Comparing the permeability of human and porcine small intestinal mucus for particle transport studies.
The gastrointestinal mucus layer represents the last barrier between ingested food or orally administered pharmaceuticals and the mucosal epithelium. This complex gel structure plays an important role in the process of small intestinal absorption. It provides protection against hazardous particles such as bacteria but allows the passage of nutrients and drug molecules towards the intestinal epithelium. In scientific research, mucus from animal sources is usually used to simulate difficult-to-obtain human small intestinal mucus for investigating the intramucus transport of drug delivery systems or food nanoparticles. However, there is a lack of evidence the human mucus can be reliably substituted by animal counterparts for human-relevant transport models. In this report, a procedure for collecting human mucus has been described. More importantly, the permeability characteristics of human and porcine small intestinal mucus secretions to sub-micron sized particles have been compared under simulated intestinal conditions. Negatively charged, 500 nm latex beads were used in multiple-particle tracking experiments to examine the heterogeneity and penetrability of mucus from different sources. Diffusion of the probe particles in adult human ileal mucus and adult pig jejunal and ileal mucus revealed no significant differences in microstructural organisation or microviscosity between the three mucus types (P > 0.05). In contrast to this interspecies similarity, the intraspecies comparison of particle diffusivity in the mucus obtained from adult pigs vs. 2-week old piglets showed better penetrability of the piglet mucus. The mean Stokes-Einstein viscosity of the piglet jejunal mucus was approx. two times lower than the viscosity of the pig jejunal mucus (P < 0.05). All mucus structures were also visualised by scanning electron microscopy. This work validates the use of porcine small intestinal mucus collected from fully-grown pigs for studying colloidal transport of sub-micron sized particles in mucus under conditions mimicking the adult human small intestinal environment.


The association between a novel inflammatory biomarker, systemic inflammatory response index and the risk of diabetic cardiovascular complications.
Systemic inflammatory response index (SIRI) is a novel inflammatory biomarker. The relationship between SIRI and the risk of diabetic cardiovascular complications is still unclear. The purpose of our study was to address the correlation between SIRI and the risk of cardiovascular diseases (CVD) in diabetes mellitus (DM) patients. A total of 8759 individuals were selected from the National Health and Nutrition Examination Survey (NHANES) (2015-2020) in our study. Comparing with control (n = 6446) and pre-DM (n = 350) individuals, the DM patients (n = 1963) show the higher SIRI level (all P < 0.001) and prevalence of CVD (all P < 0.001). Furthermore, in a fully adjusted model, we observed the increase of tertiles of SIRI was a risk factor for CVD in DM patients (the middle tertile: 1.80, 95% CI: 1.13-3.13; the highest tertile: 1.91, 95% CI: 1.03-3.22; all P < 0.05), while the relationship between hypersensitive CRP (hs-CRP) and the risk of diabetic cardiovascular complications was not observed (all P > 0.05). Furthermore, the SIRI tertiles-CVD association was significant strongly in patients with high body mass index (BMI; >24 kg/m2) than in those with a low BMI (≤24 kg/m2, P for interaction = 0.045). Using restricted cubic splines, we observed a dose-response relation between lg SIRI and the risk of CVD in DM patients. The elevated SIRI was independently associated with the increased risk of CVD in the DM population with a high BMI (>24 kg/m2), and its clinical value is greater than hs-CRP.


Disruption of thymidylate synthesis and glycine-serine interconversion by L-methionine and L-homocystine in Raji cells.
Excessive concentrations of L-methionine inhibited the folate-dependent de novo synthesis of thymidylic acid (TMP) in Raji cells, demonstrating the usefulness of this cell line for the study of methionine-folate antagonism. The effect was also produced by L-homocystine but not by other amino acids including D-methionine and L-ethionine, suggesting that this effect is exerted by a common intermediate of methionine and homocystine metabolism. L-Methionine, L-homocysteine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) are not inhibitors of thymidylate synthase activity. On the other hand the capacity of the cells to incorporate serine 3-carbon and glycine 2-carbon into DNA is impaired by the presence of L-methionine or L-homocystine. Studies with cell-free extracts demonstrated that the glycine cleavage enzyme is inhibited by 45% by L-methionine, L-homocysteine, SAM or SAH. Serine hydroxymethylase on the other hand was slightly stimulated by these sulfur-containing compounds and this stimulation was shown to occur in the intact cell as well. These findings suggest that when levels of L-methionine metabolites are elevated, there is an increase in the use of glycine to maintain the intracellular concentration of serine, which is required for homocysteine detoxification by conversion to cystathionine. The reduction in TMP synthesis caused by excess L-methionine or L-homocystine may result from increased utilization of one-carbon units for serine synthesis.


Ten-year trends in surgical management of 1207 congenital scoliosis.
To report and analyze development trends in the surgical treatment of congenital scoliosis (CS) in a large CS cohort over a 10-year period. We retrospectively searched and extracted medical records of CS inpatients receiving posterior instrumented fusion surgery at our institute from January 2010 to December 2019. We analyzed information on demographics and surgical information, including the surgical approach, number of fused segments, use of osteotomy and titanium cage implantation, length of stay, intraoperative blood loss, and rates of complications and readmission. 1207 CS inpatients were included. In the past decade, the proportion of patients younger than 5 years increased from 15.5 to 26.9%. The average number of fused segments decreased from 9.24 to 7.48, and the proportion of patients treated with short-segment fusion increased from 13.4 to 30.3%. The proportion of patients treated with osteotomy and titanium cage implantation increased from 55.65% and 12.03% to 76.5% and 40.22%. The average length of stay and blood loss decreased from 16.5 days and 816.1 ml to 13.5 days and 501.7 ml. The complication and readmission rates also decreased during these ten years. During this ten-year period, the surgical treatment of CS at our institute showed trends toward a younger age at fusion, lower number of fused segments, higher rate of osteotomy and titanium cage implantation, reduced blood loss, shorter length of stay and lower rate complications and readmission. These results suggest performing osteotomy combined with titanium cage implantation at an earlier age can achieve fewer fused segments and complications.


Is Naegleria fowleri an Emerging Parasite?
Naegleria fowleri causes an uncommon but deadly disease called primary amoebic meningoencephalitis (PAM). There has been an increase of reported PAM cases, particularly since 2000. Although water is the dominant route of transmission of PAM, infection through soil/dust is a possible alternative route. We have observed differences in epidemiology between the southern states in the USA and the Indian subcontinent (ISC). The patient age range is greater in the ISC than in the USA, and there are more infections in the ISC which are not water-associated. We show that PAM is under-reported and argue that climate change will increase the incidence of PAM, and that the geographic range of N. fowleri will spread polewards.


Plasma alpha 1B-glycoprotein allele frequencies in Finns and Swedish Lapps: evidence for a new alpha 1B allele.
A new allele (A1B*5) of human plasma alpha 1B-glycoprotein (alpha 1B) was reported. alpha 1B phenotyping was done by two-dimensional agarose gel (pH 5.4)-horizontal polyacrylamide gel (pH 9.0) electrophoresis followed by protein staining. The alpha 1B phenotypes 1-1, 1-2, 1-5 and 2-2 were observed in Finns and phenotypes 1-1, 1-2, 1-5 and 2-5 in Swedish Lapps. The respective frequencies of A1B*1, A1B*2 and A1B*5 were 0.9575, 0.0350, 0.0075 in Finns and 0.8922, 0.0653, 0.0425 in Swedish Lapps. The Swedish Lapps showed a higher degree of alpha 1B polymorphism (polymorphism information content = 0.19) than other Caucasian populations that have been studied.


Native nephrectomy in advanced pediatric kidney disease: indications, timing, and surgical approaches.
In pediatric kidney failure, native kidneys may pose a risk to successful transplant outcomes. The indications and timing of native nephrectomy represent a controversial management decision. A lack of high-quality, outcomes-based data has prevented development of evidence-based guidelines for intervention. In this article, we review the published literature on medical indications for native nephrectomy and current knowledge gaps. In addition, we provide a surgical perspective regarding timing and approach.


Occupational Challenges in Physicians with Substance Use Disorder: A Qualitative Study.
Substance use disorders (SUDs) in physicians impact their professional responsibilities toward patients. Understanding the difficulties of physicians with SUDs would facilitate early identification and reduce the complications they face in various domains, particularly in settings where there are no physician-health care programs. In this background, we aimed to understand the challenges physicians with SUDs face at their workplace. Qualitative in-depth interviews of 21 physicians receiving treatment from a tertiary care addiction medicine center for their SUD were conducted and, based on the transcripts from the interview after coding and recoding, through inductive content analysis, themes and subthemes were identified. The following occupational challenges were identified: direct consequences of the psychoactive effect of the substance, adverse effects on clinical care and service delivery, impairment in regularity and punctuality, changes in the physicians' behaviors, changes in the work environment and diverse responses of colleagues and the hospital administration toward substance use-related actions, ethical issues at workplace, and effects on career growth. SUDs in physicians have a significant impact on their functioning at work, affecting patient care, interpersonal relationships as well as career growth. Knowledge of occupational challenges among physicians with SUD will help us in understanding the severity of the problem.


PbS Colloidal Quantum Dot Inks for Infrared Solar Cells.
Infrared PbS colloidal quantum dot (CQD)-based materials receive significant attention because of its unique properties. The PbS CQD ink that originates from ligand exchange of CQDs is highly potential for efficient and stable infrared CQD solar cells (CQDSCs) using low-temperature solution-phase processing. In this review, we present a comprehensive overview of CQD inks for the development of efficient infrared solar cells, which can effectively harvest the photons from the infrared wavelength region of the solar spectrum, including the importance of infrared absorbers for solar cells, the unique properties of CQDs, ligand-exchange determined CQD inks, and related photovoltaic performance of CQDSCs. Finally, we present a brief conclusion, and the possible challenges and opportunities of the CQD inks are discussed in-depth to further develop highly efficient and stable infrared solar cells.


Tract recurrence of a follicular thyroid neoplasm following transaxillary endoscopic thyroidectomy.
Endoscopic thyroidectomy is gaining popularity, particularly in Asian countries, as an alternative to conventional cervical thyroidectomy. Multiple large case series have been published that confirm the feasibility and safety of this procedure compared to conventional methods. However, no data are available that demonstrate long-term oncologic outcomes or complications. A patient who underwent transaxillary gas insufflation thyroidectomy for a follicular neoplasm presented to the authors with a mass along the operative tract 31 months after her first surgery. The mass was found to be a recurrence of the thyroid neoplasm. Since this is a relatively new procedure, the potential complications differ from those of conventional cervical thyroidectomy. Further studies are needed to determine size limitations on nodules considered for endoscopic resection. When performing these procedures, care should be taken to ensure that the specimen is removed entirely and in one piece. Long-term outcomes data for endoscopic thyroidectomy are warranted prior to this becoming an acceptable standard of care for thyroid surgery.


Cervical Cancer and Human Papillomavirus Vaccine Awareness Among Married Bhutanese Refugee and Nepali Women in Eastern Nepal.
This study examined the sexually transmitted infections (STIs), cervical cancer, and human papillomavirus virus (HPV) vaccine-related awareness and knowledge among married Bhutanese refugee and Nepali women living in eastern Nepal. Participants were recruited from a women's health camp in Jhapa District in eastern Nepal. A demographic and health survey with questions on STIs, cervical cancer and HPV vaccine was administered to consenting participants. Women who were born in Bhutan or living in the United Nations administered refugee camps were classified as Bhutanese. Of the 630 participants, 14.3% of participants were Bhutanese and the mean age was 38.8 ± 8.2 years. A higher proportion of Bhutanese than Nepali women reported a lack of cervical cancer awareness (42.0% vs. 30.7%; p = 0.036). Only 21.5% of the participants knew HPV as the cause of cervical cancer; 13.9% were aware of an HPV vaccine; and 96% reported that they would have their children vaccinated against HPV if the vaccine was available free of cost to them. In multivariable analyses, the lack of awareness about STIs was directly associated with the lack of cervical cancer awareness [odds ratio (OR) 4.50; 95% confidence interval (CI) 2.99-6.77] and inversely associated with HPV-vaccine awareness [OR 0.53; 95% CI 0.29-0.97]. Low cervical cancer and HPV vaccine awareness and knowledge among Nepali and Bhutanese women in eastern Nepal highlight the need for increasing awareness and knowledge in the context of STIs and reproductive health education. Increasing awareness and knowledge of HPV, its role in cervical cancer, and prevention modalities is a first critical step for implementing successful targeted primary cervical cancer prevention measures focused on behavior modification and vaccine administration.


Ability of the Masimo pulse CO-Oximeter to detect changes in hemoglobin.
The decision to administer blood products is complex and multifactorial. Accurate assessment of the concentration of hemoglobin [Hgb] is a key component of this evaluation. Recently a noninvasive method of continuously measuring hemoglobin (SpHb) has become available with multi-wavelength Pulse CO-Oximetry. The accuracy of this device is well documented, but the trending ability of this monitor has not been previously described. Twenty patients undergoing major thoracic and lumbar spine surgery were recruited. All patients received radial arterial lines. On the contralateral index finger, a R1 25 sensor (Rev E) was applied and connected to a Radical-7 Pulse CO-Oximeter (both Masimo Corp, Irvine, CA). Blood samples were drawn intermittently at the anesthesia provider's discretion and were analyzed by the operating room satellite laboratory CO-Oximeter. The value of Hgb and SpHb at that time point was compared. Trend analysis was performed by the four quadrant plot technique, testing directionality of change, and Critchley's polar plot method testing both directionality and magnitude of the change in values. Eighty-eight samples recorded at times of sufficient signal quality were available for analysis. Four quadrant plot analysis revealed 94% of data within the quadrants associated with the correct direction change, and 90% of data points lay within the analysis bounds proposed by Critchley. Pulse CO-Oximetry offers an acceptable trend monitor in patients undergoing major spine surgery. Future work should explore the ability of this device to detect large changes in hemoglobin, as well as its applicability in additional surgical and non-surgical patient populations.


Application of the reversed elephant trunk technique during total thoracoabdominal replacement in patients with Marfan's syndrome.
The reversed elephant trunk operation has been applied in patients with extensive aortic involvement as a scheduled staged operation. We report application of the same technique in two patients with Marfan's syndrome. The two patients underwent total replacement of the thoracoabdominal aorta for a DeBakey IIIb aortic dissection. The proximal end of the prosthetic graft was invaginated to facilitate future proximal operation. No complication related to the trunk had been observed during the follow-up period.


Establishment of a carbohydrate binding module-based lateral flow immunoassay method for identifying hyaluronic acid.
Hyaluronic acid is a commercially important polysaccharide with wide applications. Along with the rapid development of hyaluronic acid-based products, their authenticity has aroused considerable attention from consumers. In the present study, a carbohydrate-binding module (CBM) SrCBM70 was cloned and expressed. The protein could specifically bind to hyaluronic acid with a strong affinity. A novel method for the identification of hyaluronic acid was subsequently established by integrating SrCBM70 into the lateral flow immunoassay (LFIA). Its detection limit for hyaluronic acid was approximately 0.1 μg/mL, and the assay could be completed in 5 min. The feasibility of this method in the authenticity identification of commercialized products containing hyaluronic acid was confirmed. The establishment of the SrCBM70-based LFIA method provided a solution for the on-site authenticity identification and would facilitate the market supervision of hyaluronic acid-based products.


Calcium hydroxide inactivates lipoteichoic acid from Enterococcus faecalis.
Calcium hydroxide is a widely used endodontic medicament for eliminating viable bacteria and inactivating virulence factors. Enterococcus faecalis, a pathogenic gram-positive bacterium, has been associated with refractory apical periodontitis. Because lipoteichoic acid (LTA) is a major virulence factor of gram-positive bacteria, we examined whether calcium hydroxide could detoxify LTA from E. faecalis. An enzyme-linked immunosorbent assay showed that calcium hydroxide-killed E. faecalis was less potent than heat-killed bacteria in stimulating the release of tumor necrosis factor-alpha by a murine macrophage line, RAW 264.7 (P < 0.05). Pretreatment of LTA with calcium hydroxide remarkably abrogated the ability of LTA to induce the release of tumor necrosis factor-alpha (P < 0.05). Furthermore, calcium hydroxide-treated LTA was not able to stimulate Toll-like receptor 2, which recognizes functionally intact LTA. These results suggest that calcium hydroxide could detoxify LTA, resulting in attenuation of the inflammatory responses to E. faecalis and its LTA.


The optical quality of currently manufactured intraocular lenses.
We selected 95 intraocular lenses from ten lens manufacturers for a study of optical quality. Tremendous variation in resolution from a high of 313 line pairs per millimeter to a low of 40 line pairs per millimeter was seen. All of the lenses from eight manufacturers showed greater than 100 line pairs per millimeter resolution, the American National Standards Institute proposed minimum. Five of the 95 lenses had greater than 1.0 diopter error, whereas 79 of the 95 lenses had less than 0.5 diopter error from the stated power. With respect to toricity, there were 11 lenses with greater than 0.25 diopter (built-in astigmatism), however, no lenses showed more than 0.5 diopter astigmatism. Two lenses had a built-in double image, another clinically significant problem. We believe the optical quality of the lenses from some lens manufacturers cannot be guaranteed.


Capillary electrophoresis of the scrapie prion protein from sheep brain.
Scrapie in sheep and goats causes a progressive, degenerative disease of the central nervous system and is the prototype of other transmissible spongiform encephalopathies (TSE) found in humans and in animals. In samples of TSE-affected brains, unique rod-shaped structures are found and are infectious. These rods are composed of a protease-resistant, post-translationally modified cellular protein (PrPsc) that has a molecular mass of ca. 27,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Laboratory tests used for the diagnosis of scrapie detect PrPsc. The overall concentration of PrPsc in tissues is low. The present methods to diagnose scrapie are lengthy, require relatively large quantities of starting material to detect PrPsc and lack sensitivity. We explored the use of free zone capillary electrophoresis and immunocomplex formation to detect PrPsc in the brain tissue of infected sheep. Brain tissue from both infected (as confirmed by histological and biological tests) and from normal animals was used to prepare the PrPsc. After treatment with proteinase K and non-ionic detergents, PrPsc was solubilized and reacted with a rabbit antiserum specific for a peptide of the prion protein. Immunocomplex formation was observed for the samples from scrapie-infected brain but not for samples from normal brain. When a fluorescein-labeled goat anti-rabbit immunoglobulin was used as a second antibody, the detection of immunocomplex formation was enhanced both by the immunological technique and by using laser-induced fluorescence for detection. This same rabbit antiserum was used on immunoblot analysis. Three bands were observed for material from an infected sheep but none in preparations from brain material from normal sheep.(ABSTRACT TRUNCATED AT 250 WORDS)


Is the Sciatic Functional Index always reliable and reproducible?
The Sciatic Functional Index (SFI) is a quite useful tool for the evaluation of functional recovery of the sciatic nerve of rats in a number of experimental injuries and treatments. Although it is an objective method, it depends on the examiner's ability to adequately recognize and mark the previously established footprint key points, which is an entirely subjective step, thus potentially interfering with the calculations according to the mathematical formulae proposed by different authors. Thus, an interpersonal evaluation of the reproducibility of an SFI computer-aided method was carried out here to study data variability. A severe crush injury was produced on a 5 mm-long segment of the right sciatic nerve of 20 Wistar rats (a 5000 g load directly applied for 10 min) and the SFI was measured by four different examiners (an experienced one and three newcomers) preoperatively and at weekly intervals from the 1st to the 8th postoperative week. Three measurements were made for each print and the average was calculated and used for statistical analysis. The results showed that interpersonal correlation was high (0.82) in the 3rd, 4th, 5th, 7th and 8th weeks, with an unexpected but significant (p<0.01) drop in the 6th week. There was virtually no interpersonal correlation (correlation index close to 0) on the 1st and 2nd weeks, a period during which the variability between animals and examiners (p=0.24 and 0.32, respectively) was similar, certainly due to a poor definition of the footprints. The authors conclude that the SFI method studied here is only reliable from the 3rd week on after a severe lesion of the sciatic nerve of rats.


Differences in smoking and quitting experiences by levels of smoking among African Americans.
Despite smoking fewer cigarettes per day than their White counterparts, African Americans have higher tobacco-related morbidity and mortality. Since most tobacco control efforts have focused on heavy smokers, little is known about smoking and quitting experiences of African-American occasional and light smokers. We conducted a survey of 484 African-American smokers, which included: 104 occasional (smoked in < or = 25 of last 30 days), 176 light [smoked 1-10 cigarettes per day (cpd)], 69 moderate (11-19 cpd), and 135 heavy (> or = 20 cpd) attending an inner-city clinic. The survey assessed their sociodemographic characteristics, smoking characteristics, and cessation experiences. Compared with moderate and heavy smokers, occasional and light smokers were, on average, younger, more likely to be female, and more likely to initiate regular smoking at an older age. Forty percent of occasional smokers used other tobacco products compared to 23.3%, 24.6%, and 27.4% for light, moderate, and heavy smokers, respectively. Motivation and confidence to quit were higher among occasional and light smokers. Interest in participating in a formal cessation program was equally high in all 4 groups (mean ranged from 7.6-8.0 on a scale of 1-10). The use of pharmacotherapy for smoking cessation was similar, and generally low, among all 4 groups. High levels of motivation for smoking cessation exist among African-American occasional and light smokers. The interest of these lighter smokers in smoking cessation represents a window of opportunity to design programs for a group that has been excluded from most cessation interventions.


Pediatric neck abscesses: No increase in methicillin-resistant Staphylococcus aureus.
Recent studies from Western countries showed an increased incidence rate of methicillin-resistant Staphylococcus aureus (MRSA) isolated from pediatric neck abscesses cultures. We sought to examine the microbiology and antibiotic susceptibility of such samples over a 10-year period, and particularly of Staphylococcus aureus (SA), in order to determine whether a similar trend exists in our institution. A retrospective chart review of children ≤18 years that underwent needle aspiration or surgical drainage of neck abscesses, including suppurative lymphadenitis, retropharyngeal abscesses, and parapharyngeal abscesses was conducted between 1/1/06-31/12/15. Sixty-two children were identified with a male predominance (34, 55%). The median age was 2 years. There were 37 (60%) suppurative lymphadenitis, 15 (24%) parapharyngeal abscess, and 10 (16%) retropharyngeal abscess cases. Twenty-nine (47%) children received antibiotic treatment prior to admission, most commonly β-lactam agents. Of them, 15 (52%) had positive cultures, including 7 (47%) with SA. On admission, 45 (73%) children had already received amoxicillin-clavulanate. Of those who did not improve, 16 (26%) received ceftriaxone and clindamycin. Twenty-one (38%) cultures were negative. The most common isolated bacteria were SA in 13 (24%), Streptococcus pyogenes in 7 (13%), and Streptococcus viridians group in 9 (16%). Of the SA isolates, there was only 1 (8%) case of MRSA; however, there were 4 (31%) clindamycin-resistant SA isolates. Unlike previously published data, there was no increase in MRSA incidence at our institution. However, the high prevalence of clindamycin-resistant SA was in line with previous reports. These findings should be considered when starting empirical therapy in pediatric neck abscesses.


Anticancer activity and toxicity profiles of 2-benzylidene indanone lead molecule.
3-(3',4',5'-Trimethoxyphenyl)-4,5,6-trimethoxy,2-(3″,4″-methylenedioxybenzylidene)-indan-1-one (1) is an optimized anti-cancer lead molecule obtained on modification of gallic acid, a plant phenolic acid. It exhibited potent cytotoxicities (IC50=0.010-14.76μM) against various human carcinoma cells. In cell cycle analysis, benzylidene indanone 1 induced G2/M phase arrest in both MCF-7 and MDA-MB-231 cells. It also induced apoptosis in DU145 cells which was evident by cleavage of PARP. In Ehrlich ascites carcinoma, benzylidene indanone 1 showed 45.48% inhibition of tumour growth at 20mg/kg dose in Swiss albino mice. Further, in sub-acute toxicity experiment in Swiss-albino mice, it was found to be non-toxic up to 100mg/kg dose for 28days. The lead compound benzylidene indanone 1 can further be optimized for better anti-cancer activity.


Association of serum anti-centromere protein F antibodies with clinical response to infliximab in patients with rheumatoid arthritis: A prospective study.
One-third of rheumatoid arthritis (RA) patients demonstrate no clinical improvement after receiving tumor necrosis factor inhibitors (TNFi). The presence of serum autoantibodies is a hallmark in RA and may provide information on future response to treatment. The aim of this prospective study was to search for novel serum autoantibodies useful to predict clinical response to TNFi. The autoantibody repertoire was profiled on RA patients treated with TNFi as a first line of biologic therapy (N = 185), who were recruited in three independent cohorts. The presence and levels of autoantibodies in serum at baseline were analysed in association with the clinical response after 24 weeks follow-up. A multiplex bead array built using antigens selected from an initial untargeted screening was employed to identify the autoantibodies on a discovery cohort (N = 50) and to verify and validate the results on verification (N = 61) and validation (N = 74) cohorts. Non-parametric tests, meta-analysis and Receiver Operating Curves (ROC) were performed in order to assess the clinical relevance of the observed findings. Novel autoantibodies were associated with the clinical response to TNFi, showing different reactivity profiles among the different TNFi. The baseline levels of IgG antibodies against Centromere protein F (CENPF), a protein related to cell proliferation, were significantly (p<0.05) increased in responders (N = 111) to infliximab (IFX) compared to non-responders (N = 44). The addition of anti-CENPF antibodies to demographic and clinical variables (age, sex, DAS28-ESR) resulted in the best model to discriminate responders, showing an area under the curve (AUC) of 0.756 (95% CI [0.639-0.874], p = 0.001). A further meta-analysis demonstrated the significant association of anti-CENPF levels with the patient's subsequent response to IFX, showing a standardized mean difference (SMD) of -0.65 (95% CI [-1.02;-0. 27], p = 0.018). Our study reveals for the first time the potential of circulating anti-CENPF antibodies to predict the clinical response to IFX before starting the treatment. This finding could be potentially useful to guide therapeutic decisions and may lead to further studies focusing on the role of CENPF on RA pathology.


Apixaban Reduces Hospitalizations in Patients With Venous Thromboembolism: An Analysis of the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) Trial.
In the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial, apixaban was noninferior to enoxaparin/warfarin in preventing recurrent symptomatic venous thromboembolism (VTE) or venous thromboembolism-related death, with significantly less bleeding. This analysis evaluated the effects of apixaban versus enoxaparin/warfarin on all-cause hospitalizations during AMPLIFY. Of the 5365 patients included, 2676 received apixaban and 2689 received enoxaparin/warfarin. All-cause hospitalizations during the treatment period after the index event were captured using dedicated case report forms. Outcomes included all-cause hospitalizations and time from randomization to first hospitalization. Patients were censored at death, loss to follow-up, or end of study, whichever came first. Treatment effects were assessed using Cox proportional hazards regression models. During the treatment period after the index event, 343 patients were hospitalized at least once: 153 (5.72%) in the apixaban group and 190 (7.07%) in the enoxaparin/warfarin group. Compared with enoxaparin/warfarin, apixaban significantly reduced all-cause hospitalizations (hazard ratio 0.804, 95% CI=0.650-0.995, P=0.045). All-cause hospitalization rates within the first 30 days after the index event were 2.28% and 3.35% in the apixaban and enoxaparin/warfarin groups, respectively (hazard ratio 0.676, 95% CI=0.488-0.935, P=0.018). For all patients, the average per-patient estimated mean length of hospital stay was also shorter with apixaban than enoxaparin/warfarin (0.57 days versus 1.01 days, P<0.0001). Apixaban significantly reduced all-cause hospitalizations versus enoxaparin/warfarin, and shortened the length of hospital stay in patients with acute venous thromboembolism. URL: https://Clinicaltrials.Gov/. Unique identifier: NCT00643201.


The feasibility of laparoscopic TSME preserving the left colic artery and superior rectal artery for upper rectal cancer.
Laparoscopic tumor-specific mesorectal excision (TSME) preserving the left colic artery and superior rectal artery is still a technically challenging procedure. We conducted this study to demonstrate the feasibility of this procedure for upper rectal cancer. A total of 184 patients with upper rectal cancer were retrospectively analyzed in our cancer center between April 2010 and April 2017. These patients were treated with either laparoscopic TSME (n = 46) or laparoscopic total mesorectal excision (TME) (n = 138). In the TSME group, the left colonic artery and superior rectal artery were preserved while they were not in the TME group. The operation time in the TSME group was longer than that in the TME group (218.56 ± 35.85 min vs. 201.13 ± 42.65 min, P = 0.004). Furthermore, the number of resected lymph nodes in the TSME group was greater than that in the TME group (19.43 ± 9.46 vs. 18.03 ± 7.43, P = 0.024). The blood loss between the TSME and TME groups was not significant. No mortality occurred in either the TSME or TME groups. One patient in the TME group underwent conversion to laparotomy. The total postoperative complication rates in the TSME and TME groups were 8.7% and 17.4%, respectively. There was no difference in severe complications between the two groups (anastomotic leakage and stenosis). Laparoscopic TSME preserving the left colic artery and superior rectal artery can be safely conducted for upper rectal cancer.


Alkyl-GeMe3 : Neutral Metalloid Radical Precursors upon Visible-Light Photocatalysis.
Single-electron transfer (SET) oxidation of ionic hypervalent complexes, in particular alkyltrifluoroborates (Alkyl-BF3 - ) and alkylbis(catecholato)silicates (Alkyl-Si(cat)2 - ), have contributed substantially to alkyl radical generation compared to alkali or alkaline earth organometallics because of their excellent activity-stability balance. Herein, another proposal is reported by using neutral metalloid compounds, Alkyl-GeMe3 , as radical precursors. Alkyl-GeMe3 shows comparable activity to that of Alkyl-BF3 - and Alkyl-Si(cat)2 - in radical addition reactions. Moreover, Alkyl-GeMe3 is the first successful group 14 tetraalkyl nucleophile in nickel-catalyzed cross-coupling. Meanwhile, the neutral nature of these organogermanes offset the limitation of ionic precursors in purification and derivatization. A preliminary mechanism study suggests that an alkyl radical is generated from a tetraalkylgermane radical cation with the assistance of a nucleophile, which may also result in the development of more non-ionic alkyl radical precursors with a metalloid center.


Experimental studies of the effect of bupivacaine on peripheral nerves.
0.5% Bupivacaine was administered around the sciatic nerve of rabbits by means of a catheter, over a period of ten days. Twenty nerves showed no histological changes, but in three there were areas of demyelination and axonal degeneration, especially near the surface of the nerve. However, similar changes occurred in two out of six nerves to which normal saline was administered instead, and it is suggested that the damage may have been caused by mechanical trauma from movement of the catheter.


Extensive CFTR sequencing through NGS in Brazilian individuals with cystic fibrosis: unravelling regional discrepancies in the country.
The Brazilian population has a tri-hybrid composition with a high degree of ethnic admixture. We hypothesized that Brazilian individuals with CF from different Brazilian regions have a specific distribution of CFTR variants. Individuals with CF with data available in the Patient Registry and without an established genotype were submitted to CFTR sequencing by Next Generation Sequencing (NGS) methodology, and results were anonymously incorporated to the Registry Database. Genotyping results were expressed as 'positive', 'inconclusive' or 'negative'. Logistic regression models were performed to investigate the association between demographic/clinical variables and genotyping results. Mediation analysis was conducted to estimate direct and indirect effects of Brazilian region on a binary positive genotyping response. In October 2017, data from 4,654 individuals with CF were available, and 3,104(66.7%) of them had a genotyping result. A total of 236 variants (114 new variants) were identified, with F508del identified in 46% of the alleles tested. Genotyping revealed 2,002(64.5%) individuals positive, 757(24.4%) inconclusive and 345(11.1%) negative. Distribution of genotype categories was markedly different across Brazilian Regions, with greater proportions of negative individuals in the North (45%) and Northeast (26%) regions. Newborn screening (CF-NBS) and age at diagnosis were identified as mediators of the effect of Brazilian region on a positive genotyping result. This large initiative of CFTR genotyping showed significant regional discrepancies in Brazil, probably related to socio-economic conditions, lack of adequate CF-NBS and poor access to reliable sweat testing. These results may be useful to indicate Regions where CF care demands more attention.


About the effectiveness of the ABPD methods in air-borne alpha-activity monitoring.
A modified version of the alpha-beta-pseudo-coincidence-difference (ABPD-M) method is proposed with a view to suppressing natural background radiation when measuring the transuranium radionuclide (TRU) content in aerosol samples. It is shown that complementing the traditional "pseudo-coincidence" method with a treatment of (comparatively) fast beta-alpha coincidences provides a means to significantly improve the suppression of background fluctuations and the accuracy of measurement results in comparison with the traditional method.


Frontal 'oculomotor" area in alert cat. I. Eye movements and neck activity evoked by stimulation.
(1) Stimulation within cat frontal lobe elicited saccadic eye movements whose maximum velocity was significantly greater than that of normal spontaneous saccades. (2) The majority (90%) of stimulated cortical points yielded eye movements whose directions and amplitudes were independent of the position of the eye in the orbit. The direction of these eye movements depended on the site being stimulated, with a discrete and orderly representation of directions existing within the cortex. (3) A lesser number of cortical points (10%) yielded centering movements whose directions and amplitudes depended on the position of the eye in the orbit, rather than on the site being stimulated. (4) Evoked neck muscle activation frequently preceded evoked eye movements by some 15--30 msec. This timing was compatible with a coordinated head-eye orientating response. (5) On the basis of the directions, and the latencies, of evoked eye movements, the cat frontal oculomotor area could be divided into two subregions, a 'medial' and a 'lateral', (6) The 'medial' area included the mesial wall of the hemisphere with a portion of the lower lip of the cruciate sulcus, and the medial wall of the presylvian sulcus. This area yielded contraversive eye movements with shorter latencies (average 45 msec). (7) The 'lateral' area included primarily the lateral wall of the presylvian sulcus. It yielded predominantly centering eye movements, and ipsiversive movements with longer latencies (65 msec). (8) The functional characteristics of the 'medial' area, as revealed by focal stimulation, resembled those of the monkey frontal eye field.


Glycogen synthetase kinase 3 inhibition drives MIC-A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection.
Dengue virus (DENV) is the most widespread arbovirus worldwide and is responsible for major outbreaks. The host's immune response plays a crucial role in controlling this infection but might also contribute to the promotion of viral spread and immunopathology. In response to DENV infection, NK cells preferentially produce cytokines and are cytotoxic in the presence of specific antibodies. Here, we identified that DENV-2 inhibits glycogen synthase kinase 3 (GSK-3) activity to subsequently induce MHC class-1-related chain (MIC) A and MIC-B expression and IL-12 production in monocyte-derived DCs, independently of the STAT-3 pathway. The inhibition of GSK-3 by DENV-2 or small molecules induced MIC-A/B expression on monocyte-derived DCs, resulting in autologous NK cells of a specific increase in IFN-γ and TNF-α production, in the absence of direct cytotoxicity. Together, these findings identified GSK-3 as a regulator of MIC-A/B expression and suggested its role in DENV-2 infection to specifically induce cytokine production by NK cells.


Modifying the mechanics of healing infarcts: Is better the enemy of good?
Myocardial infarction (MI) is a major source of morbidity and mortality worldwide, with over 7 million people suffering infarctions each year. Heart muscle damaged during MI is replaced by a collagenous scar over a period of several weeks, and the mechanical properties of that scar tissue are a key determinant of serious post-MI complications such as infarct rupture, depression of heart function, and progression to heart failure. Thus, there is increasing interest in developing therapies that modify the structure and mechanics of healing infarct scar. Yet most prior attempts at therapeutic scar modification have failed, some catastrophically. This article reviews available information about the mechanics of healing infarct scar and the functional impact of scar mechanical properties, and attempts to infer principles that can better guide future attempts to modify scar. One important conclusion is that collagen structure, mechanics, and remodeling of healing infarct scar vary so widely among experimental models that any novel therapy should be tested across a range of species, infarct locations, and reperfusion protocols. Another lesson from past work is that the biology and mechanics of healing infarcts are sufficiently complex that the effects of interventions are often counterintuitive; for example, increasing infarct stiffness has little effect on heart function, and inhibition of matrix metalloproteases (MMPs) has little effect on scar collagen content. Computational models can help explain such counterintuitive results, and are becoming an increasingly important tool for integrating known information to better identify promising therapies and design experiments to test them. Moving forward, potentially exciting new opportunities for therapeutic modification of infarct mechanics include modulating anisotropy and promoting scar compaction.


Synthesis of two new heteroaromatic beta-carboline-fused pentacycles. Observation of a new intercalating agent.
Five-step synthetic routes of two new polyfused heterocycles: indazolo[3,2-a]-beta-carboline (3) and benzo[4',5'][1,2,3]triazino[6,1-a]-beta-carbolinium salt (10) applying Pd(0)-catalyzed cross-coupling reaction have been elaborated.


An introduction to strong ion difference.
This brief introduction to strong ion difference represents a fundamental change from the traditional method of understanding acid-base balance. It is hoped that this platform will allow better observation and provide more complete integration of the wide variety of mechanisms that affect homeostasis, from respiratory and renal to hepatic and dietary, and thus provide better outcomes for our patients.


Outcome of infants with 10 min Apgar scores of 0-1 in a low-resource setting.
In high-resource settings, postponing the interruption of cardiopulmonary resuscitation from 10 to 20 min after birth has been recently suggested, but data from low-resource settings are lacking. We investigated the outcome of newborns with Apgar scores of 0-1 at 10 min of resuscitative efforts in a low-resource setting. This observational substudy from the NeoSupra trial included all 49 late preterm/full-term newborns with Apgar scores of 0-1 at 10 min of resuscitation. The study was carried out at Mulago National Referral Hospital (Kampala, Uganda) between May 2018 and August 2019. Outcome measures were mortality and hypoxic-ischaemic encephalopathy in the first week of life. All resuscitations were video recorded and daily reviewed by trial researchers. Median duration of resuscitation was 32 min (IQR 17-37). Advanced resuscitation was provided to 21/49 neonates (43%). Overall, 48 neonates (98%) died within 2 days of life (44 in the delivery room, three on the first day and one on the second day) and one survived at 1 week with severe hypoxic-ischaemic encephalopathy. Our study adds information from a low-resource setting to the recent evidence from high-resource settings about prolonging the resuscitation in infants with Apgar scores of 0-1 at 10 min. The vast majority died in the delivery room despite prolonged resuscitative efforts. We confirm that duration of resuscitation should be tailored to the setting, while the focus in low-resource settings should be improving the quality of antenatal and immediately after birth care.


Effects of flavonol-rich green tea cultivar (Camellia sinensis L.) on plasma oxidized LDL levels in hypercholesterolemic mice.
To examine the possible benefits of tea flavonols, we compared anti-atherogenic effects between common and flavonol-rich tea cultivars. The tea infusion made from a flavonol-rich cultivar, but not a common cultivar, significantly decreased the plasma oxidized low-density lipoprotein level in mice fed a high-cholesterol diet. The result suggests that tea flavonols have the potential to protect against cardiovascular diseases.


Cotiarinase is a novel prothrombin activator from the venom of Bothrops cotiara.
Snake venom serine proteinases (SVSPs) may affect hemostatic pathways by specifically activating components involved in coagulation, fibrinolysis and platelet aggregation or by unspecific proteolytic degradation. In this study, we purified and characterized an SVSP from Bothrops cotiara venom, named cotiarinase, which generated thrombin upon incubation with prothrombin. Cotiarinase was isolated by a two-step procedure including gel-filtration and cation-exchange chromatographies and showed a single protein band with a molecular mass of 29 kDa by SDS-polyacrylamide gel electrophoresis under reducing conditions. Identification of cotiarinase by mass spectrometric analysis revealed peptides that matched sequences of viperid SVSPs. Cotiarinase did not show fibrinogen-clotting, platelet-aggregating, fibrinogenolytic and factor X activating activities. Upon incubation with prothrombin the generation of thrombin was detected using the peptide substrate d-Phe-Pip-Arg-pNA. Moreover, mass spectrometric identification of prothrombin fragments generated by cotiarinase in the absence of co-factors (phospholipids, factor Va, factor Xa and Ca(2+) ions), indicated the limited proteolysis of this protein to release prothrombin 1, fragment 1 and thrombin. Cotiarinase is a novel SVSP that acts on prothrombin to release active thrombin that does not match any group of the current classification of snake venom prothrombin activators.


SARS-CoV-2 infection is associated with higher odds of insulin treatment but not with hemoglobin A1c at 120 days in U.S. Veterans with new-onset diabetes.
To examine associations of SARS-CoV-2 infection/COVID-19 with insulin treatment in new-onset diabetes. We conducted a retrospective cohort study using Veterans Health Administration data (March 1, 2020-June 1, 2022). Individuals with ≥1 positive nasal swab for SARS-CoV-2 (n = 6,706) comprised the exposed group, and individuals with no positive swab and ≥1 laboratory test of any type (n = 20,518) the unexposed group. For exposed, the index date was the date of first positive swab, and for unexposed a random date during the month of the qualifying laboratory test. Among Veterans with new-onset diabetes after the index date, we modeled associations of SARS-CoV-2 with most recent A1c prior to insulin treatment or end of follow-up and receipt of >1 outpatient insulin prescription starting within 120 days. SARS-CoV-2 was associated with a 40% higher odds of insulin treatment compared to no positive test (95%CI 1.2-1.8) but not with most recent A1c (ß 0.00, 95%CI -0.04-0.04). Among Veterans with SARS-CoV-2, ≥2 vaccine doses prior to the index date was marginally associated with lower odds of insulin treatment (OR 0.6, 95%CI 0.3-1.0). SARS-CoV-2 is associated with higher odds of insulin treatment but not with higher A1c. Vaccination may be protective.


Neuropsychological prediction of recovery in late-onset major depression.
To assess antidepressant response in late-onset major depression in relation to neuropsychological domains: attention, memory and planning. A neuropsychological battery was administered in 30 medication-free patients with late-onset major depression, who were then included in a 12-week antidepressant treatment regimen within a 12-month follow-up period. Logistic regression was used to define a predictive model of recovery. Eighteen patients were classed as remitters and seven as non-remitters. The 'indexrem' refers to the results of a logistic regression from verbal learning and planning and had a global predictive power of 84%. Our study suggests that the balance between verbal learning (memory) and planning (executive function)-both related to the dorsolateral prefrontal cortex-could predicts recovery.


Warming and nutrient enrichment in combination increase stochasticity and beta diversity of bacterioplankton assemblages across freshwater mesocosms.
The current climate warming and eutrophication are known to interactively threaten freshwater biodiversity; however, the interactive effects on lacustrine bacterioplankton diversity remain to be determined. Here, we analyzed the spring bacterioplankton community composition (BCC) in 24 outdoor, flow-through mesocosms (mimicking shallow lake environments) under 3 temperature scenarios and 2 nutrient regimes. Our results revealed that neither long-term warming (8.5 years) nor nutrient enrichment had significant effects on bacterioplankton alpha diversity, whereas long-term enhanced warming (elevated 50% above the IPCC A2 climate scenario) and nutrient enrichment in combination increased bacterioplankton beta diversity. We also found that BCC shifted significantly under enhanced warming and nutrient-enriched conditions towards decreased relative abundances of Actinobacteria, Bacteroidetes and Betaproteobacteria, whereas the percentages of Cyanobacteria, total rare phyla and unclassified phyla significantly increased. Null-model tests indicated that deterministic processes played a more important role than stochastic processes in determining BCC. However, the relative importance of stochasticity, primarily ecological drift, was enhanced and contributed to the increased beta diversity of BCC under enhanced warming and nutrient-enriched conditions. Overall, our study suggests that the synergetic effects of warming and nutrient enrichment may result in high variability in the composition of bacterioplankton communities in lacustrine water bodies.


Advances in molecular mechanism of HPV16 E5 oncoprotein carcinogenesis.
For a considerable duration, cervical cancer has posed a significant risk to the well-being and survival of women. The emergence and progression of cervical cancer have garnered extensive attention, with prolonged chronic infection of HPV serving as a crucial etiological factor. Consequently, investigating the molecular mechanism underlying HPV-induced cervical cancer has become a prominent research area. The HPV molecule is composed of a long control region (LCR), an early coding region and a late coding region.The early coding region encompasses E1, E2, E4, E5, E6, E7, while the late coding region comprises L1 and L2 ORF.The investigation into the molecular structure and function of HPV has garnered significant attention, with the aim of elucidating the carcinogenic mechanism of HPV and identifying potential targets for the treatment of cervical cancer. Research has demonstrated that the HPV gene and its encoded protein play a crucial role in the invasion and malignant transformation of host cells. Consequently, understanding the function of HPV oncoprotein is of paramount importance in comprehending the pathogenesis of cervical cancer. E6 and E7, the primary HPV oncogenic proteins, have been the subject of extensive study. Moreover, a number of contemporary investigations have demonstrated the significant involvement of HPV16 E5 oncoprotein in the malignant conversion of healthy cells through its regulation of cell proliferation, differentiation, and apoptosis via diverse pathways, albeit the precise molecular mechanism remains unclear. This manuscript aims to provide a comprehensive account of the molecular structure and life cycle of HPV.The HPV E5 oncoprotein mechanism modulates cellular processes such as proliferation, differentiation, apoptosis, and energy metabolism through its interaction with cell growth factor receptors and other cellular proteins. This mechanism is crucial for the survival, adhesion, migration, and invasion of tumor cells in the early stages of carcinogenesis. Recent studies have identified the HPV E5 oncoprotein as a promising therapeutic target for early-stage cervical cancer, thus offering a novel approach for treatment.


The safety of posterior tympanotomy in otitis media with effusion during cochlear implantation: clinical retrospective cohort study.
Posterior tympanotomy (PT) is an important step in cochlear implant (CI) surgery, as it is the main access to the round window. Some CI candidates, especially children, may have concomitant otitis media with effusion (OME) which may result in technical issues during PT. There is still a debate whether to wait for OME resolution preoperatively or to proceed to surgery with suspected difficulties. To evaluate the safety of PT during CI surgery in patients with OME. we included 102 consecutive pediatric candidates in this retrospective study with an age range of 12 months to 6 years. All the patients underwent CI surgery using trans-mastoid, PT to access round window (RW) area. We investigated the effect of the pathology caused by OME on the operative procedure in PT and post-operative consequences. out of 102 patients included in this study, there were 22 patients with OME who had unilateral cochlear implantation with no major operative or post-operative events. Nevertheless, some minor intra operative events and difficulties were encountered. The presence of OME in CI surgery indicates possible surgical challenges such as difficult PT, minor intra-operative risks and with no major post-operative events.


Impairment of brain mitochondrial functions by β-hemolytic Group B Streptococcus. Effect of cardiolipin and phosphatidylcholine.
Group B Streptococcus (GBS) causes severe infection in the central nervous system. In this study, brain mitochondrial function was investigated by simulating infection of isolated mitochondria with GBS, which resulted in loss of mitochondrial activity. The β-hemolysin expressing strains GBS-III-NEM316 and GBS-III-COH31, but not the gGBS-III-COH31 that does not express β-hemolysin, caused dissipation of preformed mitochondrial membrane potential (Δψm). This indicates that β-hemolysin is responsible for decreasing of the reducing power of mitochondria. GBS-III-COH31 interacted with mitochondria causing increase of oxygen consumption, due to uncoupling of respiration, blocking of ATP synthesis, and cytochrome c release outside mitochondria. Moreover, the mitochondrial systems contributing to the control of cellular Ca(2+) uptake were lost. In spite of these alterations, mitochondrial phospholipid content and composition did not change significantly, as evaluated by MALDI-TOF mass spectrometry. However, exogenous cardiolipin (CL) and dipalmitoylphosphatidylcholine (DPPC) attenuated the uncoupling effect of GBS-III-COH31, although with different mechanisms. CL was effective only when fused to the inner mitochondrial membrane, probably reducing the extent of GBS-induced proton leakage. DPPC, which is not able to fuse with mitochondrial membranes, exerted its effect outside mitochondria, likely by shielding mitochondria against GBS β-hemolysin attack.


Yolk-shell structured nanoreactor Au@Co3O4/CeO2@mSiO2 with superior peroxidase-like activity as nanozyme for ultra-sensitive colorimetric biosensing.
For yolk-shell structured nanoreactors, multiple active components can be precisely positioned on core and/or shell that can afford more exposed accessible active sites, and the internal voids can guarantee sufficient contact of reactants and catalysts. In this work, a unique yolk-shell structured nanoreactor Au@Co3O4/CeO2@mSiO2 was fabricated and applied as nanozyme for biosensing. The Au@Co3O4/CeO2@mSiO2 exhibited superior peroxidase-like activity with a lower Michaelis constant (Km) and a higher affinity to H2O2. The enhanced peroxidase-like activity was attributed to the unique structure and the synergistic effects between the multiple active components. Colorimetric essays were developed based on Au@Co3O4/CeO2@mSiO2 for the ultra-sensitive sensing of glucose in the range of 3.9 nM-1.03 mM with the limit of detection as low as 3.2 nM. In the detection of glucose-6-phosphate dehydrogenase (G6PD), the cooperation between G6PD and Au@Co3O4/CeO2@mSiO2 triggered the redox cycling between NAD+ and NADH, thereby achieving the amplification of the signal and enhancing the sensitivity of the assay. The assay showed superior performance as compared to other methods with linear response of 5.0 × 10-3-15 mU mL-1 and lower detection limit of 3.6 × 10-3 mU mL-1. The fabricated novel multi-enzyme catalytical cascade reaction system allowed rapid and sensitive biodetection, demonstrating its potential in biosensors and biomedical applications.


Chromatic and wavefront aberrations: L-, M- and S-cone stimulation with typical and extreme retinal image quality.
The first physiological process influencing visual perception is the optics of the eye. The retinal image is affected by diffraction at the pupil and several kinds of optical imperfections. A model of the eye (Thibos & Bradley, 1999), which takes account of pupil aperture, chromatic aberration and wavefront aberrations, was used to determine wavelength-dependent point-spread functions, which can be convolved with any stimulus specified by its spectral distribution of light at each point. The resulting retinal spectral distribution of light was used to determine the spatial distribution of stimulation for each cone type (S, M and L). In addition, individual differences in retinal-image quality were assessed using a statistical model (Thibos, Bradley, & Hong, 2002) for population values of Zernike coefficients, which characterize imperfections of the eye's optics. The median and relatively extreme (5th and 95th percentile) modulation transfer functions (MTFs) for the S, M and L cones were determined for equal-energy-spectrum (EES) 'white' light. The typical MTF for S cones was more similar to the MTF for L and M cones after taking wavefront aberrations into account but even with aberrations the S-cone MTF typically was below the M- or L-cone MTF by a factor of at least 10 (one log unit). More generally, the model presented here provides a technique for estimating retinal image quality for the S, M and L cones for any stimulus presented to the eye. The model is applied to some informative examples.


Single-molecule magnet behavior in heterolopetic Dy3+-chloro-diazabutadiene complexes: influence of the nuclearity and ligand redox state.
We report the synthesis, structure and magnetic properties investigations of a series of new dysprosium heteroleptic mono- and dinuclear complexes based on the association of chloride and different diazabutadiene (DAD2R = [2,6-iPr2C6H3N-CR[double bond, length as m-dash]CR-NC6H3iPr2-2,6]; R = H, Me) ligands showing different redox states. While using dianionic DAD2R ligands affords the formation of dichloro-bridged dinuclear complexes [Dy2(DAD2R)(μ-Cl)2(THF)2] (R = H (1), Me (2)), two different mononuclear complexes of general formula [DyCl2(DAD2R)(THF)2] (R = H (3), Me (4)) could be obtained with either a radical monoanionic and a monoanionic DAD2R state, respectively. Remarkably, all the complexes exhibit a slow relaxation of their magnetization where the relaxation dynamics depends on both the nuclearity of the system and the DAD2R redox state.


Critical aortic coarctation: patch aortoplasty in infants less than age 3 months.
Twenty-three infants less than age 3 months (mean age 31 days) underwent patch aortoplasty for relief of coarctation of the aorta. All had intractable congestive heart failure, despite aggressive medical therapy. Each infant had other cardiac anomalies, including patent ductus arteriosus (83 percent) and ventricular septal defect (74 percent). All patients underwent closure of the ductus arteriosus and patch angioplasty of the aorta to produce a luminal diameter of at least 16 mm. In addition, 9 of the 17 patients (53 percent) with a large shunt ventricular septal defect underwent pulmonary arterial banding. There was one hospital death 42 days after operation secondary to bowel perforation and sepsis. Hospitalization beyond 21 days postoperatively was always due to other unrepaired cardiac lesions. The three late deaths at 3, 9 and 18 months after operation were associated with additional major anomalies. Fourteen patients have had postoperative catheterization. No gradient was found across the site of coarctation repair, but one patient had a gradient between the left carotid and left subclavian arteries. Surgical repair of critical coarctation of the aorta in infants can safely be offered despite the presence of other cardiac anomalies.


Lobe-specific responses of TRAMP mice dorsolateral prostate following celecoxib and nintedanib therapy.
Delayed cancer progression in the ventral prostate of the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model has been previously reported upon celecoxib and nintedanib co-administration. Herein, we sought to further investigate the effects of these drugs association in some of their direct molecular targets (COX-2, VEGF and VEGFR-2) and in reactive stroma markers (TGF-β, αSMA, vimentin and pro-collagen 1) in the dorsolateral prostate, looking for lobe-specific responses. Male TRAMP mice were treated with celecoxib (10 mg/Kg, i.o.) and/or nintedanib (15 mg/Kg, i.o.) for 6 weeks and prostate was harvested for morphological and protein expression analyses. Results showed that combined therapy resulted in unique antitumor effects in dorsolateral prostate, especially due to the respective stromal or epithelial antiproliferative actions of these drugs, which altogether led to a complete inversion in high-grade (HGPIN) versus low-grade (LGPIN) premalignant lesion incidences in relation to controls. At the molecular level, this duality in drug action was paralleled by the differential down/upregulation of TGF-β signaling by celecoxib/nintedanib, thus leading to associated changes in stroma composition towards regression or quiescence, respectively. Additionally, combined therapy was able to promote decreased expression of inflammatory (COX-2) and angiogenesis (VEGF/VEGFR-2) mediators. Overall, celecoxib and nintedanib association provided enhanced antitumor effects in TRAMP dorsolateral as compared to former registers in ventral prostate, thus demonstrating lobe-specific responses of this combined chemoprevention approach. Among these responses, we highlight the ability in promoting TGF-β signaling and its associated stromal maturation/stabilization, thus yielding a more quiescent stromal milieu and resulting in greater epithelial proliferation impairment.


Short-term protective effect of octreotide on the lungs of rats with experimentally induced sepsis.
Acute respiratory distress syndrome is a devastating complication of severe sepsis. Preclinical models suggest that direct lung injury begins with attack to the lung epithelium, but indirect lung injury results from systemic endothelial damage due to inflammatory mediators. The aim of the present study was to explore the effect of octreotide on lungs in a surgically induced sepsis model in rats. We used 32 male Sprague Dawley rats and divided into four groups. Group 1: Normal (non-operative and orally fed control, n=8); Group 2: Sham operated (n=8); Group 3: Cecal ligation and puncture (CLP) (untreated group, n=8); and Group 4: CLP and 100 µg/kg octreotide i.p. (n=8). For sepsis, CLP procedure was performed on 16 rats to induce a sepsis model. All groups were analyzed, their blood was taken for arterial blood gas analysis. For histological examination, lung tissues were removed and sections were prepared. In histological examination, if we compare CLP + Octreotide with only CLP group in CLP + Octreotide group decreased inflammatory cell infiltration in alveolar and interstitial area as well as edema, bleeding, when CLP group was compared with octreotide group, all histopathological parameters improved significantly and the severity index decreased from 3 to 1. For arterial blood gas, when CLP and octreotide groups were compared with CLP group, it was observed that there was a significant change in favor of healing and that they almost came up to controls and sham group. It could be hypothesized that it would be beneficial to administer octreotide for ameliorate lung injury state in sepsis patients.


Circular RNA circSEMA5A facilitates colorectal cancer development by regulating microRNA-195-5p to target CCNE1 axis.
Colorectal cancer (CRC) is one of the most prevalent malignancies with a high mortality rate worldwide. Circular RNAs (circRNAs) have lately emerged as key molecules involved in cancer development and metastasis. CircSEMA5 is reported to be oncogenic in some cancers, yet its role in the pathogenesis of CRC remains unknown. Herein, we attempted to investigate the functional role and molecular mechanism of circSEMA5A underlying CRC progression. RT-qPCR and RNase R digestion assays were used to evaluate circSEMA5A expression characteristics in CRC cells. Loss-of-function assays were performed to clarify circSEMA5A role in CRC biological processes. Bioinformatics and mechanism experiments were conducted to assess the association of circSEMA5A or CCNE1 with miR-195-5p in CRC cells. Rescue assays were conducted to explore the regulatory function of circSEMA5A-miR-195-5p-CCNE1 in CRC cellular processes. Through bioinformatics and functional screening, we found that circSEMA5A was highly expressed in CRC cells and was mainly localized in the nucleus. CircSEMA5A promoted CRC proliferative, migratory, and invasive capabilities in cultured cells and facilitated the tumorigenic process in xenografts; however, circSEMA5A silencing repressed tumor metastasis in CRC cells. Mechanistically, circSEMA5A was competitively bound with miR-195-5p to upregulate CCNE1 expression. Moreover, the impact of circSEMA5A knockdown on CRC cell proliferative, migratory, and invasive capabilities was countervailed by miR-195-5p inhibitor or CCNE1 overexpression. To summarize, circSEMA5A is a novel circRNA that serves as an oncogene in CRC progression. CircSEMA5A facilitates CRC cell malignancy and tumor growth through sponging miR-195-5p to upregulate CCNE1, thus providing a new direction for CRC diagnosis and targeted therapy.


Attention-generated apparent motion.
Motion perception mechanisms have recently been divided into three categories. First-order mechanisms primarily extract motion from moving objects or features that differ from the background in luminance. Second-order mechanism extract motion from moving properties, such as a moving area of flicker in which there is no difference in mean luminance between target and background. These first- and second-order motion mechanisms are primarily monocular. The existence of purely binocular, interocular and various other unusual kinds of apparent motion has promoted conjectures of a third-order mechanism, but there has been no clear suggestion as to the actual computations that such a mechanism might perform. Here we demonstrate 'alternating feature' stimuli that produce apparent motion only when the observer selectively attends to one of the embedded features in the display. The latent motion in the alternating feature stimuli is invisible to first- or second-order motion mechanisms, and the direction of apparent motion depends on the particular feature attended. These findings suggest the mechanism of third-order motion: the locations of the most significant features are registered in a salience map, and motion is computed directly from this map.


Ectopic pancreas in the anterior mediastinum.
We report an uncommon clinical case of anterior mediastinal localization of ectopic pancreatic tissue. A 39-year-old male was referred to our institution for investigation of an abnormal mediastinal shadow on a chest X-ray, and a large cystic lesion measuring 10 x 8 cm located in the anterior mediastinum was observed on a computed tomographic scan. He underwent complete surgical resection of the lesion. The postoperative pathological examination confirmed the diagnosis of ectopic mediastinal pancreas. No recurrence or metastasis was detected during a follow-up period of 8 years. We speculate that this lesion represents abnormal differentiation of the pluripotent epithelial cells of the ventral primary foregut. Details of the clinical and histopathological features are presented.


Molecular genetic approaches to the analysis of human ophthalmic disease.
In this review of the recent literature, the contribution that the new techniques of molecular genetics has made in the analysis and diagnosis of human ophthalmic conditions is presented and discussed. Among the disorders reviewed are X-linked retinitis pigmentosa, Norrie's disease, gyrate atrophy and retinoblastoma, and there are also sections on crystallins and visual pigments.


Activities of new fluoroquinolones, ketolides, and other antimicrobials against blood culture isolates of viridans group streptococci from across Canada, 2000.
The rates of nonsusceptibility to penicillin, erythromycin, and clindamycin of 191 blood culture isolates of viridans group streptococci collected from across Canada in 2000 were 36, 42, and 10%, respectively. Although 8% of the strains were resistant to ciprofloxacin (MIC >or= 4 microg/ml), the MICs of gemifloxacin, BMS 284756, telithromycin, and ABT 773 at which 90% of the strains were inhibited were 0.06, 0.06, 0.12, and 0.03 microg/ml, respectively.


Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia.
Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.


Modeling VOCs adsorption onto activated carbon.
The activated carbon adsorption process is affected by the characteristics of adsorbent, adsorbate and environmental conditions. In this study, both adsorption and desorption processes are assumed to occur simultaneously and a numerical model was developed with a non-linear driving force in conjunction with the Langmuir model for predicting the overall adsorption process. The numerical model provides both adsorption and desorption rate constants and activation energies. The resultant equilibrium constants are of the same order of magnitude as reported by other studies. Results show that the model could well predict the adsorption isotherms and breakthrough curves under various conditions.


Generation of hydroxyl radical from linoleic acid hydroperoxide in the presence of epinephrine and iron.
When linoleic acid hydroperoxide was reacted with ferrous iron, the electron spin resonance signals characteristic of the spin adduct of 5,5-dimethyl-1-pyrroline-N-oxide and the hydroxyl radical were detected. Although the signals were not detected with the hydroperoxide and ferric iron, they were actually found if epinephrine was added, indicating that the hydroxyl radical could be generated from the hydroperoxide upon reduction of the latter with ferrous iron formed by epinephrine. The possible generation of the hydroxyl radical from lipid peroxides in vivo was discussed from the viewpoint of pathogenesis of lipid peroxide-related diseases.


[Clinical characteristics of neonatal Klebsiella pneumoniae sepsis and the antibiotic sensitivity pattern of strains].
To study the clinical characteristics of neonatal sepsis caused by Klebsiella pneumoniae and the antibiotic sensitivity pattern of Klebsiella pneumoniae strains. The clinical data of 42 cases of neonatal sepsis caused by Klebsiella pneumoniae from January, 2000 to August, 2009 were retrospectively studied. The clinical presentations were non-specific, including fever or hypothermia, tachypnea, apnea and feeding intolerance. C-reactive protein (CRP) level increased in 95% of the cases. The mortality was 21%. In neonates with early onset sepsis, Klebsiella pneumoniae strains were sensitive to amoxicillin/clavulanic-acid, piperacillin/tazobactam, cefoxitin, imipenem, cefoperazone/and sulbactam. In neonates with late onset sepsis, the sensitive antibiotics of Klebsiella pneumoniae strains were less, including cefoxitin, piperacillin/tazobactam and imipenem. Klebsiella pneumoniae strains were not sensitive to penicillins and cephalosporins in either neonates with early onset sepsis or late onset sepsis. The extended spectrum β-lactamases (ESBLs)-producing strains were found in 92% of the cases. The neonates with late onset sepsis presented a higher prevalence of ESBLs-producing strains than those with early onset sepsis (100% vs 70%; P<0.05). The clinical manifestations of neonatal sepsis caused by Klebsiella pneumoniae are usually non-specific. CRP detection is valuable for early diagnosis of sepsis. There are differences in the antibiotic sensitivity of strains between the neonates with early onset and late onset Klebsiella pneumoniae sepsis.


Induced neural stem cells from distinct genetic backgrounds exhibit different reprogramming status.
Somatic cells could be directly converted into induced neural stem cells (iNSCs) by ectopic expression of defined transcription factors. However, the underlying mechanism of direct lineage transition into iNSCs is largely unknown. In this study, we examined the effect of genetic background on the direct conversion process into an iNSC state. The iNSCs from two different mouse strains exhibited the distinct efficiency of lineage conversion as well as clonal expansion. Furthermore, the expression levels of endogenous NSC markers, silencing of transgenes, and in vitro differentiation potential were also different between iNSC lines from different strains. Therefore, our data suggest that the genetic background of starting cells influences the conversion efficiency as well as reprogramming status of directly converted iNSCs.


Vasopressin Injection Purse-String Ectopic Resection technique for laparoscopic management of cornual ectopic pregnancy.
Although cornual pregnancy is a rare form of ectopic pregnancy, the associated mortality rate is considerably higher than that of ectopic pregnancy overall. Historically, cornual ectopic pregnancy has been treated via laparotomy. With advancements in technology, equipment, and technique, laparoscopy offers a safer approach for the management of cornual pregnancy. However, laparoscopy of this nature requires excellent technique. The Vasopressin Injection Purse-String Ectopic Resection technique serves as an effective strategy for the laparoscopic management of cornual ectopic pregnancy. First, dilute vasopressin is administered into the myometrium surrounding the pregnancy. Next, a purse-string stitch is placed in the myometrium circumferential to the pregnancy. Finally, the pregnancy is excised by cornual wedge resection, and the defect is repaired using the attached remaining suture from the purse-string stitch. The Figure shows the graphical depiction of the Vasopressin Injection Purse-String Ectopic Resection technique, and the Video shows a laparoscopic recording of the Vasopressin Injection Purse-String Ectopic Resection technique. Between 2012 and 2022, 17 patients underwent a laparoscopic cornual ectopic pregnancy resection at a high-volume academic hospital and its affiliated community hospital. This case series revealed a mean operative time of 107 minutes, with a mean estimated blood loss of 41 mL for nonruptured ectopic pregnancies and 412 mL for ruptured ectopic pregnancies. No case was converted to laparotomy. Our findings suggest that the integration of the vasopressin administration and the pursue-string stitch placement minimizes blood loss and mitigates the risk of conversion to laparotomy for both nonruptured and ruptured cornual ectopic pregnancies.


Response of microbial communities to nutrient removal in coastal sediment by using ecological concrete.
Ecological concrete (eco-concrete) is a kind of environment-friendly material with porous characteristics. In this study, the eco-concrete was used to remove the total nitrogen (TN), total phosphorus (TP), and total organic carbon (TOC) in marine coastal sediment. The bacterial communities in sediment and on eco-concrete surface were also investigated by using high-throughput sequencing and quantitative PCR of 16S rRNA gene. We found that the mean removal efficiencies of TN, TP, and TOC in treatment group were 8.3%, 8.4%, and 12.3% after 28 days. The bacterial community composition in the treatment group was significantly different from that in the control group on day 28. In addition, the bacterial community composition on eco-concrete surface was slightly different from that in sediment, and the copy numbers of 16S rRNA gene were higher on eco-concrete surface than in sediment. The types of eco-concrete aggregates (gravel, pebble, and zeolite) also had effects on the bacterial community composition and 16S rRNA gene copy numbers. Furthermore, we found the abundant genus Sulfurovum increased significantly on eco-concrete surface in the treatment group after 28 days. Bacteria belonging to this genus were found having denitrification ability and were commonly detected in bioreactors for nitrate removal. Overall, our study expands the application scopes of eco-concrete and suggests that the bacterial communities in eco-concrete can potentially enhance the removal efficiency of nutrients in coastal sediment.


The use of ultrasound in benign breast disorders.
The role of ultrasonography in the diagnosis of benign conditions of the breast is presented. The images seen with common benign conditions are illustrated and diagnostic problems are discussed.


Rimmed vacuolar distal myopathy. An ultrastructural study.
An ultrastructural study of biopsied muscles was performed in seven patients with rimmed vacuolar distal myopathy, which was characterized by prominent rimmed vacuoles in the muscle fibers. The earliest changes noted were focal proliferation of the Golgi's apparatus and mitochondrial degeneration with myofibrillar loss. A proliferation of the T-system appeared later. Secondary lysosomes (autophagosomes) could be noted much later and gradually increased in number. Autophagosomes tended to coalesce and became larger autophagic vacuoles, which were surrounded in part by relatively preserved myofibrils and partly by a single membrane. Gently curved laminated structures (tubulomembranous structures) were seen in the degenerating muscle fibers and also in relatively intact fibers, satellite cells, and interstitial cells in all cases. They were closely associated with lipofuscin-like material. These findings suggest that an abnormality of the lysosomal system might be essential in the pathogenesis of rimmed vacuolar distal myopathy.


Comparison of nuclear matrix protein 22 and bladder tumor antigen in urine of patients with bladder cancer.
Recently, two new tumor markers for bladder cancer have been introduced: NMP22 test and BTA TRAK assay. This study was designed to evaluate the urinary values of these two proteins using quantitative enzyme immunoassays in well microplates. Urine samples from 47 healthy subjects, 26 with benign genitourinary disorders and 109 patients with a histological diagnosis of bladder cancer were collected. The specificity, the positive predictive value, the negative predictive value and the efficiency were established for NMP 22 and BTA, and the cut off values were fixed at a specificity of 95% in the benign disease group (12 U/ml and 23 U/ml respectively). We observed a very high concordance between the two urinary tumor markers (73%), although the overall sensitivity of BTA in bladder cancer patients seems to be better than that of NMP22 (62% vs 54% respectively), especially in the superficial disease group (36% for BTA and 14% for NMP22).


Reserpine-induced supersensitivity to the inotropic and phosphorylase activating effects of glucagon in the perfused rat heart.
Glucagon (0.125--2.0 microgram) produced a dose-dependent increase in cyclic AMP, % phosphorylase a and force of contraction in the isolated perfused rat heart. Pretreatment of animals with reserpine (2.5 mg/kg, 24 h) resulted in an enhancement of the inotropic and phosphorylase activating effects of glucagon but the effect on cyclic AMP was not altered. It is suggested that reserpine-induced supersensitivity in the rat heart occurs at a point beyond the cyclic AMP step.


Postoperative hypoxaemia and oxygen therapy.
To observe the duration of hypoxaemia 8 patients were monitored every day for the first 7 days following upper abdominal surgery. Three of these patients who had failed to regain their preoperative PO2 value by the seventh postoperative day were further monitored on alternate days until the fourteenth postoperative day. A further 3 patients were similarly monitored on alternate days for 14 days. In another group of 10 patients blood gases were monitored every 4 h for the first 48 h following major abdominal surgery, during which time the patients were given 35 per cent oxygen for the first 24 h after operation. (All patients in this group had a diminished respiratory reserve preoperatively to a sufficient degree to warrant admission to the intensive therapy unit postoperatively, and these patients were treated with oxygen for 24 h, as is the practice in our unit and in other surgical units.) Oxygen was administered using a Ventimask at 8 l/min (British Medical Journal, 1972). Nine of the 10 patients did not show postoperative hypoxaemia while being treated with 35 per cent oxygen, although the PO2 value attained were lower than expected. On withdrawal of oxygen after 24 h, the PO2 decreased below preoperative levels in all patients. The PO2 of 7 patients in this group decreased below 8 kPa during the second 24 postoperative hours, in 4 of whom the level fell below 6-7 kPa. Some recommendations to improve the respiratory care of the surgical patient are presented.


A multicenter study of the early detection of synaptic dysfunction in Mild Cognitive Impairment using Magnetoencephalography-derived functional connectivity.
Synaptic disruption is an early pathological sign of the neurodegeneration of Dementia of the Alzheimer's type (DAT). The changes in network synchronization are evident in patients with Mild Cognitive Impairment (MCI) at the group level, but there are very few Magnetoencephalography (MEG) studies regarding discrimination at the individual level. In an international multicenter study, we used MEG and functional connectivity metrics to discriminate MCI from normal aging at the individual person level. A labeled sample of features (links) that distinguished MCI patients from controls in a training dataset was used to classify MCI subjects in two testing datasets from four other MEG centers. We identified a pattern of neuronal hypersynchronization in MCI, in which the features that best discriminated MCI were fronto-parietal and interhemispheric links. The hypersynchronization pattern found in the MCI patients was stable across the five different centers, and may be considered an early sign of synaptic disruption and a possible preclinical biomarker for MCI/DAT.


Resection of the metatarsal head for diabetic foot ulcers.
Diabetic foot ulceration is a worldwide health problem. Approximately 15% of the 10 million diabetic patients in the United States will develop a foot ulceration at some time in their lives. The presence of a foot ulcer in this population is extremely debilitating and dramatically increases the risk of lower extremity amputation, accounting for approximately 67,000 lost limbs each year. Additionally, the costs associated with treating foot ulcers in diabetic patients is a major expense in the overall care of this patient group. An 11-year retrospective study was conducted to evaluate 101 consecutive patients with diabetic ulcers of the forefoot who were treated using resection of the metatarsal head as the primary means of obtaining wound closure. The results indicate that 88% of the ulcers were healed by using this technique, and relatively more rapidly than would be expected when compared with historical norms. Resection of the metatarsal head is a safe and relatively inexpensive procedure that facilitates closure of the lesion, helps to control infection, and prevents countless and costly amputations.


Renal effects of dental amalgam in children: the New England children's amalgam trial.
Mercury is nephrotoxic and dental amalgam is a source of mercury exposure. Children 6-10 years of age (n = 534) with two or more posterior teeth with caries but no prior amalgam restorations, were randomized to one of two treatments--amalgam or resin composite (white fillings)--used for caries treatment during 5 years of follow-up. The primary outcome was change in IQ, but important secondary outcomes were effects on markers of glomerular and tubular kidney function: urinary excretion of albumin, alpha-1-microglobulin (A1M), gamma-glutamyl transpeptidase (gamma-GT), and N-acetyl-beta-d-glucosaminidase (NAG). These markers were measured on several occasions during the trial, together with urinary mercury and covariates. We evaluated the results using repeated-measures analyses. There were no significant differences between treatment groups in average levels of renal biomarkers, nor significant effects of number of dental amalgams on these markers. There was, however, a significantly increased prevalence of microalbuminuria (MA) among children in the amalgam group in years 3-5 (adjusted odds ratio 1.8; 95% confidence interval, 1.1-2.9). Most of these cases are likely to be temporary MA, but 10 children in the amalgam group had MA in both years 3 and 5, versus 2 children in the composite group (p = 0.04). There were no differences in the occurrence of high levels of renal tubular markers (A1M, gamma-GT, or NAG). The increase in MA may be a random finding, but should be tested further. The results did not support recent findings in an observational study of an effect of low-level mercury on tubular biomarkers in children.


Regulation of cardiac myosin synthesis: studies of RNA content in cultured heart cells.
Contraction regulates the myosin content and the rate of myosin synthesis in cultured neonatal rat heart cells. To further explore the mechanism for this regulation we examined various parameters of RNA content and RNA synthesis in contacting versus noncontracting myocytes. While contraction stimulated myosin heavy chain (MHC) synthesis by 72% compared to that of KCl-arrested cells, simultaneous analyses of polysome profiles were no different under the two culture conditions. Incorporation of [3H]uridine monophosphate into cellular RNA revealed no change in the rate of total RNA or ribosomal subunits synthesis. In vitro translation of cellular RNA yielded similar incorporation of [35S]methionine into trichloroacetic acid precipitable protein. Specific transcription of the MHC gene was examined by dot-blot analysis and was unaltered by contraction. Northern blot analysis of the MHC sequences detected by a cDNA probe revealed an mRNA sequence corresponding to a molecular weight of approximately 30 S. These data suggest that RNA synthesis and RNA content are unaltered by contraction in cultured heart cells and therefore the changes in myosin synthesis may be mediated at a post-transcriptional control level.


Endovascular thrombectomy and thrombolysis for severe cerebral sinus thrombosis: a prospective study.
Most patients with cerebral sinus thrombosis (CST) recover after treatment with heparin, but a subgroup has a poor prognosis. Those patients may benefit from endovascular thrombolysis. Prospective case series. Patients with sinus thrombosis were selected for thrombolysis if they had an altered mental status, coma, straight sinus thrombosis, or large space-occupying lesions. Urokinase was infused into the sinuses (bolus 120 to 600 x 10(3) U; then 100 x 10(3) U/h) via a jugular catheter, in 15 cases combined with mechanical thrombus disruption or removal. We treated 20 patients (16 women), mean age 32 years. Twelve patients were comatose and 14 had hemorrhagic infarcts before thrombolysis. Twelve patients recovered (Rankin score 0 to 2), 2 survived with handicaps, and 6 died. Factors associated with a fatal outcome were leukemia (3/6 versus 0/14, P=0.02) and large hemorrhagic infarcts (4/6 versus 2/14, P=0.04). Seizures were less frequent in the fatal cases (P=0.05). Patients who died had a larger mean lesion surface than survivors (30.5 versus 13.6 cm(2); P=0.03), larger midline shift (5.2 versus 1.7 mm; P=0.02), and a more rapid course (2.7 versus 8.2 days; P=0.01). Five patients who died had large hemispheric infarcts and edema before thrombolysis, causing herniation. Five patients had increased cerebral hemorrhage (3 minor, 2 major) after thrombolysis. Thrombolysis can be effective for severe sinus thrombosis, but patients may deteriorate because of increased cerebral hemorrhage. Patients with large infarcts and impending herniation did not benefit.


Tree-ring analysis and conifer growth responses to increased atmospheric CO2 levels.
Tree-ring data of naturally grown connifers were analyzed to evaluate the possibility of enhanced tree growth due to increased atmospheric CO2. Tree cores were obtained from 34 sites in four different climatic regions in the northern hemisphere. In each of the four regions, the sampling sites were located along ecological gradients between the subalpine treeline and low elevations and, sometimes, the arid forest border. Growth trends after 1950, when the atmospheric CO2 concentration increased by more than 30 μl·l-1 indicate an increase in ring-widths at eight of the 34 sites. These chronologies were from sites which moderate temperature or water stress. In four cases the growth increase in the post-1950 period coincided with favorable climatic conditions. In the remaining four cases, the growth increase exceeded the upper bound response expected from CO2 enrichment experiments with seedling conifer species. Therefore, increased growth in any of the tree-ring chronologies examined could not be solely attributed to higher atmospheric CO2 concentrations.


Meridional variations in the line orientation discrimination of the cat.
Cat's differential orientation thresholds were measured with single lines presented in succession. Differential orientation thresholds measured at horizontal or vertical orientations were smaller (median 2.9 degrees) than those measured at oblique orientation (median 4.7 degrees). Replications of the experiments showed that the oblique effect was stable over a period of 2 years. Using the same behavioral methods grating acuity was measured and did not show an oblique effect. These behavioral observations are compared with the physiological data on orientation specificity of area 17 cells. This comparison suggests that the most likely explanation of the meridional variation in orientation discrimination is the meridional variation in orientation preference of area 17 S cells.


Psychometric evaluation of the Spanish version of the MPI-SCI.
Postal surveys. To confirm the factor structure of the Spanish version of the MPI-SCI (MPI-SCI-S, Multidimensional Pain Inventory in the SCI population) and to test its internal consistency and construct validity in a Spanish population. Guttmann Institute, Barcelona, Spain. The MPI-SCI-S along with Spanish measures of pain intensity (Numerical Rating Scale), pain interference (Brief Pain Inventory), functional independence (Functional Independence Measure), depression (Beck Depression Inventory), locus of control (Multidimensional health Locus of Control), support (Functional Social Support Questionnaire (Duke-UNC)), psychological well-being (Psychological Global Well-Being Index) and demographic/injury characteristics were assessed in persons with spinal cord injury (SCI) and chronic pain (n=126). Confirmatory factor analysis suggested an adequate factor structure for the MPI-SCI-S. The internal consistency of the MPI-SCI-S subscales ranged from acceptable (r=0.66, Life Control) to excellent (r=0.94, Life Interference). All MPI-SCI-S subscales showed adequate construct validity, with the exception of the Negative and Solicitous Responses subscales. The Spanish version of the MPI-SCI is adequate for evaluating chronic pain impact following SCI in a Spanish-speaking population. Future studies should include additional measures of pain-related support in the Spanish-speaking SCI population.


Left atrial appendage closure: First in man with the 4th generation WATCHMAN device.
To evaluate the feasibility and safety of the fourth generation WATCHMAN device. The WATCHMAN left atrial appendage (LAA) closure device has been shown to be non-inferior to conventional oral anticoagulation with warfarin for stroke prevention in patients with non-valvular atrial fibrillation. A new (fourth) generation of the WATCHMAN device was designed to facilitate easier delivery and improve safety. We conducted a prospective, non-randomized study of LAA closure with use of the 4(th) generation WATCHMAN device in 36 patients with non-valvular atrial fibrillation. Follow-up was performed at 45 days, 6 months and 12 months following implantation. The mean age of the population was 73 ± 6 years and 67% were male. The mean CHADS2 and CHA2 DS2-VASc Score were 2.5 and 4.5, respectively. The device was implanted successfully in 34/36 (94%). No serious hospital complications related to the device or procedure occurred. During 12 month follow-up, three ischemic strokes (8%), one hemorrhagic stroke (3%), one TIA (3%) and three deaths (9%) occurred. Device-associated thrombus formation was detected in one patient (3%) during six-month follow-up and was treated successfully with low molecular weight heparin. LAA closure with the 4(th) generation WATCHMAN device is feasible and safe. New technical features may contribute to a better performance of the occluder, particularly regarding the risk of pericardial effusions.


Docking-based virtual screening of TβR1 inhibitors: evaluation of pose prediction and scoring functions.
To improve the reliability of virtual screening for transforming growth factor-beta type 1 receptor (TβR1) inhibitors, 2 docking methods and 11 scoring functions in Discovery Studio software were evaluated and validated in this study. LibDock and CDOCKER protocols were performed on a test set of 24 TβR1 protein-ligand complexes. Based on the root-mean-square deviation (RMSD) values (in Å) between the docking poses and co-crystal conformations, the CDOCKER protocol can be efficiently applied to obtain more accurate dockings in medium-size virtual screening experiments of TβR1, with a successful docking rate of 95%. A dataset including 281 known active and 8677 inactive ligands was used to determine the best scoring function. The receiver operating characteristic (ROC) curves were used to compare the performance of scoring functions in attributing best scores to active than inactive ligands. The results show that Ludi 1, PMF, Ludi 2, Ludi 3, PMF04, PLP1, PLP2, LigScore2, Jain and LigScore1 are better scoring functions than the random distribution model, with AUC of 0.864, 0.856, 0.842, 0.812, 0.776, 0.774, 0.769, 0.762, 0.697 and 0.660, respectively. Based on the pairwise comparison of ROC curves, Ludi 1 and PMF were chosen as the best scoring functions for virtual screening of TβR1 inhibitors. Further enrichment factors (EF) analysis also supports PMF and Ludi 1 as the top two scoring functions.