Stability of delayed neural networks with time-varying impulses.
This paper addresses the stability problem of a class of delayed neural networks with time-varying impulses. One important feature of the time-varying impulses is that both the stabilizing and destabilizing impulses are considered simultaneously. Based on the comparison principle, the stability of delayed neural networks with time-varying impulses is investigated. Finally, the simulation results demonstrate the effectiveness of the results.


Development of the Novel Pneumonia Risk Score to Predict Radiographic Pneumonia in Children.
The diagnosis of pneumonia in children is challenging, given the wide overlap of many of the symptoms and physical examination findings with other common respiratory illnesses. We sought to derive and validate the novel Pneumonia Risk Score (PRS), a clinical tool utilizing signs and symptoms available to clinicians to determine a child's risk of radiographic pneumonia. We prospectively enrolled children 3 months to 18 years in whom a chest radiograph (CXR) was obtained in the emergency department to evaluate for pneumonia. Before CXR, we collected information regarding symptoms, physical examination findings, and the physician-estimated probability of radiographic pneumonia. Logistic regression was used to predict the presence of radiographic pneumonia, and the PRS was validated in a distinct cohort of children with suspected pneumonia. Among 1181 children included in the study, 206 (17%) had radiographic pneumonia. The PRS included age in years, triage oxygen saturation, presence of fever, presence of rales, and presence of wheeze. The area under the curve (AUC) of the PRS was 0.71 (95% confidence interval [CI]: 0.68-0.75), while the AUC of clinician judgment was 0.61 (95% CI: 0.56-0.66) (P < 0.001). Among 2132 children included in the validation cohort, the PRS demonstrated an AUC of 0.69 (95% CI: 0.65-0.73). In children with suspected pneumonia, the PRS is superior to clinician judgment in predicting the presence of radiographic pneumonia. Use of the PRS may help efforts to support the judicious use of antibiotics and chest radiography among children with suspected pneumonia.


Sleeping position and sleep apnea syndrome.
Four patients who were evaluated for hypersomnia-sleep apnea syndrome were found in all-night sleep studies to have obstructive or mixed apneas related to their sleeping positions. All four were available for comprehensive follow-up and were subsequently restudied while avoiding the supine position. Supine, prone, and lateral decubitus apnea indices were calculated for each patient for each night. The supine sleeping position was associated with significantly more apneas than the non-supine positions. Keeping these patients off their backs when they slept was effective treatment. Additionally, when results of surgical or pharmacologic treatments of apnea are evaluated, positional apnea indices should be considered.


Autocatalysis in reaction networks.
The persistence conjecture is a long-standing open problem in chemical reaction network theory. It concerns the behavior of solutions to coupled ODE systems that arise from applying mass-action kinetics to a network of chemical reactions. The idea is that if all reactions are reversible in a weak sense, then no species can go extinct. A notion that has been found useful in thinking about persistence is that of "critical siphon." We explore the combinatorics of critical siphons, with a view toward the persistence conjecture. We introduce the notions of "drainable" and "self-replicable" (or autocatalytic) siphons. We show that: Every minimal critical siphon is either drainable or self-replicable; reaction networks without drainable siphons are persistent; and nonautocatalytic weakly reversible networks are persistent. Our results clarify that the difficulties in proving the persistence conjecture are essentially due to competition between drainable and self-replicable siphons.


Retirement and physical activity: analyses by occupation and wealth.
Older adults close to retirement age show the lowest level of physical activity. Changes in lifestyle with retirement may alter physical activity levels. This study investigated whether retirement changes physical activity and how the effect differs by occupation type and wealth level. This longitudinal study used the Health and Retirement Study (1996-2002), U.S. population-based data. Analyses were conducted in 2007 and 2008. Physical activity was measured by a composite indicator of participation in either work-related or leisure-time physical activity. Fixed-effects regression models were used to account for confounders and unobserved heterogeneity. The dependent variable was a composite indicator of participation in regular physical activity either at work or during nonworking hours. Physical activity decreased with retirement from a physically demanding job but increased with retirement from a sedentary job. Occupation type interacted with wealth level, with the negative impact on physical activity of retirement exacerbated by lack of wealth and the positive effect of retirement on physical activity enhanced by wealth. Substantial differences in the effect of retirement on physical activity occurred across subgroups. As the number of people approaching retirement age rapidly increases, findings suggest that a growing segment of the nation's population may not sustain an adequate level of physical activity.


Stereospecific binding of the antidepressant rolipram to brain protein structures.
The characteristics for the binding of the selective cAMP phosphodiesterase inhibitor and antidepressant agent rolipram to brain and peripheral organs were investigated. (+/-)-[3H]Rolipram equilibrium binding and Scatchard analysis revealed saturable, reversible, stereospecific, Mg2+-dependent and heat-sensitive binding with an apparent Hill number of 1. Binding was detected both to membrane-bound and soluble sites, with dissociation constants Kd of 1.2 and 2.4 nM, respectively, and binding site concentrations (Bmax) of 19.3 and 23.6 pmol/g rat forebrain. The (-)-enantiomer of rolipram was ca. 20 times more effective than the (+)-enantiomer in displacing (+/-)-[3H]rolipram from membranes. Rolipram bound to brain tissue of all mammalian species tested including man, while tissue from bird and fish showed less binding. Organs other than brain exhibited only negligible binding. Only specific cAMP phosphodiesterase inhibitors (ICI 63.197, Ro 20-1724) were potent competitors, while rolipram itself was inactive in a variety of receptor binding assays of neuroactive ligands. The kinetics of (-)-[3H]rolipram binding to the particulate fraction revealed a complex association and dissociation behaviour. The nature of the rolipram binding protein(s) is not clear, but the low affinity binding site evident from binding kinetics may represent a rolipram-sensitive phosphodiesterase isoenzyme also common to some peripheral organs, while the high affinity binding site(s) may be related to PDE isoenzymes more confined to the central nervous system.


Increasing physical activity in Cancer Survivors through a Text-messaging Exercise motivation Program (ICanSTEP).
Cancer survivors are often sedentary. Self-monitoring may promote physical activity through self-activation. We conducted a pilot trial to evaluate whether wearable activity tracker with personalized text message feedback would increase physical activity. We enrolled 30 patients with solid tumor cancers into a non-randomized prospective intervention trial (NCT02627079): 15 had completed treatment in the past year and 15 under active treatment. Each participant received an activity tracker and daily text messages personalized to their activity level. We assessed patient-reported outcomes and 6-min walk (6 MW) at baseline and 3 months. Twenty-six participants completed the study. There was substantial variation in baseline activity. Overall, 39% of participants increased their steps taken by at least 20%, and 23% increased their 6 MW distance by 20% or more. More participants who had completed treatment strongly agreed (73%) that the intervention increased their exercise levels than those receiving active treatment (47%). At 3 months, there was a significant improvement in median Beck Depression Inventory-II and Godin Leisure Index composite scores. At 6 months, 72% still wore their activity tracker at least 4 days per week. We found that the intervention was well-accepted with a high completion rate at 3 months and continued self-use at 6 months. In this pilot study of combined activity tracker and motivational messaging, we found a signal for increased physical activity over a 3-month period. Future research is needed to study this technique for its impact on activity and other physical and psychological measures of well-being. Activity tracker with personalized motivational messaging may be useful in promoting physical activity in cancer survivors.


Investigation and treatment after non-ST segment elevation acute coronary syndrome for patients presenting to rural or urban hospitals in Aotearoa New Zealand: ANZACS-QI 75.
Compare the care patients with non-ST segment elevation acute coronary syndrome (NSTEACS) received in Aotearoa New Zealand depending on the rural-urban category of the hospital they are first admitted to. Patients with NSTEACS investigated with invasive coronary angiogram between 1 January 2014 and 31 December 2019 were included. There were three hospital categories (routine access to percutaneous coronary intervention [urban interventional], other urban [urban non-interventional] and rural) and three ethnicity categories (Māori, Pacific and non-Māori/non-Pacific). Clinical performance measures included: angiography ≤3 days, assessment of left ventricular ejection fraction (LVEF) and prescription of secondary prevention medication. Of 26,779 patients, 66.2% presented to urban-interventional, 25.6% to urban non-interventional and 8.2% to rural hospitals. A smaller percentage of patients presenting to urban interventional than urban non-interventional and rural hospitals were Māori (8.1%, 17.0% and 13.0%). Patients presenting to urban interventional hospitals were more likely to receive timely angiography than urban non-interventional or rural hospitals (78.5%, 60.8% and 63.1%). They were also more likely to have a LVEF assessment (78.5%, 65.4% and 66.3%). In contrast, the use of secondary prevention medications at discharge was similar between hospital categories. Māori and Pacific patients presenting to urban interventional hospitals were less likely than non-Māori/non-Pacific to receive timely angiography but more likely to have LVEF assessed. However, LVEF assessment and timely angiography in urban non-interventional and rural hospitals were lower than in urban interventional hospitals for both Māori and non-Māori/non-Pacific. Patients presenting to urban hospitals without routine interventional access and rural hospitals were less likely to receive LVEF assessment or timely angiography. This disproportionately impacts Māori, who are more likely to live in these hospital catchments.


Validation of the Persian version of the Schizophrenia Cognition Rating Scale (SCoRS) in patients with schizophrenia.
The Schizophrenia Cognition Rating Scale (SCoRS) is an interview-based assessment of cognition that involves interviews with patients and informants. The SCoRS has shown good reliability, validity, and sensitivity to cognitive impairment in schizophrenia, with the advantage of brief administration and scoring time. The present study aimed to test the concurrent validity of the Persian version of the SCoRS. A group of 35 patients with schizophrenia and a group of 35 healthy controls received the Persian-SCoRS in the first session, and a standardized performance-based cognitive battery, the Brief Assessment of Cognition in Schizophrenia (BACS), in the second session.Our results indicated that the Persian version of the SCoRS was sensitive to cognitive impairment in the patients. The Persian SCoRS global rating was significantly associated with the composite score generated from the Persian version of the BACS and predicted functional outcomes as measured by Global Assessment of Functioning (GAF) and World Health Organization Quality of Life (WHO QOL). A Persian version of the SCoRS, an interview based measure of cognition that included informants, is related to cognitive performance and global functioning.


Dealing with NSCLC EGFR mutation testing and treatment: A comprehensive review with an Italian real-world perspective.
Since their discovery, relevant efforts have been made to optimize the detection approaches to EGFR mutations as well as the clinical management of EGFR-mutated NSCLC. The recent shift from single gene testing to novel comprehensive detection platforms along with the development of new generation tyrosine kinase inhibitors, targeting both common and uncommon EGFR-mutations, is leading to a progressive increase in the number of patients who may benefit from targeted approaches, with subsequent impact on their long-term survival and quality of life. However, a prompt and adequate implementation of the most recent diagnostic and treatment advances in the routine practice often remains critical to be specifically addressed. In this review we provide a complete and updated overview of the different detection platforms and therapeutic options currently available for the clinical management of advanced EGFR-positive NSCLC, summarizing scientific evidence and describing molecular testing as well as treatment practice in the real-word scenario.


[Reconstruction of the mandibular arch using free vascularized iliac and scapular grafts. Arguments in favor of using scapular grafts].
In 12 cases of surgically removed mandibular symphysis malignancies, the bone and mouth floor were reconstructed using osteo-musculocutaneous flaps from the iliac crest or free osteo-cutaneous scapular flaps. In our experience, the latter provide the best results. Removed in dorsal decubitus, they allow floor replacement. During the dissection of the tumor site, we also preserve labial and clin structures, which favours a good restoration of phonation and swallowing.


Effects of prenatal cocaine exposure in the retinal ganglion cell layer of the rat. A morphometric analysis.
To study the effects of prenatal cocaine-exposure on the developing retinal ganglion cell layer of the rat, female Wistar rats were administered subcutaneously (sc) cocaine hydrochloride (60 mg/kg body wt/d) or saline, or were not manipulated from gestational d 8-22. Male offspring were sacrificed at postnatal day 14 and 30. Radial semithin sections of epon-embedded flat mounts of the retinal quadrants were used to evaluate the following parameters along the centroperipheral axis: 1. Thickness of ganglion cells plus nerve fiber layer; 2. Nuclear size of ganglion cell layer neurons; and 3. Linear density (number per unit length) of ganglion cell layer neurons. To study the effects of cocaine and age on the retinal areas (temporal/nasal, dorsal/ventral), a repeated measures analysis of variance was used for each of the parameters mentioned above. All parameters were affected by prenatal exposure to cocaine. The thickness of the ganglion cell plus nerve fiber layer was reduced in cocaine-exposed rats in comparison with the saline group. Nuclear diameters were smaller in the cocaine than in the saline and control groups. The linear density was higher in the cocaine-exposed group than in the control and saline groups. The age-dependent decrease in the linear density from postnatal day 14-30 was higher in the cocaine-exposed rats than in the saline group; the decrease in the linear density along the centroperipheral axis found in both the control and saline groups was not significant in the cocaine-treated group. These morphometric findings strongly support the view that prenatal cocaine-exposure induces marked changes in the organization of the developing retina.


Pudendal Neurolysis: 6-Step Laparoscopic Approach.
To demonstrate the safety and feasibility of the laparoscopic approach to perform pudendal neurolysis in a case of pudendal nerve entrapment syndrome [1-3]. A video tutorial that highlights the laparoscopic steps to performing pudendal neurolysis, with a focus on the main anatomic landmarks [4,5]. A tertiary care regional hospital. This video shows a 6-step approach to laparoscopic pudendal neurolysis for the treatment of pudendal nerve entrapment between the sacrospinous and sacrotuberous ligaments [2,6-8]. Step 1: Identification of the umbilical artery. Step 2: Dissection and development of the lateral paravesical space until the pelvic floor. Step 3: Identification of the arcus tendineus of the endopelvic fascia. Step 4: Identification of the ischial spine and the sacrospinous ligament covered by the coccygeus muscle. Step 5: Coagulation and section of the coccygeus muscle and the sacrospinous ligament. Step 6: Medialization of the pudendal nerve until its entrance into the Alcock canal. This video demonstrates the safety, feasibility, and reproducibility of laparoscopic pudendal neurolysis in 6 steps. A minimally invasive approach is adequate to treat the pudendal compression until the Alcock canal [2].


A combinatorial target screening strategy for deorphaning macromolecular targets of natural product.
Natural products, as an ideal starting point for molecular design, play a pivotal role in drug discovery; however, ambiguous targets and mechanisms have limited their in-depth research and applications in a global dimension. In-silico target prediction methods have become an alternative to target identification experiments due to the high accuracy and speed, but most studies only use a single prediction method, which may reduce the accuracy and reliability of the prediction. Here, we firstly presented a combinatorial target screening strategy to facilitate multi-target screening of natural products considering the characteristics of diverse in-silico target prediction methods, which consists of ligand-based online approaches, consensus SAR modelling and target-specific re-scoring function modelling. To validate the practicability of the strategy, natural product neferine, a bisbenzylisoquinoline alkaloid isolated from the lotus seed, was taken as an example to illustrate the screening process and a series of corresponding experiments were implemented to explore the pharmacological mechanisms of neferine. The proposed computational method could be used for a complementary hypothesis generation and rapid analysis of potential targets of natural products.


Poly(δ-valerolactone-co-allyl-δ-valerolactone) cross-linked microparticles: Formulation, characterization and biocompatibility.
A novel polymeric material, poly(δ-valerolactone-co-allyl-δ-valerolactone) (PVL-co-PAVL), was used to manufacture microparticles (MPs) for sustained drug delivery. PVL-co-PAVL MPs were formulated using a modified oil-in-water approach, followed by a UV-initiated cross-linking process. Prepared MPs had a smooth spherical morphology and cross-linking of the copolymer was found to improve the integrity and thermal stability of the MPs. Paclitaxel (PTX) was successfully loaded into the MPs at a high drug loading capacity, using a post-loading swelling-equilibrium method. In vitro evaluation showed that the PVL-co-PAVL MPs provide sustained release of PTX, which exhibited first-order release kinetics. A subsequent pilot pharmacokinetic study was carried out on the PTX-loaded PVL-co-PAVL MPs. During this study, serum levels of PTX were monitored following subcutaneous administration of the MPs to Sprague-Dawley rats. Overall, the in vivo release of PTX from the MPs was lower than expected based on the in vitro release studies. Detectable serum levels of PTX suggest that sustained release of drug was achieved in vivo. Minimal changes in subcutaneous tissue were observed at the site of injection. Future studies will further examine the localized and systemic distribution of drug following administration in this new polymer-based MP system.


Sequential study of the pathology of Prudhoe Bay crude oil in chicken embryos.
Ten microliters of Prudhoe Bay crude oil was applied to the shell of fertile leghorn chicken eggs on Day 9 of incubation. Gross and microscopic pathological changes were examined in embryos surviving 1, 2, 4, and 9 days after treatment. Liver necrosis, renal lesions, and extensive edema appeared 2 days after treatment and reached maximal prevalence 4 days after treatment. There was minimal repair of the lesions from Day 4 to Day 9 after treatment. Pathological changes, including liver necrosis, mineralization in the kidney, infiltration by a large number of heterophils in the liver and spleen, subcutaneous edema with formation of large blisters, and reduction in body weight and length were still present on Day 18 of incubation, close to hatching time.


Platycodon grandiflorus enhances the effect of DDP against lung cancer by down regulating PI3K/Akt signaling pathway.
Cisplatin (DDP) is a first-line drug for non-small cell lung cancer (NSCLC), but its efficacy and applications are constrained by intolerance and serious side effects. Platycodon grandiflorus (PG) is usually used as lung medicinal drug to enhance other drug's effect on lung diseases. Therefore, present study aim to investigate anti-NSCLC effect of PG with DDP and mechanism involved in the combination for the first time. The results showed that compared with DDP group, the combined groups (DDP combined with 1, 2 and 4 g/kg of PG) reduced the tumor luminescence density by 26.0%, 78.2% and 32.8% respectively, and decreased the death rates, lung index, pathological damage and inflammation in lung tissue. Protein analysis of lung tissue showed that its anticancer effect may be associated with tumor cell apoptosis. Therefore, vitro studies showed that PG combined with DDP down-regulated the expression of p-Akt and PI3K and improved the protein expression of cleaved-caspase 9 in A549 cell and PG promotes the apoptosis of DDP and these mechanisms were related by inhibition of the PI3K/Akt signaling pathway. Our study confirms that the combination of PG and DDP will help enhance efficacy of DDP and is important for improving platinum-based chemotherapy.


Pre-translational control of the differentiated state: Test for free cytoplasmic Hb-Messenger ribonucleoprotein in chick erythroblasts and chick embryo brain.
Non-ribosome-bound 9S RNA was prepared from cytoplasmic ribonucleoprotein of erythropoietic and non-erythropoietic tissues. The RNA was assayed for Hb-mRNA content in a cell-free protein synthesizing system. Free Hb-mRNA was found in the cytoplasm of chick erythroblasts but not in chick embryo brain cytoplasm.


Acute pain-related depression of operant responding maintained by social interaction or food in male and female rats.
Clinically relevant pain is often associated with functional impairment and behavioral depression, including depression of social behavior. Moreover, recovery of function is a major goal in pain treatment. We used a recently developed model of operant responding for social interaction in rats to evaluate the vulnerability of social behavior to an experimental pain manipulation and the sensitivity of pain-depressed social behavior to treatment with clinically effective analgesics. Sprague-Dawley male and female rats were trained to lever press for social access to another rat, and responding was evaluated after treatment with (a) intraperitoneal injection of dilute lactic acid (IP acid; 0.18-5.6%) administered alone as a visceral noxious stimulus, (b) the mu-opioid receptor (MOR) agonist morphine (0.32-10 mg/kg) or nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (10 mg/kg) administered alone, or (c) morphine or ketoprofen administered before IP acid. For comparison, the same treatments were evaluated in separate rats trained to lever press for food delivery. Both IP acid alone and morphine alone more potently decreased responding maintained by social interaction than by food, whereas ketoprofen did not affect responding for either reinforcer. In general, analgesics were most effective to rescue operant responding when relatively low IP acid concentrations produced significant but submaximal behavioral depression; however, morphine was not effective to rescue responding for social interaction. Operant responding maintained by social interaction was more sensitive to pain-related disruption and less responsive to opioid analgesic rescue than food-maintained operant responding. Social behavior may be especially vulnerable to depression by pain states.


Machine learning to predict myocardial injury and death after non-cardiac surgery.
Myocardial injury due to ischaemia within 30 days of non-cardiac surgery is prognostically relevant. We aimed to determine the discrimination, calibration, accuracy, sensitivity and specificity of single-layer and multiple-layer neural networks for myocardial injury and death within 30 postoperative days. We analysed data from 24,589 participants in the Vascular Events in Non-cardiac Surgery Patients Cohort Evaluation study. Validation was performed on a randomly selected subset of the study population. Discrimination for myocardial injury by single-layer vs. multiple-layer models generated areas (95%CI) under the receiver operating characteristic curve of: 0.70 (0.69-0.72) vs. 0.71 (0.70-0.73) with variables available before surgical referral, p < 0.001; 0.73 (0.72-0.75) vs. 0.75 (0.74-0.76) with additional variables available on admission, but before surgery, p < 0.001; and 0.76 (0.75-0.77) vs. 0.77 (0.76-0.78) with the addition of subsequent variables, p < 0.001. Discrimination for death by single-layer vs. multiple-layer models generated areas (95%CI) under the receiver operating characteristic curve of: 0.71 (0.66-0.76) vs. 0.74 (0.71-0.77) with variables available before surgical referral, p = 0.04; 0.78 (0.73-0.82) vs. 0.83 (0.79-0.86) with additional variables available on admission but before surgery, p = 0.01; and 0.87 (0.83-0.89) vs. 0.87 (0.85-0.90) with the addition of subsequent variables, p = 0.52. The accuracy of the multiple-layer model for myocardial injury and death with all variables was 70% and 89%, respectively.


Erratum.
In the Research News item on evoked potentials entitled "Testing babies for neurological problems" (17 July, p. 322), the affiliation of Ivan Bodis-Wollner was incorrectly given as Albert Einstein College of Medicine. It should have been Mount Sinai School of Medicine.


Applicability of sucrose laurate as surfactant in solid dispersions prepared by melt technology.
This study focused on an investigation of the applicability of sucrose laurate as surfactant in solid dispersions. Although this surfactant has a US Drug Master File, it has not been used so far in internal pharmaceutical products. High drug-loaded solid dispersion systems consisting of gemfibrozil as a model drug and PEG 6000 as a carrier, with or without sucrose laurate (D1216), were prepared by the melting method. Cytotoxicity studies on Caco-2 monolayer cells were also performed, in order to gain information on the applicability of D1216 in oral formulations. The results showed that the presence of the surface-active agent did not affect the solid-state characteristics of the model drug significantly. A markedly improved dissolution of gemfibrozil from the ternary solid dispersion systems was observed as compared with the binary solid dispersion systems. The optimum concentration range of the D1216 in the formulations was determined to be 5-10%. The effective final concentrations of D1216 in the dissolution experiments proved to be non-toxic towards CaCo-2 cells. The results suggest the potential use of D1216 in innovative internal pharmaceutical formulations.


A cross-sectional study on preferred employment settings of final-year nursing students in Israel.
Despite the growing demand for community nurses, their number remains relatively low. We examined perceptions of final-year nursing students regarding their preferred work setting after graduation and the factors affecting their choice. A cross-sectional survey using a structured questionnaire was developed specifically for this study. The questionnaire was distributed among fourth-year students from all nursing training frameworks across Israel. Of 281 respondents (76.6% women, average age, 29.3 years), most (80.9%) preferred working in hospitals, while 5% preferred community settings; 14% were undecided. Students' knowledge on hospital nurses' tasks was greater compared to their knowledge on community nurses' tasks. Moreover, hospital nurses' tasks were perceived as more important than those of community nurses. The contribution of clinical placement in hospital nursing was perceived as significantly more meaningful than the contribution of clinical placement in community nursing. The vast majority of students (94.3%) stated that they would prefer to undergo a hospital nursing internship. A significant correlation was noted between students' clinical placement, the exposure to community nursing roles, and the perception of the community nurse's role: clinical placements that were perceived as a positive experience led to a more positive perception of community nurses' roles. Nursing students' perception of community nursing is based upon limited information which does not reflect community nurses' actual role and work.


Recent Advances in the Development of Type 2 Sodium-Glucose Cotransporter Inhibitors for the Treatment of Type 2 Diabetes Mellitus.
Type 2 diabetes mellitus (T2DM) is one of the most serious and prevalent diseases worldwide. In the last decade, type 2 sodium-glucose cotransporter inhibitors (iSGLT2) were approved as alternative drugs for the pharmacological treatment of T2DM. The anti-hyperglycemic mechanism of action of these drugs involves glycosuria. In addition, SGLT2 inhibitors cause beneficial effects such as weight loss, a decrease in blood pressure, and others. This review aimed to describe the origin of SGLT2 inhibitors and analyze their recent development in preclinical and clinical trials. In 2013, the FDA approved SGLT2 inhibitors as a new alternative for the treatment of T2DM. These drugs have shown good tolerance with few adverse effects in clinical trials. Additionally, new potential anti-T2DM agents based on iSGLT2 (O-, C-, and N-glucosides) have exhibited a favorable profile in preclinical evaluations, making them candidates for advanced clinical trials. The clinical results of SGLT2 inhibitors show the importance of this drug class as new anti-T2DM agents with a potential dual effect. Additionally, the preclinical results of SGLT2 inhibitors favor the design and development of more selective new agents. However, several adverse effects could be a potential risk for patients.


The effect of baclofen and diazepam on motor skill acquisition in healthy subjects.
Antispastic medication is often used in the clinic together with physiotherapy. However, some of the antispastic drugs, e.g., baclofen and diazepam, may influence the plastic mechanisms that are necessary for motor learning and hence efficient physiotherapy. In the present study, we consequently investigated the influence of baclofen and diazepam on acquisition of a visuomotor skill. The study was designed as a semi-randomized, double-blinded, placebo-controlled, crossover study in 16 healthy human subjects. The motor skill task required the subjects to match a given force trajectory by increasing or decreasing ankle dorsiflexor torque. Subjects trained for a total of 30 min. Transcranial magnetic stimulation of the primary motor cortex leg area was applied to elicit motor evoked potentials in the anterior tibial muscle (TA). Coupling between populations of TA motor units was calculated in the frequency (coherence) domain during isometric dorsiflexion. Subjects receiving placebo showed statistically significant improvement in motor performance (q = 34.1, P = 0.014) accompanied by a statistically significant reduction in intramuscular coherence. Subjects receiving baclofen and diazepam conversely showed no progression in motor performance (P > 0.05), and the training was not accompanied by a decrease in intramuscular coherence. TA motor evoked potentials had significantly lower threshold following the training in the placebo group, whereas this was not the case in the treatment groups. These data indicate that diazepam and baclofen interfere with the acquisition of a motor skill by disrupting some of the neuroplastic changes that are involved in improved motor performance. This suggests that antispastic treatment should be used with caution in subjects receiving concomitant physiotherapy.


Reduction in mutagenicity of cigarette smoke condensate by added sugars.
The effects of adding sugars to high- and low-tar cigarettes on the mutagenicity of their smoke condensates were studied using Salmonella typhimurium TA100 and TA98 with and without metabolic activation. The sugars tested were glucose, fructose, galactose, sorbitol, sucrose and lactose. The lowest mutagenicities observed with these sugars per mg of smoke condensate assayed on TA98 with metabolic activation were 37% (high-tar cigarettes) and 22% (low-tar cigaretts) of that of smoke condensate from untreated cigarettes. Addition of sugars increased the total amounts of smoke condensates, but the mutagenicities of the total condensates were also decreased by all the sugars, the lowest values being 35% (high-tar cigarettes) and 36% (low-tar cigarettes) of that of smoke condensates from cigarettes without added sugar. On assay with TA100 with metabolic activation, decreases in both specific and total mutangenicities of condensates of high-tar cigarettes were observed with all the sugars tested except galactose and sucrose. Treatment with glucose, fructose or sorbitol decreased the specific mutagenicity of condensates of low-tar cigarettes and glucose and fructose reduced also their total mutagenicity. The effects of added sugars were more marked when assayed on TA98 than on TA100 and of the sugars tested fructose and sorbitol had the greatest effects. Addition of sugars had no effect of the mutagenicity of cigarette-smoke condensate without metabolic activation.


Continuous flooding stimulates root iron plaque formation and reduces chromium accumulation in rice (Oryza sativa L.).
Chromium (Cr) contamination in rice poses a serious threat to human health. Therefore, we conducted pot experiments to investigate the influence of water management regimes on the formation of iron plaque on rice roots, and its effect on the accumulation and translocation of Cr in rice grown on contaminated soil. The results showed that water management regimes, including continuous and intermittent flooding, exerted notable effects on soil solution concentrations of Cr(VI) and Cr(III) through changes in redox potential, pH, and dissolved Fe(II) concentrations. In particular, 69.2%-71.8% of Cr(VI) was reduced to Cr(III) under continuous flooding, whereas only 33.3%-38.6% was reduced under intermittent flooding conditions. Additionally, continuous flooding created a rhizosphere environment favorable to the formation of iron plaque. The amount of iron plaque formed increased by 28.2%-47.2% under continuous flooding conditions as compared with that under intermittent flooding conditions. Moreover, compared with intermittent flooding, under continuous flooding, more Cr (18.0%-23.9%) was adsorbed in the iron plaque, thereby sequestering Cr and reducing its mobility. The Cr concentrations in rice root, straw, husk, and grain under continuous flooding conditions were, respectively, 32.0%-36.5%, 32.7%-36.3%, 34.2%-46.9%, and 25.4%-37.7% lower than those under intermittent flooding conditions. Therefore, continuous flooding caused a substantial decrease in the Cr concentrations in rice tissues, as well as an increased distribution of Cr in the iron plaque that acted as a barrier to reduce Cr transfer to the rice roots. These results indicate that continuous flooding irrigation was effective in minimizing the accumulation of Cr in rice plants, as it not only enhanced Cr(VI) reduction in the soil but also improved the blocking capacity of the iron plaque.


Increasing the survival of extremely-immature (24- to 28-weeks' gestation) infants--at what cost?
In one tertiary perinatal centre, the advent of positive-pressure assisted ventilation in the 1970s improved the survival of neonates of 24 to 28 completed weeks of gestation. However, the rate of increase in the resources for assisted ventilation and the improvements in survival rates were stepwise and not smooth. Consequently, it has been possible to calculate the cost-effectiveness of neonatal intensive care up to the time of hospital discharge over two separate eras of stable consumption of resources for assisted ventilation. During 1977-1983, to produce one survivor at 24-weeks' gestation compared with one at 28-weeks' gestation consumed 14.4-times the number of patient-days of assisted ventilation, and 4.9-times more of the total nursery resources; the cost-effectiveness of intensive care during this period decreased with decreasing maturity. The over-all cost-effectiveness up to the time of hospital discharge for infants of 24- to 28-weeks' gestation during 1977-1983, compared with 1971-1974, when assisted ventilation was rare, was $62,268 per additional survivor. After 1983, the consumption of resources for assisted ventilation more than doubled in infants of 24- to 28-weeks' gestation. However, there was a diminishing return with respect to the gains in survival during 1984-1986 and the costs per additional survivor averaged $99,574, which was 60% more than were those for 1977-1983. We speculate that to improve survival further in the most-immature infants by increasing resources for assisted ventilation only can be more difficult and more expensive, and even less cost-effective.


Non-radioactive in situ hybridization pattern of the M13 minisatellite sequences on human metaphase chromosomes.
A classical minisatellite family, the M13 tandem repeat, is shown here to be spread over all human chromosomes. M13 shows an R-band-like pattern, in contrast to the 33.15 family of Jefferys, which preferentially clusters in the telomeric regions.


Cardioprotective effects of resistance training add to those of total activity in Americans.
Resistance training is cardioprotective independent of total activity in experimental research and is prescribed to clinical populations, but is often largely neglected at population scale. Here we determine whether these benefits are relevant to general practice. A total of 6947 Americans over 20 years old (51% male) from NHANES 2003-2006 reported resistance training and objectively tracked 1-week total activity. Activity measures were modeled as five-level predictors of objectively measured binary heart-disease risks (hypertension, dyslipidemia, overweight, and diabetes) corrected for age, ethnicity, gender, and smoking. Significance was defined as Pfor trend less than .10 that the lowest activity category differed from the average of all others. If both activity measures predicted the same risk, mutually corrected models were run. Average total activity was 20 minutes/day (SD 24). About 30% of subjects had resistance trained in the past month, reporting up to 7 sessions/day. Prevalences of hypertension, dyslipidemia, overweight, and diabetes were 32%, 46%, 68%, and 7.2%, respectively. All significant associations for resistance training (but not total activity) exhibited a threshold in dose-response curve, with comparable benefits from any dose above "none." Resistance trainers had significantly lower odds of hypertension (ORs, 0.55-0.85), overweight (ORs, 0.55-0.74), and diabetes (ORs, 0.51-0.80), but not dyslipidemia (ORs, 0.55-0.74). For total activity there was no significant trend in risk of either hypertension or dyslipidemia, but there were for overweight (ORs for each quintile above the lowest 1.04, 0.89, 0.78, and 0.49) and diabetes (ORs, 0.83, 0.68, 0.50, and 0.23; all Pfor trend <.01). Associations of resistance training with diabetes and obesity attenuated only slightly after correction for total activity, and vice versa. Cardioprotective associations of resistance training were comparable to those of total activity and clinically relevant at low doses. Largest benefits accrued to those who combined any dose of resistance training with high total activity.


Polymorphic distribution of the ovine prion protein (PrP) gene in scrapie-infected sheep flocks in which embryo transfer was used to circumvent the transmissions of scrapie.
The genetic sequence of the ovine prion protein (PrP) gene between codons 102 and 175 with emphasis on ovine PrP gene codons 136 and 171 was determined, and the polymorphic distribution of the ovine PrP gene in the scrapie-exposed Suffolk embryo donors and offspring from these donors that were transferred to scrapie-free recipient ewes was investigated in this study. The most common genotype was AA(136)QQ(171) (70% and 63% in the donor and offspring flocks, respectively), which is considered a high risk genotype in US Suffolk sheep. Although embryos were collected from scrapie-positive donors and many embryos had the high risk genotype, no scrapie occurred in the resulting offspring. Based upon the results of this study, we conclude that vertical transmission of scrapie can be circumvented using embryo transfer procedures even when the offspring have the high risk genotype.


Efficacy of ACE inhibitors in chronic heart failure with preserved ejection fraction--a meta analysis of 7 prospective clinical studies.
The effect of ACE inhibitors on the prognosis of chronic heart failure patients with preserved left ventricular ejection fraction remains controversial. To assess the impact of ACE inhibitors on the prognosis of chronic heart failure patients with preserved left ventricular ejection fraction. Seven prospective studies evaluating the effect of ACE inhibitors compared to placebo or other classes of drugs, such as monotherapy or first-line therapy, on the prognosis of chronic heart failure patients with preserved left ventricular ejection fraction were included. A total of 2554 patients (mean age: 75.1 years, female: 58%) were recruited with an average follow up of 20.9 months. The primary etiology of heart failure with preserved ejection fraction was ischemic heart disease (33.7%), hypertension (69.1%) and diabetes mellitus (25.8%). Our results demonstrated that ACE inhibitors significantly reduced all-cause mortality (odds ratio, OR = 0.52; 95% Confidence Interval (CI), 0.41 to 0.64; P<0.01). Furthermore, ACE inhibitors were able to reduce heart failure related rehospitalization or treatment over 20.9 months (p<0.05) in a subgroup of patients aged over 75 years. However, death due to worsening of heart failure, heart failure related rehospitalization and any-cause readmission were not affected (OR = 0.88; 95% CI: 0.66 to 1.17; P = 0.37 for death due to worsening of heart failure; OR = 0.81; 95% CI: 0.63 to 1.05; P = 0.11 for heart failure related rehospitalization and OR = 0.88; 95% CI: 0.68 to 1.14; P = 0.33 for any-cause readmission, respectively). In patients with chronic heart failure with preserved ejection fraction, ACE inhibitors reduced all-cause mortality without affecting mortality due to heart failure and any-cause rehospitalization.


Pro-inflammatory cytokines intensify the activation of NO/NOS, JNK1/2 and caspase cascades in immature neurons exposed to elevated levels of unconjugated bilirubin.
Hyperbilirubinemia may lead to encephalopathy in neonatal life, particularly in premature infants. Although the mechanisms were never established, clinicians commonly consider sepsis as a risk factor for bilirubin-induced neurological dysfunction (BIND). Our previous studies showed that elevated levels of unconjugated bilirubin (UCB) have immunostimulant effects, which are potentiated by lipopolysaccharide (LPS), and that immature neural cells are more vulnerable to UCB. The present study was undertaken to explore the role of nitric oxide (NO)/NO synthase (NOS), c-Jun N-terminal kinases (JNK) 1/2 and caspase activation in BIND, as well as the additional effects of inflammation, in immature neurons, incubated from 1 h to 24 h, at 37°C. UCB, at conditions mimicking those of jaundiced newborns (UCB/serum albumin=0.5), induced NO production, neuronal NOS (nNOS) expression and JNK1/2 activation in 3 days in vitro neuron cultures. As a consequence of these events, mitochondrial and extrinsic pathways of apoptosis were initiated, ultimately leading to neuronal dysfunction. Co-incubation with TNF-α+IL-1β intensified the activation of NO/NOS, JNK1/2, caspase-8, caspase-9 and caspase-3 by UCB. Cleavage of Bid into truncated Bid (tBid), as well as increased cytotoxic potential, were also observed. Interestingly, both L-NAME (NOS inhibitor) and SP600125 (JNK1/2 inhibitor) reversed the effects produced by UCB either alone, or in association with pro-inflammatory cytokines. Taken together, our data reveal not only that activation of NO/NOS, JNK1/2 and caspase cascades are important determinants of BIND, but also that the association of TNF-α+IL-1β have cumulative effects. These events provide a reason for the risk of sepsis in BIND and point to potential targets for therapeutic intervention.


Recording electrophysiological data on video tape: a superior and less costly alternative to conventional tape recorders.
Electrical potentials recorded extracellularly from the sinus gland of the isopod, Oniscus asellus, were stored on video tape with the aid of a digital-audio (DA) processor and a video cassette recorder (VCR). The DA processor transforms the analog signal to digital pulses of equal amplitude and converts these pulses into a television signal for recording on video tape. In playback, the DA processor reconverts the pulses to an analog signal with negligible distortion. When viewed on the oscilloscope screen, electrical potentials reproduced by this method were indistinguishable from electrical potentials recorded 'live' from the sinus gland. However, electrical potentials recorded from the same sinus gland and reproduced by a conventional FM tape recorder were easily differentiated from the 'live' recording. The special effects inherent in the VCR (e.g. stop action, frame advance) also permitted detailed analysis of spontaneously occurring electrical potentials. Special effects were not possible with the FM tape recorder. The price, ease of operation and ability to produce extremely high quality recordings, makes the DA processor and VCR an exceptional system for storing electrophysiological data.


Association of inhibin B serum levels with parameters of follicular response in a randomized controlled trial comparing gnRH agonist versus antagonist protocols for ovarian hyperstimulation.
To study the association of inhibin B with ovarian response to FSH stimulation, applying either GnRH agonist or antagonist. In a prospective randomized controlled trial, 46 patients undergoing COH received either triptorelin (group I, n = 15) or ganirelix (group II, n = 31). Parameters of follicular response and inhibin B serum levels were assessed. Inhibin B before FSH stimulation was significantly lower in group I than group II. The FSH stimulation phase was significantly longer in group I than group II, and the total FSH dose was significantly higher with a comparable number of retrieved oocytes. Day 1 inhibin B in group I, but not group II, was significantly correlated with the number of large ovarian follicles and retrieved oocytes. In group II, but not group I, inhibin B on day 1 was inversely correlated with the daily and total FSH dose as well as FSH stimulation duration. The association of inhibin B serum levels with parameters of follicular response in COH is different in patients assigned to GnRH agonist vs. antagonist treatment protocols.


Effect of a novel hygiene intervention on older children's handwashing in a humanitarian setting in Kahda district, Somalia: A cluster-randomised controlled equivalence trial.
Improving handwashing with soap (HWWS) among children in humanitarian emergencies has the potential to reduce the transmission of several important infectious diseases. However, there is limited evidence on which approaches are effective in increasing HWWS among children in humanitarian settings. One recent innovation - the "Surprise Soap" intervention - was shown to be successful in a small-scale efficacy trial in a humanitarian setting in Iraq. This intervention includes soap with embedded toys delivered through a short household session comprising a glitter game, instruction of how and when to wash hands, and HWWS practice. Whilst promising, this approach has not been evaluated at programmatic scale in a complex humanitarian setting. We conducted a cluster-randomised controlled equivalence trial of the Surprise Soap intervention in IDP camps in Kahda district, Somalia. Proportionate stratified random sampling was employed to recruit 200 households, with at least one child aged 5-12, across the camps. Eligible households were randomly allocated to receive the Surprise Soap intervention (n = 100) or an active comparator handwashing intervention in which plain soap was delivered in a short household session comprising standard health-based messaging and instruction of how and when to wash hands (n = 100). The primary outcome was the proportion of pre-specified occasions when HWWS was practiced by children aged 5-12 years, measured at baseline, 4-weeks, 12 weeks, and 16 weeks post invention delivery. HWWS increased in both groups (by 48 percentage points in the intervention group and 51 percentage points in the control group, at the 4-week follow up), however, there was no evidence of a difference in HWWS between the groups at the 4-week (adjusted RR (aRR) = 1.0, 95% CI 0.9-1.1), 12-week (aRR = 1.1, 95% CI 0.9-1.3), or 16-week (aRR = 1.0, 95% CI 0.9-1.2) follow-up. In this complex humanitarian setting, where soap availability and past exposure to handwashing promotion was low, it appears that well-designed, household-level targeted handwashing interventions that include soap provision can increase child HWWS and potentially reduce disease risk, but the Surprise Soap intervention offers no marginal benefit over a standard intervention that would justify the additional costs.


Evolution of Complex Spine Surgery in Neurosurgery: From Big to Minimally Invasive Surgery for the Treatment of Spinal Deformity.
Spinal instrumentation for adult spinal deformity dates back to the surgical correction of secondary complications from infectious processes, such as Pott's disease and poliomyelitis [1]. With the population aging at a longer life expectancy today, advanced degenerative spinal diseases and idiopathic scoliosis supersede as the most common causes of adult spinal deformity. Correction of the thoracolumbar malignment, specifically, has rapidly evolved with the burgeoning success of spinal instrumentation. The objective of this chapter is to review the metamorphosis of operative principles for adult thoracolumbar deformity, from aggressive osteotomies in the posterior bony elements to minimally invasive surgery (MIS) at the intervertebral disc space.


Yarning to reduce take own leave events in First Nations patients presenting to the Emergency Department-presenting the qualitative themes and co-design of the Deadly RED project.
The Deadly RED redesign and implementation research aimed to improve take own leave (TOL) rates within a Queensland emergency department by providing a culturally competent care pathway. A mixed methods pre/post evaluation of the feasibility, acceptability and usability of the Deadly RED pathway for First Nations patients presenting to ED was performed. This pathway combined early welcome and information sharing, introduction of screening and follow up for patients who TOL and enhanced access to alternative community healthcare. Yarning circles facilitated co-design of research protocols and tools while a purposefully designed research Yarn enhanced understanding of the 'story' of the people. Qualitative analysis of Yarns allowed deductive themes to be extracted. A Participatory Action Research (PAR) approach and Indigenous research methodology involving First Nations people in design, knowledge sharing and joint ownership of results was used. Common themes from the 85 yarns included the negative impact of long waiting times and positive impact from wholistic care. Unique themes identified included interpretation of waiting room placement and paracetamol prescription as a dismissal. Knowledge dissemination from yarning drove improvements in communications and processes to promote treatment completion resulting in elimination of these themes in post implementation yarns. Eighteen patients who had TOL were included in the post implementation yarns, however only eight of these believed that their treatment was incomplete. The use of yarning for consumer engagement has allowed deeper understanding of the reasons for TOL in First Nations emergency patients. The reciprocal knowledge sharing has guided targeted improvements in wholistic emergency care and communication resulting in First Nations patients feeling their care is complete even when the 'number' reports otherwise. SO WHAT?: Indigenous Research methodology including yarning with First Nations patients suggests alternative engagement methods to guide enhanced quality of care monitoring for ED presentations.


A simple assay for screening microorganisms for chalkophore production.
Recently, methanotrophs were found to exude a chalkophore, that is, a metal ligand with great affinity and specificity to copper. A rapid screening method for chalkophore expression was developed by adopting the chrome azurol S (CAS) assay originally used for detecting siderophore production in diverse groups of bacteria and fungi. In this assay, iron(III) chloride was replaced with copper(II) chloride. Both liquid and agar plate versions of the Cu-CAS assay can be used to examine the activity of either isolated methanobactin or to screen organisms for production of a chalkophore. Although here we describe the use of this assay to screen methanotrophs for chalkophore production, it can be modified as necessary to screen other organisms for chalkophore production as well. Many siderophores can also bind copper in the presence of CAS. Therefore, this assay should be done in conjunction with the original iron-CAS assay to determine if any positive Cu-CAS assay results are due to nonspecific binding of copper by a siderophore. This inexpensive assay may also aid in analyses of the genetics of chalkophore synthesis.


Assessing intervention effects in a school-based nutrition intervention trial: which analytic model is most powerful?
This article compares four mixed-model analyses valid for group-randomized trials (GRTs) involving a nested cohort design with a single pretest and posttest. This study makes estimates of intraclass correlations (ICCs) available to investigators planning GRTs addressing dietary outcomes. It also provides formulae demonstrating the potential benefits to the standard error of the intervention effect (sigma(delta)) from adjustments for both fixed and time-varying covariates and correlations over time. These estimates will allow other researchers using these variables to plan their studies by estimating a priori detectable differences and sample size requirements for any of the four analytic options. These methods are demonstrated using data from the Teens Eating for Energy and Nutrition at School study. Mixed-model analyses of covariance proved to be the most powerful analysis in that data set. The formulae may be applied to any dependent variable in any GRT given corresponding information for those variables on the parameters that define the formulae.


Dysfunctional B cells in systemic lupus erythematosus.
The classical view of B cells in the biology of autoimmune responses to infectious and self-antigens (Ag) that they promote immunity primarily by producing antibodies (Ab) is far from being complete. Indeed, studies over the last decade suggest that B cells have extraordinarily diverse functions within the immune system other than Ab production, which could contribute to autoimmunity. They normally play a role in the development of lymphoid architecture, regulating dentritic cells (DC) and T cell subsets function through cytokine production, and in activation of T cells. Receptor editing is also important in B cells which aids in immunity to infection and, possibly, prevention of autoimmunity. Both abnormalities in the distribution of B cells subsets and clinical benefit response to B cell depletion in autoimmune diseases, including systemic lupus erythematosus (SLE), highlight their pivotal function. Transgenic (Tg) animal models have shown that sensitivity of B cells to B cell Ag receptor (BCR) cross-linking is correlated to autoimmunity. Indeed, negative signaling by CD5 and other molecules, such as CD22, in maintaining tolerance through recruitment of src-homology two domain-containing protein tyrosine phosphatase-1 (SHP-1) has also been documented. In fact, we have now reached a newer area whereby B cells returned as an important contributor to autoimmune disorders.


One-stage correction of interrupted aortic arch combined with heart-lung transplantation.
A technique for correction of interrupted aortic arch during heart-lung transplantation is described. This operation was performed in a 14-year-old patient with situs solitus, absent right atrioventricular connection, large atrial septal defect, ventricular septal defect, transposition of the great arteries, type B interrupted aortic arch, and severe pulmonary hypertension. The postoperative course was uneventful. Clinical, radiologic, and nuclear magnetic resonance investigation have shown evidence of good correction of the aortic arch anomaly. We concluded that donor tissue available during heart-lung transplantation is useful in correcting extracardiac anomalies.


Potential benefits of alkali therapy to prevent GFR loss: time for a palatable 'solution' for the management of CKD.
There is increasing evidence that alkali therapy can retard progression of chronic kidney disease (CKD). We summarize recent studies and discuss a mechanism whereby alkali therapy may neutralize acid production associated with typical Western diets, which generate acid. We emphasize the rationale for using alkali therapy early in the course of CKD, even in the absence of overt metabolic acidosis, and we urge the pharmaceutical industry to develop palatable alkali-containing solutions.


The infrapatellar synovail fold: a cause for confusion in the evaluation of the anterior cruciate ligament.
The anterior cruciate ligament may be simulated by the normal infrapatellar synovial fold or ligamentum mucosum. With the aid of lateral tomography, the expected course and insertion of the structures can usually be differentiated. This distinction is important, since a torn anterior cruciate ligament can be overlooked and lead to a delay in appropriate therapy.


Activation of the Na+/K+-ATPase by interleukin-2.
Activated B61.SF.1 and CTLL-2 T lymphocyte clones which are strictly dependent on interleukin-2 (IL-2) for growth were used to study the activation of Na+/K+-ATPase. 50% of [3H]thymidine maximal incorporation was obtained when the extracellular concentration of Na+ or K+ was reduced to 50 or 2 mM, respectively. 'Quiescent' CTL clones stimulated with IL-2 showed an increase of 48-380% in ouabain-sensitive 86Rb uptake. Furthermore, this stimulation was completely inhibited by a monoclonal antibody PC.61 directed at the IL-2 receptor. The activation of the pump was dependent on the dose of IL-2, took place at the same doses of IL-2 that were required to stimulate cell proliferation and was linear for at least 30 min.


Cardiac toxicity of high-dose chemotherapy.
Cardiac toxicity is an uncommon but potentially serious complication of high-dose (HD) chemotherapy and little is known about incidence, severity and underlying mechanisms. We have systematically reviewed the literature of the last 30 years to summarize and appraise the published evidence on cardiac toxicity associated with HD chemotherapy. HD cyclophosphamide-containing regimens have been most commonly associated with cardiac toxicity, with a progressively decreasing incidence over time. Dosage, application regimens and coadministration of other chemotherapeutic agents emerged as risk factors. While cardiac toxicity has been rarely associated with other cytotoxic drugs, an unexpected incidence of severe cardiotoxicity resulted from reduced-intensity conditioning regimens containing melphalan and fludarabine. Predictive value of cardiologic examination of patients is limited, and patients with a slight depression of cardiac performance could tolerate HD chemotherapy. Clinical examination, resting electrocardiography and dosage adjustment in overweight patients remain the mainstay of prevention, with bidimensional echocardiography (2D echo) for patients with a history of anthracycline exposure. Strategies to decrease the long-term negative impact of anthracycline administration on cardiac performance are being investigated. New 2D echo-based techniques and circulating markers of cardiac function hold promise for allowing identification of patients at high risk for and early diagnosis of cardiac toxicity.


The Proximity of Spatial Clusters of Low Birth Weight and Risk Factors: Defining a Neighborhood for Focused Interventions.
Low birth weight (LBW) is associated with significant mortality and morbidity and remains a significant preventable problem. Risk factors include socioeconomic, demographics, and characteristics of the environment. Spatial analysis can uncover unusual frequencies of health problems in neighborhoods, eventually leading to insights for targeted interventions. This study's goals were to 1. Evaluate the geographic distribution of spatial clusters of LBW births and maternal risk factors. 2. Determine the spatial relationship between risk factors and LBW. This study obtained data on LBW newborns and risk factors from 19,013 births over 5 years (2012-2016) for Escambia County Census Tracts, extracted from FloridaCharts.com. Software was used to detect significant spatial clusters; these clusters were then plotted on a map. Poisson regression determined the statistical relationship between Census Tract risk factors and LBW. A separate analysis of the LBW cluster controlling for risk factors was also performed. All risk factor clusters resided in similar locations as the LBW cluster. The multiple Poisson regression model containing all risk factors fully explained the LBW cluster. On bivariate Poisson regression all risk factors in the Census Tract were significantly related to LBW whereas in multivariable Poisson regression, the proportion of births to African American women in the Census Tract remained significant after adjusting for other risk factors (p < 0.001). Clusters of LBW and risk factors were located in the same region of the county, with the proportion of births to African American women in the Census Tract remaining significant on multiple Poisson Regression. Targeted interventions should be directed at the geographic level.


Additive fault detection in nonlinear dynamic systems with saturation.
This paper describes the effects of input saturation on the performance of a model-based fault detection method based on the input-output parity equation approach. For this purpose, the level control of a chemical reactor has been chosen as the control process to be analyzed, where the saturation of the dynamic process is due to the inflow control valve, and only additive faults have been considered. This study has been carried out in two ways: first by simulation techniques and second on a real industrial system. In the simulated case, the decrease in the fault detectability due to the saturation effects is shown, and some ways of achieving higher fault detectability are explored. The results obtained in the industrial case complement those obtained in the simulated case, and also reveal the existence of a relation between the control strategy used in the process and additive fault detectability, in the sense that increases in fault detectability are obtained due to the use of faster control strategies.


Regulation of myocardial connexins during hypertrophic remodelling.
Cardiac hypertrophic remodelling, initiated by signalling cascades in response to increased workload, injury or intrinsic disease, is initially adaptive. However, prolonged hypertrophy as a consequence of pathological stress leads to maladaptive changes that increase the risk for fatal ventricular arrhythmias. One of these changes is the remodelling of myocardial gap junctions, which provide for electrical coupling of adjacent cardiomyocytes. Myocardial gap junctions are composed of three connexin isotypes, connexin40 (Cx40), -43 (Cx43), and -45 (Cx45) and each display a characteristic developmental and regional expression pattern. Alterations in the distribution and expression of Cx43, the predominant isoform in the adult ventricles, has been the main focus of examination in humans, experimental animal models and cultured cardiomyocytes in response to hypertrophy. The molecular mechanisms and signalling pathways underlying these changes have been studied less thoroughly. In this review we summarize what is known about the remodelling of myocardial gap junctions during hypertrophy, the putative underlying mechanisms and functional consequences thereof.


[Cannabis-derived medicines for the treatment of chronic pain : Problems resulting from medical appraisals in the experience of the Medical Advisory Board of the Statutory Health Insurance Funds North].
On March 10th 2017, the law amending narcotic and other regulations was expanded, thereby allowing physicians, irrespective of their specialization, to prescribe cannabis-derived medicines as magistral formulas or proprietary medicinal products at the expense of the German statutory health insurance (GKV). First prescription requires approval from the respective health insurance, which in turn commissions the Medical Advisory Board of the Statutory Health Insurance Funds (MDK) to prepare a medico-legal report. Since § 31 Para. 6 of the German Social Code, Book V (SGB V) came into effect, a multitude of imponderables have been reported regarding reimbursement. Based on the experience of the MDK Nord, problems within the fields of patients, physicians and cannabis-derived medicines are illustrated. Considering current literature, a retrospective review was conducted including approximately 2200 applications for reimbursement received in 2018 from patients residing in Hamburg and Schleswig-Holstein. A relevant problem within the field of patients resulted from the lack of a specific definition of the term "severe (chronic) disease". Although this term is mentioned several times in SGB V, it is not put into concrete terms. Circumstances like multimorbidity are not taken into account. Another problem consisted in an irreproducible anticipation of treatment with cannabis-derived medicines. Within the field of physicians, a major problem was caused by missing, fragmentary or inconsistent information regarding disease and/or therapy. Hence, initially, almost one-third of all applications could not be appraised. Amongst various cannabis-derived medicines, dried flowers were found to be the most problematic regarding doses and effective levels. Notably, a marked increase in numbers of applications for reimbursement of therapy with pure cannabidiol was noted. Numerous problems reported elsewhere and relating to prescription of cannabis-derived medicines were also observed by the MDK Nord. Many prescriptions reflected an uncertainty regarding therapeutic use of cannabis-derived medicines. Thus, one should consider restricting the prescription of cannabis-derived medicines to selected specialists. It should be noted that, in individual cases, e.g., patients suffering from neuropathic pain, treatment with cannabis-derived medicines seems to be a reasonable therapeutic option taking into account the risks and benefits.


Diversity analysis at MHC class II DQA locus in buffalo (Bubalus bubalis) indicates extensive duplication and trans-species evolution.
Variation at MHC Class II-DQA locus in riverine and swamp buffaloes (Bubu) has been explored in this study. Through sequencing of buffalo DQA, 48 nucleotide variants identified from 17 individuals, reporting 42 novel alleles, including one pseudogene. Individual animal displayed two to seven variants, suggesting the presence of more than two Bubu-DQA loci, as an evidence of extensive duplication. dN values were found to be higher than dS values at peptide binding sites, separately for riverine and swamp buffaloes, indicating locus being under positive selection. Evolutionary analysis revealed numerous trans-species polymorphism with alleles from water buffalo assigned to at least three different loci (Bubu-DQA1, DQA2, DQA3). Alleles of both the sub-species intermixed within the cluster, showing convergent evolution of MHC alleles in bovines. The results thus suggest that both riverine and swamp buffaloes share con-current arrangement of DQA region, comparable to cattle in terms of copy number and population polymorphism.


Natale et. al.'s response to Stecco's fascial nomenclature editorial.
Despite their importance in anatomy, physiology, pathology and surgery, the fasciae and the fascial spaces have been poorly described in classic textbooks. This little attention depends on the fact that these fasciae vary in thickness and composition, especially at the cervical level. Indeed, in the main literature they have been described in different forms. Furthermore, the definition itself of the fascia is not consistent in a variety of authors. As a consequence, different criteria have been used to define and classify the fascial systems. In this paper, a brief terminological history and the most common nomenclatures and classifications of the fascia have been summarized.


Recurrent herpes simplex encephalitis.
Recurrent herpes simplex virus (HSV) encephalitis is a rare disorder with only a few cases reported. We report a case of HSV encephalitis with documented recurrence in the same anatomic location, lending support to the theory of reactivation as the mechanism of disease.


Magnetic resonance image-guided stereotactic body radiation therapy for liver rhabdoid tumor in infancy: A case report.
Extracranial malignant rhabdoid tumors are rare and aggressive tumors that typically occur in the pediatric age group and have a poor prognosis. Herein, we report a case of a one year and five months old male infant who was referred with the diagnosis of malignant rhabdoid tumor of the liver. Magnetic resonance guided stereotactic body radiotherapy was administered with concomitant chemotherapy. Treatment was well tolerated with no severe acute side effects. A 40.8% volumetric reduction of the tumor was observed at the last fraction of MR guided radiotherapy.


[Cyanide poisoning: forensic toxicology observations in the study of 54 cases of fatal poisoning].
The present study describes various observations made during the examination of 54 cases of lethal cyanide intoxication at the Institute of Forensic Medicine of the University of Zürich during a period of more than 40 years. Data pertain to the scene of death, the medicolegal inspection, the autopsy, the histological examinations, the chemical analyses, the various types of poisoning observed and the diagnostic criteria used. The intoxicated victims were mostly adults who had professional access to various cyanogenic compounds and had ingested them with the intention of committing suicide. Cases of accidental and criminal poisoning were rare. In spite of this fact, and although its frequency has not increased in the last few decades, cyanide poisoning has maintained undiminished importance.


Protection against amphetamine-induced neurotoxicity toward striatal dopamine neurons in rodents by LY274614, an excitatory amino acid antagonist.
LY274614, 3SR,4aRS,6SR,8aRS-6-[phosphonomethyl]decahydr oisoquinoline-3- carboxylic acid, has been described as a potent antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Here its ability to antagonize the prolonged depletion of dopamine in the striatum by amphetamine in iprindole-treated rats is reported. A single 18.4 mg/kg (i.p.) dose of (+/-)-amphetamine hemisulfate, given to rats pretreated with iprindole, resulted in persistent depletion of dopamine in the striatum 1 week later. This prolonged depletion of dopamine in the striatum was antagonized by dizocilpine (MK-801, a non-competitive antagonist of NMDA receptors) or by LY274614 (a competitive antagonist of NMDA receptors). The protective effect of LY274614 was dose-dependent, being maximum at 10-40 mgkg (i.p.). A 10 mg/kg dose of LY274614 was effective in antagonizing the depletion of dopamine in the striatum, when given as long as 8 hr prior to amphetamine but not when given 24 hr prior to amphetamine. Depletion of dopamine in the striatum was also antagonized when LY274614 was given after the injection of amphetamine; LY274614 protected when given up to 4 hr after but not when given 8 or 24 hr after amphetamine. The prolonged depletion of dopamine in the striatum in mice, given multiple injections of methamphetamine, was also antagonized dose-dependently and completely by LY274614. The data strengthen the evidence that the neurotoxic effect of amphetamine and related compounds toward nigrostriatal dopamine neurons involves NMDA receptors and that LY274614 is an NMDA receptor antagonist with long-lasting in vivo effects in rats.


Improved glycine-extracted complement-fixing antigen for human cytomegalovirus.
High-titered, sensitive, and stable complement-fixing antigens for human cytomegalovirus were consistently produced from human diploid fibroblast cells infected at a high multiplicity of virus, harvested after 7 days of incubation, and sonically treated immediately in 0.1 M glycine buffer, pH 9.5.


COL6A1 genomic deletions in Bethlem myopathy and Ullrich muscular dystrophy.
We have identified highly similar heterozygous COL6A1 genomic deletions, spanning from intron 8 to exon 13 or intron 13, in two patients with Ullrich congenital muscular dystrophy and the milder Bethlem myopathy. The 5' breakpoints of both deletions are located within a minisatellite in intron 8. The mutations cause in-frame deletions of 66 and 84 amino acids in the amino terminus of the triple-helical domain, leading to intracellular accumulation of mutant polypeptides and reduced extracellular collagen VI microfibrils. Our studies identify a deletion-prone region in COL6A1 and suggest that similar mutations can lead to congenital muscle disorders of different clinical severity.


Atopic dermatitis made easy: The Schachner Ladder.
The vast majority of atopic dermatitis follows a mild, chronic relapsing course. In this article, we highlight the art and practice of treating atopic dermatitis based upon a foundation of maintenance care and a ladder of therapy that can teach patients and their families how to best tailor their pharmaceutical options to optimize the management of their disease.


Interactions between bioactive components determine antioxidant, cytotoxic and nutrigenomic activity of cocoa powder extract.
Numerous studies have shown, rather disappointingly, that isolated bioactive phytochemicals are not as biologically effective as natural plant products. Such a discrepancy may be explained by the concept of food synergy, which was verified in this research for cocoa extract versus its major components with regard to cancer chemoprevention. The evaluation embraced the relationship between redox properties evaluated in cell-free systems with the aid of free radicals scavenging method and differential pulse voltammetry, and redox associated anticarcinogenic activities (cellular antioxidant activity, cytotoxicity, nutrigenomic activity) in human colon adenocarcinoma cell line exposed to either cocoa powder extract or artificial mixtures of cocoa bioactives at matching concentrations. In contrast to expectations, our results showed that the stepwise enrichment with antioxidants caused no gradual increase in the antioxidant activity of the model mixtures; also, these model mixtures did not reach the reducing potential of cocoa in the cell-free systems or cellular model employed. Further, the biological activities examined in colon adenocarcinoma cells did not alter in a stepwise manner that could reflect the gradual changes in composition of bioactive ingredients. In conclusion, the experiments presented here showed that the growing complexity of a mixture of phytochemicals seems to create a new redox bioactive substance rather than enrich the mixture with new activities, characteristic of the compound added. It follows that no simple, predictable relationship can be expected between the chemopreventive potential and the composition of real food items containing a complicated set of non-toxic redox active ingredients. Our observations suggest that the interactions between different bioactive compounds and food matrix components are cooperating factors determining the final bioactivity of foods.


Investigation of Lewis phenotypes in Polynesians: evidence of a weak secretor phenotype.
The salivary ABH and Lewis antigens of Polynesians were measured using a standardised red cell agglutination microplate assay and compared with the red cell defined Lewis phenotypes. Salivary ABH substances were detected in almost all saliva samples tested, with low levels (partial secretion) of ABH substances in the saliva from Le(a+b-) and Le(a+b+) individuals. Salivary Leb substance was detected in all Le(a-b+) and Le(a+b+) samples and in almost all Le(a+b-) samples. It is evident from the results obtained that Polynesian red cell phenotypes cannot be used to predict the presence or absence of salivary substances. If the presence of a coding secretor gene is presumed responsible for salivary ABH antigens and salivary Leb antigen expression, then the incidence of a coding secretor gene in Polynesians is 98%. These results indicate that the recessive non-secretor gene is absent or rare in a Polynesian derived gene pool. Two variants of secretor individuals are found among Polynesians, secretors with expression of normal amounts of the product of the secretor gene, similar to Caucasians, and partial secretors with weak expression of the secretor gene products.


Effects of repeated experience of aggression on the aggressive motivation and development of anxiety in male mice.
The sensory contact model allowed aggressive behavior to be formed in male mice as a result of repeated experience of victory in daily social confrontations. In individuals of the low aggressivity, high emotionality line CBA/Lac, repeated experience of aggression led to the development of anxiety, assessed in the elevated cross maze test. Males showed increases in aggressive motivation, measured in terms of increases in behavioral reactions to conspecifics in the partition test. It is concluded that repeated experience of aggression provokes the development of anxiety in male mice and that the level of developing anxiety, like its behavioral correlates, depends on the duration of aggressive experience and the mouse line studied.


Prediction of future cardiac events using myocardial perfusion SPECT: a middle-term follow-up study.
Myocardial perfusion imaging (MPI) provides highly valuable information for risk stratification and determination of optimal clinical management. The goal of the present study was to assess the prognostic value of myocardial perfusion SPECT for the prediction of future cardiac events in Asian population. Five hundred and ten consecutive patients, who had undergone myocardial perfusion SPECT between 2005 and 2006, were prospectively followed-up. Patients' data were collected from recorded files. Follow-ups were performed by scripted telephone interviews by a physician blinded to the patients' MPI results and also from the hospital records. The total completed follow-ups consisted of 482 patients (follow-up rate, 94.5%). Over the mean follow-up period of 434 ± 62 days, 14 out of 482 patients (2.9%) died from cardiac events. Also in 61 patients (12.7%), the clinical condition led to a cardiac intervention (Percutaneous coronary intervention or coronary artery bypass grafting). Those patients without cardiac events on follow-up (including cardiac death or myocardial infarction) were younger and with less severity of MPI abnormalities. Severe MPI abnormalities (Summed Stress Score > 13) were found in 42.9% of those with cardiac death, while in 17.2% of those with myocardial infarction. The rate of cardiac death had a direct relationship with the severity of scan abnormalities, however, the same association was not found between the severity of MPI abnormality and the rate of myocardial infarction. MPI is a valuable tool for risk stratification and prediction of future fatal cardiac events in Asian population. The risk of cardiac death as a mid-term outcome of coronary artery disease increases significantly with severity of MPI abnormalities.


Neoadjuvant chemotherapy-related platinum resistance in ovarian cancer.
Neoadjuvant chemotherapy (NACT) has been regarded a standard treatment for advanced ovarian cancers for decades. Among patients who are poor candidates for primary debulking surgery (PDS), NACT is likely their only option in clinical practice. However, NACT failed to show any survival benefit in the reported randomized controlled trials (RCTs) and the meta-analyses, compared with PDS. This phenomenon raises concerns over the unfavorable influence of NACT, that is, the potential risk of inducing platinum resistance. In this review, we reveal the risk of NACT-related platinum resistance by summarizing the experimental and clinical evidence and discuss new attempts to avoid this phenomenon.


The effect of aging on the pharmacokinetics of nalbuphine in rabbits.
For the purpose of selecting an animal model for the study of the aging effect on the pharmacokinetics of nalbuphine, the pharmacokinetic properties in young and in aged rabbits were reported. Thirty-one healthy New Zealand white rabbits ranging in ages (mean) from three months to 43 months (six three months old, group I; nine eight months old, group II; nine 18 months old, group III; and seven 43 months old, group IV) were included in the study. After intravenous bolus injection of nalbuphine (10 mg kg-1) to each rabbit, plasma samples were collected and analysed for nalbuphine by a high-performance liquid chromatography method. The plasma concentration-time data regarding nalbuphine were successfully fitted to a linear two-compartment open model. The elimination half-life of nalbuphine in rabbits increased significantly with age. Consequently, clearance decreased significantly with age. The parameter AUCO-affinity, which is derived from dose/clearance, increased significantly with age. The effect of aging on the pharmacokinetics of nalbuphine in rabbits is quite similar to that in humans. From the present study, it is concluded that rabbits may be suitable for the study of aging effects on the pharmacokinetics of nalbuphine.


N-terminal propeptide of type 3 collagen-based sequential algorithm can identify high-risk steatohepatitis and fibrosis in MAFLD.
With metabolic dysfunction-associated fatty liver disease (MAFLD) incidence and prevalence sharply increasing globally, there is an urgent need for non-invasive diagnostic tests to accurately screen high-risk MAFLD patients for liver inflammation and fibrosis. We aimed to develop a novel sequential algorithm based on N-terminal propeptide of type 3 collagen (PRO-C3) for disease risk stratification in patients with MAFLD. A derivation and independent validation cohort of 327 and 142 patients with biopsy-confirmed MAFLD were studied. We compared the diagnostic performances of various non-invasive scores in different disease states, and a novel sequential algorithm was constructed by combining the best performing non-invasive scores. For patients with high-risk progressive steatohepatitis (i.e., steatohepatitis + NAFLD activity score ≥ 4 + F ≥ 2), the AUROC of FAST score was 0.801 (95% confidence interval (CI): 0.739-0.863), and the negative predictive value (NPV) was 0.951. For advanced fibrosis (≥ F3) and cirrhosis (F4), the AUROCs of ADAPT and Agile 4 were 0.879 (95%CI 0.825-0.933) and 0.943 (95%CI 0.892-0.994), and the NPV were 0.972 and 0.992. Sequential algorithm of ADAPT + Agile 4 combination was better than other combinations for risk stratification of patients with severe fibrosis (AUROC = 0.88), with similar results in the validation cohort. Meanwhile, in all subgroup analyses (stratifying by sex, age, diabetes, NAS, BMI and ALT), ADAPT + Agile 4 had a good diagnostic performance. The new sequential algorithm reliably identifies liver inflammation and fibrosis in MAFLD, making it easier to exclude low-risk patients and recommending high-risk MAFLD patients for clinical trials and emerging pharmacotherapies.


BEWO trophoblast cells and Toxoplasma gondii infection modulate cell death mechanisms in THP-1 monocyte cells by interference in the expression of death receptor and intracellular proteins.
Crosstalk between trophoblast and monocytes is essential for gestational success, and it can be compromised in congenital toxoplasmosis. Cell death is one of the mechanisms involved in the maintenance of pregnancy, and this study aimed to evaluate the role of trophoblast in the modulation of monocyte cell death in the presence or absence of Toxoplasma gondii infection. THP-1 cells were stimulated with supernatants of BeWo cells and then infected or not with T. gondii. The supernatants were collected and analyzed for the secretion of human Fas ligand, and cells were used to determine cell death and apoptosis, cell death receptor, and intracellular proteins expression. Cell death and apoptosis index were higher in uninfected THP-1 cells stimulated with supernatants of BeWo cells; however, apoptosis index was reduced by T. gondii infection. Macrophage migration inhibitory factor (MIF) and transforming growth factor (TGF)-β1, secreted by BeWo cells, altered the cell death and apoptosis rates in THP-1 cells. In infected THP-1 cells, the expression of Fas/CD95 and secretion of FasL was significantly higher; however, caspase 3 and phosphorylated extracellular-signal-regulated kinase (ERK1/2) were downregulated. Results suggest that soluble factors secreted by BeWo cells induce cell death and apoptosis in THP-1 cells, and Fas/CD95 can be involved in this process. On the other hand, T. gondii interferes in the mechanism of cell death and inhibits THP-1 cell apoptosis, which can be associated with active caspase 3 and phosphorylated ERK1/2. In conclusion, our results showed that human BeWo trophoblast cells and T. gondii infection modulate cell death in human THP-1 monocyte cells.


Neuroprotection by tetracyclines.
The neuroprotective properties of tetracyclines have been clearly established in rodent models of acute and chronic neurodegeneration during the past few years. Recent findings have provided novel insights into the molecular and cellular mechanisms of protection of neurons and oligodendrocytes by tetracyclines. These advances have prompted several clinical trials with minocycline, the most effective tetracycline, which are still in their early phases. Thus, tetracyclines hold great promise as therapeutic agents for the treatment of human neurodegenerative diseases.


Guillain-Barre Syndrome in a patient with uterine adenocarcinoma undergoing treatment with immune-checkpoint inhibitor therapy: A case report and review of the literature.
Use of immune checkpoint inhibitors in treatment of gynecologic malignancies is increasing. Rare, but potentially fatal, immune-related neurologic adverse events may occur as a result of treatment. A 72 year old female with recurrent metastatic uterine adenocarcinoma received pembrolizumab and lenvatinib combination therapy. Following her second dose of pembrolizumab, the patient developed multiple neurologic symptoms. She was ultimately diagnosed with Guillain-Barre Syndrome based on neurologic evaluation with imaging, serum studies, and cerebrospinal fluid analysis. The patient was successfully treated with high-dose intravenous corticosteroids and intravenous immunoglobulin. Neurologic complications related to immune checkpoint inhibitor therapy are rare. It is imperative for gynecologic oncologists to be familiar with potentially fatal hazards of therapy to allow for rapid diagnosis and treatment.


[Renal insufficiency in the context of cardio-pulmonary-renal pathophysiology].
Heart failure and renal insufficiency as well as pulmonary hypertension are pathophysiologically closely associated as a cardio-renal or cardio-pulmonary-renal syndrome. Due to the frequent hospitalization of patients affected by this syndrome, it is of high medical and also health economic relevance. Besides the inhibition of the renin-angiotensin-aldosterone system (RAAS), multimodal treatment options are available with mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors and sodium-glucose transporter 2 (SGLT-2) inhibitors. Profound knowledge of the pathophysiology and the therapeutic options is as necessary for an optimized medical care as patient-oriented, transdisciplinary and cross-sectoral care.


Sudden-death ischemic heart disease and dietary magnesium intake: is the target site coronary vascular smooth muscle?
The etiology of sudden-death ischemic heart disease (SDIHD) remains an enigma. Data will be presented which suggest that SDIHD may be due to hypomagnesemia in and around the coronary arterial and arteriolar vessels. We have found that blood vessels (especially arteries and arterioles) deficient with respect to Mg can undergo constriction and spasm; the greater the reduction in Mg2+, the greater the magnitude of the spontaneous contractile responses. The higher the Ca2+:Mg2+ ratio, the greater are the magnitudes of these contractile responses. A severe deficit in surface membrane Mg2+, in particular, results in intense vasospasm. Using direct in situ high resolution microscopy (3000 x), we have found that a lowering of Mg2+ around perfused arterioles (15--20 microns i.d.) will also result in spontaneous vasoconstriction and, in addition, increased arteriolar resistance, tissue ischemia and reduced venous outflow. We have also found that the constrictor actions of certain circulating vasoconstrictor hormones (i.e., angiotensin, serotonin, acetylcholine) are enhanced when [Mg2+] is lowered below the levels normally found in plasma. Other direct studies, from our laboratory, indicate that [Mg2+]o regulates calcium exchange and content of vascular smooth muscle. In summary, the concept to be presented suggests that a deficiency in dietary Mg2+ is a key factor in the high incidence of mortality noted in SDIHD in nations of the Western world. The hypomagnesemia produces progressive vasoconstriction, vasospasm and ischemia, which, given time, will lead to SDIHD.


Balloon-facilitated percutaneous dilational tracheostomy tube placement: preliminary report of a novel technique.
To describe a novel technique for percutaneous tracheotomy (PT) that could be an alternative to current dilational techniques. An observational animal study of PT was performed using the Seldinger guide wire technique with a tracheostomy tube preloaded onto a dilational balloon catheter. A small skin incision was done with an 11-blade scalpel, but no blunt subcutaneous tissue dissection was performed. Animal laboratory in a university hospital. Seven adult pigs (approximate weight, 16 to 21 kg). Successful tracheostomy was accomplished in all seven pigs without apparent complication. Vital signs and oximetry results remained unchanged throughout the procedure. The mean duration of the procedure was 5.5 min from tracheal puncture to ventilation. This novel procedure is a simple and effective means of PT tube placement without subcutaneous tissue dissection and could potentially have decreased complications when compared to the standard methods of PT currently employed in humans. Human studies are pending.


A Novel Digital Score for Abundance of Tumour Infiltrating Lymphocytes Predicts Disease Free Survival in Oral Squamous Cell Carcinoma.
Oral squamous cell carcinoma (OSCC) is the most common type of head and neck (H&N) cancers with an increasing worldwide incidence and a worsening prognosis. The abundance of tumour infiltrating lymphocytes (TILs) has been shown to be a key prognostic indicator in a range of cancers with emerging evidence of its role in OSCC progression and treatment response. However, the current methods of TIL analysis are subjective and open to variability in interpretation. An automated method for quantification of TIL abundance has the potential to facilitate better stratification and prognostication of oral cancer patients. We propose a novel method for objective quantification of TIL abundance in OSCC histology images. The proposed TIL abundance (TILAb) score is calculated by first segmenting the whole slide images (WSIs) into underlying tissue types (tumour, lymphocytes, etc.) and then quantifying the co-localization of lymphocytes and tumour areas in a novel fashion. We investigate the prognostic significance of TILAb score on digitized WSIs of Hematoxylin and Eosin (H&E) stained slides of OSCC patients. Our deep learning based tissue segmentation achieves high accuracy of 96.31%, which paves the way for reliable downstream analysis. We show that the TILAb score is a strong prognostic indicator (p = 0.0006) of disease free survival (DFS) on our OSCC test cohort. The automated TILAb score has a significantly higher prognostic value than the manual TIL score (p = 0.0024). In summary, the proposed TILAb score is a digital biomarker which is based on more accurate classification of tumour and lymphocytic regions, is motivated by the biological definition of TILs as tumour infiltrating lymphocytes, with the added advantages of objective and reproducible quantification.


Debilitating ossifying fibromas of a white-tailed deer associated with ear tagging.
A 2.3 kg partially ossified fibroma developed apparently within a 4-1/2 month period near a tag inserted in the right ear of a 5-1/2 year old white-tailed doe (Odecoileus virginianus). This growth caused an abnormal head carriage, disturbed feeding and resulted in emaciation. Secondary partially ossified fibromas developed at the left ear tag and in the right external acoustic meatus. The latter fibroma penterated the tympanic membrane. The puncture wounds in the ears associated with the aluminum tags probably provided sites for virus infection and subsequent fibromatosis.


Hyaluronic acid coating on the surface of curcumin-loaded ZIF-8 nanoparticles for improved breast cancer therapy: An in vitro and in vivo study.
Despite developments in surgery and chemotherapy, effective treatment of breast cancer is still an urgent problem owing to recurrence and metastasis. By combining the advantages of curcumin (Cur), zeolitic imidazolate framework-8 nanoparticles (ZIF-8), and hyaluronic acid (HA) in breast cancer therapy, Cur-loaded and HA-coated ZIF-8 (Cur@ZIF-8@HA) were synthesized using a method based on the pH-dependent solubility of Cur and the electrostatic interactions between zinc ions and carboxyl groups of HA. Cur@ZIF-8 were also prepared as a control group. Comprehensive comparisons of the physicochemical properties and anticancer activities of Cur@ZIF-8@HA and Cur@ZIF-8 were conducted. The results indicated that the degradation of Cur during the synthesis of Cur@ZIF-8 was negligible. The obtained Cur@ZIF-8 and Cur@ZIF-8@HA were truncated cubes with hydrodynamic diameters of 174 and 217 nm, respectively. Cur@ZIF-8@HA possessed better stability during storage in different media, a slower drug release rate under neutral and acidic conditions, and a greater inhibitory effect on breast cancer than Cur@ZIF-8. For 4T1 cells, treatment using Cur@ZIF-8@HA induced more cellular uptake and higher cytotoxicity, accompanied by higher lactate dehydrogenase release, cell cycle arrest in G2/M and S phases, production of reactive oxygen species, and apoptosis. In 4T1 tumor-bearing mice models, Cur@ZIF-8@HA showed a stronger inhibitory effect on tumor growth and pulmonary metastasis. Therefore, Cur@ZIF-8@HA might hold great potential as an agent for the effective therapy of breast cancer.