The prevalence of ADHD in children with enuresis: comparison between a tertiary and non-tertiary care sample.
The main aim of the current study was to determine reliable comorbidity rates of ADHD for enuretic children admitted either to non-tertiary care or to a specialized paediatric clinic, i.e. tertiary care, since previous research has failed to incorporate a possible setting effect in this comorbidity; and to use a multi-method multi-informant assessment of ADHD. Eighty children, aged between 6 and 12 y, admitted to non-tertiary care with enuresis and 120 children referred to tertiary care were screened for the presence of ADHD using a multi-method (diagnostic interview, questionnaires) multi-informant (parents, teachers) assessment. Enuretic children from the tertiary care sample have a 3.4 times increased chance of having comorbid ADHD when compared to children with enuresis admitted to non-tertiary care, corresponding to a prevalence rate of 28% and 10%, respectively. Overall, the tertiary care sample was older, showed more daytime incontinence and revealed an increasing prevalence of ADHD with older age when compared with the non-tertiary care group. The prevalence rate of ADHD is increased in an enuretic population compared to community samples (3-5%). Moreover, enuretic children admitted to tertiary care show significantly higher comorbidity than non-tertiary care patients. The ADHD prevalence in the former group increases with older age, suggesting therapy resistance and a negative prognosis for enuresis in the case of comorbidity.


Lysophosphatidylcholine potentiates vascular contractile responses by enhancing vasoconstrictor-induced increase in cytosolic free Ca2+ in rat aorta.
We investigated the effects of palmitoyl-L-alpha-lysophosphatidylcholine on the contractile responses of the endothelium-denuded rat aorta to high K+, noradrenaline, UK14,304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline) (a selective alpha2 adrenoceptor agonist) and phorbol 12-myristate 13-acetate (PMA). Lysophosphatidylcholine at concentrations from 10(-6) M to 10(-4) M did not contract aortic strips. However, lysophosphatidylcholine strongly potentiated the UK14,304-induced contraction. High K+ - and PMA-induced contractions were also potentiated. In contrast, the noradrenaline-induced contraction was only slightly potentiated by 10(-5) M lysophosphatidylcholine. In fura PE-3-loaded aortic strips, lysophosphatidylcholine (10(-5) M) markedly augmented the increase in both cytosolic free Ca2+ ([Ca2+]i) and contractile tension induced by UK14,304, high K+ and PMA. Nicardipine (10(-7) M) and 10(-6) M Ro-31-8220 (¿1-[3-(amidinothio)propyl-1H-indoyl-3-yl]-3-(1-methyl-1H-++ +indoyl-3-yl)-maleimide-methane sulfate) strongly inhibited the increase in [Ca2+]i and contractile tension induced by UK14,304 and in the presence of these inhibitors, the enhancing effects of lysophosphatidylcholine were attenuated. However, the enhancing effect on high K+ -induced contraction was not affected by Ro-31-8220. These results suggest that lysophosphatidylcholine may cause an augmentation of the increase in [Ca2+]i induced by UK14,304 which response is depend on protein kinase C activation and in this way potentiate contractile responses in the rat aorta. Protein kinase C independent mechanisms may also be involved in the enhancing effect of lysophosphatidylcholine on smooth muscle contraction.


Speech development in hearing-impaired children.
Many hearing-impaired children are unable to speak intelligibly. Research indicates, however, that patterns of errors typically found in the speech of such children could be largely avoided by systematic teaching. The purpose of this paper is to present and discuss a model for the progressive development of speech skills to the levels of automaticity required for fluent spoken language.


Barriers to physician-nurse collegiality: an anthropological perspective.
This paper discusses social and cultural factors that impede collegial interaction of physicians and nurses. While physicians encourage a form of 'team work' in which nurses are subordinate, nurses seek mutual collegiality with physicians. This phenomenon is apparent in various degrees between all educational categories of nurses and physicians. We suggest that nurse expectations of status enhancement through increased knowledge and skill--the nurse practitioner model--fail to consider the deeply rooted structures of hierarchy, in particular gender hierarchy, that pervades medical care. Physician-nurse collegiality does offer benefits to patients; to achieve it nurses must devise methods to alter these structural barriers.


A HHV-8 positive, HIV negative multicentric Castleman disease treated with R-CEOP chemotherapy and valganciclovir combination.
Multicentric Castleman disease (MCD) is a lymphoproliferative disorder characterized by systemic symptoms like recurrent lymphadenopathy, fever and hepatosplenomegaly. Human herpes virus 8 (HHV-8) can be associated with MCD whether the patient is infected with human immunodeficiency virus (HIV) or not. A 59-year-old male patient presented with fatigue, drowsiness and enlarged lymph nodes. Thoracic and abdominal computed tomography showed enlarged mediastinal, axillary, paracardiac, paraaortic, celiac, mesenteric, obturator and inguinal lymph nodes concomitant with enlarged liver and spleen. Cervical lymph node biopsy revealed HHV-8 positive plasma cell MCD. The patient's tests were negative for HIV. R-CEOP (rituximab, cyclophosphamide, etoposide, vincristin, prednisolone) and valganciclovir treatments were started simultaneously. After sixth cycle of R-CEOP, the patient achieved unconfirmed complete remission. Rituximab combined with CEOP protocol and antiviral therapy against HHV-8 might be an effective therapeutic approach without a considerable side effect for HHV-8-positive HIV-negative MCD patients.


Polypoid fibroadipose tumors of the esophagus: 'giant fibrovascular polyp' or liposarcoma? A clinicopathological and molecular cytogenetic study of 13 cases.
Giant fibrovascular polyp of the esophagus is a descriptive diagnostic term intended to encompass rare, large, polypoid esophageal masses composed of fibroadipose tissue. Despite sometimes dramatic clinical presentations, they have historically been considered to represent reactive, non-neoplastic proliferations. Recently, however, a small number of reports have described well-differentiated liposarcomas of the esophagus, mimicking giant fibrovascular polyps. In order to clarify the relationship between esophageal liposarcoma and giant fibrovascular polyp, we retrieved esophageal cases coded as 'giant fibrovascular polyp,' 'lipoma' and 'liposarcoma' from our archives and re-examined their clinicopathologic features and MDM2 amplification status. Thirteen cases were identified (lipoma (n=1), giant fibrovascular polyp (n=5), well-differentiated liposarcoma (n=3), dedifferentiated liposarcoma (n=3)). The tumors ranged from 5.2 to 19.5 cm and arose predominantly in the cervical esophagus. All consisted chiefly of mature adipose tissue, with a variable component of fibrous septa. In all cases, close inspection of these fibrous septa showed them to contain an increased number of slightly enlarged spindled cells with irregular, hyperchromatic nuclei, similar to those seen in some well-differentiated liposarcomas. Three cases, all previously classified as dedifferentiated liposarcoma, showed in addition solid zones of non-lipogenic spindle cell sarcoma. By fluorescence in situ hybridization (FISH), all cases showed MDM2 amplification, confirming diagnoses as well-differentiated (N=10) and dedifferentiated (N=3) liposarcoma. Clinical follow-up (8 cases, range 22-156 months, median 33 months) showed 3 patients with local recurrences (1 well-differentiated and 2 dedifferentiated liposarcomas), 1 patient with liver metastases (dedifferentiated liposarcoma) and 2 deaths from disease (both dedifferentiated liposarcomas). These results suggest that the great majority of large, polypoid, fat-containing masses of the esophagus represent well and dedifferentiated liposarcoma, rather than 'giant fibrovascular polyps.' We suggest that the diagnosis of 'giant fibrovascular polyp' should be made with great caution in the esophagus, and only after careful morphological study and MDM2 FISH has excluded the possibility of liposarcoma.


Interactions between the coccid, Icerya seychellarum (Westw.), and its host tree species on Aldabra Atoll : I. Euphorbia pyrifolia Lam.
(i) The growth of ca. 100 individuals of a small deciduous tree Euphorbia pyrifolia, of different ages and edaphic regimes, and with different levels of infestation by the coccid Icerya seychellarum, has been studied on Aldabra Atoll over two years (1976-1978). Infestation on leaves ranged between 0 and 1.3 mg dry weight of coccids cm-2 of total leaf area. (ii) Field observations and an experiment in which coccids were "seeded" on to transplanted trees showed a preference of coccids to feed on senescing leaves rather than on green leaves. Deterrence by green leaves is discussed. (iii) Highest infestations developed on trees which produced the most senescent leaf material early in the wet season. The rate of leaf production on the heaviest infested trees was 36% of that on lightly infested trees. (iv) The level of coccid infestation did not depend on the concentration of soluble nitrogen in senescing leaves but on the total amount of nitrogen exported. The level of soluble nitrogen in green leaves was reduced in heavily infested leaf clusters. (v) Experimental clearance of coccids by insecticide showed that 0.7 mg cm-2 of coccids reduced the rate of leaf growth by 52%. This corresponded closely to the effect of similar levels of coccids in the field. (vi) Leaf infestation was positively correlated with the percentage of dead apices per tree and negatively correlated with the degree of branch extension. (vii) It was concluded that leaf phenology influenced the development of coccid populations and that coccids significantly reduced plant growth.


Pathogenesis of primary biliary cirrhosis.
Autoimmune phenomena have been recognized in primary biliary cirrhosis (PBC) for more than 50 years and the specificity of the characteristic responses directed at highly conserved mitochondrial antigens determined in detail over the past 20. Effecter autoreactive immune responses are characterized and potential mechanisms of breakdown of tolerance to self proposed. Elements of the clinical pattern of PBC, including the recurrence of the disease across HLA boundaries after liver transplantation, remain difficult to reconcile with a simple autoimmune model. Alternative (but not necessary mutually exclusive) pathogenetic models have been outlined, including a potential role for retroviral pathogens and directly cytopathic effects.


Balancing adipocyte production and lipid metabolism to treat obesity-induced diabetes with a novel proteoglycan from Ganoderma lucidum.
Obesity is often accompanied by metabolic disorder and insulin resistance, resulting in type 2 diabetes. Based on previous findings, FYGL, a natural hyperbranched proteoglycan extracted from the G. lucidum fruiting body, can decrease blood glucose and reduce body weight in diabetic mice. In this article, the underlying mechanism of FYGL in ameliorating obesity-induced diabetes was further investigated both in vivo and in vitro. FYGL upregulated expression of metabolic genes related to fatty acid biosynthesis, fatty acid β-oxidation and thermogenesis; downregulated the expression of insulin resistance-related genes; and significantly increased the number of beige adipocytes in db/db mice. In addition, FYGL inhibited preadipocyte differentiation of 3T3-L1 cells by increasing the expression of FABP-4. FYGL not only promoted fatty acid synthesis but also more significantly promoted triglyceride degradation and metabolism by activating the AMPK signalling pathway, therefore preventing fat accumulation, balancing adipocyte production and lipid metabolism, and regulating metabolic disorders and unhealthy obesity. FYGL could be used as a promising pharmacological agent for the treatment of metabolic disorder-related obesity.


Multi-immunoaffinity column for the simultaneous analysis of bisphenol A and its analogues in Chinese foods by liquid chromatography tandem mass spectrometry.
Bisphenol A (BPA) and its four analogues have been receiving considerable attention owing to their potential endocrine disrupting effects. The European Food Safety Authority has proposed 0.04 ng/kg·body weight/day of thetemporary tolerable daily intake for BPA. Therefore, a more sensitive analytical method was urgently needed for the necessity of the risk reassessment of bisphenols (BPs). The matrix effect of Chinese foods is a challenge for the analysis of ultra-trace analytes due to the presence of various spices. A multi-immunoaffinity column (mIAC) was prepared for the purification of BPA, BPB, BPF, BPS, and BPAF in Chinese foods following ultra-high-performance liquid chromatography tandem mass spectrometry detection (UHLPC-MS/MS). The recoveries of each of BPs were ranged from 84.6% to 116.7%, and the intra-day precision and inter-day precision were ranged from 1.6% to 12.4%, and from 4.1% to 14.0%, respectively. This is the first report on the mIACs for simultaneous clean-up and analysis of BPs in complex Chinese foods.


Role of Cardiac Computed Tomography in Planning Transcatheter Mitral Valve Replacement (TMVR).
Transcatheter mitral valve replacement (TMVR) is an evolving and rapidly expanding field within structural interventions, offering renewed treatment options for patients with high-risk mitral valve disease. We aim to highlight and illustrate the importance of cardiac CT in the planning of TMVR. As TMVR has evolved, so has the specific nuances of cardiac CT planning, we now understand the importance of accurate annular sizing and valve simulation to predict complications such as neo-LVOT obstruction and paravalvular leak (PVL). More so than any other modality, cardiac CT remains instrumental in accurately planning TVMR from feasibility, device sizing, access, and fluoroscopic angles. Cardiac CT remains the key modality in TMVR evaluation, often the first step in determining patient eligibility through comprehensive procedural planning as well as informing potential outcomes and prognosis. In this review, we discuss the critical role of cardiac computed tomography (CT) and the specific considerations involved in TMVR.


Significance of TP53 mutations determined by next-generation "deep" sequencing in prognosis of estrogen receptor-positive breast cancer.
Next-generation "deep" sequencing (NGS) was used for the mutational analysis of TP53, and a DNA microarray was used for the determination of the TP53 mutation-associated gene expression signature (TP53 GES) in 115 estrogen receptor (ER)-positive breast cancers. NGS detected 27 TP53 mutations, of which 20 were also detected by Sanger sequencing (SS) and seven were detected only by NGS. A significantly higher number of mutant alleles (33.9%) was detected in the tumors with TP53 mutations detected by SS compared with those with TP53 mutations detected only by NGS (11.1%). The TP53 mutations detected by NGS were more significantly associated with a large tumor size, a high histological grade, progesterone receptor-negativity, and HER2-positivity compared with those detected by SS. The TP53 mutations detected by SS, but not those detected by NGS or the p53 immunohistochemistry, exhibited a significant association with poor prognosis. In addition, the TP53 GES more clearly differentiated low- from high-risk patients for relapse than the TP53 mutations detected by SS, regardless of the other conventional prognostic factors. Thus, NGS is more sensitive for the detection of TP53 mutations, but the prognostic significance of these mutations could not be demonstrated. In contrast, the TP53 GES proved to be a powerful prognostic indicator for ER-positive tumors.


Sorption and desorption by ideal two-compartment systems: unusual behavior and data interpretation problems.
This paper examines the current practices of fitting curves to sorption, desorption, and equilibrium data obtained from laboratory experiments. Systems of equations incorporating Freundlich isotherms and first-order kinetics for two different idealized sorbents, one "fast" and one "slow," were solved numerically to produce "data". Two-compartment curves were then fit to the data by nonlinear regression, and the parameters computed by the regression are compared with the original parameters used to produce the data. The results show that a sorbent with fast kinetics will not steadily accumulate sorbate until it reaches the equilibrium value but will overshoot equilibrium, accumulating an excess of sorbate. This overshoot will cause the sorption rates for both sorbents and the distribution between the fast and slow sorbents to be estimated incorrectly. The system may appear to be at equilibrium by external measures, but sorbate will slowly be redistributing from the fast to the slow sorbent. An isotherm constructed from data acquired during this process will have an incorrect coefficient and exponent. Consequently, the meaning of the results obtained by curve fitting may often be questionable and may say little about the phenomena occurring within the sorbate-sorbent-liquid system. Possible physical explanations for the effects observed are offered.


Auditory brainstem response and otoacoustic emissions in Duane retraction syndrome.
We aimed to investigate the origin of hearing loss with relevance to auditory brainstem responses and otoacoustic emissions in patients with Duane's retraction syndrome (DRS). 17 patients with DRS were included in the study. 14 patients were diagnosed as DRS type 1 and the remaining three as type 3. The control group consisted of nine healthy subjects. Pure tone audiogram, auditory brainstem response, as well as distortion product otoacoustic emissions were recorded in all the patients and the controls. Among the 17 patients with DRS, 15 demonstrated normal hearing according to pure tone audiogram. One patient with DRS had profound sensorineural hearing loss with a pure tone average of 110 dB, and one patient had moderate sensorineural hearing loss with a pure tone average of 60 dB. Auditory brainstem response latencies of the waves I, III and V, and interwave latencies were calculated in 15 patients with DRS and were compared with the control group. There was statistically significant increase in wave I latency of left ear in the DRS group compared to the controls (P<0.05). Amplitudes of distortion product otoacoustic emissions were also recorded at frequencies of 2, 3, 4, 6, and 8 kHz in both groups and the comparison of the DRS patients and controls revealed no statistically significant difference. We recommend auditory examinations be undertaken in patients with DRS by auditory brainstem response tests, as well as distortion product otoacoustic emissions, whereas all patients with normal results should be followed-up for future hearing loss.


99mTc-aprotinin: a new tracer for kidney morphology and function.
Aprotinin (Ap), a low-molecular-weight polypeptide (6500 dalton), is a protease inhibitor which is electively and stably accumulated in the kidney. In 112 adult patients, with either uni- or bilateral renal disease with different degrees of renal impairment (from normal GFR to advanced renal failure), renal scans were performed by means of Ap labelled with 99mTc. Highly satisfactory renal scans were obtained in all patients. In 20 patients with renal failure (serum creatinine 1.8-8.5 mg/dl, mean 4.7) a comparison was made of the renal scans obtained with 99mTc-Ap and with 99mTc-DMSA. 99mTc-Ap was slightly better than 99mTc-DMSA, especially in patients with far advanced renal failure. Some aspects of the pharmacokinetics of 99mTc-Ap were studied in 72 cases. In 22 of these patients plasma clearance of 99mTc-Ap was determined by the single injection method using a two-compartment model. In patients with GFR greater than 90 ml/min plasma clearance of 99mTc-Ap was 67.6 +/- 8.4 SD ml/min. A good correlation was observed between plasma clearance of 99mTc-Ap and GFR (r = 0.74). After IV injection 99mTc-Ap was stably fixed by the kidney. Renal radioactivity remained stable between the second and eighth hour after the injection. Urinary excretion of radioactivity measured in 35 patients in the first and in the second 2-h interval after IV injection of 99mTc-Ap was negligible in all patients (2.7 +/- 1.5 SD percent of the dose in the first 2 h; 2.8 +/- 1.4 SD between the second and fourth hour). 99mTc-Ap is an excellent agent for renal imaging. It also seems promising for renal function studies.


The influence of temperature, salt and pH on the inhibitory effect of reuterin on Escherichia coli.
The inhibitory effect of reuterin on Escherichia coli K12 was investigated at different conditions of temperature (10-30 degrees C), pH (4.5-6.5), and NaCl (0.5-3% (w/v)). The maximum specific growth rate as a function of the different environmental conditions was modelled with a polynomial model. At increasing temperatures, there was an increasing effect of reuterin, whereas neither pH nor salt showed interactions with the effect of reuterin. The model was validated against new experimental data and proved to perform satisfactorily based on the bias and accuracy factors.


Effects of hypothermia on the cat brain-stem auditory evoked response.
Effects of systemic hypothermia on the brain-stem auditory evoked responses (BAERs) in 4 pentobarbital anesthetized adult cats placed on total cardiopulmonary bypass were investigated. Hypothermia was achieved by slowly cooling the bypass blood through a heat exchanger. Serial BAERs were recorded at 2 min intervals as brain temperature was lowered from 37 to 22 degrees C and then rewarmed over a 1-2 h period. Temperatures were recorded from the brain, esophagus and rectum. Three effects were produced by controlled systemic hypothermia. First, latencies of each component wave (I-V) of the BAER increased exponentially as brain temperature was lowered to 19 degrees C. Latencies of earlier waves (I-III) increased less than those of the later waves (IV-V). Arrhenius plots of inverse latency (rate) versus reciprocal of the absolute temperature generated a family of straight lines of similar slope for each of the 5 component waves of the BAER. The activation energy for each of the 5 BAER waves was derived from the slope of the Arrhenius plot. The mean and standard deviation of the activation energy of all 5 waves was 9.7 +/- 0.5 kcal/mole degree C. The fact that the activation energy was similar for each BAER component wave (I-V) indicated that the increase in latencies for all 5 waves was governed by the same rate-limiting, temperature-dependent process(es). Second, the rise time and duration of each of the component waves of the BAER increased with decreasing temperature. Third, wave amplitudes increased from 37 to 32 degrees C in a quasiparabolic relation and then, decreased at approximately a linear rate. The BAER wave form completely disappeared below 20.3 degrees C. Slow rewarming of the brain to its initial temperature restored the BAER component waves to their original latencies and amplitudes.


Protective effects of heat shock protein 70 induced by geranylgeranylacetone on oxidative injury in rat intestinal epithelial cells.
Geranylgeranylacetone (GGA), an anti-ulcer agent, has recently been demonstrated to protect a variety of cells and tissues via induction of heat shock protein (HSP)70 against numerous stresses. We investigated whether GGA induces HSP70 and protects against an oxidative stressor, monocrolamine (NH(2)Cl), in a rat intestinal epithelial cell line (IEC-18). IEC-18 cells pretreated with GGA (0.1-10 microM) were subjected to injury induced by NH(2)Cl. Cell viability was assessed, and endogenous HSP70 levels were determined by enzyme-linked immunosorbent assay in IEC-18 cells. Treatment with GGA (0.1-10 microM) was found rapidly to elevate HSP70 levels and to protect against NH(2)Cl-induced injury in IEC-18 cells. Furthermore, quercetin, an inhibitor of HSP70 synthesis, diminished the protective effects of GGA in IEC-18 cells upon NH(2)Cl-caused injury. The results of this study suggest that GGA plays an important role in defense mechanisms against oxidative injury in the intestine, primarily via induction of HSP70.


Recovery of lost face of burn patients, perceived changes, and coping strategies in the rehabilitation stage.
Although burn is a highly traumatic experience, little has been reported on the perception of the individual burn patient in the Chinese cultural context. For developing more culturally sensitive rehabilitation strategies for burn survivors, the present study was conducted to elucidate their perceived changes and to construct a theoretical model of their subjective experience and coping strategies. Data were collected from a burn center in China in 2013. Fifteen patients recruited via a theoretical sampling method participated in semi-structured, face-to-face interviews. The grounded theory approach was used to analyze the data. Six response categories were generated from the data, and the correlations between the categories were identified to form a paradigm model. The basic elements of the paradigm model were "unexpected body suffering," "losing face," "constructing a new identity," "perceived social rejection," "self-exploratory coping," and "striving to regain their own life." The findings of the present study suggested that burn survivors encountered such challenges as "unexpected suffering," "culture-related stigma," "perceived social rejection," and "constructing a new identity." Limited and inappropriate coping strategies may hinder the effective rehabilitation of burn survivors. In addition, burns must be understood in the social-cultural context to develop effective coping strategies for reintegration into society.


Unusual clinical and echocardiographic features of severe isolated pulmonic insufficiency.
A 57-year-old psoriatic man had severe, isolated pulmonic regurgitation, with intractable right sided failure. Echocardiography showed flail pulmonic leaflet and premature opening of the valve. Cardiac catheterization documented severe pulmonic regurgitation. The right ventricular end-diastolic pressure was elevated above the pulmonary artery diastolic pressure, thus explaining the echocardiographic finding. The patient was treated successfully by pulmonic valve replacement.


Rehabilitation approach and results of using the biofeedback method (GIGER MD device) in children with neurogenic bladder.
GIGER MD device applies a biofeedback method through stimulated coordinated rhythmic and dynamic movements of the trunk and extremities in an anti-gravity position, thus helping to regain lost motor functions. In this article, the performance of the GIGER MD device was evaluated in 36 children with neurogenic bladder measuring gait speed, voiding bladder capacity, deviation from the age-adjusted bladder capacity (measured using the Koff scale), and urinary incontinence. Children using the GIGER MD device had an increase in voiding bladder capacity (33.79%, median volume increase of 50 ml) with a subsequent median decrease in median age-adjusted bladder capacity by 45.50% (median deviation before was 36% vs. 16% after treatment). The number of urinary incontinence episodes also reduced by 55.57% (7-3 episodes per day), and the 20-meter motor gait speed increased by 14.26% (from 23 to 19 s). Children who follow the GIGER MD therapy regularly for a period of 6 months show that CNS functional damage can be significantly improved.


Characterization of high-affinity binding sites for the antitussive [3H]noscapine in guinea pig brain tissue.
We have characterized the binding of the antitussive alkaloid [3H]L-alpha-noscapine ([3H]noscapine) to guinea pig brain. Binding of [3H]noscapine to brain homogenate is stereospecific, saturable, reversible, heat-sensitive and manifests high affinity (Kd = 7 nM). Binding sites are present in all major brain areas, with the thalamus exhibiting the highest density. Subcellular localization studies showed an enrichment of binding sites in the synaptosomal fraction. Some structurally related compounds with antitussive properties (narceine, hydrastine, narcotoline and papaverine) were potent competitors, while other antitussives did not inhibit [3H]noscapine binding. Various ligands that bind to known neurotransmitter receptors failed to displace [3H]noscapine binding or had IC50 values in the micromolar range. It was concluded that the noscapine binding sites are different from those previously described for antitussives such as codeine and other opiates, or dextromethorphan.


Percutaneous drainage of lung abscess.
Most lung abscesses are successfully treated with antibiotics. However, occasional patients with lung abscesses that drain poorly, causing persistent fever and toxic symptoms, may require surgical intervention. Lobectomy is the most frequent surgical procedure. Some patients are debilitated and have underlying medical conditions such as heart disease, chronic pulmonary disease, or liver disease that may render surgical intervention risky. Recently there have been reports of percutaneous drainage of lung abscess with good results. We have successfully carried out percutaneous drainage of lung abscess in 4 patients and an infected bulla in 1. All patients had failed to respond to therapy with antibiotics and postural drainage. There was prompt disappearance of the fluid level in the cavity, decline in temperature, and abatement of toxic symptoms with drainage. The cavities closed gradually over the next 6-12 weeks. The patients tolerated the chest tube well and there were no side effects from the tube drainage. Percutaneous tube drainage is the surgical treatment of choice in the medically complicated patient with a poorly draining lung abscess.


Chromatin and signaling.
Signaling involves the coordinated action of multiple molecules including stimuli, receptors and enzymes part of which interact with the transcriptional machinery and target chromatin. Signaling systems regulate the cell events responsible for survival, development and homeostasis. Many of the signaling pathways induce target gene activation through interaction with the transcription machinery, including RNA polymerase II, and with histone modifying complexes. These studies are having a broad impact on chromatin biology. Recent studies suggest that chromatin itself receives the signals. Increasing examples are illustrating novel regulatory mechanisms that promote our understanding of development and disease.


Rhodium(III)-Catalyzed Synthesis of Diverse Fluorescent Polycyclic Purinium Salts from 6-Arylpurine Nucleosides and Alkynes.
Described herein is an efficient strategy for assembling a new library of functionalized polycyclic purinium salts with a wide range of anions through RhIII-catalyzed C-H activation/annulation of 6-arylpurine nucleosides with alkynes under mild reaction conditions. The resulting products displayed tunable photoluminescence covering most of the visible spectrum. Mechanistic insights delineated the rhodium catalyst's mode of action. A purinoisoquinolinium-coordinated rhodium(I) sandwich complex was well characterized and identified as the key intermediate.


Pseudomyxoma peritonei presenting as a scrotal mass.
Pseudomyxoma peritonei may occur after intraperitoneal rupture of a mucinous adenocarcinoma. The liberated cells produce copious amounts of mucus, which mimics ascites. With the improved technology of computerized tomography and ultrasound, many of these cases are now being diagnosed preoperatively. Surgical debulking is the preferred therapy, while the role of chemotherapy and radiotherapy remains debatable. We report a case of pseudomyxoma peritonei presenting as a scrotal mass that was diagnosed preoperatively.


Global Surgery Electives: A Strategy to Improve Care to Domestic Underserved Populations?
In the United States, a shortage of general surgeons exists, primarily in rural, poor, and minority communities. Identification of strategies that increase resident interest in underserved regions provides valuable information in understanding and addressing this shortage. In particular, surgical experience abroad exposes residents to practice in low-resource and rural settings. As residency programs increasingly offer global surgery electives, we explore whether the presence of an international surgical rotation affects graduates' future practice patterns in underserved communities domestically. We surveyed general surgery residency graduates at a single academic institution. Those who finished general surgery residency from 2001 to 2018 were included. Participant demographics, current practice demographics, and perceptions related to global surgery and underserved populations were collected. Respondents were stratified based on whether they did ("after") or did not ("before") have the opportunity to participate in the Kijabe rotation (started in 2011), defined by graduation year. Out of 119 eligible program graduates, 64 (53.7%) completed the survey, and 33 (51.6%) of the respondents graduated following the implementation of the Kijabe rotation. Two participants defined their primary current practice location as international. Fifteen (45.5%) in the "After" group indicated an interest in working with underserved populations following residency, compared to 5 (17.8%) of the "Before" group (P = 0.074). Furthermore, 20 (60.6%) respondents in the "After" group expressed interest in working with underserved populations even if it meant making less money. In the "Before" group, only 13 (46.4%) responded similarly (P = 0.268). Eleven (9.2%) residents rotated at Kijabe. Those who participated in the Kijabe rotation reported an uninsured rate of 36.7% for their current patient population, compared to rate of 13.9% in those who did not rotate there (P = 0.22). At a single institution, our results suggest that participation in an international surgical rotation in a resource-constrained setting may be associated with increased care for underserved populations in future clinical practice. These results could be due to self-selection of residents who prioritize global surgery as part of their residency experience, or due to increased exposure to underserved patients through global surgery.


Centromeric alpha satellite DNA amplification and translocation in an unusually large chromosome 14p+ variant.
We report cytogenetic and molecular studies on a family that carries, in the father, an unusually large chromosome 14p+ variant [WSi-var(14)(p+)] and, in one of his children, a translocation [DSi-der(14)] involving the variant chromosome. Increase in the size of WSi-var(14)(p+) was estimated to be approximately 35% that of a normal chromosome 14. Presence of extra chromosomal material in this variant chromosome was demonstrated by G-banding using trypsin and staining with Leishman, G-banding using bromodeoxyuridine (BrdU) and Giemsa, and R-banding using BrdU and Giemsa. This material was positive using C-banding with BaOH and staining with Giemsa and negative in DAPI/distamycin staining, suggesting that it contained repetitive DNA but probably not of the types found in the heterochromatic regions of chromosomes 1, 9, 15, 16, and Y. Staining of the nucleolus organiser region (NOR) with AgNO3 indicated the retention of the NOR in WSi-var(14)(p+) but not in DSi-der(14). In situ hybridisation of metaphase cells with an alpha satellite DNA probe specific for human acrocentric chromosomes demonstrated a significantly increased amount of centromeric alpha sequences in WSi-var(14)(p+). Most or all of the extra alpha sequences were retained in DSi-der(14), indicating translocation near the very distal end of the enlarged region. The extra alpha satellite DNA material may have originated through amplification of some centromeric segments. The possible role of the amplified DNA in chromosomal translocations is discussed.


Finite element comparison of the effect of absorbers' design in the surrounding bone of dental implants.
Despite the high success rate achieved in current dental implantation, there are still important problems to solve like incomplete early osteointegration, bone damage, and long-term implant loosening. Highly compliant stress absorbers are a possible solution to these problems. Although several works examined the stress-strain distribution in bone without and with absorbers to show their favorable results, none of them analyzed their impact on long-term remodeling. Here, we analyze this effect by comparing the evolution of stress and bone mass density without and with different designs of absorbers with those of the healthy tooth. Several finite element models with ABAQUS, corresponding to each design considered, were built to obtain the mechanical conditions in bone and implant. Then a mechanobiological bone remodeling model that considers damage accumulation and its repair during the remodeling process was used to compute the bone density redistribution. This approach allows assessing both the short-term density loss and the relative micromovement between bone and implant. We analyze the stress distributions in both bone and implant as well as the relative micromovement of the implant. We also present the evolution of damage and bone volume fraction. These results show that the addition of absorbers can reduce the stress in the bone around the implant. The obtained results also show that using stress absorbers reduces damage in bone, while increasing the number of absorbers does not necessarily improves damage reduction. We conclude that using implants with a correct design of absorbers prevents damage and stress shielding, reducing implant loosening.


Inhibition of dihydropteridine reductase in rat striatal synaptosomes and from human liver by metabolites of biogenic amines.
Catecholamines are potent noncompetitive inhibitors of dihydropteridine reductase in rat striatal synaptosomal preparations or purified from human liver. Their metabolites, except homovanillic acid, also inhibit the enzyme from both sources. The inhibitory potency of these compounds depends on the presence of the catechol or the 4-hydroxyphenyl structure, but may be modified by the 2-carbon side chain and its substituents. Indoleamines which have a hydroxylated aromatic nucleus (5-hydroxytryptamine and 5,6-dihydroxytryptamine) are equally inhibitory to the enzyme. These results suggest that biogenic amines themselves rather than their metabolites may serve as physiological inhibitors of dihydropteridine reductase in rat brain.


[Not Available].
When establishing maximum limits, in addition to issues relating to preventive consumer protection and toxicological data on risk assessment, sampling procedures and methods of analysis, as well as economic and political aspects have to be considered. Therefore, various and diverse organizations tend to be involved in the process of establishing maximum limits. Specifically, the following are responsible for the toxicological evaluation of the substances in question: International Programme on Chemical Safety (IPCS), International Agency of Research on Cancer (IARC), Joint FAO/WHO Expert Committee on Food Additives (JECFA), and, within the Commission of the European Communities, the Scientific Committee for Food (SCF). The interests of world-wide trade are looked after by the Codex Alimentarius Commission, the Codex Committee of Food Additives and Contaminants, and the World Trade Organisation, WTO. On the basis of Commission Regulation (EC) no. 315/93, in 2001 the EU has adopted Commission Regulation (EC) no. 466/2001 on contaminants establishing maximum limits for nitrates, heavy metals, 3-monochlor-propan-1,2-diol, and aflatoxins in foods (peanuts, nuts, dried fruits, cereal/cereal products). In February 2002, this Regulation has been completed by Regulation (EC) no. 257/2002 (aflatoxins in cereals), and in March 2002 by Regulation (EC) no. 472/2002 (aflatoxins in spices and ochratoxin A in cereals and dried grapes). Reference is made to other mycotoxins the levels of which in certain foods should be the subject of future regulations.


Risk stratification of 2- to 5-cm gastric stromal tumors based on clinical and computed tomography manifestations.
To evaluate the risk stratification of 2- to 5-cm gastric stromal tumors (GSTs) by analyzing their clinical and computed tomography (CT) manifestations with the goal of providing imaging evidence for rational selection of surgical methods. This study involved 223 patients with pathologically diagnosed GSTs of 2 to 5 cm in diameter. According to the pathological results and malignant risk category, the patients were divided into a low-risk biological behavior group (very low and low risk) and high-risk biological behavior group (intermediate and high risk). The clinical and CT manifestations were compared between the groups. The chi-square test was used to analyze categorical variables, and the independent-samples t test was used to analyze continuous variables. Multivariate logistic regression and receiver operating characteristic curve analysis were performed for statistically significant variables. The tumor contour, necrosis, surface ulceration, and long diameter were significantly different between the low-risk group and the high-risk group (P < 0.05). Multivariate logistic regression analysis showed that the tumor contour and long diameter were independent risk factors. The area under the curve was 0.82, and the accuracy, sensitivity, and specificity were 0.78, 77.4 %, and 79.7 %, respectively. The risk associated with 2- to 5-cm GSTs can be preoperatively predicted in an indirect manner through analysis of clinical and CT manifestations, and this model has high diagnostic value.


Aminoglycoside dosing considerations in intensive care unit patients.
Factors affecting aminoglycoside dosing requirements in critically ill adult patients were reviewed. A literature search was performed from 1979 to 1992 and articles pertaining to aminoglycoside dosing were obtained. Only studies appearing in peer-reviewed journals were selected. Topics selected included: bactericidal kill kinetics, once-daily dosing regimens, critical illness, toxicity, aminoglycosides, intensive care unit, and lung penetration. Studies suggest that larger initial aminoglycoside doses are necessary in critically ill patients (tobramycin/gentamicin 3 mg/kg or amikacin 9 mg/kg) to achieve adequate peak serum concentrations. Current studies have not shown an increase in the incidence of aminoglycoside toxicity when using these larger initial doses. Follow-up monitoring is dependent upon the patient's physiology and risk factors for aminoglycoside-induced toxicity.


Air pollution and mortality in a large, representative U.S. cohort: multiple-pollutant analyses, and spatial and temporal decompositions.
Cohort studies have documented associations between fine particulate matter air pollution (PM2.5) and mortality risk. However, there remains uncertainty regarding the contribution of co-pollutants and the stability of pollution-mortality associations in models that include multiple air pollutants. Furthermore, it is unclear whether the PM2.5-mortality relationship varies spatially, when exposures are decomposed according to scale of spatial variability, or temporally, when effect estimates are allowed to change between years. A cohort of 635,539 individuals was compiled using public National Health Interview Survey (NHIS) data from 1987 to 2014 and linked with mortality follow-up through 2015. Modelled air pollution exposure estimates for PM2.5, other criteria air pollutants, and spatial decompositions (< 1 km, 1-10 km, 10-100 km, > 100 km) of PM2.5 were assigned at the census-tract level. The NHIS samples were also divided into yearly cohorts for temporally-decomposed analyses. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) in regression models that included up to six criteria pollutants; four spatial decompositions of PM2.5; and two- and five-year lagged mean PM2.5 exposures in the temporally-decomposed cohorts. Meta-analytic fixed-effect estimates were calculated using results from temporally-decomposed analyses and compared with time-independent results using 17- and 28-year exposure windows. In multiple-pollutant analyses, PM2.5 demonstrated the most robust pollutant-mortality association. Coarse fraction particulate matter (PM2.5-10) and sulfur dioxide (SO2) were also associated with excess mortality risk. The PM2.5-mortality association was observed across all four spatial scales of PM2.5, with higher but less precisely estimated HRs observed for local (< 1 km) and neighborhood (1-10 km) variations. In temporally-decomposed analyses, the PM2.5-mortality HRs were stable across yearly cohorts. The meta-analytic HR using two-year lagged PM2.5 equaled 1.10 (95% CI 1.07, 1.13) per 10 μg/m3. Comparable results were observed in time-independent analyses using a 17-year (HR 1.13, CI 1.09, 1.16) or 28-year (HR 1.09, CI 1.07, 1.12) exposure window. Long-term exposures to PM2.5, PM2.5-10, and SO2 were associated with increased risk of all-cause and cardiopulmonary mortality. Each spatial decomposition of PM2.5 was associated with mortality risk, and PM2.5-mortality associations were consistent over time.


Haplotype analysis revealed a genetic influence of osteopontin on large artery atherosclerosis.
Osteopontin (OPN) is a cytokine that involves in vascular remodeling processes in cerebrovascular diseases. The association of its gene with ischemic stroke was investigated in a Korean population. Representative sequence variants covering the entire OPN gene were genotyped in 455 controls and 271 patients with ischemic stroke including large artery atherosclerosis (LAA), small vessel occlusion, and cardioembolism. Analysis with the individual tagging variants and their haplotypes revealed an evidence of association only with LAA. Significances were shown with the haplotypes, especially with the TCA at the loci C2140T, C5891T, and A7385G conferring a risk of 2.09 for LAA (P < 0.05). The CG at the loci C1013T and A7385G was the most protective haplotype (OR = 0.66, P < 0.05). Our findings suggested that several haplotypes of OPN gene contributed to determining risk factors as well as protective factors of LAA.


An appraisal of the gut health modulatory effects of a calf faecal-origin probiotic Lactobacillus salivarius CPN60 using Wistar rats with dextran sulfate sodium-induced colitis.
Probiotics of varied origins are being developed for augmenting the gut health of human and animals. The present study aimed to evaluate the effect of a calf-origin probiotic supplement on the gut health of Wistar rats for both healthy and colitis conditions. Forty-eight rats were randomly distributed into four equal groups. The 42-day study involved feeding basal diet alone (CON) or diet supplemented with the calf-origin Lactobacillus salivarius strain CPN60 (PRO). The third (CONc) and fourth (PROc) groups of rats also received the same dietary treatments (CON and PRO, respectively) but were subjected to dextran sulfate sodium (DSS)-induced colitis after 32 days of feeding. The results of a digestion trial conducted after 5 days of DSS administration revealed no influence of probiotic on the digestibility of nutrients. However, the reduced digestibility of protein and fat seen in the CONc rats was improved in the PROc group. The concentrations of lactate and acetate, propionate and butyrate, as well as total short-chain fatty acids (SCFA), were increased (P < 0.05) in the caecal and colonic digesta upon probiotic supplementation, together with significantly reduced colonic ammonia levels. Furthermore, there were reductions (P < 0.05) in acetate, butyrate and total SCFA levels in the caecal contents as a result of colitis. Probiotic supplementation increased (P < 0.05) lactobacilli and bifidobacteria counts in the colon, whereas clostridia and coliform counts were reduced (P < 0.05). These were reversed by the probiotic supplementation. Dietary supplementation of L. salivarius CPN60 had a positive effect with respect to improving the overall gut health of healthy rats, as well as that of rats exposed to experimental colitis. © 2020 Society of Chemical Industry.


Adenosine receptors and the nucleoside transporter in human brain vasculature.
Evidence suggests that adenosine modulates neuronal and cerebral vascular functions by interacting with specific receptors on brain cells and blood vessels. Adenosine and other nucleosides are also transported across the blood-brain barrier via a saturable, carrier-mediated mechanism. Using direct ligand binding methods, we studied the two adenosine receptor subtypes, A1 and A2 and the nucleoside transporter moiety in human brain microvessels, pial vessels, choroid plexus, and cerebral cortex membranes. The following specific tritiated ligands were used: cyclohexyladenosine (CHA) for A1 receptors; 5'-N-ethylcarboxamide adenosine (NECA) for A2 receptors; nitrobenzylthioinosine (NBMPR) and dipyridamole (DPY) for nucleoside transporters. We find that cerebral microvessels, pial vessels, and choroid plexus have few, if any, A1 receptors, in contradistinction to cerebral membranes, which have a 10-20-fold higher density of A1 receptor sites. Specific high-affinity NECA binding to A2 receptors in cerebral microvessels, pial vessels, and choroid plexus was saturable and was equivalent to that of cerebral cortical membranes. The Bmax and Kd of the high-affinity NECA binding to vessel preparations were approximately 1.3 pmol/mg protein and approximately 250 nM, respectively, which is similar to our previous findings in the rat and pig. NBMPR and DPY binding were also saturable and were consistent with a single class of high-affinity binding sites. The density of nucleoside transporters was approximately four-fold higher in cerebral microvessels than in cerebral cortex, pial vessels, and choroid plexus. These results suggest that human cerebral microvessels have A2, but not A1, receptors and are particularly enriched with the adenosine transporter moiety.


Recombinant human interleukin 6 (B-cell stimulatory factor 2) is a potent inducer of differentiation of mouse myeloid leukemia cells (M1).
Recombinant human interleukin 6 (IL-6), a lymphokine involved in the final differentiation of activated B-cells into antibody-forming cells, greatly suppressed proliferation and induced differentiation of murine myeloid leukemia cells (M1) into mature macrophage-like cells. When M1 cells were treated with IL-6, their growth was completely arrested as early as on day 2, and they were induced to differentiate morphologically into macrophage-like cells. Differentiation-associated properties such as phagocytic activity, adherence to the dish surface, Fc and C3 receptors, were also induced within 24 h by IL-6, and they reached their respective maximal levels on day 2 or 3. The potency of IL-6 in suppressing proliferation and inducing differentiation was much greater than that of 1 alpha,25-dihydroxyvitamin D3 one of the most potent inducers of M1 cells. The present report indicates that IL-6 is involved in the differentiation of not only B-cells but also myeloid leukemia cells.


Interaction of prostaglandins and adenosine 5'-triphosphate in the noncholinergic neurotransmission in rabbit detrusor.
Part of the excitatory transmission in rabbit detrusor is noncholinergic and nonadrenergic, and prostaglandins (PGs) and adenosine 5'-triphosphate (ATP) have been implicated in this transmission. The present experiments investigate the possibility of an interaction between PGs and ATP in rabbit detrusor. Indomethacin (2.8 muM) depressed the contraction produced by ATP although it did not antagonize the contraction produced by carbachol. Treatment of detrusor strips with 1.5 mM ATP depressed the frequency response curve in field stimulated tissues. This depression was additive with that produced by atropine. In the present experiments indomethacin did not significantly augment the effect of desensitization with ATP. It is suggested that the atropine-resistant neurotransmission in rabbit detrusor may involve both ATP and PGs acting in cooperation.


Serum-free growth medium for the cultivation of a wide spectrum of mammalian cells in stirred bioreactors.
A serum free medium was developed, that could be used for the large scale propagation of various cell lines in bioreactors. The medium is based on a 1:1 mixture of Iscove's Modified Dulbecco's Medium and Ham's Medium F12, supplemented with transferrin, insulin and a BSA/oleic acid complex. Several myelomas, hybridomas derived from different myelomas and spleen cells, and other lymphoid and non-lymphoid cell lines were cultivated at growth rates comparable to those observed using serum-supplemented media. There was furthermore no reduction in the formation of products such as monoclonal antibodies or recombinant human interleukin-2.


Suppression of the histamine-induced wheal and flare response by fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily and placebo in healthy Japanese volunteers.
The effects of the selective H1-receptor antagonist fexofenadine have been widely demonstrated in Western populations; however, to date, limited data comparing the effects of fexofenadine with other antihistamines have been reported in Japanese subjects. To investigate the effect of fexofenadine and loratadine on the histamine-induced cutaneous wheal and flare response in healthy Japanese volunteers. Eighteen healthy male and female Japanese volunteers aged 20-53 years were randomized to receive fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily or placebo in a 1-day, three-period, double-blind, crossover study. For each treatment, the wheal and flare response to 100 mg/mL histamine was assessed at baseline and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 8, 12 and 24 hours post-dose. Blood samples were taken for pharmacokinetic analysis. Fexofenadine produced significantly greater percentage suppression of the overall wheal response compared with placebo and loratadine (43.1% versus 10.0% and 15.2%, respectively; p < 0.001). Similarly, fexofenadine significantly suppressed the overall flare response compared with placebo and loratadine (43.0% versus 3.5% and -8.9%, respectively; p < 0.01). Loratadine was statistically no different from placebo in terms of both overall wheal and flare suppression. Area under the curve analysis for wheal and flare reduction (0-12 hours post-dose) confirmed these findings. For wheal inhibition, fexofenadine had a significantly faster onset of action (defined as time to > or = 35% inhibition) compared with placebo (p < 0.001) and loratadine (p < 0.01); for flare, fexofenadine had a significantly faster onset of action than loratadine (p < 0.01). Mean maximum inhibition (the mean of the greatest inhibition achieved from baseline for each treatment) for wheal was achieved significantly faster with fexofenadine than loratadine (p < 0.01), and fexofenadine had a significantly longer duration of effect on suppressing wheal and flare compared with placebo and loratadine (p < 0.05 for all). The antihistamine effects of fexofenadine correlated significantly with its Cmax, while loratadine activity did not correlate significantly with its plasma levels. Fexofenadine is a potent suppressor of the histamine-induced wheal and flare response in healthy Japanese volunteers. These results support findings in Caucasian subjects, and confirm that fexofenadine has greater antihistaminergic activity than loratadine in this human model.


Distribution of epithelial membrane antigen in normal and neoplastic human ependyma.
The ependyma and choroid plexus of 23 normal brains and 20 ependymal tumors were examined immunohistochemically for expression of epithelial membrane antigen (EMA) using a specific monoclonal antibody. The ependyma of normal brains showed three patterns of immunoreactivity: membrane immunoreactivity confined to the luminal surface; irregular punctate intracytoplasmic immunoreactivity in the subependymal layer; and spherical and ring-like intracytoplasmic immunoreactivity in the subependymal layer. Of 13 differentiated ependymomas 11 reflected the immunoreactive patterns of normal ependyma. The anaplastic ependymomas and ependymoblastomas had no immunoreactivity. Our results indicate that EMA has a highly selective distribution in the ependyma, and is a marker for differentiated ependymoma.


Enzymic dephosphorylation of bovine casein to improve acid clotting properties and digestibility for infant formula.
To improve acid clotting properties, enzymic dephosphorylation of caseins with calf intestinal alkaline phosphatase (CAP) or potato acid phosphatase (PAP) was investigated. Greater dephosphorylation was achieved using alpha s1- or beta-casein as substrates, compared to whole casein or skim milk. Electrophoresis of PAP-modified caseins revealed bands with lower mobility and a multibanded pattern in the beta-casein region which was similar to that of human beta-casein. On the other hand, CAP modification produced electrophoretic bands having lower mobility of the beta-casein component, but with higher mobility in the alpha s1-casein component as well as increased net negative charge in the CAP-casein. PAP-casein formed a fine dispersion upon acidification to pH 4, with a microstructure similar to that of acidified human casein. Greater initial rates of hydrolysis by pepsin at pH 4 were observed for both CAP- and PAP-modified caseins, compared to bovine and human caseins. The rate and extent of hydrolysis remained high for CAP-casein but tended to level off with PAP-casein during sequential digestion with pepsin and pancreatin. There may be advantages in the use of partial dephosphorylation to improve acid clotting and digestibility properties of bovine casein for infant feeding.


The reported active metabolite of methoxychlor, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane, inhibits testosterone formation by cultured Leydig cells from neonatal rats.
Methoxychlor (MC) is an insecticide that is presently used on agricultural crops, especially after the ban on the use of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) in the United States. Following administration in vivo, MC is converted to 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which is thought to be the active agent. However, both MC and HPTE have been reported to have weak estrogenic and antiandrogenic activities, and they are thought to exert their potential adverse (endocrine disruptive) effects through the estrogen and androgen receptors, respectively. In a recent study, HPTE was shown to inhibit both basal and hCG-stimulated testosterone production by cultured Leydig cells from immature and adult rats, and these effects were reported to be mediated through the estrogen receptor. Because fetal Leydig cells represent a separate population from adult Leydig cells and many of the reported adverse actions of endocrine disruptors are thought to have their effects during gestational exposure, the present studies examined the effects of HPTE on testosterone formation by cultured fetal Leydig cells from neonatal rats to determine whether these cells are sensitive to HPTE. Our studies demonstrated that HPTE inhibited both basal and hCG-stimulated testosterone formation in a dose-dependent manner. Significant declines in testosterone were observed at about 100nM HPTE, and this effect was detected as early as 1h after exposure. The main effects of HPTE appeared to be localized to the cholesterol side-chain cleavage step which converts cholesterol to pregnenolone. In addition, this effect did not appear to be mediated through the estrogen receptor as a weak estrogen or the androgen receptor as an antiandrogen, which are the currently proposed modes of action of MC and HPTE.


The role of the Agouti-Related Protein in energy balance regulation.
The Agouti-Related Protein (AgRP) is a powerful orexigenic peptide that increases food intake when ubiquitously overexpressed or when administered centrally. AgRP-deficiency, on the other hand, leads to increased metabolic rate and a longer lifespan when mice consume a high fat diet. In humans, AgRP polymorphisms have been consistently associated with resistance to fatness in Blacks and Whites and resistance to the development of type-2 diabetes in African Blacks. Systemically administered AgRP accumulates in the liver, the adrenal gland and fat tissue while recent findings suggest that AgRP may also have inverse agonist effects, both centrally and peripherally. AgRP could thus modulate energy balance via different actions. Its absence or reduced functionality may offer a benefit both in terms of bringing about negative energy balance in obesigenic environments, as well as leading to an increased lifespan.


Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types.
Recent studies have shown the significance of metabolic reprogramming in immune and stromal cell function. Yet, the metabolic reconfiguration of RA macrophages (MΦs) is incompletely understood during active disease and in crosstalk with other cell types in experimental arthritis. This study elucidates a distinct regulation of glycolysis and oxidative phosphorylation in RA MΦs compared to fibroblast (FLS), although PPP (Pentose Phosphate pathway) is similarly reconfigured in both cell types. 2-DG treatment showed a more robust impact on impairing the RA M1 MΦ-mediated inflammatory phenotype than IACS-010759 (IACS, complexli), by reversing ERK, AKT and STAT1 signaling, IRF8/3 transcription and CCL2 or CCL5 secretion. This broader inhibitory effect of 2-DG therapy on RA M1 MΦs was linked to dysregulation of glycolysis (GLUT1, PFKFB3, LDHA, lactate) and oxidative PPP (NADP conversion to NADPH), while both compounds were ineffective on oxidative phosphorylation. Distinctly, in RA FLS, 2-DG and IACS therapies constrained LPS/IFNγ-induced AKT and JNK signaling, IRF5/7 and fibrokine expression. Disruption of RA FLS metabolic rewiring by 2-DG or IACS therapy was accompanied by a reduction of glycolysis (HIF1α, PFKFB3) and suppression of citrate or succinate buildup. We found that 2-DG therapy mitigated CIA pathology by intercepting joint F480+iNOS+MΦ, Vimentin+ fibroblast and CD3+T cell trafficking along with downregulation of IRFs and glycolytic intermediates. Surprisingly, IACS treatment was inconsequential on CIA swelling, cell infiltration, M1 and Th1/Th17 cytokines (IFN-γ/IL-17) and joint glycolytic mediators. Collectively, our results indicate that blockade of glycolysis is more effective than inhibition of complex 1 in CIA, in part due to its effectiveness on the MΦ inflammatory phenotype.


Controlled generation of nanopatterned electrical DNA interface.
Techniques that manipulate DNA, a biomolecule with electrical properties, are in demand in various medical fields. This study fabricated a nanochannel with a conductive/semi-conductive interface using focused ion beams (FIBs) and introduced a nanochip technology to freely align, attach, and detach lambda DNAs in the interface via electrophoresis. Two-step fabrication process of nanochannels was quantitatively characterized according to the different conditions of the FIB dose (1~30 nC/μm2) and current (1~500 pA). For electrophoresis test, four different nanofluidic channels with depths of 200 nm and lengths of 0.5, 1.0, 1.5, and 2.0 μm were processed at the center of the rectangular channel (10 μm × 10 μm). Different voltages (1~30 V) were applied for 15 min to attach the DNAs. As the voltage increased, more lambda DNAs attached to the nanochannel interface. Furthermore, an inverse voltage (-30 V) was applied to the lambda DNAs attached to the interface for 15 min to confirm that DNAs could be successfully detached. The results showed that this method could produce a highly promising nanochip technology to align and manipulate DNAs in the desired direction according to a conductive/semi-conductive nano-sized interface, which is applicable in various biomedical fields.


Production of fusarenon-X, nivalenol, and zearalenone by Gibberella zeae isolates, and their toxicity in fibroblasts and rats.
Three isolates ofGibberella zeae, the perfect stage ofFusarium graminearum, were isolated from ground corn cultures obtained from Taiwan in 1985 and identified asGibberella zeae l-1, G. zeae I-5, andG. zeae l-7. The isolates were grown on a solid rice medium and extracts prepared with 75% aqueous methanol. The extracts were examined for toxicity in the following systems: (1) cytotoxicity to cultured normal human diploid skin fibroblasts and mouse fibroblasts; and (2) toxicity to rats of unextracted cultures. The three extracts were highly cytotoxic as indicated by the ability to cause death and disintegration of 3T3 Swiss mouse fibroblasts and human diploid skin fibroblasts during 3 to 4 days in culture. The unextracted cultures of the isolates were highly toxic to rats, causing hemorrhage of tissues (bladder, stomach, and intestine), uterine enlargement, small thymuses, small spleens, weight loss, and death. The extracts were tested for production of trichothecenes (nivalenol and fusarenon-X) and zearalenone on rice grains. Production of the three mycotoxins was greater at room temperature than in the cold room. Detection of the three mycotoxins from the cultures was variable, ranging from 273 to 817ppm for nivalenol, 268 to 662 ppm for fusarenon-X, and 162 to 1095 ppm for zearalenone at room temperature, and 159 to 413 ppm for nivalenol, 113 to 125 ppm for fusarenon-X and 44 to 202 ppm for zearalenone in the cold room (10°C).


Extracellular matrix components in uterine leiomyoma and their alteration during the tumour growth.
It was found that both normal human myometrium and uterine leiomyoma contain several glycosaminoglycans. In contrast to many normal and tumour tissues the amount of hyaluronic acid is very low and the proportional amount of sulphated glycosaminoglycans is distinctly higher. It is of interest that heparan sulphate is the major glycosaminoglycan component both in normal myometrium, and in leiomyoma. The amount of hyaluronic acid in myometrium and in the leiomyoma is very low. No significant change in hyaluronate content was observed during the tumour growth. In contrast to that the amount of some sulphated glycosaminoglycans (heparan sulphate, keratan sulphate, chondroitin sulphates and heparin) distinctly increased. It is suggested that some of the GAGs participate in the creation of a storage depot for biologically active molecules (growth factors, enzymes) which are thereby stabilized and protected. Hydrolytic degradation of some GAGs may result in the release of some cytokines which may promote the tumour growth and stimulate collagen biosynthesis by tumour cells.


Incidence of acute glaucoma in Finland from 1973 to 1982.
The incidence of acute closed-angle glaucoma was studied in 1796 patients derived from the hospital discharge registry of Finland for the years 1973-1982 (469 males and 1327 females). The average incidence was 3.8 cases/100,000 per year. The incidence showed a steep rise with age. The highest incidence was observed in both sexes in the group 80 years of age and older. The incidence was higher (Chi-square 7.81, df = 1, P less than 0.01) among women (5.3/100,000 per year) than among men (2.0/100,000 per year). The age-adjusted incidence for the whole period of 1973-1982 showed no statistically significant rise. The seasonal variation of incidence was statistically significant (P less than 0.001). In winter (December, January, February) and in autumn (September, October, November) the incidences were higher compared to spring (March, April, May) and summer (June, July, August). This association was greater (P less than 0.001) among females than among males (P less than 0.05). Mean sunshine hours showed a reverse association with the incidence of acute glaucoma. The association was statistically significant when both sexes were pooled together (P less than 0.001). There was no sex interaction with regard to the association of incidence of acute glaucoma and mean sunshine hours.


An initial study of family accommodation in children and adolescents with chronic tic disorders.
This initial study examined the nature, incidence, and clinical correlates of family accommodation in youth with tic disorders, and validated a brief self-report measure of tic-related family accommodation, the Tic Family Accommodation Scale (TFAS). Seventy-five youth aged 6-18 who were diagnosed with a tic disorder and their parent completed a diagnostic clinical interview, and clinician and parent-report measures of tic severity, depressive symptoms, anxiety symptoms, behavioral problems, family accommodation and impairment. An exploratory factor analysis of the TFAS showed a two-factor structure, with good internal consistency for the Total score, Modification of Child Environment and Modification of Parent Environment subscales (α = 0.88, 0.86, and 0.81, respectively). Family accommodation was not associated with tic severity. Family accommodation was associated with increased anxiety and depressive symptoms, higher externalizing, rule breaking, aggressive behaviors and social problems, and with greater tic-related functional impairment. Anxiety and externalizing problems (but not depressive symptoms) predicted family accommodation when controlling for tic severity. Family accommodation predicted high levels of functional impairment over and above the effect of tic severity, anxiety, depression and externalizing problems. Family accommodation is a common phenomenon for youth with tic disorders, with modifications typically encompassing changes to the child and/or parent environments. Accommodation was not associated with tic severity, but was related to higher levels of anxiety, depressive symptoms, externalizing symptoms, aggression, and rule breaking behaviors. Results suggest that other emotional symptoms are more likely to drive accommodation practices than the tic symptoms per se.


A Cost-effectiveness Analysis of an Internet-delivered Pain Management Program Delivered With Different Levels of Clinician Support: Results From a Randomised Controlled Trial.
There is growing interest in the potential of internet-delivered pain management programs (PMPs) to increase access to care for people with chronic pain. However, very few economic evaluations of these interventions have been reported. Using existing data, the current study examined the cost-effectiveness of an internet-delivered PMP for a mixed group chronic pain patients (n = 490) provided with different levels of clinician support. The findings indicated that each additional clinical outcome (defined as a ≥ 30% reduction in disability, depression, anxiety, and pain) was associated with cost-savings when the intervention was provided in a self-guided format (ICER range: -$404--$808 AUD) or an optional-guided format (ICER range: -$314--$541 AUD), and a relatively small fixed cost when provided in the clinician-guided format (ICER range: $88-$225 AUD). The results were driven by a reduction in service use costs among the treatment groups, which offset the costs of providing the internet-delivered PMP in the self-guided and optional-guided formats. The same general pattern of results was found when more stringent clinical outcomes (defined as a ≥ 50% reduction) were employed. These findings suggest that carefully developed and administered internet-delivered PMPs, provided with different levels of clinician support, can be highly cost effective for patients with a broad range of pain conditions. PERSPECTIVE: This study examines the cost-effectiveness of an internet-delivered PMP provided to adults with a broad range of chronic pain conditions. Evidence of cost-effectiveness was found across a broad range of clinical outcomes and with different levels of clinician support.


Sonic irrigation for removal of calcium hydroxide in the apical root canal: A micro-CT and light-coupled tracking analysis.
This study aimed to evaluate the efficacy of three sonic irrigation systems for removal of calcium hydroxide dressing from the apical root canal. A total of 96 single-rooted teeth in three categories of root canal curvatures (straight: 0-5°, moderate: 6-20°, and severe: > 20°) were allocated to four groups: conventional needle irrigation, EndoActivator, EQ-S, and Vibringe. The root canals were instrumented using Protaper NEXT and filled with calcium hydroxide. After removal of calcium hydroxide, the remaining volume of calcium hydroxide was measured by micro-CT analysis. Data were compared among root canal curvatures and irrigation systems using the Kruskal-Wallis test and Mann-Whitney test (p < .05). The oscillating range of each irrigation system was measured using light-coupled motion tracking. The volumes of calcium hydroxide remaining in the canals with severe curvature were significantly higher than in those of straight curvature (p < .05). In the canals of moderate or severe curvature, EQ-S showed the highest removal percentage, followed by EndoActivator, Vibringe, and needle irrigation (p < .05). Light-coupled tracking showed the largest oscillating range in EQ-S (p < .05). Sonically activated irrigation systems with a flexible tip can be beneficial for calcium hydroxide intracanal dressing removal in the curved apical canals.


Four methods to analyze H3K27M mutation in diffuse midline gliomas.
The histone H3 K27M mutation has been frequently reported in the majority of diffuse midline gliomas, which is considered as a prognostic and predictive biomarker. A number of different methods and platforms including pyrosequencing (PSQ), sanger sequencing, immunohistochemistry (IHC), Mass array and NGS (Next Generation Sequencing) have been used to detect H3K27M mutation in diffuse midline gliomas. However, controversy remains about the most appropriate method to use for analyzing H3K27M status. The H3K27 M mutation status of a total of 50 diffuse midline gliomas was examined using PSQ, sanger sequencing, IHC and Mass array in parallel. Using PSQ as a recommended standard method, the sensitivity, specificity and correlation with the other assays were calculated. Among 50 diffuse midline glioma cases, the H3K27M mutation was positive in 64 %, 66 %, 62 % and 62 % of the cases by PSQ, IHC, sanger sequencing and mass array, respectively. The sensitivity and specificity of IHC were 100 % and 94.4 %, respectively. The sensitivity and specificity of sanger sequencing and mass array were both 96.9 % and 100 %, respectively. This study demonstrated that IHC is an effective and rapid detection method for routine use in pathology laboratories for the identification of H3K27M mutation. A combination of IHC and sanger sequencing assays can provide 100 % sensitivity and specificity for the prediction of H3K27M status.


Three-Dimensional Volumetric Magnetic Resonance Imaging Analysis of Syringomyelia Evolution After Posterior Fossa Decompression for Chiari Malformation Type1.
This study aims to introduce a method of three-dimensional (3D) volume magnetic resonance imaging (MRI) measurements to evaluate the evolution of syringomyelia (SM) in adults with Chiari malformation type 1 (CM-1) after posterior fossa decompression (PFD), to provide reproducible and accurate measurements. Radiologic and clinical data were obtained for 28 patients. MRI 3D syrinx volumes were evaluated by 2 observers using Philips Healthcare Tumor Tracking tool. The mean SM preoperative volume was 9.1 ± 15.3 cm3 versus 4.6 ± 8.7 cm3 postoperatively, corresponding to a volume variation reduced by -50% ± 33.4%. A total of 21 patients (75%) showed >25% reduction in SM volume postoperatively and 25 patients (89.2%) showed good to excellent postoperative clinical outcomes. Very high interobserver and intraobserver agreement was noted for 3D volumetric analysis with Cohen weighted κ coefficients (0.899-0.991). A negative correlation was found between the number of involved metameres and the postoperative SM volume reduction (Pearson correlation coefficient = 0.378; P = 0.047). Patients with better clinical outcomes had fewer syrinx septae (F = 8.830; P = 0.001). Similarly, better syrinx volume reduction was associated with fewer septae (F = 1.554; P = 0.233). A positive relationship was observed between clinical outcomes and postoperative syrinx volume reduction (F = 1.554; P= 0.233), with data similar to the reported literature. This study shows that 3D volume measurement of the syrinx cavity on MRI is a reproducible and accurate method to assess the postoperative evolution of SM in CM-1 after PFD. Most patients (75%) showed a reduction of SM volume, with a mean volume decrease of 50%. The reliability is yet to be validated in further larger studies.


Evidence of an imbalance of angiogenic/antiangiogenic factors in massive perivillous fibrin deposition (maternal floor infarction): a placental lesion associated with recurrent miscarriage and fetal death.
Massive perivillous fibrin deposition (MPFD) is associated with serious complications of pregnancy including recurrent spontaneous abortion, fetal growth restriction, and fetal demise. The aim of this study was to determine whether maternal plasma concentrations of angiogenic/antiangiogenic factors in MPFD differ from those of uncomplicated pregnancies. This retrospective longitudinal case-control study included MPFD cases (n = 10) and control patients (n = 175) with uncomplicated pregnancies who were enrolled in a longitudinal study and delivered at term. Serial plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor (sVEGFR)-1 and -2 were determined by an enzyme-linked immunosorbent assay (cases, n = 28 samples; controls, n = 723 samples). Individual analyte concentrations were averaged across gestational age at specimen collection intervals. Linear mixed models were used to test for differences in log-transformed mean analyte concentrations both overall and as a function of time. The following results were found: (1) patients with MPFD had a lower mean plasma PlGF concentration (P = .03) and higher mean plasma concentrations of sVEGFR-1 and sEng (both P < .01) than controls, adjusted for potential confounders; (2) the mean plasma concentration of PlGF differed further among cases and controls as a function of gestational age interval (P < .0001); however, mean sVEGFR-1 and sEng group differences as a function of gestational age interval approached but did not reach significance (P = .09 and P = .11, respectively); (3) patients with MPFD had lower mean plasma concentrations of PlGF/sVEGFR-1 (P < .0001) and PlGF/sEng (P < .001): both of these relationships differed further as a function of gestational age interval (both P < .0001); and (4) differences in mean sVEGFR-1, sEng, and the ratios of PlGF to sVEGFR-1 and PlGF to sEng were observed before 20 weeks of gestation. An imbalance of angiogenic/antiangiogenic factors is present in patients with MPFD prior to the diagnosis. We propose that these changes participate in the mechanisms responsible for adverse pregnancy outcomes in patients with MPFD.


Investigations on the Temperature-Dependent Interaction of Water Vapor with Tin Dioxide and Its Implications on Gas Sensing.
This work presents an operando infrared spectroscopic study of the temperature-dependent water adsorption on pristine SnO2 surfaces and discusses the possible implications on the oxygen ionosorption and gas-sensing mechanism. The impact of water on the sensor resistance, CO-sensing performance, and CO conversion was studied, and the obtained phenomenological results provide the basis for discussing the operando spectroscopic investigation findings. The provided information allows identification of three different water adsorption regimes ranging from physisorption and dominant associative adsorption to mainly dissociative water adsorption. In these regions, water has different impacts on the surface composition, sensor resistance, and gas-sensing performance.


The Neurohumanities: An Emerging Partnership for Exploring the Human Experience.
Neuroscience has an extraordinary opportunity to investigate issues historically addressed by the arts, humanities, and social sciences. As a guide, we suggest three features of meaningful progress in the collaborative field, the neurohumanities, which we illustrate through a discussion of "neural schemas."


Positive and negative ion mass spectrometry of tricyclic antidepressants.
Positive electron impact (EI), positive chemical ionization (CI), and negative CI mass spectra of eight tricyclic antidepressants are presented. In the positive EI mode, peak(s) at m/z 193 and/or 195, which corresponded to the tricyclic nucleus, appeared for five compounds; a peak at m/z 58 was common to compounds having a gamma-dimethylaminopropyl group as their side chain. Molecular ions appeared for all compounds though they were very small in some compounds in the positive EI mode. In the positive CI mode, [M + H]+ quasi-molecular peaks appeared together with [M + C2H5]+ peaks in five compounds; the ion at m/z 196, which corresponded to the tricyclic nucleus also appeared in five compounds. In the negative CI mode with 1 Torr chamber pressure, [M - 1]- quasi-molecular ions were observed for all compounds except for lofepramine; [M + 43]- anions, which probably corresponded to [M + C3H4]-, appeared in five compounds; strong [M + Cl]- ions appeared in carpipramine and clocapramine. The anions due to the tricyclic nucleus also appeared in this mode. In the negative CI mode at low pressure (0.01 Torr), the spectra were generally similar to those in the 1 Torr negative CI mode. However, the cluster anions never appeared at the low pressure. Some data on extraction for some antidepressants from human urine and plasma, and their separation by gas chromatography, are also presented.


U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis.
On November 16, 2011, the U.S. Food and Drug Administration (FDA) granted full approval to ruxolitinib, (Jakafi; Incyte Corp.), an inhibitor of the Janus kinases 1 and 2, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. This approval was based on the results of 2 large randomized phase III trials that enrolled patients with intermediate-2 or high-risk myelofibrosis and compared ruxolitinib with placebo (study 1) or best available therapy (study 2). The primary efficacy endpoint was the proportion of patients who experienced a reduction in spleen volume of ≥ 35% at 24 weeks (study 1) or 48 weeks (study 2). The key secondary endpoint in study 1 was the proportion of patients who experienced a ≥ 50% improvement from baseline in myelofibrosis total symptom score at 24 weeks. The results of these studies showed that a greater proportion of patients treated with ruxolitinib experienced a ≥ 35% reduction in spleen volume as compared with those treated with placebo (42% vs. 1%, P < 0.0001) or best available therapy (29% vs. 0%, P < 0.0001). A greater proportion of patients in study 1 experienced a ≥ 50% reduction in the myelofibrosis total symptom score during treatment with ruxolitinib than with placebo (46% vs. 5%, P < 0.0001). Ruxolitinib treatment was associated with an increased incidence of grades III and IV anemia, thrombocytopenia, and neutropenia. This is the first drug approved for myelofibrosis.


BODIPY-based fluorescent chemosensor for phosgene detection: confocal imaging of nasal mucosa and lung samples from mouse exposed to phosgene.
The improper use of phosgene, either as a chemical warfare agent or a leak during chemical production, causes significant risks to human life and property. Therefore, it is particularly important to develop a rapid and highly selective method for the detection of phosgene. In this article, a highly selective fluorescent sensor ONB with a BODIPY unit as a fluorophore and o-aminophenol as a reactive site was constructed for the selective and rapid detection of phosgene in solution. The ONB-containing nanofibers were sprayed onto a non-woven fabric by electrostatic spinning and cut into test films, which can be used well for the detection of gaseous phosgene. While, there were no reported bio-imaging applications for phosgene detection. In this work, nasal mucosa and lung samples from the mice exposed to gaseous phosgene after dropping the ONB solution through the nasal cavity achieved bio-imaging applications successfully.


Resolution of translation start site for the human Kell glycoprotein.
The human Kell blood group system currently contains 35 antigens determined by allelic polymorphisms in the Kell glycoprotein, a single-pass Type II transmembrane protein. The Kell glycoprotein was initially cloned through screening of a cDNA library; however, direct amino acid sequencing of most of the Kell glycoprotein has not been reported. The N-terminus of the Kell glycoprotein contains two potential translational start sites, which result in differences in the cytoplasmic tail. Protein extracts were isolated from human red blood cell membranes and were digested with trypsin. The resulting peptides were subjected to liquid chromatography-tandem mass spectrometry, allowing resolution of peptides from the N-terminus of the Kell glycoprotein. Peptides were isolated and sequenced that correspond to the upstream methionine start site predicted by the full cDNA sequence. No evidence of internal translation initiation at Methionine 20 was detected. These findings identify the translational start site and define the full cytoplasmic tail of the human Kell glycoprotein.


From insulin to Akt: Time delays and dominant processes.
Akt/PKB regulates numerous processes in the mammalian cell, including cell survival and proliferation, and glucose uptake in response to insulin. Abnormalities in Akt signalling are linked to the development of Type 2 diabetes, cardio-vascular disease, and cancer. In the absence of insulin, Akt is predominantly found in the inactive state in the cytosol. Following insulin stimulation, Akt translocates to the plasma membrane, docks, and is phosphorylated to take on the active conformation. In turn, the activated Akt travels to and phosphorylates its many downstream substrates. Although crucial to the activation process, the translocation of Akt from the cytosol to the plasma membrane is currently not well understood. Here we detail the parameter optimisation of a mathematical model of Akt translocation to experimental data. We have quantified the time delay between the application of insulin and the downstream Akt translocation response, indicating the constraints on the timing of the intermediate processes. A delay of approximately 0.4 min prior to the Akt response was determined for the application of 1 nM insulin to cells in the basal state, whereas it was found that a further transition from physiological insulin to higher stimuli did not incur a delay. Furthermore, our investigation indicates that the dominant processes regulating the appearance of Akt at the plasma membrane differ with the insulin level. For physiological insulin, the rate limiting step was the release of Akt to the plasma membrane in response to the insulin signal. In contrast, at high insulin levels, regulation of the recycling of Akt from the plasma membrane to the cytosol was also required.


The disulfide bridges of the immunoreactive forms of human pancreatic stone protein isolated from pancreatic juice.
Following the complete sequence elucidation of human pancreatic stone protein (immunoreactive form PSP S1 isolated from pancreatic juice) [(1987) Eur. J. Biochem. 168, 201-207], the location of the three S-S bridges of the protein was investigated. The cystine-containing peptides, detected after the separation of the peptic or chymotryptic digests on SP-Sephadex or Sephadex G-50, were submitted to Edman degradation and/or to oxidation. The cysteic peptides after separation on SP-Sephadex or Sephadex G-50 were characterized by their amino acid compositions. The pairing of the half-cystines: Cys 3-Cys 14, Cys 31-Cys 129 and Cys 104-Cys 121 was determined. The same experiments carried out with PSP S2-5 (other immunoreactive forms) gave an identical characterization.


Variability in opioid pain medication prescribing for adolescent trauma patients in a sample of US pediatric trauma centers.
The primary objective of this study was to examine opioid prescription frequency and identify differences across a national cohort of pediatric trauma centers in rates of prescribing opioids to injured adolescents at discharge. This was a retrospective observational study using electronic health records of injured adolescents (12-17 years) admitted to one of 10 pediatric trauma centers. Of the 1345 electronic health records abstracted, 720 (53.5%, 95% CI 50.8 to 56.2) patients received opioid prescriptions at discharge with variability across sites (28.6%-72%). There was no association between patient factors and frequency of prescribing opioids. Center's trauma volume was significantly positively correlated with a higher rate of opioid prescribing at discharge (r=0.92, p=0.001). There was no significant difference between the frequency of opioid prescriptions at discharge among alcohol and other drugs (AOD)-positive patients (53.8%) compared with AOD-negative patients (53.5%). Across a sample of 10 pediatric trauma centers, just over half of adolescent trauma patients received an opioid prescription at discharge. Prescribing rates were similar for adolescent patients screening positive for AOD use and those screening negative. The only factor associated with a higher frequency of prescribing was trauma center volume. Consensus and dissemination of outpatient pain management best practices for adolescent trauma patients is warranted. III-prognostic. NCT03297060.


Infants use phonetic detail in speech perception and word learning when detail is easy to perceive.
Infants successfully discriminate speech sound contrasts that belong to their native language's phonemic inventory in auditory-only paradigms, but they encounter difficulties in distinguishing the same contrasts in the context of word learning. These difficulties are usually attributed to the fact that infants' attention to the phonetic detail in novel words is attenuated when they must allocate additional cognitive resources demanded by word-learning tasks. The current study investigated 15-month-old infants' ability to distinguish novel words that differ by a single vowel in an auditory discrimination paradigm (Experiment 1) and a word-learning paradigm (Experiment 2). These experiments aimed to tease apart whether infants' performance is dependent solely on the specific acoustic properties of the target vowels or on the context of the task. Experiment 1 showed that infants were able to discriminate only a contrast marked by a large difference along a static dimension (the vowels' second formant), whereas they were not able to discriminate a contrast with a small phonetic distance between its vowels, due to the dynamic nature of the vowels. In Experiment 2, infants did not succeed at learning words containing the same contrast they were able to discriminate in Experiment 1. The current findings demonstrate that both the specific acoustic properties of vowels in infants' native language and the task presented continue to play a significant role in early speech perception well into the second year of life.


Controversies in behavioral neurology: the use of atypical antipsychotic drugs to treat neurobehavioral symptoms in dementia.
"Atypical" antipsychotic drugs are widely used in patients with neurobehavioral disturbances related to dementia. Recent reports have highlighted the risks of these agents, including increased mortality, and the US Food and Drug Administration (FDA) has issued black-box warnings concerning their use. Studies of efficacy have shown only limited evidence that these drugs are more effective than placebo in controlling abnormal behaviors or improving the lives of patients with dementia and their caregivers. Recent evidence suggests that the older, "typical" antipsychotic drugs have at least as much risk as the atypical agents, and FDA warnings have been extended to these agents. In managing the behavioral disturbances of demented patients, clinicians must weigh the benefits and risks of these agents, use them only for severely disruptive behaviors, discontinue medications when ineffective, and inform families of the benefits and risks of treatment.


Low back pain and telecommuting in Japan: Influence of work environment quality.
This study examined the relationship between frequency of working from home and low back pain (LBP), considering the quality of work environment. The study was based on a cross-sectional internet-based survey. Of 33 302 respondents, data from 12 774 desk workers were retained for analysis. We used a 0-10 numerical rating scale to assess LBP. Work environment was assessed using five subjective questions. Mixed-effects logistic regression nested by city level was used to analyze the relationship between frequency of working from home and LBP, stratified by work environment condition. The prevalence of LBP was 21.0%. Among those reporting a poor work environment, as opposed to almost never working from home, the multivariate odds ratio (OR) of LBP were as follows: working from home less than 1 day per week: OR = 1.25, 95% CI: 0.89-1.76, p = .190; 2-3 days per week: OR = 1.58, 95% CI: 1.16-2.16, p = .004; and 4 or more days per week: OR = 1.82, 95% CI: 1.38-2.40, p < .001. By contrast, among those reporting a good work environment, the OR of LBP did not increase as the frequency of working from home increased. The relationship between LBP and frequency of working from home was found to vary with the quality of the work environment; more specifically, LBP was associated with frequency of teleworking in a poor work environment. This study suggests that employers should give more support to their employees in promoting a good work environment to prevent LBP. (Words: 240/250).


The RESOLVE concept: approaching pathophysiology of fibroproliferative disease in aged individuals.
After reaching adulthood, orderly repair is probably one of the most important mechanisms throughout lifetime. Regular wound healing after an injury consists of a well-ordered sequence of overlapping phases of repair and essentially repeats the complex process of organ development. Organ failure in the ageing organism frequently represents the lost capacity to achieve an orderly reactivation of organ development, yet in varying and complex pathologic settings. One of the most aggressive manifestations of age-dependent and dysbalanced wound healing is a disease called idiopathic pulmonary fibrosis. Essentially, the disease replaces functional lung tissue with spreading scar tissue over a period of just 5 years. By a systematic comparison of wound healing conditions, the large-scale collaborative FP7-EU project RESOLVE has addressed these difficulties in a successful way. Background and outlining of the project are discussed.


Effects of bile acids on liver cell injury by cultured supernatant of activated liver adherents cells.
When heat-killed Propionibacterium acnes (P. acnes) is intravenously injected into mice followed by an intravenous injection of a small amount of lipopolysaccharide (LPS) 7 days later, most of the mice die of massive hepatic cell necrosis within 24 hours of LPS injection. In addition, when the liver adherent cells including Kupffer cells are separated from the mice 7 days after P. acnes injection and incubated in vitro with LPS, remarkable activity of the cytotoxic factor is found in the culture supernatant. This cytotoxic factor is thought to cause liver injury. Using this experimental model, the effects of various bile acids on liver cell injury were studied. As a result, ursodeoxycholic acid and dehydrocholic acid suppressed liver cell injury induced by the cytotoxic factor. However, cholic acid, deoxycholic acid and chenodeoxycholic acid did not have any hepatocytoprotective effects.


NOACs for thromboprophylaxis in medical patients.
The risk of venous thrombosis extends for an indeterminate length of time following admission to hospital with a medical or surgical condition. Observational studies in surgery show this risk extends for months and perhaps more than one year, for medical patients the risk extends for at least several weeks. Large bodies of evidence support the heightened risk status of hospitalised surgical and medical patients, and that prophylactic measures significantly reduce the risk of thrombosis. Extending thromboprophylaxis for 4-6 weeks with anticoagulants both old and new has been shown to be efficacious and safe in surgical patients. However in populations of medical patients although prolonged anticoagulant thromboprophylaxis has been shown to be efficacious it also results in more bleeding and the risk benefit is not clear. Hence no therapies are approved for prolonged thromboprophylaxis in medical patients. In this area there have been one phase III study of low molecular weight heparin and two completed phase III studies of NOACs. This article briefly summarises our understanding of the background to preventing venous thromboembolism in hospitalised medical patients and reviews the details of the studies using NOACs.


Lactate metabolism.
Lactate is the end product of the anaerobic metabolism of glucose, and its accumulation in the blood signals an increase in production or a decrease in utilization, or both. The most common etiology of lactic acidosis is hypoperfusion, which represents an imbalance between systemic oxygen demand and oxygen availability with resultant tissue hypoxia. A wide variety of other etiologies of hyperlactatemia have been identified or implicated. However, most of these are uncommon causes, and many actually represent an associated perfusion failure. Clinical recognition of hyperlactatemia is facilitated by an awareness of the clinical settings in which it is likely to occur. Serum electrolyte and arterial blood gas studies are helpful to recognize lactic acidosis, but direct assay of blood lactate is necessary to identify milder degrees of lactate elevation, to confirm and quantitate the severity of more severe degrees, and to monitor the progress of therapy. Therapy should be directed toward measures to ensure adequate systemic oxygen delivery and specific treatment of the underlying causes.