Pectin lyase-modified red ginseng extract improves glucose homeostasis in high fat diet-fed mice.
Red ginseng has long been used as a traditional folk medicine for various diseases including diabetes. Recently, a preparation of red ginseng extract by pectin lyase modification has been developed and named as GS-E3D. The aim of this study is to evaluate the preventive effect of GS-E3D on hyperglycemia induced by feeding a high fat diet (HFD) in mice. GS-E3D was orally administered to C57BL/6J mice at different doses (250, 500, or 1000 mg/kg/day) for 6 weeks while on a HFD. Body weight and blood glucose were monitored weekly, and oral glucose tolerance test (OGTT) was performed at 5th week of the experiment. Glycemic indications and metabolic parameters were further measured in serum. Six weeks of GS-E3D treatment to mice significantly inhibited HFD-induced body weight gain, hyperglycemia, hyperinsulinemia and hypertriglyceridemia. Notably, GS-E3D treated mice at doses of 250, 500 and 1000 mg/kg showed 41.8%, 45.0% and 55.1% reduction in insulin resistance index, respectively, compared to HFD control mice. OGTT revealed that GS-E3D markedly prevented steep rise of blood glucose and insulin levels after glucose challenge and ameliorated HFD-induced glucose and insulin intolerance. The histological analysis showed enlarged adipocytes in HFD-fed mice whereas the adipocyte hypertrophy was prevented in GS-E3D treated mice in a dose-dependent manner. Furthermore, when peripheral glucose uptake level was assessed by total and membranous glucose transporter type 4 (GLUT4) protein contents, GS-E3D restored GLUT4 protein expression to the levels of regular diet fed mice, and dose-dependently translocated them to the plasma membrane. The results collectively show that GS-E3D ameliorates obesity-related impaired glucose tolerance by improving insulin sensitivity in the epidydimal adipose tissue.


Shifts in Unintentional Exposure to Drugs Among People Who Use Ecstasy in the Electronic Dance Music Scene, 2016-2019.
Electronic dance music (EDM) party attendees who use ecstasy (3,4-methylenedioxymethamphetamine [MDMA], Molly) are at high risk for ingesting adulterant drugs, but little is known regarding trends in exposure. We sought to determine whether adulteration has shifted in recent years. Adults entering EDM events at nightclubs and dance festivals in NYC were surveyed in 2016 and 2019. We tested hair samples from a subsample of those reporting past-year ecstasy use using ultra-high performance liquid chromatography-tandem mass spectrometry. Differences in unreported drug exposure and suspected adulteration were compared between 2016 (n = 90) and 2019 (n = 72). MDMA detection was stable at 72-74%. We detected decreases in unreported use of methamphetamine (from 22.2% to 5.6% [P = .003], an 74.8% decrease), new psychoactive substances (from 31.1% to 2.8% [P < .001], a 91.0% decrease), and synthetic cathinones in particular (from 27.8% to 2.8% (P < .001, an 89.9% decrease). Unreported ketamine exposure increased from 18.9% to 34.7% (P = .022, an 83.6% increase). We also detected decreases in participants' suspicion of their ecstasy being adulterated with methamphetamine (from 20.0% to 5.6% [P = .010], an 72.0% decrease) and "bath salts" (synthetic cathinones, from 8.9% to 1.4% [P = .044], an 84.3% decrease). Unknown exposure to adulterants among people who use ecstasy in the EDM scene is shifting. Monitoring of exposure to adulterants is needed to inform harm reduction. This was among the first studies to examine unintentional exposure to drugs over time in this population and unintentional exposure to synthetic cathinones in particular appears to be declining. (Am J Addict 2021;30:49-54).


Robust spatially resolved pressure measurements using MRI with novel buoyant advection-free preparations of stable microbubbles in polysaccharide gels.
MRI of fluids containing lipid coated microbubbles has been shown to be an effective tool for measuring the local fluid pressure. However, the intrinsically buoyant nature of these microbubbles precludes lengthy measurements due to their vertical migration under gravity and pressure-induced coalescence. A novel preparation is presented which is shown to minimize both these effects for at least 25 min. By using a 2% polysaccharide gel base with a small concentration of glycerol and 1,2-distearoyl-sn-glycero-3-phosphocholine coated gas microbubbles, MR measurements are made for pressures between 0.95 and 1.44 bar. The signal drifts due to migration and amalgamation are shown to be minimized for such an experiment whilst yielding very high NMR sensitivities up to 38% signal change per bar.


Does the Degree Matter? MD and DO Students Who Match Into OB/GYN Report Different Experiences in US Undergraduate Medical Education.
Although allopathic (MD) and osteopathic (DO) students have similar curricular requirements, little is known about differences in MD and DO preparedness for obstetrics and gynecology (OB/GYN) residency. To assess differences in experiences and confidence of MD vs DO students who matched to OB/GYN. This cross-sectional survey study was open to all fourth-year medical students who matched to OB/GYN in the United States in April 2021. The survey included demographic data, clinical experiences, confidence (5-point sliding scale), and a 11-item knowledge test. Survey responses were compared to assess for disparities in experiences and confidence. Survey response rate was 72.0% (1057 of 1469) students matched to OB/GYN postgraduate year 1 positions. Of the 871 MD and 175 DO responding students, MDs were more likely to have clerkships ≥6 weeks (78.1% vs 15.4%; P<.001) and a home sub-internship (92.0% vs 53.4%; P<.001). DOs reported more hands-on experiences with procedures (MD median=35 [20-35] vs DO median=40 [25-65]; P=.002). There was no difference in self-reported confidence in knowledge, technical skills, or having a realistic sense of internship, and no difference in baseline knowledge test scores. DOs felt less confident about their medical school preparation (aOR 0.40; 95% CI 0.25-0.66; P<.001) and were more likely to perceive inequity of residency preparation (aOR 1.88; 95% CI 1.18-3.00; P=.002). MD students matched to US OB/GYN residency programs reported longer clerkship and more home sub-internships, while DO students reported more hands-on experiences. Despite reporting similar confidence in knowledge and skills, DO students felt less prepared for internship.


Hemolytic, but not cell-invasive activity, of adenylate cyclase toxin is selectively affected by differential fatty-acylation in Escherichia coli.
Adenylate cyclase toxin from Bordetella pertussis requires posttranslational acylation of lysine 983 for the ability to deliver its catalytic domain to the target cell interior and produce cyclic adenosine monophosphate (cell-invasive activity) and to form transmembrane channels (hemolytic activity). When the toxin is expressed in Escherichia coli, it has reduced hemolytic activity, but comparable cell-invasive activity to that of adenylate cyclase toxin from B. pertussis. In contrast to the native protein from B. pertussis, which is exclusively palmitoylated, recombinant toxin from E. coli is acylated at lysine 983 with about 87% palmitoylated and the remainder myristoylated. Furthermore, the recombinant toxin contains an additional palmitoylation on approximately two-thirds of the lysines at position 860. These observations suggest that the site and nature of posttranslational fatty-acylation can be dictated by the bacterial host used for expression and can have a significant, but selective, effect on protein function.


Biomaterials and biotechnology: from the discovery of the first angiogenesis inhibitors to the development of controlled drug delivery systems and the foundation of tissue engineering.
This paper describes the discovery of the first inhibitors of angiogenesis; the discoveries that led to the development of the first biocompatible controlled release systems for macromolecules, and findings that helped to create the field of tissue engineering. In addition, new paradigms for creating biomaterials, early work on nanotechnology in medicine and intelligent drug delivery systems are discussed.


Updating the use of the Madrid Sonographic Enthesis Index (MASEI): a systematic review of the literature.
To perform a systematic review of the literature to evaluate the use of the enthesis ultrasound Madrid Sonographic Entesis Index (MASEI) from its publication. A systematic search of MEDLINE, EMBASE, and Cochrane Central Register databases was performed. The search strategy was constructed to identify publications containing terms related to enthesis and ultrasound. The only applied filter was studies conducted in humans. One reviewer systematically screened the search. A second reviewer verified the selection. The data extraction was focused on study characteristics, including population and components of the OMERACT filter. Sixty-eight of the 1581 identified studies had used MASEI, including 41 (60%) abstracts and 27 (40%) articles. Of the 27 articles, MASEI was mainly used for spondyloarthritis and related diseases in 12 (44%) articles, followed by both psoriatic arthritis and rheumatoid arthritis in five (19%) articles; however, it was also used in diseases such as Behçet disease, FM, familiar Mediterranean fever, SS, crystal arthropathies and systemic sclerosis. The feasibility of MASEI was reported in three (11%) articles, and the reliability in 12 (44%) with good to excellent values. No article evaluated the responsiveness to treatment. The construct validity of MASEI was assessed using biomarkers in seven (26%) articles, clinical examination in 13 (48%) and imaging procedures (only X-rays) in two (7%). The discriminative validity was assessed in 16 (59%) articles, not only in SpAs. MASEI is a feasible, reliable and valid ultrasound score for the study of enthesis in spondyloarthritis, psoriatic arthritis and other diseases.


Presence: A Step Closer to Spiritual Care in Nursing.
This article argues that while not all nurses are comfortable with spiritual care, nurses may be comfortable with enacting presence. Presence, an encompassing element in spiritual care, might be a more accessible first step for nurses toward spiritual care. To further highlight this viewpoint, the nature, consequences, and cultivation of presence are also discussed.


Treatment of ovarian cancer: the state of the art.
The state of the art in the treatment of ovarian cancer is reviewed. Development in strategies for early and advanced ovarian cancer stages as well as prospects for the future are described.


The Checkpoint Immunotherapy Revolution: What Started as a Trickle Has Become a Flood, Despite Some Daunting Adverse Effects; New Drugs, Indications, and Combinations Continue to Emerge.
What started as a trickle of new agents that help the body's immune system fight cancer has now become a flood, despite some daunting adverse effects. This report discusses the new drugs, indications, and combinations that continue to emerge.


A prospective study between two different techniques for the repair of a large recurrent ventral hernia: a double mesh intraperitoneal repair versus onlay mesh repair.
Massive ventral hernias are difficult to repair, especially with multiple recurrences. Numerous methods of repair have been described with an overall recurrence rate up to 33% after first repair and 44% after second repair, mostly occurring within 3 years of the repair. This is a prospective study on 41 patients who underwent surgery between January 2000 and August 2004 for recurrent large ventral hernias. Patients were randomized into two groups: group A included 22 patients, who were subjected to suture repair with an onlay polypropylene mesh, and group B, which included 19 patients, who were subjected to a tailored double mesh (Vicryl + polypropylene) intraperitoneal repair. Superficial wound infection occurred in two patients (4.8%), one in each group. By a median follow up of 30 months, seroma formation or hernia recurrence was not found in group B in comparison to seven and six cases, respectively, in group A (p < or = 0.000). There was no intraabdominal complication in the cases subjected to double mesh intraperitoneal repair due to the protective effect of the inner Vicryl layer, which is characterized by its low reactivity. A double mesh intraperitoneal repair (ADMIR) is successful for the repair of recurrent large ventral hernias as it is applicable to all sites of ventral hernias. The mesh is mostly hidden within the abdomen with relatively affordable pain allowing for early mobilization, the complication rate is low and so far no recurrence was reported. A long-term follow up with a larger number of cases is advisable in order to determine the long-term success of this kind of repair.


Sapindus saponins' impact on hydrocarbon biodegradation by bacteria strains after short- and long-term contact with pollutant.
The introduction of high toxicity petroleum contaminants to the natural environment causes damage to ecosystems and the aesthetics of the surroundings. Therefore it is critical to enhance microbial community performance to manage the degradation process. This paper analyses the effect of natural surfactants from the tree Sapindus mukorossi on biodegradation of hydrocarbons. Analysis of cell surface hydrophobicity and zeta potential confirmed effective modifications of the cell surface parameters essential for the bioavailability of contaminants to microorganisms. Interestingly, favorable differences were observed only for microorganisms from non-contaminated soil. There was also recorded an increase in diesel oil biodegradation to 41% for Sphingomonas sp. and 56% for Pseudomonas alcaligenes on addition of 100mgL(-1) of Sapindus saponins. The addition of natural surfactants has no significant impact on bacterial strains isolated from long-term contaminated soil. This research demonstrates that the addition of Sapindus extract could be a useful tool to improve the effectiveness of microbial degradation of hydrocarbon pollutants by environmental strains in recently contaminated.


Provider Prescription Drug Monitoring Program Utilization and Self-Auditing-A Pilot Study.
Alabama has the highest prescription rate in the country. The national incidence of overdose deaths from prescription opioids exceeds the combined death rates from heroin and cocaine overdose. Monitoring prescription access should be an essential activity among providers and can be used to protect patient health and well-being. Prescription drug monitoring programs (PDMPs) are tools that assist in diminishing opioid therapy risks such as diversion, abuse, overdose, and death. The purpose of the study was to examine the effects of an educational intervention on opioid prescriptive rates, frequency of self-auditing and days of opioid supply among healthcare providers. The anticipated goal of the project was that rates and days of supply for opioid prescriptions would decrease. A pretest-posttest design was used to assess a sample of 21 DEA licensed providers who attended a PDMP presentation and conducted a self-audit using the PDMP. Analysis showed that 81% of the participants had never conducted a self-audit prior to the intervention. Self-report data indicated that 85.7% of the providers planned to increase their self-auditing use postintervention and 14.3% planned to make no changes to their current use of the PDMP. Among those who prescribed opioids, the range of monthly prescriptions written was 3-142 preintervention (M = 32.28, SD = 41.04) and 3-149 postintervention (M = 32.26, SD = 43.32). Analysis also found the days of opioid supply prescribed were also high. In both cases, these numbers were correlated to patient census. The PDMP is an effective surveillance tool that provides aggregate data to state public health officials. For a PDMP to be effective, it must be used by prescribing providers. While the anticipated goal for this study was not achieved, the PDMP is an effective surveillance tool for monitoring the controlled substance prescription histories of patients. Using the PDMP before prescribing can aid providers in distinguishing those who legitimately have a need from those who may be seeking to misuse the medications. Additionally, use of a PDMP can provide aggregate data to state public health officials so that education programs, for practitioners and patients, can be developed.


Advanced techniques for performing photodynamic therapy in deep-seated tissues.
Photodynamic therapy (PDT) is a promising localized cancer treatment modality. It has been used successfully to treat a range of dermatological conditions with comparable efficacy to conventional treatments. However, some drawbacks limit the clinical utility of PDT in treating deep-seated tumors. Notably, the penetration limitation of UV and visible light, commonly applied to activate photosensitizers, makes PDT incompetent in treating deep-seated tumors. Development in light delivery technologies, especially fiber optics, led to improved clinical strategies for accessing deep tissues for irradiation. However, PDT efficacy issues remained partly due to light penetration limitations. In this review, we first summarized the current PDT applications for deep-seated tumor treatment. Then, the most recent progress in advanced techniques to overcome the light penetration limitation in PDT, including using functional nanomaterials that can either self-illuminate or be activated by near-infrared (NIR) light and X-rays as transducers, and implantable light delivery devices were discussed. Finally, current challenges and future opportunities of these technologies were discussed, which we hope may inspire the development of more effective techniques to enhance PDT efficacy against deep-seated tumors.


Catch bond models may explain how force amplifies TCR signaling and antigen discrimination.
The TCR integrates forces in its triggering process upon interaction with pMHC. Force elicits TCR catch-slip bonds with strong pMHCs but slip-only bonds with weak pMHCs. We develop two models and apply them to analyze 55 datasets, demonstrating the models' ability to quantitatively integrate and classify a broad range of bond behaviors and biological activities. Comparing to a generic two-state model, our models can distinguish class I from class II MHCs and correlate their structural parameters with the TCR/pMHC's potency to trigger T cell activation. The models are tested by mutagenesis using an MHC and a TCR mutated to alter conformation changes. The extensive comparisons between theory and experiment provide model validation and testable hypothesis regarding specific conformational changes that control bond profiles, thereby suggesting structural mechanisms for the inner workings of the TCR mechanosensing machinery and plausible explanations of why and how force may amplify TCR signaling and antigen discrimination.


Predictors of survival after total laryngectomy for recurrent/persistent laryngeal squamous cell carcinoma.
Total laryngectomy remains the treatment of choice for recurrent/persistent laryngeal squamous cell carcinoma (SCC) after radiotherapy (RT) or chemoradiotherapy (CRT). However, despite attempts at aggressive surgical salvage, survival in this cohort remains suboptimal. A prospectively maintained single-institution database was queried for patients undergoing total laryngectomy for recurrent/persistent laryngeal SCC after initial RT/CRT between 1998 and 2015(n = 244). Demographic, clinical, and survival data were abstracted. The Kaplan-Meier survival curves and hazard ratios (HRs) were calculated. Five-year overall survival (OS) was 49%. Five-year disease-free survival (DFS) was 58%. Independent predictors of OS included severe comorbidity (Adult Comorbidity Evaluation-27 [ACE-27] scale; HR 3.76; 95% confidence interval [CI] 1.56-9.06), and positive recurrent clinical nodes (HR 2.91; 95% CI 1.74-4.88). Severe comorbidity status is the strongest predictor of OS, suggesting that increased attention to mitigating competing risks to health is critical. These data may inform a risk prediction model to allow for focused shared decision making, preoperative health optimization, and patient selection for adjuvant therapies.


Tumor necrosis factor-alpha in low doses preactivates and activates macrophages by increasing their ability to produce reactive oxygen species and oxidize low-density lipoproteins: protective effect of antioxidants.
Tumor necrosis factor-alpha in low doses activated rat peritoneal macrophages and intensified production of reactive oxygen species (zymosan-depended chemiluminescence). Single or 2-fold incubation with tumor necrosis factor-a activated and preactivated human blood macrophages and promoted oxidative modification of low-density lipoproteins (increased their mobility in agarose gel). Antioxidants (potassium phenosan, probucol, and desferal) suppressed oxidative modification of low-density lipoproteins induced by nonactivated, preactivated, and activated macrophages. Our results show that antioxidants hold much promise for the prevention and therapy of atherosclerosis.


A novel method of manual positioning based on anatomical mark (shoulder-to-shoulder) to prevent postoperative leg-length discrepancy for femoral neck fractures in hip arthroplasty.
To determine whether the two lower extremities are of equal length after hip arthroplasty for femoral neck fractures, we developed a novel method of manual positioning based on anatomical mark (shoulder-to-shoulder) in hip arthroplasty. Patients with femoral neck fractures requiring hip arthroplasty from July 2020 to March 2022 in the orthopedic department of Jinjiang Municipal Hospital, Fujian Province, China were recruited. Hip arthroplasty was performed using the proposed "shoulder-to-shoulder" method of manual positioning based on anatomical mark in 52 patients with femoral neck fractures who met the inclusion criteria. "Shoulder-to-shoulder" was achieved by alignment of the marked femoral "shoulder" and the "shoulder" of prosthesis stem. There were 16 male and 36 female patients, with 27 undergoing total hip arthroplasty (THA) and 25 undergoing hip hemiarthroplasty (HA). The fractures were categorized according to the Garden classification: type II, type III, and type IV in 5, 11, and 36 patients, respectively. The vertical distance from the apex of the medial margin of the femoral trochanter to the tear drop line on both sides which was regarded as the length of both limbs were compared via postoperative imaging, and the apex-shoulder distance on the ipsilateral side measured via postoperative imaging was compared with those measured intraoperatively. All patients completed the surgery successfully. The measurement results for the lower extremities after THA were as follows: contralateral group, 43.87 ± 5.59 mm; ipsilateral group, 44.64 ± 5.43 mm. The measurement results for the lower extremities after HA were as follows: contralateral group, 45.18 ± 7.82 mm; ipsilateral group, 45.16 ± 6.43 mm. The measurement results for the lower extremities after all arthroplasties were as follows: contralateral group, 44.50 ± 6.72 mm; ipsilateral group, 44.89 ± 5.90 mm. The results for the apex-shoulder distance were as follows: postoperative imaging, 19.44 ± 3.54 mm; intraoperative apex-shoulder distance, 27.28 ± 2.84 mm. Statistical analysis results indicated no statistically significant difference in the postoperative bilateral lower extremity length after hip arthroplasty (P = 0.75), while a statistically significant difference was found between the intraoperative and postoperative imaging measurements of the apex-shoulder distance (P < 0.01). The novel method of manual positioning based on anatomical mark (shoulder-to-shoulder) for femoral neck fractures in hip arthroplasty is simple and accurate, making it effective for preventing postoperative bilateral leg length discrepancy.


Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy.
We aimed to characterize the ocular phenotype of patients with ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome and their response to therapy. Single-center observational case study. Eleven patients with a diagnosis of ROSAH syndrome and mutation in ALPK1 were included. Patients with molecularly confirmed ROSAH syndrome underwent ophthalmic evaluation, including visual acuity testing, slit-lamp and dilated examinations, color fundus and autofluorescence imaging, fluorescein angiography, OCT, and electrophysiologic testing. Visual acuity, electrophysiology, fluorescein angiography, and OCT findings. Eleven individuals (6 female and 5 male patients) from 7 families ranging in age from 7.3 to 60.2 years at the time of the initial evaluation were included in this study. Seven patients were followed up for a mean of 2.6 years (range, 0.33-5.0 years). Best-corrected visual acuity at baseline ranged from 20/16 to no light perception. Variable signs or sequelae of intraocular inflammation were observed in 9 patients, including keratic precipitates, band keratopathy, trace to 2+ anterior chamber cells, cystoid macular edema, and retinal vasculitis on fluorescein angiography. Ten patients were observed to show optic disc elevation and demonstrated peripapillary thickening on OCT. Seven patients showed retinal degeneration consistent with a cone-rod dystrophy, with atrophy tending to involve the posterior pole and extending peripherally. One patient with normal electroretinography findings and visual evoked potential was found to have decreased Arden ratio on electro-oculography. Leveraging insights from the largest single-center ROSAH cohort described to date, this study identified 3 main factors as contributing to changes in visual function of patients with ROSAH syndrome: optic nerve involvement; intraocular inflammation, including cystoid macular edema; and retinal degeneration. More work is needed to determine how to arrest the progressive vision loss associated with ROSAH syndrome. Proprietary or commercial disclosure may be found after the references.


Intrahypothalamic infusions of a synthetic heroin substitute, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, potentiate mating behaviour in the female rat.
Acute microinfusions of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) bilaterally into the arcuate-ventromedial area of the hypothalamus (ARC-VMH) produced a dose-dependent facilitation of lordosis behaviour in oestrogen- and oestrogen-progesterone-treated ovariectomized female rats. This facilitation could be blocked by pretreatment of the ARC-VMH site with pargyline but not by a potent antagonist analogue of gonadotropin releasing hormone (GnRH). MPTP was not effective in potentiating lordosis when microinfused into other brain sites which are intimately involved in the neural circuitry for this oestrogen-dependent behavioural response. This action of MPTP in the ARC-VMH may be dependent upon the high MPTP receptor densities which are known to occur in the arcuate and periventricular hypothalamic nuclei. Chronic infusions of MPTP (once daily for 21 days) into the ARC-VMH did not result in any significant cell loss and did not interfere with the ability of a later acute MPTP infusion to potentiate lordosis nor with the ability of oestrogen and progesterone to promote the full display of lordosis behaviour. These results provide the first demonstration of neurally placed MPTP in the regulation of a specific hormone-dependent neuroendocrine response.


Plant molecular stress responses face climate change.
Environmental stress factors such as drought, elevated temperature, salinity and rising CO₂ affect plant growth and pose a growing threat to sustainable agriculture. This has become a hot issue due to concerns about the effects of climate change on plant resources, biodiversity and global food security. Plant adaptation to stress involves key changes in the '-omic' architecture. Here, we present an overview of the physiological and molecular programs in stress adaptation focusing on how genes, proteins and metabolites change after individual and multiple environmental stresses. We address the role which '-omics' research, coupled to systems biology approaches, can play in future research on plants seemingly unable to adapt as well as those which can tolerate climatic change.


Acquisition of thermotolerance during development of Blastocladiella emersonii.
In the fungus Blastocladiella emersonii the synthesis of heat-shock proteins is developmentally regulated; particular subsets of heat-shock proteins are induced by heat shock during sporulation, germination and growth and some heat shock-related proteins are spontaneously expressed during sporulation (Bonato et al., 1987, Eur. J. Biochem., in press). Nevertheless, acquisition of thermotolerance can be induced at any stage of the life cycle. The development of thermotolerance is correlated with the enhanced synthesis of some heat-shock proteins: hsp 82a, hsp 82b, hsp 76, hsp 70, hsp 60, hsp 25, hsp 17b. Other hsps are not specifically involved in thermotolerance.


Solid state fluorescence of lyophilized proteins.
Fluorescence spectroscopy has been used to measure changes in the tertiary structure of proteins in the solution state. The sensitivity of fluorescence to the protein tryptophan environment has made it a useful tool for studying protein conformation and stability. Using fluorescence spectroscopy to probe structural alterations in lyophilized proteins has been limited due to technical challenges and overwhelming background light scattering. We have investigated the possibility of analyzing lyophilized proteins using the Cary-Eclipse spectrofluorometer by monitoring the fluorescence of the protein therapeutic after subjecting the lyophilized cake to heat-induced accelerated degradation. We have been able to obtain reproducible fluorescence spectra, detecting possible structural changes under these conditions. Fluorescence and circular dichroism spectroscopic analyses of the reconstituted proteins indicated that changes in fluorescence intensities observed in the solid state could be correlated to that in solution and to possible tertiary structural changes. Size exclusion chromatography analysis of protein Y subject to accelerated degradation showed a correlation between decreasing fluorescence intensity and increasing protein Y tetramer in solution, consistent with long-term stability. This suggests that solid state, intrinsic protein fluorescence measurements using the Cary-Eclipse holder may be feasible for long-term stability studies and formulation development.


Pulmonary hypertension adversely affects short- and long-term survival after mitral valve operation for mitral regurgitation: implications for timing of surgery.
We investigated the impact of preoperative pulmonary hypertension (PH) on early and late outcomes after mitral valve operation for mitral regurgitation. Systolic pulmonary artery pressure (sPAP) was measured before operation in 873 consecutive patients who underwent mitral valve surgery for mitral regurgitation between January 2002 and January 2010. PH was classified as none (sPAP < 40 mm Hg), mild (40 ≤ sPAP < 50 mm Hg), moderate (50 ≤ sPAP < 60 mm Hg), or severe (sPAP ≥ 60 mm Hg). Increased preoperative sPAP was associated with greater left ventricular dysfunction and dilation, left atrial enlargement, more atrial fibrillation, and tricuspid regurgitation. Operative mortality was correlated with the degree of preoperative PH (2%, 3%, 8%, and 12% for none, mild, moderate, and severe PH, respectively, P < .0001). Long-term survival was related to preoperative sPAP (5-year survival: 88%, 79%, 65%, and 53% for none, mild, moderate, and severe PH, respectively; P < .0001). In multivariable analyses, sPAP was a predictor of both operative mortality (odds ratio, 1.023 per 1 mm Hg increase; 95% confidence interval, 1.003-1.044; P = .0270) and late death (hazard ratio, 1.018 per 1 mm Hg increase; 95% confidence interval, 1.007-1.028; P = .001). Among 284 patients with isolated degenerative mitral regurgitation due to leaflet prolapse, actuarial survival was 97.5%, 91.2%, and 80.5% for none, mild, and moderate to severe PH, respectively (P = .0002). Preoperative sPAP is a powerful predictor of early and late survival after mitral valve operation for mitral regurgitation. Even modest increases in sPAP adversely affect outcomes. Mitral valve operation should be performed before the development of PH.


Design and synthesis of a novel peptidomimetic inhibitor of HIV-1 Tat-TAR interactions: squaryldiamide as a new potential bioisostere of unsubstituted guanidine.
By performing RNA-targeted structure-activity relationship studies, we discovered a novel peptidomimetic containing squaryldiamide as a potential bioisostere replacement for guanidine that binds transactivation responsive RNA with high affinity.


High Serum Irisin Level as an Independent Predictor of Diabetes Mellitus: A Longitudinal Population-Based Study.
Irisin, a novel exercise-induced myokine, has been suggested to regulate energy homeostasis and insulin sensitivity. However, it remains unclear whether circulating irisin plays a role in the development of DM in human. We investigated the possible association between circulating irisin levels and incident DM in a 2.6-year longitudinal study of a population-based cohort comprised of rural Korean subjects.We conducted a longitudinal study within the Korean Genome and Epidemiology Study on Atherosclerosis Risk of Rural Areas in the Korean General Population (KoGES-ARIRANG) study from November 2005 to January 2008. Cases (n=85) were patients with incident DM during the follow-up period and controls (n = 85) were matched to incident DM cases based on sex and age at baseline. The relative risk of serum irisin/adiponectin level for incident DM was analyzed using conditional logistic regression analysis.Baseline irisin_ENREF_1 levels were significantly higher in subjects who developed DM than in subjects who did not. The serum irisin level was positively associated with glycated hemoglobin (HbA1c) and postprandial glucose. Irisin was negatively associated with adiponectin (R = -0.189, P = 0.014). After adjustment for potential confounders, including body mass index, the odds ratios [95% confidence intervals] for incident DM increased in a graded manner as the serum irisin level increased (Quartile 1 vs Quartile 2 vs Quartile 3 vs Quartile 4 = 1 vs 0.80 [0.28-2.35] vs 3.33 [1.11-10.00] vs 4.10 [1.35-12.44], respectively), whereas the odds ratios for incident DM decreased in a graded manner as the serum adiponectin level increased.High serum irisin was independently associated with the development of DM, indicating that irisin may be a useful predictor of DM in Korean adults.


Treatment of upper urinary calculi with Chinese minimally invasive percutaneous nephrolithotomy: a single-center experience with 12,482 consecutive patients over 20 years.
The Chinese minimally invasive percutaneous nephrolithotomy (MPCNL) was a modified version of standard PCNL which utilizes smaller tract and sheaths. The aim of this study was to present our experience on its efficacy and safety, and to grade its complications according to the modified Clavien classification. Between 1992 and 2011, 12,482 patients who underwent 13,984 MPCNL procedures entered this study. Data on stone size, access number, operative time, hospital length of stay, stone-free rate (SFR), and complications according to the modified clavien system were evaluated prospectively. Their mean age of patients was 47.6 years (range 0.6-93). The mean stone size was 3.2 ± 0.8 (1.4-7.4) cm. The mean operative time was 83 ± 38 min. Mean hemoglobin drop was 13.5 ± 11.3 g/L. Mean hospital stay was 10.3 ± 6.4 days (2-22 days). The initial SFR after first procedure was 78.6 %. In 14.7 % of cases with a second look, the SFR increase to 89.9 %. At 3 months after auxiliary procedures (re-PCNL, ureterorenoscopy, and shock wave lithotripsy), the overall SFR was achieved to 94.8 %. A total of 3,624 complications (25.92 %) were observed in 2,591 (18.53 %) procedures. There were 2,355 grade I (16.84 %), 706 grade II (5.05 %), 553 grade III (3.95 %), 7 grade IV (0.05 %), and three death of grade V (0.02 %) complications. This large-scale, contemporary analysis confirms MPCNL is still a safe and efficacious treatment option of kidney stones with a high stone-free rate and uncommon rate of high grade complications.


Aspergillus flavus expressed sequence tags and microarray as tools in understanding aflatoxin biosynthesis.
Aflatoxins are the most toxic and carcinogenic naturally occurring mycotoxins. They are produced primarily byAspergillus flavus andA. parasiticus. In order to better understand the molecular mechanisms that control aflatoxin production, identification of genes usingA. flavus expressed sequence tags (ESTs) and microarrays is currently being performed. Sequencing and annotation ofA. flavus ESTs from a normalizedA. flavus cDNA library identified 7,218 unique EST sequences. Genes that are putatively involved in aflatoxin biosynthesis, regulation and signal transduction, fungal virulence or pathogenicity, stress response or antioxidation, and fungal development were identified from these ESTs. Microarrays containing over 5,000 uniqueA. flavus gene amplicons were constructed at The Institute for Genomic Research. Gene expression profiling under aflatoxin-producing and non-producing conditions using this microarray has identified hundreds of genes that are potentially involved in aflatoxin production. Further investigations on the functions of these genes by gene knockout experiments are underway. This research is expected to provide information for developing new strategies for controlling aflatoxin contamination of agricultural commodities.


Assessment of the invisible blood contamination on nurses' gloved hands during vascular access procedures in a hemodialysis unit.
A prospective study was conducted to assess potential invisible blood contamination on nurses' gloved hands during vascular access procedures using the occult blood detection method in a hemodialysis unit. 60.13% (273/454) of samples tested positive for hemoglobin. These results highlighted the importance of hand hygiene and glove change during hemodialysis access care.


Severe hyperlactatemia with normal base excess: a quantitative analysis using conventional and Stewart approaches.
Critically ill patients might present complex acid-base disorders, even when the pH, PCO2, [HCO3-], and base excess ([BE]) levels are normal. Our hypothesis was that the acidifying effect of severe hyperlactatemia is frequently masked by alkalinizing processes that normalize the [BE]. The goal of the present study was therefore to quantify these disorders using both Stewart and conventional approaches. A total of 1,592 consecutive patients were prospectively evaluated on intensive care unit admission. Patients with severe hyperlactatemia (lactate level > or = 4.0 mmol/l) were grouped according to low or normal [BE] values (<-3 mmol/l or >-3 mmol/l). Severe hyperlactatemia was present in 168 of the patients (11%). One hundred and thirty-four (80%) patients had low [BE] levels while 34 (20%) patients did not. Shock was more frequently present in the low [BE] group (46% versus 24%, P = 0.02) and chronic obstructive pulmonary disease in the normal [BE] group (38% versus 4%, P < 0.0001). Levels of lactate were slightly higher in patients with low [BE] (6.4 +/- 2.4 mmol/l versus 5.6 +/- 2.1 mmol/l, P = 0.08). According to our study design, the pH, [HCO3-], and strong-ion difference values were lower in patients with low [BE]. Patients with normal [BE] had lower plasma [Cl-] (100 +/- 6 mmol/l versus 107 +/- 5 mmol/l, P < 0.0001) and higher differences between the changes in anion gap and [HCO3-] (5 +/- 6 mmol/l versus 1 +/- 4 mmol/l, P < 0.0001). Critically ill patients may present severe hyperlactatemia with normal values of pH, [HCO3-], and [BE] as a result of associated hypochloremic alkalosis.


Childhood malignancy and maternal diabetes or other auto-immune disease during pregnancy.
Among 4380 children born in 1987-1997 of women with a diagnosis of diabetes and alive at the age of one, 10 were registered in the Swedish Cancer Registry before the end of 1998. The odds ratio for having a childhood cancer after maternal diabetes, stratified for year of birth, maternal age, parity, multiple birth, and 500 g birth weight class was 2.25 (95%CI 1.22-4.15). Among 5842 children born during the period 1973-1997 whose mothers had other auto-immune diseases (SLE, rheumatoid arthritis, Crohn, ulcerous colitis, multiple sclerosis or thyroiditis), the number of observed childhood cancers (9) was close to that expected (8.5). Maternal diabetes but not other auto-immune diseases may be a risk factor for childhood cancer.


Trends in health inequalities by educational level in a Norwegian total population study.
To describe levels of inequality and trends in self reported morbidity by educational level in a total Norwegian county population in the mid-1980s and mid-1990s. Two cross sectional health surveys at an interval of 10 years in the Nord-Trøndelag Health Study, HUNT I (1984-86) and HUNT II (1995-97). Primary health care, total county population study. Men and women, 25-69 years. There was a consistent pattern of increasing self reported health problems with decreasing educational level for three health variables: perceived health, any longstanding health problem, and having a chronic condition. A stable or slight decrease in inequalities over time was found. The prevalence odds ratio for perceived health less than good were 2.71 for men (95% confidence intervals (CI): 2.39 to 3.09) and 2.13 for women (95% CI: 1.85 to 2.46) in the first survey, 2.51 for men (95% CI: 2.27 to 2.78) and 2.06 for women (95% CI: 1.88 to 2.26) 10 years later. The magnitude of the socioeconomic gradients in health in this population seemed somewhat lower than in Norway as a whole and close to the average in studies from other European countries. There was a slight trend towards smaller differences despite rapid structural changes in working life, turbulence in economy, and more people experiencing unemployment.


Associations of sleep quality, sleep apnea and autonomic function with insulin secretion and sensitivity: HSCAA study.
Although sleep disorders are shown to be involved in occurrence of diabetes, impacts of several quantitative parameters related to sleep on insulin secretion and sensitivity is yet to be elucidated. We cross-sectionally examined relationships among quantitative sleep quality, sleep apnea, and autonomic function with insulin secretion and sensitivity in 399 patients without previous diagnosed diabetes who underwent 75-g oral glucose tolerance test (75gOGTT). Poor sleep quality (PSQ) was defined as an activity index ≥50 by actigraphy. Sleep apnea was measured by apnomonitor, while standard deviation of all normal-to-normal R-R intervals (SDNN) was measured by active tracer. Parameters of insulin secretion and sensitivity were measured by 75gOGTT. Patients with PSQ exhibited significantly lower insulinogenic index (r = 0.155, p < 0.01), a parameter of insulin secretion, with the association independent of other clinical factors including apnea and SDNN (β = -0.156, p < 0.01). In contrast, presence of sleep apnea (r = -0.143, p < 0.05) and the lower SDNN (r = -0.150, p < 0.01) were significantly and inversely associated with BIGTT-S, an insulin sensitivity parameter, with the association of SDNN with BIGTT-S remaining significant even after adjustments for PSQ and sleep apnea (β = -0.111, p < 0.05). Poor sleep quality is an independent predictor of pancreatic β-cell function, which could be involved in occurrence of type 2 diabetes.


A novel FLCN gene mutation causing Birt-Hogg-Dubé syndrome in a Korean family.
Spontaneous pneumothorax is a common manifestation of Birt-Hogg-Dubé (BHD) syndrome, an inherited disorder caused by mutation of the folliculin (FLCN) gene. A 44-year-old female with a history of breast cancer was diagnosed with recurrent pneumothorax. Chest CT showed multiple cysts with left lung pneumothorax, and she received surgery for the diagnosis. Because the patient also had a family history of spontaneous pneumothorax, a FLCN genetic examination was conducted. A novel heterozygous, likely pathogenic variant (NM_144997.5:c.779+2T > C) was detected in the proband, her mother, and aunt. This is the first report of a new mutation of FLCN gene in a BHD syndrome patient.


Experimental infection of dusky-footed wood rats (Neotoma fuscipes) with Ehrlichia phagocytophila sensu lato.
Dusky-footed wood rats, Neotoma fuscipes, have been implicated in the natural maintenance of Ehrlichia phagocytophila sensu lato, the agent of human granulocytic ehrlichiosis (HGE), in northern California based on high seroprevalence and amplification of E. phagocytophila s.l. DNA from wood rat blood. In order to further assess granulocytic ehrlichiosis in wood rats, we examined wild-caught wood rats for infection and then performed experimental intra-peritoneal infections with E. phagocytophila s.l. in horse or wood rat blood, and tested animals for 120 days by polymerase chain reaction (PCR) and serology. Of 15 wood rats collected from northern California, three were antibody and PCR-positive for E. phagocytophila s.l. at the time of capture. The naturally infected wood rats remained PCR-positive for a mean of 52 days (+/- 7 SD). Experimental i.p. passage of E. phagocytophila s.l. in wood rat blood was successful in three of four wood rats and the mean duration of PCR-positivity was 75 days (+/- 21.2 SD). Experimental infection with E. phagocytophila s.l. in horse blood succeeded in all four of the recipients and the mean duration of PCR-positivity of 81 days (+/- 17.5 SD). No infected individual appeared to be ill based on feeding behavior, activity, and hydration status. These data confirm that wood rats are susceptible to E. phagocytophila s.l., may develop prolonged infection without clinical ehrlichiosis, and may play a role in maintaining E. phagocytophila s.l. in nature.


Two distinct light regulated G-proteins in octopus photoreceptors.
Two distinct light-regulated G-proteins were found in octopus photoreceptors. Gip, a 41 kDa protein from washed microvilli, was ADP ribosylated by pertussis toxin in the presence of GDP in the dark. Light and GTP analogues were inhibitory as with transducin (Gt; G-protein in vertebrate photoreceptors). G34, a 34 kDa protein from fresh octopus retina, was ADP ribosylated by both cholera and pertussis toxin in the dark. Light inhibited labeling of the 34 kDa protein by both toxins. Unlike Gip, G34 is soluble and is very labile to heat, freezing and thawing. Prolonged incubation of octopus retina with cholera toxin and labeled NAD produced an additional radioactive band at 46 kDa. Labeling of the 46 kDa protein, Gsp, was greatly enhanced by GTP analogues, but inhibited by a GDP analogue as with Gs in hormone-sensitive adenylate cyclase. In contrast to Gip and G34, labeling of the 46 kDa protein (Gsp) was not influenced by light. The two distinct light-regulated G-proteins, Gip and G34, found in octopus photoreceptors might be involved in either phototransduction or photoadaptation. The function of Gsp is not known.


The human cytomegalovirus IE2 86-kilodalton protein interacts with an early gene promoter via site-specific DNA binding and protein-protein associations.
The 86-kDa immediate-early 2 protein (IE2 86) of human cytomegalovirus is a powerful transactivator of homologous and heterologous promoters, including the human cytomegalovirus 1.2-kb RNA early promoter. Two potential mechanisms for gene activation by IE2 86 include interaction with cellular proteins and direct DNA binding. In this report, we show that the 1.2-kb RNA promoter contains a cis-acting AP-1 site, critical for its activation by IE2 86 in vivo, and that IE2 86, purified as a glutathione S-transferase-IE86 fusion protein, can interact with c-Jun and JunB. Additionally, by coimmunoprecipitation, we document that JunB and IE2 86 do associate in vivo. Further in vitro analysis reveals that Fos proteins are able to associate with glutathione S-transferase-IE86 only when present as a Jun-Fos heterodimer. With a set of IE2 86 mutants, we demonstrate that three independent regions of the IE2 86 interact in vitro with c-Jun, two of which are essential for activation of the 1.2-kb RNA promoter in vivo. We also show that IE2 86 can bind directly to this promoter through a sequence located just upstream of the AP-1 site between nucleotides -125 and -97. This discrete domain shares sequence homology with the cis-repression signal on the IE gene.


Trade-offs in the response of mayflies to low oxygen and fish predation.
We examined how mayfly larvae (Ephemeroptera,Callibaetis montanus) balance the conflicting demands of avoiding both benthic hypoxia and fish predators. Using vertical oxygen and temperature gradients typical of ice-covered lakes, we observed the behavior of mayflies in the presence and absence of fish. In the absence of fish and with adequate oxygen, mayflies spent most of the time on the bottom substrate. As benthic oxygen concentration declined, mayflies increased their activity and moved up in the water column. In the presence of fish and with adequate oxygen, mayflies spent even more time associated with the bottom substrate and reduced their activity levels. As benthic oxygen concentrations declined, mayflies increased their activity and moved up in the water column, but to a lesser extent than when fish were absent. Because of this depression in activity and reluctance to leave the bottom substrate, mayflies endured lower oxygen concentrations in the face of predation threat relative to when fish were absent. Despite this trade-off, benthic hypoxia resulted in increased mortality due to fish predation. Because benthic invertebrates vary in their ability to tolerate hypoxia and in their vulnerability to fish predators, periods of benthic hypoxia could lead to selective predation on some taxa and be an important force structuring benthic invertebrate assemblages.


Linking the soil moisture distribution pattern to dynamic processes along slope transects in the Loess Plateau, China.
Soil moisture pulses are a prerequisite for other land surface pulses at various spatiotemporal scales in arid and semi-arid areas. The temporal dynamics and profile variability of soil moisture in relation to land cover combinations were studied along five slopes transect on the Loess Plateau during the rainy season of 2011. Within the 3 months of the growing season coupled with the rainy season, all of the soil moisture was replenished in the area, proving that a type stability exists between different land cover soil moisture levels. Land cover combinations disturbed the trend determined by topography and increased soil moisture variability in space and time. The stability of soil moisture resulting from the dynamic processes could produce stable patterns on the slopes. The relationships between the mean soil moisture and vertical standard deviation (SD) and coefficient of variation (CV) were more complex, largely due to the fact that different land cover types had distinctive vertical patterns of soil moisture. The spatial SD of each layer had a positive correlation and the spatial CV exhibited a negative correlation with the increase in mean soil moisture. The soil moisture stability implies that sampling comparisons in this area can be conducted at different times to accurately compare different land use types.


Enuresis Nocturna in children with asthma: prevalence and associated risk factors.
Enuresis Nocturna (EN) is a common disorders in childhood. Although many different underlying pathophysiological mechanisms have been proposed to explain EN, its etiology is multifactorial. Some reports demonstrate that there is an association between EN and allergic diseases. To study (1) the prevalence of EN in children with asthma, (2) to determine the possible risk factors for EN in asthmatic children. Five hundreds and six children aged 6-14 years-old diagnosed with asthma and 380 age-matched non-asthmatic controls were enrolled into this cross-sectional case-control study. We studied an allergy panel that included skin prick tests with (8 inhalant allergens), total IgE, and blood eosinophil count for both groups. Semi-structured interviews were conducted with the parents of children presenting EN. Factors associated with EN in children with asthma were analyzed using a logistic regression model. The prevalence of EN was significantly higher in children with asthma as compared to the controls: 132 (26 %), 43 (11.5 %) respectively (p = 0.001). Emergency visits frequency, and family history of enuresis were higher in the asthmatic children with EN than in asthmatic children without EN. According to the logistic regression analysis, positive pollen sensitization (p = 0.027, OR = 1.94), allergic rhinitis (p = 0.032, OR = 2.36), and high eosinophil count (p = 0.004, OR = 1.40) were independent risk factors for EN in children with asthma. This study showed that the prevalence of EN in children with asthma was higher than in same age controls. Sensitization to pollens, allergic rhinitis and high blood eosinophil count associate to the EN in children with asthma.


Glucosephosphate isomerase deficiency, a new variant in a Dutch family. Case report.
The clinical course and the biochemical findings are reported from a patient suffering from glucosephosphate isomerase (G.P.I EC 220.127.116.11) deficiency type Nijmegen. This disorder decleares itself as a non-spherocytic hemolytic anemia, presenting in the neonatal period. In the patient hemolysis was of the same degree during the years. However, trivial infections could often trigger an increase in hemolysis requiring treatment by blood transfusions. Enzyme studies revealed that the GPI deficiency in this patient was caused by a double heterozygous state for two different GPI deficient alleles. The presence of one of these deficient alleles in the proband's parents and grandparents, was not accompanied by any sign of hemolysis, as for instance a shortened red-cell survival.


Inferring a tumor progression model for neuroblastoma from genomic data.
The knowledge of the key genomic events that are causal to cancer development and progression not only is invaluable for our understanding of cancer biology but also may have a direct clinical impact. The task of deciphering a model of tumor progression by requiring that it explains (or at least does not contradict) known clinical and molecular evidence can be very demanding, particularly for cancers with complex patterns of clinical and molecular evidence. We formalize the process of model inference and show how a progression model for neuroblastoma (NB) can be inferred from genomic data. The core idea of our method is to translate the model of clonal cancer evolution to mathematical testable rules of inheritance. Seventy-eight NB samples in stages 1, 4S, and 4 were analyzed with array-based comparative genomic hybridization. The pattern of recurrent genomic alterations in NB is strongly stage dependent and it is possible to identify traces of tumor progression in this type of data. A tumor progression model for neuroblastoma is inferred, which is in agreement with clinical evidence, explains part of the heterogeneity of the clinical behavior observed for NB, and is compatible with existing empirical models of NB progression.


Staphylococcus aureus alpha-toxin-induced cell death: predominant necrosis despite apoptotic caspase activation.
Recent data suggest that alpha-toxin, the major hemolysin of Staphylococcus aureus, induces cell death via the classical apoptotic pathway. Here we demonstrate, however, that although zVAD-fmk or overexpression of Bcl-2 completely abrogated caspase activation and internucleosomal DNA fragmentation, they did not significantly affect alpha-toxin-induced death of Jurkat T or MCF-7 breast carcinoma cells. Caspase inhibition had also no effect on alpha-toxin-induced lactate dehydrogenase release and ATP depletion. Furthermore, whereas early assessment of apoptosis induction by CD95 resulted solely in the generation of cells positive for active caspases that were, however, not yet permeable for propidium iodide, a substantial proportion of alpha-toxin-treated cells were positive for both active caspases and PI. Finally, electron microscopy demonstrated that even in the presence of active caspases, alpha-toxin-treated cells displayed a necrotic morphology characterized by cell swelling and cytoplasmic vacuolation. Together, our data suggest that alpha-toxin-induced cell death proceeds even in the presence of activated caspases, at least partially, in a caspase-independent, necrotic-like manner.


From seizures to epilepsy and its substrates: neurocysticercosis.
Neurocysticercosis (NCC) is the main risk factor for late-onset seizures in many Taenia solium endemic countries and is also increasingly recognized in high income countries, where it was once thought to have been eliminated. The course and outcome of NCC-associated seizures and epilepsy are poorly understood. Substrates underlying NCC-associated seizures and epilepsy are unknown. Another unknown is if there is an association between NCC and hippocampal sclerosis (HS) and if it leads to intractable epilepsy. We review evidence regarding the structural basis of seizures and epilepsy in NCC and its association with HS. There are only a limited number of prospective studies of NCC-associated seizures and epilepsy. From these, it can be inferred that the risk of seizure recurrence is high following a first seizure, even though seizures are well-controlled with antiepileptic drugs. The single most important risk factor for ongoing or recurrent seizures is the persistence of either degenerating or residual calcified cysticercus cysts in the brain parenchyma on follow-up imaging studies. Medically intractable epilepsy requiring surgical treatment appears to be rare in people with NCC. In few cases that have been operated, gliosis around the cysticerci is the principal pathologic finding. Reports of the association between NCC and HS might be categorized into those in which the calcified cysticercus is located within the hippocampus and those in which the calcified cysticercus is located remote from the hippocampus. The former are convincing cases of medically intractable epilepsy with good seizure control following hippocampal resection. In the remaining, it is unclear whether a dual pathology relationship exists between HS and the calcified cysticercus. Carefully planned, follow-up studies incorporating high-resolution and quantitative imaging are desirable in order to clarify the outcome, the structural basis of NCC-associated epilepsy, and also its association with HS.


Enhanced dewaterability of sewage sludge in the presence of Fe(II)-activated persulfate oxidation.
The potential benefits of Fe(II)-activated persulfate oxidation on sludge dewatering and its mechanisms were investigated in this study. Capillary suction time (CST) was used to evaluate sludge dewaterability. Both extracellular polymeric substances (EPS) and viscosity were determined in an attempt to explain the observed changes in sludge dewaterability. The optimal conditions to give preferable dewaterability characteristics were found to be persulfate (S(2)O(8)(2-)) 1.2 mmol/gVSS, Fe(II) 1.5 mmol/gVSS, and pH 3.0-8.5, which demonstrated a very high CST reduction efficiency (88.8% reduction within 1 min). It was further observed that both soluble EPS and viscosity played relatively negative roles in sludge dewatering, whereas no correlation was established between sludge dewaterability and bound EPS. Three-dimensional excitation-emission matrix (EEM) fluorescence spectra also revealed that soluble EPS of sludge were degraded and sludge flocs were ruptured by persulfate oxidation, which caused the release of water in the intracellular pace and subsequent improvement of its dewaterability.


Axonal branch patterning and neuronal shape diversity: roles in developmental circuit assembly: Axonal branch patterning and neuronal shape diversity in developmental circuit assembly.
Recent progress in human genetics and single cell sequencing rapidly expands the list of molecular factors that offer important new contributions to our understanding of brain wiring. Yet many new molecular factors are being discovered that have never been studied in the context of neuronal circuit development. This is clearly asking for increased efforts to better understand the developmental mechanisms of circuit assembly [1]. Moreover, recent studies characterizing the developmental causes of some psychiatric diseases show impressive progress in reaching cellular resolution in their analysis. They provide concrete support emphasizing the importance of axonal branching and synapse formation as a hotspot for potential defects. Inspired by these new studies we will discuss progress but also challenges in understanding how neurite branching and neuronal shape diversity itself impacts on specificity of neuronal circuit assembly. We discuss the idea that neuronal shape acquisition itself is a key specificity factor in neuronal circuit assembly.


Plasma renin activity and aldosterone concentration in dogs with acquired portosystemic collaterals.
The renin-angiotensin-aldosterone system (RAAS) is activated in humans with portal hypertension (PH) associated with liver disease. However, involvement of RAAS in dogs with intrahepatic PH is not clear. To measure plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in dogs with PH (chronic hepatitis [CH] and primary hypoplasia of the portal vein [PHPV]), dogs with extrahepatic congenital portosystemic shunt (EH-CPSS), and healthy dogs and to determine whether the RAAS is activated in dogs with PH. Twenty-seven dogs with acquired portosystemic collaterals (APSCs; 15 dogs with CH, 12 dogs with PHPV), 9 dogs with EH-CPSS, and 10 healthy dogs. Retrospective study. Plasma renin activity and PAC were measured by radioimmunoassay. Plasma renin activity was significantly higher in the CH group (median, 4.4 ng/mL/h) than in the EH-CPSS (median, 1.0 ng/mL/h; P < .01) and the healthy (median, 1.1 ng/mL/h; P < .01) groups. No significant differences were found between the PHPV group (median, 2.2 ng/mL/h) and other groups. Plasma aldosterone concentration was significantly higher in the CH (median, 111.0 pg/mL) and PHPV (median, 89.5 pg/mL) groups than in the EH-CPSS (median, 1.0 pg/mL; P < .001, P < .01, respectively) and healthy (median, 14.5 pg/mL; P < .001, P < .05, respectively) groups. Activation of the RAAS contributes to the pathophysiology of intrahepatic PH in dogs, suggesting that spironolactone may not only be effective for the treatment of ascites but also for the suppression of intrahepatic PH.


Identification of H-2Kb binding and immunogenic peptides from human papilloma virus tumour antigens E6 and E7.
Peptides can be used to induce MHC class I restricted cytotoxic T cells (CTL) through in vivo immunization. This approach may enable the development of peptide vaccination schemes for immunization against viral infection in humans. Human papillomavirus (HPV) is one of a few viruses associated with human cancer and the development of an anti-cancer vaccine seems possible. As a model approach, we searched the E6 and E7 proteins of the human papillomavirus type 16 for possible murine MHC class I restricted peptide epitopes. We utilized the mouse H2-Kb peptide binding motif which consists of phenylalanine or tyrosine at position five and leucine at the carboxy-terminus with the modification that leucine could be replaced by other aliphatic but non-aromatic amino acids. Four peptide sequences from E6 and two from E7 were selected. These peptides were tested for their ability to bind and stabilize Kb and for their immunogenicity in vivo. It was shown that one peptide from E6, E6.1 (50-57), bound Kb, but was not able to prime mice in vivo. In contrast, the two selected E7 peptides E7.1 (21-28) and E7.2 (48-55) bound Kb and were immunogenic in vivo. The peptide induced CTL lysed syngeneic EL-4 cells transfected with the open reading frame of E7 but not vector only transfectants. This implies that both peptides were naturally processed and presented by Kb on the surface of target cells. MHC class I peptide binding motifs therefore appear to be an effective and useful tool to predict peptide epitopes of proteins associated with cancer.


Multimedia fate of petroleum hydrocarbons in the soil: oil matrix of constructed biopiles.
A dynamic multimedia fugacity model was used to evaluate the partitioning and fate of petroleum hydrocarbon fractions and aromatic indicator compounds within the soil: oil matrix of three biopiles. Each biopile was characterised by four compartments: air, water, soil solids and non-aqueous phase liquid (NAPL). Equilibrium partitioning in biopile A and B suggested that most fractions resided in the NAPL, with the exception of the aromatic fraction with an equivalent carbon number from 5 to 7 (EC(5-7)). In Biopile C, which had the highest soil organic carbon content (13%), the soil solids were the most important compartment for both light aliphatic fractions (EC(5-6) and EC(6-8)) and aromatic fractions, excluding the EC(16-21) and EC(21-35). Our starting hypothesis was that hydrocarbons do not degrade within the NAPL. This was supported by the agreement between predicted and measured hydrocarbon concentrations in Biopile B when the degradation rate constant in NAPL was set to zero. In all scenarios, biodegradation in soil was predicted as the dominant removal process for all fractions, except for the aliphatic EC(5-6) which was predominantly lost via volatilization. The absence of an explicit NAPL phase in the model yielded a similar prediction of total petroleum hydrocarbon (TPH) behaviour; however the predicted concentrations in the air and water phases were significantly increased with consequent changes in potential mobility. Further comparisons between predictions and measured data, particularly concentrations in the soil mobile phases, are required to ascertain the true value of including an explicit NAPL in models of this kind.


Clustering of lifestyle and health behaviours in Australian adolescents and associations with obesity, self-rated health and quality of life.
The primary aim of this study was to identify clusters of lifestyle and health behaviours and explore their associations with health outcomes in a nationally representative sample of Australian adolescents. The study participants were 3127 adolescents aged 14-15 years who participated in the eighth wave of the birth cohort of the Longitudinal Study of Australian Children (LSAC). A latent class analysis (LCA) was performed to identify clusters based on the behaviours of physical activity, alcohol consumption, smoking, diet, eating disorders, sleep problems and weight consciousness. Multinomial logistic regression models were fitted to the following health outcome variables: obesity, self-rated general health and pediatric health-related quality of life, to investigate their associations with LCA clusters. Based on the prevalence of health behaviour related characteristics, LCA identified gender based distinct clusters of adolescents with certain outward characteristics. There were five clusters for male and four clusters for female participants which are named as: healthy lifestyle, temperate, mixed lifestyle, multiple risk factors, and physically inactive (male only). Adolescents in the healthy lifestyle and temperate clusters reported low and moderately active health risk behaviours, for example, low physical activity, inadequate sleep and so on, while these behaviours were prevailing higher among adolescents of other clusters. Compared to adolescents of healthy lifestyle clusters, male members of physically inactive (OR = 3.87, 95% CI: 1.12 - 13.33) or mixed lifestyle (OR = 5.57, 95% CI: 3.15 - 9.84) clusters were over three to five times more likely to have obesity; while for female adolescents, members of only multiple risk factors clusters (OR = 3.61, 95% CI: 2.00 - 6.51) were over three time more likely to have obesity compared to their counterpart of healthy lifestyle clusters. Adolescents of physically inactive (b = -9.00 for male only), mixed lifestyle (b = -2.77 for male; b = -6.72 for female) or multiple risk factors clusters (b = -6.49 for male; b = -6.59 for female) had a stronger negative association with health-related quality of life scores compared to adolescents of healthy lifestyle clusters. The study offers novel insights into latent class classification through the utilisation of different lifestyles and health-related behaviours of adolescents to identify characteristics of vulnerable groups concerning obesity, general health status and quality of life. This classification strategy may help health policy makers to target vulnerable groups and develop appropriate interventions.


Peptide nanotube/hemin composite with enhanced peroxidase activity for the detection of dopamine in food and drug samples.
Inspired by natural enzymes, artificial enzymes have been widely studied due to their ease of mass production, robustness to harsh environments and high stability. In this work, a peptide nanotube/hemin composite (KL@hemin) as an artificial enzyme was prepared by immobilizing hemin onto self-assembled peptide nanotubes (PNTs). The successful loading of hemin was determined by a series of characterizations. The multiple noncovalent interactions between the PNTs and hemin endow KL@hemin with strong stability. Subsequent enzyme activity tests showed that the prepared KL@hemin exhibited enhanced peroxidase activity. Further experiments indicate that PNTs as carriers can not only protect hemin from dimerization to maintainenzyme activity but also increase the affinity of hemin to the substrate for faster binding and accelerate mass transfer, thus promoting the whole catalytic process. Coupled with a peroxidase-catalyzed chromogenic system, a colorimetric method for dopamine detection was constructed based on KL@hemin. The strategy shows high sensitivity and selectivity and has been applied to the determination of dopamine in dopamine injection and meat samples.


Occurrence and treatment trials of endocrine disrupting chemicals (EDCs) in wastewaters.
This study demonstrates that both synthetic and natural endocrine disrupting chemicals (EDCs) (e.g., bisphenol A, estrone and 17beta-estradiol) were found in the crude wastewaters from two wastewater treatment works (WwTWs). Conventional biological processes can lower EDCs concentrations to several tens to hundreds ngl(-1). Since natural EDCs (e.g., estrone and 17beta-estradiol) have biological activity and adverse impact on the environment at extremely low concentrations (several tens of ngl(-1)), further treatment after conventional biological processes is required. Preliminary trials with ferrate(VI) and electrochemical oxidation process demonstrated that both processes can effectively reduce EDCs to very low levels, ranging between 10 and 100ngl(-1), but the former is more effective than the latter to reduce COD concentration in wastewater for given studying conditions.


Ultrahigh Supramolecular Cascaded Room-Temperature Phosphorescence Capturing System.
An ultrahigh supramolecular cascaded phosphorescence-capturing aggregate was constructed by multivalent co-assembly of cucurbit[7]uril (CB[7]) and amphipathic sulfonatocalix[4]arene (SC4AD). The initial dibromophthalimide derivative (G) generated a weak phosphorescent emission at 505 nm by host-guest interaction with CB[7], which further assembled with SC4AD to form homogeneously spherical nanoparticles with a dramatic enhancement of both phosphorescence lifetime to 1.13 ms and emission intensity by 40-fold. Notably, this G⊂CB[7]@SC4AD aggregate exhibited efficient phosphorescence energy transfer to Rhodamine B (RhB) and benzothiadiazole (DBT) with high efficiency (ϕET ) of 84.4 % and 76.3 % and an antenna effect (AE) of 289.4 and 119.5, respectively, and then each of these can function as a bridge to further transfer their energy to second near-IR acceptors Cy5 or Nile blue (NiB) to achieve cascaded phosphorescence energy transfer. The final aggregate with long-range effect from 425 nm to 800 nm and long-lived photoluminescence was further employed as an imaging agent for multicolour cell labeling.


Association of trajectories of cognitive function with cause-specific mortality and medical and long-term care costs.
Cognitive decline increases mortality risk through dementia-related pathways and might be associated with increased healthcare costs. Using up to 12 years of repeated measures data, we identified trajectories in cognitive function among community-dwelling older Japanese adults. We then examined whether these trajectories were associated with all-cause and cause-specific mortality, and differences in healthcare costs. A total of 1736 adults aged ≥65 years who were free of disabling dementia completed annual assessments during 2002-2014. Cognitive function was assessed with the Mini-Mental State Examination. The average number of follow-up assessments was 3.9, and the total number of observations was 6824 during the follow-up period. We identified five trajectory patterns in cognitive function (high, second, third, fourth, and low) during the 12-year follow-up period. The low (2.0%) and fourth (2.2%) trajectory groups had higher hazard ratios for cardiovascular disease mortality, and hazard ratios for other cause mortality were significantly higher for the third (16.8%) and second (38.8%) trajectory groups than for the high trajectory group (40.3%). Until 5 years of follow up, participants in the two lower-trajectory groups had higher mean combined monthly medical and long-term care costs. After 8 years of follow up, mean costs were highest for the third trajectory. The risk of death from cardiovascular disease was higher in the two lower-trajectory groups in cognitive function, and they showed higher healthcare costs during the first 5 years of follow up. After 8 years of follow up, the third trajectory had the highest healthcare costs, perhaps because of hospitalizations attributable to gradual cognitive decline. Geriatr Gerontol Int 2019; 19: 1236-1242.


Effect of temperature on blood flow and metabolism in a neurovascular island skin flap.
Using the buttock flap in 29 white Yorkshire pigs, blood flow and O2 consumption were measured at dermal temperatures between 35 degrees C and 15 degrees C. Flow was measured with an electromagnetic flowmeter and O2 consumption was calculated as the product of blood flow and the difference in flap A-VO2. Baseline flow was 6.6 +/- .9 (SE) ml/100 g/min at 35 degrees C and 3.1 +/- .02 (SE) ml/10 g/min at 15 degrees C. Blood flow through the flap stopped completely at a dermal temperature of 14 degrees C. Oxygen consumption was 0.16 +/- .02 (SE) ml/100 g/min at 35 degrees C and 0.04 +/- 0.01 (SE) ml/100 g/min at 15 degrees C. At 20 degrees C blood flow was 4.3 ml/100 g/min and metabolism was .04 ml/100 g/min. In other words, blood flow was 65% of baseline, while O2 consumption was only 25% of baseline. The therapeutic effect of local cooling at 20 degrees C deserves further investigation. The cessation of flow at 14 degrees C may be caused by increased plasma viscosity.


Study on the relationship between the incidence of influenza and climate indicators and the prediction of influenza incidence.
In recent 2 years, the incidence of influenza showed a slight upward trend in Guangxi; therefore, some joint actions should be done to help preventing and controlling this disease. The factors analysis of affecting influenza and early prediction of influenza incidence may help policy-making so as to take effective measures to prevent and control influenza. In this study, we used the cross correlation function (CCF) to analyze the effect of climate indicators on influenza incidence, ARIMA and ARIMAX (autoregressive integrated moving average model with exogenous input variables) model methods to do predictive analysis of influenza incidence. The results of CCF analysis showed that climate indicators (PM2.5, PM10, SO2, CO, NO2, O3, average temperature, maximum temperature, minimum temperature, average relative humidity, and sunshine duration) had significant effects on the incidence of influenza. People need to take good precautions in the days of severe air pollution and keep warm in cold weather to prevent influenza. We found that the ARIMAX (1,0,1)(0,0,1)12 with NO2 model has good predictive performance, which can be used to predict the influenza incidence in Guangxi, and the predicted incidence may be useful in developing early warning systems and providing important evidence for influenza control policy-making and public health intervention.


Folate Functionalized and Evodiamine-Loaded Pluronic Nanomicelles for Augmented Cervical Cancer Cell Killing.
Evodiamine (Evo) is a natural, biologically active plant alkaloid with wide range of pharmacological activities. In the present study Evo-loaded folate-conjugated Pluronic F108 nano-micelles (ENM) is synthesized to enhance the therapeutic efficacy of Evo against cervical cancer. ENM are synthesized, physicochemically characterized and in vitro anticancer activity is performed. The study demonstrates that ENM have nanoscale size (50.33 ± 3.09 nm), monodispersity of 0.122 ± 0.072, with high drug encapsulation efficiency (71.30 ± 3.76%) and controlled drug release at the tumor microenvironment. ENM showed dose-dependent and time-dependent cytotoxicity against HeLa human cervical cancer cells. The results of in vitro anticancer studies demonstrated that ENM have significant anticancer effects and greatly induce apoptosis as compared to pure Evo. The cellular uptake study suggests that increased anticancer activity of ENM is due to the improved intracellular delivery of Evo through overexpressed folate receptors. Overall, the designed ENM can be a potential targeted delivery system for hydrophobic anticancer bioactive compound like Evo.


Prevalence, clinical presentations and impact on relationship of sexual dysfunction in Parkinson's Disease
Sexual dysfunction is one of the commonest non-motor symptoms in Parkinson's disease (PD) and has been found about twice as high in PD patients compared to age-matched controls. The quality of sexual life is reduced in PD patients compared to healthy peers and impairment affects wide aspects of physical sexual function as well as sexual desire, sexual satisfaction and sexual partnership. Overall, male PD patients are more frequently affected by sexual disorders than females and seem to suffer more from sexual impairment. The reported frequencies and presentations of various sexual dysfunctions vary widely in the literature, which is likely related to the patient cohorts examined, in particular with regard to age and gender, duration and severity of disease and applied measurement instruments. This chapter gives an overview of the prevalence, phenotype and clinical presentation of sexual dysfunction in PD and its influence on the partnership.


Highly sensitive determination of methotrexate at poly (l-lysine) modified electrode in the presence of sodium dodecyl benzene sulfonate.
A simple and sensitive electrochemical sensor based on poly (l-lysine) modified glassy carbon electrode (PLL/GCE) was developed to sensitively detect methotrexate (MTX) in the presence of sodium dodecyl benzene sulfonate (SDBS). Fourier transform infrared spectroscopy, electrochemical impedance spectroscopy and cyclic voltammetry were carried out to characterize PLL film which exhibits excellent electrocatalytic activity toward the oxidation of MTX in 0.1M phosphate buffer solution. In addition, the oxidation peak of MTX remained stable at PLL/GCE in the presence of SDBS and its current increased 8 times compared with that at bare GCE without SDBS. Experimental parameters were optimized with regard to pH, electro-polymerization segment, accumulation time and concentration of SDBS. Under optimum conditions, the square wave voltammograms exhibited that the oxidation peak current was linearly proportional to the concentration of MTX in the range of 5nM - 0.2μM with detection limit of 1.7 (±0.06) nM (S/N=3). Moreover, this method was applied to detect MTX in medicinal tablets with satisfying results.


Creating stable trapping force and switchable optical torque with tunable phase of light.
Light-induced rotation of microscopic objects is of general interest as the objects may serve as micromotors. Such rotation can be driven by the angular momentum of light or recoil forces arising from special light-matter interactions. However, in the absence of intensity gradient, simultaneously controlling the position and switching the rotation direction is challenging. Here, we report stable optical trapping and switchable optical rotation of nanoparticle (NP)-assembled micromotors with programmed phase of light. We imprint customized phase gradients into a circularly polarized flat-top (i.e., no intensity gradient) laser beam to trap and assemble metal NPs into reconfigurable clusters. Modulating the phase gradients allows direction-switchable and magnitude-tunable optical torque in the same cluster under fixed laser wavelength and handedness. This work provides a valuable method to achieve reversible optical torque in micro/nanomotors, and new insights for optical trapping and manipulation using the phase gradient of a spatially extended light field.


Fluorescence detection of adenosine triphosphate through an aptamer-molecular beacon multiple probe.
An aptamer-molecular beacon (MB) multiple fluorescent probe for adenosine triphosphate (ATP) assay is proposed in this article. The ATP aptamer was used as a molecular recognition part, and an oligonucleotide (short strand, SS) partially complementary with the aptamer and an MB was used as the other part. In the presence of ATP, the aptamer bound with it, accompanied by the hybridization of MB and SS and the fluorescence recovering. Wherever there is only very weak fluorescence can be measured in the absence of ATP. Based on the relationship of recovering fluorescence and the concentration of ATP, a method for quantifying ATP has been developed. The fluorescence intensity was proportional to the concentration of ATP in the range of 10 to 500 nM with a detection limit of 0.1 nM. Moreover, this method was able to detect ATP with high selectivity in the presence of guanosine triphosphate (GTP), cytidine triphosphate (CTP), and uridine triphosphate (UTP). This method is proved to be simple with high sensitivity, selectivity, and specificity.


Combination of surgical excision and carbon dioxide laser vaporization for multifocal vulvar intraepithelial neoplasia.
Ten patients with multifocal grade 3 vulvar intraepithelial neoplasia were treated by a combination of surgical excision and carbon dioxide laser vaporization of selected areas. The lesions treated by the laser were either on the clitoris or distal to the vulva. These areas could be functionally and anatomically deformed if surgically excised. Combining the carbon dioxide laser with surgery, however, resulted in a satisfactory cosmetic outcome and provided an adequate specimen for histopathologic diagnosis.


Thresholds in fMRI studies: reliable for single subjects?
Many studies have investigated test-retest reliability of active voxel classification for fMRI, which is increasingly important for emerging clinical applications. The implicit impact of voxel-wise thresholding on this type of reliability has previously been under-appreciated. This has had two detrimental effects: (1) reliability studies use different fixed thresholds, making comparison of results is challenging; (2) typical studies do not assess reliability at the individual level, which could provide information for selecting activation thresholds. To show the limitations of traditional fixed-threshold approaches, we investigated the threshold dependence of fMRI reliability measures, with the goal of developing an automated threshold selection routine. For this purpose, we demonstrated threshold dependence of both novel (ROC-reliability or ROC-r) and established (Rombouts overlap or RR) reliability measures. Both methods rely minimally on statistical assumptions, and provide a data-driven summary of the threshold-reliability relationship. We applied these methods to data from eight subjects performing a simple finger tapping task across repeated fMRI sessions. We showed that the reliability measures varied dramatically with threshold. This variation depended strongly on the individual tested. Finally, we demonstrated novel procedures using ROC-r and overlap analysis to optimize thresholds on a case-by-case basis. Ultimately, a method to determine robust individual-level activation maps represents a critical advance for fMRI as a diagnostic tool.


Renal artery stenting may not be appropriate for patients with atherosclerotic renal artery stenosis.
This study compared aortorenal bypass to renal artery stenting to determine the most efficacious and financially sound method for treating patients with atherosclerotic renal artery stenosis (RAS). A decision analysis using direct and indirect costs, and value of statistical life (VSL) was completed. Direct costs were obtained using the Nationwide Inpatient Sample (NIS), indirect costs from the National Institute of Diabetes and Digestive and Kidney Diseases, and VSL from the Department of Transportation. A variance-based sensitivity analysis was completed to assess the accuracy of the decision analysis. Aortorenal bypass has a 95% five-year patency, a 98% 30-day survival, a 26% rate of overall complications, and a 70% five-year dialysis-free survival. Renal artery stenting has a 56% five-year patency, a 99% 30-day survival, a 40% rate of complications, and a 65% five-year dialysis-free survival. Renal artery stenting has an overall cost of $305,370 and aortorenal bypass has an overall cost of $103,453 per patient. After accounting for VSL, renal artery stenting has a negative value of -$182,270 and aortorenal bypass has a value of $415,881. Lower five-year patency and higher rate of complications from renal artery stenting that ultimately lead to significantly lower five-year dialysis-free survival.


Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer.
To determine whether genetically predicted circulating levels of cytokines are associated with risk of overall breast cancer (BC), estrogen receptor (ER)-positive and ER-negative BC, we conducted two-sample MR analyses using data from the most comprehensive genome-wide association studies (GWAS) on cytokines in 8293 Finnish participants and the largest BC GWAS from the Breast Cancer Association Consortium (BCAC) with totally 122,977 BC cases and 105,974 healthy controls. We systematically screened 41 cytokines (of which 24 cytokines have available instruments) and identified that genetically predicted circulating levels (1-SD increase) of MCP1 (OR: 1.08; 95% CIs: 1.03-1.12; P value: 3.55 × 10-4), MIP1b (OR: 1.02; 95% CIs: 1.01-1.04; P value: 2.70 × 10-3) and IL13 (OR: 1.06; 95% CIs: 1.03-1.10; P value: 3.33 × 10-4) were significantly associated with increased risk of overall BC, as well as ER-positive BC. In addition, higher levels of MIP1b and IL13 were also significantly associated with increased risk of ER-negative BC. These findings suggest the crucial role of cytokines in BC carcinogenesis and potential of targeting specific inflammatory cytokines for BC prevention.


Brain tumor detection and screening using artificial intelligence techniques: Current trends and future perspectives.
A brain tumor is an abnormal mass of tissue located inside the skull. In addition to putting pressure on the healthy parts of the brain, it can lead to significant health problems. Depending on the region of the brain tumor, it can cause a wide range of health issues. As malignant brain tumors grow rapidly, the mortality rate of individuals with this cancer can increase substantially with each passing week. Hence it is vital to detect these tumors early so that preventive measures can be taken at the initial stages. Computer-aided diagnostic (CAD) systems, in coordination with artificial intelligence (AI) techniques, have a vital role in the early detection of this disorder. In this review, we studied 124 research articles published from 2000 to 2022. Here, the challenges faced by CAD systems based on different modalities are highlighted along with the current requirements of this domain and future prospects in this area of research.


In situ functionalization of HPLC monolithic columns based on divinylbenzene-styrene-4-vinylbenzyl chloride.
The properties of chromatographic columns are largely determined by functional groups located on the sorbent surface. For monolithic columns, surface functional groups can be created during synthesis stage or by chemical bonding with the complete surface of the sorbent. One of sorbent modification approach is to use on-column click reactions with surface reactive groups. In this study, the surface treatment of monolithic sorbent based on divinylbenzene (DVB), styrene (St) and 4-vinylbenzyl chloride (4VBC) copolymer by heterocyclic nitrogen-containing compounds 1-methylimidazole (1MI), 2-methylimidazole (2MI), 2-methylpyridine (2 MP) and 4-methylpyridine (4 MP) is described. The reaction of nitrogen-containing heterocycles with chloromethyl fragments on the surface results in formation of ion pairs and significantly changes the selectivity of monolithic columns. The chromatographic properties of prepared columns are studied. Modified columns can be operated in reversed-phase (RP) chromatography or in hydrophilic interaction liquid chromatography (HILIC) with different composition of the mobile phase. Separation examples of various chemical substances classes are given.


A quantitative review of self-help research with the severely and profoundly mentally retarded.
Eighty-seven studies published since 1964 through 1982 on training self-help skills to severely and profoundly mentally retarded persons were analyzed according to 19 parameters reflecting their methodological details. The results showed a steady interest in this research area over time, but 63% of the studies focused on toileting and feeding with fewer studies looking at other self-help skills. Package treatments composed primarily of accelerative techniques were most frequently used to train these skills. Methodologically, it was found that these studies typically involved profoundly mentally retarded people (33% of studies) who were trained by residential staff (69% of studies) in institutional settings (63% of studies). The results also indicated an increase over time in the number of studies rated acceptable on the reliability and design parameters. Finally, very few studies reported assessments of generalization, maintenance, or social validity. It was concluded that, (a) researchers need to broaden their interests in terms of settings, trainers, and behaviors studied to best meet the needs of this population, (b) the experimental quality of this literature is improving, and (c) the social impact of observed behavior changes has yet to be fully explored.


Development of a validated quality of life tool specific to children with bladder dysfunction.
To date there have not been any generic or continence-specific measurement tools that allow clinicians to investigate quality of life in children with bladder dysfunction. The aim of this research was to create a cross-cultural tool to assess and measure the wider psychosocial impact of current and new interventions for bladder dysfunction in children. The study was conducted in three parts: expert consultation with continence clinicians; design and administration of a child-completed international questionnaire; item analysis, validity and reliability testing, and design of a new tool. The need for a pediatric incontinence QoL measure evaluation was strongly endorsed by clinicians. Data from 156 child-completed questionnaires collected in 10 countries was analyzed for item characteristics and found to be free of item correlation and ceiling and floor effects. Factor analysis revealed 2 factors, which were labeled intrinsic and extrinsic. Rasch analyses showed the internal validity of both subscales was reasonable good. Cronbach's alpha for each factor was 0.91 and 0.72. After analysis, items were selected for the new tool, PinQ, and evaluated for ambiguity, clarity, comprehension level required, choice of words and phrases, and age-appropriate concepts. Twenty-one items were finally selected and randomly positioned within the tool. A cross-cultural tool that quantifies the holistic effect of bladder dysfunction in children has been designed and tested for validity.


Des-acyl ghrelin fragments evoke endothelium-dependent vasodilatation of rat mesenteric vascular bed via activation of potassium channels.
The mechanisms that subserve ghrelin-evoked vasodilatation have not been elucidated in previous studies. Changes in perfusion pressure evoked by ghrelin and its N-terminal fragments were examined ex vivo in phenylephrine-constricted perfused mesenteric vascular beds of male Sprague Dawley rats maintained at a constant flow rate. Both ghrelin (maximum effect [E(max)] 45%) and des-acyl ghrelin (E(max) 43%) evoked vasodilatation at concentrations between 10 pM and 1 nM, compared to acetylcholine (median effective concentration [EC(50)] 3 nM; E(max) 93%). Those responses were abolished in endothelium-denuded preparations, and in endothelium-intact preparations exposed to either calcium-activated potassium channel, or a depolarizing stimulus, or in the presence of a combination of either apamin and 1,2-chlorophenyl diphenylmethyl-1 H-pyrazole (triarylmethane-34 [TRAM-34]), or ouabain and barium. ATP-activated potassium channel blockade, or a combination of nitric oxide synthase and cyclooxygenase inhibition had no effect. The classical growth hormone secretagogue antagonist, [d-Lys(3)]-growth hormone-releasing peptide (10 nM), or several N-terminal fragments of des-acyl ghrelin, including the tripeptide glycine-serine-serine (G-S-S [1 nM]), showed endothelium-dependent vasodilatation like des-acyl ghrelin, while responses to glycine-serine or serine-serine were relatively lower. A higher concentration (100 muM) of l-serine, but not glycine, evoked vasodilatation of similar magnitude. The serine dense N-terminal sequence of des-acyl ghrelin mediates endothelium-dependent vasodilatation via activation of apamin+TRAM-34 sensitive small- and intermediate-conductance calcium-activated potassium channels present on the mesenteric endothelium. Thus, the vasodilator response to ghrelins in the perfused rat mesenteric vascular bed is not mediated by the classical growth hormone secretagogue receptor type 1a.


Experimental study on multidisciplinary treatment of pancreatic cancer.
We investigated the antitumor effects of intratumoral (IT) injection of mitomycin-C (MMC), 5-fluorouracil (5FU), adriamycin (ADR), cisplatin (CDDP), streptozotocin (STZ), and interleukin-2 (IL-2) on well-differentiated pancreatic ductal adenocarcinoma (WD PaCa), a solid tumor model in the Syrian golden hamster. The growth of established palpable WD PaCa was not suppressed by intraperitoneal (IP) injection of these anticancer agents, whereas IT injection of MMC (1.0 mg/kg or more), 5FU (12.5 mg/kg or more), and CDDP (2.5 mg/kg or more) caused significant and marked suppression. The growth of established palpable WD PaCa was transiently suppressed by 50 Gy of local irradiation. The antitumor effect of irradiation was not enhanced by it injection of MMC before irradiation, whereas it was significantly enhanced by it injection after irradiation. Intraperitoneal injection of IL-2 (5 or 10 micrograms/d, 18 d) slightly suppressed the growth of established palpable tumors, but it injection of IL-2 caused significant and marked suppression, eliminating the tumor in 10-20% of the animals. Findings in this animal model of pancreatic cancer suggest that it treatment of anticancer agents or IL-2 might become an effective therapy for advanced pancreatic cancer.


Disruption of the mouse Shmt2 gene confers embryonic anaemia via foetal liver-specific metabolomic disorders.
In a previous study, we proposed that age-related mitochondrial respiration defects observed in elderly subjects are partially due to age-associated downregulation of nuclear-encoded genes, including serine hydroxymethyltransferase 2 (SHMT2), which is involved in mitochondrial one-carbon (1C) metabolism. This assertion is supported by evidence that the disruption of mouse Shmt2 induces mitochondrial respiration defects in mouse embryonic fibroblasts generated from Shmt2-knockout E13.5 embryos experiencing anaemia and lethality. Here, we elucidated the potential mechanisms by which the disruption of this gene induces mitochondrial respiration defects and embryonic anaemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. Metabolomic profiling revealed that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation. Given that foetal livers function to produce erythroblasts in mouse embryos, growth retardation in foetal livers directly induced depletion of erythroblasts. By contrast, mitochondrial respiration defects in foetal livers also induced depletion of erythroblasts as a consequence of the inhibition of erythroblast differentiation, resulting in the manifestation of anaemia in Shmt2-knockout E13.5 embryos.