Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms.
Mutations of the JAK2 gene are frequent aberrations in the aging hematopoietic system and in myeloid neoplasms. While JAK-inhibitors efficiently reduce hyperinflammation induced by the constitutively active mutated JAK2 kinase, the malignant clone and abundance of mutated cells remains rather unaffected. Here, we sought to assess for genetic vulnerabilities of JAK2-mutated clones. We identified lysine-specific demethylase KDM4C as a selective genetic dependency that persists upon JAK-inhibitor treatment. Genetic inactivation of KDM4C in human and murine JAK2-mutated cells resulted in loss of cell competition and reduced proliferation. These findings led to reduced disease penetrance and improved survival in xenograft models of human JAK2-mutated cells. KDM4C deleted cells showed alterations in target histone residue methylation and target gene expression, resulting in induction of cellular senescence. In summary, these data establish KDM4C as a specific dependency and therapeutic target in JAK2-mutated cells that is essential for oncogenic signaling and prevents induction of senescence.


Effect of topical dimethylarsinic acid on the expression of apoptosis-related proteins in mouse skin.
We investigated the effect of the topical application of dimethylarsinic acid (DMA) on skin thickness and the expression of several apoptosis-related proteins in skin. After administration of DMA during pregnancy, skin thickness and skin expression of Bcl-2, Bcl-3, Bad, Bid, and caspases-3, -6, -8, -9, and -12 were examined in dams and their offspring. DMA treatment caused significant increases in skin thickness (p < 0.05) and the expression of Bcl-2, Bad, and capase-12 in the skin of dams at the mRNA and protein levels (p < 0.01). However, maternal exposure to DMA did not significantly alter the expression of the studied apoptosis-related factors in the skin of the offspring. These findings indicate that DMA may induce skin apoptosis, in part, by modulating the expression of Bcl-2, Bad, and caspase-12 in maternal skin. Additionally, our results suggest that maternal exposure to DAM during pregnancy may not induce apoptosis in the skin of the offspring.


Effects of combination therapy with atenolol and amlodipine on blood pressure control and stroke prevention in stroke-prone spontaneously hypertensive rats.
To test the effects of atenolol and amlodipine, either alone or in combination, on blood pressure, blood pressure variability (BPV), baroreflex sensitivity (BRS), and the prevalence of stroke in stroke-prone spontaneously hypertensive rats (SHR-SP). In the first set of the study, 24 8-month-old, female SHR-SP rats were randomly divided into 3 groups. Blood pressure, heart period, and BRS were determined before and after the intragastric administration of atenolol (10 mg/kg) and amlodipine (1.0 mg/kg), either alone or in combination. In the second set of the study, 40 male and 40 female rats were randomly assigned to 1 of the following 4 groups: control, atenolol (10 mg.kg(-1).d(-1)), amlodipine (1.0 mg.kg(-1).d(-1)), and both (10 male and 10 female in each group). The stroke incident and survival time were recorded. Atenolol and amlodipine, either alone or in combination, significantly decreased blood pressure, with the exception of the amlodipine-induced effect on diastolic blood pressure. Meanwhile, only the combination treatment significantly decreased the BPV levels for the same period. The q-values calculated by the probability sum analysis were 1.17 and 2.67 for systolic and diastolic blood pressure, respectively, and were 2.48 and 2.10 for systolic and diastolic BPV, respectively, following administration. Neither drug exhibited any significant effect on BRS. Atenolol and amlodipine, either alone or in combination, significantly increased the lifespan of SHR-SP, with the best effect elicited by the combination therapy. A significant synergism exists between atenolol and amlodipine in lowering and stabilizing blood pressure in SHR-SP. Combination therapy may be an optimal strategy for the prevention of stroke in hypertension.


Modification of adenoviral vectors with polyethylene glycol modulates in vivo tissue tropism and gene expression.
Polyethylene glycol (PEG) is a hydrophilic polymer that has been used to coat adenoviral (Ad) vectors to improve their pharmacology. To analyze the effects of PEG on Ad5 tropism, Ad5 was covalently modified with different sizes of PEG and in vitro and in vivo transduction was analyzed. All tested PEGs ablated in vitro transduction. When protein C (PC) and factors VII, IX, and X were added, only factors IX and X increased transduction by the PEGylated vectors with the largest effect by X. Inactivation of these factors with warfarin drastically reduced liver transduction in mice by the PEGylated vectors after intravenous (i.v.) injection. Ad5 conjugated with 5 kd PEG maintained normal liver transduction while conjugation with larger 20 and 35 kd PEGs significantly reduced liver transduction. When intraperitoneal (i.p.) injection was tested, Ad transduced the peritoneum efficiently with only low level liver transduction. When Ad5 was modified with 5 kd PEG, peritoneal transduction was reduced and the virus preferentially transduced the liver. These data demonstrate the effects of different sizes of PEG on in vivo Ad tropism and suggest that this approach may be useful in retargeting and detargeting Ad in vivo.


[Clinical picture, treatment and prognosis of kidney pelvis and ureteral neoplasms].
It is reported on clinical and therapeutic measures in tumours of the upper urinary tracts. Diagnosis is often made too late, which, as we know, conditions a bad prognosis. Since we found malignant recidivations in papillomas and a stump recidivation in the carcinoma of the renal pelvis also in exclusive nephrectomy, we recommend the nephro-ureterectomy as a therapeutic measure.


Viscoelastic substances in ophthalmology.
The desirable properties of a viscoelastic substance for ophthalmologic applications are intimately tied to its chemical and rheologic properties. This report describes the relevant rheologic properties (e.g., viscosity, viscoelasticity, pseudoplasticity, cohesiveness, and coatability) of the available viscoelastic substances and presents the general principles of their use as well as some specific technical aspects. In addition, the various uses of viscoelastic substances in ophthalmic surgery are outlined. There is no single ideal substance for all circumstances. With a knowledge of the rheologic properties of each substance, the ophthalmologist will be able to choose among the different ones as necessary to suit each clinical situation.


The comparison of the effects of three physiotherapy techniques on hamstring flexibility in children: a prospective, randomized, single-blind study.
The aim of the study was to evaluate changes in hamstring flexibility in 120 asymptomatic children who participated in a 6-week program consisting of one physiotherapy session per week and daily home exercises. The recruitment criteria included age (10-13 years), no pain, injury or musculoskeletal disorder throughout the previous year, physical activity limited to school sport. Subjects were randomly assigned to one of the three groups: (1) post-isometric relaxation - PIR (n = 40), (2) static stretch combined with stabilizing exercises - SS (n = 40) and (3) stabilizing exercises - SE (n = 40). Hamstring flexibility was assessed with straight leg raise (SLR), popliteal angle (PA) and finger-to-floor (FTF) tests. The examinations were conducted by blinded observers twice, prior to the program and a week after the last session with the physiotherapist. Twenty-six children who did not participate in all six exercise sessions with physiotherapists were excluded from the analysis. The results obtained by 94 children were analyzed (PIR, n = 32; SS, n = 31; SE, n = 31). In the PIR and SS groups, a significant (P<0.01) increase in SLR, PA, FTF results was observed. In the SE group, a significant (P<0.001) increase was observed in the SLR but not in the PA and FTF (P>0.05). SLR result in the PIR and SS groups was significantly (P<0.001) higher than in the SE group. As far as PA results are concerned, a significant difference was observed only between the SS and SE groups (P = 0.014). There were no significant (P = 0.15) differences regarding FTF results between the three groups. Post-isometric muscle relaxation and static stretch with stabilizing exercises led to a similar increase in hamstring flexibility and trunk forward bend in healthy 10-13-year-old children. The exercises limited to straightening gluteus maximus improved the SLR result, but did not change the PA and FTF results.


Assessment of combustion residual leachate volume, composition, and treatment costs.
Combustion residuals and the resulting leachate from storage sites represent a large volume of wastewater in the United States (U.S.) that has not been quantified. This work estimates the constituents present, volume of wastewater, and costs of treatment for both combustion residual landfill leachate and the leachate from surface impoundment closures. Combustion residual landfill leachate produced from contact with bituminous coal combustion byproducts is generally predicted to be higher in lithium and manganese, whereas landfill leachate produced from contact with subbituminous coal combustion byproducts is generally predicted to be higher in mercury and vanadium. The annual volume of a single landfill with combustion residual leachate can reach more than 800,000 cubic meters. This leachate represents an annual volume of 26.8-42.8 million cubic meters nationally. Closing surface impoundments can yield between 830 and 1040 cubic meters of leachate nationally for a three-year closure period. Costs as low as $1.5/m3 or as high as $95/m3 are observed. Treatment trains will need to remove 72% of total suspended solids (TSS), 87% of arsenic, and 64% of mercury from landfill leachate. When applied to impoundments, these treatment trains would need to remove 97% of arsenic.


Cryptic mycotic abdominal aortic aneurysms: diagnosis and management.
The incidence of cryptic mycotic abdominal aortic aneurysms has relatively increased since antibiotic therapy has become available. The causative organism is the salmonella group in about 50 per cent of cases. This diagnosis should be strongly entertained in patients with fever of unknown origin, vague abdominal pain, and progressive appearance of a pulsatile abdominal mass. Aortography may be helpful in establishing the diagnosis. Some postoperative graft infections may be due to unrecognized cryptic mycotic infection of the aorta and not from external contamination, as previously supposed. Construction of an axillofemoral bypass graft through clean tissue is advised for the successful treatment of the grossly infected infrarenal aortic aneurysm. Three surviving patients with cryptic mycotic abdominal aortic aneurysms are added to the sixteen surviving patients already reported in the literature.


The cytoarchitecture and some efferent projections of the centromedian-parafascicular complex in the lesser bushbaby (Galago senegalensis).
The morphology of neurons in the centromedian (CM) and parafascicular (PF) nuclei in the lesser bushbaby (Galago senegalensis) is described in coronal and horizontal brain sections using Golgi-, horseradish peroxidase (HRP)-, and Nissl-staining procedures. The CM contains two types of cells referred to as principal neurons and Golgi type II (like) neurons. Cell bodies of principal neurons are relatively large in cross-sectional area (mean = 130.42 micron2), round to spindle in shape, support short somatic spines, and give rise to three to five primary dendrites. The dendrites branch in a "radiate" pattern and possess numerous appendages consisting of narrow, stalk-supported swellings. The presumed axons of these cells are impregnated only in their initial segments. On the basis of the similarity of principal neuron soma shapes and cross-sectional areas with those of HRP-reactive somata following cortical HRP implantation, it is concluded that at least some of the principal neurons in Galago CM project to somatic sensory-motor cortex. Golgi type II (like) neurons have small (mean = 79.43 micron2), round somata which support several spines and give rise to three to four small-diameter dendrites. The dendrites are infrequently branched, sinuous in their courses, and give rise to complex appendages and beaded processes. However, the axons of these cells could not be seen to ramify in the immediate vicinity of the dendritic field or soma, and there is considerable overlap in the cross-sectional areas of Golgi type II (like) neurons seen in Golgi preparations and HRP-stained cells following cortical implant of HRP pellets. Consequently, although Golgi type II (like) cells have traits characteristic of classically described intrinsic neurons, a cortical projection of these cells cannot be ruled out by the present study. The parafascicular nucleus contains two groups of large, radiate cells characterized by the presence or absence of somatic spines. Cells with somatic spines also contain numerous appendages on the dendrites. Cells without somatic spines support only a few, isolated, short dendritic appendages. Numerous small cell-bodied neurons are present in Nissl-stained sections of PF; however, cells which resemble Golgi type II neurons were not observed in the PF in the present Golgi-impregnated material. In contrast to the CM, the large cell-bodied neurons in PF were not found to project to somatic sensory-motor cortex in Galago.


Genome-wide systematic characterization and expression analysis of the phosphatidylinositol 4-phosphate 5-kinases in plants.
Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) are key enzymes in the process of phosphatidylinositol signaling pathway and have essential functions in growth, development, and biotic and abiotic stresses responses in plants. However, the evolutionary history and patterns of PIP5K genes in plants have not been examined systematically. Here, we use whole-genome sequences from eight plant species of land plants and algae to define the evolutionary relationships between these proteins in plants. 85 PIP5K genes were identified and divided into two subfamilies based on phylogenetic analyses. PIP5K members in subfamily II underwent several duplication events in land plants, resulting in multiple gene copies in angiosperms, while PIP5K members in subfamily I displayed low-copy numbers and lost in eudicots. Furthermore, PIP5K genes within the same subfamily had similar motifs and intron/exon features. Nine duplicated soybean gene pairs, four duplicated Arabidopsis gene pairs and two rice duplicated gene pairs were identified and many of them localized in synteny genomic regions. These duplicate events were formed by Whole-genome duplication (WGD)/segmental duplications. In addition, the ratios of non-synonymous to synonymous substitutions (Ka/Ks) showed that the PIP5K family had undergone purifying selection in higher plants. Expression analysis showed that PIP5K genes had complex and variable expression patterns in different developmental stages. The specificity of these genes is utilized to provide evidence for selective expression in the evolutionary process.


Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with advanced solid tumors.
This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical effects of volasertib, a selective Polo-like kinase inhibitor that induces mitotic arrest and apoptosis, in Japanese patients with advanced solid tumors (NCT01348347; 1230.15). In this phase I, open-label, dose-escalation trial, sequential patient cohorts (3 + 3 dose-escalation design) received volasertib (200-350 mg) as a single dose by intravenous infusion over 2 h on day 1 every 21 days until disease progression or unacceptable toxicity. The primary endpoint was the MTD of volasertib in Japanese patients with an advanced solid tumor; secondary endpoints included safety, pharmacokinetics, and clinical benefit. Fifteen patients with an advanced solid tumor were treated. Dose-limiting toxicities of grade 4 neutropenia for ≥7 days and grade 4 thrombocytopenia were both experienced by 2/6 patients in the 350 mg cohort. The MTD of volasertib in Japanese patients was 300 mg. The most common (≥3 patients) drug-related non-hematologic adverse events included fatigue, decreased appetite, and nausea. Exposure to volasertib and its metabolite increased with increasing doses. A partial response in a patient with gastric cancer and stable disease in eleven patients were observed. Volasertib had a manageable safety profile up to the MTD determined as 300 mg. Exposure to volasertib and its metabolite increased with increasing doses. The safety profile of volasertib in Japanese patients is comparable with those previously obtained in Caucasian patients. These data support enrollment of Japanese patients in global clinical trials without dose modification.


[Ethics and coma].
Advances in intensive care enable certain comatose patients to be kept alive, with the risk of them developing serious neurological sequelae. Ethical problems are therefore raised in the acute stage, with questions relating to the continuation of complex intensive care in a non-autonomous patient whose neurological condition remains unstable. The accuracy of the prognosis during the care may give rise to the possibility, in the event of an unfavourable evolution, of limiting or stopping treatments. This decision must take into account the family, be discussed collectively and assumed by the whole nursing team.


[Aetiology, symptoms and complications of a paediatric stroke].
In children, as in adults, a stroke corresponds to an acute neurological deficit, secondary to an injury to the cerebral parenchyma which may be of haemorrhagic or ischemic origin, or both. The term 'stroke' comprises a number of pathologies which are extremely heterogenous in terms of physiopathology, risk factors, clinical presentation, evolution and treatment.


Initial pulmonary metastasis after pancreatectomy for pancreatic ductal adenocarcinoma.
Patients who undergo pancreatectomy for pancreatic ductal adenocarcinoma (PDA) develop relatively early recurrence, but pulmonary metastasis from PDA is rare. Between January 2008 and December 2016, a total of 120 consecutive patients underwent pancreatectomy for primary PDA at Osaka Medical College Hospital. Among these, 13 patients developed pulmonary metastasis and 6 patients underwent pulmonary metastasectomy. Among these patients, the median disease-free survival following initial pancreatic surgery was 26.1 months, and the median overall survival (OS) interval was 39 months. On the other hand, seven patients did not undergo pulmonary resection. The median OS interval of these patients was 33 months. The 1-, 3-, and 5-year OS rates were 100%, 80%, and 60%, respectively, for patients who underwent pulmonary metastasectomy and 100.0%, 42.8%, and 0%, respectively, for those who did not undergo the procedure. Our experience has shown that surgical resection may lengthen the survival time of patients who tolerate surgery.


Prevalence of adverse reactions to food in Germany - a population study.
A population study was performed to identify the prevalence of all kinds of adverse reactions to food. In a representative cross-sectional survey performed in 1999 and 2000 in Berlin, 13 300 inhabitants of all ages were addressed by questionnaire. This questionnaire was answered by 4093 persons. All respondents mentioning any sign of food intolerance or the existence of allergic diseases (n = 2298) were followed up by telephone and, in case food intolerance could not be ruled out by patient history, were invited to attend to the clinic for personal investigation including double-blind, placebo-controlled food challenge tests (DBPCFC). The self-reported lifetime prevalence of any adverse reaction to food in the Berlin population (mean age 41 years) was 34.9%. Eight hundred and fourteen individuals were personally investigated according to the guidelines. The point prevalence of adverse reactions to food confirmed by DBPCFC tests in the Berlin population as a mean of all age groups was 3.6% (95% confidence interval [3.0-4.2%]) and 3.7% in the adult population (18-79 years, 95% confidence interval [3.1-4.4.%]). Two and a half percent were IgE-mediated and 1.1% non-IgE-mediated, females were more frequently affected (60.6%). Based on a statistical comparison with available data of adults from the nationwide German Health Survey from 1998, adverse reactions to food in the adult population of Germany (age 18-79) were calculated with 2.6% [2.1-3.2%]). The study gives for the first time information about the point prevalence of both immunological and nonimmunological adverse reactions to food and underlines the relevance of this issue in public health. The data also show that an individualized stepwise approach including provocation tests is mandatory to confirm the diagnosis.


Primary hypertrophic osteoarthropathy: ultrasound and MRI findings.
Primary hypertrophic osteoarthropathy is a rare genetic disorder related to failures in prostaglandin metabolism. Patients present with joint pain, limb enlargement, skin thickening and finger clubbing. Radiographs show characteristic periosteal reaction and thickening along the long bones. We present MRI and US findings in a child with the condition. Ultrasound showed echogenic tissue surrounding the long bones, presumably reflecting oedema and inflammatory tissue. Doppler sonograms demonstrated increased vascularity on the surface of some superficial bony structures.


Aimed movements to visual targets in hemiplegic and normal children: is the "good" hand of children with infantile hemiplegia also normal?
The accuracy, reaction and movement time of pointing movements to visual targets were examined in children aged 3-13 yr with infantile hemiplegia and compared to those of comparably aged normal children. Hemiplegic children pointed with the "good" hand (i.e. ipsilateral to the lesion). Half the normal children used the preferred hand, half the non-preferred hand. Movements were made with unrestricted/restricted visual feedback, when movement distance was short/medium/long, and when number of target alternatives were 2/4/8. Normal children using the preferred hand were more accurate but reacted more slowly than children using the non-preferred hand. The performance of most of the hemiplegic children with bilateral and/or unilateral lesions was impaired; degree of accuracy was related to the extent of the brain lesion; and reaction time was related to the level of intelligence. It was concluded that unilateral lesions in children can result in bilateral visuomotor impairment.


Transcapillary exchange of indium 111-labeled anticardiac myosin Fab and thallium 201 in isolated reperfused rabbit hearts.
The physiologic mechanisms of 111In-labeled anticardiac myosin antibody [111In]-AM) imaging are fairly well established. However, to better understand the transcapillary exchange characteristics of normal and reperfused myocardium, a standard first-pass, indicator-dilution analysis was undertaken in hearts subjected to global no-flow and low-flow ischemia. The first-pass myocardial transport of 201Tl and [111In]-AM was evaluated in an in vitro rabbit model of no-flow ischemia/reperfusion with indicator-dilution analysis during normal and ischemic flows and whole-blood perfusate. The maximum extraction fraction (Emax) of 201Tl was dominated by flow rate as expected and averaged 0.75 (+/- 0.009) and 0.57 (+/- 0.008) during ischemic and normal flows, respectively (p < 0.01). Emax values for [111In]-AM, which were 0.02 or less in all hearts at control, increased to 0.06 or greater at moderate to longer perfusion times after 50 or more minutes of no-flow ischemia. Permeability surface area (in milliliters per minute per gram) tended to decline for 201Tl with longer reperfusion periods in both ischemic and normal flow groups and paralleled the changes observed for Emax for [111In]-AM. These data demonstrate that the first-pass extraction of [111In]-AM is quite low in this model of acute coronary occlusion and reflow and enhanced only in severe ischemia-reperfusion treatment. Therefore in this model there appears to be no significant [111In]-AM uptake in either normal or mildly ischemic myocardium. Consequently, [111In]-AM uptake into myocardium must depend on tracer recirculation, as well as sarcolemmal cell wall disruption, to achieve specific and sufficient [111In]-AM uptake for localization of clinical imaging.


Adherence to Current COPD Guidelines in Turkey.
INTRODUCTION-OBJECTIVE: Despite the availability of national and international guidelines, chronic obstructive pulmonary diseases (COPD) treatment is not always prescribed according to these recommendations. We aimed to see if COPD patients in Turkey have been treated appropriately according to COPD guidelines. This is a cross-sectional study carried out in six different chest diseases clinics. The COPD outpatients were categorized by spirometry classification (SC) and the combined classification (CC) of COPD. The treatment protocols were evaluated to check whether they were suitable for both classifications. Overall, 307 patients were included in the study. Of the treatment protocols, 40.4% were suitable for both classifications: 30.9% for CC and 20.8% for SC. A total of 51.8% of the patients were reported to be using an unsuitable therapy for SC and 38.4% for CC. Ninety-eight per cent of the unsuitable treatment was overtreatment. Fifty-eight per cent of the patients were using LABA + LAMA + ICS. Improper ICS usage was identified in 97.1% in CC, 93.1% in SC. The cost savings of all patients in one year would be 17,099$ with an appropriate treatment protocol following COPD guidelines. The most common type of inappropriate COPD treatments is overtreatment, generally with ICS. As treatment protocols following COPD guidelines change over time, there is still a low rate of adherence by clinicians in their clinical practice to guideline recommendations. Awareness of these guidelines by pulmonary specialists should be improved.


PROMO: detection of known transcription regulatory elements using species-tailored searches.
We have developed a set of tools to construct positional weight matrices from known transcription factor binding sites in a species or taxon-specific manner, and to search for matches in DNA sequences.


Microsomal prediction of in vivo clearance and associated interindividual variability of six benzodiazepines in humans.
The intrinsic clearances (CLint) of midazolam, triazolam, diazepam, nordiazepam, flunitrazepam and alprazolam were determined from two liver banks (n=21) by formation kinetics of ten metabolites. A literature-collated database of in vivo CLint values (811 subjects) was used to assess predictions and variability. The in vivo clearance of six benzodiazepines was generally underpredicted by in vitro data and the degree of bias was in agreement with a database of structurally diverse compounds (n=37). The variability observed for in vitro clearances (11--19--fold for midazolam, diazepam and nordiazepam in liver bank 1; 101--269--fold for triazolam, flunitrazepam and alprazolam in liver bank 2) exceeded the in vivo variability for the same compounds (4--59 and 10--29, respectively). This mismatch may contribute to the bias in microsomal predictions and it highlights the need for careful selection of representative livers for human liver banks.


A pan-cancer analysis of the role of hexokinase II (HK2) in human tumors.
More and more evidence show that HK2 is closely related to tumors. But no pan-cancer analysis is available. This paper aimed to explore the potential roles of HK2 across thirty-three tumors based on the datasets of the cancer genome Atlas (TCGA) and gene expression omnibus. HK2 is highly expressed in most tumors and related to the progression of some tumors. HK2 expression was associated with the infiltration of T follicular helper cells for the TCGA tumors of uveal melanoma, breast invasive carcinoma (BRCA), breast invasive carcinoma-luminalA (BRCA-LumA), head and neck squamous cell carcinoma (HNSC), head and neck squamous cell carcinoma with HPV positive (HNSC-HPV+), and cancer-associated fibroblasts for the tumors of brain lower grade glioma and stomach adenocarcinoma. Our first pan-cancer study offers a relatively comprehensive understanding of the roles of HK2 in different tumors.


Multiple modes of cytoplasmic dynein regulation.
In performing its multiple cellular functions, the cytoplasmic dynein motor is subject to complex regulation involving allosteric mechanisms within the dynein complex, as well as numerous extramolecular interactions controlling subcellular targeting and motor activity. Recent work has distinguished high- and low-load regulatory modes for cytoplasmic dynein, which, combined with a diversity of targeting mechanisms, accounts for a very broad range of functions.


Dynamical indicators in time series of healthcare expenditures predict mortality risk of older adults following spousal bereavement.
The process of aging renders older people susceptible for adverse outcomes upon stress. Various indicators derived from complex systems theory have been proposed for quantifying resilience in living organisms, including humans. We investigated the ability of system-based indicators in capturing the dynamics of resilience in humans who suffer the adversity of spousal bereavement and tested their predictive power in mortality as a finite health transition. Using longitudinal register data on weekly healthcare consumption of all Danish citizens over the age of 65 from January 1st, 2011, throughout December 31st, 2016, we performed statistical comparisons of the indicators 'average', 'slope', 'mean squared error', and 'lag-1 autocorrelation' one year before and after spousal bereavement, stratified for age and sex. The relation between levels of these indicators before bereavement and mortality hazards thereafter was determined by time to event analysis. We assessed the added value for mortality prediction via the time dependent area (AUC) under the receiver operating characteristic curve. The study included 934,003 citizens of whom 51,890 experienced spousal bereavement and 2862 died in the first year thereafter. Healthcare consumption is increased, more volatile and accelerating with aging and in men compared to women (all p-values < 0.001). All dynamic indicators before bereavement were positively related with mortality hazards thereafter (all p-values < 0.001). The average discriminative performance for the 1-year mortality risk of the model with only age as a predictor (AUC: 68.9% and 70.2%) was significantly increased with the addition of dynamical indicators (78.5% and 82.4%) for males and females, respectively. Dynamic indicators in time series of health care expenditures are strong predictors of mortality risk and could be part of predictive models for prognosis after life stressors, such as bereavement.


The transport of pteridines in CCRF-CEM human lymphoblastic cells.
The transport routes used by CCRF-CEM human lymphoblastoid cells for the influx and efflux of unconjugated pteridines were analyzed using [3H]6-hydroxymethylpterin as a model compound. Influx proceeds by a mechanism that exhibits a Km of 66.7 microM and a Vmax of 0.077 nmol/min per mg cellular protein. The process is somewhat sensitive to metabolic inhibitors, particularly uncouplers of oxidative phosphorylation, and is significantly affected by the presence of other pteridines in the extracellular medium. The results suggest that pterins with either no 6-substituent (pterin) or those with methyl, hydroxyl, or formyl groups in this position, which exhibit Ki values between 25 and 77 microM, may share the same pathway for uptake. 6-Carboxypterin exhibits low affinity for the system (Ki greater than 500 microM), as do 7-substituted and 6,7-di-substituted derivatives and compounds with larger groups at the 6-position, such as neopterin and biopterin (Ki = 250-300 microM). Efflux of [3H]6-hydroxymethylpterin occurs rapidly and can proceed by at least two routes. The first, comprising approximately 50% of total efflux, is inhibited by extracellular pterins and exhibits similar properties to the uptake system in both its pattern of sensitivity to metabolic inhibitors and its specificity for pteridine structure. The route by which the remaining efflux occurs is relatively insensitive to metabolic inhibition. Adenine significantly inhibits 6-hydroxymethylpterin influx and efflux (Ki = 10.6 microM for uptake) but does not appear to share the same transport system. Similarly, methotrexate and folic acid exhibit little affinity for the unconjugated pteridine transport routes.


Optimizing Value in the Evaluation of Chronic Spontaneous Urticaria: A Cost-Effectiveness Analysis.
Chronic spontaneous urticaria (CSU) affects approximately 1% of the general population. The cost-effectiveness of routine laboratory testing for secondary causes of CSU has not been formally evaluated. To characterize the cost-effectiveness of routine laboratory screening in adults with CSU. A Markov model using cohort analysis and microsimulations was created for adult patients aged 20 years, over a 10-year time horizon, randomized to receive screening laboratory testing or a no-testing approach. Laboratory results were derived from a previously published retrospective analysis of adult patients with CSU. Cost-effectiveness was evaluated at a willingness to pay threshold of $100,000/quality-adjusted life-year using the incremental cost-effectiveness ratio (ICER) in patients with untreated CSU, and patients treated with antihistamines, cyclosporine, or omalizumab. Average laboratory costs per simulated patient with CSU were $573 (standard deviation [SD], $41), with only 0.16% (SD, 3.99%) of tests resulting in improved clinical outcomes. Testing costs per laboratory-associated positive outcome were $358,052 (no therapy), $357,576 (antihistamine therapy), $354,115 (cyclosporine), and $262,121 (omalizumab). Screening tests were not cost-effective, with ICERs of $856,905 (no therapy), $855,764 (antihistamine therapy), $847,483 (cyclosporine), and $627,318 (omalizumab). In the omalizumab-treated subgroup, testing could be cost-effective below $220 or if it resulted in a 0.73% rate of CSU resolution. From a simulated US population perspective, nation-wide screening costs could reach $941,750,741 to $1,833,501,483. In CSU, the likelihood of clinical improvement from laboratory testing is very low, and testing is not cost-effective. These data support recommendations to not routinely perform laboratory testing in patients with CSU with otherwise normal histories and physical evaluations.


Fever control using external cooling in septic shock: a randomized controlled trial.
Fever control may improve vascular tone and decrease oxygen consumption, but fever may contribute to combat infection. To determine whether fever control by external cooling diminishes vasopressor requirements in septic shock. In a multicenter randomized controlled trial, febrile patients with septic shock requiring vasopressors, mechanical ventilation, and sedation were allocated to external cooling (n = 101) to achieve normothermia (36.5-37°C) for 48 hours or no external cooling (n = 99). Vasopressors were tapered to maintain the same blood pressure target in the two groups. The primary endpoint was the number of patients with a 50% decrease in baseline vasopressor dose after 48 hours. Body temperature was significantly lower in the cooling group after 2 hours of treatment (36.8 ± 0.7 vs. 38.4 ± 1.1°C; P < 0.01). A 50% vasopressor dose decrease was significantly more common with external cooling from 12 hours of treatment (54 vs. 20%; absolute difference, 34%; 95% confidence interval [95% CI], -46 to -21; P < 0.001) but not at 48 hours (72 vs. 61%; absolute difference, 11%; 95% CI, -23 to 2). Shock reversal during the intensive care unit stay was significantly more common with cooling (86 vs. 73%; absolute difference, 13%; 95% CI, 2 to 25; P = 0.021). Day-14 mortality was significantly lower in the cooling group (19 vs. 34%; absolute difference, -16%; 95% CI, -28 to -4; P = 0.013). In this study, fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock.


Predictors of Acute Radiation Dermatitis and Esophagitis in African American Patients Receiving Whole-Breast Radiation Therapy.
Adjuvant whole breast radiation therapy after breast-conserving surgery is the standard of care in the management of early-stage breast cancer. Two of the most common acute toxicities of breast radiation therapy are radiation esophagitis (RE) and radiation dermatitis (RD). African American individuals are at higher risk for experiencing treatment-related toxic effects and are often underrepresented in clinical trials. An institutional database was developed to include all African American patients with a history of breast cancer or ductal carcinoma in situ undergoing adjuvant radiation therapy at a single institution from 2013 to 2019. Records were reviewed to identify patient age, body mass index (BMI), radiation dose, prone versus supine position, inclusion of boost, and inclusion of regional nodal irradiation. Radiation treatment plans were reviewed to identify breast size as well as dosimetric parameters to the breast and esophagus. Medical records were reviewed to identify which patients were prescribed Silvadene or Mylanta-lidocaine during or immediately after their course of radiation therapy, which was used as a surrogate for grade 2 (G2) or higher RD or RE, respectively. A total of 272 patients were included in the final analysis. On univariable analysis, patients with morbid obesity were more likely to develop G2RD, whereas hypofractionated radiation therapy was associated with lower rates of G2RD. On multivariable analysis, greater breast volume was associated with higher rates of G2RD. In the subset of patients receiving regional node irradiation, 19% of the patients experienced G2RE, and the best predictor on multivariable analysis was the mean radiation dose (Dmean) to the esophagus. Radiation dermatitis and esophagitis are common toxic effects in African American patients undergoing adjuvant breast radiation therapy. In this study, greater breast size, irrespective of the patient's BMI, was associated with a higher rate of dermatitis. Prone positioning during treatment and hypofractionated radiation reduced rates of G2RD. The Dmean to the esophagus was the dosimetric parameter most correlated with G2RE. These results may be used to help select patients at higher risk for toxic effects of G2 or greater during radiation therapy.


The effect of wait times on oncological outcomes from periampullary adenocarcinomas.
Overall few patients presenting with periampullary adenocarcinomas have resectable lesions. We postulated that rapid diagnosis and treatment would enhance the likelihood of successful resection, improving survival. A retrospective analysis of patients undergoing surgery for resection of a pancreatic or periampullary lesion was conducted. Resection rate, disease stage and survival were evaluated as a function of wait times. Pancreatic resections were booked in 355 patients. Of 193 patients with periampullary adenocarcinomas, 119 patients (61.7%) had resectable disease. There was no difference in median time from initial physician consultation to surgery in patients with resectable and unresectable disease (61 days vs. 64 days, respectively). The likelihood of successful resection was virtually identical in patients with wait times ≤ 30 and > 30 days (from surgical consultation to procedure). There was a trend toward a higher T-stage in patients who waited >30 days for surgery (P = 0.055). However, there was no difference in survival as a function of wait time. This series does not demonstrate an advantage for rapid diagnosis and surgery, in terms of resection rate and survival. However, further study is required in a larger cohort of patients, to confirm these findings.


Re-operations after Secondary Bariatric Surgery: a Systematic Review.
This paper reviews reoperations rates for short- and long-term complications following secondary bariatric procedures and need for further bariatric surgery. The search revealed 28 papers (1317 secondary cases) following at least 75 % of patients for 12 months or more. For adjustable gastric banding (AGB), rebanding had higher re-revisional rates than conversions into other procedures. Conversion of AGB to Roux-en-Y gastric bypass had the highest number of short- (10.7 %) and long-term (22.0 %) complications. We estimated 194 additional reoperations per 1000 patients having a secondary procedure, 8.8 % needing tertiary surgery. Despite being poorly reported, risks of reoperations for long-term complications and tertiary bariatric surgery are higher than usually reported risks of short-term complications and should be taken into account when choosing a secondary bariatric procedure and for economic evaluations.


Identification and genetic characterization of Trypanosoma congolense in domestic animals of Fontem in the South-West region of Cameroon.
To understand the circulation and the spread of Trypanosoma congolense genotypes in animals of Fontem in the southwest region of Cameroon, T. congolense forest and T. congolense savannah were investigated in 397 domestic animals in eight villages. Out of the 397 domestic animals, 86 (21.7%) were found infected by trypanosomes, using the capillary tube centrifugation test. The PCR with specific primers identified 163 (41.1%) and 81 (20.4%) animals infected by T. congolense forest and T. congolense savannah, respectively; showing for the first time the circulation of T. congolense savannah in the Fontem region. No infection with T. congolense savannah was found in pigs whereas goats and sheep were infected by T. congolense forest and/or T. congolense savannah. The prevalence of trypanosomes varied significantly amongst villages and animal species. The genotyping of T. congolense forest positive samples using microsatellites markers showed that multiple genotypes occurred in 27.2% (44/163) of animals sampled, whereas single genotypes were found in 73.8% (119/163) of samples. Some alleles were found in all animal species as well as in all villages and were responsible for major genotypes, whereas others (rare alleles) were identified only in some animals of few villages. These rare alleles were characteristic of specific genotypes, assimilated to minor genotypes which can be spread in the region through tsetse flies. The microsatellite markers show a low genetic variability and an absence of sub-structuration within T. congolense forest. The analysis of the microsatellite data revealed a predominant clonal reproduction within T. congolense forest. Pigs were the animal species with the highest number of different genotypes of T. congolense forest. They seem to play an important epidemiological role in the propagation and spread of different genotypes of T. congolense.


Genetic Diversity in Mycobacterium tuberculosis Clinical Isolates and Resulting Outcomes of Tuberculosis Infection and Disease.
Tuberculosis claims more human lives than any other bacterial infectious disease and represents a clear and present danger to global health as new tools for vaccination, treatment, and interruption of transmission have been slow to emerge. Additionally, tuberculosis presents with notable clinical heterogeneity, which complicates diagnosis, treatment, and the establishment of nonrelapsing cure. How this heterogeneity is driven by the diversity ofclinical isolates of the causative agent, Mycobacterium tuberculosis, has recently garnered attention. Herein, we review advances in the understanding of how naturally occurring variation in clinical isolates affects transmissibility, pathogenesis, immune modulation, and drug resistance. We also summarize how specific changes in transcriptional responses can modulate infection or disease outcome, together with strain-specific effects on gene essentiality. Further understanding of how this diversity of M. tuberculosis isolates affects disease and treatment outcomes will enable the development of more effective therapeutic options and vaccines for this dreaded disease.


Clinical significance of kallikrein-related peptidase (KLK10) mRNA expression in colorectal cancer.
Colorectal cancer (CRC) is one of the three most common cancers in both genders. Even though several biomarkers are in use in diagnosis and prognosis of the disease, they are marred by limited specificity and sensitivity. The human kallikrein-related peptidase 10 (KLK10) gene is a member of the human tissue kallikrein family. Because prostate specific antigen (PSA), the best biomarker for detecting and monitoring prostate cancer, is a member of this family, many other members, including KLK10, have been widely examined as novel biomarkers for different cancer types. In previous studies, KLK10 has been proposed as a diagnostic biomarker for ovarian carcinoma, while its methylation on exon 3 has been proposed as a prognostic marker for early-stage breast cancer patients. The purpose of this study was to analyse KLK10 mRNA expression and examine its prognostic value and potential clinical application as a novel molecular tissue biomarker in CRC. The study group consisted of 190 colorectal samples. Total RNA was extracted from pulverised tissues and cDNA was prepared by reverse transcription. KLK10 was amplified by real-time PCR. B2M was used as a reference gene and HT-29 cells as positive control. KLK10 expression was significantly higher in cancer tissues (P<0.001). Tumours of advanced TNM and Dukes' stage showed high KLK10 expression status (P=0.036; P=0.025). Patients with high KLK10 expression had a shorter disease-free and overall survival rates (P=0.014; P=0.020). Our results suggest that KLK10 may serve as a new marker of unfavourable prognosis of colorectal cancer.


Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2.
TCR signaling leading to thymocyte apoptosis is mediated through the expression of the Nur77 family of orphan nuclear receptors. MEF2 has been shown to be the major transcription factor responsible for calcium-dependent Nur77 transcription. Cabin1 was recently identified as a transcriptional repressor of MEF2, which can be released from MEF2 in a calcium-dependent fashion. The molecular basis of repression of MEF2 by Cabin1, however, has remained unknown. We report that Cabin1 represses MEF2 by two distinct mechanisms. Cabin1 recruits mSin3 and its associated histone deacetylases 1 and 2; Cabin1 also competes with p300 for binding to MEF2. Thus, activation of MEF2 and the consequent transcription of Nur77 are controlled by the association of MEF2 with the histone deacetylases via the calcium-dependent repressor Cabin1.


DNA-fluorescence-cytometry and prognosis (grading) of meningiomas--a study of 104 surgically removed tumors.
A total of 104 meningiomas of various histological types were examined microscopically and with flow fluorescence cytometry using the EBR staining technique and either an ICP 11 or an ICP 22 (PHYWE). Also tissue culture cells of 72 tumors were studied for their DNA content. There was a variable DNA distribution, which allowed a grading of malignancy according to a 3 or 4 grade scale. Useful information on the nature of a meningioma and its proliferative activity can be obtained during the surgical treatment. A majority of meningiomas show slowly proliferative DNA patterns typical for benign tumors. More than one third of the meningiomas show an intermediate configuration, probably associated with more or less semi-benign proliferative activity. 5.8% of our cases showed primary malignant tumors--except meningosarcomas.


Molecular biology of malignant melanoma.
The incidence of melanoma has increased more rapidly than any other type of cancer. In this review, we summarize the most important genetic alterations that contribute to the development of malignant melanoma. Our knowledge of the genetic and biological events involved in the genesis and progression of this disease has been benefited from the evolvement of a wealth of genetically engineered animal models. Hopefully, the understanding generated by all these studies will contribute to develop new therapeutic strategies to handle this fatal malignancy.


Psychiatric disorders during pregnancy in asymptomatic and mildly symptomatic SARS-CoV-2 positive women: Prevalence and effect on outcome.
The effect of psychiatric comorbidity on pregnancy outcome among SARS-CoV-2 positive women with asymptomatic and mildly symptomatic infections remains largely unknown. We reviewed the electronic medical records of all pregnant women who received care at Mayo Health System and tested positive for SARS-CoV-2 (RT-PCR) from March 2020 through October 2021. Among 789 patients, 34.2% (n = 270) had psychiatric comorbidity. Of those with psychiatric comrobidity, 62.2% (n = 168) had depression prior to pregnancy, and 5.2% (n = 14) reported new-onset depression during pregnancy. Before pregnancy, 65.6% (n = 177) had anxiety, and 4.4% (n = 12) developed anxiety during pregnancy Thirteen percent of SARS-CoV-2 positive pregnant women (n = 108) received psychotropic medication during pregnancy. In addition, 6.7% (n = 18) and 10.7% (n = 29) of pregnant women with psychiatric comorbidity had documented nicotine, cannabis and/ or illicit substance use during and prior to pregnancy, respectively. We depicted a significantly higher risk for cesarean delivery [35.6% vs. 24.9%) in asymptomatic and mildly symptomatic SARS-CoV-2 positive pregnant women with psychiatric comorbidity. In conclusion, the prevalence rates of depression, anxiety, and prescribed antidepressant medications during pregnancy among asymptomatic and mildly symptomatic SARS-CoV-2 infected women were substantially higher than average, which negatively impacted pregnancy and neonatal outcomes.


Cerebrospinal fluid and plasma procalcitonin for the diagnosis of neonatal bacterial meningitis.
There is a paucity of data on cerebrospinal fluid (CSF) procalcitonin (PCT) to diagnose neonatal meningitis. We evaluated CSF PCT to diagnose bacterial meningitis among neonates with suspected sepsis. Neonates undergoing lumbar puncture (LP) as part of sepsis workup were included. CSF PCT, plasma PCT, CSF:plasma PCT ratio and CSF cytochemistry. Reference Standards: 'Definite meningitis' defined by positive CSF culture and/or gram stain and/or broad-based primer 16S rDNA polymerase chain reaction. 'Definite or probable' meningitis is defined as definite meningitis or abnormal cytochemistry. Of 216 eligible neonates, 18 had 'definite meningitis' and 37 'definite or probable meningitis'. Median (Q1 , Q3 ) CSF PCT level was significantly higher in 'definite meningitis' compared to 'no definite meningitis' (0.429 (0.123, 1.300) vs. 0.181 (0.119, 0.286) ng/mL respectively, P = 0.028). Likewise, it was significantly higher in 'definite or probable meningitis' compared to no meningitis (0.245 (0.136, 0.675) vs. 0.170 (0.116, 0.28), P = 0.01). The area under the receiver operator characteristics curve of CSF PCT level for definite meningitis was 0.656 and for 'definite or probable meningitis' 0.635. Paired comparisons of area under the receiver operator characteristics curve of CSF PCT with the other index tests showed no significant differences. Based on a priori cut-off of 0.2 ng/mL, CSF PCT level had a sensitivity (95% confidence interval) of 67% (50, 80), specificity 58% (54, 61), LR+ 1.6 (1.1, 2.0) and LR- 0.6 (0.3, 0.9). Higher values of CSF PCT are associated with neonatal bacterial meningitis. However, the diagnostic performance of CSF PCT is modest and not significantly different from standard tests.


Respiratory muscle strength training and neuromuscular electrical stimulation in subacute dysphagic stroke patients: a randomized controlled trial.
To evaluate the effectiveness of inspiratory/expiratory muscle training (IEMT) and neuromuscular electrical stimulation (NMES) to improve dysphagia in stroke. Prospective, single-blind, randomized-controlled trial. Tertiary public hospital. Sixty-two patients with dysphagia were randomly assigned to standard swallow therapy (SST) (Group I, controls, n=21), SST+ IEMT (Group II, n=21) or SST+ sham IEMT+ NMES (Group III, n=20). All patients followed a 3-week standard multidisciplinary rehabilitation program of SST and speech therapy. The SST+IEMT group's muscle training consisted of 5 sets/10 repetitions, twice-daily, 5 days/week. Group III's sham IEMT required no effort; NMES consisted of 40-minute sessions, 5 days/week, at 80Hz. Dysphagia severity, assessed by Penetration-Aspiration Scale, and respiratory muscle strength (maximal inspiratory and expiratory pressures) at the end of intervention and 3-month follow-up. Maximal respiratory pressures were most improved in Group II: treatment effect was 12.9 (95% confidence interval 4.5-21.2) and 19.3 (95% confidence interval 8.5-30.3) for maximal inspiratory and expiratory pressures, respectively. Swallowing security signs were improved in Groups II and III at the end of intervention. No differences in Penetration-Aspiration Scale or respiratory complications were detected between the 3 groups at 3-month follow-up. Adding IEMT to SST was an effective, feasible, and safe approach that improved respiratory muscle strength. Both IEMT and NMES were associated with improvement in pharyngeal swallowing security signs at the end of the intervention, but the effect did not persist at 3-month follow-up and no differences in respiratory complications were detected between treatment groups and controls.


Application of ethnic food composition data for understanding the diet and nutrition of South Asians in the UK.
Lack of food composition data, recipe information and portion sizes for ethnic foods are commonly reported problems for dietary assessment of ethnic minority groups. One of the main aims of this study was to use food composition data to validate portion sizes, identify important sources of nutrients and describe the characteristics of the South Asian diet. The top five ethnic foods containing highest levels of selected nutrients were lamb balti (3mg/100g iron), lamb kebab (3.2mg/100g zinc), mixed dhal (62μg/100g folate), fish curry (1.4μg/100g vitamin D), ghee (968μg/100g retinol) and toor dhal (9.1g/100g dietary fibre). Typical adult South Asian diets included traditional cereals (chapatti, rice and paratha) and low consumption of meat dishes; with vegetable curries contributing most towards energy intake. A higher consumption of full fat milk and fruit juices by toddlers and school children were observed when compared with the National Diet and Nutrition Survey of the UK.


1,6-O,O-diacetylbritannilactones inhibits IkappaB kinase beta-dependent NF-kappaB activation.
To determine the chemical constituents responsible for pharmacological effects of Inula britannica-F., three specific sesquiterpene lactones in Inula britannica were isolated from chloroform extract and identified, including britannilactone (BL), 1-O-acetylbritannilactone (ABLO), and 1,6-O,O-diacetylbritannilactone (ABLOO). Electrophoretic mobility shift assay (EMSA) was performed to detect the nuclear translocation of nuclear factor-kappaB (NF-kappaB) p65. The expressions of IkappaBalpha, pIkappaBalpha, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IkappaB kinase alpha/beta (IKKalpha/beta) and NF-kappaB kinase (NIK) were detected by Western blot and RT-PCR. We found that acetyl side groups enhanced the inhibitory action of the agents on LPS/IFN-gamma-induced iNOS and COX-2 expression. Their inhibiting activity was positive correlation with the acetyl side group number. The effects of LPS/IFN-gamma were reversed by ABLOO, and BL without acetyl side groups showed only a weak inhibitory action. Further study indicated that ABLOO markedly inhibited the phosphorylation of IKKbeta down to based level, but not IKKalpha, corresponding with decreased in IkappaBalpha degradation and phosphorylation induced by LPS/IFN-gamma, resulting in the suppression of NF-kappaB nuclear translocation and activity. These results suggest that the acetyl moieties add to the lipophilicity, and consequently enhance cellular penetration, so that ABLOO possess the most anti-inflammatory effect and may be a potent lead structure for the development of therapeutic and cytokine-suppressing remedies valuable for the treatment of various inflammatory diseases.


Treatment of gilts with leukocytes from the sire does not improve reproductive performance.
The effectiveness of pretreatment of gilts with leukocyte antigens on reproductive performance was studied. Two experiments were carried out that involved the treatment of gilts with leukocytes prior to artificial or natural insemination. Gilts were randomly assigned to one of three treatment groups. Group A gilts received two doses of 2 x 10(8) sire's leukocytes; one injected intra-peritoneal at first estrus and the other infused into the uterus immediately prior to insemination at the second estrus cycle. Group B gilts were similarly treated with the 'gilt's own' (autologous) leukocytes and Group C animals received phosphate buffered saline as controls. The same boars were used as sires across all three treatment groups. Gilts were slaughtered during the fifth week of pregnancy and their reproductive performance assessed. When data from the three groups were compared there were significant differences in embryo survival and placental weights between the sire's leukocyte treatment and PBS control groups. Embryo survival rate (No viable embryos/No corpora lutea x 100) at the fifth week of gestation was lower (p < 0.05) and placental weights were higher in the sire's leukocyte treatment group (p < 0.05). However, the latter may likely be due to fewer developing embryos. Embryo survival and placental weights did not vary significantly between the sire's and autologous leukocytes treatment groups. The treatment of gilts with leukocytes from the boars used as sires showed no improvement on subsequent reproductive outcome over that observed for the autologous leukocytes or PBS control treatments. Consequently, in a healthy well managed herd leukocytes treatment offers no advantage to pig reproductive function.


Effects of penicillamine on serum immunoglobulins and immune complex-reactive material in primary biliary cirrhosis.
Although penicillamine is used in the treatment of primary biliary cirrhosis, its mechanism of action in this disease is unknown. As an immunologic action had been attributed to the drug, we investigated whether penicillamine might alter serum immunoglobulin levels or immune complex-reactive material in patients with primary biliary cirrhosis. Immunoglobulin levels and immune complex reactivity were measured and clinical tests were performed in 53 consecutive patients entering a double-blind randomized trial of 750 mg vs. 250 mg of penicillamine. Measurement of immune complex reactivity was determined by laser nephelometry, 125I-C1q binding, and Raji cell assays. Immune complex reactivity was detected by at least one assay in 75% of patients tested before treatment. Sixty-two percent were positive in the C1q assay, 28% in the Raji cell assay, and 39% by nephelometry. After therapy with either dose, we found no change in immune complex-reactive material by any assay. Concentrations of immunoglobulins G and M fell (p less than 0.05) after 12 mo of therapy. Concentrations of immunoglobulin A decreased (p less than 0.05) only in the high-dose group. Correlation was not consistent between results of immune complex assays and clinical liver tests. Although immunoglobulin levels fell during penicillamine therapy, no decrease in immune complex-reactive material was detected. The effect of penicillamine in primary biliary cirrhosis is not mediated through alteration of immune complex-reactive material.


Early symptom change contributes to the outcome prediction of cognitive behavioral therapy for depression patients: A machine learning approach.
Limited evidence exists regarding the association between early symptom change and later outcomes of cognitive behavioral therapy (CBT). This study aimed to apply machine learning algorithms to predict continuous treatment outcomes based on pre-treatment predictors and early symptom changes and to uncover whether additional variance could be explained compared to regression methods. Additionally, the study examined early subscale symptom changes to determine the most significant predictors of treatment outcome. We investigated CBT outcomes in a large naturalistic dataset (N = 1975 depression patients). The sociodemographic profile, pre-treatment predictors, and early symptom change, including total and subscale scores were used to predict the Symptom Questionnaire (SQ)48 score at the 10th session as a continuous outcome. Different machine learners were compared to linear regression. Early symptom change and baseline symptom score were the only significant predictors. Models with early symptom change explained 22.0 % to 23.3 % more variance than those without early symptom change. Specifically, the baseline total symptom score, and the early symptom score changes of the subscales pertaining to depression and anxiety were the top three predictors of treatment outcome. Excluded patients with missing treatment outcomes had slightly higher symptom scores at baseline, indicating possible selection bias. Early symptom change improved the prediction of treatment outcomes. The prediction performance achieved is far from clinical relevance: the best learner could only explain 51.2 % of the variance in outcomes. Compared to linear regression, more sophisticated preprocessing and learning methods did not substantially improve performance.


Use of the pBUTR Reporter System for Scalable Analysis of 3' UTR-Mediated Gene Regulation.
Posttranscriptional control of mRNA subcellular localization, stability, and translation is a central aspect of gene regulation and expression. Much of this control is mediated via recognition of a given mRNA transcript's 3' untranslated region (UTR) by microRNAs and RNA-binding proteins. Here we describe how a novel, scalable piggyBac-based vector, pBUTR, can be utilized for analysis of 3' UTR-mediated posttranscriptional gene regulation (PTGR) both in vitro and in vivo. This vector is specifically designed to express a selection marker, a control reporter, and an experimental reporter from three independent transcription units. Expression of spliced reporter transcripts from medium-copy non-viral promoter elements circumvents several potential confounding factors associated with saturation and stability, while stable integration of these reporter and selection elements in the context of a DNA transposon facilitates experimental reproducibility.


A gene (Carg1) that regulates tissue resistance to Candida albicans maps to chromosome 14 of the mouse.
Tissue susceptibility and resistance to infection with the yeast Candida albicans is genetically regulated. Analysis of the strain distribution pattern of the C. albicans resistance gene (Carg1) and additional gene and DNA segment markers in the AKXL recombinant inbred (RI) set showed that 13/15 RI strains were concordant for Carg1, Tcra and Rib1. Therefore, Carg1 is probably located within a 17 cM segment of chromosome 14, within approximately 4 cM of the other two genes.


Maternal methionine supplementation during gestation alters alternative splicing and DNA methylation in bovine skeletal muscle.
The evaluation of alternative splicing, including differential isoform expression and differential exon usage, can provide some insights on the transcriptional changes that occur in response to environmental perturbations. Maternal nutrition is considered a major intrauterine regulator of fetal developmental programming. The objective of this study was to assess potential changes in splicing events in the longissimus dorsi muscle of beef calves gestated under control or methionine-rich diets. RNA sequencing and whole-genome bisulfite sequencing were used to evaluate muscle transcriptome and methylome, respectively. Alternative splicing patterns were significantly altered by maternal methionine supplementation. Most of the altered genes were directly implicated in muscle development, muscle physiology, ATP activities, RNA splicing and DNA methylation, among other functions. Interestingly, there was a significant association between DNA methylation and differential exon usage. Indeed, among the set of genes that showed differential exon usage, significant differences in methylation level were detected between significant and non-significant exons, and between contiguous and non-contiguous introns to significant exons. Overall, our findings provide evidence that a prenatal diet rich in methyl donors can significantly alter the offspring transcriptome, including changes in isoform expression and exon usage, and some of these changes are mediated by changes in DNA methylation.


Respiratory sensations during heavy exercise in subjects without respiratory chemosensitivity.
Breathlessness arises from increased medullary respiratory center activity projecting to the forebrain (respiratory corollary discharge hypothesis). Subjects with congenital central hypoventilation syndrome (CCHS) lack the normal hyperpnea and breathlessness during hypercapnia. The corollary discharge hypothesis predicts that if CCHS subjects have normal hyperpnea during exercise, they will experience normal breathlessness during exercise. To test this, we studied four CCHS subjects and six matched controls during an exhausting constant-load cycling test requiring substantial anaerobiosis. CCHS subjects rated significantly less breathlessness at the end of the test than controls, but ventilation (index of respiratory corollary discharge) was also somewhat lower in CCHS (not significant). In both groups, breathlessness increased disproportionately more than ventilation towards the end of exercise. These data failed to disprove the corollary discharge hypothesis of breathlessness, but do suggest that the relationship between ventilation and breathlessness is non-linear and/or that projections of chemoreceptor afferents to the forebrain (presumed lacking in CCHS) is one source of breathlessness in normals.


CD8+ T cells specific for cancer germline gene antigens are found in many patients with multiple myeloma, and their frequency correlates with disease burden.
The expression of cancer germline antigens (CGAgs) is normally restricted to the testis but is also present in many types of malignant cells including plasma cells from patients with myeloma. Because T-cell immune responses to CGAg have been identified in patients with solid tumors, this may offer a novel target for immunotherapy in patients with myeloma. We have used 12 peptide epitopes from a range of CGAgs to screen for CGAg-specific T cells in blood from patients with multiple myeloma at various stages of their disease. T cells from 15 of 37 patients responded to one or more CGAg peptides and the magnitude of the CGAg-specific CD8+ T-cell response ranged between 0.0004% and 0.1% of the total CD8+ T-cell pool. Serial analyses showed that these immune responses were detectable in individual patients at multiple time points during the course of their disease. In patients undergoing treatment or in disease relapse, the magnitude of the CGAg-specific T-cell response was positively correlated with the level of paraprotein. Functional T cells specific for CGAgs are therefore present in a proportion of patients with multiple myeloma and offer the possibility of a novel approach for immunotherapy in this disease.


Efficacy and appropriateness of novel antibiotics in response to antimicrobial-resistant gram-negative bacteria in patients with sepsis in the ICU.
There is an ever-increasing range of antibiotic-resistant pathogens that have led to higher community-acquired infections, and substantial mortality rates in critically ill patients. We have critically appraised available evidence through a structured literature review, investigating effective empiric antibiotic administration and appropriateness on outcomes of critically ill patients with an increased risk of developing resistant pathogens. The use of new antibiotics should be determined based on relevant knowledge of their spectrum and properties to provide effective mode of action for critically ill patients. Restricting severely ill patients access to new broad-spectrum empirical drugs is not the answer. Rather there should be a focus on identifying host response to infection to differentiate between colonization or contamination and true infection, and the sensitivity to antibiotics used in the intensive care unit (ICU). Management relies on adequate antibiotic administration, the ability to monitor response, and facilitate the cessation of antibiotic treatment. The major determinant of patient success in a patient with a severe infection is the 'right' antibiotic or complementary course of treatment. As an overarching criterion, the following three appropriate "Ds" should be considered: Dosing, Duration, and De-escalation to empirically assess the right antibiotic optimal antimicrobial selection.


Laminar processing in the visual cortical column.
Sensory regions of neocortex are organized as arrays of vertical columns composed of cells that share similar response properties, with the orientation columns of the cat's visual cortex being the best known example. Interest in how sensitivity to different stimulus features first emerges in the columns and how this selectivity is refined by subsequent processing has fueled decades of research. A natural starting point in approaching these issues is anatomy. Each column traverses the six cortical layers and each layer has a unique pattern of inputs, intrinsic connections and outputs. Thus, it makes sense to explore the possibility of corresponding laminar differences in sensory function, that is, to examine relationships between morphology and physiology. In addition, to help identify general patterns of cortical organization, it is useful to compare results obtained from different sensory systems and diverse species. The picture that emerges from such comparisons is that each cortical layer serves a distinct role in sensory function. Furthermore, different cortices appear to share some common strategies for processing information but also have specialized mechanisms adapted for the demands of specific sensory tasks.


Prolonged low-level cadmium intake and atherosclerosis.
The frequencies of 10 diseases in a cadmium (and zinc) contaminated region in The Netherlands were analysed by comparing hospital admissions with those of a non-contaminated region and with national values. No significant differences were found for diseases which are commonly associated with increased cadmium uptake such as renal insufficiency, nephrolithiasis, hypertension, cancer, immaturity of the new-born. For the contaminated region a significantly higher frequency was only found for atherosclerosis; this was relatively strong for men aged > 40 yrs. However, no higher death frequency for atherosclerosis was observed. The results are discussed in relation to limitations in the evaluation techniques used. The absence of major health risks in the contaminated area is obvious, but the possible influence of long term-low level cadmium uptake on atherosclerosis requires more attention.


Astrocyte-neuron lactate shuttle plays a pivotal role in sensory-based neuroprotection in a rat model of permanent middle cerebral artery occlusion.
We have previously demonstrated protection from impending cortical ischemic stroke is achievable by sensory stimulation of the ischemic area in an adult rat model of permanent middle cerebral artery occlusion (pMCAo). We have further demonstrated that a major underpinning mechanism that is necessary for such protection is the system of collaterals among cerebral arteries that results in reperfusion of the MCA ischemic territory. However, since such collateral flow is weak, it may be necessary but not sufficient for protection and therefore we sought other complementary mechanisms that contribute to sensory-based protection. We hypothesized that astrocytes-neuron lactate shuttle (ANLS) activation could be another potential underpinning mechanism that complements collateral flow in the protection process. Supporting our hypothesis, using functional imaging, pharmacological treatments, and postmortem histology, we showed that ANLS played a pivotal role in sensory stimulation-based protection of cortex and therefore serves as the other supporting mechanism underpinning the protection process.


The proprotein convertase furin is required for trophoblast syncytialization.
The multinucleated syncytial trophoblast, which forms the outermost layer of the placenta and serves multiple functions, is differentiated from and maintained by cytotrophoblast cell fusion. Deficiencies in syncytial trophoblast differentiation or maintenance likely contribute to intrauterine growth restriction and pre-eclampsia, two common gestational diseases. The cellular and molecular mechanisms governing trophoblast syncytialization are poorly understood. We report here that the proprotein convertase furin is highly expressed in syncytial trophoblast in the first trimester human placentas, and expression of furin in the syncytiotrophoblast is significantly lower in the placentas from pre-eclamptic patients as compared with their gestational age-matched control placentas. Using multiple experimental models including induced fusion of choriocarcinoma BeWo cells and spontaneous fusion of primary cultured cytotrophoblast cells or placental explants, we demonstrate that cytotrophoblast cell fusion and syncytialization are accompanied by furin expression. Furin-specific siRNAs or inhibitors inhibit cell fusion in BeWo cells, as well as trophoblast syncytialization in human placental explants. Furthermore, type 1 IGF receptor (IGF1R) is indicated in this study as a substrate of furin, and processing of IGF1R by furin is an essential mechanism for syncytialization. Finally, using lentivirus-mediated RNAi targeting to mouse trophectoderm, we demonstrate that furin function is required for the development of syncytiotrophoblast structure in the labyrinth layer, as well as for normal embryonic development.


Reproductive physiology in the blood feeding insect, Rhodnius prolixus, from copulation to the control of egg production.
The study of copulation and the control of egg production in the blood-feeding insect, Rhodnius prolixus, continues to offer a fertile ground for the cultivation of new insights into the physiological processes associated with reproduction. We begin this paper by describing the male organs of copulation showing that the aedeagus contains a structure which may serve as part of a pumping mechanism or valve to enable the male to fully pack the vagina with his secretions. We then summarize previously published work which identifies possible sensory and chemical aids that can be used by the male as he forms a naked spermatophore within the vagina of the female. With respect to the control of egg production, published anatomical and endocrinological experiments give rise to the intriguing possibility that a vascular portal system exists in the head of this insect, and that this system explains why circulation is required for egg production. By documenting the steps taken by the male during copulation, and by providing a new paradigm to explain the control of egg production, this paper identifies some assumptions that need verification, and offers a foundation upon which future scientists can explore reproductive physiology in this incredible bug.


Common genetic components of obesity traits and serum leptin.
To estimate common and distinct genetic influences on a panel of obesity-related traits and serum leptin level in adults. In a cross-sectional study of 625 Danish, adult, healthy, monozygotic, and same-sex dizygotic twin pairs of both genders, we carried out detailed anthropometry (height, weight, waist and hip, and skin-fold thickness, body composition assessment by bioimpedance (fat mass and fat-free mass), and measurement of serum leptin level. Bivariate variance component analyses estimated the additive genetic correlations between these measurements. The genetic correlations between the traits for overall fatness (BMI and fat mass index, kg/m(2)) were 0.94 in men and 0.98 in women, and their correlations with the various local fatness measures ranged from 0.49 to 0.83 in men and from 0.70 to 0.87 in women. The correlations between the truncal measures (waist circumference and truncal skin folds) and between the peripheral measures (hip circumference and peripheral skin folds) were 0.57 and 0.47 in men and 0.71 and 0.70 in women, respectively. The correlations between the truncal and peripheral measures ranged between 0.49 and 0.72 in men and between 0.61 and 0.82 in women. For leptin vs. the various measures of overall and local fatness the correlations ranged from 0.54 to 0.74 in men and from 0.48 to 0.75 in women. All correlations were significantly <1.00. The study supports control of overall fat mass and peripheral and truncal fat mass by both shared and different genetic components, which suggests that it is important to distinguish between the different phenotypes in the search for genes involved in the development of obesity.


Effects of suramin on the proliferation of primary epithelial cell cultures derived from normal, benign hyperplastic and cancerous human prostates.
Primary epithelial cultures (PECs) derived from normal, benign hyperplastic (BPH), and cancerous human prostate tissue were treated with increasing doses of suramin, and assayed for cell proliferation over a period of days. The suramin IC50 (inhibitory concentration 50%) value was 0.5 to 1.0 x 10(-4) M, whereas doses between 2.5 x 10(-4) and 5 x 10(-4) M resulted in total growth inhibition. This inhibition was reversible by exchange with suramin-free medium up to day 6. Concentrations > or = 5 x 10(-4) M resulted in increased cytotoxicity as exposure time increased. No differential response to suramin could be demonstrated among the prostate PECs derived from different tissues. The established cell lines, PC-3 and DU 145, grown in serum containing medium exhibited IC50s comparable to the PECs grown in serum free medium. EGF, bFGF, alpha, or beta ECGF at the concentrations tested did not reverse suramin inhibition. Increasing concentrations of bovine pituitary extract (BPE) increased cell growth in both the treated and the control cells. However, the percent growth inhibition by suramin at each concentration of BPE remained constant. Flow cytometry examination of cells treated for 7 days with suramin (0-10(-3) M) failed to detect any significant cell cycle alterations compared to control. At high concentrations of suramin (> or = 10(-4) M), large numbers of viable and dead cells were detectable in the medium. The increase in unattached viable cells was most prevalent (80%) in cultures treated with suramin at the time of plating, but also occurred with cells (25-30%) plated hours prior to the addition of suramin. Treatment for several days with low concentrations of suramin (10(-7) to 10(-5) M) transiently enhanced cell growth compared to controls.


Okadaic acid inhibits angiotensin II, adrenocorticotropin and potassium-dependent aldosterone secretion.
The present study was designed to assess the effect of okadaic acid (OA), a protein phosphatase inhibitor, on aldosterone secretion in response to angiotensin II (AII), adrenocorticotropin (ACTH) and rises in external potassium concentration (K+). AII (10nM) caused a 20-fold increase in aldosterone production and OA reduced this response by 45%. ACTH (10nM) caused an 8.6-fold increase in aldosterone secretion and OA reduced this by 83%. Increasing K+ concentration from 3 to 12mM caused a 13-fold increase in aldosterone production, which OA inhibited by 36%. These results suggest that protein phosphatases participate in the control of adrenal steroid production, even though ACTH, AII and K+ act via different intracellular messenger systems.


Medullary thyroid cancer diagnosis: an appraisal.
Since its first description in 1951, a timely diagnosis of medullary thyroid carcinoma (MTC) may represent a diagnostic challenge in clinical practice. Several contributions have been addressed to the treatment and follow-up of MTC, but review articles focused on the diagnostic problems of this cancer in clinical practice are sparse. As a delayed diagnosis and an inadequate initial treatment may severely affect the prognosis of this thyroid malignancy, the appropriate use and the correct interpretation of the available diagnostic tools for MTC are of crucial importance. The purpose of the present article is to provide an easy-to-use guide reviewing the main issues of MTC diagnosis: (1) basal serum calcitonin; (2) stimulated serum calcitonin; (3) additional serum markers for MTC; (4) ultrasound and other imaging techniques; (5) fine-needle aspiration (FNA) cytology; (6) calcitonin measurement on FNA washout; (7) rearranged during transfection (RET) mutations; and (8) scope of the problem.


Dry season distribution of land crabs, Gecarcinus quadratus (Crustacea: Gecarcinidae), in Corcovado National Park, Costa Rica.
The land crab Gecarcinus quadratus is an engineering species that controls nutrient cycling in tropical forests. Factors regulating their coastal distribution are not fully understood. We quantified land crab distribution during the dry season at Sirena Field Station in Corcovado National Park, Costa Rica, and found that land crab burrow density decreases with increasing distance from the ocean. Leaf litter depth and tree seedling density are negatively correlated with land crab burrow density. Burrows are strongly associated with sand substrate and burrow density is comparatively low in clay substrate. Results suggest that G. quadratus is limited to a narrow coastal zone with sand substrate, and this distribution could have profound effects on plant community structure.


Strength and stiffness of interim materials and interim fixed dental prostheses when tested at different loading rates.
How the loading rate might affect the mechanical properties of interim materials and interim fixed dental prostheses is unclear. The purpose of this in vitro study was to compare the material stiffness, material strength, and structural strength of interim 3-unit fixed dental prostheses fabricated from 3 interim materials when stressed at different loading rates. Bar-shaped specimens and anatomically correct interim 3-unit fixed dental prostheses with a modified-ridge lap pontic were fabricated from polyethyl methacrylate resin (Trim) and 2 bis-acrylic composite resins (TempSmart; Integrity) (n=10). Flexural modulus and strength of the bar specimens, representing material stiffness and strength, were determined with a 4-point bend test in a universal testing machine. The structural strength of the prosthesis was assessed from the failure load from a vertical force applied on the occlusal surface of the pontic. Three loading rates, 0.5, 5, or 10 mm/min, were evaluated. Results were statistically analyzed with 2-way analysis of variance and multiple comparisons (α=.05). Loading rate and material significantly affected flexural modulus, flexural strength, and structural strength (P<.05). Increasing loading rate significantly increased the flexural modulus of all materials (P<.05), but the effect of loading rate on the flexural strength of bis-acrylic composite resins was mostly insignificant. Polyethyl methacrylate specimens did not fracture when loaded at 0.5 or 5 mm/min, and the interim fixed dental prostheses made from polyethyl methacrylate did not fracture at the 0.5 mm/min loading rate. Dual-polymerizing bis-acrylic composite resin had significantly higher flexural modulus and strengths than autopolymerizing bis-acrylic composite resin. Polyethyl methacrylate resin had the lowest stiffness among the interim materials tested and did not fracture but excessively deformed at the low loading rate. Dual-polymerizing bis-acrylic composite resin consistently had higher stiffness and material strength and provided higher structural strength than the autopolymerizing bis-acrylic composite resin. Loading rate significantly affected the mechanical properties of polyethyl methacrylate resin (P<.05), but the effect was indistinct for the bis-acrylic materials.


Factors associated with nurses' willingness to handle abuse of older people.
The aim of this study was to explore predictors of nurses' willingness to handle abuse of older people. Abuse of older people is a long-discussed healthcare issue worldwide. Although nurses are considered capable of identifying and reporting cases of abuse of older people, no study has been conducted in Taiwan on nurses' willingness to handle abuse of older people. A cross-sectional design was used. The study was conducted from May to June 2019. A convenience sampling was adopted to survey 555 nurses from a medical center in Taiwan. Data were collected using the Knowledge of Abuse of Older People Scale, Attitudes Towards Older People Scale, Attitudes Towards Handling Abuse of Older People Scale, Willingness to Handle Abuse of Older People Scale, and personal characteristics. Pearson correlation coefficient analysis, independent sample t-test, one-way analysis of variance, and multiple linear regression were performed. Participants scored an average of 2.98 out of 4 on the Willingness to Handle Abuse of Older People Scale, indicating that they were inclined to do so. Attitudes towards older people, knowledge, attitudes towards handling abuse of older people, awareness of the hospital's reporting procedure and dissemination of information related to abuse of older people, sex, age, and clinical work experience explained 41.4% of the variance of willingness. Participants' attitudes toward handling abuse of older people was the most important predictor of their willingness to do so. To improve nurses' willingness to handle cases of abuse of older people, particularly that of male nurses, hospital authorities should provide in-service training and education and disseminate information on the subject matter. Nursing schools should prioritize offering gerontological nursing courses to foster nursing students' positive attitudes toward older adults and handling abuse of older people. Nurses' attitudes toward handling abuse of older people were the most important predictor of their willingness to handle abuse of older people.


Neutrophil-to-lymphocyte ratio is associated with carotid intraplaque neovascularization in asymptomatic carotid stenosis patients.
Neutrophil-to-lymphocyte ratio (NLR) has been suggested as an available systemic inflammatory biomarker. This study aims to evaluate whether intraplaque neovascularization assessed by contrast-enhanced ultrasound (CEUS) is associated with NLR in asymptomatic carotid stenosis patients. One hundred and forty-four asymptomatic patients with carotid luminal stenosis >30% were assessed using contrast-enhanced ultrasound imaging. The contrast enhancement within the plaque was classified on a visual semiquantitative grading scale. The data collected included the patient's risk factors, laboratory results, cardiovascular disease history, and drug use history. Univariate and multivariate analyses were assessed to identify independent factors related to intraplaque neovascularization with adjustment for potential confounders. Patients with CEUS grade 2 plaques had a higher level of LDL-C (p < .001), neutrophil count (p < .001), and blood glucose (p = .005), but lower level of lymphocyte count (p = .021). The presence of grade 2 plaques was significantly associated with high NLR values (OR 1.21, 95% CI 1.03-1.43, p = .017). Patients were divided into four groups according to the quartile of NLR values. Compared to the patients in the first quartile of NLR (<1.73), the patients in the fourth NLR quartile (≥3.38) were characterized by the most prevalence of CEUS grade 2 plaques (OR 4.55, 95% CI 1.69-12.25, p = .003). Multivariate logistic regression analysis after adjusting various variables demonstrated NLR remained an independent risk factor for the presence of CEUS grade 2 plaques. Intraplaque neovascularization is significantly associated with NLR in asymptomatic carotid stenosis patients.


Specific and non-specific immunosuppressive factors in salamander pregnancy serum.
In vitro experiments employing pregnant Salamandra salamandra have previously shown a maternal specific cytotoxic cellular reaction against larval cells and an inhibition of this reaction by maternal serum. Two serum fractions, 19S and 13S, have been implicated in this inhibition. In the present work, the site of action and the identity of the factors responsible for this activity have been determined. Pre-incubation experiments indicate that the 19S fraction from pregnancy serum specifically protects embryonic epithelial cells derived from the same pregnant female. The 13S fraction non-specifically inhibits cytotoxic activity of maternal cells. Both factors implicated in these reactions are respectively an IgM and an alpha 2-macroglobulin. The question of whether the alpha 2M is responsible for immunosuppression is discussed, with particular reference to its vitellogenin analogue and also in view of the fact that the presence of this alpha 2M is not always linked with the immunosuppressive properties (except during pregnancy).


A Rare Ocular Complication of Autologous Fat Injection: Subconjunctival Fat Infiltration.
The aim of this brief clinical study to describe and discuss the subconjunctival fat infiltration encountered in a patient with autologous fat injection. A 50-year-old female patient, who had an autologous fat injection 2 days ago, applied to our clinic with the complaint of redness and burning in the left eye. On anterior segment examination, a raised 20 × 15 mm adipose tissue was observed in the temporal region under the conjunctiva. Infiltrated fat tissue was surgically removed from the subconjunctival area. Subconjunctival fat infiltration is an extremely rare complication after autologous fat injection.


Effects of Pb2+ added in vitro on Ca2+ movements in isolated mitochondria and slices of rat kidney cortex.
We have studied the effects of Pb2+ added in vitro on the movements of Ca2+ in renal cortical mitochondria and tissue slices. The isolated mitochondria rapidly accumulated 45Ca2+ at 25 degrees by a mechanism that was dependent on respiration and inhibited 96% by ruthenium red. A concentration of 10 microM Pb2+ inhibited the Ca2+ accumulation at least as effectively as did ruthenium red. About 20% of the Ca2+ accumulation persisted at 1 degrees with a similar sensitivity to inhibitors, including 60% inhibition by Pb2+. Similar results were obtained when the accumulation of Ca2+ at 25 degrees was measured by means of a calcium-sensitive electrode, Pb2+ inhibiting by 80%. Calcium that had been accumulated by mitochondria at 25 degrees was released completely by the ionophore A23187 or by 10 microM Pb2+. The release induced by Pb2+ was greatly inhibited by ruthenium red. The Ca2+ content of tissue slices of renal cortex increased 4-fold during incubation at 1 degree while the Ca2+ content of mitochondria within the slices more than doubled, the latter being determined by isolation of mitochondria from the slices after incubation. The presence of Pb2+ (200 microM) in the incubation medium of the slices substantially reduced the entry of Ca2+ into the whole slices and into mitochondria within the slices. When the slices preincubated at 1 degree were warmed to 25 degrees in oxygenated medium, they brought about a net extrusion of Ca2+, some of which was derived from the mitochondria; Pb2+ did not alter the final level of Ca2+ then attained in the slices, but it caused a significant decrease in the quantity retained in the mitochondria. We conclude that Pb2+ both inhibits the uptake of Ca2+ by renal cortical mitochondria and displaces Ca2+ from them, these effects occurring whether the mitochondria are isolated or in situ.


Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer.
The human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. However, the clinical relevance of germline HLA-mediated immunity in gastrointestinal (GI) cancer remains elusive. This study retrospectively analyzed the genomic profiling data from 84 metastatic GI cancer patients treated with immune checkpoint blockade (ICB) recruited from Peking University Cancer Hospital (PUCH). A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was employed as the validation cohort. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood samples from all patients. Tumor tissues from 76 patients were subjected to WES analysis and immune oncology-related RNA profiling. We studied the associations of two parameters of germline HLA as heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) with the clinical outcomes of patients in both cohorts. Our data showed that neither HLA heterozygosity nor HED at the HLA-A/HLA-C locus correlated with the overall survival (OS) in the PUCH cohort. Interestingly, in both the PUCH and MSK GI cohorts, patients with high HLA-B HED showed a better OS compared with low HLA-B HED subgroup. Of note, a combinatorial biomarker of HLA-B HED and tumor mutational burden (TMB) may better stratify potential responders. Furthermore, patients with high HLA-B HED were characterized with a decreased prevalence of multiple driver gene mutations and an immune-inflamed phenotype. Our results unveil how HLA-B evolutionary divergence influences the ICB response in patients with GI cancers, supporting its potential utility as a combinatorial biomarker together with TMB for patient stratification in the future.


Pathophysiology of parkinsonism.
The motor signs of Parkinson's disease are thought to result in large part from a reduction of the level of dopamine in the basal ganglia. Over the last few years, many of the functional and anatomical consequences of dopamine loss in these structures have been identified, both in the basal ganglia and in related areas in thalamus and cortex. This knowledge has contributed significantly to our understanding of the link between the degeneration of dopamine neurons in the midbrain and the development of parkinsonism. This review discusses the evidence that implicates electrophysiologic changes (including altered discharge rates, increased incidence of burst firing, interneuronal synchrony, oscillatory activity, and altered sensorimotor processing) in basal ganglia, thalamus, and cortex, in parkinsonism. From these studies, parkinsonism emerges as a complex network disorder, in which abnormal activity in groups of neurons in the basal ganglia strongly affects the excitability, oscillatory activity, synchrony and sensory responses of areas of the cerebral cortex that are involved in the planning and execution of movement, as well as in executive, limbic or sensory functions. Detailed knowledge of these changes will help us to develop more effective and specific symptomatic treatments for patients with Parkinson's disease.


Quantitative clinical outcomes of therapy for head and neck lymphedema.
Head and neck surgery and radiation cause tissue fibrosis that leads to functional limitations and lymphedema. The objective of this study was to determine whether lymphedema therapy after surgery and radiation for head and neck cancer decreases neck circumference, increases cervical range of motion, and improves pain scores. A retrospective review of all patients with squamous cell carcinoma of the oral cavity, oropharynx, or larynx who were treated with high-dose radiation therapy at a single center between 2011 and 2012 was performed. Patients received definitive or postoperative radiation for squamous cell carcinoma of the oral cavity, oropharynx, or larynx. Patients were referred to a single, certified, lymphedema therapist with specialty training in head and neck cancer after completion of radiation treatment and healing of acute toxicity (typically 1-3 months). Patients underwent at least 3 months of manual lymphatic decongestion and skilled fibrotic techniques. Circumferential neck measurements and cervical range of motion were measured clinically at 1, 3, 6, 9, and 12 months after completion of radiation therapy. Pain scores were also recorded. Thirty-four consecutive patients were eligible and underwent a median of 6 months of lymphedema therapy (Range, 3-12 months). Clinically measured total neck circumference decreased in all patients with 1 month of treatment. Cervical rotation increased by 30.2% on the left and 27.9% on the right at 1 month and continued to improve up to 44.6% and 55.3%, respectively, at 12 months. Patients undergoing therapy had improved pain scores from 4.3 at baseline to 2.0 after 1 month. Lymphedema therapy is associated with objective improvements in range of motion, neck circumference, and pain scores in the majority of patients.


Revealing dynamics of gene expression variability in cell state space.
To decipher cell state transitions from single-cell transcriptomes it is crucial to quantify weak expression of lineage-determining factors, which requires computational methods that are sensitive to the variability of weakly expressed genes. Here, I introduce VarID, a computational method that identifies locally homogenous neighborhoods in cell state space, permitting the quantification of local variability in gene expression. VarID delineates neighborhoods with differential gene expression variability and reveals pseudo-temporal dynamics of variability during differentiation.