesoporous materials.
Mesoporous SBA-15 functionalized with aggregation-induced emission (AIE) luminogens serves as an efficient and recyclable fluorescent sensor for the detection of picric acid (PA), with a quenching constant of up to 2.5 × 10(5) M(-1) in a water solution, presenting a new model for the supersensitive detection of explosives.


Aging skeletal muscle: response to exercise.
The mass of many weight-bearing muscles declines in old rats, secondary to the atrophy of fibers, particularly of type IIb, with relatively little loss of muscle fibers during most of the adult life span. In humans, muscle atrophy is the result of a combination of progressive fiber loss and fiber atrophy. In both species, the proportion of histochemically determined fiber types is relatively stable across the adult portion of the life span. The loss of strength in old age is predominantly accounted for by reduced muscle mass in humans and rats. Resistance training leads to increased muscle mass and strength in old humans and rats, primarily by increasing fiber CSA. Muscle capillarity is unchanged in old rats but decreases in old dogs. Apparently, capillarity declines in truly sedentary older people. Endurance training enhances capillarity, and old rats and humans can attain levels of capillarity comparable to their active young counterparts, even when performing considerably less exercise. Blood flow during contractile activity is reduced in male rats and humans but not in old female rats or dogs. Oxidative capacity declines in many muscles of sedentary old rats and humans. With endurance training, old individuals from both species attain levels of muscle oxidative capacity quite similar to those in identically training young individuals. Muscle insulin-stimulated glucose transport is enhanced in rats after a bout of exercise, regardless of age. Endurance training elevates muscle GLUT-4 levels in young and middle-aged, but not old, rats, perhaps because the old rats trained at slower treadmill speeds. Middle-aged (47-62 yr) men and women can substantially increase muscle GLUT-4 with relatively brief (12-14 wk) endurance training; older humans (> 70-80 yr) have not been studied. Endurance training leads to reduced LDH activity without altering PFK or phosphorylase in old rats and humans. Muscle glycogen depletion, CP depletion, and lactate accumulation during contractile activity are exaggerated in old rats, apparently secondary to reduced muscle oxidative capacity and blood flow. Resting muscle glycogen concentration is diminished in older humans, probably in part because of a more sedentary lifestyle. Although several months of endurance training raises muscle glycogen concentration in older people, it does not restore it to youthful levels. Endurance training can greatly improve endurance in old age, at least in part by the same mechanism originally described in youth, i.e., an increase in muscle oxidative capacity, which contributes to reduced glycogen depletion.(ABSTRACT TRUNCATED AT 400 WORDS)


[Xanthinuria with xanthine lithiasis in a patient with Lesch-Nyhan syndrome under allopurinol therapy].
It is the intention of this report to identify appropriate analytical tests which allow for the monitoring of allopurinol treatment of patients with Lesch-Nyhan syndrome and the prevention of uric acid or xanthine lithiasis. A 12 year old boy with Lesch-Nyhan syndrome presented with signs of compulsive automutilation, motoric and mental retardation and cerebral palsy. Paraclinical patient showed hyperuricemia and significant hyperuricosuria. During administration of allopurinol (200 mg/d) he developed fever, an urinary tract infection and dilatation of pelviureteric junction which was suspected of being nephrolithiasis. During hospitalisation, the purine metabolism was intensively monitored. The allopurinol treatment was adjusted according to clinical and laboratory data. The renal scanning diagnostic showed the develepment of a functionally impaired left kidney. Later this kidney had no part in tubulo-secretorical function. It was necessary to remove surgical two renal stones. The composition of the stones was exclusively xanthine. Serum concentration and urinary excretion of xanthine and hypoxanthine were massively enlarged. The elimination of uric acid in urine was normal. But subsequently, the left kidney had to be removed despite intensive care. Lesch-Nyhan syndrome is a disorder caused by congenital absence of the enzyme hypoxanthineguanine phosphoribosyltransferase and an increase of the enzyme activity of adenine phosphoribosyltransferase. Treatment should be adjusted to patient's age and weight. An adapt treatment with allopurinol and optimal fluid intake reduce the risk of uric acid or xanthine lithiasis. Laboratory monitoring includes testings for serum concentration and urinary excretion of uric acid, xanthine and hypoxanthine. Sole a normal concentration of uric acid is not sufficient for therapy control. Assessment of the urine sediment by microscopy or infrared spectroscopy will enable early detection of uric acid or xanthine lithiasis.


Congenital cholesteatomata with other anomalies.
Congenital (primary) cholesteatomata may arise in the petrous apex, mastoid, middle ear, or external auditory canal. Histological studies of the temporal bones of a 20-year old man with bilateral combined deafness show bilateral congenital cholesteatomata of the middle ears associated with dalivary choristomata and other anomalies of the middle and inner ears.


Young age increases risk for lymph node positivity but decreases risk for non-small cell lung cancer death.
Non-small cell lung cancer (NSCLC) prognosis and risk of lymph node positivity (LN+) are reference points for reasonable treatments. The aim of the current study was to investigate the effect of age on LN+ and NSCLC death. Data from the Surveillance, Epidemiology, and End Results (SEER) registry were used to identify 82,253 patients with NSCLC diagnosed between 1988 and 2008. All the patients underwent standard lung cancer surgery with lymph node examination. Demographic and clinicopathological parameters were extracted and compared among each age group. Impact of age on LN+ and NSCLC death was evaluated by the Cochran-Armitage trend test and logistic univariate and multivariate analyses for all T stages. Overall, 22,711 (27.60%) patients of the entirety had lymph node metastasis and 28,968 (35.22%) patients died of NSCLC within 5 years. With the increase in age, LN+ rates decreased regardless of T stages (P<0.001), whereas NSCLC-specific mortality increased in stages T1-T3 (P<0.001). Controlling other covariates in multivariable logistic regression, age remained an independent risk factor for LN+ in all T stages (P<0.05) and in stages T1-T3 (P<0.05). Our SEER analysis demonstrated a higher rate of LN+ and lower mortality in younger patients with NSCLC, after accounting for other covariates.


A time-motion study of residents and medical students performing patient discharges from general internal medicine wards: a disjointed, interrupted process.
Patients are at high risk for adverse events after discharge from a hospital admission. As a critical and often time-consuming aspect of care for hospitalized patients, the purpose of this study was to describe the physician time, events and workflow in performing a patient discharge. On General Internal Medicine (GIM) wards at two academic medical centers in Toronto, a time-motion study was performed on 11 residents and 2 medical students performing 32 patient discharges. Using a paper data collection tool, a research associate aimed to capture the distribution of activities and the nature and frequency of workflow interruptions during patient discharges from the perspective of resident and medical student housestaff. Thirty-two GIM patient discharges by the 13 housestaff were observed over a period of 116 h. Discharges required 69.2 ± 41.2 min of housestaff-dedicated time to complete, but spanned over a mean 3.7 h from start to finish. On average, 32.8 min (47.3%) of time spent on discharges was dedicated to documentation activities; 13.5 min (19.6%) to direct patient communication; 10.8 min (15.6%) to communication with other clinicians and providers; 6.5 min (9.4%) to arranging outpatient care; 5.7 min (8.2%) to time in transit and waiting. For each discharge, housestaff were interrupted a mean of 5.5 times and switched tasks 8.7 times. During the discharge process, housestaff mainly dedicated themselves to documentation activities and focused minimally on direct patient communication. Clinicians were also found to experience several workflow inefficiencies and interruptions. The present study can be used to identify opportunities to improve and further focus efforts in characterizing this dynamic process.


Nonclinical assessment of carcinogenic risk and tumor growth enhancement potential of prasugrel, a platelet-inhibiting therapeutic agent.
Prasugrel, a thienopyridine ADP receptor antagonist, is an orally administered prodrug requiring in vivo metabolism to form the active metabolite that irreversibly inhibits platelet activation and aggregation mediated by the P2Y12[sub 12] receptor. A comprehensive nonclinical safety assessment including genotoxicity and carcinogenicity studies supported the chronic use of prasugrel in patients with atherothrombotic disease. In addition, a special assessment of the potential for prasugrel to enhance tumor growth was undertaken to address regulatory concerns relating to increases in human cancers. Prasugrel demonstrated no evidence of genotoxicity and was not oncogenic in a 2-year rat carcinogenicity study. In the 2-year mouse study, an increase in hepatocellular adenomas was considered secondary to enzyme induction and not relevant to human safety. Further, the absence of any increase in common background tumors at any other organ site in either rodent study indicated a lack of tumor promoting activity (apart from the CYP450 induction-related increase in mouse liver tumors). Cell culture studies with 3 human tumor cell lines (lung, colon, prostate) demonstrated that exposure of serum-starved cells to prasugrel's active and major circulating human metabolites does not increase cell proliferation relative to starved cells stimulated to proliferate by addition of 10% FBS. Prasugrel also did not increase tumor growth relative to vehicle controls in nude mice implanted with 3 human tumor cell lines. Thus, traditional genotoxicity and 2-year bioassays as well as specially designed tumor growth enhancement studies in human tumor cell lines and mouse xenograft models clearly demonstrated prasugrel's lack of tumorigenic potential.


IgE to staphylococcal enterotoxins are undetectable in sera from patients with nasal polyposis.
Nasal polyposis is a frequent disease, sometime associated with asthma and non steroidal anti-inflammatory drugs intolerance. Staphylococcus aureus colonization can play a pathogenetic role in same cases by a severe eosinophilic inflammation, which can suggest new therapeutic approaches. Staphylococcus aureus colonization has been demonstrated by local specific enterotoxins IgE dosage in polyps homogenates. This study demonstrate lack of detection of serum enterotoxins specific IgE to staphylococcal in patients with nasal polyposis, compared with healthy subjects.


Experimental evidence of van der Pol-Fitzhugh-Nagumo dynamics in semiconductor optical amplifiers.
Thermo-optical pulsing in semiconductor amplifiers is experimentally shown to correspond to a very common excitable scenario (the van der Pol-Fitzhugh-Nagumo system). Self-sustained oscillations appear in the sequence predicted by this simple dynamical model as we change either the injection level or the bias current. Periodic modulation of these parameters leads to the characteristic phase-locking structure. Furthermore, coherence resonance is observed when external noise is added to the system.


Effect of growth on the estrogen receptor levels in MCF-7 cells.
MCF-7 cells have been shown to contain estrogen receptor in several cell fractions following homogenization: nuclei, microsomes, and cytosol. The amount of 17 beta-estradiol-binding capacity found in each cellular compartment depended on the inclusion of detergent in homogenization buffers and on the use of 0.25 M sucrose in the nuclear washes. 17 beta-Estradiol receptor (E2R) associated with nuclei (whole nuclei exchange assay, 0.6 M KCl soluble, and that found on membranes sheared from crude nuclear pellets by centrifugation in 0.25 M sucrose buffer) displayed a dissociation constant (Kd) of 0.77 +/- 0.01 (S.D.) nM (n = 7). KdS of the cytoplasmic (microsomes and soluble) receptors were determined to be 0.33 +/- 0.10 nM (n = 9). Exchangeable ligand on partially purified nuclei assumed its highest level in MCF-7 cells during logarithmic growth in serum-containing media (0.8 pmol/micrograms DNA) but declined after the culture reached confluence (0.2 pmol/micrograms DNA). Seventy-five % of the nuclear E2R declined linearly after feeding MCF-7 cells in logarithmic growth phase an estrogen- and serum-free medium (t1/2 3.5 days). Another class of salt-extractable nuclear receptor (0.2 pmol/micrograms DNA) persisted in postconfluent cultures whether fed estrogen (serum-containing media) or not (serum-free media). This residual binding capacity remained in nuclei of MCF-7 cells for an extended period of time. MCF-7 cells demonstrated functionality of E2R throughout their growth phases as evidenced by the replenishment of cytosolic E2R and the induction of progesterone receptor when given 17 beta-estradiol.


Migration of a Hem-o-Lok Clip to the Ureter Following Laparoscopic Partial Nephrectomy Presenting With Lower Urinary Tract Symptoms.
We report a case of ureteral migration of a surgical clip after partial nephrectomy in which the clip was misdiagnosed as a ureteral stone. A 37-year-old woman had undergone laparoscopic partial nephrectomy of right renal cell carcinoma at another hospital 2 years previously. Postoperatively, she had gradually acquired lower urinary tract symptoms. Then, she complained of sudden right flank pain for a week. A plain X-ray and enhanced abdominopelvic computed tomography scan were performed. A 0.5 cm×1.0 cm right upper ureteral opacity with borderline hydronephrosis was seen but could not be found on the X-ray. Ureteroscopy revealed a medium-sized Hem-o-Lok clip on the right upper ureter that was removed with a stone basket. We concluded that a Hem-o-Lok clip used for collecting system sealing had migrated to the ureter and had been misdiagnosed as a ureteral stone on a computed tomography scan.


Distribution patterns of over-represented k-mers in non-coding yeast DNA.
Over-represented k-mers in genomic DNA regions are often of particular biological interest. For example, over-represented k-mers in co-regulated families of genes are associated with the DNA binding sites of transcription factors. To measure over-representation, we introduce a statistical background model based on single-mismatches, and apply it to the pooled 500 bp ORF Upstream Regions (USRs) of yeast. More importantly, we investigate the context and spatial distribution of over-represented k-mers in yeast USRs. Single and double-stranded spatial distributions of most over-represented k-mers are highly non-random, and predominantly cluster into a small number of classes that are robust with respect to over-representation measures. Specifically, we show that the three most common distribution patterns can be related to DNA structure, function, and evolution and correspond to: (a) homologous ORF clusters associated with sharply localized distributions; (b) regulatory elements associated with a symmetric broad hill-shaped distribution in the 50-200 bp USR; and (c) runs of As, Ts, and ATs associated with a broad hill-shaped distribution also in the 50-200 bp USR, with extreme structural properties. Analysis of over-representation, homology, localization, and DNA structure are essential components of a general data-mining approach to finding biologically important k-mers in raw genomic DNA and understanding the 'lexicon' of regulatory regions.


Disruptive effects of protein on performance of liquid membrane-based ion-selective microelectrodes.
The effects of addition of protein [bovine serum albumin (BSA)] to the calibration solutions of various liquid membrane-based ion-selective microelectrodes have been assessed. Protein at typically cytosolic levels of 100 mg/ml had no effect on the response of Na(+)-, K(+)-, Mg(2+)-, Ca(2+)-, H(+)-, NO3(-)-, and Cl(-)- selective microelectrodes at ion concentrations well above the respective detection limits. By contrast, this level of protein resulted in a pronounced increase in the detection limits of Na(+)-, K(+)-, Mg(2+)-, Ca2+, and Cl(-)-selective microelectrodes; H+ and NO3- microelectrodes were largely unaffected by the protein. The effect of BSA on detection limit is independent of pH and ionic strength, nor is it due to hysteresis, to binding of ions to the protein, or to the generation of junction potentials. More extensive studies on Na(+)-selective microelectrodes revealed that other proteins and large molecules (e.g., polyethylene glycol) also increase detection limits, with the extent of this effect apparently correlated positively with the molecular weight. Because biological macromolecules at physiological concentrations can influence the properties of alkali- and alkali earth cation-selective microelectrodes, care must be taken if the use of these electrodes entails cytosolic measurements close to their detection limits.


Myristoylation: An Important Protein Modification in the Immune Response.
Protein N-myristoylation is a cotranslational lipidic modification specific to the alpha-amino group of an N-terminal glycine residue of many eukaryotic and viral proteins. The ubiquitous eukaryotic enzyme, N-myristoyltransferase, catalyzes the myristoylation process. Precisely, attachment of a myristoyl group increases specific protein-protein interactions leading to subcellular localization of myristoylated proteins with its signaling partners. The birth of the field of myristoylation, a little over three decades ago, has led to the understanding of the significance of protein myristoylation in regulating cellular signaling pathways in several biological processes especially in carcinogenesis and more recently immune function. This review discusses myristoylation as a prerequisite step in initiating many immune cell signaling cascades. In particular, we discuss the hitherto unappreciated implication of myristoylation during myelopoiesis, innate immune response, lymphopoiesis for T cells, and the formation of the immunological synapse. Furthermore, we discuss the role of myristoylation in inducing the virological synapse during human immunodeficiency virus infection as well as its clinical implication. This review aims to summarize existing knowledge in the field and to highlight gaps in our understanding of the role of myristoylation in immune function so as to further investigate into the dynamics of myristoylation-dependent immune regulation.


[Preparation and primary analysis of monoclonal antibodies against VP5 protein of chicken infectious bursal disease virus].
Infectious bursal disease virus (IBDV), the causative agent of a highly contagious disease in chickens, carries a small nonstructural protein (NS). In this study, vvIBDV Gx-VP5 genes were cloned into plasmid pET30a( + ) and expressed in E. coli with IPTG inducing. BALB/c mice were immunized with the purified recombinant fusion protein. SP2/0 myeloma cells and spleen cells of BALB/c mice were fused by PEG(MW1500), three hybridoma cell lines were examined by indirect ELISA and clone for three times by limited dilution, and were named as 4B4, 6D12, 3E8. The subtype of the monoclonal antibodies were IgG1 with a subtype identified ELISA kit, and light chains were kappa. The ascites titers of monoclonal antibodies were 5 x 10(4), 3.5 x 10(4), 3 x 10(4) by indirect ELISA, respectively. Indirect ELISA and Western blot results showed that the monoclonal antibodies only acted with VP5 protein, IF analysis indicated that three monoclonal antibodies acted with IBDV Gt. There were specific fluorescence in detected Vero E6 cells which transient expressed VP5 protein by IFA. Therefore, monoclonal antibodies specific to IBDV VP5 proteins are specific method for detected VP5 proteins, and base on establish stabilize expressed VP5 protein Vero cell lines to research IBDV VP5 protein function.


Predictors of response to individual and group cognitive behaviour therapy of social phobia.
Increased knowledge of factors that predict treatment outcome is important for planning and individualizing of treatment. This study analysed predictors of response to individual cognitive therapy (ICT), and intensive (3-week) group cognitive treatment (IGCT) for social phobia. Participants (n = 54) met diagnostic criteria for social phobia within a randomized controlled trial. Predictors assessed were fear of negative evaluation, anticipatory worry, self-directedness (SD) and cluster C personality disorder. Results were analysed by means of multiple regression analyses with both groups combined, and for each of the treatment groups. Anticipatory worry, an aspect of a harm-avoidance personality trait, was the strongest negative predictor of outcome in ICT and IGCT both at post-treatment and 1-year follow-up. Whereas low SD, signs of cluster C personality disorder and fear of negative evaluation were negative predictors of post-treatment outcome in ICT, the corresponding pattern of results was not to be found in IGCT. Anticipatory worry appears to be a particularly important trait for explaining variance in the outcome of social phobia. The finding is consistent with the assumed stability of such personality traits over time. Further studies are warranted to replicate the finding.


Gender differences in HIV-related coping and depression.
Our study examined differences in HIV-related coping in relation to depression in men and women. Ethnically diverse participants (n = 247, 46% women) were recruited in Dallas/Fort Worth and completed medical and demographic information, the Coping with HIV Scale (CHIV), and the Center for Epidemiological Studies-Depression scale (CES-D). Multiple regression analyses revealed that in men, depression was associated with symptoms, higher use of distraction, blame, expression and lower use of positive growth. In women, depression was associated with symptoms and higher use of blame. These results shed light on the ways in which each gender copes with HIV and may help researchers develop interventions tailored to the needs of the HIV-positive population.


A spontaneously healing collodion baby: a light and electron microscopical study.
Skin biopsies from a collodion baby, spontaneously healing at the end of the third month, were taken on the 1st and 15th day after delivery and examined by light and electron microscopy. The microscopical features observed were different from those known to occur in collodion babies evolving into lamellar ichthyosis and may contribute to a more precise, early diagnosis and prognosis of this heterogeneous neonatal syndrome.


[Thrombophilia - a risk factor of retinal vein occlusion?].
To evaluate thrombophilia as a risk factor of retinal vein occlusion in comparison with a control group and a general polish population. Fifty nine consecutive patients with retinal vein occlusion were enrolled in this study. The diagnosis of retinal vein occlusion was based on the presence of typical findings in the eye fundus, fluorescein angiography, and optical coherence Stomography. Control group consisted of 59 subjects matched for age, sex, body mass index (BMI), medications, and cardiovascular risk factors. In all patients the following thrombophilic factors were evaluated: factor V mutation, 20210A prothrombin mutation, MTHFR (methy-lenetetrahydrofolatereductase) mutation C677T, protein C and free protein S level, antithrombin activity, factor VIII activity, anty-beta2 glikoprotein I antibodies level, anticardiolipin antibodies level, the presence of lupus anticoagulant, total homocysteine concentration. In both groups with retinal vein occlusion and control group a high incidence of factor V Leiden was observed: 10.2% and 15.6%, respectively. In one patient the presence of 20210A prothrombin mutation was noted and in one the deficiency of free S protein was observed. Antiphospholipid antibodies were present in 11.8% of cases and factor VIII concentration > 150% in 3% of patients with retinal vein occlusion. In 8.5% of patients with retinal vein occlusion genotype TT MTHFR was present. Hyper-homocysteinemia was found in 5 cases with retinal vein occlusion (8.5%) and in 7 in a control group (11.9%). In a venous blood of patients with retinal vein occlusion homocysteine level was lower by 14.5% as compared with a control group (9.4 [7.0-11.3] vs. 11.0 [9.4-12 .8] micromol/l, p = 0.001). The results of thrombophilia screening in patients with retinal vein occlusion showed no statistical differences as compared with a control group matched for age, sex, and cardiovascular risk factors. However patients with retinal vein occlusion showed statistically significant lower serum homocysteine concentration as compared with a control group. Two times higher prevalence of factor V Leiden was observed in patients with retinal vein occlusion than in Polish general population.


Measurement of Typhi Vi antibodies can be used to assess adaptive immunity in patients with immunodeficiency.
Vaccine-specific antibody responses are essential in the diagnosis of antibody deficiencies. Responses to Pneumovax II are used to assess the response to polysaccharide antigens, but interpretation may be complicated. Typhim Vi® , a polysaccharide vaccine for Salmonella typhoid fever, may be an additional option for assessing humoral responses in patients suspected of having an immunodeficiency. Here we report a UK multi-centre study describing the analytical and clinical performance of a Typhi Vi immunoglobulin (Ig)G enzyme-linked immunosorbent assay (ELISA) calibrated to an affinity-purified Typhi Vi IgG preparation. Intra- and interassay imprecision was low and the assay was linear, between 7·4 and 574 U/ml (slope = 0·99-1·00; R2 > 0·99); 71% of blood donors had undetectable Typhi Vi IgG antibody concentrations. Of those with antibody concentrations > 7·4 U/ml, the concentration range was 7·7-167 U/ml. In antibody-deficient patients receiving antibody replacement therapy the median Typhi Vi IgG antibody concentrations were < 25 U/ml. In vaccinated normal healthy volunteers, the median concentration post-vaccination was 107 U/ml (range 31-542 U/ml). Eight of eight patients (100%) had post-vaccination concentration increases of at least threefold and six of eight (75%) of at least 10-fold. In an antibody-deficient population (n = 23), only 30% had post-vaccination concentration increases of at least threefold and 10% of at least 10-fold. The antibody responses to Pneumovax II and Typhim Vi® correlated. We conclude that IgG responses to Typhim Vi® vaccination can be measured using the VaccZyme Salmonella typhi Vi IgG ELISA, and that measurement of these antibodies maybe a useful additional test to accompany Pneumovax II responses for the assessment of antibody deficiencies.


Longitudinal cognitive function and brain metabolites in women receiving chemotherapy for stage 1 to 3 breast cancer: Observational study.
Few proton magnetic resonance spectroscopy studies have explored chemotherapy-related biochemical changes in brain regions. This observational study aimed to longitudinally assess short-term cognitive changes and brain metabolite concentrations in women undergoing chemotherapy for breast cancer. We analyzed 11 women with newly diagnosed stage 1 to 3 breast cancer. Patients were evaluated via objective cognitive testing, and patient self-report tests. Patients were examined using single voxel proton magnetic resonance spectroscopy in the medial frontal cortex, posterior cingulate gyrus, and left thalamus at baseline and after the completion of chemotherapy on a 1.5 Tesla scanner. At the posttreatment evaluation as compared to baseline, 7 of the 10 (70%) patients reported worsening memory on the MD Anderson symptom inventory (annualized change = 1.82 ± 2.88, P = .08), while the delayed recall raw score of the Rey Osterrieth complex figure test did not change from pre- to post-chemotherapy (mean annualized change = 5.00 ± 14.38, P = .30). The annualized change in the creatine concentration in the posterior cingulate gyrus was statistically significant. The annualized change in the MD Anderson symptom inventory was negatively correlated with the annualized change in the medial frontal N-acetylaspartate (Spearman correlation coefficient [rho] = -0.78, P = .01) and positively correlated with the annualized change in the posterior cingulate gyrus creatine (rho = 0.66, P = .04). Annualized changes in the Rey Osterrieth complex figure test were positively correlated with annualized changes in choline (rho = 0.83, P = .01) in the medial frontal cortex, choline (rho = 0.76, P = .04) in the left thalamus, and creatine (rho = 0.73, P = .02) in the medial frontal cortex. Our data suggest that chemotherapy may lead to the worsening of self-reported memory function, which is associated with alterations in brain metabolites.


Chronic treatment with talipexole dihydrochloride on abnormal involuntary movement in humans.
Two cases of severe dystonia and dyskinesia were treated with talipexole, a dopamine autoreceptor agonist, and the metabolites of dopamine, norepinephrine, and serotonin in cerebrospinal fluid (CSF) were determined. Despite significant reductions in these metabolites in CSF, behavioral amelioration of these cases could not be observed. The present findings argue for further studies to explore the clinical usefulness of dopaminergic agonists such as talipexole.


Tissue stem cells: definition, plasticity, heterogeneity, self-organization and models--a conceptual approach.
The classical definition of adult tissue stem cells (TSC) is fundamentally based on a functional perspective. A TSC is an undifferentiated cell, capable of proliferation, self-renewal, production of a large number of differentiated functional progeny, regenerating tissue after injury and a flexibility in the use of these options. Here, we discuss the necessity for amending this definition in the light of recent insight into stem cell biology regarding stem cell heterogeneity, lineage plasticity, clonal fluctuation and cell-environment interactions. We conclude that the definition needs amendments. A decade ago the flexibility criterion has attracted little attention but recent findings have indicated its importance. Flexibility and reversibility of tissue and lineage specification (tissue plasticity) and of properties within a tissue (within-tissue plasticity) have major implications with regard to concepts of stem cell function. We advocate to give up the view of TSC as being entities with a preprogrammed development and to replace it by a concept that makes the capabilities for flexible and regulated tissue self-organization based on cell-cell and cell-environment interactions the new paradigm. This concept would permit to incorporate the context-dependent lineage plasticity, within-lineage plasticity and generation of stem cell heterogeneity as a result of a dynamically regulated process. Such concepts need a rigorous examination by formal modeling including simulation studies. We provide some general ideas on how to proceed with such theories and illustrate this with worked models for tissue stem cells of the hematopoietic system and the intestinal epithelium.


An open trial of methyltetrahydrofolate in elderly depressed patients.
5-methyltetrahydrofolate (MTHF) is a naturally occurring substance involved in the synthesis of s-adenosyl-l-methionine (SAMe), a major source of methyl groups in the brain. To assess the efficacy of a gastro-resistant, oral preparation of MTHF, 20 elderly patients with a DSM-III-R diagnosis of depressive disorder and a HAM-D-21 score > or = 18 underwent 6-weeks of open-label treatment with 50 mg per day of oral MTHF. Of these 20 patients, 16 completed at least 4 weeks of treatment and showed a markedly significant improvement in their depressive symptoms at endpoint, with 81% of them being considered responders. There were no clinically relevant changes in the routine laboratory tests during the study, and no adverse events considered to be definitely drug-related were reported.


PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells.
Both positive and negative regulatory roles have been suggested for the B7 family member PD-L1(B7-H1). PD-L1 is expressed on antigen-presenting cells (APCs), activated T cells, and a variety of tissues, but the functional significance of PD-L1 on each cell type is not yet clear. To dissect the functions of PD-L1 in vivo, we generated PD-L1-deficient (PD-L1(-/-)) mice. CD4(+) and CD8(+) T cell responses were markedly enhanced in PD-L1(-/-) mice compared with wild-type mice in vitro and in vivo. PD-L1(-/-) dendritic cells stimulated greater wild-type CD4(+) T cell responses than wild-type dendritic cells, and PD-L1(-/-) CD4(+) T cells produced more cytokines than wild-type CD4(+) T cells in vitro, demonstrating an inhibitory role for PD-L1 on APCs and T cells. In vivo CD8(+) T cell responses also were significantly enhanced, indicating that PD-L1 has a role in limiting the expansion or survival of CD8(+) T cells. Studies using the myelin oligodendrocyte model of experimental autoimmune encephalomyelitis showed that PD-L1 on T cells and in host tissues limits responses of self-reactive CD4(+) T cells in vivo. PD-L1 deficiency converted the 129S4/SvJae strain from a resistant to experimental autoimmune encephalomyelitis-susceptible strain. Transfer of encephalitogenic T cells from wild-type mice into PD-L1(-/-) recipients led to exacerbated disease. Disease was even more severe in PD-L1(-/-) recipients of PD-L1(-/-) T cells. These results demonstrate that PD-L1 on T cells, APCs, and host tissue inhibits naïve and effector T cell responses and plays a critical role in T cell tolerance.


FORALL: an interactive shiny/R web portal to navigate multi-omics high-throughput data of pediatric acute lymphoblastic leukemia.
Pediatric acute lymphoblastic leukemia (ALL) is the most common cancer among children worldwide. The availability of easily accessible multi-omics data provides unprecedented resources and opportunities for discovering and refining disease biology, cancer biomarkers, and drug mechanisms of action. This has led to exponential growth of omics data available in public repositories. However, delivering the useful information and knowledge extraction from this data is one of the bottlenecks of multi-omics. Presenting, navigating, and downloading ALL omics data in a user-friendly interface provide a valuable platform for biologists and clinicians to get most of the omics data. Our in-house data provides in-depth mass spectrometry-based protein abundance data for a large panel of commercially available ALL cell lines. Providing this data to the scientific community in the form of a user-friendly web-portal allows for easy and detailed exploration of the data. We have developed the Functional Omics Resource of Acute Lymphoblastic Leukemia (FORALL) web-portal. FORALL is a shiny-based web portal designed to navigate in-depth mass spectrometry-based proteomics data of 51 cell lines. The proteomics data can be navigated and visualized along with matched RNA expression data as well as drug sensitivity data of 528 investigational and approved drugs. FORALL is available at https://proteomics.se/forall/.


The effect of enzyme inhibition on the metabolism and activation of tacrine by human liver microsomes.
1. Tacrine (1,2,3,4-tetrahydro-9-aminoacridine-hydrochloride: THA) underwent metabolism in vitro by a panel (n = 12) of human liver microsomes genotyped for CYP2D6, in the presence of NADPH, to both protein-reactive and stable metabolites. 2. There was considerable variation in the extent of THA metabolism amongst human livers. Protein-reactive metabolite formation showed a 10-fold variation (0.6 +/- 0.1%-5.2 +/- 0.8% of incubated radioactivity mg-1 protein) whilst stable metabolites showed a 3-fold variation (24.3 +/- 1.7%-78.6 +/- 2.6% of incubated radioactivity). 3. Using cytochrome P450 isoform specific inhibitors CYP1A2 was identified as the major enzyme involved in all routes of THA metabolism. 4. There was a high correlation between aromatic and alicyclic hydroxylation (r = 0.92, P < 0.0001) consistent with these biotransformations being catalysed by the same enzymes. 5. Enoxacin (ENOX), cimetidine (CIM) and chloroquine (CQ) inhibited THA metabolism by a preferential decrease in the bioactivation to protein-reactive, and hence potentially toxic, species. The inhibitory potency of ENOX and CIM was increased significantly upon pre-incubation with microsomes and NADPH. 6. Covalent binding correlated with 7-OH-THA formation before (r = 0.792, P < 0.0001) and after (r = 0.73, P < 0.0001) inhibition by CIM, consistent with a two-step mechanism in the formation of protein-reactive metabolite(s) via a 7-OH intermediate. 7. The use of enzyme inhibitors may provide a useful tool for examining the relationship between the metabolism and toxicity of THA in vivo.


Ciprofloxacin-induced erythema multiforme.
Ciprofloxacin is one of the most commonly used antibacterial agents with relatively few side effects. Serious adverse reactions reported with ciprofloxacin are rare with an incidence of 0.6%. One of the side effects of ciprofloxacin is erythema multiforme (EM). EM is an acute, self -limiting mucocutaneous hypersensitivity syndrome. It exhibits a diverse etiology, often recurs, has unusual clinical features and is of uncertain etiopathogenesis. It usually exhibits a distinctive skin or mucosal lesions that are characterized by combination of bullae, papules, macules or ulcers. It is most probably an immunologically mediated process. With the use of ciprofloxacin becoming more and more widespread, fatal complications of ciprofloxacin should be borne in mind. In this article we present a case of ciprofloxacin induced erythema multiforme in 40 year old woman.


Patient- and relative-activated critical care outreach: a 7-year service review.
Five years following the introduction of a whole-hospital, 24-hour critical care outreach (CCO) service, an additional service was introduced that enabled patients and their families to directly call the CCO team if they had concerns that were not being acknowledged by the patient's clinical team. The aim of this review was to report on 7 years of patient and family referrals using quantitative and free text data extracted from the CCO referral database. Information on demographics, frequency, nature and reason for the referrals have been reported that highlight the feasibility of such a service, and the potential to prevent patient deterioration. By tapping into the rich source of information from family concerns, future hospital services could be designed that could not only have an impact on patient outcome, but also positively influence the quality of the patient experience.


Effects of an excess and a deficiency of endogenous parathyroid hormone on volumetric bone mineral density and bone geometry determined by peripheral quantitative computed tomography in female subjects.
Peripheral quantitative computed tomography (pQCT) is useful for evaluating volumetric bone mineral density (vBMD) as well as bone mineral density (BMD) of cortical and trabecular bones separately. Although PTH affects cortical and trabecular bones differently, the effects of endogenous PTH on vBMD and bone geometry have not previously been examined with pQCT. We, therefore, investigated the effects of an excess and a deficiency of endogenous PTH on bone by employing dual-energy x-ray absorptiometry and pQCT in 36 female patients with primary hyperparathyroidism (hyper), nine female patients with idiopathic or postoperative hypoparathyroidism (hypo), and 100 normal controls matched to age, gender, and body size (cont). Lumbar BMD by dual-energy x-ray absorptiometry was higher in the order: hypo > cont = hyper, and radius-1/3 BMD was significantly higher in the order: hypo > cont > hyper. The area of radius-1/3 was significantly higher in hyper than in cont. As for pQCT, trabecular vBMD was significantly higher in the order: hypo > cont > hyper at the 4% site (hypo, 157.5 +/- 36.7 mg/cm(3); cont, 123.4 +/- 47.5 mg/cm(3); hyper, 98.4 +/- 41.7 mg/cm(3)). Cortical vBMD was higher in the order: hypo > cont > hyper at the 20% site (hypo, 1141.1 +/- 53.1 mg/cm(3); cont, 1090.2 +/- 72.9 mg/cm(3); hyper, 1038.6 +/- 89.1 mg/cm(3)). Total bone area and endosteal and periosteal circumferences were significantly higher in hyper than in cont and hypo. Cortical area and thickness were higher in the order: hypo > cont > hyper. Bone strength indices were not significantly different among the three groups. In conclusion, vBMD evaluation revealed that an excess of endogenous PTH was catabolic for both cortical and trabecular bones, and that bone mass (especially trabecular bone mass) was preserved under a condition of deficient endogenous PTH. An excess of endogenous PTH stimulated periosteal bone formation, which might partly compensate for a decrease in bone strength induced by low BMD.


Does Income Inequality Harm Green Growth? The BRICS Experience.
Green growth plays a vital role in ensuring sustainable development. Managing economic growth without disrupting the environment is considered the need of the present time. Therefore, the empirics have turned their attention toward finding the determinants of green growth. Hence, we aim to investigate the impact of income inequality on green growth in BRICS economies from 1993 to 2020. Findings of the panel autoregressive distributed lag (ARDL) model confirm that the long-run estimate attached to GINI is negatively significant, implying that higher inequality in the BRICS economies lowers the rate of green growth. The country-wise results highlighted the negative impact of GINI on green growth in India and China only and insignificant in other countries. In the short run, the estimates are inconclusive and mixed, be it group-wise or individual estimates. Our findings imply that the target of lower inequality and environmental sustainability can be achieved simultaneously.


A pharmacoproteomics study of the cancer cell line EKVX using capillary-LC/MS/MS.
The chemotherapeutic agent camptothecin, 10-OH (CPT,10-OH), was shown to act synergistically with the epithelial growth factor receptor (EGFR) inhibitor (AG1478) against several transformed cell lines. To study the cellular response to these drugs, the non-small-cell lung carcinoma cell line, EKVX, was treated with these compounds either alone or in combination. We performed a proteomic analysis using capillary-HPLC coupled with electrospray ion trap mass spectrometry (capillary-LC-ESI/MS) of a tryptic digest to obtain a global protein profile of the EKVX cell line and identify changes in protein expression. The combination of AG1478 and CPT,10-OH showed synergistic cytotoxicity and also changed the expression of multiple proteins, while individual treatments showed a lesser effect on protein expression. Thus, the synergistic action of AG1478 and CPT,10-OH was reflected in altered protein profiles, showing that a proteomic analysis can serve to evaluate chemotherapeutic agents and their combinations.


Epidemiology and diagnosis of rabies in Greece.
During the decade 1951-1960, 8626 rabies cases were reported among domestic animals in Greece and 53 deaths in humans. During the decades 1961-1970, 1971-1980 cases were reduced to 3009 and 242, respectively, while no more cases in man occurred since 1970. Vaccination campaigns of dogs, besides the low prevalence of rabies among wild animals, resulted in its eradication from the country. Immunofluorescence is the method used for diagnosis.


NO, way to go: critical amino acids to replenish nitric oxide production in treating mucositis.
There is still an unmet need for preventive and treatment strategies for chemotherapy-induced and radiotherapy-induced mucositis and its associated systemic inflammatory response (SIR) in cancer patients. Because of citrulline depletion due to cytotoxic therapy, nitric oxide (NO) production can be reduced, limiting its effect in many physiological processes. Restoring NO production could relieve mucositis severity by supporting host damage control mechanisms. Amino acids glutamine, arginine and citrulline are involved in NO production. This review including recent literature of preclinical and clinical studies will discuss the potential benefits of glutamine, arginine and citrulline on mucositis development with focus on NO production. Mucositis severity is more defined by host response to DNA damage than by DMA damage itself. Citrulline depletion because of afunctional enterocytes could be responsible for NO depletion during cytotoxic therapy. Restoring NO production during cytotoxic therapy could have a beneficial effect on mucositis development. Citrulline seems a more promising NO donor than glutamine or arginine during cytotoxic therapy, although clinical studies in mucositis patients are currently lacking. Glutamine, arginine and citrulline show in-vitro beneficial effects on inflammatory processes involved in mucositis. Translation to the clinic is difficult as demonstrated with use of glutamine and arginine. Citrulline, being the most potent NO donor with excellent oral bio-availability, is very promising as treatment choice for mucositis and its use deserves to be investigated in clinical trials with mucositis patients.


Risks and Benefits of Kidney Transplantation during the COVID-19 Pandemic: Transplant or Not Transplant?
COVID-19 has significantly affected the transplant community, by leading to decreased transplant activity and increased waiting list time. As expected, COVID-19 causes substantial mortality in both ESKD and kidney transplant populations. This is due to underlying CKD and a high prevalence of comorbid conditions, such as diabetes mellitus, hypertension, and cardiovascular disease in this group. Transplant programs have faced the difficult decision of weighing the risks and benefits of transplantation during the pandemic. On one hand, there is a risk of COVID-19 exposure leading to infection while patients are on maximum immunosuppression. Alternatively, there are risks of delaying transplantation, which will increase waitlist times and may lead to waitlist-associated morbidity and mortality. Cautious and thoughtful selection of both the recipient's and donor's post-transplant management has been required during the pandemic, to mitigate the risk of morbidity and mortality associated with COVID-19. In this review article, we aimed to discuss previous publications related to clinical outcomes of COVID-19 disease in kidney transplant recipients, patients with ESKD on dialysis, or on the transplant waiting list, and the precautions transplant centers should take in decision making for recipient and donor selection and immunosuppressive management during the pandemic. Nevertheless, transplantation in this milieu does seem to be the correct decision, with careful patient and donor selection and safeguard protocols for infection prevention. Each center should conduct risk assessment on the basis of the patient's age and medical comorbidities, waitlist time, degree of sensitization, cold ischemia time, status of vaccination, and severity of pandemic in their region.


Macrophage and Fibroblast Interactions in Biomaterial-Mediated Fibrosis.
Biomaterial-mediated inflammation and fibrosis remain a prominent challenge in designing materials to support tissue repair and regeneration. Despite the many biomaterial technologies that have been designed to evade or suppress inflammation (i.e., delivery of anti-inflammatory drugs, hydrophobic coatings, etc.), many materials are still subject to a foreign body response, resulting in encapsulation of dense, scar-like extracellular matrix. The primary cells involved in biomaterial-mediated fibrosis are macrophages, which modulate inflammation, and fibroblasts, which primarily lay down new extracellular matrix. While macrophages and fibroblasts are implicated in driving biomaterial-mediated fibrosis, the signaling pathways and spatiotemporal crosstalk between these cell types remain loosely defined. In this review, the role of M1 and M2 macrophages (and soluble cues) involved in the fibrous encapsulation of biomaterials in vivo is investigated, with additional focus on fibroblast and macrophage crosstalk in vitro along with in vitro models to study the foreign body response. Lastly, several strategies that have been used to specifically modulate macrophage and fibroblast behavior in vitro and in vivo to control biomaterial-mediated fibrosis are highlighted.


Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: similar hemofilter survival but significantly less bleeding.
Regional citrate anticoagulation (RCA) may be a valuable alternative to systemic heparin anticoagulation during continuous venovenous hemodialysis (CVVH). RCA does not increase the risk of bleeding, but carries the risk of metabolic derangements. Clotting-free circuit survival may be increased with RCA. Critically ill patients at low risk for bleeding were randomized for CVVH with RCA or systemic heparin anticoagulation. A maximum of 4 consecutive CVVH circuits were analyzed for every patient. Clotting-free circuit survival, adverse metabolic events and bleeding complications were recorded. Forty-eight patients were included in the study and randomized for RCA (n=21) or systemic heparin (n=27). A total of 142 CVVH circuits were analyzed with a median of 3 circuits per patient. Uncensored circuit survival and median clotting-free circuit survival were similar for both groups. No significant adverse metabolic events occurred in the RCA group. Major bleedings were not recorded in the RCA group, compared with 10 events in the heparin group (p<0.01). The number of red blood cell units given per day of CVVH was significantly higher in the heparin group (0.88 vs 0.43 units/day, p=0.01). Also, the mean decrease in hemoglobin concentration per day in the nontransfused stable patients, was significantly higher in the heparin group. RCA during CVVH can be performed safely, with a circuit survival similar to systemic heparin anticoagulation, but significantly lower incidence of bleeding. Citrate anticoagulation should be advocated as first choice, also for critically ill patients considered to be at low risk for bleeding.


Activation of the cell membrane angiotensin AT2 receptors in human leiomyosarcoma cells induces differentiation and apoptosis by a PPARγ - dependent mechanism.
Angiotensin II (Ang II), the main effector peptide of the renin-angiotensin system (RAS), acting on AT1 and AT2 receptors participates in the regulation of proliferation, differentiation and apoptosis in tumour cells. The peroxisome-proliferator activated receptor γ (PPARγ) and its ligands exert anti-tumour effects in various human cancer cell lines. The present study investigates the effects initiated by AT1- and AT2 receptor stimulation in SK-UT-1 cells, a human leiomyosarcoma cell line, and clarifies the role of the PPARγ in the AT2 receptor-induced differentiation and apoptosis.Selective stimulation of AT1- and AT2 receptors was achieved by incubation of the cells with Ang II (10-6 M) in the presence of the selective AT2 receptor antagonist, PD 123177 (10-6 M) and the AT1 receptor antagonist, losartan (10-5 M), respectively, the selective PPARγ antagonist, GW 9662, was used at concentration 10-6 M. The expression of smooth muscle cell differentiation markers, SM22α and calponin, was analysed at RNA- and protein levels using RT PCR and Western blot, which was also used to quantify Bcl-2-, Bax- and cleaved caspase-3 proteins. The translocation of the AT2-receptor interacting protein 1 (ATIP1) to the nuclei was studied by Western blot and immunofluorescence staining. The mitochondrial status and the metabolic activity in response to AT1- and AT2 receptor activation were assessed by the quantification of 99mTc - sestamibi and 2´-deoxy-2´-[18F]fluoro-D-glucose uptake.AT1 receptor stimulation did not exert any profound effects in quiescent SK-UT-1 cells. The effects induced by Ang II acting on AT2 receptors were time-dependent. A short, 3 - 6 h lasting stimulation promotes differentiation, i.e increases in the mRNA- and protein levels of SM22α and calponin, whereas a sustained stimulation for 48 h activates the intrinsic apoptotic pathway, as evidenced by reduced cell numbers, down-regulation of the anti-apoptotic Bcl-2 protein and increased levels of the Bax protein and cleaved caspase-3. The effects were reversed by the PPARγ antagonist, GW 9662, clearly implying a PPARγ-dependent mechanism. Our results also demonstrate a co-localisation of the AT2-receptor interacting protein, ATIP1, and the PPARγ in nuclei of SK-UT-1 cells and an accumulation of ATIP1 in the nuclear fraction in response to AT2 receptor stimulation. The regulation of the differentiation and apoptosis via the AT2 receptor favours an important functional role of this receptor in quiescent, slow-cycling SK-UT-1 cells and provides the rationale for the use of AT1 receptor antagonists for the treatment of human leiomyosarcomas.


Dislocation of the Temporomandibular Joint and Relocation Procedures.
Temporomandibular joint (TMJ) dislocation requires prompt medical attention due to the crucial impact of airway, nutrition acquisition, and communication. Recognition of this injury by the practitioner, based on clinical presentation and history, is paramount for identification of accurate diagnosis and prompt treatment of TMJ dislocation. Relocation or reduction methods vary on the basis of the severity of the injury and whether it is an acute or chronic dislocation.


Crystal structure of HLA-DP2 and implications for chronic beryllium disease.
Chronic beryllium disease (CBD) is a fibrotic lung disorder caused by beryllium (Be) exposure and is characterized by granulomatous inflammation and the accumulation of Be-responsive CD4(+) T cells in the lung. Genetic susceptibility to CBD has been associated with certain alleles of the MHCII molecule HLA-DP, especially HLA-DPB1*0201 and other alleles that contain a glutamic acid residue at position 69 of the beta-chain (betaGlu69). The HLA-DP alleles that can present Be to T cells match those implicated in the genetic susceptibility, suggesting that the HLA contribution to disease is based on the ability of those molecules to bind and present Be to T cells. The structure of HLA-DP2 and its interaction with Be are unknown. Here, we present the HLA-DP2 structure with its antigen-binding groove occupied by a self-peptide derived from the HLA-DR alpha-chain. The most striking feature of the structure is an unusual solvent exposed acidic pocket formed between the peptide backbone and the HLA-DP2 beta-chain alpha-helix and containing three glutamic acids from the beta-chain, including betaGlu69. In the crystal packing, this pocket has been filled with the guanidinium group of an arginine from a neighboring molecule. This positively charged moiety forms an extensive H-bond/salt bridge network with the three glutamic acids, offering a plausible model for how Be-containing complexes might occupy this site. This idea is strengthened by the demonstration that mutation of any of the three glutamic acids in this pocket results in loss of the ability of DP2 to present Be to T cells.


Evaluation of two distinct methods to quantify the uptake of crocidolite fibers by mesothelial cells.
Exposure to asbestos fibers increases the risk of mesothelioma in humans. One hypothetical carcinogenic mechanism is that asbestos fibers may directly induce mutations in mesothelial cells. Although the uptake of asbestos fibers by mesothelial cells is recognized, methods for the quantification of the uptake have not been well established. In the present study, we evaluated two distinct methods, using crocidolite fibers and MeT5A mesothelial cells. One method is histological evaluation using the cell-block technique, which allows for the direct cross-sectional observation of cells and fibers. We found the bright field observation with ×1000 magnification (oil-immersion) of the sample with Kernechtrot staining was most suitable for this purpose. The other method is flow cytometric analysis, which permits the evaluation of a much larger number of cells. We observed that the side scatter (SSC) increased with the intracellular fibers, and that the "mean SSC ratio (treated/control)" was useful for quantification. We could collect the cells with abundant internalized crocidolite fibers by sorting. Results of the two methodologies were correlated well in the experiments. The quantities of internalized fibers increased with incubation time and loaded dosage, but they were inversely associated with cellular density in culture.


Dewetting transition assisted clearance of (NFGAILS) amyloid fibrils from cell membranes by graphene.
Clearance of partially ordered oligomers and monomers deposited on cell membrane surfaces is believed to be an effective route to alleviate many potential protein conformational diseases (PCDs). With large-scale all-atom molecular dynamics simulations, here we show that graphene nanosheets can easily and quickly win a competitive adsorption of human islet amyloid polypeptides (hIAPP22-28) NFGAILS and associated fibrils against cell membrane, due to graphene's unique two-dimensional, highly hydrophobic surface with its all-sp(2) hybrid structure. A nanoscale dewetting transition was observed at the interfacial region between the fibril (originally deposited on the membrane) and the graphene nanosheet, which significantly assisted the adsorption of fibrils onto graphene from the membrane. The π-π stacking interaction between Phe23 and graphene played a crucial role, providing the driving force for the adsorption at the graphene surface. This study renders new insight towards the importance of water during the interactions between amyloid peptides, the phospholipidic membrane, and graphene, which might shed some light on future developments of graphene-based nanomedicine for preventing/curing PCDs like type II diabetes mellitus.


Capuchin monkeys (Cebus apella) let lesser rewards pass them by to get better rewards.
Self-control is defined as foregoing an immediate reward to gain a larger delayed reward. Methods used to test self-control comparatively include inter-temporal choice tasks, delay of gratification tasks, and accumulation tasks. To date, capuchin monkeys have shown different levels of self-control across tasks. This study introduced a new task that could be used comparatively to measure self-control in an intuitive context that involved responses that required no explicit training. Capuchin monkeys (Cebus apella) were given a choice between two food items that were presented on a mechanized, revolving tray that moved those foods sequentially toward the monkeys. A monkey could grab the first item or wait for the second, but was only allowed one item. Most monkeys in the study waited for a more highly preferred food item or a larger amount of the same food item when those came later, and they inhibited the prepotent response to grab food by not reaching out to take less-preferred foods or smaller amounts of food that passed directly in front of them first. These data confirm that the mechanisms necessary for self-control are present in capuchin monkeys and indicate that the methodology can be useful for broader comparative assessments of self-control.


Assessment of myocardial oxidative metabolic reserve with positron emission tomography and carbon-11 acetate.
We have previously demonstrated that positron emission tomography (PET) with [11C]acetate allows noninvasive regional quantification of myocardial oxidative metabolism. To assess the metabolic response of normal myocardium to increased work (oxidative metabolic reserve), clearance of myocardial 11C activity after administration of [11C]acetate i.v. was measured with PET in seven normal subjects at rest and during dobutamine infusion. At rest, clearance of 11C was monoexponential and homogeneous. The rate constant of the first phase of 11C clearance, k1, averaged 0.054 +/- 0.014 min-1 at a rate-pressure produce (RPP) of 7329 +/- 1445 mmHg X bpm. During dobutamine infusion, RPP increased by an average of 141% to 17,493 +/- 3582 mm Hg Z bpm. Clearance of 11C became biexponential and remained homogeneous. k1 averaged 0.198 +/- 0.043 min-1 with a mean coefficient of variation of 16%.. k1 and RPP correlated closely (r = 0.91; p less than 0.001), and the slope of the k1/RPP relation remained consistent in all subjects (1.48 +/- 0.42). These findings suggest that PET with [11C]acetate and dobutamine stress may provide a promising approach for evaluation of regional myocardial oxidative metabolic reserve in patients with cardiac diseases of diverse etiologies and for assessment of the efficacy of interventions designed to enhance the recovery of metabolically comprised myocardium.


Fluorescence-based analysis of the intracytoplasmic membranes of type I methanotrophs.
Most methanotrophic bacteria maintain intracytoplasmic membranes which house the methane-oxidizing enzyme, particulate methane monooxygenase. Previous studies have primarily used transmission electron microscopy or cryo-electron microscopy to look at the structure of these membranes or lipid extraction methods to determine the per cent of cell dry weight composed of lipids. We show an alternative approach using lipophilic membrane probes and other fluorescent dyes to assess the extent of intracytoplasmic membrane formation in living cells. This fluorescence method is sensitive enough to show not only the characteristic shift in intracytoplasmic membrane formation that is present when methanotrophs are grown with or without copper, but also differences in intracytoplasmic membrane levels at intermediate copper concentrations. This technique can also be employed to monitor dynamic intracytoplasmic membrane changes in the same cell in real time under changing growth conditions. We anticipate that this approach will be of use to researchers wishing to visualize intracytoplasmic membranes who may not have access to electron microscopes. It will also have the capability to relate membrane changes in individual living cells to other measurements by fluorescence labelling or other single-cell analysis methods.


Circulating Tumor DNA Using Tagged Targeted Deep Sequencing to Assess Minimal Residual Disease in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy.
In breast cancer patients undergoing neoadjuvant chemotherapy before surgery, there is an unmet need for noninvasive predictive biomarkers of response. The analysis of circulating tumor DNA (ctDNA) in particular has been the object of several reports, but few of them have studied the applicability of tagged targeted deep sequencing (tTDS) to clinical practice and its performance compared with droplet digital PCR (ddPCR). Here, we present the first results from an ongoing study involving a prospectively accrued, monocentric cohort of patients affected by invasive breast cancer, undergoing neoadjuvant chemotherapy followed by surgery with curative intent as per clinical practice. A pretreatment tumor biopsy and plasma samples were collected before and during treatment, after surgery, and every six months henceforth or until relapse, whichever came first. Pretreatment biopsies were sequenced with a 409-gene massive parallel sequencing (MPS) panel, allowing the identification of target mutations and their research in plasma by tTDS and ddPCR as a complementary approach. Using tTDS, we demonstrated the presence of at least one deleterious mutation in all the relapsed cases we studied (n = 4), with an average lead time of six months before clinical relapse. The association with ddPCR was suboptimal, and only one relapsed patient could be identified with such method. tTDS shows potential as an early noninvasive method for the detection of MRD in BC patients.


Risk Factors for Neonatal Sepsis: A Retrospective Case-Control Study among Neonates Who Were Delivered by Caesarean Section at the Trauma and Specialist Hospital, Winneba, Ghana.
The third Sustainable Development Goal (SDG) for child health, which targets ending preventable deaths of neonates and children under five years of age by 2030, may not be met without substantial reduction of neonatal sepsis-specific mortality in developing countries. This study aimed at assessing the prevalence and risk factors for neonatal sepsis among neonates who were delivered via caesarean section. A retrospective case-control study was conducted among neonates who were delivered via caesarean section at the Trauma and Specialist Hospital, Winneba, Ghana. Data collection lasted for 4 weeks. The extracted data were double-entered using Epidata software version 3.1 to address discrepancies of data entry. Descriptive statistics such as frequencies and percentages of neonatal characteristics were generated from the data. Both univariate and multivariate logistic regression were used to determine associations between neonatal sepsis and neonatal characteristics with odds ratios, 95% confidence intervals, and p values calculated using variables that showed significant association (p<0.05) in the chi-square analysis for the multivariate logistic regression. A total of 383 neonates were recruited; 67 (17.5%) had sepsis (cases). The neonatal risk factors associated with sepsis were birth weight (χ2=6.64, p=0.036), neonatal age (χ2=38.31, p<0.001), meconium passed (χ2=12.95, p<0.001), reason for CS (χ2=24.27, p<0.001), and the duration of stay on admission (χ2=36.69, p<0.001). Neonatal sepsis poses a serious threat to the survival of the newborn as the current study uncovered 6.0% deaths among sepsis cases. The findings of this study highlight the need for routine assessment of neonates in order to identify risk factors for neonatal sepsis and to curb the disease burden on neonatal mortality.


Is Mutation Random or Targeted?: No Evidence for Hypermutability in Snail Toxin Genes.
Ever since Luria and Delbruck, the notion that mutation is random with respect to fitness has been foundational to modern biology. However, various studies have claimed striking exceptions to this rule. One influential case involves toxin-encoding genes in snails of the genus Conus, termed conotoxins, a large gene family that undergoes rapid diversification of their protein-coding sequences by positive selection. Previous reconstructions of the sequence evolution of conotoxin genes claimed striking patterns: (1) elevated synonymous change, interpreted as being due to targeted "hypermutation" in this region; (2) elevated transversion-to-transition ratios, interpreted as reflective of the particular mechanism of hypermutation; and (3) much lower rates of synonymous change in the codons encoding several highly conserved cysteine residues, interpreted as strong position-specific codon bias. This work has spawned a variety of studies on the potential mechanisms of hypermutation and on causes for cysteine codon bias, and has inspired hypermutation hypotheses for various other fast-evolving genes. Here, I show that all three findings are likely to be artifacts of statistical reconstruction. First, by simulating nonsynonymous change I show that high rates of dN can lead to overestimation of dS. Second, I show that there is no evidence for any of these three patterns in comparisons of closely related conotoxin sequences, suggesting that the reported findings are due to breakdown of statistical methods at high levels of sequence divergence. The current findings suggest that mutation and codon bias in conotoxin genes may not be atypical, and that random mutation and selection can explain the evolution of even these exceptional loci.


Examining theories of cognitive ageing using the false memory paradigm.
Changes in memory performance with advancing age have been well documented, even in the absence of brain injury or dementia. The mechanisms underlying cognitive ageing are still a matter of debate. This article describes a comparison between young (18-25 years old) and older (60+ years) adults using the Deese-Roediger-McDermott false memory paradigm and manipulating the number of words included in the memory lists. Two key theories of cognitive ageing (the Inhibitory Deficit Hypothesis and the Transmission Deficit Hypothesis) predict opposing patterns on this task. Results showed that longer lists increase the likelihood that a lure is retrieved and that older adults are more susceptible to false memories than are younger adults. We argue that these findings are supportive of the Inhibitory Deficit Hypothesis and cannot easily be reconciled with the Transmission Deficit Hypothesis account.


Psychiatric clinics in general practice. An extension of community care.
The patients seen at five psychiatric clinics in general practice (GP) serving an urban population of 78,200 are described, and their attitudes to the clinic compared with those for conventional out-patient clinics. The GP psychiatric clinics were strongly preferred, mainly because of their ease of access and absence of stigma; 19 per cent of the patients seen would not have attended a hospital clinic. The patients seen encompassed the entire range of psychiatric disorder, but most were treated in the clinic or by other members of the primary care team. It is concluded that GP psychiatric clinics offer a way of achieving better community psychiatry without any need for increased resources.


Derivation of the effect of atmospheric and aerosol emissions on IR imaging device performance.
The authors have previously called attention to the importance of atmospheric and aerosol emission in IR imaging device performance. The present paper derives a more precise and general result than the empirically derived expressions in the earlier paper. The same general conclusion, that atmospheric and aerosol emissions are an important factor in IR imaging performance, is supported, assuming that the system is photon noise-limited.


Deciphering host migrations and origins by means of their microbes.
Mitochondrial DNA and microsatellite sequences are powerful genetic markers for inferring the genealogy and the population genetic structure of animals but they have only limited resolution for organisms that display low genetic variability due to recent strong bottlenecks. An alternative source of data for deciphering migrations and origins in genetically uniform hosts can be provided by some of their microbes, if their evolutionary history correlates closely with that of the host. In this review, we first discuss how a variety of viruses, and the bacterium Helicobacter pylori, can be used as genetic tracers for one of the most intensively studied species, Homo sapiens. Then, we review statistical problems and limitations that affect the calculation of particular population genetic parameters for these microbes, such as mutation rates, with particular emphasis on the effects of recombination, selection and mode of transmission. Finally, we extend the discussion to other host-parasite systems and advocate the adoption of an integrative approach to both sampling and analysis.


Corneal inflammation from pine processionary caterpillar hairs.
Hairs from the caterpillar of the pine processionary moth, Thaumetopoea pityocampa, located in the pine forests of southern Europe and elsewhere, can become embedded in the cornea and conjunctiva. Disorders produced by the urticating hairs can be classified into a broad spectrum of severity from mild keratoconjunctivitis to anaphylactic shock. This report presents 3 cases that illustrate the range of corneal responses to embedded hairs of the processionary moth caterpillar. Case series and review of the literature. A 51-year-old man (case 1), a 46-year-old woman (case 2), and a 67-year-old man (case 3) presented different manifestations as a result of contact with pine processionary caterpillar hairs. Case 1 had acute keratitis with decreased vision. He was treated with a corneal depot steroid 4 times daily for 3 months. After 4 months, he was asymptomatic. Case 2 had acute keratitis without vision symptoms. She was released without treatment, and 1 month later was asymptomatic. Case 3 experienced dry gritty sensations, probably because of blepharitis, but also presented asymptomatic caterpillar hairs embedded in the corneal stroma. He was instructed regarding lid hygiene for his blepharitis, and after 3 months the embedded caterpillar hairs had disappeared. The most common ocular presentation of embedded hairs from the pine processionary moth caterpillar is keratitis. The urticating hairs can cause corneal infiltrates that disappear progressively over time. Steroid eye drops accelerate the resorption of these infiltrates.


Efficient combination of large DNA in vitro: in gel site specific recombination (IGSSR) of PAC fragments containing alpha satellite DNA and the human HPRT gene locus.
In an attempt to combine a cloned genomic copy of a selectable gene with different cloned centromeric sequences to develop mammalian artificial chromosomes (MAC) we used site specific recombination mediated by purified Cre recombinase acting on the loxP sequence in PAC vector DNA. A new method was required to purify highly concentrated, virtually 100% intact PAC DNA which could be stored for a long period. Here we show the efficient linking of linearized PACs containing alpha satellite DNA from chromosomes X and 17 with sizes of 125 and 140 kb, respectively, to a 95 kb restriction fragment derived from a 175 kb PAC containing the intact human HPRT gene locus.