DNA replication fading as proliferating cells advance in their commitment to terminal differentiation.
Terminal differentiation is the process by which cycling cells stop proliferating to start new specific functions. It involves dramatic changes in chromatin organization as well as gene expression. In the present report we used cell flow cytometry and genome wide DNA combing to investigate DNA replication during murine erythroleukemia-induced terminal cell differentiation. The results obtained indicated that the rate of replication fork movement slows down and the inter-origin distance becomes shorter during the precommitment and commitment periods before cells stop proliferating and accumulate in G1. We propose this is a general feature caused by the progressive heterochromatinization that characterizes terminal cell differentiation.


The treatment of maxillofacial trauma in austere conditions.
Caring for severely injured patients, whether they be in the theater of combat or after natural disasters, can be a rewarding and even life-changing experience for all involved. Sound surgical principles and an attempt to achieve a high standard of care should still guide the treating surgeon. The surgical team undoubtedly face numerous obstacles, but with careful and considerate planning, many of these can be minimized.


[New findings in diet therapy and nutritional pharmacology].
The author gives an account on the effect of a number of nutrients prepared by the pharmaceutical industry and their use in enteral and parenteral nutrition. They are natural substances which promote the action of other pharmaceutical preparations. Their main importance is in prevention: they prevent a number of complications, have no side-effects and there is no risk of overdosage.


MALDI-TOF mass spectrometry reveals a highly complex bacterial profile of otitis media with effusion.
With conventional microbiological methods, a significant proportion of middle ear effusion (MEE) proves to be sterile. Accurate molecular biological techniques have been used to identify only pathogenic bacteria. Matrix assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) is an adequate tool for the precise and simultaneous identification of a wide range of bacterial species from a small sample. The aim of this study was to explore the use of MALDI-TOF MS in revealing the frequency and complexity of bacterial flora in MEE in otitis media with effusion (OME). MEEs from 40 children with chronic otitis media with effusion were examined for 2000 pathogenic, facultative pathogenic and nonpathogenic bacterial species using MALDI-TOF MS. Two middle ear samples from children who underwent cochlear implantation with healthy middle ear were also examined in the same way. No bacteria were found in healthy control samples and 92% of OME samples were positive for at least one bacterium. In 52% of the samples more than one bacterium was identified. In total 39 bacterial species were found in the middle ear samples. Of the positive samples 19% contained those pathogens which were previously thought to contribute OME. MALDI-TOF MS is a suitable tool for identifying a wide range of bacterial species in MEE. Results show that bacterial flora of MEE in OME is more diverse and abundant than it was formerly thought. This previously unreported bacterial invasion may help to obtain proper understanding and therapy of OME.


Effect of phentolamine on the somatostatin-induced inhibition of glucagon and insulin secretion.
Synthetic cyclic somatostatin was infused into either the cranial pancreaticoduodenal artery or the femoral vein of anesthetized dogs with or without previous administration of phentolamine. Somatostatin infused into the pancreatic artery at a dose of 50 ng/kg/min for 10 min caused significant decreases in blood flow and plasma basal concentrations of both glucagon and insulin in the cranial pancreaticoduodenal vein, resulting in a profound decline of bihormonal output during the infusion. Arterial plasma glucose was not reduced during the administration of somatostatin in the pancreatic artery. These somatostatin-induced decreases failed to be eliminated by a 0.2 mg/kg injection of phentolamine into the femoral vein followed by a 9-min infusion of this alpha-adrenergic blocker (0.02 mg/kg/min) into the pancreatic artery immediately prior to the somatostatin administration. An inhibition of glucagon and insulin output and a fall of plasma glucose caused by somatostatin (1.7 microgram/min) infused into the femoral vein for 30 min also were not abolished by a prolonged and simultaneous infusion of phentolamine (0.2 mg/min) into the femoral vein over a period of 2 hr. These results indicate that alpha-adrenergic receptor mechanisms do not play a major role in the inhibition of islet glucagon and insulin secretion by somatostatin.


Mitral valve replacement in medically unresponsive congestive heart failure due to papillary muscle dysfunction.
Forty patients with a mean age of 65 years (range 44-76 years) were operated on; 30 of 40 patients (75%) had prior myocardial infarction. All had severe therapy-resistant congestive heart failure, 75% (30 of 40 patients) were symptomatic at rest, and 25% (10 of 40 patients) were symptomatic on minimal exertion. Cardiac index ranged from 1.24-2.84 L/min/m2 (mean 1.99). Left ventricular end-diastolic pressure ranged from 3-36 mm Hg (mean 18). All patients had significant mitral insufficiency and contractility was reduced markedly to moderately in 63% (25 of 40 patients). Significant coronary artery disease (obstruction greater than or equal to 75%) was present in all patients. All had mitral valve replacement, 30 had bypass surgery, and 7 left ventricular aneurysmectomy. Five died during surgery or before discharge (early mortality 12.5%). After a mean follow-up period of 16 months, another eight patients died, two with causes not related to the cardiovascular system (total mortality 32.5%). Of 20 patients with a cardiac index greater than or equal to 1.5 L/min/m2 and an ejection fraction greater than or equal to 0.40, 17 survived surgery and improved postoperatively. Mitral valve replacement for this group of patients is recommended.


Neuropsychological deficits in drug naïve, non-depressed obsessive-compulsive disorder patients.
There are several studies that compared neuropsychological performance of OCD patients with healthy controls. However, there are hardly any studies which have used drug-naïve as well as non-depressed OCD subjects in their studies. The present study compared eighteen drug-naïve non-depressed OCD patients with similar number of age, education and sex matched healthy controls on neuropsychological tests. The tests used are block design, object assembly, Visuospatial Working Memory Test, Verbal Working Memory Test, Complex Figure Test, Stroop Test and Wisconsin Card Sorting Test. In addition to usual significance testing, Effect Sizes were calculated. In addition, correlation was done between neuropsychological test variables and clinical variables. The results did not show any significant correlation between any of the clinical variables and neuropsychological test variables. On the other hand, patients showed significant deficits mainly in executive functions and organizational strategy with respect to visuospatial functions. The observed deficits can be attributed to both dorsolateral prefrontal cortex and orbitofrontal cortex involvement.


Physician associate graduates in England: a cross-sectional survey of work careers.
Physician associates (PAs) are a new healthcare professional group in the UK. While PAs have been known as a stable but flexible workforce in the USA for over 50 years, little is known about their career paths in the UK's NHS. A cross sectional online survey (January 2020 - May 2020) of graduates from the longest running UK PA course investigated stability and factors influencing job retention or movement. One-hundred and sixty-two (71%) graduates provided a full response. Descriptive analysis was by early graduates (2006-2013), mid-graduates (2014-2017) and recent graduates (2018-2020). Early and mid-graduates held their first jobs for a mean of 3 years. For early graduates, the longest held job was 11 years, with a mode of 7 years. Enjoyment of the work, learning opportunities and working with supportive consultants were the most highly rated factors in PA job retention.


Structure and assembly pattern of a freshwater short-tailed cyanophage Pam1.
Despite previous structural analyses of bacteriophages, quite little is known about the structures and assembly patterns of cyanophages. Using cryo-EM combined with crystallography, we solve the near-atomic-resolution structure of a freshwater short-tailed cyanophage, Pam1, which comprises a 400-Å-long tail and an icosahedral capsid of 650 Å in diameter. The outer capsid surface is reinforced by trimeric cement proteins with a β-sandwich fold, which structurally resemble the distal motif of Pam1's tailspike, suggesting its potential role in host recognition. At the portal vertex, the dodecameric portal and connected adaptor, followed by a hexameric needle head, form a DNA ejection channel, which is sealed by a trimeric needle. Moreover, we identify a right-handed rifling pattern that might help DNA to revolve along the wall of the ejection channel. Our study reveals the precise assembly pattern of a cyanophage and lays the foundation to support its practical biotechnological and environmental applications.


High prevalence of hyperuricemia in adolescent Taiwan aborigines.
To explore the prevalence and related factors of hyperuricemia among adolescent Taiwan aborigines in tribes with a high prevalence of adult gout, compared with adolescents of low prevalence aboriginal and non-aboriginal tribes. The participants were aborigines and non-aborigines in Taiwan, age 12 to 15 years and free of gout. Each participant provided information on sex, age, and parents' tribal background as well as body weight and height. Serum samples were analyzed for biochemical markers. A logistic regression model was used to study factors related to hyperuricemia. In total 940 adolescents participated. The hyperuricemia rate in tribes with high gout prevalence (57.7%) was higher than in non-aborigines (48.2%) and in aboriginal tribes with low gout prevalence (34.0%). Factors statistically significantly related to hyperuricemia were tribe, sex, obesity, creatinine, and cholesterol levels in preliminary analysis. After adjustment by the logistic regression model, obese boys with higher creatinine were most likely to have hyperuricemia. Adolescents whose parents originated from tribes with high gout prevalence had a tendency to have hyperuricemia, and those aborigines from tribes with low gout prevalence had a low prevalence of hyperuricemia compared to non-aborigines. The prevalence of hyperuricemia in aboriginal adolescents mirrors the incidence of adult gout, implying a predisposition for adult gout in childhood, with genetic and/or environmental components presumably contributing to the differences between tribes; this may be of potential benefit to preventive efforts.


Hemispheric asymmetry in the effects of cerebral cortical ablations on mitogen-induced lymphoproliferation and plasma prolactin levels in female rats.
Female rats were subjected to unilateral left or right, bilateral, or sham ablation of the cerebral cortex. Eight weeks after surgery, the rats were sacrificed by decapitation and spleen cells were grown in culture for 96 h in the presence or absence of the T-cell mitogen concanavalin A or the B-cell mitogen lipopolysaccharide. Mitogenesis was determined by the addition of [3H]thymidine 24 h prior to harvesting. Both T- and B-cell mitogenesis were significantly depressed in subjects bearing cortical ablations in the right hemisphere, whereas left hemisphere ablation was without reliable effect. Prolactin in plasma collected at sacrifice was elevated in rats bearing right but not left hemisphere ablation and was significantly negatively correlated with both T- and B-cell immune responses. These results demonstrate a lateralized modulatory influence of cerebral cortex on immune function in female rats and they implicate elevated prolactin levels as a possible mediator of this effect.


Copula-based analysis of socio-economic impact on water quantity and quality: A case study of Yitong River, China.
Socio-economic development has a significant impact on both water quantity and quality. However, few studies have considered the complex relationship between water quantity and quality when evaluating such impact. In this study, three indicators based on copula model were proposed, namely, water quantity improvement degree (WQIDw), water quality improvement degree (WQIDq) and water quantity and quality joint improvement degree (WQJID). These indicators were used to assess the impact of social economy on water quantity and quality, and applied to a case study in Yitong River in Northeast China from 2021 to 2025. Four scenarios were set to explore the impact of socio-economic development and water resources protection on WQIDw, WQIDq and WQJID. The maximum WQIDw, WQIDq and WQJID were <1 under the business-as-usual scenario, which showed that the present socio-economic pattern caused great damage to river water quantity and quality. The combined effect of socio-economic development and water resources protection increased the WQJID of COD and NH3-N by 1.67 and 1.30. This showed that attention should be paid to water resources protection while developing social economy. Compared with comprehensive evaluation, separate evaluation of water quality will underestimate the impact of social economy on rivers, while separate evaluation of water quantity will overestimate the impact. The relationships between WQIDw, WQIDq and WQJID were quantified. Meanwhile, the uncertainty of the evaluation was controlled by the selection of water quality indicators. The WQIDq, WQIDw and WQJID proposed in this study provide a comprehensive assessment tool for guiding water resources management.


Predictors of improvement in diastolic function after transcatheter aortic valve implantation.
Aortic stenosis is associated with concentric left ventricle (LV) hypertrophy or remodeling resulting in impaired diastolic function and elevated left-sided filling pressure. We investigated the changes in LV geometry and LV filling hemodynamics, giving emphasis to parameters associated with changes in diastolic function after transcatheter aortic valve implantation (TAVI). Comprehensive diastolic assessment was performed before and six months after TAVI in 70 patients with severe aortic stenosis. Patients with any degree of mitral stenosis or >mild left-sided valvular regurgitation were excluded. In the entire cohort six months after TAVI, LV end-diastolic diameter increased (44.1 ± 6 versus 45 ± 6 mm, P = 0.02), whereas LV mass and relative wall thickness (RWT) decreased (270.1 ± 76 versus 245.1 ± 75 g and 0.53 ± 0.15 versus 0.46 ± 0.1, respectively; P < 0.0001 for both). Lateral e' increased (5.8 ± 2 versus 6.6 ± 3 cm/s, P = 0.03) and left atrium (LA) volume, E/e' ratio, and systolic pulmonary pressure decreased (88.1 ± 30 versus 80 ± 28 cc, 18 ± 7.8 versus 16.3 ± 5.5, and 42.7 ± 14.9 versus 38.7 ± 12 mmHg, respectively; P < 0.05 for all), suggesting reduction in LA pressure. The improvement in LA volume and E/e' was almost exclusively seen in patients with LV hypertrophy before TAVI (P < 0.05 both), as opposed to patients with concentric remodeling. In our preliminary study, TAVI resulted in LV and LA reverse remodeling, and improved LV relaxation and LA filling pressure in patients with severe aortic stenosis and concentric hypertrophy. Patients with concentric remodeling at baseline seem to have limited improvement in LV diastolic function and filling pressure following TAVI, but larger clinical trials would be required to conclude if they have no improvement at all.


Receptive fields of thalamic neurons projecting to the motor cortex in the cat.
The locations and receptive fields of thalamic neurons projecting to the motor cortex were examined and the following results were obtained. (1) Neurons located at the border area between nucleus ventralis lateralis (VL) and nucleus ventralis posterolateralis (VPL) could be activated antidromically from the motor cortex. (2) These neurons received topographically organized somesthetic inputs arising from skin and deep receptors. (3) The receptive fields of neurons in the small area of the motor cortex where these thalamic neurons projected could be examined in 8 instances. In 6 instances, the cortical neurons and the thalamic projection neurons were activated by exactly the same stimuli in the periphery. (4) Removal of the sensory cortex did not significantly change the characteristics of afferent inputs from the periphery to the motor cortex. (5) It is concluded that the motor cortex receives somesthetic inputs directly from the thalamus. The functional role of these inputs was discussed in relation to the known cortical reflexes.


Taurine effects on 45Ca2+ transport in retinal subcellular fractions.
The effect of taurine on 45Ca2+ transport by subcellular fractions from the chick retina was examined. An inhibitory action of taurine on 45Ca2+ uptake was observed in retinal fractions incubated for 1--5 min in a Krebs--bicarbonate medium, pH 7.4. In the crude nuclear fraction, 25 mM taurine produced a decrease of 50% in 45Ca2+ uptake; in the crude synaptosomal fraction, taurine reduced 45Ca2+ accumulation by 70%; the maximum inhibitory effect of taurine on 45Ca2+ uptake (80%) was observed in a fraction containing outer segments and pigment epithelium cells. Taurine effect was specific, dose-dependent and related to osmotically sensitive particles. The results suggest a role for taurine in the regulation of calcium fluxes in the retina.


Early detection of psychosis - establishing a service for persons at risk.
The establishment phase of an early detection centre for prodromal psychosis is introduced and characterised, along with its detaining and promoting factors within a universal multi-payer health care system. Across the first six years (1998-2003), users' characteristics are compared between different diagnostic groups and to the local population statistics; and, for an exemplary 12-months period (3-1-2002 to 2-28-2003), the characteristics of telephone contacts with the service are studied. Rising steadily in number across the first three years, 872 persons, predominantly of German citizenship and higher education, consulted the service until 2003, 326 with first-episode psychosis and 144 not fulfilling criteria for a current or beginning psychosis. Of the 402 putatively prodromal patients, 94% reported predictive basic symptoms, 68.9% attenuated and 20.6% transient psychotic symptoms. Most contacts by persons meeting any prodromal criterion were initiated by mental health professionals (psychiatrists or psychologists) and counselling services. Supported by public awareness campaigns, an early detection service is well received by its users and private practitioners as reflected by the large proportion of referrals from the latter. However, persons of non-German background as well as of lower education were underrepresented indicating that these sub-groups should be approached by tailored programmes.


Draft Genome Sequences of Three Novel Clostridium Isolates from Northern Iraq.
Three Clostridium sp. strains were isolated from soil and sediment collected from the Kurdistan region of Iraq. All three isolates were found to harbor putative prophages, with a CRISPR-Cas system found in strains C105KSO13 and C105KSO14.


Association between physical activity and insulin resistance using the homeostatic model assessment for insulin resistance independent of waist circumference.
Only a few studies have evaluated the relationship between physical activity (PA) and Homeostatic model assessment for insulin resistance (HOMA-IR). Therefore, we aimed to analyze the association between HOMA-IR and PA. We included 280,194 Korean without diabetes who underwent health examinations. The short form of the International Physical Activity Questionnaire was completed. PA level was divided into sedentary, mild PA, and health-enhancing PA (HEPA). The HOMA-IR levels were calculated. Confounding factors including waist circumference were adjusted. The median follow-up duration was 4.13 years. A significant inverse relationship was observed between PA level and HOMA-IR (p < 0.001). Compared with the sedentary group, HOMA-IR was lower in the HEPA group (p < 0.001), even when HEPA group decreased PA level over time (p < 0.001). Mild PA (p < 0.001) or HEPA showed a lower risk of HOMA-IR progression (p < 0.001). Increasing PA or maintaining HEPA was significantly associated with a lower HOMA-IR (p < 0.001), HOMA-IR improvement (p < 0.001), and a lower risk of HOMA-IR progression (p < 0.001). Our findings support the inverse relationship between PA and HOMA-IR in a population without diabetes. PA might improve IR and prevent its progression among populations without diabetes, independent of the waist circumference.


"If somebody had told me I'd feel like I do now, I wouldn't have believed them…" older adults' experiences of the BELL trial: a qualitative study.
This study examined older adults' experiences of participating in the Ballistic Exercise of the Lower Limb (BELL) trial, involving 12-weeks of group-based hardstyle kettlebell training. In the BELL trial, 28 insufficiently active older adults (15 women, 13 men, 59-79 years) completed six weeks of face-to-face group training, and six weeks of home-based training. In-depth semi-structured interviews were audio recorded, transcribed, and inductively coded, with themes constructed from patterns of shared meaning. Four higher-order themes were developed that reflect older adults' experiences participating in a group-exercise program of hardstyle kettlebell training. These included: (1) "It's one of the best things we've done"-enjoying the physical and psychosocial benefits, (2) "It's improved it tremendously!"-change in a long-term health condition, (3) "It put me on a better course"-overcoming challenges, and (4) "I wasn't just a number"-feeling part of a group/community. Findings highlight the perceived physical and psychological benefits of older adults participating in hardstyle group kettlebell training, and the value attributed to being part of an age-matched community of like-minded people engaged in group exercise. Implications for program design and delivery, and future research, are discussed.


A Luciferase Reporter Gene Assay to Measure Ebola Virus Viral Protein 35-Associated Inhibition of Double-Stranded RNA-Stimulated, Retinoic Acid-Inducible Gene 1-Mediated Induction of Interferon β.
During Ebola virus (EBOV) infection, the type I interferon α/β (IFN-α/β) innate immune response is suppressed by EBOV viral protein 35 (VP35), a validated drug target. Identification of EBOV VP35 inhibitors requires a cellular system able to assess the VP35-based inhibitory functions of viral double-stranded RNA (dsRNA) IFN-β induction. We established a miniaturized luciferase gene reporter assay in A549 cells that measures IFN-β induction by viral dsRNA and is dose-dependently inhibited by VP35 expression. When compared to influenza A virus NS1 protein, EBOV VP35 showed improved inhibition of viral dsRNA-based IFN-β induction. This assay can be used to screen for EBOV VP35 inhibitors.


Coenzyme reorientations in the active sites of aspartate aminotransferase isoenzymes studied by linear dichroism method.
Cytosolic and mitochondrial pig heart aspartate aminotransferases (cAspAT and mAspAT) and chicken heart cAspAT have been oriented in a compressed slab of polyacrylamide gel and their linear dichroism LD spectra have been recorded. The coenzyme's tilt angles in the active sites of chicken cAspAT and pig mAspAT and their quasisubstrate complexes imitating catalytic intermediates have been computed. The computations are based on reduced linear dichroism values (delta A/A), the known directions of the transition dipole moments in the coenzyme ring and atomic coordinates of the coenzyme obtained by X-ray crystallography. It has been found that formation of the enzyme complex with glutarate and protonation of the internal pyridoxal-lysine aldimine induce reorientations of the coenzyme. As a result of protonation, the coenzyme ring tilts by 27 degrees in cAspAT and 13 degrees in mAspAT. Formation of the external aldimine with 2-methylaspartate is accompanied by tilting of the coenzyme ring by 44 degrees in cAspAT and 39 degrees in mAspAT. For the quinonoid complex with erythro-3-hydroxyaspartate, the tilt angles were found to be 63 degrees in cAspAT and 53 degrees in mAspAT. It is inferred that the basic features of the active site dynamics are similar in the three AspAT's studied. The differences in the coenzyme tilt angles between cAspAT and mAspAT may be linked to catalytic and structural peculiarities of the isoenzymes.


Influence of cold plastic deformation on critical pitting potential of AISI 316 L and 304 L steels in an artificial physiological solution simulating the aggressiveness of the human body.
The effect of cold working on critical pitting potential of AISI 316 L and 304 L steels in a buffered physiological solution has been studied. In particular, the importance of deformation degree, orientation of the specimen surface to the deformation direction, and cold working temperature in lowering the critical pitting potential is shown.


Interactions between K+ and ATP binding to the (Na+ + K+)-dependent ATPase.
K+ appears to decrease the affinity of the (Na+ + K+)-dependent ATPase (ATP phosphohydrolase, EC 184.108.40.206) for its substrate, Mg2+ - ATP, and Mg2+ - ATP, in turn, appears to decrease the affinity of the enzyme for K+. These antagonisms have been investigated in terms of a quantitative model defining the magnitude of the effects as well as identifying the class of K+ sites on the enzyme involved. K+ increased the apparent Km for Mg2+ - ATP, an effect that was antagonized competitively by Na+. The data can be fitted to a model in which Mg2+ - ATP binding is prevented by occupancy of alpha-sites on the enzyme by K+ (i.e. sites of moderate affinity for K+ accessible on the "free" non-phosphorylated enzyme, in situ on the external membrane surface). By contrast, occupancy of these alpha-sites by Na+ has no effect on Mg2+ - ATP binding to the enzyme. On the other hand, Mg2+ - ATP decreased the apparent affinity of the enzyme for K+ at the alpha-sites, in terms of (i) the KD for K+ measured by K+-accelerated inactivation of the enzyme by F-, and (ii) the concentration of K+ for half-maximal activation of the K+-dependent phosphatase reaction (which reflects the terminal hydrolytic steps of the overall ATPase reaction). These data fit the same quantitative model. Although this formulation does not support schemes in which ATP binding effects the release of transported K+ from discharge sites, it is consistent with observations that K+ can inhibit the enzyme at low substrate concentrations, and that Li+, which has poor efficacy when occupying these alpha-sites, can stimulate enzymatic activity at high K+ concentrations by displacing the inhibitory K+.


Regulation of glutathione levels in mouse spleen lymphocytes by transport of cysteine.
Cysteine and cystine transport activities of resting and activated mouse spleen lymphocytes were characterized in order to examine the contributions of cysteine and cystine to intracellular glutathione contents. Following stimulation with lipopolysaccharide, the lymphocytes markedly increased their capacity to transport cysteine. The uptake of cysteine was mediated mainly by the ASC system (Na+-dependent neutral amino acid transport system especially reactive with alanine, serine, and cysteine). On the other hand, both the resting and the activated lymphocytes had extremely low cystine transport activities. Because of the instability of cysteine, the culture media usually contained cystine but not cysteine. Therefore, both the resting and the activated lymphocytes rapidly decreased their glutathione contents owing to their poor capacities to take up cystine. The effects of freshly added cysteine on the cellular glutathione contents were examined in the presence of bathocuproinedisulfonate, a nontoxic copper-specific chelator that inhibits autoxidation of cysteine. Cysteine added at 25-400 microM only partially prevented the rapid decrease of the glutathione contents in fresh resting lymphocytes. In the lipopolysaccharide-activated cells, however, cysteine enhanced the cellular glutathione contents in a dose-dependent manner. These results indicate that the enhanced activity of the ASC system increases the level of intracellular glutathione in the presence of cysteine.


Activation of clg, a novel dbl family guanine nucleotide exchange factor gene, by proviral insertion at evi24, a common integration site in B cell and myeloid leukemias.
Retroviruses induce leukemia in inbred strains of mice by activating cellular proto-oncogenes and/or inactivating tumor suppressors. The proviral integration sites in these leukemias provide powerful genetic tags for disease gene identification. Here we show that Evi24, a common site of retroviral integration in AKXD B cell and BXH-2 myeloid leukemias, contains a novel Dbl family guanine nucleotide exchange factor gene. We have designated this gene Clg (common-site lymphoma/leukemia guanine nucleotide exchange factor). Proviral integrations on chromosome 7 at Evi24 are located 7.6-10.3 kb upstream of Clg and increased Clg expression 2-5-fold compared with leukemias lacking proviral integrations at Evi24. Clg contains Dbl/pleckstrin homology domains with substantial sequence homology to many Rho family activators, including the transforming Dbl and Dbs/Ost oncogenes. Nucleotide exchange assays indicated that Clg specifically activated nucleotide exchange on Cdc42, but not RhoA or Rac1, in vitro. NIH 3T3 transfection studies showed that overexpression of full-length and carboxyl-terminally truncated forms of Clg morphologically transformed NIH 3T3 cells. This study and studies showing that the human homolog of EVI24 is located in a region of 19q13 frequently amplified in B cell lymphomas and pancreatic and breast cancers implicate Clg and Cdc42 activation in mouse and human cancers.


Crossover design for the dose determination of an angiotensin converting enzyme inhibitor in hypertension.
In order to determine the dose regimen of new antihypertensive compounds, between-patient trials are usually performed. However, the combined use of a crossover design and a precise methodology to measure blood pressure (BP) and biological effects can provide relevant data with a minimal number of patients, if there is no carryover effect which invalidates the experiment. Such goals were successfully achieved with just 25 hypertensive patients who were randomly allocated in double-blind fashion every 2 weeks to a new angiotensin converting enzyme (ACE) inhibitor, benazepril [10 mg once a day (o.d.), 20 mg o.d., 10 mg twice a day (b.i.d.) and 20 mg b.i.d.], or a placebo. The mean BP fall [systolic (SBP)/diastolic (DBP), measured in mmHg] just before drug intake was significantly greater with benazepril: -14/-9 (10 mg o.d.); -15/-8.5 (20 mg o.d.); -22.5/-14 (10 mg b.i.d.), and -21/-13 (20 mg b.i.d.) in comparison with placebo (-3/-3). Mean active plasma renin (measured in pg/ml), assessed by an immunoradiometric assay based on two monoclonal antibodies, increased significantly in a dose-dependent manner, by +0.7 (placebo), +15.0 (10 mg o.d.), +23.4 (20 mg o.d.), +44.4 (10 mg b.i.d.) and +78.8 (20 mg b.i.d.), whereas plasma ACE decreased (by 67 and 78% after 10 and 20 mg o.d., respectively, and by 91-92% after 10 and 20 mg b.i.d.). In the clinical development of an antihypertensive drug, the earlier use of such within-patient studies, with the random insertion of one placebo period between the active periods, should help in the dose-response curve search.(ABSTRACT TRUNCATED AT 250 WORDS)


Nomographic representation of logistic regression models: a case study using patient self-assessment data.
Logistic regression models are widely used in medicine, but difficult to apply without the aid of electronic devices. In this paper, we present a novel approach to represent logistic regression models as nomograms that can be evaluated by simple line drawings. As a case study, we show how data obtained from a questionnaire-based patient self-assessment study on the risks of developing melanoma can be used to first identify a subset of significant covariates, build a logistic regression model, and finally transform the model to a graphical format. The advantage of the nomogram is that it can easily be mass-produced, distributed and evaluated, while providing the same information as the logistic regression model it represents.


Dissipative structures and amplification of enantiomeric excess (an experimental point of view).
Various mathematical models have been proposed to account for the origin of chiral molecules in biological systems. Most of these models invoke non-linear phenomena, and are based on the general concept of dissipative structures. These theoretical models define the fundamental criteria which must be obeyed by the experimental systems that we have investigated. Our initial approach to this problem was an extensive search of the literature data in order to select a few systems or experimental situations which would satisfy the criteria defined by the theoretical models. For these reasons, we carried out a study of the possibility of stereospecific autocatalysis in the asymmetric polymerisation of benzofuran. Similarly, the formation of spatial dissipative structures by coupling of a transport process with an interfacial reaction was investigated as a simple experimental example of symmetry breaking.


Fingolimod Alleviates Cognitive Deficit in Type 2 Diabetes by Promoting Microglial M2 Polarization via the pSTAT3-jmjd3 Axis.
Sphingosine receptors (S1PRs) are implicated in the progression of neurodegenerative diseases and metabolic disorders like obesity and type 2 diabetes (T2D). The link between S1PRs and cognition in type 2 diabetes, as well as the mechanisms that underpin it, are yet unknown. Neuroinflammation is the common pathology shared among T2D and cognitive impairment. However, the interplay between the M1 and M2 polarization state of microglia, a primary driver of neuroinflammation, could be the driving factor for impaired learning and memory in diabetes. In the present study, we investigated the effects of fingolimod (S1PR1 modulator) on cognition in high-fat diet and streptozotocin-induced diabetic mice. We further assessed the potential pathways linking microglial polarization and cognition in T2D. Fingolimod (0.5 mg/kg and 1 mg/kg) improved M2 polarization and synaptic plasticity while ameliorating cognitive decline and neuroinflammation. Sphingolipid dysregulation was mimicked in vitro using palmitate in BV2 cells, followed by conditioned media exposure to Neuro2A cells. Mechanistically, type 2 diabetes induced microglial activation, priming microglia towards the M1 phenotype. In the hippocampus and cortex of type 2 diabetic mice, there was a substantial drop in pSTAT3, which was reversed by fingolimod. This protective effect of fingolimod on microglial M2 polarization was primarily suppressed by selective jmjd3 blockade in vitro using GSK-J4, revealing that jmjd3 was involved downstream of STAT3 in the fingolimod-enabled shift of microglia from M1 to M2 polarization state. This study suggested that fingolimod might effectively improve cognition in type 2 diabetes by promoting M2 polarization.


Excess mortality among people with podoconiosis: secondary analysis of two Ethiopian cohorts.
While morbidity attributable to podoconiosis is relatively well studied, its pattern of mortality has not been established. We compared the age-standardised mortality ratios (SMRs) of two datasets from northern Ethiopia: podoconiosis patients enrolled in a 1-y trial and a Health and Demographic Surveillance System cohort. The annual crude mortality rate per 1000 population for podoconiosis patients was 28.7 (95% confidence interval [CI] 17.3 to 44.8; n=663) while that of the general population was 2.8 (95% CI 2.3 to 3.4; n=44 095). The overall SMR for the study period was 6.0 (95% CI 3.6 to 9.4). Podoconiosis patients experience elevated mortality compared with the general population and further research is required to understand the reasons.


Atrial fibrillation, an epiphenomenon of acute Stanford type-A aortic dissection with suspected intimo-intimal intussusception.
Supraventricular arrhythmias can sometimes be "only" epiphenomena appearing during acute hypoxia, pneumonia, pulmonary embolism, and thrombosis. Indeed, atrial fibrillation is not rare in acute aortic dissection as it is estimated in about one half of patients and may be secondary to a perfusion deficit of the sinoatrial node artery.


Benzodiazepine antagonist in the treatment of human hepatic encephalopathy.
Recently it was suggested that hepatic encephalopathy (HE) is mediated by an increased GABA-ergic tone. The logical consequence of such a hypothesis is the use of antagonists of the GABA -benzodiazepine receptor for treatment of HE. The experience with these drugs in human HE is limited. In order to get an estimate of the efficacy of this type of drug in humans 20 consecutive episodes of HE in 17 patients with acute or chronic liver failure were treated with flumazenil. All patients entered into the study were encephalopathic for up to 120 hours and failed to respond to conventional therapy. After an observation period of 8 hours, 15 mg of flumazenil were infused intravenously over 3 hours. Before and after treatment patients were examined neurologically and the Glasgow coma scale was calculated. In addition, somatosensory evoked potentials were recorded. In 5 out of 11 episodes in 10 patients with fulminant hepatic failure and in 7 out of 9 episodes in 7 patients with cirrhosis an unequivocal amelioration of HE was observed. The response to treatment occurred very rapidly. After stopping treatment in 8 out of these 12 episodes HE worsened again after 2 to 4 hours. The favourable clinical response was also documented by improvement of somatosensory evoked potentials. In 5 of the 8 episodes not reacting to flumazenil patients had signs of increased intracranial pressure. These findings indicate that flumazenil may be valuable in treatment of acute HE occurring in fulminant hepatic failure or in decompensated cirrhosis.


Genome-wide estimation of gender differences in the gene expression of human livers: statistical design and analysis.
Gender differences in gene expression were estimated in liver samples from 9 males and 9 females. The study tested 31,110 genes for a gender difference using a design that adjusted for sources of variation associated with cDNA arrays, normalization, hybridizations and processing conditions. The genes were split into 2,800 that were clearly expressed (expressed genes) and 28,310 that had expression levels in the background range (not expressed genes). The distribution of p-values from the 'not expressed' group was consistent with no gender differences. The distribution of p-values from the 'expressed' group suggested that 8% of these genes differed by gender, but the estimated fold-changes (expression in males/expression in females) were small. The largest observed fold-change was 1.55. The 95% confidence bounds on the estimated fold-changes were less than 1.4 fold for 79.3%, and few (1.1%) exceed 2-fold. Observed gender differences in gene expression were small. When selecting genes with gender differences based upon their p-values, false discovery rates exceed 80% for any set of genes, essentially making it impossible to identify any specific genes with a gender difference.


Development and validation of a real-time PCR assay for a novel HTLV-1 tax sequence detection and proviral load quantitation.
A quantitative real-time PCR (qPCR) assay using SYBR Green dye was established in order to detect and quantify the proviral DNA of HTLV-1 in peripheral blood mononuclear cells (PBMCs). Primers were designed, and the assay was standardized to amplify a novel, conserved HTLV-1 tax region. Proviral load was normalized to the amount of cellular DNA by quantitation of the human albumin gene. Firstly, the qPCR was assessed determining the specificity, sensitivity, dynamic range and intra- and inter-assay reproducibility of the technique. The limit of detection as determined by PROBIT analysis using dilutions of the standard was 2.97 copies. The assay had an excellent dynamic range from 10⁵ to 10¹ copies per reaction and good intra- and inter-assay reproducibility, CVs less than 2%. Secondly, the performance of the qPCR was tested on 40 HTLV-1 seropositive individuals. Proviral load for HTLV-1 carriers ranged from 2.2×10² to more than 8.3×10⁴ copies/10⁶ PBMCs. The high sensitivity and wide dynamic range allowed the determination of a broad range of HTLV-1 proviral loads in infected individuals. This assay is a valuable alternative diagnostic tool when current available serological assays are insufficient. In addition, it will facilitate the study of the relationship between proviral load and pathogenesis.


Reasons for satisfaction with the use of the 52-mg levonorgestrel intrauterine system.
To assess the reasons to use, reasons they liked, satisfaction with, and possibilities of recommendation to other women of the levonorgestrel 52-mg intrauterine system (LNG-IUS) by users. A cross-sectional study was conducted at the University of Campinas, Campinas, Brazil from January to July 2021. We enrolled users who came to the clinic, and we applied a pre-tested structured questionnaire with open-ended questions. We performed descriptive analyses of the variables, assessing the level of satisfaction with, and the reasons regarding the possibility of continuing to use, the IUS. Of the 517 enrolled women, 251 (48%) were aged 35 years or older (mean age 33.9 ± 9.0 years), 276 (53%) were white, 14 (3%) were adolescents, 155 (30%) were nulligravidas, and 307 (59.4%) reported experiencing amenorrhea in the last 90 days. Common reasons why women liked to use the LNG-IUS included both the reduction of menstrual bleeding (419 women; 81%) and dysmenorrhea (290 women; 56.1%). Nine out of 10 users (517 women; 91%) were satisfied with the method, and the majority would recommend it to other women. We found a high satisfaction rate among LNG-IUS users mainly due to the reduction of both menstrual bleeding and dysmenorrhea.


Kinetics of photochromic reactions in condensed phases.
A review of kinetic data reported for a few organic photochromic systems is given. The kinetics of processes taking place in solid matrices and in crystals was briefly discussed. The effect of solid matrices manifests itself in the kinetics being controlled by distributions rather than by discrete rate constants. The photochromic reactions often require a substantial free volume to occur, hence they seldom take place in crystals without a destruction of the crystal lattice. The activation energies of thermally driven reactions are in this case related rather to crystal parameters than to the reactions themselves.


Process research: compare and contrast the recovery-orientated strengths model of case management and usual community mental health care.
The strengths model of case management (SMCM), which was developed by Rapp and Goscha through collaborative efforts at the University of Kansas, assists individuals with mental illness in their recovery by mobilizing individual and environmental resources. Increasing evidence has shown that the utilization of the SMCM improves outcomes, including increased employment/educational attainment, reduced hospitalization rates, higher self-efficacy, and hope. However, little is known about the processes through which the SMCM improves outcomes for mental health service users. This study explores the views of case workers and service users on their experience of providing or receiving the SMCM intervention. A qualitative design was employed using individual interviews with service users and case workers drawn from two study conditions: the SMCM group and the control group (treatment as usual). For both study conditions, service users were recruited by either centres-in-charge or case workers from integrated community centres for mental wellness (ICCMWs) operated by three non-governmental organizations (NGOs) in different districts of Hong Kong. Through purposeful sampling, 24 service users and 14 case workers from the SMCM and control groups joined the study. We used an inductive approach to analyse the qualitative data. We identified two overarching themes: service users' and case workers' (1) perceptions of the impacts of the interventions (SMCM and control group) and (2) experiences of the interventions, such as features of the interventions and the factors that facilitated the outcomes. The results showed that there were improvements in the functional recovery of the SMCM group in areas such as employment and family relationships, how self-identified goals were achieved, and how service users gained a better understanding of their own strengths and weaknesses. Regarding their experience of the interventions, participants in both the SMCM group and the control group reported that a good relationship between service users and case workers was vital. However, some concerns were raised about the use of SMCM tools, including the strengths assessment and the personal recovery plan (PRP) and the risk of case workers being subjective in the presentation of cases in group supervision sessions. The results were promising in terms of supporting the use of the SMCM, with some refinements, in mental health services for Chinese clients. The Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617001435370 , registered on 10/10/2017.


[Treatment of burns].
Because of the unsatisfactory results hitherto achieved in the bactericidal and bacteriostatic local therapy of burns, Betaisodona ointment was tested and, in view of its good effect, put to further therapeutic use. The advantages of the preparation, apart from the good local tolerance and absence of effect on metabolism, are the good bactericidal and tanning effects on the wound eschar. In no case were smearing coats observed; the necrotic skin remained dry and firm. Except in two patients with second degree burns, epithelization was not influenced by clinically visible infection. In third degree burns accumulation of exudate in the zone of demarcation was only observed in two cases. Bacteriological examinations of the wound surface revealed sterility in several cases; in the other patients the bacterial count did not exceed 10(5)/cm2. In view of the comparative tests, this result must be considered very positive. The above trial has, however, not made use of all testing possibilities. In further studies an iodine absorption test for determining the penetration depth as well as a bacterial count in the tissue will be developed. Furthermore the use of Betaisodona solution for instillation in the zone of demarcation will be examined.


Hydrogen peroxide induced chemokine production in the glia-rich cultured cerebellar granule cells under acidosis.
We have documented the time-dependent production of chemotactic cytokine, i.e., IL-8, in the extracellular fluid of astrocyte-rich cultured rat cerebellar granule cells under acidified conditions. In this paper, the mechanism of this production was evaluated based on the production of hydrogen peroxide (H2O2). Significant and time-dependent increases of cytosolic H2O2 were detected under acidosis in astrocyte-rich cultured cell. Upon exposure to 10 microM H2O2, significant levels of IL-8 appeared in the extracellular fluid of astrocyte-rich cells, although an initial transient increase of IL-8 was also seen in the intracellular space. Concurrently, after H2O2 exposure cell injury and a delayed increase of cytosolic Ca2+ levels were detected in astrocyte-rich cells. However, in the absence of extracellular Ca2+, the cell injury and the increase of IL-8 production were significantly attenuated. A synergistic effect of cyclosporine A (an inhibitor of the Ca2+/calmodulin-regulated protein phosphatase) and trifluoperazine (an inhibitor of phospholipase A2) on the suppression of H2O2-induced IL-8 production was clearly evident. These results suggest that extracellular acidosis induced Ca2+-dependent H2O2 production, which in turn stimulated IL-8 expression. which is regulated by the cytosolic Ca2+ cascade. Thus, the production of IL-8 from glia cells may have a role in regulating in the process of cell injury.


[Behaviour of a wild Saccharomyces cerevisae killer yeast and its isogenic sensitive one with respect to different nitrogen sources in mixed cultures].
Wine chemical composition is the outcome of complex chemosensory interactions that are difficult to predict because of the influences of many variables, like as yeast-yeast interactions. Killer phenomenon implicates the secretion of a toxic protein by some yeasts, that kill other yeasts called sensitive. The knowledge of the behaviour of killer-sensitive mixed cultures in aerobic conditions is useful to be related with the first stages of oenological fermentation. In these stages it can be defined the killer prevalence in the medium. Also, the use of cured plasmid mutants allows better comparisons. The objective was to analyse the mechanism of substrate competition in Saccharomyces cerevisiae killer strains and its sensitive cured plasmid mutant, using different nitrogen sources. When samples were incubated at the toxin inactivation temperature, the infraestimation of sensitive cells is avoided. Results obtained in co-cultures (50%K-50%S) show the role of the nitrogen source in killer activity. Results obtained with 10%K-90%S inoculum, show that there are another competence variables than the competitive exclusion model for killer yeasts.


Feasibility of PROMIS using computerized adaptive testing during inpatient rehabilitation.
There has been an increased significance on patient-reported outcomes in clinical settings. We aimed to evaluate the feasibility of administering patient-reported outcome measures by computerized adaptive testing (CAT) using a tablet computer with rehabilitation inpatients, assess workload demands on staff, and estimate the extent to which rehabilitation inpatients have elevated T-scores on six Patient Reported Outcomes Measurement Information System® (PROMIS®) measures. Patients (N = 108) with stroke, spinal cord injury, traumatic brain injury, and other neurological disorders participated in this study. PROMIS computerized adaptive tests (CAT) were administered via a web-based platform. Summary scores were calculated for six measures: Pain Interference, Sleep Disruption, Anxiety, Depression, Illness Impact Positive, and Illness Impact Negative. We calculated the percent of patients with T-scores equivalent to 2 standard deviations or greater above the mean. During the first phase, we collected data from 19 of 49 patients; of the remainder, 61% were not available or had cognitive or expressive language impairments. In the second phase of the study, 40 of 59 patients participated to complete the assessment. The mean PROMIS T-scores were in the low 50 s, indicating an average symptom level, but 19-31% of patients had elevated T-scores where the patients needed clinical action. The study demonstrated that PROMIS assessment using a CAT administration during an inpatient rehabilitation setting is feasible with the presence of a research staff member to complete PROMIS assessment.


Host biomarkers for early identification of severe imported Plasmodium falciparum malaria.
Severe imported P. falciparum malaria is a source of morbi-mortality in non-endemic regions. WHO criteria don't accurately classify patients at risk of complications. There is a need to evaluate new tools such as biomarkers to better identify patients with severe imported malaria. A case-control study was conducted in Barcelona, from January 2011-January 2021. Adult patients with microbiologically confirmed P. falciparum malaria were classified according to WHO criteria. Patients with imported non-malarial fevers were included as controls. In each group, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), soluble triggering receptor expressed on myeloid cells (sTREM-1), C-reactive protein (CRP) and platelets were measured and their concentrations were compared between groups. New groups were made with a modified WHO severity classification and biomarkers' performance was evaluated using multiple imputation models. 131 participants were included: 52 severe malaria, 30 uncomplicated malaria and 49 non-malarial fever cases. All biomarkers except sTREM-1 showed significant differences between groups. Using the modified WHO severity classification, Ang-2 and CRP presented the best AUROC; 0.79 (95%CI 0.64-0.94) and 0.80(95%CI 0.67-0.93). A model combining CRP and Ang-2 showed the best AUROC, of 0.84(95%CI 0.68-0.99), with the highest sensitivity and specificity: 84.6%(95%CI 58.9-98.1) and 77.4% (95%CI 65.9-87.7), respectively. The combination of Ang-2 and CRP may be a reliable tool for the early identification of severe imported malaria. The use of a rapid prognostic test including the mentioned biomarkers could optimize imported malaria management, with the potential to decrease the rate of complications and hospitalizations in patients with imported malaria.


[The bacterial cell wall and penicillin resistance: facts, questions and hopes].
The simplest conceivable event at the level of the gene can result in the emergence of antibiotic-resistant determinants. The bacterial world behaves as an enormous organism the cells of which exchange their genes with great ease and, likewise, the opportunities for the exchange of genetic material in nature is, probably, limitless. This knowledge cannot be ignored. It leads to the important conclusion that the antibiotics are societal drugs. A resistance gene which has appeared somewhere in the world can travel far and fast.


Evaluating of HPV-DNA ISH as an adjunct to p16 testing in oropharyngeal cancer.
Current guidelines recommend p16 immunohistochemistry (IHC) for testing human papillomavirus (HPV) in oropharyngeal carcinoma (OPSCC). We evaluated the value of adding DNA in situ hybridization (ISH) to p16 IHC. Fifty patients with OPSCC were analyzed. Concordance between HPV-DNA ISH and p16 IHC was measured by Gwet's agreement coefficient. p16 IHC was positive in 35/48 (72.9%), negative in 8/48 (16.7%) patients. Wide spectrum DNA-ISH was positive in 9/23 (39%) and negative in 14/23 (60.9%) patients. High-risk 16/18 (HR) HPV DNA-ISH was positive in 11/23 (47.8%) and negative in 12 (52.2%) patients. The agreement between HPV DNA-ISH and p16 IHC is fair (Gwet's AC1 = 0.318). The agreement between p16 IHC and HPV-DNA ISH was fair. However, ISH sensitivity was low. Our findings add to the current data that p16 IHC testing is reliable and may be enough as a stand-alone test for HPV detection in OPSCC.


Cost of hospitalisation for non-communicable diseases in India: are we pro-poor?
To estimate out-of-pocket (OOP) expenditure due to hospitalisation from NCDs and its impact on households in India. The study analysed nationwide representative data collected by the National Sample Survey Organisation in 2014 that reported health service utilisation and healthcare-related OOP expenditure by income quintiles and by type of health facility (public or private). The recall period for inpatient hospitalisation expenditure was 365 days. Consumption expenditure was collected for a recall period of 1 month. OOP expenditure amounting to >10% of annual consumption expenditure was termed as catastrophic. Weighted analysis was performed. The median expenditure per episode of hospitalisation due to NCDs was USD 149 - this was ~3 times higher among the richest quintile compared to poorest quintile. There was a significantly higher prevalence of catastrophic expenditure among the poorest quintile, more so for cancers (85%), psychiatric and neurological disorders (63%) and injuries (63%). Mean private-sector OOP hospitalisation expenditure was nearly five times higher than that in the public sector. Medicines accounted for 40% and 27% of public- and private-sector OOP hospitalisation expenditure, respectively. Strengthening of public health facilities is required at community level for the prevention, control and management of NCDs. Promotion of generic medicines, better availability of essential drugs and possible subsidisation for the poorest quintile will be measures to consider to reduce OOP expenditure in public-sector facilities.


The effect of baseline cognition and delirium on long-term cognitive impairment and mortality: a prospective population-based study.
There is an unmet public health need to understand better the relationship between baseline cognitive function, the occurrence and severity of delirium, and subsequent cognitive decline. Our aim was to quantify the relationship between baseline cognition and delirium and follow-up cognitive impairment. We did a prospective longitudinal study in a stable representative community sample of adults aged 70 years or older who were registered with a Camden-based general practitioner in the London Borough of Camden (London, UK). Participants were recruited by invitation letters from general practice lists or by direct recruitment of patients from memory clinics or patients recently discharged from secondary care. We quantified baseline cognitive function with the modified Telephone Interview for Cognitive Status. In patients who were admitted to hospital, we undertook daily assessments of delirium using the Memorial Delirium Assessment Scale (MDAS). We estimated the association of pre-admission baseline cognitive function with delirium prevalence, severity, and duration. We assessed subsequent cognitive function 2 years after baseline recruitment using the Telephone Interview for Cognitive Status. Regression models were adjusted by age, sex, education, illness severity, and frailty. We recruited 1510 participants (median age 77 [IQR 73-82], 57% women) between March, 2017, and October, 2018. 209 participants were admitted to hospital across 371 episodes (1999 person-days of assessment). Better baseline cognition was associated with a lower risk of delirium (odds ratio 0·63, 95% CI 0·45 to 0·89) and with less severe delirium (-1·6 MDAS point, 95% CI -2·6 to -0·7). Individuals with high baseline cognition (baseline Z score +2·0 SD) had demonstrable decline even without delirium (follow-up Z score +1·2 SD). However, those with a high delirium burden had an even larger absolute decline of 2·2 SD in Z score (follow-up Z score -0·2). Once individuals had more than 2 days of moderate delirium, the rates of death over 2 years were similar regardless of baseline cognition; a better baseline cognition no longer conferred any mortality benefit. A higher baseline cognitive function is associated with a good prognosis with regard to likelihood and severity of delirium. However, those with a high baseline cognition and with delirium had the highest degree of cognitive decline, a change similar to the decline observed in individuals with a high amyloid burden in other cohorts. Older people with a healthy baseline cognitive function who develop delirium stand to lose the most after delirium. This group could benefit from targeted cognitive rehabilitation interventions after delirium.


Assessment of low-dose paranasal sinus CT imaging using a new deep learning image reconstruction technique in children compared to adaptive statistical iterative reconstruction V (ASiR-V).
To compare the effects of deep learning image reconstruction (DLIR) and adaptive statistical iterative reconstruction V (ASiR-V) on image quality in low-dose computed tomography (CT) of paranasal sinuses in children. Low-dose CT scans of the paranasal sinuses in 25 pediatric patients were retrospectively evaluated. The raw data were reconstructed with three levels of DLIR (high, H; medium, M; and low, L), filtered back projection (FBP), and ASiR-V (30% and 50%). Image noise was measured in both soft tissue and bone windows, and the signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) of the images were calculated. Subjective image quality at the ethmoid sinus and nasal cavity levels of the six groups of reconstructed images was assessed by two doctors using a five-point Likert scale in a double-blind manner. The patients' mean dose-length product and effective dose were 36.65 ± 2.44 mGy·cm and 0.17 ± 0.03 mSv, respectively. (1) Objective evaluation: 1. Soft tissue window: The difference among groups in each parameter was significant (P < 0.05). Pairwise comparisons showed that the H group' s parameters were significantly better (P < 0.05) than those of the 50% post-ASiR-V group. 2. Bone window: No significant between-group differences were found in the noise of the petrous portion of the temporal bone or its SNR or in the noise of the pterygoid processes of the sphenoids or their SNRs (P > 0.05). Significant differences were observed in the background noise and CNR (P < 0.05). As the DLIR intensity increased, image noise decreased and the CNR improved. The H group exhibited the best image quality. (2) Subjective evaluation: Scores for images of the ethmoid sinuses were not significantly different among groups (P > 0.05). Scores for images of the nasal cavity were significantly different among groups (P < 0.05) and were ranked in descending order as follows: H, M, L, 50% post-ASiR-V, 30% post-ASiR-V, and FBP. DLIR was superior to FBP and post-ASiR-V in low-dose CT scans of pediatric paranasal sinuses. At high intensity (H), DLIR provided the best reconstruction effects.


Effects of antibodies against chicken riboflavin carrier protein on fetal hepatic cell ultrastructure.
Day 12 pregnant mice administered antibodies to cRCP exhibited riboflavin deprival, which resulted in progressive alteration in the fetal hepatic cell structure, which eventually led to fetal wastage and termination of pregnancy. These changes were evident as early as 1 h following antiserum treatment. Three hours following treatment, other degenerative changes such as disorganization of glycogen particles and endoplasmic reticulum and degranulation of mitochondria were observed. Nuclear pycnosis, and increased myelin figures, accumulation of lysosomes, all indicative of autolytic changes, occurred 6 h following treatment.


Dose response of inhaled gallopamil (D600), a calcium channel blocker, in attenuating airway reactivity to methacholine and exercise.
To determine if there is a dose-response relationship for calcium channel blockers in preventing experimentally induced bronchoconstriction, we evaluated the effects of inhaled gallopamil (D600), a potent methoxy derivative of verapamil, on airway reactivity to methacholine and exercise in volunteers with mild asthma. Methacholine challenges were completed by 11 subjects 2 hours before and 20 minutes after placebo, and 1, 2, 5, 10, and 20 mg of inhaled gallopamil administered in a single-blind, randomized manner on different days. Gallopamil did not significantly alter FVC, FEV1, or forced expiratory flow rate between 25% and 75% of FVC, but increased the dose of methacholine required to produce a 20% decrease in FEV1 from baseline (p less than 0.0001). The mean +/- SEM fold increase in the dose of methacholine required to produce a 20% decrease in FEV1 from baseline was 1.0 +/- 0.1 after placebo, 2.4 +/- 0.2 after 1 mg, 2.2 +/- 0.2 after 2 mg, 2.5 +/- 0.2 after 5 mg, 2.5 +/- 0.3 after 10 mg, and 2.3 +/- 0.2 after 20 mg. Thirty minutes before a standardized exercise challenge, 10 subjects inhaled 1 and 10 mg of gallopamil or placebo in a randomized, double-blind, crossover manner. The mean +/- SEM maximum decrease in FEV1 after exercise was 25.1 +/- 5% after 10 mg of gallopamil (p less than 0.01), 34.4 +/- 5% after 1 mg (p greater than 0.05), and 39.0 +/- 6% after placebo. We conclude that inhaled gallopamil only modestly alters airway reactivity to methacholine; increasing the dose greater than 1 mg did not provide greater benefit.(ABSTRACT TRUNCATED AT 250 WORDS)


In contrast to the nematode and fruit fly all 9 intron positions of the sea anemone lamin gene are conserved in human lamin genes.
We identified the single gene for nuclear lamin in the genome draft of the sea anemone Nematostella vectensis, a member of the cnidaria, a very old metazoan phylum. The gene consists of 10 exons and 9 introns. Strikingly all 9 intron positions are conserved in the human lamin B genes, which have only 1 (lamin B1) or 2 (lamin B2) additional introns. Using the information on neighboring genes we propose that the human lamin B1 gene on chromosome 5 is the true homolog of the Nematostella lamin gene, while the lamin B2 gene on chromosome 19 arose during vertebrate evolution. In marked contrast to this conservation of gene structure are the results in the rapidly evolving genomes of Drosophila and Caenorhabditis elegans. Here the lamin genes have much fewer introns and these occur often at novel positions. In the single nematode lamin gene and the Drosophila lamin Dmo gene no intron position coincides with an intron in the sea anemone lamin gene.


Debottlenecking product inhibition in 1,3-propanediol fermentation by In-Situ Product Recovery.
The present work describes the application of liquid-liquid extraction as an In-Situ product recovery (ISPR) technique to overcome the problem of product inhibition in 1,3-PD fermentation. As a part of initial screening experiments, six solvents were subjected to phase separation and biocompatibility tests to find the best extractant for in-situ removal of 1,3-PD from the bioreactor. These included tributylphosphate, ethyl acetate, butyl acetate, oleyl alcohol, oleic acid and hexanol. Of these, ethyl acetate was found to be the most suitable solvent for 1,3-PD extraction. Use of the selected extractant in continuous integrated fermentation-extraction was established by batch and fed-batch extractive fermentations which demonstrated a significantly improved 1,3-PD production of 35g/L and 74.5g/L, respectively. A steady state 1,3-PD concentration of 58g/L was obtained in continuous extractive system. Continuous cultivation with in-situ cell retention and in-situ 1,3-PD removal demonstrated a 5-fold enhancement in 1,3-PD productivity over non-extractive batch.


Reduction of visceral adipose tissue during weight loss.
The aims of the present study were to retrospectively: (1) compare how weight loss affects the reduction of adipose tissue from three different sites between men and women; and (2) to verify whether gender differences in the reduction of adipose tissue are influenced by changes in fat mass (FM) and initial levels of fat in different compartments. Double-blind randomized treatment with fenfluramine once daily coupled to a non-macronutrient specific energy restriction. Seventeen obese men (age 43.9+/-1.5 and body mass index (BMI) 34.3+/-0.7) and 17 obese women (age 41.2+/-1.2 and BMI 35.7+/-0.6). Subjects were given fenfluramine (60 mg) or placebo once daily and were also subjected to a non-macronurient specific energy restriction of -2.9 MJ/day (-700 kcal/day) for 15 weeks. Body weight, FM, fat-free mass (FFM), waist circumference, BMI, as well as visceral (VAT), subcutaneous abdominal (SAT) and thigh (TAT) adipose tissue were all significantly reduced. Men lost significantly more VAT (-41.6%) than SAT (-22.5%), or than TAT (-20.5%) while no site difference in fat loss was observed in women when changes were calculated as a percentage of initial levels. Men lost about twice as much fat from the VAT compartment than did women (P<0.05), even after having considered changes in FM as a potential covariate. In absolute values, TAT was reduced to a lesser extent in men than in women. However, when initial levels of respective fat depots were also taken into account, gender differences in VAT and TAT loss were no longer statistically significant. These results suggest that gender differences in VAT reduction during weight loss are independent of changes in FM. However, once initial levels of VAT are also taken into account, gender differences in the reduction of this tissue during weight loss are no longer apparent.


SCARA5 in bone marrow stromal cell-derived exosomes inhibits colorectal cancer progression by inactivating the PI3K/Akt pathway.
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer worldwide. Bone marrow stromal cells (BMSCs) play an essential role in tumor development by secreting exosomes. Scavenger receptor class A member 5 (SCARA5) is a newly identified tumor suppressor. This study aimed to investigate the effects of BMSCs-derived exosomes (BMSCs-Exos) on CRC development and to explore their regulatory mechanisms. BMSCs-Exos showed an oval-shaped, bilayer membrane structure. BMSCs-Exos inhibited growth and motility of CRC cells, while BMSCs-Exos with SCARA5 knockdown significantly promoted cell proliferation and movement. Exosomal SCARA5 also effectively suppressed colorectal tumor growth in mouse xenografts. Further analysis revealed that exosomal SCARA5 inhibited the phosphorylation of protein kinase B and phosphoinositide 3-kinase in both CRC cells and tumors. In conclusion, SCARA5 in BMSCs-Exos inhibited CRC progression by inactivating PI3K/Akt, thus suggesting the potential clinical application of SCARA5-containing BMSCs-Exos for CRC treatment.


Adverse dermatologic reactions to transdermal drug delivery systems.
Transdermal drug delivery systems are marketed in the United States for four different drugs, and others are in various stages of development. Cutaneous side effects occur frequently with these systems and sometimes necessitate discontinuation of therapy. This article will review these adverse reactions.


Suspected resistance of Ostertagia ostertagi in cattle to levamisole.
Observations on a beef cattle farm in Flanders led to the suspicion of resistance to levamisole in a strain of Ostertagia ostertagi. After treating a group of six animals with levamisole (5 mg kg-1 L.W., i.m.) the reduction in the number of trichostrongylid eggs per gram of faeces varied between 0 and 66.6%, whereas a similar group treated with fenbendazole (7.5 mg kg-1 L.W., p.o.) showed a reduction in worm burdens of 100%. Coproculture showed that the remaining eggs in the first treatment group were all Ostertagia sp. The suspected field strain was compared with a reference strain of O. ostertagi by means of the in vitro larval paralysis test. This test showed LC95 values of 9.12 micrograms ml-1 and of 99.04 micrograms ml-1 for the reference and the field strain respectively, which indicates a resistance factor for the latter of 10.9. These results were not unequivocally confirmed by the post mortem findings on a tracer calf necropsied 4 days after treatment with levamisole.


The effect of ageing on the rheological properties of gelatin gels.
The effect of ageing at 4 degrees on the viscoelastic properties of 1-5 and 2-0% acid and alkaline processed gelatin gels has been investigated. Viscoelastic properties were not markedly affected by ageing time although evidence of a decrease in gel structure with increasing ageing time was apparent. This has been tentatively attributed to hydrolysis of amide links. 1-5% alkaline gels were shown to be more rigid than the corresponding acid gels and this has been discussed in terms of differences in molecular weight, polydispersity, charge and charge distribution.


Benefits of prophylactic percutaneous gastrostomy in patients with nasopharyngeal cancer receiving concurrent chemoradiotherapy: A multicenter analysis.
Prophylactic percutaneous endoscopic gastrostomy (PPEG) is widely used for patients with head and neck cancer undergoing concurrent chemoradiation (CCRT). Nevertheless, the necessity of its use in patients with nasopharyngeal cancer (NPC) is uncertain. This study aimed to evaluate the benefits of PPEG on prevention of weight loss and treatment tolerance in patients with NPC receiving CCRT. A retrospective multicenter chart review of 904 patients, 378 in the PPEG group and 526 in the non-PPEG group, was conducted. Baseline characteristics, weight loss, and treatment tolerance were analyzed and compared between the two groups. There was no significant difference in the mean baseline body mass index (BMI) between the groups. At the end of CCRT, no difference in weight loss was found between the 2 groups (non-PPEG group, 6.6%; PPEG group, 5.9%). Nonetheless, the subgroup analysis demonstrated that a baseline BMI < 18.5 kg/m2 (underweight) and non-intensity-modulated radiation therapy (IMRT) technique were independent factors associated with prevention of weight loss by PPEG. More patients in the PPEG group were able to complete planned cycles of chemotherapy (73.3% vs. 49.0%, P < .0001). Although the benefits of PPEG on prevention of weight loss were not observed for the entire cohort, we found a potentially protective effect of PPEG in some subgroups of patients. Additionally, PPEG significantly enhanced chemotherapy tolerance. Therefore, PPEG tube insertion should be strongly considered for patients with NPC receiving CCRT, particularly for underweight patients and those undergoing a non-IMRT technique.


1H, 13C, 15N resonance assignments of the extracellular loop 1 domain (ECL1) of Streptococcus pneumoniae D39 FtsX, an essential cell division protein.
FtsX is an integral membrane protein from Streptococcus pneumoniae (pneumococcus) that harbors an extracellular loop 1 domain (FtsX(Spn)ECL1) that interacts with PcsB, an peptidoglycan hydrolase that is essential for cell growth and division. Here, we report nearly complete backbone and side chain resonance assignments and a secondary structural analysis of FtsX(Spn)ECL1 (residues 47-168 of FtsX) as first steps toward structure determination of FtsX(Spn)ECL1.


Preferential binding of E. coli with type 1 fimbria to D-mannobiose with the Manα1 → 2Man structure.
Manα1 → 2Man, Manα1 → 3Man, Manα1 → 4Man, and Manα1 → 6Man were converted to the glycosylamine derivatives. Then, they were mixed with monobenzyl succinic acid to obtain their amide derivatives. After removing the benzyl group by hydrogenation, the succinylamide derivatives were coupled with the hydrazino groups on BlotGlyco™ beads in the presence of water-soluble carbodiimide. d-Mannobiose-linked beads were incubated with fluorescence-labeled Escherichia coli with type 1 fimbria, and the number of the fluorescent dots associated with the beads was counted in order to determine the binding preference among d-mannobiose isomers. The results showed that the bacteria bind strongly to Manα1 → 2Man1 → beads, Manα1 → 3Man1 → beads, Manα1 → 4Man1 → beads, and Manα1 → 6Man1 → beads, in order. In the presence of 0.1 M methyl α-d-mannopyranoside, most of the bacteria failed to bind to these beads. These results indicate that E. coli with type 1 fimbria binds to all types of d-mannobiose isomers but preferentially to Manα1 → 2Man disaccharide.


Creating a secure clinical 'Bring Your Own Device' BYOD photography service to document and monitor suspicious lesions in the lid oncology clinic.
Ophthalmic examinations are mostly documented using sketches and written descriptions. Improvements in app security and IT infrastructure mean that high-quality anterior segment photographs can be routinely collected with smartphones alone. The lid oncology team relied on pre-operative formal slit-lamp imaging in the one-stop biopsy clinic, a lengthy process with capacity limitations, that risked delays to care. A Bring Your Own Device (BYOD) photography service was developed through a series of iterations and collaborations. Healthcare Assistants took photographs on iPhone SE with Quikvue lens attachments in Pando app. Lesions requiring a slit lamp were photographed by the doctor. Images were uploaded to the patient record twice weekly. The service was evaluated using time-motion studies, imaging quality and utility grading, and patient feedback. BYOD photography saved lid oncology patients 41 min (one-third of total appointment time) and reduced delays to treatment to zero. A patient survey reflected the acceptability of the service, with 100% feeling photography was important at every visit. In terms of utility, 97.5% of smartphone images were suitable for monitoring lesions and making management decisions. The management plan based on the smartphone photographs was consistent with the management plan formulated face-to-face in clinic in 92.5% images. BYOD photography has replaced formal slit-lamp imaging in the lid oncology service. This sustainable, cost-effective BYOD solution requires little training and can be adapted, reproduced, and scaled globally. BYOD photography can offer detailed records to monitor progress, contribute to remote care models, improve patient experience, and reducing medical error.


Elevated prostate-specific antigen levels up to 25 years prior to death from prostate cancer.
We tested the hypothesis that prostate-specific antigen (PSA) levels would be higher among prostate cancer deaths as compared with controls over time in the 25-year follow-up of the Multiple Risk Factor Intervention Trial of participants ages 35-57 at entry. The initial stored serum samples were collected in 1973-1975 and the mean length of follow-up to prostate cancer death was 17 years. There were 63 prostate cancer deaths and 63 controls matched by age, clinical site, and length of follow-up. The mean PSA level for prostate cancer decedents was 2.84 ng/ml as compared with 1.10 ng/ml for controls (P = 0.002 for difference). There were nine men who died from prostate cancer and no controls with PSA levels > 4 ng/ml. Risk of prostate cancer death increased with increasing PSA levels, with increased risk observed even at moderate levels of PSA. Many of those with high PSA levels in 1973-1975 died from prostate cancer many years after the elevated PSA. PSA levels measured from blood obtained before the introduction of widespread PSA testing were a strong predictor of prostate cancer death over 25 years of follow-up. Studies of prostate cancer etiology and chemoprevention need to focus on middle-aged or younger men with longer follow-up.


Postresuscitation myocardial dysfunction.
Postresuscitation myocardial dysfunction is common after prolonged cardiac arrest and can have life-threatening consequences. Experimental data suggest that systolic and diastolic left ventricular function can be adversely effected following successful resuscitation. Such dysfunction can resolve and represents true global myocardial stunning. Identified factors contributing to postresuscitation myocardial dysfunction include prolonged CPR, use of vasoconstricting drugs, and high-energy defibrillation. Potential treatments include dobutamine, KATP channel activators, and 21-aminosteroids. In the author's efforts to improve long-term survival from cardiac arrest, more attention is needed to the postresuscitation period.


LncRNA-LINC00460 facilitates nasopharyngeal carcinoma tumorigenesis through sponging miR-149-5p to up-regulate IL6.
Long non-coding RNAs (lncRNAs) have played crucial roles in various cancers, including nasopharyngeal carcinoma (NPC). In our study, we focused on the biological function and clinical significance of lncRNA LINC00460 in NPC. It was indicated that LINC00460 was markedly increased in NPC tissues and cells compared to their corresponding controls. Silencing LINC00460 was able to suppress NPC cell growth in vitro while overexpressing LINC00460 reversed this process. Moreover, in vivo tumor xenografts were established using CNE-1/SUNE-1 cells to detect the function of LINC00460 in NSCLC tumorigenesis. Rescue assay was performed to further confirm that LINC00460 contributed to the progression of NPC through regulating miR-149-5p/IL6 signal pathway. In conclusion, we have uncovered that LINC00460 could be regarded as a novel prognostic biomarker and therapeutic target in NPC diagnosis and treatment.


Disorder and Photogeneration Efficiency in Organic Semiconductors.
An analytical description of the separation probability of a geminate pair in organic semiconductors is given. The initial diffusion of "hot" twins is anomalously strong due to energy disorder. This circumstance significantly increases the photogeneration quantum yield at low temperatures and weakens its temperature dependence relative to predictions of the Onsager model, in agreement with Monte Carlo and experimental results.


Short-term effectiveness of spinal manipulative therapy versus functional technique in patients with chronic nonspecific low back pain: a pragmatic randomized controlled trial.
Chronic low back pain (LBP) is a prevalent condition associated with pain, disability, decreased quality of life, and fear of movement. To date, no studies have compared the effectiveness of spinal manipulation and functional technique for the management of this population. This study aimed to compare the effectiveness of spinal manipulation and functional technique on pain, disability, kinesiophobia, and quality of life in patients with chronic LBP. A single-blind pragmatic randomized controlled trial conducted in a university research clinic was carried out. Sixty-two patients (62% female, age: 45±7) with chronic LBP comprised the patient sample. Data on disability (Roland-Morris Disability Questionnaire [RMQ], Oswestry Low Back Pain Disability Index [ODI]), pain intensity (Numerical Pain Rate Scale [NPRS]), fear of movement (Tampa Scale of Kinesiophobia [TSK]), quality of life (Short Form-36 [SF-36] quality of life questionnaire), isometric resistance of abdominal muscles (McQuade test), and spinal mobility in flexion (finger-to-floor distance) were collected at baseline immediately after the intervention phase and at 1 month postintervention by an assessor blinded to group allocation of the patients. Patients were randomly assigned to the spinal manipulative therapy group or the functional technique group and received three once-weekly sessions. In comparison to patients receiving functional technique, those receiving spinal manipulation experienced statistically, although not clinically, significant greater reductions in terms of RMQ (standardized mean difference in score changes between groups at post-treatment: 0.1; at 1 month: 0.1) and ODI (post-treatment: 2.9; at 1 month: 1.4). Linear longitudinal analysis showed a significant improvement in both groups over time for RMQ (manipulative: F=68.51, p<.001; functional: F=28.58, p<.001) and ODI (manipulative: F=104.66, p<.001; functional: F=32.15, p=.001). However, significant treatment-by-time interactions were not detected for pain intensity (p=.488), TSK (p=.552), any domains of the SF-36 quality of life questionnaire (p≤.164), McQuade test (p=.512), and finger-to-floor distance (p=.194). Differences between and within groups were not clinically meaningful in any of the reported measures. In comparison to functional technique, spinal manipulative therapy showed greater reduction in disability in patients with chronic LBP, but not in terms of pain, fear of movement, quality of life, isometric resistance of trunk flexors, or spinal mobility. However, differences in disability were not clinically meaningful; therefore, spinal manipulative therapy did not result in any clinically important short-term benefits over functional technique therapy. In addition, as neither group met the threshold for minimum clinically important difference following treatment, neither treatment resulted in a clinically meaningful benefit.


[Peroxidase distribution pattern and cochlear microphonics in the impulse-noise exposed cochlea of the guinea pig (author's transl)].
Morphological findings evidenced the impulse noise trauma primarily a mechanical lesion of cells. The loss of mechanically damaged sensory cells results in the initial decline of cochlear microphonics. Due to mechanical lesions many sites of leakage in the wall of the cochlear duct give way to the diffusion of components of either lymph, which will produce a general functional disturbance associated with additional decline of microphonics. The functional restoration of the inner ear requires the previous repair of the endo/perilymphatic barrier.


Violence Against Women - A Global Perspective.
Gender-based violence (GBV) affects more than 700 million women and girls, worldwide, manifesting systemically (eg, human trafficking) and at the interpersonal level (eg, rape, intimate partner violence) and conveying significant negative economic, social, mental, and physical health impacts. It is important for the clinician to be prepared for providing emergency, urgent, and longer-term care to women who are survivors of GBV. Panzi Hospital in the Democratic Republic of the Congo provides an example of person-centered, holistic care for survivors of GBV, including conflict-related and nonconflict-related sexual violence.


Exposure to Head Impacts and Cognitive and Behavioral Outcomes in Youth Tackle Football Players Across 4 Seasons.
Repetitive head impacts have been posited to contribute to neurocognitive and behavioral difficulties in contact sport athletes. To identify associations between cognitive and behavioral outcomes and head impacts measured in youth tackle football players over 4 seasons of play. This prospective cohort study was conducted from July 2016 through January 2020, spanning 4 football seasons. The setting was a youth tackle football program and outpatient medical clinic. Players were recruited from 4 football teams composed of fifth and sixth graders, and all interested players who volunteered to participate were enrolled. Data analysis was performed from March 2020 to June 2021. Impacts were measured using helmet-based sensors during practices and games throughout 4 consecutive seasons of play. Impacts were summed to yield cumulative head impact gravitational force equivalents per season. Ten cognitive and behavioral measures were completed before and after each football season. There were 70 male participants aged 9 to 12 years (mean [SD] age, 10.6 [0.64] years), with 18 completing all 4 years of the study. At the post-season 1 time point, higher cumulative impacts were associated with lower self-reported symptom burden (β = -0.6; 95% CI, -1.0 to -0.2; P = .004). After correcting for multiple comparisons, no other associations were found between impacts and outcome measures. At multiple times throughout the study, premorbid attention-deficit/hyperactivity disorder, anxiety, and depression were associated with worse cognitive or behavioral scores, whereas a premorbid headache disorder or history of concussion was less often associated with outcomes. In this cohort of youth tackle football players, premorbid conditions, including attention-deficit/hyperactivity disorder, anxiety, and depression, were associated with cognitive and behavioral outcomes more often than cumulative impact.


DDR1 autophosphorylation is a result of aggregation into dense clusters.
The collagen receptor DDR1 is a receptor tyrosine kinase that promotes progression of a wide range of human disorders. Little is known about how ligand binding triggers DDR1 kinase activity. We previously reported that collagen induces DDR1 activation through lateral dimer association and phosphorylation between dimers, a process that requires specific transmembrane association. Here we demonstrate ligand-induced DDR1 clustering by widefield and super-resolution imaging and provide evidence for a mechanism whereby DDR1 kinase activity is determined by its molecular density. Ligand binding resulted in initial DDR1 reorganisation into morphologically distinct clusters with unphosphorylated DDR1. Further compaction over time led to clusters with highly aggregated and phosphorylated DDR1. Ligand-induced DDR1 clustering was abolished by transmembrane mutations but did not require kinase activity. Our results significantly advance our understanding of the molecular events underpinning ligand-induced DDR1 kinase activity and provide an explanation for the unusually slow DDR1 activation kinetics.


Transplantable human prostatic carcinoma (PC-82) in athymic nude mice: I. Hormone dependence and the concentration of androgens in plasma and tumor tissue.
This paper is the first part of a series of three describing a number of observations made on the PC-82 human prostatic carcinoma, xenografted into nude mice. The previously described androgen-dependence, one of the main properties of this tumor, has been the subject of subsequent studies. The impact of hormonal manipulation on the growth of the tumor and on plasma and tissue concentrations of androgens is discussed in this first part of the series. The great variability of plasma testosterone (T) levels in intact male mice (range: 1-90 nmol/liter) has been levelled out by the use of T-containing Silastic implants, resulting in levels ranging from 18 to 35 nmol/liter. Moreover, this route of administration also facilitated hormonal manipulation of tumor bearing mice. Androgen withdrawal from male mice with growing PC-82 tumors caused 80% tumor regression at ten weeks after androgen deprivation; the decline of the tumor volume followed a biphasic course. Delayed androgen substitution in castrated male mice grafted with PC-82 30 days before resulted in growth of the tumor tissue. This indicates that cells do not die and keep the capability to respond to androgens. It was concluded that the growth of the PC-82 tumor is not compatible with plasma T levels lower than 1 nmol/liter. Variable concentrations of endogenous T and dihydrotestosterone (DHT) were detected in total homogenates of PC-82 tumor tissue. Androgen withdrawal from T-implanted, tumor-bearing female mice caused a rapid reduction (90% within one day) of the tissue-T and a slower decline (up to 90% within seven to ten days) of tissue-DHT concentrations.


Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone. The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2 mg/kg). Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above-mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo. Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodone.


Gene mutation of thiopurine S-methyltransferase in Uygur Chinese.
This study was to investigate the gene mutation of thiopurine S-methyltransferase (TPMT) in Uygur Chinese. Polymerase chain reaction-based methods were used to analyze three commonly reported inactivating mutations-G238C, G460A and A719G. One TPMT*3A heterozygote and five TPMT*3C heterozygotes were found in 160 Uygur Chinese subjects, and allele frequencies of TPMT*3A and TPMT*3C were 0.3% and 1.6%, respectively. TPMT*3C is a common mutant allele in Uygur Chinese, while TPMT*3A is a rare mutant allele in Uygur Chinese.


Off to a good start after a cancer diagnosis: implementation of a time out consultation in primary care before cancer treatment decision.
Supportive care for cancer patients may benefit from improving treatment decisions and optimal use of the family physicians' and specialists' strengths. To improve shared decision-making (SDM) and facilitate continuity of primary care during treatment, a cancer care path including a "time out consultation" (TOC) in primary care before treatment decision, was implemented. This study assesses the uptake of a TOC and the added value for SDM. For patients with metastatic lung or gastro-intestinal cancer, a TOC was introduced in their care path in a southern region of The Netherlands, from April until October 2016. Uptake of a TOC was measured to reflect on facilitation of continuity of primary care. The added value for SDM and overall experiences were evaluated with questionnaires and semi-structured interviews among patients, family physicians, and specialists. Of the 40 patients who were offered a TOC, 31 (78%) had a TOC. Almost all patients, family physicians, and specialists expressed that they experienced added value for SDM. This includes a stimulating effect on reflection on choice (expressed by 83% of patients) and improved preparation for treatment decision (75% of patients). Overall added value of a TOC for SDM, only evaluated among family physicians and specialists, was experienced by 71% and 86% of these physicians, respectively. The first experiences with a TOC in primary care before cancer treatment decision suggest that it may help to keep the GP "in the loop" after a cancer diagnosis and that it may contribute to the SDM process, according to patients, family physicians, and specialists.


Stage sensitivity of eggs of the teleost Oryzias latipes to cadmium exposure.
The stage sensitivity of eggs of the teleost Oryzias latipes to cadmium exposure was examined. First, using eggs at the blastula stage, the proper concentration of cadmium to which the eggs should be exposed was estimated. The eggs were, therefore, exposed to cadmium solutions ranging from 10.0 to 300.0 mg Cd/liter for 1 hr, and then they were transferred to cadmium-free medium. The cumulative mortality of the eggs was estimated by counting dead eggs within 24 hr. Mortality (1.1 +/- 0.7%) indistinguishable from that of the control (1.0 +/- 0.2%) was obtained in the solution of 10.0 mg Cd/liter. Relatively higher mortalities of 13.2 +/- 1.5, 18.0 +/- 1.0, and 20.7 +/- 3.1% could be seen in the solutions containing 50.0, 100.0, and 150.0 mg Cd/liter, respectively. Moreover, the exposure of the eggs to 200.0 and 300.0 mg Cd/liter increased mortality rates to 32.0 +/- 0.8 and 34.7 +/- 2.4%, respectively. Consequently, the concentration of 200.0 mg Cd/liter was selected for examining the stage sensitivity. Eggs at 11 different developmental stages were exposed to cadmium at a concentration of 200.0 mg Cd/liter for 1 hr. The mortalities obtained at the 4- to 16-cell stage, 32-cell stage, and morula stage were 99.2 +/- 1.0, 97.4 +/- 2.6, and 89.6 +/- 10.6%, respectively. With the progress of embryonic development, the eggs became more resistant to cadmium toxicity. After the morula stage, the mortalities decreased abruptly. In order to ascertain whether the change in mortalities of the eggs with development was related to the amount of cadmium combined with the eggs, the cadmium content was determined. In contrast to the remarkable change in the stage sensitivity to cadmium, the curve of cadmium content in the eggs remained constant at about 520 ng/egg throughout the experimental period.


Effects of the mutant sigma allele rpoD800 on the synthesis of specific macromolecular components of the Escherichia coli K12 cell.
Escherichia coli K12 strains containing the mutant sigma allele rpoD800 are temperature-sensitive for growth. We have compared gene expression in isogenic rpoD+ and rpoD800 cells during steady-state growth and after temperature shift, in order to define the role of the sigma subunit in vivo. We have shown that sigma synthesis is regulated. After temperature shift-up, sigma behaves like other heat-shock proteins. The stimulation of sigma synthesis by heat shock is greater in mutant than in wild-type cells, possibly because the cell is responding to sigma limitation at high temperature by over-producing sigma. Mutant cells continue protein synthesis for a short time after shift-up and then shut off the synthesis of all proteins in response to the decreasing intracellular concentration of sigma. During the initial period of high protein synthesis, the relative expression of many proteins is changed in mutant cells. We argue that these changes are predominantly an indirect, rather than a direct effect of mutant sigma and are due to a change in the physiological state of mutant cells. Finally, we have shown that degradation of mutant sigma results in a decrease in synthesis of all major messenger RNA and stable RNA species. If other sigma factors are present in exponentially growing cells, they do not appear to be involved in a significant fraction of RNA synthesis.