Implantable device therapy.
Sudden cardiac death (SCD) accounts for two-thirds of fatal events related to heart disease. Coronary heart disease and non-ischemic cardiomyopathy are the most common causes of SCD. Data from major randomized trials have consistently shown that therapy with an implantable cardioverter defibrillator (ICD) results in a significant and meaningful effect on survival through a reduction in the risk of SCD in these population. These data have resulted in a marked increase in the application of implantable device therapy in the past 2 decades from secondary prevention with an implantable cardioverter/defibrillator (ICD) in survivors of a cardiac arrest to primary prevention of SCD in asymptomatic patients with ischemic and non-ischemic left ventricular dysfunction, and prevention of symptomatic heart failure progression and death with cardiac resynchronization therapy (CRT), and devices that combine CRT and ICD therapies (CRT-D). However, there are still areas of uncertainty regarding device therapy that include inconsistent benefit in risk-subgroups of patients with low ejection fraction; increased risk of heart failure after life-prolonging ICD therapy, and a considerable rate of device malfunction despite increasing sophistication. In the present review we focus on current data regarding the clinical indications as well as the safety and efficacy of implantable device therapy, including ICD, CRT, and CRT-D.


CT-Guided CTO-PCI Overcoming Bypass Surgery-Induced Native Coronary Artery Tenting.
Antegrade wire crossing of a mid calcified left anterior descending (LAD) artery was achieved. However, the wire was seen deflecting in a different pathway than the angiographically anticipated course of the vessel. Therefore, the computed tomography images were reanalyzed and the wire was seen to be within the tented site of the left internal mammary artery to the LAD anastomosis and correctly positioned according to the vessel course.


Reactivity-based screening for natural product discovery.
Natural products have traditionally been a fruitful source of chemical matter that has been developed into novel therapeutics. Actinomycetes and several other bacterial taxa are especially gifted in biosynthesizing natural products. However, many decades of intense bioactivity-based screening led to a large rediscovery problem, rendering industrial natural product discovery pipelines uneconomical. Numerous methods for circumventing the rediscovery problem have been developed, among them various chemistry-focused strategies, including reactivity-based screening. Emerging from the field of chemical proteomics, reactivity-based screening relies on a reactive probe that chemoselectively modifies a functional group of interest in the context of a complex biological sample. Reactivity-based probes for several distinct functional groups have been deployed to discover new polyketide and peptidic natural products. This chapter describes the protocols to conduct a reactivity-based screening campaign, including bacteria cultivation and screening of cellular extracts with phenylglyoxal-, tetrazine-, thiol-, and aminooxy-functionalized probes, which respectively target primary uriedo, electron-rich olefins, Michael acceptors, and reactive carbonyls. In addition, a recent case study is presented that employs reactivity-based screening as a component of a forward genetics screen to identify a previously unknown peptidyl arginine deiminase. We anticipate that these methods will be useful for those interested in discovering natural products that evade detection by traditional, bioassay-guided methods and others who wish to rapidly connect metabolic chemotype with genotype.


Alcohol Use and Antiretroviral Therapy Non-Adherence Among Adults Living with HIV/AIDS in Sub-Saharan Africa: A Systematic Review and Meta-Analysis.
Antiretroviral therapy (ART) is efficacious in improving clinical outcomes among people living with HIV (PLWH) and reducing HIV transmission when taken regularly. Research examining modifiable factors associated with ART non-adherence is critical for informing novel intervention development in settings with high HIV prevalence. Alcohol use has been linked with ART non-adherence in studies in sub-Saharan Africa; however, no review has pooled estimates across studies. We reviewed studies of alcohol use and ART non-adherence conducted in sub-Saharan Africa. We searched PubMed, CINAHL, EMBASE, and PsycINFO through August 2019 with terms related to ART non-adherence, alcohol use, and sub-Saharan Africa. One author reviewed titles/abstracts (n = 754) and two authors reviewed full texts (n = 308) for inclusion. Discrepancies were resolved by group consensus. Studies were retained if they quantitatively measured associations between alcohol use and ART non-adherence or viral non-suppression. We defined ART non-adherence using the definitions from each parent study (e.g., patients with > 5% missed ART doses during the previous four, seven or 30 days were considered non-adherent). A random effects meta-analysis was conducted to pool associations and we conducted additional analyses to assess between-study heterogeneity and publication bias and sensitivity analyses to determine robustness of our results when considering only certain study designs, alcohol use or ART scales, or studies that used viral non-suppression as their primary outcome. Of 56 articles meeting our inclusion criteria, 32 articles were included in the meta-analysis. All studies measured alcohol use via self-report. ART non-adherence was assessed using self-report, pill counts, or pharmacy records and definition of non-adherence varied depending on the measure used. Individuals who used alcohol had twice the odds of ART non-adherence compared with those who did not use alcohol (34% non-adherence among alcohol users vs. 18% among non-users; pooled odds ratio: 2.25; 95% confidence interval: 1.87-2.69; p < 0.001). We found evidence of a high degree of heterogeneity between studies (Cochrane Q statistic: 382.84, p< 0.001; I2 proportion: 91.9%) and evidence of publication bias. However, the magnitude of our pooled odds ratio was consistent across a number of sensitivity analyses to account for heterogeneity and publication bias. In a secondary analysis with studies using viral non-suppression as their primary outcome, we also estimated a statistically significant pooled effect of alcohol use on viral non-suppression (pooled odds ratio: 2.47; 95% confidence interval: 1.58-3.87). Evidence suggests alcohol use is associated with ART non-adherence in Sub-Saharan Africa, potentially hindering achievement of the UNAIDS 90-90-90 HIV treatment targets.


Esculetin protects human corneal epithelial cells from oxidative stress through Nrf-2 signaling pathway.
Dry eye formation often originates from oxidative damage to the ocular surface, which can be caused by external environment or internal pathologic factors. Esculetin (6, 7-dihydroxycoumarin) is a natural product found in many plants, and has been reported to have multiple pharmacological activities. The objective of our present study is to investigate if esculetin could protect the corneal epithelial cells from oxidative damages and its underlying antioxidant molecular mechanisms. Our experimental results demonstrated that pretreatment with esculetin markedly increased the cell viability while decreased the apoptosis in H2O2-treated human corneal epithelial (HCE) cells, by regulating Bcl-2, Bax and caspase-3 protein expressions and by altering the imbalance of activities of intracellular reactive oxygen species (ROS) and superoxide dismutase (SOD). Our data revealed that esculetin played an antioxidant role not only through its antioxidant activity, but also by highly inducing Nrf-2 translocation to the nucleus, which in turn, enhanced Nrf2 signaling regulated antioxidant genes (HO-1, NQO1, GCLM, SOD1 and SOD2) mRNA expression levels in H2O2-treated HCE cells. In the present study, the protective effects of esculetin on the corneal epithelium were also confirmed by a murine desiccating stress induced dry eye model in vivo. These data illustrated, for the first time, that esculetin may have the ability to protect human corneal epithelial cells from oxidative damages through its scavenging of free radical properties and through the activation of Nrf2 signaling.


Selective attrition causes overestimates of treatment effects in studies of weight loss.
Selective attrition causes serious threats to the validity of experimental trials. Experimental studies in behavior therapy typically include only data from those who complete an experiment. In this paper, we examine the probability of dropping out of a study contingent upon failure to achieve desired benefits. The data are derived from an experimental trial evaluating the effects of weight loss for patients with Diabetes Mellitus. Seventy-six percent of the original participants completed the intervention and the follow-up assessments. However, the probability of failing to appear for follow-ups over an 18 month period was examined. The chances of dropping out of the study were significantly higher for those who did not achieve a goal of weight reduction. This selective loss to follow-up results in an overestimate of treatment effectiveness. By failing to acknowledge drop-outs, treatment failures may be systematically eliminated from the analyses.


Novel Diagnostics for Kaposi Sarcoma and Other Skin Diseases in Resource-Limited Settings.
In resource-limited settings, point-of-care diagnostic devices have the potential to reduce diagnostic delays and improve epidemiologic surveillance of dermatologic conditions. We outline novel-point-of care diagnostics that have recently been developed for dermatologic conditions that primarily affect patients living in resource-limited settings, namely, Kaposi sarcoma, cutaneous leishmaniasis, leprosy, Buruli ulcer, yaws, onchocerciasis, and lymphatic filariasis. All of the technologies described in this article are prototypes, and some have undergone field testing. These devices still require validation in real-world settings and effective pricing to have a major impact on dermatologic care in resource-limited settings.


A nonlinear, geometric Hall effect without magnetic field.
The classical Hall effect, the traditional means of determining charge-carrier sign and density in a conductor, requires a magnetic field to produce transverse voltages across a current-carrying wire. We demonstrate a use of geometry to create transverse potentials along curved paths without any magnetic field. These potentials also reflect the charge-carrier sign and density. We demonstrate this effect experimentally in curved wires where the transverse potentials are consistent with the doping and change polarity as we switch the carrier sign. In straight wires, we measure transverse potential fluctuations with random polarity demonstrating that the current follows a complex, tortuous path. This geometrically induced potential offers a sensitive characterization of inhomogeneous current flow in thin films.


Enhancing Intestinal Absorption of a Model Macromolecule via the Paracellular Pathway using E-Cadherin Peptides.
Membrane permeation enhancers have received significant attention in recent years for enabling the oral absorption of poorly permeable drug molecules. In this study, we investigated the ability of His-Ala-Val (HAV) and Ala-Asp-Thr (ADT) peptides derived from the extracellular-1 (EC1) domain of E-cadherin proteins to increase the paracellular permeation and intestinal bioavailability of the poorly permeable model macromolecule, fluorescein-isothiocyanate dextran with average molecular weight 4000 (FD4). The in vitro enzymatic stability of linear and cyclic E-cadherin peptides was characterized under simulated gastric and intestinal conditions, and the cyclic E-cadherin peptides, HAVN1 and ADTC5, which demonstrated excellent stability in vitro, were advanced to in vivo intestinal instillation studies and compared against the established surfactant membrane permeation enhancer, sodium caprate (C10). Cyclic HAVN1 and ADTC5 peptides increased FD4 bioavailability by 7.2- and 4.4-fold compared to control, respectively (not statistically significant). In contrast, C10 provided a statistically significant 10.7-fold relative bioavailability enhancement for FD4. Importantly, this study represents the first report of cyclic E-cadherin peptides as intestinal membrane permeation enhancers. The findings described herein demonstrate the potential of enzymatically stabilized cyclic E-cadherin peptides for increasing poorly permeable drug absorption via the oral route.


Radiofrequency ablation for liver metastasis from gastric cancer.
Several studies have reported the benefit of hepatic resection for metastatic tumor from gastric cancer. However, the value of treatment with radiofrequency ablation (RFA) has not been clearly defined. Between Jan 2002 and Dec 2007, 21 patients with primary gastric cancer were diagnosed with synchronous or metachronous liver metastases. All patients were treated with RFA, and the complication, survival, and recurrence rates were assessed. The postoperative complication rate was 5% (1/21), with no mortality. The median actuarial survival time was 14 months. The 1-yr, 2-yr, 3-yr, and 5-yr survival rates after RFA were 70%, 11%, 5%, and 3%, respectively. With a median follow-up time of 19 months, local recurrence at the RFA site was 19% (4/21). Solitary metastasis had significantly longer survival than multiple lesions after RFA (22 vs 10 months, P = 0.004). RFA provides a minimally invasive and safe modality of treatment patients with liver metastasis from gastric cancer. Patients with solitary liver lesion were considered appropriate candidates for RFA.


Mefenamic acid bi-directionally modulates the transient outward K+ current in rat cerebellar granule cells.
The effect of non-steroidal anti-inflammatory drugs (NSAIDs) on ion channels has been widely studied in several cell models, but less is known about their modulatory mechanisms. In this report, the effect of mefenamic acid on voltage-activated transient outward K(+) current (I(A)) in cultured rat cerebellar granule cells was investigated. At a concentration of 5 microM to 100 microM, mefenamic acid reversibly inhibited I(A) in a dose-dependent manner. However, mefenamic acid at a concentration of 1 microM significantly increased the amplitude of I(A) to 113+/-1.5% of the control. At more than 10 microM, mefenamic acid inhibited the amplitude of I(A) without any effect on activation or inactivation. In addition, a higher concentration of mefenamic acid induced a significant acceleration of recovery from inactivation with an increase of the peak amplitude elicited by the second test pulse. Intracellular application of mefenamic acid could significantly increase the amplitude of I(A), but had no effect on the inhibition induced by extracellular mefenamic acid, implying that mefenamic acid may exert its effect from both inside and outside the ion channel. Furthermore, the activation of current induced by intracellular application of mefenamic acid was mimicked by other cyclooxygenase inhibitors and arachidonic acid. Our data demonstrate that mefenamic acid is able to bi-directionally modulate I(A) channels in neurons at different concentrations and by different methods of application, and two different mechanisms may be involved.


Initial experience with off-pump coronary artery bypass grafting.
Off-pump coronary artery bypass grafting (OPCAB) is clearly preferable for patients with extracardiac complications. The aim of this study was to evaluate the initial outcome of OPCAB, and its validity for patients with extracardiac complications. One hundred and fifty-seven consecutive coronary artery bypass graft (CABG) patients were divided into two groups: 30 OPCAB patients and 127 on-pump CABG patients. The early outcomes of the two groups were compared. Preoperatively, OPCAB patients had more extracardiac risk factors than on-pump CABG patients. There were no differences in age or cardiac function between the groups, but the off-pump group had a higher incidence of previous surgery, cerebrovascular disease, and renal failure. There were no differences in graft patency, stroke, or mortality between the two groups, even though the OPCAB patients had more risk factors than the on-pump patients. Our initial experience with OPCAB showed that it is acceptable for high-risk patients in view of the serious nature of their extracardiac condition.


Long-term functional outcomes of children after critical illnesses: A cohort study.
To assess children's functional outcomes one year after critical illness and identify which factors influenced these functional outcomes. Ambispective cohort study. Pediatric intensive care unit (PICU) in a tertiary academic center. Children (1 month-17-year-old) and their caregivers. None. Demographic, clinical, and functional status. Of 242 patients screened, 128 completed the year follow-up. These children had significant changes in functional status over time (p<0.001). The functional decline occurred in 62% of children at discharge and, after one year, was persistent in 33%. Age>12 months was a protective factor against poor functional outcomes in two regression models (p<0.05). A moderately abnormal functional status and a severely/very severely abnormal functional status at discharge increased the risks of poor functional outcomes by 4.14 (95% CI 1.02-16.72; p=0.04), and 4.76 (CI 95% 1.19-19.0; p=0.02). A functional decline at discharge increased by 6.86 (95%CI: 2.16-21.79; p=0.001) the risks of children's long-term poor functional outcomes, regardless of the FSS scores. This is the first study evaluating long-term functional outcomes after pediatric critical illnesses in Latin America. Our findings show baseline data and raise relevant questions for future multicentre studies in this field in Latin America, contributing to a better understanding of the effects of critical illnesses on long-term functional outcomes in children.


A retrospective case series of segmental zoster paresis of limbs: clinical, electrophysiological and imaging characteristics.
Segmental zoster paresis (SZP) of limbs, characterized by focal weakness of extremity, is recognized as a rare complication of herpes zoster (HZ). The following study analyzes the clinical characteristics and data from electromyography and MRI scans in patients with motor weakness after zoster infection. One thousand three hundred ninety-three patients from our database (Shandong Provincial Qianfoshan Hospital) suffering from HZ were retrospectively reviewed from June 2015 to July 2017. Patients who fulfilled the diagnostic criteria for SZP were included in the analysis. The clinical characteristics, as well as electromyography findings and MRI scans were analyzed. SZP was present in 0.57% of patients with HZ (8/1393). The average age of symptom onset in 8 SZP patients was 69 years old (SD: 13, range 47-87). The severity of muscle weakness ranged from mild to severe. The electrophysiological testing revealed the characteristics of axonopathy. Radiculopathy (2/8), plexopathy (2/8), radiculoplexopathy (3/8) and combined radiculopathy and mononeuropathy (1/8) were also identified. MRI revealed hyperintensity of the affected spinal dorsal horns, nerve roots or peripheral nerves. SZP is associated with obvious limb weakness, nerve axons lesions and localization to nerve roots, plexus or peripheral nerves.


Hydrogen Sulfide Recruits Macrophage Migration by Integrin β1-Src-FAK/Pyk2-Rac Pathway in Myocardial Infarction.
Myocardial infarction (MI) triggers an inflammatory reaction, in which macrophages are of key importance for tissue repairing. Infiltration and/or migration of macrophages into the infarct area early after MI is critical for infarct healing, vascularization, and cardiac function. Hydrogen sulfide (H2S) has been demonstrated to possess cardioprotective effects post MI and during the progress of cardiac remodeling. However, the specific molecular and cellular mechanisms involved in macrophage recruitment by H2S remain to be identified. In this study, the NaHS (exogenous sources of H2S) treatment exerted an increased infiltration of macrophages into the infarcted myocardium at early stage of MI cardiac tissues in both wild type (WT) and cystathionine-γ-lyase-knockout (CSE-KO) mice. And NaHS accelerated the migration of macrophage cells in vitro. While, the inhibitors not only significantly diminished the migratory ability in response to NaHS, but also blocked the activation of phospho-Src, -Pyk2, -FAK(397), and -FAK(925). Furthermore, NaHS induced the internalization of integrin β1 on macrophage surface, but, integrin β1 silencing inhibited macrophage migration and Src signaling activation. These results indicate that H2S may have the potential as an anti-infarct of MI by governing macrophage migration, which was achieved by accelerating internalization of integrin β1 and activating downstream Src-FAK/Pyk2-Rac pathway.


Astrocytes in neurodegenerative diseases (I): function and molecular description.
Astrocytes have been considered mere supporting cells in the CNS. However, we now know that astrocytes are actively involved in many of the functions of the CNS and may play an important role in neurodegenerative diseases. This article reviews the roles astrocytes play in CNS development and plasticity; control of synaptic transmission; regulation of blood flow, energy, and metabolism; formation of the blood-brain barrier; regulation of the circadian rhythms, lipid metabolism and secretion of lipoproteins; and in neurogenesis. Astrocyte markers and the functions of astrogliosis are also described. Astrocytes play an active role in the CNS. A good knowledge of astrocytes is essential to understanding the mechanisms of neurodegenerative diseases.


Enhancement of immunohistochemical staining. Effects of serum volume and mixing.
The present paper describes two simple procedures which enhance immunohistochemical staining. One is to cover the sections with a plastic film to keep the serum uniformly distributed and minimize its evaporation. Secondly, rocking of the slides has been introduced, causing the serum to flow back and forth under the plastic film. Using this system, it has been possible to test for the effect of mixing on an immunohistochemical reaction (the demonstration of calcitonin in thyroid C cells). It has been found that mixing definitely enhances the reaction during the first 8 h. No effect of serum volume was observed.


The SINTART 1 study. A phase II non-randomised controlled trial of induction chemotherapy, surgery, photon-, proton- and carbon ion-based radiotherapy integration in patients with locally advanced resectable sinonasal tumours.
Sinonasal tumours are rare diseases with poor prognosis. Multimodal approach including surgery is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment-induction chemotherapy (ICT), surgery and radiotherapy (RT)-modulated by histology and response to ICT. Patients with untreated, operable sinonasal tumours with selected histotypes (squamous cell carcinoma, intestinal-type adenocarcinoma, sinonasal undifferentiated and neuroendocrine carcinoma, olfactory neuroblastoma) were enrolled in a single-arm, phase II, multicenter clinical trial. Patients were treated with up to 5 ICT cycles, whose regimen was selected according to histotype, followed either by curative chemo-RT for pts with ≥80% reduction of initial tumour diameter or surgery and adjuvant (chemo)RT. Photon and/or proton/carbon ion-based RT was employed according to the disease site and stage. Primary end-point was 5-year progression-free survival (PFS), secondary end-points were overall survival (OS), ICT objective response rate (ORR) per RECIST 1.1 and safety. Thirty-five patients were evaluable for primary end-point. Fourteen patients (40%) were treated with definitive (CT)RT and 20 (57%) underwent surgery. Five-year PFS was 38% (95% confidence interval [CI], 21-69), with a median PFS of 26 months. Five-year OS was 46% (95% CI, 28-75), with a median OS of 36 months. Three-year PFS-OS for pts achieving PR/CR versus stable disease (SD)/PD to ICT were 49.8-57% versus 43.2-53%, respectively. Three-year PFS for patients achieving major volumetric partial response (≥80% reduction of initial tumour volume, major partial volumetric response [mPRv]) versus non-mPRv were 82% versus 28% and 3-year OS were 92% versus 36% (p value 0.010 and 0.029, respectively). The ORR to ICT was 54% and 60% across all histotypes and in the sinonasal undifferentiated carcinoma (SNUC) subpopulation, respectively, with 6/15 SNUCs (40%) achieving mPRv. Treatment of advanced sinonasal cancer with histology-driven ICT followed by (CT)RT in responsive patients was feasible. Overall, these findings suggest a possible role of ICT as the primary approach in newly diagnosed, resectable sinonasal tumours-especially SNUC-to select patients with favourable prognosis. Histology heterogeneity limits generalisation of trial results.


The role of non-coding RNAs in ferroptosis regulation.
Ferroptosis is a newly recognized form of cell death that is distinct from apoptosis, necrosis, autophagy in morphology, biochemistry, and heredity. The basic process of ferroptosis involves disordered permeability of plasma membrane, which is caused by abnormal accumulation of lipids and reactive oxygen species (ROS). The regulatory mechanism of ferroptosis is important due to its involvement in tumor progression, neurotoxicity, neurodegenerative diseases, acute renal failure, and ischemia-reperfusion injury. Recent studies have shown that in ferroptosis metabolism, non-coding RNAs (ncRNAs) can interfere with multiple signaling pathways at both the pre-transcriptional and post-transcriptional levels. Despite great progress, current research on the mechanism of ncRNAs and ferroptosis remains insufficient. This review provides an overview of the main mechanisms and targets of ferroptosis and focuses on the mechanisms of non-coding RNA regulation. Analyzing the deficiencies in current research may provide ideas for future studies to investigate.


Cadaveric-biomechanical evaluation of bone-implant construct of proximal humerus fractures (Neer type 3).
A biomechanical cadaver study was performed to test the stability and strength of screw osteosynthesis of surgical neck fractures of the humerus. After bone density measurement, 64 cadaver proximal humerus bones were bent to create a subcapital fracture. The fracture was then stabilized by means of screw osteosynthesis randomly assigned to subgroups of screw positioning, size of screw, and stress test (torsion/bending). Two screws applied laterally and parallel were 34.2% more stable than the normal arrangement. Bone density had a dominant role with regard to maximal bending and torsion force, but no significance was found with respect to additional screws through the major tuberculum or diameter of screws. Two of the smaller 4.5-mm cannulated screws should be applied parallel from the lateral direction. Only range-of-motion exercises that produce a bending stress should be considered early after surgery, avoiding axial stress.


Increased serum prolactin but normal TSH during prolonged domperidone treatment in children.
The influence of the dopamine receptor blocking agent domperidone on prolactin and TSH secretion was studied in 16 infants, aged 10-360 days, who were treated for gastroesophageal reflux. The pretreatment serum prolactin levels were not statistically different from the levels in age-matched controls and showed the well-known inverse relationship with age. During treatment with domperidone a significant increase in prolactin level was observed on days 1, 4 and 21-28, the mean values on these three days not being statistically different. No correlation could be found between the serum prolactin levels and the corresponding plasma domperidone levels. One infant of this series and three not included in this series developed reversible breast hypertrophy with galactorrhoea in three of them: in none of them was the prolactin level, corrected for age, above 1 SD of the mean. All had received relatively high doses of domperidone. In 13 patients domperidone did not influence TSH secretion.


Care providers, access to care, and the Long-term Care Nursing Insurance in China: An agent-based simulation.
China piloted a publicly funded Long-term Care Nursing Insurance (LTCNI) with an aim to improve access to long-term care (LTC) for older people in China in 2012. Existing studies showed that the scheme has been successful in meeting some goals, but little is known on how the availability, price and quality of the local care providers affect access to care. Using an Agent-based Modelling approach, this paper simulates the effects of the LTCNI on access to care by considering quality, costs and availability of the local care providers. Our simulation is based on Qingdao city-the first city in China that piloted the LTCNI. We found considerable discrepancies in terms of access to services among the LTCNI beneficiaries. The poor are more likely to choose nursing home care with low costs albeit these services may be of poor quality. The demand for home-based services is high, but these services are not distributed according to population needs and are not available in some districts with high concentration of older people. Consequently, a large proportion of disabled older people have no access to home-based services. We urge policy makers to improve the benefit package of the LTCNI, especially for the poor. We also suggest that more resources should be directed to promote and improve the availability of home-based services in areas with a large number of older people.


A muscle spindle abnormity in one laryngeal muscle would be sufficient to cause stuttering.
Muscle spindles are increasingly recognized as playing a pivotal role in the cause of dystonia. This development and own laryngeal observations that support the idea of causally "well-intentioned" stuttering motivated us to present the following hypothesis: stuttering events compensate for a sensory problem that arises when the abductor/adductor ratio of afferent impulse rates from the posterior cricoarytenoid and lateral cricoarytenoid muscle spindles is abnormally reduced and processed for the occasional determination of the vocal fold position. This hypothesis implies that functional and structural brain abnormalities might be interpreted as secondary compensatory reactions. Verification of this hypothesis (using technologies such as microneurography, dissection and muscle afferent block) is important because its confirmation could relink dystonia and stuttering research, change the direction of stuttering therapy and destigmatize stuttering radically.


Treatment of suspected fetal macrosomia: a cost-effectiveness analysis.
Treatment of fetal macrosomia presents challenges to practitioners because a potential outcome of shoulder dystocia with permanent brachial plexus injury is costly both to families and to society. Practitioner options include labor induction, elective cesarean delivery, or expectant treatment. We performed a cost-effective analysis to evaluate the treatment strategies that were preferred to prevent the most permanent brachial plexus injuries with the least amount of dollars spent. Using decision analysis techniques, we compared 3 strategies for an infant with an estimated fetal weight of 4500 g: labor induction, elective cesarean delivery, and expectant treatment. The following baseline assumptions were made: Probability of shoulder dystocia in vaginal delivery, .145; labor induction, .03; cesarean delivery, .001; probability of plexus injury, .18; probability of permanent injury, .067; probability of cesarean delivery with induction, .35; with expectant treatment, .33; cost of vaginal delivery, dollar 3376; cost of elective cesarean delivery, dollar 5200; cost of cesarean delivery with labor, dollar 6500; lifetime cost of brachial plexus injury, dollar 1,000,000. Sensitivity analyses were performed. Under baseline assumptions for an infant who weighs 4500 g, expectant treatment is the preferred strategy at a cost of dollar 4014.33 per injury-free child, compared with elective cesarean delivery at a cost of dollar 5212.06 and an induction cost of dollar 5165.08. Sensitivity analyses revealed that, if the incidence of shoulder dystocia and permanent injury remained <10%, expectant treatment is the preferred method. Fetal macrosomia with possible permanent plexus injuries is a concern. Our analysis would suggest that expectant treatment is the most cost-effective approach to this problem.


DNA methylation of the MAP3K10 gene may participate in the development of intracranial aneurysm.
The goal of this study was to explore the association between mitogen-activated protein kinase kinase kinase 10 (MAP3K10) methylation and blood lipid levels and intracranial aneurysm (IA) risk. A total of 96 age- and sex-matched investigators participated in the assessment of MAP3K10 methylation. Fourteen CpG sites of the MAP3K10 gene were selected for methylated-pyrosequencing. Human brain vascular smooth muscle cell was used to assess the regulatory role of DNA methylation in MAP3K10 gene transcription. MAP3K10 mean methylation was positively correlated with triglyceride (TG, r = 0.388; p = 0.007) in men, but negatively correlated with TG (r = -0.434; p = 0.002) in women. MAP3K10 methylation in patients with IA was significantly lower than that in controls (p < 0.05), and this phenomenon was more significant in women (12 CpG sites presented significance at p < 0.05). MAP3K10 methylation might be a potential predictor of the risk of IA (CpG1, AUC = 0.81, p < 0.001; mean methylation, AUC = 0.69, p = 0.001). The predictive value was also more significant in women (CpG1: AUC = 0.86, p < 0.001; mean methylation: AUC = 0.73, p = 0.006). No significant association was found between DNA methylation and MAP3K10 gene transcription in vitro experiment. Patients with IA had lower MAP3K10 methylation levels than healthy controls. MAP3K10 methylation may be a potential predictor of IA risk, particularly in women.


Lipidic liquid crystalline cubic phases for preparation of ATP-hydrolysing enzyme electrodes.
The lipidic liquid-crystalline cubic phase (LCP) is a membrane-mimetic material useful for the stabilization and structural analysis of membrane proteins. Here, we focused on the incorporation of the membrane ATP-hydrolysing sodium/potassium transporter Na+/K+-ATPase (NKA) into a monoolein-derived LCP. Small-angle X-ray scattering was employed for the determination of the LCP structure, which was of Pn3m symmetry for all the formulations studied. The fully characterized NKA-LCP material was immobilized onto a glassy carbon electrode, forming a highly stable enzyme electrode and a novel sensing platform. A typical NKA voltammetric signature was monitored via the anodic reaction of tyrosine and tryptophan residues. The in situ enzyme activity evaluation was based on the ability of NKA to transform ATP to ADP and free phosphate, the latter reacting with ammonium molybdate to form the ammonium phosphomolybdate complex under acidic conditions. The square-wave voltammetric detection of phosphomolybdate was performed and complemented with spectrophotometric measurement at 710nm. The anodic voltammetric response, corresponding to the catalytic ATP-hydrolysing function of NKA incorporated into the LCP, was monitored at around + 0.2V vs. Ag/AgCl in the presence or absence of ouabain, a specific NKA inhibitor. NKA incorporated into the LCP retained its ATP-hydrolysing activity for 7 days, while the solubilized protein became practically inactive. The novelty of this work is the first incorporation of NKA into a lipidic cubic phase with consequent enzyme functionality and stability evaluation using voltammetric detection. The application of LCPs could also be important in the further development of new membrane protein electrochemical sensors and enzyme electrodes.


The impact of detubularization on ileal reservoirs.
For many years, parts of the large or small bowel have been used for bladder augmentation and substitution. Recent controversy over the advantages and disadvantages of continent urinary diversion using detubularized ileum (the Kock pouch) and tubular ileum (the Camey procedure) focussed on how a highly compliant urinary reservoir should be formed. We compared the compliance of isolated intact ileal segments and ileal pouches constructed after transection of the antimesenteric border. Hydrodynamic data was obtained at four different points in time: acute (immediately after pouch construction), and after two, six and twelve weeks. Over the first six weeks the reservoirs were connected to the bladder for drainage. At six weeks, subtotal cystectomy and separate anastomosis of the tubular ileal loop and the detubularized ileal pouch to the trigone was performed to study the influence of cyclic reservoir distention. Statistical analysis of the pressure-volume curves revealed significantly better compliance of the detubularized ileal pouch as compared to the intact ileal segments. The area under the pressure curve values (AUC) were p less than 0.025, p less than 0.02, p less than 0.005 and p less than 0.02 for the acute experiment, after two weeks, after six weeks, and after 12 weeks respectively. Our findings suggest that transection of the circular intestinal wall is an important step in the creation of a good-compliant urinary reservoir.


RT-CGM in adults with type 1 diabetes improves both glycaemic and patient-reported outcomes, but independent of each other.
To examine in adults with type 1 diabetes (a) the effect of initiation of real-time continuous glucose monitoring (RT-CGM) on glycaemic and patient-reported outcomes (PROs), and (b) factors related to clinically relevant improvements and sustained device use. 60 persons initiating RT-CGM completed questionnaires at device start and six months later. Demographics and clinical characteristics including (dis)continuation up until July 31st 2018 were obtained from medical records. After six months, 54 adults were still using RT-CGM. Short-term discontinuation (10%) was mainly related to end of pregnancy (wish). Longer-term discontinuation in those with an initial non-pregnancy indication was related to changes in the medical condition and behavioural/psychological reasons. After six months, HbA1c, diabetes-specific worries and self-efficacy improved (range d = |0.4|-|0.8|), while hypoglycaemia rate or awareness and more general distress did not change. More suboptimal scores at baseline were related to meaningful improvements in HbA1c (≥10 mmol/mol; 0.9%) and PROs (≥0.5 SD). Changes in glycaemic variables and PROs were not related. People with more suboptimal HbA1c and PRO values appear to benefit most from RT-CGM. Given the lack of association between improvements in medical outcomes and PROs, both should be included in evaluations of RT-CGM therapy on an individual level.


NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor.
Constitutive nuclear factor κB (NF-κB) activation is a hallmark of colon tumor growth. Cyclin-dependent kinases (CDKs) are critical cell-cycle regulators, and inhibition of CDK activity has been used successfully as anticancer therapy. Here, we show that the NFE2L3 transcription factor functions as a key regulator in a pathway that links NF-κB signaling to the control of CDK1 activity, thereby driving colon cancer cell proliferation. We found that NFE2L3 expression is regulated by the RELA subunit of NF-κB and that NFE2L3 levels are elevated in patients with colon adenocarcinoma when compared with normal adjacent tissue. Silencing of NFE2L3 significantly decreases colon cancer cell proliferation in vitro and tumor growth in vivo. NFE2L3 knockdown results in increased levels of double homeobox factor 4 (DUX4), which functions as a direct inhibitor of CDK1. The discovered oncogenic pathway governing cell-cycle progression may open up unique avenues for precision cancer therapy.


Physiological and metabolic consequences of obesity.
Fasting plasma insulin levels provide an indirect indication of insulin resistance. Glucose utilization rate, measured by the euglycemic clamp technique, is a direct measure of insulin sensitivity. Insulin sensitivity decreases with increasing body mass index (BMI) in the range of 27 to 35 kg/m2. A higher waist-to-hip ratio is associated with lower insulin sensitivity, after adjusting for BMI. Obese patients have higher plasma free fatty acid levels and less suppression of lipolysis by insulin than lean individuals. The increased supply of fatty substrates and their competition with glucose for oxidation constitute a component of insulin resistance in obesity. Both systolic and diastolic blood pressure are increased with BMI. The hemodynamic effects may be due to an increase in cardiac output and enhanced activity of the adrenergic nervous system.


The Role of Subgenomic RNA in Discordant Results From Reverse Transcription-Polymerase Chain Reaction Tests for COVID-19.
Reverse transcription-polymerase chain reaction (RT-PCR) is the standard method of diagnosing COVID-19. An inconclusive test result occurs when 1 RT-PCR target is positive for SARS-CoV-2 and 1 RT-PCR target is negative for SARS-CoV-2 within the same sample. An inconclusive result generally requires retesting. One reason why a sample may yield an inconclusive result is that one target is at a higher concentration than another target. To understand the role of subgenomic RNA transcripts in discordant results from RT-PCR tests for COVID-19. A panel of 6 droplet digital PCR assays was designed to quantify the ORF1, E-gene, and N-gene of SARS-CoV-2. This panel was used to quantify viral cultures of SARS-CoV-2 that were harvested during the eclipse phase and at peak infectivity. Eleven clinical nasopharyngeal swabs were also tested with this panel. In culture, infected cells showed higher N-gene/ORF1 copy ratios than culture supernatants. The same trends in the relative abundance of copies across different targets observed in infected cells were observed in clinical samples, although trends were more pronounced in infected cells. This study showed that a greater copy number of N-gene relative to E-gene and ORF1 transcripts could potentially explain inconclusive results for some RT-PCR tests on low viral load samples. The use of N-gene RT-PCR target(s) as opposed to ORF1 targets for routine testing is supported by these data.


Stromal-epithelial interactions: II. Regulation of prostatic growth by embryonic urogenital sinus mesenchyme.
Embryonic urogenital sinus mesenchyme (UGM) has been demonstrated previously to be a potent inductor of prostatic morphogenesis and functional differentiation when associated with either embryonic urogenital sinus epithelium (UGE) or urothelium derived from adult urinary bladder (ABLE) and grown in male hosts. To determine the role of mesenchyme in prostatic acinar growth, homotypic tissue recombinants of 16-day-old embryonic mouse urogenital sinus mesenchyme and epithelium (UGM mouse + UGE mouse) were prepared in which the relative amounts of UGM to UGE were varied from approximately 0.1:1 to 100:1. Recombinants were grown for 1 month in intact male hosts after which the amount of acinar growth was assessed by histological analysis and by determination of wet weight and DNA content. The latter criteria are valid measures of acinar content of histologically normal prostatic tissue because the rodent prostate is composed of greater than 80% ductal-acinar tissue. From this analysis the amount of acinar growth was found to be determined by the amount of mesenchymal tissue and was independent of the amount of epithelium utilized to prepare the tissue recombinants. Similarly, the magnitude of growth in hetero-specific rat-mouse tissue recombinants prepared with urogenital sinus epithelium or adult bladder epithelium (ABLE) and urogenital sinus mesenchyme (UGM mouse + UGE rat, UGM mouse + ABLE rat, UGM rat + UGE mouse, or UGM rat + ABLE mouse) is determined by the source of UGM. Although the initial DNA content per UGM is comparable between mouse and rat, the overall acinar growth induced by UGM rat is about 10-fold greater than that induced by UGM mouse when recombined reciprocally with UGE mouse and UGE rat, respectively. These results suggest that UGM is of fundamental importance as a regulator of prostatic epithelial growth. The relevance of this finding to the development of human benign prostatic hyperplasia is discussed.


Isolation and identification of group B arboviruses from the blood of birds captured in Czechoslovakia.
Three West Nile (WN) virus strains were isolated from the blood of birds (Tringa ochropus, Vanellus vanellus and Streptopenia turtur) captured in south Slovakia. One strain of tick-borne encephalitis (TE) virus was isolated from the blood of Tringa ochropus captured in south Moravia.


NO synthase inhibitors attenuate locus coeruleus catecholamine metabolism and behavior induced by morphine withdrawal.
The effects of nitric oxide synthase (NOS) inhibitors were examined simultaneously on the behavior and on the catecholaminergic metabolism in the locus coeruleus (LC) during morphine withdrawal using microdialysis in freely moving rats. Morphine withdrawal was precipitated by naltrexone administration to morphine-treated rats. Acute pretreatment of rats with NOmicron-nitro-L-arginine-p-nitroanilide (L-NAPNA) or 7-nitroindazole (7-NI) before naltrexone challenge attenuated the behavioral expression of morphine withdrawal and strongly reduced the withdrawal-induced increase in 3,4-dihydroxyphenylacetic acid (DOPAC) in the LC. The two NOS inhibitors also decreased DOPAC in absence of naltrexone challenge. These results suggest a role for NO in the expression of morphine withdrawal syndrome that may be mediated, at least in part, by LC noradrenergic neurons.


Biomechanical evaluation of a bioabsorbable expansion bolt for hamstring graft fixation in ACL reconstruction: an experimental study in calf tibial bone.
The purpose of our study was to evaluate and compare the primary fixation strength of a novel bioabsorbable two shell expansion bolt (EB) with that of a well-established interference screw-fixation technique in hamstring reconstruction of the anterior cruciate ligament. Thirty calf tibia plateaus (age 5-6 months) were assigned to three groups: In group I (n = 10) triple-stranded hamstring grafts were fixed with titanium interference screws (7 mm thread / 8 mm head x 25 mm). Specimens of group II (n = 10) received bioabsorbable poly-L-lactide interference screws (8 x 23 mm). In group III (n = 10), the grafts were fixed using bioabsorbable poly-D,L-lactide expansion bolts (5.8/8.5/10 mm x 35 mm). The tensile axis was placed parallel to the bone tunnel. The construction was then loaded until failure under a displacement rate of 1 mm per second. There were no significant differences concerning the maximum pullout force (group I: 357 N +/- 61; group II: 326 N +/- 92; group III: 343 N +/- 55). In case of the expansion bolt, we found the stiffness to be higher (61 N/mm) when compared to group I (48 N/mm), and group II (52N/mm) (P < 0.01 I vs. III). Using interference screws, we were able to demonstrate a strong correlation between torque and pullout forces (group I: r2 = 0.7; group II: r2 = 0.92). Ruptures of the suturing material occurred only in groups I and II. We conclude that hamstring graft fixation, using the presented expansion bolt, demonstrates fixation strength similar to the established screw fixation and can therefore be regarded as a reasonable alternative fixation method. Especially, since some specific disadvantages of screw fixation can be prevented by application of the bolt fixation.


Renal artery thrombosis in a pediatric case of systemic lupus erythematosus without antiphospholipid antibodies.
A 13-year-old Japanese boy with an 11-month history of systemic lupus erythematosus (SLE) without antiphospholipid antibodies (APAs) suddenly developed severe hypertension, associated with fever and generalized seizures, and mild abdominal pain. Emergency abdominal computed tomography (CT) confirmed left renal artery thrombosis, and a renal scintiscan revealed reduced blood flow to the left kidney. Promptly instituted intravenous anticoagulant therapy was not effective for controlling the infarction-reduced renal arterial blood supply. Moreover, he developed stupor due to central nervous system (CNS) lupus a week after the occurrence of the hypertensive episode. Finally, a percutaneous transluminal angioplasty successfully relieved the occlusion of the left renal artery at its origin. The CNS lupus was also successfully treated with intravenous methylprednisolone pulse therapy combined with intrathecal methotrexate and dexamethasone. Although it is well known that SLE patients with APAs have a high incidence of thrombotic complications, to date, renal artery thrombosis has rarely been reported in young patients. This APA-negative SLE patient unusually manifested renal thrombosis associated with CNS lupus.


Synthesis, antiproliferative and anti-dengue virus evaluations of 2-aroyl-3-arylquinoline derivatives.
A number of 2-aroyl-3-arylquinoline derivatives was synthesized and evaluated for their anti-Dengue virus activity. Both 2-(hydroxyphenylmethyl)-3-(4-methoxyphenyl)quinoline (13a) and 2-(4-hydroxybenzoyl)-3-(4-hydroxyphenyl)quinoline (17) were found to significantly inhibit the DENV2 RNA expression in Huh-7-DV-Fluc cells with a potency approximately equal to that of ribavirin and the inhibition is in a dose-dependent manner. Compounds 13a and 17 reduced DENV replication in both viral protein and mRNA levels, and no significant cell cytotoxicity was detected, with greater than 50% viability of Huh-7-DV-Fluc cells at a concentration of 100 μM. However, significant cytotoxicity was detected for the positive ribavirin. In addition, we performed infectious assay to further verify the inhibitory activity of 13a and 17 on DENV replication in protein and RNA levels. On the other hand, compounds 19a-19c exhibited IC50 values ranged from 4.47 to 8.68 μM against A549, H1299, MCF-7, and Huh-7 which were approximately equal potent to the positive topotecan. Structural optimization of lead compounds, 13a and 17, and their detailed molecular mechanism of action are ongoing.


Essential ("precursor") chemical control for heroin: impact of acetic anhydride regulation on US heroin availability.
To reduce heroin availability, the United Nations (UN) has encouraged nations to control acetic anhydride, an essential ("precursor") chemical typically necessary to the drug's production. This effort, a major environmental prevention policy, has received little evaluation. The United States, per the UN's lead, implemented acetic anhydride regulation in 11/1989. The present study examines whether the US regulation impacted US heroin availability. Monthly series of three heroin availability indicators-heroin purity, heroin price, and amount of heroin seized-were constructed for the conterminous United States, the US Southwest (supplied predominantly with Mexican-produced heroin), and the US Northeast (supplied predominantly, at the time, with Southeast Asian-produced heroin). Data came from the System to Retrieve Information from Drug Evidence (01/1987-04/2011). Impacts were assessed using ARIMA-intervention time series analysis. In each US area, heroin purity and amount seized rose and price decreased throughout the pre-intervention period. All of the indicators then reversed course at the time of the regulation. In the conterminous United States, the US Northeast, and the US Southwest, purity decreased (-40%, -25% and -50%, respectively); amount seized decreased (-27%, -37% and -39%, respectively); and price rose (+93%, +102% and +296%, respectively). Impacts lasted 2-5 years. US heroin availability decreased in association with the US acetic anhydride regulation. The impacts in the US Southwest and US Northeast suggest that heroin production in Mexico and Southeast Asia, respectively, was constrained. This study lends support to the contention that essential ("precursor") chemical control can be used to help address heroin.


Decrease of palmitoyl-CoA elongation in platelets and leukocytes in the patient of hereditary methemoglobinemia associated with mental retardation.
Effect of the deficiency of NADH-cytochrome b5 reductase on fatty acid elongation was studied in the platelets and leukocytes taken from a patient of hereditary methemoglobinemia associated with mental retardation. The activity of fatty acid elongation was determined by measuring the incorporation of [2-14C]malonyl-CoA into palmitoyl-CoA. The de novo biosynthesis of fatty acids was blocked by the addition of phosphotransacetylase, and the elongation system could be assayed in the homogenates separated from de novo biosynthesis. As compared to normal subjects approximately 40% decrease of fatty acid elongation was observed both in the platelets and leukocytes from the patient.


Transcriptome-wide association study for persistent hepatitis B virus infection and related hepatocellular carcinoma.
Previous genome-wide association studies (GWAS) have identified multiple susceptible variants associated with persistent hepatitis B virus (HBV) infection. However, most of these variants are located in the noncoding regions, which make it difficult to determine the effective genes underlying these associations. We performed a two-stage study, in the first stage we integrated RNA sequencing data of liver tissues and high-density genotyping data from the Genotype-Tissue Expression (GTEx) project with our previous GWAS data to conduct a transcriptome-wide association study (TWAS) on HBV infection. Firstly, the cis-heritable genes were screened by a genetic relatedness matrix of genome-wide complex trait analysis (GCTA) from GTEx data. Then, the genetic expression of 2587 cis-heritable genes was predicted by restricted maximum likelihood (REML) of genome-wide efficient mixed-model association (GEMMA) in our GWAS data with 951 HBV carrier cases and 937 HBV cleared controls. Next, we investigated the associations between predictive expression levels and persistent HBV infection risk. Gene set enrichment analysis (GSEA) was applied to infer the function of the identified genes. To identify the causal single nucleotide polymorphisms (SNPs) of HBV infection risk, we conducted the expression quantitative trait loci (eQTL)-based stepwise logistic regression analysis in the regions around 1 Mb of these genes and validated the association between 994 health controls and 994 HBV-persistent infection cases by genotyping experiment. In the second stage, 1538 HBV-related hepatocellular carcinoma (HCC) cases and 1465 persistent HBV infection controls were collected to determine the effect of these variants on HBV-related HCC as well, which were examined by the additive model in logistic regression analysis. We identified seven genes associated with HBV infection. In the classic human leukocyte antigen (HLA) region, three novel genes BAK1, HLA-DOB and C4A (Z range from -3.95 to -3.64, P range from 7.84 × 10-5 to 2.00 × 10-4 ), as well as two genes (HLA-DPA1 and HLA-DPB1) were reported by previous GWAS. In the non-HLA region, immune related at newly identified loci, PARP9 (Z = 3.69, P = 2.20 × 10-4 ) at 3q21.1. At 22q11.21, we identified TMEM191A (Z = 3.55, P = 3.80 × 10-4 ) as a target gene in addition to the reported non-cis-heritable gene UBE2L3. After further stepwise logistic regression analysis and validation, we identified eight variants independently associated with persistent HBV infection. Among those variants, the additive model showed that two SNPs associated with HBV-related HCC risk (rs9272714 and rs9394194, OR range from 1.20 to 1.25, P range from 1.19 × 10-4 to 3.97 × 10-4 ). By integrating transcriptome data, our study not only identified new susceptibility loci of persistent HBV infection but also determined the potential target genes at reported loci, which provided insight into the genetic aetiology of persistent HBV infection and related HCC.


Removal of cobalt and strontium by adsorption using Brewer's spent grain formed by pyrolysis.
One byproduct of brewing beer is Brewer's spent grain (BSG), which is reused in animal feed. However, BSG has valuable potential for other products such as biochar because of its high protein and fiber content. Radioactive waste is one of the biggest concerns in Korea because of the permanent shutdown of the Gori nuclear power plant. In this study, we aimed to use BSG-850, a biochar originating from BSG after pyrolysis at 850 °C, for the adsorption of cobalt (Co) and strontium (Sr), which are two radionuclides that contribute to radioactive waste. The adsorption capacity of Co and Sr was reinforced with increased temperature which are 3.304, 4.659, 5.516 mg/g (Co) and 1.462, 2.54, 3.036 mg/g (Sr) at 298, 308, and 318 K, respectively. The reusability of BSG-850 capacity was 75.3, 47.8, 43.6, 36.2% and 93.6, 84.2, 57.2, and 32.7% after 1, 2, 3, and 4 cycles, for Co and Sr, respectively. In the presence of other competitive ions, the adsorption capacity decreased. The adsorption capacity and properties of BSG-origin biochar for Co and Sr were confirmed and BSG can be a desirable option for solving radioactive waste issue.


[The new OCT generation offers deep insights: imaging of the choroid using the Cirrus OCT].
Until now depiction of the choroid using time domain optical coherence tomography (OCT) (Stratus III) was barely possible. Visualization of choroidal perfusion was carried out using indocyanine green angiography (ICGA). The spectral-domain OCT, such as Cirrus OCT (C-OCT) is able to image the choroid better because it offers higher resolution, increased penetration depth of the scan beam and faster acquisition of A-scan data. The aim of the study was to evaluate the potential of choroidal imaging in patients suffering from macular disease. The advanced visualization tool of C-OCT was primarily used and converted to a z-axis topography. Because of a special algorithm developed by our team, targeted imaging of the choroidal vessels was possible through the scanned two dimensional retinal areas. This image offers an extended image of choroidal vessels (large and small vessels) in several levels. In total 20 patients eyes (n = 15 with various macular diseases and n = 5 normal conditions) who underwent C-OCT and ICG angiography (HRA 2) were chosen to participate in this special algorithm. A precise correlation of ICG and choroid OCT in a semitransparent manner was carried out. The first prototype of the recognition software prototype produced clear imaging of the choroid in 100% of cases but only in 55% in the macular region depending on the extent of macular disease. Limitations were low signal intensity and penetration depth as well as a poorly defined retinal pigment epithelium (RPE) and choriocapillaris especially in macular diseases of the RPE layer. After a black and white conversion in OCT using the software it was possible in all cases to integrate the choroidal OCT with the ICG angiogram in a semitransparent manner. This confirms that the choroidal vessels in C-OCT correlated identically with the ICG angiography. In contrast to the ICG where the contrast agent in the vessel emits a signal, the choroidal vessels are visible due to different reflectivity in the merging tissue. These investigations showed that non-invasive topographic imaging of the choroid using spectral domain OCT, such as Cirrus OCT is now possible. Distinguishability of smaller vessels was excellent. The ICG (perfusion) and C-OCT (morphology) methods are two very different vessel imaging techniques. The integration of both methods is possible. The clinical relevance of the new image information still has to be researched.


Adherence to non-pharmacological preventive measures among healthcare workers in a middle-income country during the first year of the COVID-19 pandemic: Hospital and community setting.
This study assessed, using a self-reported questionnaire, the adherence to PPE (mask, gowns, and gloves) at the workplace, as well as to non-pharmacological preventive measures (NPPM) (physical distance defined as hardly ever and/or never approaches other people within 1.5 meters, social isolation as leaving home less than once a week, hand hygiene was defined as performing hand hygiene ≥ 6 times per period, and adherence to the use of a mask outside of the workplace was defined as on all outings and hardly ever and/or never removes the mask) outside of the workplace among 1,296 health care workers (HCWs), including if NPPM adherence was associated with COVID-19 in HCWs. High adherence to PPE was independently associated with younger age, professional category, work in an area of direct patient assistance; use of public transportation, or adherence to NPPM outside of the workplace.


Correlated metabolism of proteoglycans and hyaluronic acid in bovine cartilage organ cultures.
Proteoglycans exist in cartilage as complexes in which many proteoglycan molecules are bound to a central filament of hyaluronic acid. Many studies have investigated changes taking place in proteoglycan monomer structure during cartilage catabolism usually under the assumption that hyaluronic acid is a relatively inert metabolic component of the complex. In this paper we present organ culture data supporting a new hypothesis that the catabolism of proteoglycans and hyaluronic acid are coordinately regulated by chondrocytes. The data indicates that: 1) newly synthesized hyaluronate and proteoglycan maintain a nearly constant ratio, almost identical to that existing for the total chemical amounts of these two components in cartilage tissue; 2) these two components are catabolized with virtually identical kinetics; and 3) this catabolic relationship in vitro reflects the loss of hyaluronate and proteoglycans from native, undissociated aggregates as isolated from the tissue. We conclude that hyaluronate catabolism is an integral part of the overall mechanism of proteoglycan resorption in cartilage and that further understanding of this process may be key to the elucidation of the regulatory pathways for proteoglycan resorption in health and disease.


Nonelectric shaving of endometrial polyp by hysteroscopy - A new technique to eliminate thermal damage.
To present a new technique for complete endometrial polypectomy, using the bipolar loop hysteroscope, but without the activation of electrical energy, and follow its efficiency and safety for the patient. This is a prospective descriptive study conducted at a university hospital. Forty four patients were recruited to the study according to an intra uterine polyp diagnosed by transvaginal ultrasound (TVS). Out of them 25 really had an endometrial polyp which was inspected by hysteroscopy. Eighteen were at menopause age and seven in their reproductive age. The hysteroscopic removal of the endometrial polyp was performed using the operative loop resectoscope without using electricity, meaning by cold loop. We called this unique technique SHEPH: Shaving of Endometrial Polyp by Hysteroscopy. The range age was 21-77 years old. All patients with apparently endometrial polyp, underwent a complete removal of the polyp which could be directly seen through hysteroscopy. No bleeding was seen in all cases. The other nineteen patients had normal uterine cavity, so a biopsy was taken according to the indication. The specimen from all cases were sent to histological evaluation. An endometrial polyp was histologically confirmed in all cases who underwent the SHEPH technique, while fragments of an endometrial polyp was revealed by histology in six cases from the group that had normal uterine cavity. No complications were noted for the short and long periods. Nonelectric Shaving of Endometrial Polyp by Hysteroscopy (SHEPH technique) is a safe and effective procedure which allows the surgeon to achieve a complete endometrial polypectomy but without using electrical energy within the body of the patient. The technique which is easy to learn, is new and unique by eliminate thermal damage in a very common gynecologic indication.


Epigenetic upregulation of Bak by ZBP-89 inhibits the growth of hepatocellular carcinoma.
Zinc-binding protein-89 regulates Bak to facilitate apoptosis in cancer cells. This study examined if zinc-binding protein-89 regulates Bak through an epigenetic mechanism in hepatocellular carcinoma. We first demonstrated that the expression of Bak was reduced but the levels of deoxyribonucleic acid methyltransferase 1 and histone deacetylase 3 were increased in hepatocellular carcinoma cancer tissues compared to the corresponding non-cancer tissues. Moreover, there was a negative correlation between Bak expression and deoxyribonucleic acid methyltransferase 1 levels in hepatocellular carcinoma. Administration of zinc-binding protein-89 downregulated histone deacetylase 3 expression and suppressed the activities of histone deacetylase and deoxyribonucleic acid methyltransferase, which led to maintenance of histone acetylation status, inhibited the binding of methyl-CpG-binding protein 2 to genomic deoxyribonucleic acid and demethylated CpG islands in the Bak promoter in hepatocellular carcinoma cells. Using the xenograft mouse tumor model, we demonstrated that zinc-binding protein-89 or inhibitors of either epigenetic enzymes could stimulate Bak expression, induce apoptosis, and arrest tumor growth and that the maximal effort was achieved when zinc-binding protein-89 and the enzyme inhibitors were used in combination. Conclusively, zinc-binding protein-89 upregulates the expression of Bak by targeting multiple components of the epigenetic pathway in hepatocellular carcinoma.


Harsh voice: vocal effort perceptual ratings and spectral noise levels of hearing-impaired children.
This study investigated the relationship between spectral noise levels and ratings of perceived vocal effort in the voices of severely to profoundly hearing-impaired children as compared to normal-hearing children, aged 6-11. Spectral noise levels served as an index of the inharmonic (noise) components present from 100 to 2500 Hz for sustained vowels. A nine-point perceptual rating scale was devised as the subjective measure of vocal effort. The severely to profoundly hearing-impaired children could be differentiated on the basis of significantly higher ratings for perceived vocal effort in addition to higher physical measurements of spectral noise levels. Tentative therapeutic implications are discussed.


Proactive inter-disciplinary CME to improve medication management in the elderly population.
The absence of collaboration between health professionals is known to influence prescriptions' quality, also disadvantaging elderly frail patients' polytherapies. This study aims to improve the adherence to medications of elderly patients suffering from multiple diseases through interpersonal continuing medical education (CME). The CME was organized for general practitioners (GPs) by hospital pharmacists (HPs) from a Territorial Pharmaceutical Centre of Piedmont, in collaboration with pharmacists from the Drug Science and Technology Department of the University of Turin, to enhance awareness on the management of chronic therapies and de-prescription. Pharmacists set face-to-face lessons for GPs between April 2018 and November 2018, while therapies' reconciliation and delivery of the Illustrated Therapy Schedules (ITS) lasted until September 2019. Polytherapies were evaluated by pharmacists and GPs in terms of appropriateness (number of potentially inappropriate prescriptions - PIPs according to 2019 Beers Criteria) and number of drug-drug interactions (DDIs), using a clinical decision support system (CDSS - NavFarma©) to help health professionals dealing with the process of review, reconciliation and individuation of possible adverse reactions. From the CME organization it emerged that the collaboration between health professionals supported by a CDSS could improve the quality of elderly patients polytherapies. Two-hundred fifteen patients were enrolled by GPs; patients included were aged - results reported as average (sd) - 76.4 (6.3), mostly men (54.9%), number of daily medications per patient was 8.1 (2.4); 2.1 (1.8) DDIs per patient were individuated, 12.9% of which were solved thanks to the CME. Average number of PIPs found was 2.5 (1.4) per patient. The CME represented a proactive approach by HPs to the management of elderly patients' polytherapies. Moreover, clinicians' engagement is a mean to enhance quality, safety, professionalism and communication in health processes.


Solitary subcutaneous meningioma appearing as an osteolytic skull defect.
Intraosseous meningiomas rarely present with osteolytic skull lesions. This case shows that meningioma must be added to the differential diagnosis of an osteolytic skull lesion.


Greater vertical loading rate in obese compared to normal weight young adults.
Obesity is a risk factor for knee osteoarthritis. Altered gait biomechanics are common in obese individuals, and may contribute to the development of knee osteoarthritis. Research has focused on older obese adults with knee osteoarthritis, and it is unclear if young obese individuals display similar aberrant biomechanics. The purpose of this study was to compare gait biomechanics between normal-weight and obese young adults. 15 normal-weight (body mass index=21.5 (1.1)) and 15 obese (body mass index=33.5 (3.7)) young adults were recruited and categorized by body mass index. Lower extremity kinematics and kinetics were collected while participants walked at standardized (1m/s) and self-selected speeds. Analysis of variance (group by condition) was used to compare peak vertical ground reaction force, vertical loading rate, peak internal knee extension moment, peak internal knee abduction moment, peak knee flexion angle, and knee flexion excursion between groups. Gait biomechanics did not differ between groups during walking at a self-selected speed. When walking at a standardized speed, obese subjects displayed greater instantaneous vertical loading rates (46.2 vs. 35.0 N/s, P<0.001), and lesser knee flexion excursion (5.5° vs. 7.7°, P=0.04). Instantaneous vertical loading rate was greater during walking at a self-selected speed compared to a standardized speed in the obese (P=0.007) and normal weight groups (P=0.001). As greater loading rates are related to cartilage degeneration, these results suggest that obesity may contribute to knee osteoarthritis. Prospective studies are needed to identify the influence of higher loading rates on knee osteoarthritis.


Intrathecal administration of nociceptin/orphanin FQ receptor agonists in rats: A strategy to relieve chemotherapy-induced neuropathic hypersensitivity.
Oxaliplatin and paclitaxel are considered central components in the treatment of colorectal and breast cancer, respectively. The development of neuropathy during chronic treatment represents the major dose-limiting side effect that leads to discontinuation or interruption of therapies. The management of neuropathy is a challenge to individuate innovative therapeutic strategies based on new targets and correct routes of administration. We evaluated the hypersensitivity reliever effect of different opioid receptor agonists in rat models of oxaliplatin and paclitaxel-induced neuropathy. Compounds were spinally infused by intrathecal catheter. In oxaliplatin-treated rats, 0.3 nmol morphine induced the reversion of the mechanical hypersensitivity (Paw-pressure test), nociceptin/orphanin FQ (N/OFQ; 0.3-3 nmol) significantly increased the pain threshold without reaching the values of the control animals. The N/OFQ peptide (NOP) receptor full agonist UFP-112 reverted pain threshold alterations at lower dosage (0.1 nmol) vs morphine and N/OFQ, the partial agonist UFP-113 (0.1-1 nmol) was similar to N/OFQ. The higher efficacy of morphine vs N/OFQ was highlighted also in paclitaxel-treated rats. The mechanical hypersensitivity was fully reverted by 0.1 nmol UFP-112 and UFP-113. In conclusion, intrathecal μ opioid peptide (MOP) and NOP receptor agonists relieved chemotherapy-induced neuropathic pain. The synthetic peptides showed valuable potency and efficacy suggesting the NOP system as an exploitable target.


Psoriatic arthritis under the influence of IFNγ.
Psoriasis is a common multifactorial autoimmune disease of the skin, and in a large percentage of patients, immune responses involve nail and joint pathology, which develop psoriatic arthritis (PsA). Historically, T helper 1 (Th1)-derived-IFN-γ was abundantly detected in psoriatic skin and its correlation with development and severity of PsO, led to an early classification of psoriasis as a Th1-mediated disease. Investigations of the cellular and molecular mechanisms of PsO pathogenesis in recent years, together with impressive results of biologics against interleukin 17A (IL-17) have shifted focus on IL-17A. However, the contributions of IFN-γ in IL-17 induced pathology and its involvement in the development of PsA have been largely overshadowed. This review summarizes the current knowledge on IFN-γ and provides new insights on the contribution of IFN-γ to PsO and PsA disease pathogenesis and development.


Revised guidelines for second-look surgery in patients with colon and rectal cancer.
Proper indications for a second surgical intervention in patients with colorectal cancer have always been a controversial subject. Surgeons find benefit in a second-look operation where a limited extent of cancer is discovered and resected with negative margins. However, a negative exploratory laparotomy or an intervention that is unable to achieve an R0 resection provides little or no benefit. Unfortunately, this type of intervention may place the patient in a worse condition, leading to morbidity or mortality. This manuscript attempts to define clinical parameters of primary colorectal cancer that are associated with a pattern of recurrence and that can be definitively addressed by second-look surgery. Also, new surgical technologies that may assist in achieving a potentially curative resection of local-regional recurrence are described. Cytoreductive surgery with peritonectomy and perioperative intraperitoneal chemotherapy with hyperthermia is presented as a new treatment option for reoperative surgery. A new management plan utilized in patients at high risk for local-regional recurrence may result in a high likelihood of conversion of a second-look cancer-positive patient to a long-term survivor.


Time-dependent changes in plasma prolactin level and stress controllability in rats.
1. Numerous studies have shown the importance of controllability factors in the neurochemical, hormonal and behavioural changes associated with presentation of stress stimuli. 2. Previous work from our laboratory revealed that animals exposed to escapable shock had significantly higher prolactin levels than those treated with inescapable shock. 3. The present experiment examined the time-course of plasma prolactin change as a function of shock controllability. 4. Rats were exposed to intermittent escapable, inescapable or no shock for 5, 10, 30 or 60 min and sacrificed for plasma prolactin determination. Additional groups received 60 min shock condition followed by 30 or 60 min rest period prior to sacrifice. 5. Results showed that subjects exposed to 5, 10 or 30 min of escapable shock exhibited higher prolactin levels than inescapable shock or no-shock treated animals. These findings show that the prolactin response to stress is sensitive to controllability factors and is time-dependent.


A de novo deafwaddler mutation of Pmca2 arising in ES cells and hitchhiking with a targeted modification of the Pparg gene.
We observed severe ataxia in mice homozygous for modification of the Pparg locus. Genetic analysis and nucleotide sequencing revealed that ataxia is caused by a T692K substitution in plasma membrane calcium ATPase 2 (Pmca2), which is tightly linked to Pparg, but not by modified PPARgamma itself. We traced this mutation and found that it arose spontaneously during clonal expansion of the targeted embryonic stem (ES) cells. Consistent with the deafwaddler phenotype in other Pmca2 mutants, homozygous T692K Pmca2 mutants exhibit severe balance disorder, impaired neurologic reflexes, and motor coordination, and have profound hearing loss. Heterozygous mutants have normal movement and motor function but are severely deficient in hearing. Our findings represent a cautionary example since, although rare, spontaneous mutations do arise in ES cells during culture and hitchhike onto the targeted gene mutation.


Exploring the advance care planning needs of moderately to severely ill people with COPD.
There is no clear consensus on how to approach advance care planning (ACP) with people with chronic obstructive pulmonary disease (COPD). This study aimed to explore the perceived ACP needs of people with COPD and to investigate the usefulness of a DVD in meeting these needs. A qualitative descriptive design was used. Twelve people with moderate to severe COPD were interviewed in an outpatient clinic. From the themes elicited, a mental model was created to demonstrate how the participants engaged in a process of mental work to accept their own mortality and subsequently engage in ACP. Health professionals should not rely solely on illness severity to initiate ACP. Rather, patients from different illness categories should be approached, but with sensitivity to their emotional cues. Participants who were receptive to end-of-life issues enjoyed the DVD. The DVD is a good medium to facilitate discussion, but would be more effective if patients were screened for readiness prior to viewing.


Prevalence and Predictors of Potentially Inappropriate Medication Prescription Among Older Adults: A Cross-Sectional Study in the State of Qatar.
Potentially inappropriate medications (PIMs) often lead to sub-optimal or poor health outcomes in older adults. The objective of this study was to determine the prevalence and predictors of PIM prescription among older adults in Qatar. This was a cross-sectional, retrospective study using data from the electronic medical records of Qatari patients (age ≥ 65 years) attending the 23 primary healthcare (PHC) centers in Qatar from April 1, 2017 to September 30, 2017. PIMs were identified based on the Beers 2015 criteria: (1) medications to avoid for many or most older adults, and (2) medications to be used with caution in older adults. Descriptive statistics were used to estimate the prevalence of PIM prescription; multivariable logistic regression analysis was performed to identify predictors of PIM prescription among the study population. 5639 older adults were included with a mean age of 72.8 (± 6.5) years; 53.8% were females. The prevalence of PIMs that should be avoided was 60.7%, with the most prevalent ones being gastrointestinal (84.2%), pain (49.9%), and central nervous system (10.4%) drugs. Most patients (61.1%) were prescribed one PIM, 26.9% two PIMs, and 12.0% three or more PIMs. The prevalence of PIMs that should be used with caution was 40.6%, with diuretics (83.1%), antidepressants (25.7%), and antiplatelets (18.3%) as the most prevalent drug classes. Multivariable logistic regression showed female gender, polypharmacy, and certain comorbidities to be significant predictors of PIM prescription. Older adults attending Qatar's 23 PHC centers are prescribed a high number of PIMs. Because of the high risk of PIM prescription, the practice of medication reconciliation should be strengthened and reinforced.


New Interpretation of Neonatal Outcomes by Phenotypically Classified Preterm Syndrome: A Retrospective Cohort Study.
The global aim to lower preterm birth rates has been hampered by the insufficient and incomplete understanding of its etiology, classification, and diagnosis. This study was designed to evaluate the association of phenotypically classified preterm syndromes with neonatal outcomes; to what extent would these outcomes be modified after the obstetric interventions, including use of glucocorticoid, magnesium sulfate, and progesterone. This was a retrospective cohort study conducted at Tongji Hospital (composed of Main Branch, Optical Valley Branch and Sino-French New City Branch) in Wuhan. A total of 900 pregnant women and 1064 neonates were retrospectively enrolled. The outcomes were the distribution of different phenotypes among parturition signs and pathway to delivery, the association of phenotypically classified clusters with short-term unfavorable neonatal outcomes, and to what extent these outcomes could be modified by obstetric interventions. Eight clusters were identified using two-step cluster analysis, including premature rupture of fetal membranes (PPROM) phenotype, abnormal amniotic fluid (AF) phenotype, placenta previa phenotype, mixed condition phenotype, fetal distress phenotype, preeclampsia-eclampsia & hemolysis, elevated liver enzymes, and low platelets syndrome (PE-E&HELLP) phenotype, multiple fetus phenotype, and no main condition phenotype. Except for no main condition phenotype, the other phenotypes were associated with one or more complications, which conforms to the clinical practice. Compared with no main condition phenotype, some phenotypes were significantly associated with short-term adverse neonatal outcomes. Abnormal AF phenotype, mixed condition phenotype, PE-E&HELLP phenotype, and multiple fetus phenotype were risk factors for neonatal small-for gestation age (SGA); placenta previa phenotype was not associated with adverse outcomes except low APGAR score being 0-7 at one min; mixed condition phenotype was associated with low APGAR scores, SGA, mechanical ventilation, and grade HI-W intraventricular hemorrhage (IVH); fetal distress phenotype was frequently associated with neonatal SGA and mechanical ventilation; PE-E&HELLP phenotype was correlated with low APGAR score being 0-7 at one min, SGA and neonatal intensive care unit (NICU) admission; multiple fetus phenotype was not a risk factor for the outcomes included except for SGA. Not all neonates benefited from obstetric interventions included in this study. Our research disclosed the independent risk of different preterm phenotypes for adverse pregnancy outcomes. This study is devoted to putting forward the paradigm of classifying preterm birth phenotypically, with the ultimate purpose of defining preterm phenotypes based on multi-center studies and diving into the underlying mechanisms.


Brief report: Use and misuse of thyroid ultrasound in the initial workup of patients with suspected thyroid problems referred by primary care physicians to an endocrine clinic.
Thyroid ultrasound (TUS) plays an important but limited role in the evaluation of some complaints related to the thyroid gland. This study was designed to examine how primary care physicians use TUS before referring patients to an endocrine clinic. We audited all charts of first-time referrals for appropriateness of TUS use. Recommendations in practice guidelines and current textbooks defined appropriate indications for TUS: (1) patients with a thyroid nodule and a history of head or neck irradiation; (2) follow-up of patients with nodules not surgically removed; and (3) evaluation of patients with amiodarone-induced thyrotoxicosis. Endocrine referral clinic in a teaching hospital in Israel. Two hundred and eight unselected referrals were reviewed. Sixty-nine (33%) of the patients presented with a TUS. Documented reasons for TUS were suspected thyroid mass (n=35, 51%), thyroid dysfunction (n=21, 30%), neck pain (n=5, 7%), dyspnea (n=4, 6%), and dysphagia (n=2, 3%). Of the 69 TUS reviewed, 64 (93%) were not appropriate. Primary care clinicians obtain TUS studies in patients without recommended indications prior to referral to an endocrinologist.


Increased lung water without hypocapnia does not cause central sleep apnoea in a lamb model.
Central sleep apnoea (CSA) in patients with heart failure is associated with an extremely poor prognosis. It is unclear as to whether pulmonary congestion contributes to CSA. We developed a sheep model of congestive cardiac failure (CCF) to address the question of whether pulmonary congestion without hypocapnia could cause CSA. Fourteen lambs were given CCF by overdrive pacing for 3 weeks. CCF was defined by a pulmonary artery occlusion pressure (PAOP) > or = 15 mmHg. There were 11 controls. Extravascular lung water (EVLW) was measured by the double indicator dilution method. The CCF lambs had a PAOP = 18 +/- 3 mmHg and controls had a PAOP = 10 +/- 2 mmHg (P < 0.01). EVLW was 12.6 +/- 1.8 (CCF) compared to 8.9 +/- 2 mL/kg (controls) (P < 0.01). The respiratory rate was 74 +/- 21 b.p.m. (CCF) compared to 47 +/- 6 b.p.m. (controls) (P < 0.05). Acute volume loading with saline raised PAOP without changing respiration. pH and PaCO(2) were the same in both groups (PaCO(2)-37 mmHg). These results support the view that hypocapnia is essential for CSA, and demonstrated that increased EVLW causes tachypnoea but not CSA.


Foot ulceration due to arterial insufficiency: role of cilostazol.
Left untreated, peripheral arterial disease can lead to chronic leg ischaemia, causing pain, foot ulcers and gangrene, and increasing the risk of amputation. The ulcers of two patients treated with cilostazol after revascularisation healed completely


Influence of neck shaft angle of humerus in prosthesis design.
A better understanding of the proximal humerus is essential for anatomical reconstruction of the glenohumeral joint during prosthetic replacement. The neck-shaft angle is critical for correct calcar screw positioning when fixing a proximal humeral fracture with a locking plate. It's essential for exact implant placement and treatment of any soft-tissue or bone pathology. Improper implants cause discomfort and post-operative complications, therefore understanding the humeral neck shaft angle is fundamental in the design and manufacturing of prostheses. This study looked into the necessity regional data of the humeral neck shaft angle (NSA) and its importance in shoulder prosthesis manufacturing. This cross-sectional investigation was conducted on 300 dry cadaveric humeri of unknown gender and age that were free of damage or deformity. The Goniometer was used to measure the neck shaft angle. The data was analysed using SPSS software. The standard deviation and mean were calculated. The statistical difference between the right and left humeri was assessed using the students' t' test. The NSA of the humerus was 131.265.82° on average. The NSA mean values were substantially higher on the right side. A statistically significant difference between the right and left humeri was revealed by a P value of 0.001. Success of the shoulder arthroplasty demands anatomical reconstruction of the normal neck-shaft angle of the humerus. Racial variations in the morphometry of the neck-shaft angle needs to be considered in prosthesis design.


Corneal endothelial dysfunction caused by Asclepias curassavica in a young farmer.
To introduce a case of corneal endothelial toxicity caused by Asclepias curassavica (Milkweed) in Korea. A 37-year-old Asian man presented with decreased vision and redness in the right eye, which developed after contact with Asclepias curassavica. At presentation, best-corrected visual acuity (BCVA) was 20/60 in the right eye. Slit lamp examination demonstrated severe corneal stromal edema with Descemet's folds and conjunctival hyperemia. We prescribed topical prednisolone acetate 1% eye drops (8 times a day), cyclosporine 0.1% (once a day) and oral prednisolone (30 mg a day for 3 days). One day later, the BCVA improved to20/40 and marked improvement in corneal edema was observed. At 5 days, BCVA was 20/22 and anterior segment examination showed minimal corneal edema with resolution of Descemet's folds. At 2 weeks, BCVA was 20/20 in the right eye and corneal edema completely resolved. This case suggests that high index of suspicion for toxicity from Asclepias species is necessary when encountered with patients who present with corneal edema after exposure to these plants. Aggressive anti-inflammatory treatment might be helpful for early recovery, at least for young patients.


Primary internal ophthalmoplegia due to head injury.
Six cases of internal ophthalmoplegia due to direct head injury are presented. All six patients had a dilated, nonreactive pupil. Four had no extraocular palsies or ptosis and two had partial extraocular palsies or ptosis. Disturbance of consciousness was absent or very mild, and all patients fully recovered within 1 to 7 days after the traumatic event. No patient had a history that suggested a cause for oculomotor nerve palsy, and emergency CTscans showed no mass lesions. The internal ophthalmoplegia was recognized immediately after trauma. Although minimal oculomotor nerve palsies due to unruptured intracranial aneurysms have been described, none of our patients complained of periorbital or retroorbital pain either before or after the trauma, which rules out intracranial aneurysms as the cause of the internal ophthalmoplegia. Therefore, we concluded that the internal ophthalmoplegia was due to direct head injury. The pathophysiological mechanism of the internal ophthalmoplegia appeared to be slight injury of the pupillomotor fibres on the ventromedial surface of the third nerve at the posterior petroclinoid ligament, which acted as the fulcrum due to the downward displacement of the brainstem at the time of impact.


Vector population monitoring tools for insecticide resistance management: Myth or fact?
Insecticide resistance is a large and growing problem for the control of mosquito disease vectors. The World Health Organization (WHO) established the Global Plan for Insecticide Resistance Management (GPIRM) in 2012. In that context, both classical and molecular tools, as well as entomological databases and decision support platforms have been developed and used for IRM. Despite major advances in the molecular elucidation of resistance mechanisms and the development of diagnostic tools, their impact on disease control programs has been limited. In most cases diagnostic tools provide a retrospective examination of changes imposed by insecticides rather than a prospective analysis to guide vector control strategies. The uncertainty of the predictive value of markers, the assay robustness and the common misconceptions in resistance diagnosis terminology are continuing challenges in monitoring vector resistance. Furthermore, an often logistics, as opposed to systematic scientific evidence, based approach to decision for the use of the very few alternative chemicals in vector control, has reduced the value of resistance monitoring in practice. The current deployment of new insecticidal active ingredients should necessitate the application of companion diagnostics (CDx) and the development of modern ways for interpretation and management of the data by trained programme managers. This will establish their real value for use in decision-making, in line with evidence based choice of chemicals in agriculture and medical applications.


Protein tyrosine kinase but not protein kinase C inhibition blocks receptor induced alveolar macrophage activation.
The selective enzyme inhibitors genistein and Ro 31-8220 were used to assess the importance of protein tyrosine kinase (PTK) and protein kinase C (PKC), respectively, in N-formyl-methionyl-leucyl-phenylalanine (FMLP) induced generation of superoxide anion and thromboxane B(2) (TXB(2)) in guinea-pig alveolar macrophages (AM). Genistein (3-100 muM) dose dependently inhibited FMLP (3 nM) induced superoxide generation in non-primed AM and TXB(2) release in non-primed or in lipopolysaccharide (LPS) (10 ng/ml) primed AM to a level > 80% but had litle effect up to 100 muM on phorbol myristate acetate (PMA) (10 nM) induced superoxide release. Ro 31-8220 inhibited PMA induced superoxide generation (IC(50) 0.21 +/- 0.10 muM) but had no effect on or potentiated (at 3 and 10 muM) FMLP responses in non-primed AM. In contrast, when present during LPS priming as well as during FMLP challenge Ro 31-8220 (10 muM) inhibited primed TXB(2) release by > 80%. The results indicate that PTK activation is required for the generation of these inflammatory mediators by FMLP in AM. PKC activation appears to be required for LPS priming but not for transducing the FMLP signal; rather, PKC activation may modulate the signal by a negative feedback mechanism.


Effect of age on the short- and long-term outcomes of patients undergoing curative liver resection for HCC.
Few studies have evaluated the outcomes of curative liver resection (LR) in octogenarian patients, analysed cancer-specific survival (CSS) with HCC-related death or explored the age-varying effect of HCC-related death in elderly patients undergoing LR. We aim to determine the effect of age on the short and long-term outcomes of LR for HCC. Between 2000 and 2018, 1,092 patients with primary HCC who underwent LR with curative intent were retrospectively reviewed. The log-rank test and Gray's test were used to assess the equality of survivor functions and competing risk-adjusted cumulative incidence functions between patients in the three age categories respectively. Regression adjustment was used to control for confounding bias via a Principal Component Analysis. Quantile, Firth logistic, Cox, and Fine-Gray competing risk regression were used to analyse continuous, binary, time-to-event, and cause-specific survival respectively. Restricted cubic splines were used to illustrate the dose-effect relationship between age and patient outcomes. The study comprised of 764 young patients (<70 years), 278 septuagenarians (70-79 years old) and 50 octogenarians (≥80 years). Compared to young patients, octogenarians had significantly lower 5-year OS(62.1% vs 37.7%, p < 0.001). However, there was no significant difference in 1-year RFS(73.1% vs 67.0%, p = 0.774) or 5-year CSS (5.4% vs 15.2%, p = 0.674). Every 10-year increase in age was significantly associated with an increase length of stay (p < 0.001), postoperative complications (p = 0.004) and poorer OS(p = 0.018) but not significantly associated with major complications (p = 0.279), CSS(p = 0.338) or RFS(p = 0.941). Age by itself was associated with OS after LR for HCC but was not a significant risk factor for HCC-related death.


The tyrosyl residues in creatine kinase. Modification by iodine.
The effect of the iodination of tyrosyl residues in creatine kinase from rabbit muscle has been investigated at alkaline pH after reversible masking of the reactive thiol groups. The conversion of 4-5 tyrosyl residues to monoiodotyrosines as measured by spectrotitration and by radioactive iodine labelling resulted in almost total loss of enzymic activity. The modified enzyme was unable to bind its nucleotide substrates but no significant conformational change was revealed by optical rotatory dispersion or Stokes radius measurements. However, change in the reactivity of some non-essential thiol groups, presumably those located near the active thiol groups, was observed.


Maternal and post-weaning high-fat, high-sucrose diet modulates glucose homeostasis and hypothalamic POMC promoter methylation in mouse offspring.
Substantial evidence demonstrated that maternal dietary nutrients can significantly determine the susceptibility to developing metabolic disorders in the offspring. Therefore, we aimed to investigate the later-life effects of maternal and postweaning diets interaction on epigenetic modification of the central nervous system in the offspring. We examined the effects of dams fed a high-fat, high-sucrose (FS) diet during pregnancy and lactation and weaned to FS diet continuously until 32 weeks of age. Then, DNA methylation and gene expressions of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in the offspring. Offspring of FS diet had heavier body weight, impaired glucose tolerance, decreased insulin sensitivity and higher serum leptin level at 32-week age (p < 0.05). The expression of POMC and MC4R genes were significantly increased in offspring exposed to FS diet during gestation, lactation and into 32-week age (p < 0.05). Consistently, hypomethylation of POMC promoter in the hypothalamus occurred in the FS diet offspring (p < 0.05), compared with the C group. However, no methylation was detected of MC4R promoter in both the two groups. Furthermore, POMC-specific methylation (%) was negatively associated with glucose response to a glucose load (r = -0.273, p = 0.039). Maternal and post-weaning high-fat diet predisposes the offspring for obesity, glucose intolerance and insulin resistance in later life. Our findings can advance our thinking around the DNA methylation status of the promoter of the POMC and MC4R genes between long-term high-fat, high-sucrose diet and glucose homeostasis in mouse.


Development of stereological analysis software for the calculation of volume, number and surface density.
COSAS, an acronym for COmputerized Stereological Analysis System, is software designed to facilitate the process of quantitative morphological analysis. It is a flexible, reliable, and easy to use software system which provides the biologist with a simple means for performing stereological analysis. It provides for estimation of volume and surface density and allows for direct calculation of diameter information from planimetric data. The latter capability is unique to COSAS and provides the ability to calculate longest and shortest diameters for convex profiles, enabling calculation of number density. Access to all intermediate calculations is possible, so the process of transformation of raw data into the stereological descriptors can be completely exposed. This serves two purposes: (1) it provides a means for tracing results; (2) the intermediate values can be utilized independently. This system was used to analyze peroxisomes in tissues from patients with Zellweger's disease and neonatal-onset adrenoleukodystrophy. The system was also used to facilitate an immunocytochemical analysis of cytochrome P450 topology in the endoplasmic reticulum membrane.