Role of endogenous opioid receptor agonists in regulation of heart resistance to the arrhythmogenic action of short-term ischemia and reperfusion.
Preliminary selective block of mu-, delta1-, delta2-, and kappa-opioid receptors had no effect on the incidence of ventricular arrhythmias during 10-min coronary occlusion-reperfusion in ketamine-narcotized rats. Repetitive short-term immobilization of rats for 2 weeks improved heart resistance to the arrhythmogenic action of coronary occlusion and reperfusion. Selective mu-opioid receptor antagonist CTAP completely abolished, while selective delta- and kappa-opioid receptor antagonists did not modulate the antiarrhythmic effect of adaptation. Probably, endogenous agonists of mu-opioid receptors play an important role in the adaptive improvement of heart resistance to arrhythmogenic factors, but are insignificant for the modulation of heart resistance to the arrhythmogenic action of short-term local ischemia-reperfusion in non-adapted animals.


Low-frequency MEG activity and MRI evaluation in Parkinson's disease.
Low - frequency activity has been reported in Parkinson disease (PD). We investigated the magnetoencephalographic (MEG) recordings from PD patients and healthy volunteers in the frequency domain. The MEG recordings were carried out in a magnetically shielded room with a whole-head 122-channel gradiometer. Nine patients suffering from PD and 9 age and gender matched healthy subjects were included in the study. MRI with T1-w and T2-w images, was available in patients' records. Frequency analysis may be usefully combined in the analysis of data sets, which contain oscillatory components. Prominent low frequencies can be seen in the spectrum obtained from the PD patients whereas in the control group the frequency range was 6Hz in the majority of channels. MRI did not disclose specific findings in any case. It is suggested that the MEG could be a complementary method in the diagnostic evaluation of PD using spatial distribution of the raw data in the frequency domain.


The drug metabolism systems of liver and liver tumors: a comparison of activities and characteristics.
Transplantable rat liver tumors 5123 t.c., 7288 ct.c., 5123 t.c.(H) and the Novikoff hepatoma have active mixed function oxidase systems capable of metabolizing a variety of drug and polycyclic hydrocarbon substrates. The tumor drug metabolism systems are at best 20% as active as rat liver. The tumor drug metabolism activities are induced by pretreatment with phenobarbital or beta-naphthoflavone and can be inhibited with specific inhibitors such as carbon monoxide or 7,8-benzoflavone. Tumor drug metabolism systems appear to consist of cytochrome P-450 and cytochrome P-450 reductase. The properties of the two protein components from tumors are highly similar to the corresponding components of the liver drug metabolism system. Cytochrome P-450 reductase has been at least partially purified from the Novikoff hepatoma and hepatoma 5123 t.c.(H). The kinetic and physical properties of the tumor reductases are similar to those of the liver reductase except that the Km of hepatoma 5123 t.c.(H) reductase, but not of the Novikoff hepatoma reductase for NADPH, is elevated an order of magnitude over the Km of the liver reductase. The mechanism for the interaction of electron donor and electron acceptor with liver or tumor reductases seems to be a sequential reaction mechanism. Experiments on the NADP-inhibition of the interaction of NADPH and cytochrome c with liver reductase indicate that NADP is competitive with NADPH and noncompetitive with cytochrome c. This result is consistent with the postulate of a sequential reaction for NADPH-cytochrome P-450 reductases of liver and tumors. These data support the conclusions that an active drug metabolism system is present in liver tumors and that the tumor systems are constituted like the liver system.


Qinzhu Liangxue inhibits IL-6-induced hyperproliferation and inflammation in HaCaT cells by regulating METTL14/SOCS3/STAT3 axis.
Psoriasis, an immune-mediated chronic inflammatory skin condition, is treatable with Qinzhu Liangxue (QZLX), a therapeutic medicinal plant formula used in clinical practice. However, further investigation is needed to clarify its molecular mechanisms of action. The potential biological mechanisms of QZLX to alleviate psoriasis involving IL-6-induced hyperproliferation and inflammation by regulating METTL14/SOCS3/STAT3 axis. HaCaT cell model was induced by IL-6, and dealt with serum containing QZLX. In addition, shRNAs and siRNAs were used for gene silencing, viruses were collected 48 h post-transfection and infected HaCaT cells. Cell viability was detected by CCK-8 assay, cell cycle was determined by flow cytometry. Finally, psoriasis mice model was induced by IMQ cream, then back skin tissue was used for hematoxylin and eosin (H&E). The content of IL-1β, IL-6, and IL-8 in cell supernatants were analyzed using ELISA kits. Analysis of SOCS3 was used by quantitative RT-PCR, the expression level of SOCS3, METTL3, METTL14, WTAP, SOCS3, YTHDF2, p-STAT3 and STAT3 in HaCaT cells transduced with METTL14 overexpression was detected by Western blot. All results indicated that QZLX could significantly alleviate IL-6-induced HaCaT cell viability, cell cycle progression, and inhibit the level of IL-1β, IL-6, and IL-8. The m6A levels and level of METTL14 in HaCaT cells treated with IL-6 were enhanced, while it was reversed by QZLX. METTL14 silencing could inhibit IL-6-induced HaCaT cell viability, cell cycle progression and inflammation response, while SOCS3 overexpression also suppressed METTL14-induced HaCaT cell viability, cell cycle progression and inflammation. QZLX could significantly enhance the expression level of SOCS3, while inhibit the level of METTL14, and p-STAT3/STAT3. In addition, QZLX inhibits METTL14-induced HaCaT cell viability, cell cycle progression, and inhibits the level of IL-1β, IL-6, and IL-8. Our finding suggested that QZLX ameliorated the inflammation response of psoriasis and performed the potential anti-psoriasis effect by regulating METTL14/SOCS3/STAT3 axis in both mice and HaCaT cells psoriasis model. Therefore, our study demonstrated a significant strategy for inhibiting psoriasis inflammation via targeting METTL14/SOCS3/STAT3 axis.


Sex differences in the relationships between electrocardiographic abnormalities and the extent of left ventricular hypertrophy by echocardiography.
Several criteria have been proposed for the electrocardiographic diagnosis of left ventricular hypertrophy (LVH). However, their diagnostic accuracy is questionable. Furthermore, the diagnostic accuracy of abnormalities in ST-T patterns for LVH is known to be uncertain, especially in women. We examined the relationship between electrocardiographic abnormalities and the extent of LVH. We studied 76 men and 48 women who satisfied electrocardiographic voltage criteria for LVH (RV(5) or RV(6)> or = 2.6 mV, SV(1) + RV(5) or SV(1) + RV(6)> or = 3.5 mV). They were classified into three groups based on ST-T pattern: normal, early strain, and strain. We defined echocardiographic evidence of LVH as an LV wall thickness > or = 12 mm. LVH was identified by echocardiography in 55.3% of men and in 47.9% of women. In strain and early strain groups, the prevalence of echocardiographic LVH was significantly higher in men than in women (strain group: 100 vs 75%, P < 0.05, early strain group: 81.8 vs 42.1%, P < 0.05), it did not differ significantly between men and women in normal group. In men, QRS voltage values were significantly correlated with echocardiographic indices. In group strain of men, significant good correlations were observed between QRS voltage values and echocardiographic indices. However, in women, there were no significant correlation between QRS voltage values and echocardiographic indices even in strain group. The combined criteria of both QRS voltage and ST-T classification could provide a greater accuracy in diagnosing LVH compared to the criteria using QRS voltage alone in men rather than in women.


A Feasibility Study on Clinical Utility, Efficacy and Limitations of 2 Types of Flexible and Navigable Suction Ureteral Access Sheaths in Retrograde Intrarenal Surgery for Renal Stones.
To evaluate stone-free rate, device maneuverability, and complications after retrograde intrarenal surgery (RIRS) using 2 different sizes of flexible and navigable suction ureteral access sheaths (FANS). A retrospective analysis was performed for patients who underwent RIRS for renal stones of any size, number, and location between November 2021 and October 2022. Group 1 had FANS of 12 French. Group 2 had FANS of 10 French. Both sheaths have a Y-shaped suction channel. Tip of 10 French FANS has 20% more flexibility. Lithotripsy was achieved using either thulium fiber or high-power holmium lasers. A 5-point Likert scale was used to assess the performance of each sheath. There were 16 patients in Group 1 and 15 patients in Group 2. Baseline demographics and stone parameters were similar. Four patients in Group 2 had the same session bilateral RIRS. Sheath insertion was successful in all renal units but one. Ten French FANS had a higher percentage of excellent scores for ease of use, manipulation, and visibility. Neither of the sheaths had an average or difficult rating for all evaluation scales. A fornix rupture requiring prolonged stenting occurred in group 2. All patients were discharged within 24 hours of surgery. One patient in each group visited the emergency department (analgesic treatment). There were no infectious complications. At 3 months, a computed tomography scan showed that the absence of residual fragments >2 mm was significantly higher in Group 2 (94.7% vs 68.8%, P = 0.01). The 10 Fr FANS showed a higher stone-free rate. There was no infectious complication using both sheaths.


The cerebro-hepato-renal (Zellweger's) syndrome: report of four cases.
Four cases of cerebro-hepato-renal syndrome are described. Radiographic findings of scimitar-shaped calcifications of the patellae and stippled cartilage califications have previously been described. We noted calcifications in the area of the greater trochanters in 2 of our patients, and bell-shaped thoraces in all patients. One of our patients is the longest survivor of the children affected by this syndrome.


Evaluation of the central nervous function in resuscitated comatose patients by multilevel evoked potentials.
Multilevel evoked potentials were examined in 17 patients who became comatose after cardiac arrest and resuscitation. In 4 patients, the P1 through N3 components of the somatosensory evoked cerebral potential (SECP) were present altogether within 100 ms after the ischemic insults. They all subsequently regained consciousness, though three of them developed intelligence and motor disturbances to some extent. In 11 patients who regained consciousness, or remained in a vegetative state, the evoked potentials which reflect brainstem functions, such as the auditory evoked brainstem potential, the R1 wave of the orbicularis oculi reflex and the slow positive wave of the somatosensory evoked brainstem potential, were recognized. The somatosensory evoked spinal potential and spinal monosynaptic reflex showed normal appearances in the state of vegetation and even after the determination of brain death. The measures of SECP could be useful in predicting restoration of consciousness.


Questionnaire Survey on Vaccination Willingness and the Status of COVID-19 Vaccination Among Patients with Rheumatic Disease: A Single-Center Survey in China.
The COVID-19 pandemic is an ongoing global pandemic. Patients with rheumatic disease are more likely to be infected with COVID-19 than the general population, and they should be vaccinated against COVID-19 for protection. This study aimed to understand the willingness to receive the COVID-19 vaccine among these patients. Patients who came to the Rheumatology and Immunology Department of our hospital from July 3-20, 2021, were randomly selected for a self-designed survey via an online questionnaire platform. Four hundred seventeen questionnaires were validated. Males were more likely to underestimate the risk of COVID-19 infection than females, and medical workers had a higher perception of COVID-19 infection risk than nonmedical workers (both P <0.05). Among the included patients, 149 (35.73%) patients were hesitant to be vaccinated, while 268 (64.27%) patients are willing to accept vaccination. Logistic regression analysis showed that men were more willing to be vaccinated than women, and nonmedical workers were more willing to be vaccinated than medical workers (both P <0.05). A total of 55.40% of the patients did not receive the COVID-19 vaccine. The incidence of adverse reactions for the 167 patients who received the COVID-19 vaccine was 8.98%. The vaccination rate of the patients with rheumatic disease was relatively low, as was their vaccination willingness. Patient sex, whether the patient was a medical worker, and the patient's level of knowledge about the risk of COVID-19 infection and the impact of vaccination on the disease were key factors.


Regorafenib in patients with advanced Child-Pugh B hepatocellular carcinoma: A multicentre retrospective study.
Regorafenib is an approved agent in patients with advanced hepatocellular carcinoma (HCC) who progressed on sorafenib, but little is known about its clinical outcomes in Child-Pugh B patients. We aimed to investigate the safety and effectiveness of regorafenib in Child-Pugh B HCC patients. This multicentre retrospective study included 59 patients with Child-Pugh B HCC who received regorafenib. Comparative analyses were performed with an independent cohort of Child-Pugh class A patients from the same registry (n = 440). The median age was 58 years (range, 19-83). All patients had progression on prior sorafenib. Regorafenib was given as 2nd line, and 3rd-4th line systemic therapy in 37 (62.7%) and 22 (37.3%) patients respectively. Compared to Child-Pugh A cohort, grade 3-4 AEs were more common in the Child-Pugh B cohort (27.1% vs 14.1%, P = .017). The median progression-free survival (PFS) and overall survival (OS) were 1.8 and 4.6 months, respectively, and these were significantly poorer than the Child-Pugh A cohort (P = .008 and P < .001 respectively). Child-Pugh B patients with albumin-bilirubin (ALBI) grade 3 had a significantly higher frequency of increased bilirubin (P = .01 for any grade and P = .01 for grade 3-4) and showed significantly poorer OS (P = .021), compared to those with ALBI grade 1 or 2. Regorafenib's poor clinical outcomes and increased frequency of severe adverse events lead us to discourage its use in the Child-Pugh B population. In particular, regorafenib should not be used in Child-Pugh B patients with ALBI grade 3.


Tissue distribution of DNA adducts in male Fischer rats exposed to 500 ppm of propylene oxide: quantitative analysis of 7-(2-hydroxypropyl)guanine by 32P-postlabelling.
7-(2-Hydroxypropyl)guanine (7-HPG) constitutes the major adduct from alkylation of DNA by the genotoxic carcinogen, propylene oxide. The levels of 7-HPG in DNA of various organs provides a relevant measure of tissue dose. 7-Alkylguanines can induce mutation through abasic sites formed from spontaneous depurination of the adduct. In the current study the formation of 7-HPG was investigated in male Fisher 344 rats exposed to 500 ppm of propylene oxide by inhalation for 6 h/day, 5 days/week, for up to 20 days. 7-HPG was analyzed using the 32P-postlabelling assay with anion-exchange cartridges for adduct enrichment. In animals sacrificed directly following 20 days of exposure, the adduct level was highest in the respiratory nasal epithelium (98.1 adducts per 10(6) nucleotides), followed by olfactory nasal epithelium (58.5), lung (16.3), lymphocytes (9.92), spleen (9.26), liver (4.64), and testis (2.95). The nasal cavity is the major target for tumor induction in the rat following inhalation. This finding is consistent with the major difference in adduct levels observed in nasal epithelium compared to other tissues. In rats sacrificed 3 days after cessation of exposure, the levels of 7-HPG in the aforementioned tissues had, on the average, decreased by about one-quarter of their initial concentrations. This degree of loss closely corresponds to the spontaneous rate of depurination for this adduct (t 1/2 = 120 h), and suggests a low efficiency of repair for 7-HPG in the rat. The postlabelling assay used had a detection limit of one to two adducts per 10(8) nucleotides, i.e. it is likely that this adduct could be analyzed in nasal tissues of rats exposed to less than 1 ppm of propylene oxide.


Mendelian predisposition to herpes simplex encephalitis.
Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis in the Western world. The pathogenesis of HSE, which affects a small minority of HSV-1-infected individuals, has long remained elusive. Mendelian defects in the TLR3-interferon (IFN) and IFN-responsive pathways were recently shown to predispose to HSE, at least in some children. Autosomal recessive STAT-1 deficiency and X-linked NEMO deficiency were found in children with both mycobacterial disease and HSE. Autosomal recessive UNC-93B deficiency and autosomal dominant TLR3 deficiency were then described in children with isolated HSE. These discoveries provided proof-of-principle that HSE may result from a novel group of single-gene inborn errors of interferon (IFN)-mediated immunity. The TLR3-UNC-93B-dependent production of IFN-α/β and IFN-λ is essential to confer protective immunity to HSV-1 in the central nervous system during the course of primary infection in childhood.


Plasticity in fecundity highlights the females' importance in the spiny-cheek crayfish invasion mechanism.
Invasion is one of the most consequential phenomena affecting the distribution of native species. Few in number of species, European crayfish are losing the competition with introduced North American crayfish. The spiny-cheek crayfish, Orconectes limosus, is an outstanding example, successfully competing against the native narrow-clawed crayfish, Astacus leptodactylus. For four years, we collected data regarding crayfish occurrences, their relative abundance, and the structure of populations in the ongoing colonisation process of O. limosus in the lower Danube. The mature females of both invasive and indigenous crayfish species were analysed with respect to biometry and production of oocytes in relation to the dynamics of invasion. The interspecific comparisons showed no significant differences regarding body size, with an average of approximately 102 mm total length and 31 g wet weight for both species. However, the fecundity of the indigenous species was found to be constant throughout the investigated area, whereas the number of eggs produced by the invasive females was significantly increased at the active front of the invasion. The maximum number of ovarian eggs found was 887 and 1156 in the indigenous species and the invasive species, respectively. We propose the scenario that the invasive species, which carries the deadly crayfish plague, creates an ecological advantage by reducing the populations of indigenous crayfish. Subsequently, the invasive females opportunistically use the available resources to enhance their fecundity, resulting in the acute growth of populations. However, the long-term competitiveness and colonisation success of O. limosus still remain in question.


Action plan co-optimization reveals the parallel encoding of competing reach movements.
Several influential cognitive theories propose that in situations affording more than one possible target of action, we prepare multiple competing movements before selecting one. Here we provide direct evidence for this provocative but largely untested idea and demonstrate why preparing multiple movements is computationally advantageous. Using a reaching task in which movements are initiated after one of two potential targets is cued, we show that the movement generated for the cued target borrows components of the movement that would have been required for the other, competing target. This interaction can only arise if multiple potential movements are fully specified in advance and we demonstrate that it reduces the time required to launch a given action plan. Our findings suggest that this co-optimization of motor plans is highly automatic and largely occurs outside conscious awareness.


The toxicity assessment of extract of Peganum harmala L. seeds in Caenorhabditis elegans.
Peganum harmala L. is a medicinal herb extensively used in traditional Chinese medicine (TCM). So far, relevant reports on the toxicity of Peganum harmala L. seeds (PHS) are hardly available. Especially, we still know little about the in vivo mechanism for PHS toxicity. This study aims to evaluate the toxicity effects of PHS in Caenorhabditis elegans (C. elegans), investigate the possible mechanism of the toxicity effects of PHS, and provide reference for the pharmacological research of PHS. In the present study, the C. elegans was exposed to 0.25, 0.50, 1.00 mg/mL of PHS in nematode growth medium (NGM) at 22 °C in the presence of food. Lethality, lifespan, growth, reproduction, and locomotion behavior assays were performed to evaluate the toxicity effects of PHS in C. elegans. We then determined the mechanism of the toxicity effect of PHS by quantitative real-time polymerase chain reaction (qRT-PCR), acetylcholinesterase (AChE) activity assay, and oxidative stress resistance assays. The main components of PHS were detected by high performance liquid chromatography (HPLC). Compared with the control group, the lethality of C. elegans was significantly increased when they were exposed to the ethanol extract of PHS at 0.25, 0.50 and 1.00 mg/mL (P < 0.01), and the mean lifespan was significantly decreased (P < 0.01). We also observed that PHS exposure could induce the toxicity on body length, brood size, and locomotion behavior. Our study shows that the ethanol extract of PHS exerts obvious toxic effects on C. elegans, which would provide new ideas and methods for the biological evaluation of the toxicity of Chinese medicinal materials.


The significance of better utilization of patients' preoperative information in predicting outcomes of velopharyngeal surgery: a prospective cohort study.
To compare the efficiency of a TCM scoring system that includes 3 independent predictors obtained by physical examination, computed tomography, and polysomnography with the standard Friedman staging system that includes only physical examination variables for predicting surgical outcomes in patients with obstructive sleep apnea syndrome who undergo velopharyngeal surgery. This prospective study was carried out in 265 patients with obstructive sleep apnea syndrome who underwent velopharyngeal surgery. All these patients were re-examined with polysomnography for evaluation of surgical outcomes at least 3 months after surgery. The efficacies in the surgical outcome prediction of 2 systems were calculated and compared. The overall response rate and cure rate was 63.8% (169/265) and 22.3% (59/265), respectively. There were 32 patients with Friedman stage I, with a response rate and cure rate of 81.3% (26/32) and 28.1% (9/32), respectively, and 70 patients with TCM scores of < 14 with a response rate and cure rate of 91.4% (64/70) and 42.9% (30/70), respectively. Friedman stage and TCM grade were the only 2 factors independently predictive of surgical response (P < .05, odds ratio value = 0.642 and 0.382). The receiver operating characteristic curve analysis for surgical response showed that the area under the curve value was 0.600 for Friedman stage, which was significantly lower than that for TCM grade, 0.718 (P = .005). Apnea-hypopnea index and TCM grade were the only 2 factors independently predictive of surgical cure (P < .05, odds ratio value = 0.981 and 0.465). Compared with the Friedman staging system, the TCM scoring system was more efficient in selecting proper candidates for velopharyngeal surgery. The main reason may be its better utilization of patients' preoperative information, especially the inclusion of physiological factors. Registry: Chinese Clinical Trials Register; Name: Clinical Phenotypes and Precise Treatment of Adult OSA (Obstructive Sleep Apnea): A Multicenter Study; URL: http://www.ChiCTR.org.cn/showproj.aspx?proj=21189; Identifier: ChiCTR-ONC-17013132. Zhang J, Cao X, Yin G, et al. The significance of better utilization of patients' preoperative information in predicting outcomes of velopharyngeal surgery: a prospective cohort study. J Clin Sleep Med. 2022;18(3):843-850.


In utero exposure to maternal low protein diets induces hypertension in weanling rats, independently of maternal blood pressure changes.
The association between maternal nutrition, fetal growth and the later development of hypertension was investigated in the rat. Animals were habituated to diets containing 18% (control) or 9% (low) protein by weight. The rats were mated and maintained on the diets until the end of pregnancy. Lactating dams were transferred onto standard chow diet. Systolic blood pressure was determined in male and female weanling offspring, using an indirect tail-cuff method. To assess the direct effects of low protein diets upon blood pressure of adult animals, a group of male and female rats were fed 18% or 9% protein for 14 days. Blood pressure was determined at the beginning and end of the feeding period. Blood pressure was additionally assessed over 14 days in pregnant rats fed control or low protein diets. Low protein diets did not alter systolic blood pressure in adult male or female rats. The blood pressures of pregnant females fed 18% or 9% protein diets did not significantly differ at any stage of pregnancy. Rats fed 9% protein diets gave birth to significantly smaller pups. Litter sizes were unaltered, and no differences in perinatal mortality were observed. Pups exposed to maternal low protein in utero had higher systolic blood pressure at the age of 4 weeks, when compared to control pups. The phenomenon was observed in both male and female offspring. Blood pressures at 4 weeks of age were strongly associated with maternal protein intake (r = -0.55). Associations were also noted between blood pressure and maternal weight at mating (r = 0.48), and weight gain in pregnancy (r = -0.30). Fetal exposure to maternal low protein diets induces hypertension in rats. The phenomenon is observed early in life and is independent of sex and the influence of maternal blood pressure. The low protein diet itself did not produce an increase in the blood pressure of adult rats.


[Role of hypnotherapy in the treatment of debilitating tinnitus].
Hypnotherapy is currently used for tinnitus therapy in our university hospital. The aim of this study was to evaluate its efficacy. This study was performed on 110 patients suffering from distressing tinnitus. They were treated during five sessions with hypnotherapy, supplemented by instruction on self-hypnotherapy. A subjective evaluation was done by the practitioner at the end of the sessions of hypnotherapy. Then a questionnaire on psychologic distress (Wilson 1991) was sent retrospectively to the patients. We received 65 responses which were used for this study. Before treatment, the mean value of the Wilson score was 54 (28-104). After treatment, it was: 31 (0-86). 69% of the patients felt an improvement > or = 5 points Wilson score. These results were compared with the evaluation carried out by the practitioner at the end of the sessions of hypnosis. There was a "significant correlation" between the evaluation of the felt benefice, analyzed by the practitioner at the end of the sessions of hypnosis, and by the patient questioned long after the treatment. These results had significant correlation with the evaluation made by the therapist at the end of the five sessions of hypnotherapy. They show, how effective (68% improvement) this therapeutic approach can be. Hypnotherapy can be regarded as an effective treatment against distressing tinnitus.


The impact of emotion on numerosity estimation.
Both time and numerosity can be represented continuously as analog properties whose discrimination conforms to Weber's Law, suggesting that the two properties may be represented similarly. Recent research suggests that the representation of time is influenced by the presence of emotional stimuli. If time and numerosity share a common cognitive representation, it follows that a similar relationship may exist between emotional stimuli and the representation of numerosity. Here, we provide evidence that emotional stimuli significantly affect humans' estimation of visual numerosity. During a numerical bisection task, enumeration of emotional stimuli (angry faces) was more accurate compared to enumeration of neutrally valenced stimuli (neutral faces), demonstrating that emotional stimuli affect humans' visual representation of numerosity as previously demonstrated for time. These results inform and broaden our understanding of the effect of negative emotional stimuli on psychophysical discriminations of quantity.


Tryptophan hydroxylase-2 gene polymorphisms in rhesus monkeys: association with hypothalamic-pituitary-adrenal axis function and in vitro gene expression.
Tryptophan hydroxylase-2 (TPH2) is a newly identified second form of TPH responsible for serotonin synthesis in the brain and has been increasingly implicated as a contributor to the etiology of various psychiatric disorders. In this study, we have identified the constellation of polymorphisms in rhesus monkey TPH2 and investigated genotype/phenotype association as well as gene expression effects of specific polymorphisms. Genomic DNA was obtained from 247 rhesus monkeys, among which 24 had been previously examined for plasma cortisol level, dexamethasone suppression, and combined dexmethasone/ACTH challenge. Polymorphisms in all exons, splicing junctions and approximately 2 kb of the 5'-flanking region (5'-FR) of TPH2 were identified by sequencing. We identified 17 single nucleotide polymorphisms (SNPs) including two that are predictive of amino-acid change (25Pro>His and 75Gly>Ser, respectively), two mononucleotide repeats, one dinucleotide repeat, and one 159-bp insertion polymorphism. The 3'-UTR polymorphisms were significantly associated with hypothalamic-pituitary-adrenal (HPA) axis activity, especially 2051A>C, which was strikingly correlated with plasma cortisol level in the morning only (F=10.203, P=0.001). Luciferase reporter gene assays showed that the 3'-UTR polymorphisms and haplotypes had a profound effect on in vitro gene expression. Accordingly, these investigations revealed that polymorphisms in 3'-UTR of rhesus monkey TPH2 modulate HPA axis function, presumably by affecting levels of TPH2 expression.


A Systematic Review of Eligibility and Outcomes in Tinnitus Trials: Reassessment of Tinnitus Guideline.
To analyze existing tinnitus treatment trials with regard to eligibility criteria, outcome measures, study quality, and external validity and to recognize the effect of patient demographics, symptom duration, severity, and otologic comorbidity on research findings to help practitioners apply them to patient encounters. Systematic literature search conducted by an information specialist for development of the American Academy of Otolaryngology-Head and Neck Surgery Foundation's tinnitus clinical practice guideline. Articles were assessed for eligibility with the PRISMA protocol (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and data extracted by 2 independent investigators. Studies were assessed for methodological quality, inclusion and exclusion criteria, patient demographics, and outcome measures. A total of 147 randomized trials met inclusion criteria. Nearly all studies took place in a specialist setting. More than 50% did not explicitly define tinnitus, and 44% used a subjective severity threshold, such as "severely disturbing." Fifty-four percent required symptom duration of at least 6 months for study eligibility, and up to 33% excluded patients with "organic" hearing loss or otologic conditions. Mean age was 52.2 years, and median follow-up was 3 months. Only 20% had a low risk of bias. Randomized trials of tinnitus interventions are most applicable to older adults with tinnitus lasting ≥ 6 months who are evaluated in specialty settings. High risk of bias, short follow-up, and outcome reporting raise concerns about the validity of findings and may influence how clinicians apply trial results to individual patients and establish treatment expectations, thus demonstrating the need for further quality research in this field.


Inhibition of posterior capsule opacification with an immunotoxin specific for lens epithelial cells: 24 month clinical results.
To assess the safety and effectiveness of an immunotoxin, MDX-RA, designed to inhibit posterior capsule opacification (PCO). Eleven private practices in the United States. This study comprised 63 eyes of 63 patients having extracapsular cataract extraction by phacoemulsification; these patients were enrolled in a Phase I/II clinical investigation of the immunotoxin MDX-RA. At the close of surgery, 21 patients were treated with placebo, 23 patients with 50 units of the immunotoxin, and 19 patients with 175 units of the immunotoxin as an aqueous solution. The patients were monitored for 24 months after primary cataract surgery using external eye and slitlamp examinations, visual acuity assessment, ophthalmoscopy, pachymetry, tonometry, endothelial cell counts, and lens capsule photography. Posterior capsule opacification, recorded on lens capsule photographs, was graded independently by a committee of 3 cataract surgeons. The incidence of neodymium:YAG (Nd:YAG) capsulotomy was projected from the opacification results. The immunotoxin, at the 50 unit dose, was well tolerated and effective in inhibiting PCO. At the 175 unit dose, there was a trend toward increased postoperative inflammation that was transient with no residua. From 6 to 24 months postoperatively, the 50 unit dose significantly inhibited PCO compared with the placebo (P < .05). This significant reduction in PCO translated into a significantly lower projected need for Nd:YAG capsulotomy in the 50 unit than the placebo group (P < .004). About 60% in the placebo group and 4% in the 50 unit group were projected to need an Nd:YAG capsulotomy by 3 years postoperatively. The immunotoxin was well tolerated and was effective in reducing PCO for up to 24 months after cataract surgery. Although these preliminary results are encouraging, a larger study is underway to determine whether the reduction in PCO by the immunotoxin decreases the need for Nd:YAG capsulotomy.


Lateral geniculate cell responses to electrical stimulation of the retina.
Electrical stimulation of the retina evokes at the optic tract level rhythmic bursts of activity whose temporal structure is predictable from the polarity of the stimulation and the receptive field type. The reaction of lateral geniculate units to this input was studied in fast and slow relay cells as well as in interneurons. The results revealed that fast relaty cells presented a response whose temporal structure remained essentially unmodified in comparison to that observed at the optic tract level: that both anodal and cathodal polarities produced rythmic pattern of excitation the latency of which depended upon receptive field type and polarity applied. In slow relay cells and interneurons responses with equal latencies could be evoked for both polarities. Following cortical depression with 3 M KCl the latency of first bursts was unaffected in relay cells, while about one third of interneurons showed a temporal pattern which was similar to that recorded at the optic tract level after the treatment. This suggests that both ON and OFF retinal networks converge upon one geniculate slow P cell and interneuron, whereas fast relay cells are mostly driven by one of the two systems. Furthermore this convergence may be achieved through visual cortex in some units.


Senescence recovering by dual drug-encapsulated liposomal nanoparticles for large-scale human cell expansion.
Although regenerative therapy and bioartificial tissues and organs require a sufficient number of human cells, current cell expansion processes are accompanied by accumulation of senescent cells that are related to deterioration of cellular functions and induction of senescence-associated secretory phenotype (SASP). Therefore, suppression of replicative senescence during expansion is one of the crucial issues for dissemination of regenerative medicine. We herein developed dual drug-encapsulated liposomal nanoparticles (LNPs) to suppress cellular senescence in human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) and natural killer (NK) cells by removal of dysfunctional mitochondria from the senescent cells. We found that LNP treatment reduced senescent makers; downregulation of p21 expression and reduction of SA-β-Gal activity in both cells provably due to mitophagy reactivation in the cells. Moreover, SASP secretion in hAT-MSCs and tumor cytotoxicity in NK cells were also improved upon LNP treatments. These findings may contribute to the production of highly effective expanded cells for regenerative medicine and bioartificial tissues and organs.


Proliferating fibroblasts at the invading tumour edge of colorectal adenocarcinomas are associated with endogenous markers of hypoxia, acidity, and oxidative stress.
Stroma frequently forms at sites of active tumour invasion, and may be important for tumour growth and progression. The term "stromatogenesis" is used to describe this unique process that involves host peritumorous fibroblasts and is very different to reactive fibrosis. To investigate the activation status of host fibroblasts at the invading tumour edge, assessed as MIB1 proliferation index and thymidine phosphorylase (TP) expression. Results were related to vascular density and certain properties of invading cancer cells-MIB1 proliferation activity, TP expression, expression of endogenous markers of hypoxia (hypoxia inducible factor-1alpha; HIF1alpha) and acidity (lactate dehydrogenase-5; LDH5). Standard immunohistochemical techniques were applied to 150 colorectal adenocarcinomas. Normal fibroblasts at the tumour edge had a median MIB1 index of 2%-significantly higher than normal submucosal fibroblasts (0.3%) and significantly lower than cancer cells (40%). Normal peritumorous fibroblasts with a proliferation rate above the median strongly expressed TP and were supported by an increased vascular network. Cancer cells close to these fibroblasts had a high MIB1 proliferative index, high HIF1alpha and LDH5 reactivity, and a clear trend to extramural extension. All associations were significant. These results suggest that activated fibroblastic status at the invading tumour front sets the stage for stromatogenesis and new blood vessel formation, facilitating deep transmural invasion in colorectal adenocarcinomas. This complicity of peritumorous fibroblasts in the overall aggressiveness/invasive and metastatic ability of colorectal tumours, occurring within the framework of cancer-stromal cell interactions, is probably favoured by the altered microenvironmental conditions of hypoxia and acidity.


The tick Ixodida: an unusual foreign body in the ear.
We report a patient with a hard tick in her left ear, adherent to the tympanic membrane.


Choline transport and metabolism in soman- or sarin-intoxicated brain.
The metabolism and blood-brain transport of choline (Ch) were investigated in perfused canine brain under control conditions and for 60 min after inhibition of brain cholinesterases by the organophosphorus (OP) compounds soman (pinacolylmethylphosphonofluoridate). Ch and acetylcholine (ACh) in blood and brain samples were analyzed using gas chromatography-mass spectrometry methods. Net transport of Ch was determined by Ch analysis in arterial and venous samples. Unidirectional transport of [3H]Ch was determined using the indicator dilution method. During control perfusion periods of 90 min, net efflux of brain Ch occurred at a rate of 1.6 +/- 0.4 nmol/g/min, and the Ch content of the recirculated perfusate increased 10-fold to approximately 8 microM. Brain Ch content increased in proportion to the increase in perfusate Ch level, but brain ACh was unaltered. Rapid administration of soman (100 micrograms) or sarin (400 micrograms) into the arterial perfusate after a 40-min control period resulted in a greater than 10-fold increase in ACh content in cerebral cortex, brainstem, and hippocampus. The ACh content of cerebellum increased only slightly. The Ch level in all four brain regions studied also increased two- to fourfold above control levels. Ch efflux from brain, however, decreased to 0.2 +/- 0.1 nmol/g/min during the 60 min after OP exposure. Unidirectional influx of [3H]Ch was 0.49 +/- 0.07 nmol/g/min before and did not change significantly 10 or 40 min after OP exposure, thus indicating that the Ch transporter of the brain endothelial cell is not directly inhibited.2+ Based on these results, it is proposed that (a) efflux of brain Ch occurs from the extracellular compartment, which becomes depleted when ACh breakdown is inhibited;(ABSTRACT TRUNCATED AT 250 WORDS)


A morphological study of the nucleus subpretectalis of the pigeon.
In pigeons, the tectofugal system is functionally as well as structurally lateralized. So for example the right nucleus rotundus is less modulated by right forebrain influences than the left nucleus rotundus by the left ones. This functional lateralization pattern may depend on a dynamic balance between left and right tectal processing. Apart from inhibitory interactions at tectal level, suppressive influences might directly affect rotundal neurons by GABAergic input from a cluster of nuclei, the bed nuclei of the tecto-thalamic tract. A major afferent of these nuclei is the side branch of the tectorotundal projection which is of bilateral origin and which is involved in the regulation of ipsilateral as well as bilateral visual processing. Hence, an important role of the bed nuclei could be the interhemispheric communication and in turn the mediation of functional asymmetries. In a first step to unravel asymmetric influences of these nuclei, the present study investigated if the largest of the bed nuclei, the nucleus subpretectalis displays morphological asymmetries in the pigeon. We found that the nucleus subpretectalis in fact exhibits asymmetric cell sizes with larger cell bodies on the left side. This asymmetrical pattern was not present in dark-incubated animals indicating that cell size asymmetries within nucleus subpretectalis are induced by asymmetric photic stimulation during embryonic development.


High Anal Canal Pressure and Rectal Washouts Contribute to the Decrease of Anal Basal Pressure After Botulinum Toxin Injections in Paediatric Patients With Chronic Constipation.
Chronic constipation can be treated by injecting botulinum toxin into the anal sphincter to decrease anal basal pressure. To assess the effect of botulinum toxin, we investigated the factors that contribute to changes in anal basal pressure after injection. This was a retrospective study conducted in a tertiary hospital in the Netherlands. We included children with chronic constipation treated with botulinum toxin injections and measured anal basal pressure before and after each injection. Multivariable linear regression analyses were used. We investigated 30 cases with idiopathic constipation. Their median age was 20.5 (7.75-53.25) months. Anal basal pressure decreased after injection in 20 cases. The mean decrease of anal basal pressure after injection was 18.17 ± 35.22 mmHg. The anal basal pressure change was linearly correlated with preinjection pressure (R 2 = 0.593, P < 0.001). A significant decrease of pressure was observed in patients with preinjection pressure > 70 mmHg. Preinjection anal basal pressure (β = -0.913, P < 0.001) and rectal washouts (β = -21.015, P = 0.007) contributed significantly to pressure changes. Changes in anal basal pressure were also significantly associated with patients' weights (β = 0.512, 95% CI, 0.011-1.013) and sex (β = 22.971, 95% CI, 9.205-36.736). Botulinum toxin significantly decreases anal basal pressure when preinjection pressure is higher than 70 mmHg. In patients with severely elevated anal basal pressure, we recommend rectal washouts to promote the decrease of anal basal pressure.


Valvular heart disease: clinical approach to acute decompensation of left-sided lesions.
Acute valvular heart disease is often life-threatening. The diagnosis of acute valvular decompensation is made by attention to the physical assessment and appropriate use of diagnostic techniques. Recent advances in valvular heart disease have centered around noninvasive diagnostics. Doppler echocardiography can accurately diagnose and quantify stenotic and regurgitant lesions; its use with M-mode and two-dimensional echocardiography makes these the noninvasive diagnostic procedures of choice. Acute decompensation is often related to preexisting critical aortic or mitral stenosis, or more commonly, acute severe regurgitation. Although of different etiologies, acute mitral and aortic regurgitation are associated with similar diagnostic and therapeutic modalities. Emergency treatment consists of vasodilator and, possibly, inotropic therapy. However, definitive therapy generally requires surgical intervention.


Relationship Between Vasospasm and Serum Chromogranin A Levels in an Experimental Subarachnoid Hemorrhage Model.
To analyze Chromogranin A levels on vasospasm in an experimental subarachnoid heamorrhage (SAH) model. Sixteen Wistar Albino male rats were used in study. Two groups are formed; first was consisting of 8 rats that experimental SAH was performed on them, second group was control group that nothing was done. Animals were sacrified fourtyeight hours later subarachnoid heamorrhage was occured. Peripheral venous blood samples were taken from the experimental group before SAH formation, 15 minutes, 75 minutes after experimental SAH formation and 48 hours as peak of vasospasm. Simultaneous peripheral venous blood samples were also collected from the control group. Blood samples were biochemically evaluated after centrifugation and serum Chromogranin A levels were studied. Serum chromogranin A levels increased statistically significant (p < 0.05) at the 15th minute after SAH, as the samples obtained from the experimental and control groups were anticipated as a result of the statistical analysis of the data after the biochemical examinations. In all these findings, we concluded that Chromogranin A could be used as a marker for the investigation of endocrine stress in the early period of post-SAH vasospasm and it could be proved by more studies.


The Executive Training For Research Application (EXTRA) program: perceptions of the first cohort of fellows.
The Canadian Health Services Research Foundation (CHSRF) and partners have created an innovative training program to support health care executives who use research evidence to inform decision-making. This article describes the Executive Training for Research Application (EXTRA) program and the perceptions of its first cohort of fellows (n = 24). Despite challenges in balancing the time required to participate in this trusting learning environment, which encouraged and supported networking, the fellows were able to develop and apply a considerable knowledge base for evidence-informed decision-making.


Immunisation status of children in Germany: temporal trends and regional differences.
In Germany, a low coverage with hepatitis B and measles vaccines and a considerable delay in administration of all recommended vaccines were previously apparent. Whether there have been improvements and whether there are regional differences within Germany is not known. Using representative nationwide telephone interviews on 2,701 children born 1996-2003, we assessed vaccination coverage for the first dose or full primary series (2/3 doses, depending on vaccine used) at 24 months of age. The proportions vaccinated with the first dose, full priming and full immunisation (2/3 doses plus booster in the 2nd year of life) until the end of the recommended age (3, 5 and 15 months, respectively, for diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b (Hib) and hepatitis B vaccines (DTPPolioHibHep), and 15 for the first measles, mumps and rubella dose (MMR) were used as indicators of compliance with national guidelines. Coverage for polio, Hib and hepatitis B vaccines increased, while coverage for the first MMR dose remained constantly low at about 70%. Vaccination coverage differed substantially among the German states and was highest for the new states. Compliance with national guidelines increased from 2.5% to 15% for the full primary DTPPolioHibHep series, from 16.2% to 44.7% for the first MMR dose and from 1.0% to 19.3% for the full immunisation with all recommended vaccines (DTPPolioHibHepMMR). Vaccination coverage at 24 months and compliance with national guidelines has improved for most vaccines in Germany. However, improving coverage for measles, mumps, rubella and eliminating the regional disparities remain a major challenge for the public health sector.


The ethics of creating children with three genetic parents.
This article on mitochondrial replacement technology briefly explains and defends the legitimacy of such terms as 'three-parent embryos', 'three-parent babies' and 'three-person IVF'. Next, it reviews select ethical objections to mitochondrial replacement technology that fall into four, sometimes overlapping, categories: (i) harms to egg providers; (ii) harms to potential offspring and future generations; (iii) harms to specific interest groups; and (iv) harms to society. Taken together, these ethical objections are cause for serious concern and yet the development and future use of mitochondrial replacement technology is likely inevitable.


Integrated genomics and proteomics analysis of Paenibacillus peoriae IBSD35 and insights into its antimicrobial characteristics.
Antimicrobial resistance has been developing fast and incurring a loss of human life, and there is a need for new antimicrobial agents. Naturally occurring antimicrobial peptides offer the characteristics to counter AMR because the resistance development is low or no resistance. Antimicrobial peptides from Paenibacillus peoriae IBSD35 cell-free supernatant were salted out and purified using chromatography and characterized with liquid chromatography-tandem-mass spectrometry. The extract has shown a high and broad spectrum of antimicrobial activity. Combining the strain IBSD35 genome sequence with its proteomic data enabled the prediction of biosynthetic gene clusters by connecting the peptide from LC-MS/MS data to the gene that encode. Antimicrobial peptide databases offered a platform for the effective search, prediction, and design of AMPs and expanded the studies on their isolation, structure elucidation, biological evaluation, and pathway engineering. The genome-based taxonomy and comparisons have shown that P. peoriae IBSD35 is closely related to Paenibacillus peoriae FSL J3-0120. P. peoriae IBSD35 harbored endophytic trait genes and nonribosomal peptide synthases biosynthetic gene clusters. The comparative genomics revealed evolutionary insights and facilitated the discovery of novel SMs using proteomics from the extract of P. peoriae IBSD35. It will increase the potential to find novel bio-molecules to counter AMR.


The role of bile duct reactive change in the pathogenesis of liver fibrosis due to hepatitis C.
The question addressed here is: does the bile duct reactive component of hepatitis C disease progress during the progression of the disease to cirrhosis? The question is important because if the answer to the question is yes, then an important correllated question is: does the bile duct reactive component contribute to the fibrotic change which leads to cirrhosis? The first question is addressed in the present study of a series of liver biopsies taken at the four stages of liver fibrosis in patients with hepatitis C. Sixty-four patients with hepatitis who had been biopsied for staging purposes were reviewed retrospectively. The liver biopsies were routinely stained with antibodies for liver cells, bile duct cells, activated stellate cells and cells in S phase of the cell cycle and histochemical stains for collagen and basement membrane. Selective biopsies were stained for stem cells and oval cells. There was a progressive increase in metaplastic bile ductules but the increase did not reach a significant level until stages III and IV of fibrosis. There was a positive correlation between the number of ductules formed and the stage of liver fibrosis. The incidence of proliferating metaplastic ductules was low and did not change significantly during the progression of the stage of the fibrosis. Stains for oval cells and stem cells were negative. It is concluded that the answer to the question posed is: bile ductule reaction does increase during the development of cirrhosis caused by hepatitis C but the increase is due to bile ductular metaplasia, not due to proliferation.


Parachordoma: a clinicopathologic and immunohistochemical study of four cases of an unusual soft tissue neoplasm.
Four soft tissue tumors corresponding with the previously reported parachordoma are described. Three of the patients were men, and one was a woman, and their ages ranged from 14 to 53 years (mean age, 29). The tumors were located either superficially or within muscle, and, in one case, involved a tendon. Histologically, the tumors displayed whorls, nests, and pseudoglandular cords of uniform polygonal cells with eosinophilic, vacuolated cytoplasm, in a focally myxoid stroma. Transitions were seen between fascicles of ovoid-spindled cells, with scanty cytoplasm in a fibrous stroma, and, in one case, whorls of bland spindly cells were also present. Electron microscopy of one case showed cells with short interdigitating microvilli and ill-defined junctions. The principal cells in all cases were positive for S100 protein, Leu-7, keratin (CAM5.2), and epithelial membrane antigen (EMA). All tumors were negative with antibody AE1 and with antibodies to cytokeratins CK7 and CK19. No tumor displayed immunoreactivity for carcinoembryonic antigen (CEA), muscle specific actin (MSA), smooth muscle actin (SMA), desmin, glial fibrillary acid protein (GFAP), CD31, or CD34. Parachordoma appears to be an entity with clinical and pathological differences from chordoma, which has a different cytokeratin profile, behaves in a more aggressive fashion, and can dedifferentiate. The differential diagnosis includes myxoid chondrosarcoma, myoepithelial cell tumor, ossifying fibromyxoid tumor, and chondroid lipoma.


What Do Unusual Faces Teach Us About the Ethics of Recognition?
With close attention to the film Wonder, this article examines how a narrative of community acceptance offers sustaining relationships for people with unusual facial appearance. This article argues that premodern responses of wonder can help reframe modern understandings of looking different.


Natural killer group 2D receptor and its ligands in cancer immune escape.
The immune system plays important roles in tumor development. According to the immune-editing theory, immune escape is the key to tumor survival, and exploring the mechanisms of tumor immune escape can provide a new basis for the treatment of tumors. In this review, we describe the mechanisms of natural killer group 2D (NKG2D) receptor and NKG2D ligand (NKG2DL) in tumor immune responses.Natural killer (NK) cells are important cytotoxic cells in the immune system, and the activated NKG2D receptor on the NK cell surface can bind to NKG2DL expressed in tumor cells, enabling NK cells to activate and kill tumor cells. However, tumors can escape the immune clearance mediated by NKG2D receptor/NKG2DL through various mechanisms. The expression of NKG2D receptor on NK cells can be regulated by cells, molecules, and hypoxia in the tumor microenvironment. Tumor cells regulate the expression of NKG2DL at the level of transcription, translation, and post-translation and thereby escape recognition by NK cells. In particular, viruses and hormones have special mechanisms to affect the expression of NKG2D receptor and NKG2DL. Therefore, NKG2D\NKG2DL may have applications as targets for more effective antitumor therapy.


Modified technique of tension band wiring in flexion injuries of the middle and lower cervical spine.
This study evaluated simple modifications in tension-band wiring for 52 patients with acute flexion injuries of the middle and lower cervical spine. To determine the usefulness and effectiveness of a modified technique for stabilizing unstable flexion injuries of the cervical spine. The prevalent surgical techniques of Segal et al and Davey et al fix unstable injuries of the cervical spine by passing two transverse "K" wires through the skin and the spinous process itself, with tricortical iliac crest grafts placed on the sides. This is supplemented with "figure of 8" wiring for long-term stability. Fifty-two patients with acute flexion injuries of the cervical spine were fixed with tension-band wiring with slotted grafts placed over the "K" wires and passed through the spinous process, instead of the "K" wire being passed through grafts. Patients free of neurologic symptoms achieved mobility early with the cervical collar. All patients achieved posterior bony fusion. There was no migration or rupture of tension bandwires or tricortical graft in our series. The modifications used were simple to apply and resulted in good fixation and fusion in patients with acute flexion injuries of the cervical spine.


Assessment of left ventricular diastolic filling by two-dimensional echocardiography.
Although two-dimensional echocardiography has provided accurate measurements of left ventricular ejection fraction, the technique has been limited in the evaluation of diastolic function. First half-filling fraction, representing the difference between mid-diastolic and end-systolic volumes divided by stroke volume, is a recently introduced index of diastolic function. We developed a method for determining half-filling fraction by two-dimensional echocardiography with the use of the average of left ventricular internal diameters measured at the base, middle, and apical third of the ventricular cavity in multiple longitudinal planes. In 27 patients with a wide range of ventricular function, we compared angiographic measurements of half-filling fraction to results obtained by two-dimensional echocardiography. Half-filling fraction measured angiographically averaged (mean +/- SD) 0.58 +/- 0.15 (range 0.26 to 0.77) and measured by two-dimensional echocardiography averaged 0.58 +/- 0.15 (range 0.35 to 0.90). A significant correlation was found between angiographic and echocardiographic half-filling fractions (r = 0.84, SEE = 0.08). Results were similar in the presence or absence of segmental wall motion abnormalities. All seven patients with half-filling fractions below 0.50 by echocardiography had depressed half-filling fractions by angiography; three of these patients had ejection fractions of greater than or equal to 0.55. Thus half-filling fraction can be derived with two-dimensional echocardiography providing a noninvasive assessment of diastolic function.


Relationship between alcohol consumption and breast cancer morbidity rates in Western Australia, 1971--1984.
Per adult (greater than or equal to 15 years) consumption of beer, wine, spirits and absolute alcohol for a 14-year period (1971--1984) was related to female breast cancer morbidity rates in Western Australia. Mann-Whitney U-tests showed that during the 7 years of highest wine consumption the highest rates for breast cancer occurred for females aged 30--59 years, but for women over 60 years of age the result was insignificant. The findings are consistent with a number of previous studies which have shown a positive association between alcohol consumption and increased risk of breast cancer.


Unravelling patient pathways in the context of antibacterial resistance in East Africa.
A key factor driving the development and maintenance of antibacterial resistance (ABR) is individuals' use of antibiotics (ABs) to treat illness. To better understand motivations and context for antibiotic use we use the concept of a patient treatment-seeking pathway: a treatment journey encompassing where patients go when they are unwell, what motivates their choices, and how they obtain antibiotics. This paper investigates patterns and determinants of patient treatment-seeking pathways, and how they intersect with AB use in East Africa, a region where ABR-attributable deaths are exceptionally high. The Holistic Approach to Unravelling Antibacterial Resistance (HATUA) Consortium collected quantitative data from 6,827 adult outpatients presenting with urinary tract infection (UTI) symptoms in Kenya, Tanzania, and Uganda between February 2019- September 2020, and conducted qualitative in-depth patient interviews with a subset (n = 116). We described patterns of treatment-seeking visually using Sankey plots and explored explanations and motivations using mixed-methods. Using Bayesian hierarchical regression modelling, we investigated the associations between socio-demographic, economic, healthcare, and attitudinal factors and three factors related to ABR: self-treatment as a first step, having a multi-step treatment pathway, and consuming ABs. Although most patients (86%) sought help from medical facilities in the first instance, many (56%) described multi-step, repetitive treatment-seeking pathways, which further increased the likelihood of consuming ABs. Higher socio-economic status patients were more likely to consume ABs and have multi-step pathways. Reasons for choosing providers (e.g., cost, location, time) were conditioned by wider structural factors such as hybrid healthcare systems and AB availability. There is likely to be a reinforcing cycle between complex, repetitive treatment pathways, AB consumption and ABR. A focus on individual antibiotic use as the key intervention point in this cycle ignores the contextual challenges patients face when treatment seeking, which include inadequate access to diagnostics, perceived inefficient public healthcare and ease of purchasing antibiotics without prescription. Pluralistic healthcare landscapes may promote more complex treatment seeking and therefore inappropriate AB use. We recommend further attention to healthcare system factors, focussing on medical facilities (e.g., accessible diagnostics, patient-doctor interactions, information flows), and community AB access points (e.g., drug sellers).


A star-shaped POSS-containing polymer for cleaner leather processing.
A water-based silsesquioxane (POSS)-containing polymer, POSS-PAA, was synthesized by using octavinyl-POSS (V-POSS) and acrylic acid (AA) via interfacial polymerization. The TEM of POSS-PAA showed that the polymer formed a core-shell structure in aqueous solution and was well-dispersed. The star-shaped POSS-PAA and linear PAA were both tanned with 3.5% chromium tanning agent, and leather hide was tanned with 3.5% chromium tanning agent as a control. The results showed that the shrinkage temperature of wet-blue leather treated by POSS-PAA was increased by 3.5 °C than that of the control. The thickening rate of the POSS-PAA treated wet-blue leather samples was increased by 21% and 96% than the linear PAA-treated leather and the control leather, respectively. The EDS results suggested that the POSS-PAA pre-treated leather had a higher chromium content than the others, and the chromium distribution from the leather flesh side to the grain side was uniform. Moreover, the Cr2O3 content in both the POSS-PAA and the PAA pre-treated tanning waste water was reduced by about 50%, compared to the control waste. The COD and BOD of the POSS-PAA pre-tanning waste were decreased compared to the others. Therefore, POSS-PAA appeared to be promising for promoting the development of cleaner leather production.


No-carrier-added nucleophilic 18F-labelling in an electrochemical cell exemplified by the routine production of [18F]altanserin.
A new type of electrochemical cell with anodic deposition of no-carrier-added [(18)F]fluoride and variable reaction volume has been developed. The reactor is designed for small reaction volumes and non-thermal drying of [(18)F]fluoride. The implementation of this reactor into a complete remotely controlled synthesis device is described for the routine production of [(18)F]altanserin. A radiochemical yield of 23+/-5% was obtained via cryptate-mediated nucleophilic (18)F-fluorination. Batches of up to 6 GBq [(18)F]altanserin, suitable for human application, with a molar activity of >500 GBq/micromol were obtained within 75 min.


Antimicrobial effect of a local release system containing metronidazole against a Porphyromonas gingivalis biofilm.
The aim of this study was to evaluate a semi-solid system containing metronidazole (MDZ) in presence of challenging conditions for drug release, as well its antimicrobial effect against Porphyromonas gingivalis biofilm. Biofilms grown in culture medium were exposed to a formulation containing MDZ or its vehicle. After 24, 48, and 72 h, biofilm viability were analyzed while MDZ was quantified in culture medium and buffer solution (control). MDZ formulation reduced bacterial viability when compared to control groups. The vehicle formulation also affected bacterial viability in relation to control at all periods. Culture medium impaired MDZ release compared to buffer solution at 24 h. The semi-solid system reported herein is able to release MDZ and maintain its levels at concentrations that control viability of P. gingivalis in 1- to 3-day-old biofilms.


Evidence that increases in circulating catecholamines of adrenal origin are not involved in pressor response to bilateral carotid occlusion in anaesthetized dogs.
1. We studied whether or not circulating catecholamines of adrenal origin play a major role in cardiovascular responses evoked by bilateral carotid artery occlusion (3 min) in anaesthetized dogs. 2. In the control group, the following parameters increased significantly (P less than 0.05) during bilateral carotid occlusion: aortic systolic pressure, heart rate, net adrenal catecholamine output, net renal noradrenaline output, and plasma catecholamine concentrations in aortic blood. Similar responses were obtained during the second occlusion performed approximately 25 min after the first occlusion. 3. After functional adrenalectomy (ADRX: diversion of adrenal venous blood flow), the increase in aortic adrenaline concentration observed during bilateral carotid occlusion was abolished. The increase in aortic noradrenaline concentration during the occlusion was significantly attenuated by approximately 60% (P less than 0.01) after ADRX. 4. The increase in net renal noradrenaline output during bilateral carotid occlusion after ADRX was not different from that observed before ADRX. Similarly, the response of aortic systolic pressure and heart rate during the occlusion was unaffected by ADRX. Furthermore, the increase in net adrenal catecholamine output during the occlusion was not affected by ADRX itself. 5. From these results, we conclude that the increase in circulating catecholamines of adrenal origin during bilateral carotid occlusion is not a major determinant for the increases in aortic pressure and heart rate. The results suggest that these cardiovascular responses during the occlusion are mediated principally by neuronal noradrenaline released from peripheral sympathetic nerve terminals.


[Caries epidemiological study of 7-10-year old school children in Weil am Rhein].
Children aged between 7 and 10 in four years at the primary schools in the town of Weil am Rhein were examined for the prevalence of tooth decay by a team which had already carried out the same investigations, applying the same criteria, in other towns. The data were analyzed with a standardized computer program.


The effect of ozone on the biodegradation of 17α-ethinylestradiol and sulfamethoxazole by mixed bacterial cultures.
The potential development of antibacterial resistance and endocrine disruption has led to increased research investigating the removal of contaminants from wastewater (WW) such as sulfamethoxazole (SMX) and 17α-ethinylestradiol (EE2). These compounds react quickly with ozone (O(3)), thus ozonation during WW treatment may result in their complete removal. Also, O(3) has demonstrated the ability to increase the biodegradability of WW and certain pharmaceuticals, suggesting its potential as a pretreatment to activated sludge (AS, biological treatment). The objective of this study was to determine whether ozonation, conducted at doses lower than commonly applied to treated WW, would lead to an increased biodegradability of SMX and EE2. The results show that after ozonation performed at lab-scale the bacterial mixtures removed 5 % to 40 % more SMX; however, 2 % to 23 % less EE2 was removed, which was attributed to the observed preferential degradation of a by-product of EE2 ozonation. These results suggest that although ozonation, used as a pretreatment, was shown in literature to increase the overall biodegradability of AS as well as some specific antibiotic compounds and a blood lipid regulator, the potential for increased removal of pharmaceuticals seems to be compound-dependent and cannot yet be extrapolated to this entire class of compounds.


Return to work after burns: a qualitative research study.
As yet no qualitative research studies looking at return to work following burns have been published. The aim of this study was to investigate the "hows" and "whys" of return to work, by purposively selecting a cross-section of burns patients who returned to the same/similar job, those who returned to work but either on a part-time basis or in a different role/job and those who became or remained unemployed, and using semi-structured interviews to explore their experiences. Using matrix analysis methodology, and with the general themes that emerged from these transcripts, it was possible to place patients into 5 broad groups, the "defeated", the "burdened", the "affected", the "unchanged" and the "stronger". We anticipate that use of these general groups will be useful in targeting multi-disciplinary return to work strategies, and discuss how this qualitative research has changed practice at the Queen Victoria Hospital Burns Centre.


Physiological and Pathophysiological Aspects of Diabetic Foot Ulcer and its Treatment Strategies.
Diabetes foot ulcers (DFU) are among the most common complications in diabetic patients, leading to amputation and psychological distress. This mini-review covers the general physiology of ulcer healing as well as the pathophysiology of DFU and its therapies. Only a few treatments have been sanctioned and numerous compounds from various pharmacological groups are now being tested at various stages for the prevention and treatment of DFUs. The main objective of this mini-review is to give concise information on how diabetes mellitus impairs the healing of chronic ulcers by disrupting numerous biological systems of the normal healing process, resulting in diabetic foot ulceration, and the current therapeutic approaches. A review of accessible material from systemic searches in the PubMed/Medline, Scopus, Cochrane Database of Systematic Reviews, published review articles, and Clinical Trials databases (US National Library of Medicine) with no period of limitation was conducted. The treatment of DFUs comprises wound dressings, use of matrix metalloproteinase inhibitors in wound dressing, antibiotics, skin substitutes, pressure off-loading growth factors and stem cells, gene therapy, topical oxygen therapy, etc. Conclusion: The majority of these treatments are aimed at treating diabetic foot ulcers and preventing diabetic wounds from becoming infected. Yet, there is no single therapy that can be advised for diabetic foot ulcer patients. Future treatment strategies should be considered an appropriate treatment option for persistent wounds.


Depressive symptoms and mortality two years after coronary artery bypass graft surgery (CABG) in men.
Depression has been related to mortality in patients with CAD and to medical morbidity after CABG; however, prior studies have not examined the contribution of presurgical depressive symptoms to mortality after CABG. The purpose of this study was to determine the independent contribution of presurgical symptoms of depression to 2-year cardiac mortality after CABG. Eighty-nine consecutive veteran nonemergent CABG patients recruited between December 1996 and June 1998 completed the BDI 1 to 7 days before surgery. Mortality risk was assessed by medical co-morbidity and RIS. Significant univariate contributions to two-year cardiovascular mortality were found for RIS (chi2 = 6.57, p <.01), history of CHF (chi2 = 4.94, p <.02), history of COPD (chi2 = 5.19, p <.02), and elevated depressive symptoms (chi2 = 4.70, p <.03). The multivariate model revealed that the RIS (chi2 = 4.70, p <.03) and elevated depressive symptoms (chi2 = 3.86, p <.05) remained significant in the prediction of 2-year cardiovascular mortality, with no other variables being found significant. Elevated depressive symptoms before CABG surgery appear to be an important independent contributor to long-term mortality. Future research should focus on replication with larger, more diverse samples, and identification of pathophysiological mechanisms.


Treatment with a clinically-relevant dose of methylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex.
Methylphenidate (Ritalin, MPH) is the most commonly prescribed psychoactive drug for children. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, its cellular mechanisms of action and potential long-term effects are poorly understood. We recently reported that a clinically relevant (1 mg/kg i.p., single injection) dose of MPH significantly decreased neuronal excitability in the juvenile rat prefrontal cortical neurons. Here we further explore the actions of acute treatment with MPH on the level of NMDA receptor subunits and NMDA receptor-mediated short- and long-term synaptic plasticity in the juvenile rat prefrontal cortical neurons. We found that a single dose of MPH treatment (1 mg/kg, intraperitoneal) significantly decreased the surface and total protein levels of NMDA receptor subunits NR1 and NR2B, but not NR2A, in the juvenile prefrontal cortex. In addition, the amplitude, decay time and charge transfer of NMDA receptor-mediated EPSCs were significantly decreased whereas the amplitude and short-term depression of AMPA receptor-mediated EPSCs were significantly increased in the prefrontal neurons. Furthermore, MPH treatment also significantly increased the probability and magnitude of LTP induction, but had only a small effect on LTD induction in juvenile rat prefrontal cortical neurons. Our data thus present a novel mechanism of action of MPH, i.e., changes in glutamatergic receptor-mediated synaptic plasticity following early-life treatment. Furthermore, since a single dosage resulted in significant changes in NMDA receptors, off-label usage by healthy individuals, especially children and adolescents, may result in altered potential for plastic learning.


Formulation of antiretroviral nanocrystals and development into a microneedle delivery system for potential treatment of HIV-associated neurocognitive disorder (HAND).
HIV/AIDS remains a major global public health issue. While antiretroviral therapy is effective at reducing the viral load in the blood, up to 50% of those with HIV suffer from some degree of HIV-associated neurocognitive disorder, due to the presence of the blood-brain barrier restricting drugs from crossing into the central nervous system and treating the viral reservoir there. One way to circumvent this is the nose-to-brain pathway. This pathway can also be accessed via a facial intradermal injection. Certain parameters can increase delivery via this route, including using nanoparticles with a positive zeta potential and an effective diameter of 200 nm or less. Microneedle arrays offer a minimally invasive, pain-free alternative to traditional hypodermic injections. This study shows the formulation of nanocrystals of both rilpivirine (RPV) and cabotegravir, followed by incorporation into separate microneedle delivery systems for application to either side of the face. Following an in vivo study in rats, delivery to the brain was seen for both drugs. For RPV, a Cmax was seen at 21 days of 619.17 ± 73.32 ng/g, above that of recognised plasma IC90 levels, and potentially therapeutically relevant levels were maintained for 28 days. For CAB, a Cmax was seen at 28 days of 478.31 ± 320.86 ng/g, and while below recognised 4IC90 levels, does indicate that therapeutically relevant levels could be achieved by manipulating final microaaray patch size in humans.


Simultaneous PET-MRI imaging of cerebral blood flow and glucose metabolism in the symptomatic unilateral internal carotid artery/middle cerebral artery steno-occlusive disease.
Cerebral blood flow (CBF) and glucose metabolism are important and significant factors in ischaemic cerebrovascular disease. The objective of this study was to use quantitative hybrid PET/MR to evaluate the effects of surgery treatment on the symptomatic unilateral internal carotid artery/middle cerebral artery steno-occlusive disease. Fifteen patients diagnosed with ischaemic cerebrovascular disease were evaluated using a hybrid TOF PET/MR system (Signa, GE Healthcare). The CBF value measured by arterial spin labelling (ASL) and the standardized uptake value ratio (SUVR) measured by 18F-FDG PET were obtained, except for the infarct area and its contralateral side, before and after bypass surgery. The asymmetry index (AI) was calculated from the CBF and SUVR of the ipsilateral and contralateral cerebral hemispheres, respectively. The ΔCBF and ΔSUVR were calculated as the percent changes of CBF and SUVR between before and after surgery, and paired t tests were used to determine whether a significant change occurred. Spearman's rank correlation was also used to compare CBF with glucose metabolism in the same region. The analysis primarily revealed that after bypass surgery, a statistically significant increase occurred in the CBF on the affected side (P < 0.01). The postprocedural SUVR was not significantly higher than the preprocedural SUVR (P > 0.05). However, the postprocedural AI values for CBF and SUVR were significantly lower after surgery than before surgery (P < 0.01). A significant correlation was found between the AI values for preoperative CBF and SUVR on the ipsilateral hemisphere (P < 0.01). The present study demonstrates that a combination of ASL and 18F-FDG PET could be used to simultaneously analyse changes in patients' cerebral haemodynamic patterns and metabolism between before and after superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery. This therefore represents an essential tool for the evaluation of critical haemodynamic and metabolic status in patients with symptomatic unilateral ischaemic cerebrovascular disease.


Maturation and refinement of the maculae and foveae in the Anolis sagrei lizard.
The fovea is a pit in the center of the macula, which is a region of the retina with a high concentration of photoreceptor cells, which accounts for a large degree of visual acuity in primates. The maturation of this primate visual acuity area is characterized by the shallowing and widening of the foveal pit, a decrease in the diameter of the rod-free zone, and an increase in photoreceptor cells packing after birth. Maturation occurs concurrently with progressing age, increasing eye size, and retinal length/area. These observations have led to the hypothesis that the maturation of the fovea might be a function of mechanical variables that remodel the retina. However, this has never been explored outside of primates. Here, we take advantage of the Anolis sagrei lizard, which has a bifoveated retina, to study maturation of the fovea and macula. Eyes were collected from male and female lizards-hatchling, 2-month, 4-month, 6-month, and adult. We found that Anolis maculae undergo a maturation process somewhat different than what has been observed in primates. Anole macular diameters actually increase in size and undergo minimal photoreceptor cell packing, possessing a near complete complement of these cells at the time of hatching. As the anole eye expands, foveal centers experience little change in overall retina cell density with most cell redistribution occurring at macular borders and peripheral retina areas. Gene editing technology has recently been developed in lizards; this study provides a baseline of normal retina maturation for future genetic manipulation studies in anoles.


Shortness of breath in the patient with chronic liver disease.
Shortness of breath is a common complaint in those with chronic liver disease. The differential diagnosis for this complaint includes primary pulmonary disorders, systemic disorders that affect the liver and lungs, and extrahepatic manifestations of portal hypertension. Orthotopic liver transplant, when appropriate, is the most effective therapy for many patients with dyspnea and chronic liver disease, although therapies to treat the underlying complications of cirrhosis may provide relief. Shortness of breath in patients with cirrhosis often portends a poor prognosis, and these patients should be evaluated for orthotopic liver transplant because this therapy is most likely to provide long-lasting benefit.


Predicting the emissions of VOCs/SVOCs in source and sink materials: Development of analytical model and determination of the key parameters.
The emissions of volatile organic compounds (VOCs) and semi-volatile organic compounds (SVOCs) from indoor materials pose an adverse effect on people's health. In this study, a new analytical model was developed to simulate the emission behaviors for both VOCs and SVOCs under ventilated conditions. Based on this model, we further introduced a hybrid optimization method to accurately determine the key parameters in the model: the initial emittable concentration, the diffusion coefficient, the material/air partition coefficient, and the chamber surface/air partition coefficient (for SVOCs). Experiments for VOC emissions from solid wood furniture were performed to determine the key parameters. We also evaluated the hybrid optimization method with the data of flame retardant emissions from polyisocyanurate rigid foam and VOC emissions from a panel furniture in the literature. The correlation coefficients are high during the fitting process (R2 = 0.92-0.99), demonstrating effectiveness of this method. In addition, we observed that chemical properties could transfer from SVOC-type to VOC-type with the increase of temperature. The transition temperatures from SVOC-type to VOC-type for the emissions of tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) phosphate (TCIPP) were determined to be about 45 ℃ and 35 ℃, respectively. The present study provides a unified modelling and methodology analysis for both VOCs and SVOCs, which should be very useful for source/sink characterization and control.


Nystatin increases hepatic alkaline phosphatase activity.
The activity of alkaline phosphatase is increased significantly in the livers of rats after the intraperitoneal administration of nystatin. Studies with cycloheximide suggested that de novo protein synthesis was essential for the effect of nystatin on alkaline phosphatase activity. The induction of hepatic alkaline phosphatase by nystatin is not secondary to the release of glucocorticoids because the response of the enzyme to the administration of nystatin was not affected by bilateral adrenalectomy.


Right ventricle in congenital heart disease: is it just a "weaker" left ventricle?
The RV is the dominant ventricle during fetal life. Postnatally, the RV rapidly loses its ability to sustain systemic load. In several forms of congenital heart disease, the RV is the dominant or systemic ventricle. Patients with these lesions often develop progressive RV dysfunction over time. This may be related to differences in morphology, genetic profile and hemodynamic exposure between the LV and RV. This review explores the evolutionary and developmental differences between the LV and RV, the molecular basis of these differences and the potential impact of these differences on long term RV adaptation and function in heart disease.


Multi-omics approach identifies PI3 as a biomarker for disease severity and hyper-keratinization in psoriasis.
Psoriasis is an immune-mediated inflammatory skin disease. Psoriasis severity evaluation is important for clinicians in the assessment of disease severity and subsequent clinical decision making. However, no objective biomarker is available for accurately evaluating disease severity in psoriasis. To define and compare biomarkers of disease severity and progression in psoriatic skin. We performed proteome profiling to study the proteins circulating in the serum from patients with psoriasis, psoriatic arthritis and ankylosing spondylitis, and transcriptome sequencing to investigate the gene expression in skin from the same cohort. We then used machine learning approaches to evaluate different biomarker candidates across several independent cohorts. In order to reveal the cell-type specificity of different biomarkers, we also analyzed a single-cell dataset of skin samples. In-situ staining was applied for the validation of biomarker expression. We identified that the peptidase inhibitor 3 (PI3) was significantly correlated with the corresponding local skin gene expression, and was associated with disease severity. We applied machine learning methods to confirm that PI3 was an effective psoriasis classifier, Finally, we validated PI3 as psoriasis biomarker using in-situ staining and public datasets. Single-cell data and in-situ staining indicated that PI3 was specifically highly expressed in keratinocytes from psoriatic lesions. Our results suggest that PI3 may be a psoriasis-specific biomarker for disease severity and hyper-keratinization.


Antipsychotic drugs: pro-cancer or anti-cancer? A systematic review.
Important data was recently published on the potential genotoxic or carcinogenic effects of antipsychotics, as well as on their cytotoxic properties on cancer cells, that must be considered by psychiatrists in the benefit/risk ratio of their prescriptions. To answer whether or not antipsychotics, as a class or only some specific molecules, may influence cancer risk among treated patients. METHODS ELIGIBILITY CRITERIA: All studies (in vitro, animal studies and human studies) concerning effects of antipsychotic drugs on cancer development were included. The search paradigm [neoplasms AND (antipsychotic agents OR neuroleptic OR phenothiazine)] was applied to Medline (1966-present) and Web of Science (1975-present). Ninety-three studies were included in the qualitative synthesis. Results can be summarized as follows: (1) patients with schizophrenia may be less likely to develop cancer than the general population, (2) antipsychotics as a class cannot be considered at the moment as at risk for cancer, even if some antipsychotics have shown carcinogenic properties among rodents, (3) phenothiazines seem to have antiproliferative properties that may be useful in multidrug augmentation strategies in various cancer treatments, but their bad tolerance may decrease usage amongst non-psychotic patients, and (4) clozapine appears to have a separate status given that this molecule shows antiproliferative effects implied in agranulocytosis as well as a potential increased risk for leukemia. Benefit/risk ratio regarding cancer risk is in favor of treating patients with schizophrenia with antipsychotic drugs. The practicing clinician should be reassuring on the subject of cancer risk due to antipsychotic drugs.


Fluctuations in motor output of a hand muscle can be altered by the mechanical properties of the position sensor.
Fluctuations in motor output are typically quantified by the standard deviation (SD) of displacement or acceleration. The aim of the study was to determine the influence of a linear variable-displacement transducer (LVDT) on the SDs and spectral content of displacement and acceleration during steady isometric and anisometric contractions performed with the first dorsal interosseus muscle. Thirteen young adults supported six loads when performing position-holding and position-tracking tasks when the LVDT either was or was not attached to the index finger. The LVDT reduced the magnitude of the SDs in displacement and acceleration and disrupted the load-dependent modulation of the spectral properties of these signals. When the LVDT was not connected to the finger, the displacement SD was greatest during concentric contractions, the acceleration SD was greatest during eccentric contractions, and there were load-dependent changes in the power density spectra. Although the LVDT may be used for assessing relative changes in displacement, its ability to provide absolute measures of fluctuations in motor output is limited. The results provide baseline measures of the fluctuations in motor output during steady contractions with a hand muscle and how the method used to detect displacement alters these measures.


Proteolytic modification of membrane-associated phospholipase C-beta by mu-calpain enhances its activation by G-protein beta gamma subunits in human platelets.
Membrane-associated phosphoinositide-phospholipase C (PI-PLC)-beta (150 kDa) and its truncated forms (100 kDa and 45 kDa) were purified from human platelets. The 100 kDa PI-PLC-beta was found to be activated to a greater extent by brain G-protein beta gamma subunits compared to the intact 150 kDa enzyme. Furthermore, treatment with mu-calpain of the intact PI-PLC-beta (150 kDa) caused a marked augmentation of its activation by beta gamma subunits. This enhanced PLC activation by beta gamma subunits was due to truncation by mu-calpain, producing a 100 kDa PI-PLC, but not by another protease, thrombin.


Autoantibodies to calcium channels in type 1 diabetes mediate autonomic dysfunction by different mechanisms in colon and bladder and are neutralized by antiidiotypic antibodies.
Autoantibodies (Abs) directed against L-type voltage-gated calcium channels (VGCCs) have been shown to contribute to autonomic dysfunction of the gastrointestinal tract and bladder in patients with Type 1 diabetes mellitus (T1D). We used a passive transfer model to determine whether the functional activity of the Ab requires crosslinking of channels in colon and bladder and can be neutralized by intravenous immunoglobulin (IVIg). Mice were injected with mono- and divalent F(ab) fragments of patient IgG with anti-VGCC activity and tested for gut and bladder function using a colonic migrating motor complex (MMC) assay and bladder-filling cystometry. The ability of IVIg to neutralize anti-VGCC IgG-mediated autonomic dysfunction was investigated by injection of mice with an equimolar concentration of IVIg prior to T1D IgG injection, or by injection with T1D IgG passed over a sepharose 4B column coupled with F(ab')(2) from IVIg. Passive transfer of T1D IgG and its F(ab')(2) or F(ab) fragments reduced the amplitude of spontaneous colonic motility. In contrast, intact IgG and F(ab')(2,) but not F(ab), produced the urodynamics features of an overactive bladder. T1D IgG-mediated colonic and bladder dysfunction was neutralized in vivo by prior injection of animals with equimolar IVIg. Moreover, anti-VGCC activity was depleted by preabsorption of patient IgG on a IVIg F(ab')(2) column. The activity of anti-VGCC IgG is mediated by the antigen-binding site consistent with a true functional Ab. The pathogenic effect on the bladder requires crosslinking of the channel, whereas monovalent binding of Ab is sufficient for disruption of colon motility. The anti-VGCC Abs are neutralized by antiidiotypic antibodies present in IVIg that may prevent the emergence of these Abs in healthy individuals.


Influence of estrogens on vascular transudation and mucus production in the rabbit endocervix.
The manner in which estrogens mediate cyclical changes in the viscoelastic properties and volume of cervical mucus is unclear. To identify the response to estrogens of each of the major mucus components (mucin[s], soluble proteins, and small electrolytes and water), the authors quantitated their accumulation rates before and during estrogen stimulation in the rabbit. Circulating radiolabeled markers (35S-sulfate and 131I-albumin) were used to monitor the incorporation of small and large molecular weight intravascular substances into the cervical mucus. The accumulation rate of mucins was unaffected by exogenous estrogen administration, despite significant increases in mucus volume. This increase in mucus volume was attributed to a significantly increased transudation of water and small electrolytes increasing mucus hydration as early as the first 2 hours of estrogen administration. Water, small electrolytes, and soluble proteins significantly increased during the third and fourth hours of estrogen administration, not only when compared with the unstimulated basal levels, but also when compared with the levels found during the first 2 hours of estrogen administration. No significant change occurred in mucin production, while significant changes occurred in the accumulation of proteins and small electrolytes, whether estrogen was given initially or terminally in the experiment protocol.


Conventional Photodynamic Therapy for Necrobiosis Lipoidica: Successful Treatment in a Series of 4 Cases.
Necrobiosis lipoidica is a rare chronic granulomatous disease. Multiple treatment approaches are available, but results are generally minimal and inconsistent. Some publications report variable results with photodynamic therapy (PDT) as a second line of treatment for refractory cases. We report 4 cases of necrobiosis lipoidica treated satisfactorily with conventional PDT using methyl aminolevulinate or 5-aminolevulinic acid BF-200 as the photosensitizing agent. All 4 patients were women with diabetes mellitus who had undergone treatment at least twice in the past, with little improvement. The lesions resolved completely with PDT, leaving only residual atrophy after a mean of 3.2 sessions per lesion.


The Effect of Physical Limitations on Depressive Symptoms Over the Life Course: Is Optimism a Protective Buffer?
We examined the extent to which optimism buffers the effects of physical limitations on depressive symptoms across 4 mid- and later-life age groups (ages 40-49, 50-64, 65-74, 75 and older at baseline). Analyses are motivated by stress theories, which propose that the protective effects of coping resources are evidenced only at high levels of stress. We further explore whether these purportedly protective effects diminish with age, as health-related stressor(s) intensify and become irreversible. We use data from 2 waves (2004-2006 and 2013-2014) of the Health and Retirement Study (HRS, n = 4,515) and Midlife in the United States (MIDUS, n = 2,138). We estimate ordinary least squares regression models with 3-way interaction terms to examine prospectively the benefits of optimism as a coping resource for persons with physical limitations across 4 age groups. Physical limitations are assessed with a composite measure encompassing mobility and activity of daily living limitations. In HRS and MIDUS, persons with 3+ limitations reported significantly more depressive symptoms than persons with 0-2 limitations, yet these disparities diminished at higher levels of optimism. Buffering effects of optimism vary by age. For midlife and young-old persons with 3+ limitations, optimism is strongly and inversely related to depressive symptoms at follow-up. Comparable protective effects are not evident among the oldest sample members. Stress and coping models should consider more fully factors that limit older adults' capacity to deploy purportedly protective personal resources. Investments in structural or institutional supports may be more effective than interventions to enhance positive thinking.


Hormonal regulation of Sertoli cell function.
The Sertoli cell is clearly influenced, directly and indirectly, by hormones. Among these are FSH, T, insulin and Vitamin A, but others may also be involved. Mechanisms are still not well understood. The biochemical effects of these hormones can be divided into quantitative and qualitative influences, with the former predominating. Specific cellular and secretory proteins and metabolites are affected, in many cases by more than one hormone. Often these same functions are influenced by other factors in the environment of the testis as well. Hormonal responsiveness of the Sertoli cell is determined in part by the maturational state of the cell. Some secreted products bind to specific cell types in the testis and epididymis and may influence the process of spermatogenesis. However, detailed mechanisms are not known at the present time. Understanding Sertoli cell function at the biochemical level and its control by hormones is clearly of key importance in understanding the control of the spermatogenic process.


Meta-review of high-quality systematic reviews of interventions in key areas of liaison psychiatry.
When planning and delivering a liaison psychiatry service it is important to have an understanding of the research evidence supporting the use of interventions likely to be delivered by the service. To identify high-quality systematic reviews for all interventions in three defined areas of liaison psychiatry, to summarise their clinical implications and to highlight areas where more research is needed. The three areas were the psychological effects of physical illness or treatment, somatoform disorders and self-harming behaviour. Computerised database searching, secondary reference searching, hand-searching and expert consultation were used to identify relevant systematic reviews. Studies were reliably selected, and quality-assessed, and data were extracted and interpreted by two reviewers. We found 64 high-quality systematic reviews. Only 14 reviews included meta-analyses. Many areas of liaison psychiatry practice are not based on high-quality evidence. More research in this area would help inform development and planning of liaison psychiatry services.