Chicken ovalbumin contains an internal signal sequence.
Ovalbumin is shown to contain an internal rather than an amino-terminal signal sequence. This internal signal can be recovered in a tryptic fragment which comprises residues 229--276 of mature ovalbumin and contains a region of striking sequence homology to amino-terminal cleaved signals of two other oviduct secretory proteins. The isolated tryptic fragment is used as a probe to demonstrate that a signal receptor is present in membrane vesicles derived from the rough but not in those derived from the smooth endoplasmic reticulum.


DREADD activation of the lateral orbitofrontal increases cocaine-taking and cocaine-seeking in male and female rats during intermittent access self-administration under risky conditions.
Addiction is a disorder that can be characterized in part as the constant pursuit of a particular substance despite negative consequences. Although the orbitofrontal cortex (OFC) is known to regulate risk-taking more generally and be critical to the development of addiction, its role in regulating drug use under risk-taking conditions is unknown. To address this, we examined drug-taking and drug-seeking in male and female rats under conditions where cocaine infusions were paired with foot shock punishment 50% of the time and combined this paradigm with cFos immunohistochemistry. We found that rats that showed higher levels of drug-taking and drug-seeking prior to punishment showed decreased responding during self-administration sessions under risky conditions and lower levels of c-Fos expression in the lateral but not medial OFC. However, despite these initial differences in responses to infusions paired with foot shocks, all rats showed decreased responding with additional punishment sessions. We then used chemogenetic viral approaches to examine how altering activity of the lateral OFC affects drug-taking and drug-seeking during punished drug use. Although there was no effect of Gi/o DREADD-mediated inhibition of the lateral OFC on these behaviors, Gq DREADD-mediated activation increased drug-taking and drug-seeking when drug use was associated with foot shock 50% of the time. Interestingly, this manipulation had no effect on non-risky self-administration behavior. These results suggest that the involvement of lateral OFC in cocaine use is context-sensitive and influences decision-making based on negative outcomes.


Effects of vitamin D metabolites on healing of low phosphate, vitamin D-deficient induced rickets in rats.
A model of low-phosphate, vitamin D-deficient rachitic rats was used to compare the effects of 1 alpha(OH)D3, 1,25(OH)2D3, and 24,25(OH)2D3 on cartilage and bone. The rats were maintained for 3 weeks on a high-calcium, low-phosphate, vitamin D-deficient diet, during which period they developed severe rickets. The rachitic rats were injected for 2 or 3 consecutive days with a physiologic dose of either metabolite. Other littermates were given a single dose of 50,000 IU of cholecalciferol in combination with a normal diet. Samples of cartilage fluid (Cfl) and of blood were removed prior to sacrifice for biochemical studies of some parameters of calcification. These parameters were correlated with the results of light and electron microscopic studies of the growth plate cartilage and bone. Treatment with 1 alpha (OH)D3 or with 1,25(OH)2D3, in spite of increasing Ca and P levels in the Cfl, induced only partial healing of the rickets. In contrast, 24,25(OH)2D3 or vitamin D with a normal diet resulted in complete morphologic and biochemical healing of the rickets. Transmission electron microscopic (TEM) studies have shown partial mineralization of the wide hypertrophic zone of the growth plate following treatment with 1 alpha(OH)D3 or with 1,25(OH)2D3. Mineralization was more complete with 24,25(OH)2D3 treatment. The results of this study emphasize the importance of 24,25(OH)2D3 for normal endochondral bone formation and mineralization.


Indomethacin inhibition of prostaglandin-mediated inflammation following intraocular surgery.
Indomethacin treatment before lens extraction and vitrectomy-lensectomy reduces postoperative inflammation as measured by protein determination of the ocular fluid.


Pathological tissue formation and degradation biomarkers correlate with patient reported pain outcomes: an explorative study.
The lack of disease modifying drugs in Osteoarthritis (OA) may be attributed to the difficulty in robust response based on patient-reported outcomes (PROs) linked to drug mechanism of action. Joint tissue turnover biomarkers are associated with disease progression. A subset of patients has elevated serum levels of CRP metabolite (CRPM). This explorative study investigates the associations between PROs and joint tissue turnover markers in patients with high or low CRPM. Serum of 146 knee OA patients of the New York Inflammation cohort and 21 healthy donors were assessed for biomarkers of collagen degradation (C1M, C2M, C3M, C4M), formation (PRO-C1, PRO-C2, PRO-C3, PRO-C4), and CRPM. Mean (SD) age was 62.5 (10.1); BMI, 26.6 (3.6); 62% women; and, 67.6% had symptomatic OA. WOMAC pain, stiffness, function, and total were recorded at baseline and at two-year follow-up. Associations were adjusted for race, sex, age, BMI, and NSAID. There was no difference in markers between donors and patients. C2M correlated with the WOMAC scores in all CRPM groups. Significant correlations were observed between PROs and PRO-C4, C1M, and C3M in the CRPMhigh group. The best predictive models for improvement were found for function and total with AUCs of 0.74 (p < 0.01) and 0.78 (p < 0.01). The best predictive models for worsening were found for function and total with AUCs of 0.84 (p < 0.01) and 0.80 (p < 0.05). We hypothesize that collagen markers are prognostic tools for segregating patient populations in clinical trials.


Generating Convergent Laguerre-Gaussian Beams Based on an Arrayed Convex Spiral Phaser Fabricated by 3D Printing.
A convex spiral phaser array (CSPA) is designed and fabricated to generate typical convergent Laguerre-Gaussian (LG) beams. A type of 3D printing technology based on the two-photon absorption effect is used to make the CSPAs with different featured sizes, which present a structural integrity and fabricating accuracy of ~200 nm according to the surface topography measurements. The light field vortex characteristics of the CSPAs are evaluated through illuminating them by lasers with different central wavelength such as 450 nm, 530 nm and 650 nm. It should be noted that the arrayed light fields out from the CSPA are all changed from a clockwise vortex orientation to a circular distribution at the focal plane and then a counterclockwise vortex orientation. The circular light field is distributed 380-400 μm away from the CSPA, which is close to the 370 μm of the focal plane design. The convergent LG beams can be effectively shaped by the CASPs produced.


Fluency disorders in genetic syndromes.
The characteristics of various genetic syndromes have included "stuttering" as a primary symptom associated with that syndrome. Specifically, Down syndrome, fragile X syndrome, Prader-Willi syndrome, Tourette syndrome, Neurofibromatosis type I, and Turner syndrome all list "stuttering" as a characteristic of that syndrome. An extensive review of these syndromes indicated clients diagnosed with these syndromes do show evidence of nonfluency patterns, but not all would be considered stuttering. Many of the syndromes are marked by degrees of mental retardation that probably contribute to a higher than average prevalence of stuttering, as well as a higher than average prevalence of other fluency disorders (when compared to the population at large). An in-depth analysis of the available data indicates that some of these genetic syndromes show patterns of stuttering that may be indicative of only that syndrome (or similar syndromes) that can be differentially diagnosed from developmental stuttering. Among these patterns are the word-final nonfluencies noted in Prader-Willi syndrome; the presence of stuttering in the absence of secondary behaviors noted in Prader-Willi syndrome and; the presence of palilalia, word-final and word-medial nonfluencies, and word-medial and word-final nonfluencies in Tourette syndrome. Implications for future research are discussed in light of these findings. The reader will be able to: (1) describe the various different genetic syndromes that are associated with fluency disorders; (2) describe the types of nonfluencies that are associated with the major types of genetic syndromes that have fluency disorders; (3) describe the behaviors that may assist in differentially diagnosing different types of speech characteristics associated with various genetic syndromes.


Indirect oxidation of the antitumor agent procarbazine by tyrosinase--possible application in designing anti-melanoma prodrugs.
The interaction of tyrosinase with the anticancer drug procarbazine has been investigated. In the presence of the enzyme alone no oxidation of this dialkylhydrazine above the background level was observed. However, when phenolic substrates (4-tert-butylcatechol or N-acetyl-l-tyrosine) were included in the reaction mixture, procarbazine was rapidly degraded. Oxygen consumption measurements showed that in a mixture both the phenolic substrate and the drug were oxidized. The major product of procarbazine degradation was isolated and identified as azoprocarbazine, the first active metabolite of this drug detected in previous in vivo and in vitro studies. This indirect oxidation of the hydrazine group in this anticancer agent indicates possible application of a hydrazine linker in construction of tyrosinase-activated anti-melanoma prodrugs.


Differential survival and recurrence patterns of patients operated for breast cancer according to the new immunohistochemical classification: analytical survey from 1997 to 2012.
Breast cancer can no longer be considered only one condition. It should be regarded rather as a heterogeneous group of diseases with different molecular outlines. The aim of this study is to establish a correlation between immunohistochemical tumor sub-typing and surgical treatment, local recurrence rates, distant metastases, and cancer-specific mortality at 5 and 10 years. At least, four tumor sub-types have been described, which were associated with variable risk factors, different natural clinical course, and different response to both local and systemic therapies. For Luminal A: ER + and/or PR + HER2- Ki67 <15 %; Luminal B: ER + and/or PR + HER2- Ki67 ≥ 15 %; Pure HER2: ER-PR-HER2+; Triple Negative: ER-PR-HER2-. One thousand four hundred seventy-seven patients operated for 1,511 invasive breast tumors were included. Disease-free survival, overall mortality, and breast cancer-specific mortality at 5 and 10 years were calculated. Distant metastases prevalence ranged from 8 to 28 % across sub-types, increasing stepwise from Luminal A, Luminal B, and pure HER2 through triple negative. Conversely, larger tumors with significant axillary burden were more likely to belong to HER2 or triple negative groups. Luminal A sub-type patients showed significantly lower mortality rates both overall and specific at 5 and 10 years, as compared to the rest. Luminal B patients showed lower mortality rates only when compared with triple negative patients. Simple classification of breast cancer patients based on immunohistochemistry and other risk factors is quite useful to establish groups with bad or even worse prognosis. Although results from immunohistochemical classification were not taken into account for surgical procedure decision-making, we found that pure HER2 and triple negative patients received nevertheless higher rates of radical treatment.


Bone mineral content in patients on home parenteral nutrition.
Bone mineral content (BMC) was monitored in 15 patients with short bowel syndrome receiving home parenteral nutrition (HPN). Thirteen patients had Crohn's disease and 2 ulcerative colitis (mean age 36 years, range 23-69 years). During the study the patients received HPN for a mean period of 62 months, range 20-106 months. At the time of inclusion the patients had a significantly reduced BMC of lumbar spine and femoral neck compared to normals (Z-scores = -3.35 +/- 3.49, p < 0.05 and Z-score = -2.23 +/- 2.11, p < 0.05). During HPN the Z-score of lumbar spine BMC decreased in 8 patients and increased slightly or was unchanged in 7 patients. The mean Z-score of BMC of lumbar spine declined by 1.46 +/- 2.48 (p < 0.05) and the Z-score of femoral neck BMC declined by 0.831 +/- 1.14 (p < 0.05). This corresponds to a yearly decrease of lumbar spine BMC of 4%. There was no correlation between the decline in BMC during the study and the period of length the patients were on HPN. We conclude that patients on HPN have a low bone mineral density and that the bone loss continues during prolonged HPN.


Temporal and Geographic Patterns of Social Media Posts About an Emerging Suicide Game.
Rates of suicide are increasing rapidly among youth. Social media messages and online games promoting suicide are a concern for parents and clinicians. We examined the timing and location of social media posts about one alleged youth suicide game to better understand the degree to which social media data can provide earlier public health awareness. We conducted a search of all public social media posts and news articles on the Blue Whale Challenge (BWC), an alleged suicide game, from January 1, 2013, through June 30, 2017. Data were retrieved through multiple keyword search; sources included social media platforms Twitter, YouTube, Reddit, Tumblr, as well as blogs, forums, and news articles. Posts were classified into three categories: individual "pro"-BWC posts (support for game), individual "anti"-BWC posts (opposition to game), and media reports. Timing and location of posts were assessed. Overall, 95,555 social media posts and articles about the BWC were collected. In total, over one-quarter (28.3%) were "pro"-BWC. The first U.S. news article related to the BWC was published approximately 4 months after the first English language U.S. social media post about the BWC and 9 months after the first U.S. social media post in any language. By the close of the study period, "pro"-BWC posts had spread to 127 countries. Novel online risks to mental health, such as prosuicide games or messages, can spread rapidly and globally. Better understanding social media and Web data may allow for detection of such threats earlier than is currently possible.


Estimation of human spine orientation with inertial measurement units (IMU) at low sampling rate: How low can we go?
Studying people in their daily life is important for understanding conditions with multi-faceted aetiology such as chronic low back pain. Inertial measurement units can be used to reconstruct the posture and motion of the body outside of laboratories to enable this research. The battery life of these sensors strongly affects the usability of the system, since recharging them frequently is inconvenient and can lead to additional errors. A major determinant of the battery life for these sensors is sampling rate, but the relationship between sampling rate and accuracy in motion reconstruction is not well documented. We measured the spine of 12 participants using inertial measurement units across a variety of tasks such as sitting, standing, walking, and jogging. The orientation of the spine was reconstructed using several filters, including a novel filter developed specifically for high performance at low sampling frequencies. Benchmarking against optical motion capture, we developed a model showing that the error of all tested filters depends exponentially on the sampling frequency, with the optimal filter gains showing a similar exponential relationship. Using this model of error, we developed a criterion for recommending minimum sampling frequencies for accurate motion estimates for each task, finding frequencies ranging from about 13 to 35 Hz sufficient depending on the task. Although we only studied the spine, these models should provide insight into optimizing sampling rate and filter parameters for inertial measurements in general use.


Air quality changes in NE Romania during the first Covid 19 pandemic wave.
This study analyzes for the first time uniformly and causally the level of pollution and air quality for the NE-Romania Region, one of the poorest region in the European Union. Knowing the level of pollution and air quality in this region, which can be taken as a benchmark due to its positional and economic-geographical attributes, responds to current scientific and practical needs. The study uses an hourly database (for five pollutants and five climate elements), from 2009 to 2020, from 19 air quality monitoring stations in northeastern Romania. Pollutant levels were statistically and graphically/cartographically modeled for the entire 2009-2020 interval on the distributive-spatial and regime, temporal component. Inter-station differences and similarities were analyzed causally. Taking advantage of the emergency measures between March 16 and May 14, 2020, we observed the impact of the event on the regional air quality in northeastern Romania. During the emergency period, the metropolitan area of Suceava (with over 100,000 inhabitants) was quarantined, which allowed us to analyze the impact of the quarantine period on the local air quality. We found that, in this region, air quality falls into class I (for NO2, SO2 and CO), II for O3 and III for PM10. During the lockdown periods NO2 and SO2 decreased for the entire region by 8.6 and 14.3%, respectively, and in Suceava by 13.9 and 40.1%, respectively. The causes of the reduction were anthropogenic in nature.


Virtual Bronchoscopy: Highly Sensitive Time and Life Saving Investigation in the Diagnosis of Foreign Body Aspiration-Our Experience.
Foreign body airway is a common cause of morbidity and mortality in children. Virtual bronchoscopy is a new investigative technique useful in locating non radiopaque FB missed on plain radiography. The aim of the study was to study the clinical profile of patients with suspected foreign body aspiration and to evaluate the changing trends in the diagnosis and quicker management of foreign body aspiration as a way of virtual bronchoscopy. This was a retrospective and prospective cross sectional study conducted in the Department of Otorhinolaryngology M.G.M.M.C. and M.Y. Hospital Indore for a period of 10 years. The medical records of patients with foreign body aspiration, from August 2006 to September 2016 were reviewed. Data was collected regarding their clinical presentation, examination and chest X-ray, virtual bronchoscopy, rigid bronchoscopy findings. Patients with suspected foreign body aspiration were subjected to virtual bronchoscopy and rigid bronchoscopy was performed. The techniques and methods to extract different types of foreign bodies has been elaborated in this study. In the 150 subjects, we observed mean age group of presentation was 2.1 years, male is to female ratio was 4.1, 70% of the cases came from the rural areas, 86% were vegetative foreign bodies, and remaining non vegetative were aspirated mostly during the winter season. Betel nut was the most common aspirated foreign body 0.63% had a positive history of foreign body aspiration, where as 37% had a negative history. Right main bronchus was the most common site of lodgement. Breathlessness and reduced air entry were the most common symptoms and signs. We also observed, that chest radiograph were normal in as many as 40% cases. Hence negative chest radiographs does not rule out FB. In 150 patients with foreign body aspiration, which was detected by virtual bronchoscopy, 148 patients were diagnosed to have foreign body on rigid bronchoscopy. This amounts to a positive predictive value of 97.3% which was similar to the positive predictive value of rigid bronchoscopy which was 99%. Virtual bronchoscopy is the only imaging modality which gives 99.9% reassurance about the presence or absence of a foreign body, because of its high sensitivity and specificity, hence proves to be a life saving tool.


Isolation and identification of polysaccharides from Pythium arrhenomanes and application to strawberry fruit (Fragaria ananassa Duch.) preservation.
In this study, we extracted exopolysaccharides from Pythium arrhenomanes and purified them to obtain three polysaccharides (PEPS-1, PEPS-2, PEPS-3). The composition of these polysaccharides was determined. PEPS-2 and PEPS-3 showed outstanding antioxidant activities. PEPS-2 was chosen as a polysaccharide-based coating for strawberry fruit, and its effects on postharvest preservation of the fruit were determined. Strawberries coated with PEPS-2 exhibited significant delay in decay index and lower malondialdehyde, higher soluble solids content, anthocyanin content and vitamin C content, and greater DPPH radical-scavenging activity than uncoated control fruit. The developed method could be beneficial for improving the shelf-life of strawberries.


Lung uptake of technetium 99m sestamibi: relation to clinical, exercise, hemodynamic, and left ventricular function variables.
Technetium 99m sestamibi (2-methoxyisobutyl isonitrile [MIBI]) is a relatively new radiopharmaceutical with improved imaging characteristics for exercise myocardial perfusion studies compared with thallium 201. Although increased lung uptake of 201Tl has been shown to have important clinical significance, reflecting severity of coronary artery disease and left ventricular function, the factors affecting MIBI lung uptake are unknown. Therefore we examined the potential clinical, exercise, hemodynamic, myocardial perfusion, and ventricular function determinants of lung uptake of MIBI on exercise myocardial perfusion studies. The study cohort consisted of 103 patients referred for evaluation of coronary artery disease with exercise MIBI myocardial perfusion imaging. All patients underwent both a standard 1-day rest-stress MIBI planar imaging protocol and rest echocardiography. With the anterior-view stress images obtained 1 hour after MIBI injection, regions of interest were drawn over peak lung and myocardial activities and a lung/heart ratio was calculated. Multivariate regression analysis was used to relate the lung/heart ratio to clinical, exercise and hemodynamic, myocardial perfusion, and echocardiographic left ventricular function scores. We found no significant relation between lung/heart ratio and any patient variable. Unlike 201Tl, lung uptake of MIBI is not related to indexes of exercise, left ventricular dysfunction, or perfusion abnormalities. Thus MIBI lung uptake does not appear to have the same clinical significance as 201Tl lung uptake.


Chronic relapsing experimental allergic encephalomyelitis in strain 13 guinea pigs; presence of myelin basic protein in the local tissue long after the immunization.
In order to obtain a clue to understand the induction mechanism of chronic form of EAE we studied the immunized site of EAE animals with immunocytochemical techniques. There were numerous vacuoles associated with inflammatory reactions in the subcutaneous tissue of immunized feet. Immunocytochemical staining with antiserum to myelin basic protein (MBP) disclosed remaining of MBP in and around the vacuoles. The MBP remained more in early stage and less in chronic stage; it remained even on 326th day of postimmunization. A possible role of the remained antigen in chronic EAE was discussed.


An epigastric mass? And what if it was an intra-abdominal esophageal duplication cyst: Case report.
Duplication of the alimentary tract are uncommon congenital malformations that may be found anywhere from mouth to anus. Esophageal cystic duplication is a congenital cystic malformation of the alimentary tract consisting of a duplication of the segment of the esophagus to which it is adjacent. We report the case of a 29-year-old female who had complained of intermittent epigastric pain and post prandial nausea for several weeks. Physical examination was without particularity except for the presence of abdominal epigastric mass. Transabdominal sonography combined with CT scan showed an epigastric cyst with no topographic relation to the pancreas measuring about 80 mm in diameter. Because of persistence of the epigastric pain and the nausea we decided to operate the patient. Histological exam than showed that the cystic mass was in fact an esophageal cystic duplication with no histological signs of malignancy. Here we describe a case of intra-abdominal esophageal duplication cyst in adult patient. Most of duplications cause symptoms in infancy or early childhood. Digestive duplication revealed at adulthood is a condition considered rare. Esophageal duplication cysts are uncommon developmental lesions arising from the primitive foregut, when diagnosed or encountered incidentally. The diagnosis of this anomaly in adulthood is exceptional and requires surgery.


The use of vertebral ring epiphyseal union for age estimation in two cases of unknown identity.
The objective of this case study was to demonstrate the utility of thoracic and first two lumbar vertebral ring epiphyseal union as an accurate and reliable method of age estimation for teenage and young adult skeletons. Vertebral ring epiphyseal union was used as a method of age estimation in two cases of osteological analysis for individuals of unknown identity. Case 1 involved male skeletal remains where postmortem damage by carnivores had destroyed most of the age markers. Data from vertebral ring epiphyseal union contributed to a narrower age estimation when used in conjunction with data from the other skeletal age indicators. Case 2 involved the fresh remains of an unknown female. Union of the vertebral ring epiphyses was consistent with an age range of 18 to 22 years, which was generally compatible with the age ranges obtained from the other skeletal sites (16 to 20 years). From this information, a narrower range of 18 to 20 years was then considered the most likely age at death. For each of the two cases, age information from observations of epiphyseal union of the vertebral centra has (1) been consistent with age information gathered from other skeletal age indicators and or (2) helped narrow down otherwise broader age estimation ranges. This method is recommended for use in estimating age at death from teenage and young adult skeletal remains.


Analysis on Clinical Outcomes of Low-Molecular Weight Heparin Combined with Magnesium Sulfate in Patients with Pre-Eclampsia.
We aimed to investigate the clinical effect of low molecular weight heparin (LMWH) combined with magnesium sulfate in patients with severe pre-eclampsia (PE). A total of 70 patients with severe PE admitted in Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, China from Jun 2020 to May 2021 were enrolled and randomized into observation and control groups. The control group was treated with magnesium sulfate only, and the observation group was treated with small-dose LMWH combined with magnesium sulfate. The clinical effects and artery blood flow index were analyzed. The observation group had higher coagulation function than that in the control group. RI, S/D, and PI in the observation group after treatment were lower than those in the control group, with statistically significant differences (P <0.05). In serum and placental tissues, both kininase expression and TGF-1 levels of the observation group were higher than those of the control group, with lower PAPP-A, VCAM-1 and E selectin levels than those in the control group. Small-dose LMWH combined with magnesium sulfate can promote the expression of endogenous kallikrein, weaken the infiltration of cytotrophoblast, and improve the maternal blood clotting state in patients with severe PE. It also improves placental microblood flow and effectively prolong pregnancy, promotes fetal growth, and improves the clinical effects.


Mobility of the first metatarsal-cuneiform joint in patients with and without hallux valgus: in vivo three-dimensional analysis using computerized tomography scan.
Hallux valgus (HV) deformity is closely correlated to the hypermobility of the first metatarsal-cuneiform joint, but adequate understanding of the three-dimentional (3D) mobility of this joint in normal or HV feet is lacking. This study was conducted to investigate the mobility of the first metatarsal-cuneiform joint in multiple planes during body weight-bearing conditions for both normal and HV patients. A total of 10 female volunteers (20 feet) and 10 female HV patients (20 feet) participated in this study. Using a custom-made foot-loading device, computerized tomography (CT) scans of each pair of feet were taken under both unloaded and body weight-bearing conditions. 3D models were reconstructed for the first metatarsal and the medial cuneiform. Rotational and translational motions of the first metatarsal-cuneiform joint in multiple planes from unloaded to loaded conditions were quantitatively evaluated by reverse-engineering software. During body weight-bearing conditions, the first metatarsal-cuneiform joint in HV feet dorsiflexed at an average of 2.91° (standard deviation, SD 1.71) versus 1.18° (SD 0.47) in controls (t = 4.158, P = 0.001); supinated 2.17° (SD 2.28) versus 0.98° (SD 0.81) in controls (t = 2.080, P = 0.045); and internally rotated 2.65° (SD 2.22) versus 0.96° (SD 0.57) in controls (t = 3.114, P = 0.006). Moreover, the joint in HV feet widened significantly compared with the controls (t = 2.256, P = 0.030) and tended to translate more in the dorsal-plantar direction (t = 1.928, P = 0.063); the translation in the medial-lateral direction was not significantly different between the two groups. During weight-loading process, the first metatarsal-cuneiform joint turns dorsiflexed, supinated, and internally rotated. For HV feet, hypermobility of the first metatarsal-cuneiform joint can be observed in multiple planes. This study promotes further understanding of the physiological and pathological mobility of the first metatarsal-cuneiform joint.


Association Study of Single-Nucleotide Polymorphisms of STAT2/STAT3/IFN-γ Genes in Cervical Cancer in Southern Chinese Han Women.
Interferon-γ (IFN-γ) and signal transducers and activators of transcription (STATs) each play an important role in carcinogenesis associated with viral infection. Cervical cancer is almost invariably associated with infection by human papillomavirus (HPV), and previous studies suggested that dysregulation of the signal pathway involved in IFN-γ and STATs is associated. Our objective was to evaluate the association of SNPs in STAT2, STAT3, and IFN-γ with cervical cancer susceptibility in Chinese Han women in Hunan province. Genomic DNA was extracted from peripheral blood samples of 234 cervical cancer patients and 216 healthy female controls. STAT2 and STAT3 genotyping was performed using polymerase chain reaction-restriction enzyme (PCR-RE) analysis. IFN-γ genotyping was detected by PCR-amplification of specific allele (PASA). For STAT2 rs2066807 polymorphisms, there was no significant difference of genotype distribution (P=0.827) and allele frequencies (P=0.830, OR=1.09, 95% CI: 0.51-2.31) between cases and controls. For STAT3 rs957970 polymorphisms, there was no significant difference of genotype distribution (P=0.455) and allele frequencies (P=0.560, OR=0.92, 95% CI: 0.71-1.20) between cases and controls. For IFN-γ +874A/T polymorphisms, there was no significant difference of genotype distribution (P=0.652) and allele frequencies (P=0.527, OR=1.12, 95% CI: 0.79-1.59) between cases and controls. These results suggest that polymorphisms in STAT2, STAT3 and IFN-γ genes are not likely to be strong predictors of cervical cancer in Han women in southern China.


Occipitocervical arthrodesis using contoured plate fixation. An early report on a versatile fixation technique.
A simple, inexpensive, and rigid technique for occipitocervical fixation was evaluated in 14 patients with occipitocervical instability. Posterior arthrodeses of the occipitocervical region were performed using pelvic reconstruction plates and screws as internal fixation devices. At follow-up, which averaged 11.7 months, all patients had fused with minimal complications. This versatile technique, readily adapted to complex deformities and extensible for subaxial fixation, was reviewed.


Effectiveness of diffusion-weighted imaging in predicting cervical lymph node metastasis in head and neck malignancies.
The aim of this study was to evaluate the effectiveness of diffusion-weighted imaging (DWI) in predicting cervical lymph node metastasis in head and neck malignancies. Of the 67 patients with head and neck malignancies included in the study, 36 patients (the DWI group) underwent DWI examination with magnetic resonance imaging (MRI) of the cervical lymph nodes, and 31 patients (the conventional MRI group) underwent MRI only. Radiologists classified the lymph nodes as "metastatic" or "benign" in the DWI group by using MRI features and the apparent diffusion coefficients (ADCs) calculated from DWI, and in the conventional MRI group with MRI only. Histopathologic diagnosis of the nodes was the gold standard. The average ADC value of metastatic lymph nodes was significantly lower than that of benign lymph nodes (P = .020). An optimal threshold ADC value effectively distinguished the ADCs of metastatic versus benign lymph nodes (P = .003). Diagnostic performance was significantly better in the DWI group (P = .044), with significantly higher values for sensitivity, positive predictive value, and area under the receiver operating characteristic curve (P ≤ .039). ADC is effective in distinguishing metastatic lymph nodes from benign lymph nodes. The addition of ADC values to the morphologic evaluation of MRI results in significantly better diagnostic outcomes compared with evaluation of MRI alone.


[Past, present and future development of the project of manned space medico-engineering in China].
Based on the research work of manned space medico-engineering at different stages of its development in China, the formation and development of the subject was summarized. The relations among the main fields of space medico-engineering, that is, depend on each other for existence, influence, co-operation and infiltration in the system, were discussed. Considering the ongoing tasks of manned space flight in China, directions and contents of research work of manned space medico-engineering were pointed out. And to make the ongoing tasks more successful, methods of development of the subject were put forward, namely, teaching, research and project should promote each other and develop together.


Investigation of the inhibition effect of arachidonic acid on the core structure of the HIV-1 gp41.
The gp41 transmembrane domain of the envelope glycoprotein of the human immunodeficiency virus (HIV) modulates the conformation of the viral envelope spike. During the HIV fusion process, C-terminal heptad repeat (CHR, C34) wrap antiparallel to the N-terminal heptad repeat (NHR, N36) helices to form a stable six-helix bundle (6-HB) core structure, which brings the viral and cell membranes into close proximity for fusion. Therefore, inhibiting the formation of 6-HB is considered to be a key activity of an effective HIV-1 fusion inhibitor. The level of arachidonic acid (AA) is increased in HIV infected patients. Our study provides a new insight into the functional role of AA during the formation of HIV-1 gp41 6-HB. Native polyacrylamide gel electrophoresis (N-PAGE), enzyme-linked-immunosorbent serologic assay (ELISA) and circular dichroism (CD) spectroscopy were used to investigate the inhibition of AA for the formation of 6-HB. Molecular docking technique was adopted to explore the underlying mechanism. HIV-1 JR-FL (R5 strain) Envelope was adopted to determine the inhibition effect of AA. AA is shown to interfere with the formation of α-helical complexes of N36 and C34 by N-PAGE, ELISA and CD spectroscopy. The isotherm titration microcalorimetry (ITC) results indicate there is a single class of binding site on N36. ΔH and ΔS are -12.43 kJ mol-1 and 70.07 J mol-1 K-1, respectively, indicating hydrophobic interaction and electrostatic forces are the main acting forces. The molecular docking results manifest that AA interacts with the hydrophobic residues (Trp-571, Leu-568, Val-570 and Leu-576) and ionic interactions occur between Arg-579 and the -COOH of AA. The inhibitory activity of AA on HIV-1 JR-FL is quantified by 50% effective concentration (EC50) and 90% effective concentration (EC90), which are 31.42 ± 1.08 and 133.47 ± 18.10 μg mL-1, respectively. All the results indicate that AA is able to inhibit the formation of 6-HB but cannot disrupt the preformed 6-HB. Therefore, AA is a potential inhibitor for the viral fusion/entry.


Extraction and isolation of saponins.
Due to their special structural features, extraction and isolation of saponins poses a serious challenge. Conventional methods have been explored as well as the recent, relatively greener, efficient, solvent-economic, time-saving, newer methods of extraction. Both traditional and recent methods of isolation are also discussed. Finally, examples are given involving both conventional and newer methods of extraction and isolation. Though in general it is difficult to use a single technique for isolation of saponins, recent literature work seems to point to the fact that high speed counter-current separation coupled to evaporative light scattering detector (ELSD) gives superior separation. The ELSD appears to have circumvented the long-standing problem of saponin detection as most of these do not have a chromophore, and hence making UV detection only nonspecific and at range 200-210 nm.


A comparative randomized trial of vinca alkaloids in patients with metastatic breast carcinoma.
The therapeutic efficacy of vincristine, vinblastine, and vindesine were evaluated in a prospective randomized trial in patients with metastatic breast carcinoma. All patients were refractory to doxorubicin-containing chemotherapy. Vincristine was administered at 0.4 mg/m2/1/day by continuous infusion (CI), vinblastine at 1.7 mg/M2/1/day by CI, and vindesine at 1.2 mg/M2/1/day by CI or intermittent bolus (IB) over 5 days. The courses were administered at 2-week intervals for vincristine and 3-week intervals for vinblastine and vindesine. Ninety-nine patients were evaluable for response. The 15 patients treated with vincristine had no objective response. Of 23 patients treated with vinblastine, there were 2 complete responses (9%) and 5 partial responses (22%). Of 31 patients treated with CI vindesine, there were 6 partial responses (19%). Of 30 patients treated with IB vindesine, there were 5 partial responses (17%). The median duration of disease control was 13 weeks (range, 8-140+) for vinblastine, 18 weeks (range, 8-34) for CI vindesine, and 20 weeks (range, 12-47) for IB vindesine. These data illustrate that vinblastine (CI) and vindesine (CI or IB) have significant antitumor activity in patients with refractory metastatic breast carcinoma and that vincristine has not antitumor activity in similar patients.


A non-inferiority trial of an attenuated combination strategy ('COBRA-light') compared to the original COBRA strategy: clinical results after 26 weeks.
Early, intensive treatment of rheumatoid arthritis (RA) with the combination of (initially high dose) prednisolone, methotrexate and sulfasalazine (COBRA therapy) considerably lowers disease activity and suppresses radiological progression, but is infrequently prescribed in daily practice. Attenuating the COBRA regimen might lessen concerns about side effects, but the efficacy of such strategies is unknown. To compare the 'COBRA-light' strategy with only two drugs, comprising a lower dose of prednisolone (starting at 30 mg/day, tapered to 7.5 mg/day in 9 weeks) and methotrexate (escalated to 25 mg/week in 9 weeks) to COBRA therapy (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks, methotrexate 7.5 mg/week and sulfasalazine 2 g/day). An open, randomised controlled, non-inferiority trial in 164 patients with early active RA, all treated according to a treat to target strategy. At baseline patients had moderately active disease: mean (SD) 44-joint disease activity score (DAS44) 4.13 (0.81) for COBRA and 3.95 (0.9) for COBRA-light. After 6 months, DAS44 significantly decreased in both groups (-2.50 (1.21) for COBRA and -2.18 (1.10) for COBRA-light). The adjusted difference in DAS44 improvement between the groups, 0.21 (95% CI -0.11 to 0.53), was smaller than the predefined clinically relevant difference of 0.5. Minimal disease activity (DAS44 <1.6) was reached in almost half of patients in both groups (49% and 41% in COBRA and COBRA-light, respectively). At 6 months COBRA-light therapy is most likely non-inferior to COBRA therapy. 55552928.


The influence of attachment orientation on weight loss, eating behaviour and other health outcomes among patients undergoing bariatric surgery: A scoping review.
Attachment orientation is a psychological factor concerning our expectations of ourselves and others in interpersonal relationships. An emerging literature has suggested that attachment orientation may influence a range of outcomes associated with bariatric surgery. The purpose of this scoping review was to map the literature and examine the role of attachment orientation in the context of bariatric surgery. Studies conducted with patients who are undergoing or have undergone bariatric surgery, with a measure of attachment orientation and published by 21st July 2019, were located through electronic searches including Scopus, PubMed and Web of Science. 21180 studies were identified, of which 18 were retained for narrative synthesis. The major outcome themes reported were (1) post-surgery weight-loss/body mass index (k = 10), (2) eating behaviour (k = 9), (3) attachment orientation differences in bariatric surgery patients compared with control groups (k = 4) and 4) other mental and physical health outcomes (k = 12). Overall, the results showed that there was little evidence to suggest that poor attachment orientation is predictor of weight-loss following surgery. There was evidence to suggest that poorer attachment orientation relates to poorer eating behaviours both before and after surgery, that patients undergoing bariatric surgery are more likely to have a poorer attachment orientation and attachment orientation is related to mental health outcomes but not physical health outcomes for patients. However, where relationships were identified, there were considerable inconsistencies regarding the dimension of attachment orientation that drove the relationship. Future studies should consider appropriate sample sizes for studies, replication of key findings and longer durations for longitudinal studies.


Determination of palladium by on-line flow-injection direct spectrophotometry in environmental samples using 2,2'-furyldioxime as a chelator.
A new, sensitive, and accurate on-line spectrophotometric method for the determination of palladium was developed. The method is based on the reaction between Pd(II) and 2,2'-furyldioxime in nitric acid medium. The absorbance of the complex is spectrophotometrically measured at 410 nm with a diode-array detector. Several factors that influence the analytical performance of the method such as acidity, flow rates of the reagent and sample solutions, concentration of the reagent, and effect of interfering ions were investigated. The calibration curve was obtained in the range of 0.01-10.0 mg L(-1) Pd(II). The detection limit was 0.1 µg L(-1) while the relative standard deviation of the method was found to be 1.2% (n=13) at 4.0 mg L(-1) Pd(II) level. The sample throughput was 275 h(-1). The method was successfully applied to the determination of palladium in catalytic converter, anodic slime, road sediment, ore, and water samples.


Effects of reduced energy intake on protein utilization in obese children.
Dietary treatment of pediatric obesity is a challenge given the need for adequate nutrients to support the maintenance of lean tissue and growth. The primary purpose of this investigation was to assess the effects of reduced energy intake on protein turnover in obese children aged 8 to 10 years. Following a 2-week baseline period, 16 subjects reduced energy intake during a 6-week intervention period. At baseline and following the intervention, 15N-glycine methodology was used to measure nitrogen flux (Q), protein synthesis (PS), protein breakdown (PB), and net turnover ([NET] PS - PB). Other criterion measures included resting metabolic rate (RMR), fat mass (FM), fat-free mass (FFM), urinary creatinine to height ratio (Cr:Ht), and nitrogen balance (NB). On average, subjects lost 2.2 +/- 0.3 kg, of which greater than 85% was FM. Decreased Q (P = .03) indicated downregulation of protein turnover in response to diet-induced weight loss. While PB did not change, NET declined slightly (P = .06) as a consequence of reduced PS (P = .03). Reductions in FFM (P = .09), Cr:Ht (P = .02), and NB (P = .03) accompanied alterations in protein turnover, but there was no change in the RMR. In conclusion, while short-term therapy promoted the loss of FM and did not compromise RMR, practitioners must be cautious when prescribing diets, given the observed changes in protein utilization and somatic protein status. Longitudinal studies are needed to further characterize the metabolic responses of obese children to long-term diet therapy.


Erythromelalgia: Incidence and clinical experience in a single centre in Sweden.
Erythromelalgia (EM) incidence has not been well studied and there are only two studies published on this subject as far as we know. The aims are to study the incidence of this rare condition in the south of Sweden, to report the clinical experience from a single centre including characterisation of comorbidity and to report on prognosis. Retrospective study of a population-based analysis of data from the southernmost part of Sweden corresponding to the median age of the patients (Statistics Sweden). The diagnosis of EM is based on the medical record reflecting the triad of redness, burning pain and increased temperature of the feet or hands or both. We evaluated the presence or absence of EM triad by recording the history, physical examination, laboratory analysis, cold provocation test and laser Doppler imaging, and by searching for any confounding disease in cases of suspected EM. During a 10.5 year period we clinically identified 27 patients with EM. Median age was 49 [IQR (34 - 68)] years, 19 (70 %) were women. The mean delay from the onset of the symptoms to the time of diagnosis was 4.5 (SD ± 3.9) years. Gender and age adjusted incidence of EM for our region was calculated to be 0.36 per 100 000 persons per year. Three patients developed intraabdominal cancer during the follow up, but there was no mortality directed related to EM. The overall population-based incidence of erythromelalgia was 0.36 per 100 000 which is identical with a previous report in a Scandinavian population.


Binding of the cytotoxic and antitumor triterpenes, cucurbitacins, to glucocorticoid receptors of HeLa cells.
1. The binding of cucurbitacins to glucocorticoid receptors in HeLa cell-free systems and in intact cells was studied by competition with [3H]cortisol. Cucurbitacins were found to diminish the [3H]cortisol binding. 2. The difference in binding affinity at two temperatures suggest that cucurbitacins are metabolized under physiological conditions. 3. A linear correlation was observed between logarithms of relative binding affinities and of cytotoxic activities of cucurbitacins. Hence, the cucurbitacin binding to glucocorticoid receptors seems to be a necessary step for cytotoxic action of these compounds. 4. Cucurbitacin I was found to form cytoplasmic and nuclear salt-extractable complexes with glucocorticoid receptors of intact HeLa cells at 37 degrees C. Unlike cortisol, cucurbitacin I did not produce salt-resistant nuclear complexes.


Identification and isolation of embryonic stem cells in reproductive endocrinology: theoretical protocols for conservation of human embryos derived from in vitro fertilization.
Embryonic stem cells (ESC) are pluripotent cells obtained from the inner cell mass (ICM) of blastocysts derived from in vitro culture associated with reproductive endocrinology therapy. Human ESCs are regarded as highly significant since they retain the capacity to differentiate into any of approximately 200 unique cell types. Human ESC research is controversial because to acquire such cells, the ICM of human blastocysts must be manipulated in a way that renders embryos nonviable and unsuitable for transfer in utero. Techniques to yield competent ESCs with conservation of source blastocysts would satisfy many objections against ESC research, but at present such approaches remain largely untested. We contrast experimental culture of single blastomeres obtained by 1) non-destructive biopsy of embryos destined for transfer, and 2) isolation of karyotypically normal blastomeres from disaggregated ("dead") embryos considered unsuitable for transfer, and evaluate these approaches with regard to production of ESCs. Pluripotency was confirmed by morphological criteria and by quantification of divergent homeodomain proteins specific to undifferentiated cell development. Following ESC isolation and identification, assessment was conducted according to a novel ESC grading system, also proposed here. The role of reproductive endocrinology in ESC research remains paramount. In this report, we hypothesize new and expand on existing strategies having the potential to enhance human ESC isolation, identification and in vitro maintenance.


Transethnic meta-analysis of exome-wide variants identifies new loci associated with male-specific metabolic syndrome.
Metabolic syndrome (MetS) is a group of very common human conditions promoting strong understand the impact of rare variants, beyond exome-wide association studies, to potentially discover causative variants, across different ethnic populations. We performed transethnic, exome-wide MetS association studies on MetS in men. We analyzed genotype data of 5302 European subjects (2658 cases and 2644 controls), in the discovery stage of the European METabolic Syndrome In Men study, generated from exome chips, and 2481 subjects (714 cases and 1767 controls), in the replication stage, across 6 independent cohorts of 5 ancestries (T2D-GENES consortium), using whole-exome sequencing. We therefore evaluated gene-level and variant-level associations, of rare variants for MetS, using logistic regression (LR) and multivariate analyses (MulA). Gene-based association found the gene for the cholesteryl ester transfer protein (CETP) (from MulA, p value = 4.67 × 10-9; from LR, p value = 0.009) to well associate with MetS. At two missense variants, from 8 rare variants in CETP, Ala390Pro (rs5880) (from MulA, p value = 1.28 × 10-7; from LR, p value = 1.34 × 10-4) and Arg468Gln (rs1800777) (from MulA, p value = 2.40 × 10-5; from LR, p value = 1.49 × 10-3) significantly associated with MetS across five ancestries. Our findings highlight novel rare variants of genes that confer MetS susceptibility, in Europeans, that are shared with diverse populations, emphasizing an opportunity to further understand the biological target or genes that underlie MetS, across populations.


Symptomatic bilateral cerebellar mass lesions: an unusual presentation of intracranial xanthogranuloma.
Xanthogranulomas are a group of benign lesions with an incidence of 1.6-7.0% in various autopsy series. Although the lateral ventricle is the most frequent intracranial site involved, most symptomatic cases occur in the choroid plexus, involving the third ventricle. Multicentric bilateral symptomatic cerebellar xanthogranuloma has not been reported previously. We describe a 35-year-old man who presented with a complaint of vertigo, with nystagmus and left-side cerebellar signs found on clinical examination. Radiological evaluation revealed bilateral cerebellar lesions abutting the cerebellopontine angle cistern. The left-side lesion was excised and diagnosed as xanthogranuloma up on histopathological examination. The right-side lesion was subsequently excised 4 years later when it became symptomatic. The role of histopathology cannot be overemphasized in the diagnosis of this rare lesion and long-term follow-up is advised in cases managed conservatively owing to the propensity of this tumor to grow over time.


A-to-I RNA editing as a tuner of noncoding RNAs in cancer.
Recent advancement in RNA technology and computation biology shows the abundance and impact of RNA editing at the genome-wide level. Of RNA editing events, Adenosine-to-inosine (A-to-I) RNA editing is one of the most frequent types of RNA editing catalyzed by ADAR proteins. Indeed, A-to-I RNA editing occurs at the various coding and noncoding regions, triggering abnormal signaling pathways involved in cancer pathogenesis. Noncoding RNAs such as microRNA and long noncoding RNA have emerged as key regulators of pathways in cancer. The RNA editing including A-to-I editing is enriched in noncoding regions because of the abundance of noncoding RNAs accounting for 99% of total transcripts in the human genome. The effects of A-to-I editing in coding genes have been investigated and reported. However, those in noncoding RNAs have been less known in spite of the high frequency of editing events in noncoding regions. In this review, we will briefly discuss current findings and potential directions of A-to-I RNA editing research of noncoding RNAs and cancer. We will also introduce the concept of A-to-I editing, ADAR proteins, RNA editing technologies and databases.


The effects of TGF-β1 on the expression of type IV collagenases in mouse peritoneal macrophages.
Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that plays a critical role in modulating immune response and inflammation. We have investigated the effects of TGF-β1 on the expression of type IV collagenases, matrix metalloproteinase (MMP)-2 and MMP-9, in mouse peritoneal macrophages. TGF-β1 alone enhanced the secretion of MMP-9, while it blocked lipopolysaccharide (LPS)-stimulated MMP-9 production. We have shown that this biphasic effect of TGF-β1 is exerted at the mRNA level of the MMP-9 gene. Although TGF-β1 increased both basal and LPS-induced MMP-2 production at the protein and mRNA levels, the extent of the increase was smaller in LPS-activated macrophages than in control macrophages. The expression of type I and type II receptors for TGF-β was significantly decreased upon activation, suggesting that the lesser effect of TGF-β1 in activated macrophages may result from the decreased expression of TGF-β receptors. In addition, the expression of endogenous TGF-β1 mRNA was decreased significantly in activated macrophages. These findings suggest that activated macrophages not only produce less TGF-β1, but also respond less well to TGF-β to provide for inflammatory response.


Leflunomide abrogates neuroinflammatory changes in a rat model of Alzheimer's disease: the role of TNF-α/NF-κB/IL-1β axis inhibition.
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is associated with disrupted cognition and behavior. Neuroinflammatory pathogenesis is the main component that contributes to AD initiation and progression through microglial activation and neuronal damage. Thus, targeting inflammatory pathways may help manage AD. In this study, for the first time, the potential prophylactic and therapeutic effects of leflunomide were investigated either alone or in combination with rivastigmine in aluminum chloride (AlCl3)-induced AD-like rats using behavioral, biochemical, and histological approaches. Thirty-six adult male albino rats were divided into two protocols: the treatment protocol, subdivided into five groups (n = 6)-(1) control group, (2) AlCl3 (50, 70, 100 mg/kg/I.P) group, (3) reference group (rivastigmine 2 mg/kg/P.O.), (4) experimental group (leflunomide 10 mg/kg/P.O.), and (5) combination group (rivastigmine + leflunomide); and the prophylactic protocol (leflunomide 10 mg/kg/P.O.), which started 2 weeks before AlCl3 induction. The results showed that AlCl3 disrupted learning and memory parameters in rats and increased amyloid-β plaque deposition and neurofibrillary tangle aggregation. Moreover, AlCl3 administration markedly elevated acetylcholinesterase activity, nuclear factor-kappa β, tumor necrosis factor-α, and interleukin-1 beta, and marked degenerative changes in the pyramidal neurons. However, administration of leflunomide alone or with rivastigmine in AlCl3-induced AD rats restored most of the behavioral, biochemical, and histological parameters triggered by AlCl3 in rats. Our findings suggest that leflunomide can potentially restore most of the neuronal damage in the hippocampal tissues of AlCl3-induced AD rats. However, these preclinical findings still need to be confirmed in clinical trials.


Long-term outcomes of open radical retropubic prostatectomy for clinically localized prostate cancer in the prostate-specific antigen era.
To determine long-term oncological outcomes and complication rates for patients with clinically organ confined prostate adenocarcinoma (PCa) treated with open radical retropubic prostatectomy and pelvic lymph node dissection (RRP/PLND) in the prostate-specific antigen (PSA) era. Outcomes data were obtained from a prospectively maintained prostate cancer database. Patients with cT1/cT2 PCa undergoing RRP/PLND without neoadjuvant therapy between July 1988 and June 2008 were included. Kaplan-Meier and Cox proportional regression models were used to evaluate factors influencing biochemical recurrence, clinical recurrence, and overall survival (OS). A total of 2487 patients met inclusion criteria, and median follow-up was 7.2 years (range 1-21 years). Of the patients, 49.7% were low risk, 33.2% intermediate risk, and 16.1% high risk by D'Amico criteria, and 6% were LN+. The 10-year biochemical recurrence-free survival (BCRFS) for low-, intermediate-, and high-risk patients was 92%, 83%, and 76%, respectively (P < .001), and 10 year OS was 91%, 83%, and 74%, respectively (P < .001). BCRFS at 10 years was 76% and 88% for patients with positive and negative margins, respectively (P < .001). Of the 2487 patients, 11% developed BCR, and 3.7% experienced CR, with 9 local recurrences. The overall complication rate was 2.3%, and the cancer specific mortality rate was 2%. D'Amico risk group, margin status, and LN status are significantly correlated with outcomes in patients undergoing RRP/PLND for clinically localized PCa. Local recurrence and death from prostate cancer are rare in patients undergoing open RRP/PLND for clinically organ confined disease in the PSA era.


Positive darwinian selection promotes heterogeneity among members of the antifreeze protein multigene family.
A variety of organisms have independently evolved proteins exhibiting antifreeze activity that allows survival at subfreezing temperatures. The antifreeze proteins (AFPs) bind ice nuclei and depress the freezing point by a noncolligative absorption-inhibition mechanism. Many organisms have a heterogeneous suite of AFPs with variation in primary sequence between paralogous loci. Here, we demonstrate that the diversification of the AFP paralogues is promoted by positive Darwinian selection in two independently evolved AFPs from fish and beetle. First, we demonstrate an elevated rate of nonsynonymous substitutions compared to synonymous substitutions in the mature protein coding region. Second, we perform phylogeny-based tests of selection to demonstrate a subset of codons is subjected to positive selection. When mapped onto the three-dimensional structure of the fish antifreeze type III antifreeze structure, these codons correspond to amino acid positions that surround but do not interrupt the putative ice-binding surface. The selective agent may be related to efficient binding to diverse ice surfaces or some other aspect of AFP function.


Anti-inflammatory Activity of Constituents Isolated from Aerial Part of Angelica acutiloba Kitagawa.
Recently, the resources of medicinal plants have been exhausting. The root of Angelica acutiloba is one of the most important ingredients in Japanese Kampo medicine for the treatment of gynecological diseases. In our search for alternative medicinal plant resources of the root of A. acutiloba, we found that its aerial part has the anti-inflammatory potency as well as the root. Phytochemical investigation of the aerial part resulted in the isolation of four compounds including a new dimeric phthalide, namely tokiaerialide (2), along with Z-ligustilide (1), falcarindiol (3), and bergaptol (4). Next, we investigated the in vitro anti-inflammatory activity of 1-4 in lipopolysaccharide-stimulated RAW264 macrophages. Among the isolated compounds, 1 exhibited the most potent inhibition against lipopolysaccharide-induced production of prostaglandin E2 , nitric oxide, and pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor-α). Compounds 3 and 4 also inhibited all inflammatory mediators, but their inhibitory abilities were weaker than those of 1. Furthermore, 1, 3, and 4 strongly also induced heme oxygenase-1. These results suggest that 1, 3, and 4 potentially exert anti-inflammatory activity, and the aerial part of A. acutiloba may be considered to be a useful medicinal resource for inflammatory diseases.


Application of the synergetic algorithm on the classification of lymph tissue cells.
A synergetic classification algorithm for lymphocyte discrimination is developed. By improving the ISODATA algorithm, it is possible to cluster the cell types in the training set with respect to the cluster center samples which plays a role as the cell prototype set types. Based on synergetic theory, a two-step synergetic competition mechanism was established: (1) the order parameter competition was introduced between the test cell sample and the prototypes of each prototype set, by setting the prototype of the maximum order parameter as the best prototype of each set; (2) similar matching competition was performed between the test cell sample and the best prototypes. After that the classification is achieved by selecting the most similar result as the final result. This classification method was applied on four cell groups, i.e. mantle cells, follicular centrocytes, follicular centroblastic cells and centroblastic lymphoma cells. The results show that the averaged lymphocyte classification accuracy is up to 94.1%


Associated Factors of Sarcopenia in Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis.
(1) Background: To review the associated factors of sarcopenia in community-dwelling older adults. (2) Methods: PubMed, Embase, Web of Science, and four Chinese electronic databases were searched for observational studies that reported the associated factors of sarcopenia from inception to August 2021. Two researchers independently selected the literature, evaluated their quality, and extracted relevant data. The pooled odds ratio (OR) and its 95% confidence interval (CI) were calculated for each associated factors of sarcopenia using random-effects/fixed-effects models. Publication bias was assessed using funnel plot and the Eggers test. We performed statistical analysis using Stata 15.0 software. (3) Results: A total of 68 studies comprising 98,502 cases were included. Sociodemographic associated factors of sarcopenia among community-dwelling older adults included age (OR = 1.12, 95% CI: 1.10-1.13), marital status (singled, divorced, or widowed) (OR = 1.57, 95% CI: 1.08-2.28), disability for activities of daily living (ADL) (OR = 1.49, 95% CI: 1.15-1.92), and underweight (OR = 3.78, 95% CI: 2.55-5.60). Behavioral associated factors included smoking (OR = 1.20, 95% CI: 1.10-1.21), physical inactivity (OR = 1.73, 95% CI: 1.48-2.01), malnutrition/malnutrition risk (OR = 2.99, 95% CI: 2.40-3.72), long (OR = 2.30, 95% CI: 1.37-3.86) and short (OR = 3.32, 95% CI: 1.86-5.93) sleeping time, and living alone (OR = 1.55, 95% CI: 1.00-2.40). Disease-related associated factors included diabetes (OR = 1.40, 95% CI: 1.18-1.66), cognitive impairment (OR = 1.62, 95% CI: 1.05-2.51), heart diseases (OR = 1.14, 95% CI: 1.00-1.30), respiratory diseases (OR = 1.22, 95% CI: 1.09-1.36), osteopenia/osteoporosis (OR = 2.73, 95% CI: 1.63-4.57), osteoarthritis (OR = 1.33, 95% CI: 1.23-1.44), depression (OR = 1.46, 95% CI: 1.17-1.83), falls (OR = 1.28, 95% CI: 1.14-1.44), anorexia (OR = 1.50, 95% CI: 1.14-1.96), and anemia (OR = 1.39, 95% CI: 1.06-1.82). However, it remained unknown whether gender (female: OR = 1.10, 95% CI: 0.80-1.51; male: OR = 1.50, 95% CI: 0.96-2.34), overweight/obesity (OR = 0.27, 95% CI: 0.17-0.44), drinking (OR = 0.92, 95% CI: 0.84-1.01), hypertension (OR = 0.98, 95% CI: 0.84-1.14), hyperlipidemia (OR = 1.14, 95% CI: 0.89-1.47), stroke (OR = 1.70, 95% CI: 0.69-4.17), cancer (OR = 0.88, 95% CI: 0.85-0.92), pain (OR = 1.08, 95% CI: 0.98-1.20), liver disease (OR = 0.88, 95% CI: 0.85-0.91), and kidney disease (OR = 2.52, 95% CI: 0.19-33.30) were associated with sarcopenia. (4) Conclusions: There are many sociodemographic, behavioral, and disease-related associated factors of sarcopenia in community-dwelling older adults. Our view provides evidence for the early identification of high-risk individuals and the development of relevant interventions to prevent sarcopenia in community-dwelling older adults.


Does the T1 subdivision correlate with the risk of recurrence of papillary thyroid cancer?
Based on the AJCC seventh TNM classification, T1 intraglandular tumors are subdivided into T1a (≤10 mm) and T1b (11-20 mm), but the differences in prognosis remain controversial. The present study aimed to determine the clinicopathological features and outcomes of T1a and T1b patients. A retrospective study of 2518 T1 patients, including 1840 T1a (73 %) and 678 (27 %) T1b patients who underwent surgery for PTC from 1978 to 2014, was conducted. In patients with a preoperative or operative diagnosis of PTC, a total thyroidectomy (TT) with prophylactic (macroscopically N0) or therapeutic (evident N1) lymph node dissection (LND) was performed. Other patients had a TT or partial thyroidectomy without LND. The mean follow-up time was 8.9 ± 8.8 years (median, 6.5 years; range, 1-36.4 years). A TT was performed in 2273 patients (90 %), including 1184 (52 %) with LND. Other patients (n = 245) had a single lobectomy with isthmectomy. Multifocality, bilaterality, number of tumors, sum of the largest size of all foci, vascular invasion, and (in patients with LND) LN metastases were significantly more frequent in T1b than in T1a patients. Of the 1184 patients with LND, 278 had LN metastases (N1, 23 %), including 136/680 T1a (20 %) and 142/504 (28 %) T1b patients (p = 0.002). These LN metastases were diagnosed after a prophylactic LND in 86/609 T1a (14 %) and 93/440 T1b (21 %) patients (p = 0.001). Recurrences were more frequent in T1b (n = 26, 3.8 %) than in T1a patients (n = 35, 1.9 %, p = 0.005). In the multivariate analysis, independent prognostic factors for recurrence in both groups were the number of tumors, the sum of the largest size of all foci and, in patients who had LND, LN metastases and extranodal extension. For N0-x patients, the recurrence rate was significantly higher in the T1b than in the T1a group (2.4 vs. 0.9 %, respectively, p = 0.005), although this rate was similar in N1 patients (16.2 % for T1a and 9.2 % for T1b patients, p = 0.1). The 5-year disease-free survival rates for T1a and T1b patients were 98.3 and 96.6 %, respectively (p = 0.01). For PTC patients, T1b had poorer clinicopathological features and increased risk of recurrence than T1a.


1 H-NMR Based Metabolomics Profiling of Citrus Juices Produced in Veracruz, México.
This study describes the 1 H-NMR-based metabolomics profiling of juices from citrus fruits harvested in the state of Veracruz, México. The hydrophilic profile of commercial lemons (Agrio and Persian), tangerines (Fremont and Mónica), oranges (Valencia and Washington Navel), and grapefruits (Red Ruby and Rio Red) was determined. According to our results, 35 metabolites were identified in the 1 H-NMR profiling. The statistical differences obtained by PCA and OPLS-DA revealed that specific amino acids, sugars, and organic acids were differential metabolites in the species and cultivars studied. High endogenous levels of sucrose (10-190 mM), α-glucose, β-glucose (α- and β-isomers, 40-205 mm), and fructose (36-170 mm) were detected in the juices of grapefruits, oranges, and tangerines, whereas citric acid (40-530 mm) was the principal organic acid in the juices of lemons. To calculate the specific amounts of metabolites from these species and their cultivars, the results were finely analyzed using the qNMR method. According to these calculations, Valencia oranges had the highest concentration of ascorbic acid (>2 mm). The described 1 H-NMR method is highly reproducible, inexpensive, and highly robust in comparison to other analytical methods used to determine the hydrophilic profile of citrus juices.


Factors Associated with HIV Testing Among Participants from Substance Use Disorder Treatment Programs in the US: A Machine Learning Approach.
HIV testing is the foundation for consolidated HIV treatment and prevention. In this study, we aim to discover the most relevant variables for predicting HIV testing uptake among substance users in substance use disorder treatment programs by applying random forest (RF), a robust multivariate statistical learning method. We also provide a descriptive introduction to this method for those who are unfamiliar with it. We used data from the National Institute on Drug Abuse Clinical Trials Network HIV testing and counseling study (CTN-0032). A total of 1281 HIV-negative or status unknown participants from 12 US community-based substance use disorder treatment programs were included and were randomized into three HIV testing and counseling treatment groups. The a priori primary outcome was self-reported receipt of HIV test results. Classification accuracy of RF was compared to logistic regression, a standard statistical approach for binary outcomes. Variable importance measures for the RF model were used to select the most relevant variables. RF based models produced much higher classification accuracy than those based on logistic regression. Treatment group is the most important predictor among all covariates, with a variable importance index of 12.9%. RF variable importance revealed that several types of condomless sex behaviors, condom use self-efficacy and attitudes towards condom use, and level of depression are the most important predictors of receipt of HIV testing results. There is a non-linear negative relationship between count of condomless sex acts and the receipt of HIV testing. In conclusion, RF seems promising in discovering important factors related to HIV testing uptake among large numbers of predictors and should be encouraged in future HIV prevention and treatment research and intervention program evaluations.


Inhibition of leukocyte migration by tumor-associated antigen and its modification by serum; IgA as a blocking factor.
Based on the investigations of patients the migration inhibition assay proved to be a useful method for the detection of antitumorous cellular immunity. Out of the twenty patients tested 15 gave migratory inhibitory effect against specific tumor antigen. In 8 cases out of the above 15 the blocking activity of sera has been proved. This blocking activity is bound to IgA subclass. The complement played an "unblocking" role. The modifying role of serum factors in cellular immunity against tumors was discussed.


The ultimate model organism: progress in experimental medicine.
Experimental medicine is the use of innovative measurements, models and designs in studying human subjects for establishing proof of mechanism and concept of new drugs, for exploring the potential for market differentiation for successful drug candidates, and for efficiently terminating the development of unsuccessful ones. Humans are the ultimate 'model' because of the uncertain validity and efficacy of novel targets and drug candidates that emerge from genomics, combinatorial chemistry and high-throughput screening and the use of poorly predictive preclinical models. The in-depth investigation of the effects of drugs and the nature of disease progression is becoming ever more feasible because of advances in clinical biomarkers.


The impact on colorectal cancer survival of cases registered by 'death certificate only': implications for national survival rates.
This paper describes the effect of including death certificate only (DCO) registrations on 5 year relative survival rates for colorectal cancer in four district health authorities (DHAs) in south-east England. A retrospective case note study was set up to examine all cases of colorectal cancer listed in the Thames Cancer Registry (TCR) as having been diagnosed in 1983 and 1988 and resident in one of four districts, A, B, C and D. A total of 673 sets of cases notes were requested from all hospitals within the four districts, including 150 sets on DCO cases. Of 465 (69%) sets of case notes retrieved, 378 (72.3%) were non-DCO cases. Of these, 14 were excluded from survival analysis because of missing dates of diagnosis or death in the notes. Eighty-seven (58.0%) sets of case notes were retrieved on DCO registrations, of which seven were excluded because no date of diagnosis was available in the notes. Retrieval rates on case note registrations varied by DHA of residence: 73.3% in DHA A, 96.6% in DHA B, 34.5% in DHA C and 79.2% in DHA D. The corresponding figures for DCO registrations were 63.5%, 69.0%, 7.4% and 76.2%. Cumulative relative 5 year survival rates by DHA of residence were calculated first for cases registered from case notes and then for all cases including those registered solely from a death certificate. The total number of cases used in the survival analysis was 444 (18% DCOs). In all four DHAs, 5 year survival decreased with the inclusion of DCO registrations: by 9.1% in district A (from 52.8 to 43.7), by 4.5% in district B (from 59.6 to 55.1), by 4.8% in district C (from 80.0 to 75.2) and by 7.6% in district D (from 31.4 to 23.8). The overall reduction in survival was 8.6%. The exclusion of death certificate only registrations from survival data is an important source of bias. Using TCR data, we compared DCO proportions for colorectal cancer with other sites. DCO proportions were shown to vary by tumour site and survival time. The DCO registration is an important quality measure of ascertainment and follow-up. OPCS should publish DCO proportions by registry area and cancer site. Registries should implement DCO monitoring as part of quality improvement programmes.


Soluble Corin Predicts the Risk of Cardiovascular Disease: A 10-Year Follow-Up Study.
As a key enzyme of the natriuretic peptides system, corin may participate in the development of cardiovascular disease (CVD). Its level in circulation predicted CVD recurrence in patients with myocardial infarction and heart failure, but no study examined this prediction in general populations. This study sought to examine the prospective association between corin and CVD in a community-based population of Chinese adults. The Gusu cohort included 2,498 participants (mean age 53 years, 39% men) who were free of CVD at baseline. Serum corin was measured by enzyme-linked immunosorbent assay kits at baseline and CVD events were followed every 2 years for all participants. A competing-risks survival regression model was used to examine the association between serum corin and CVD. During 10 years of follow-up, 210 participants developed CVD including 88 stroke events. A higher serum corin (after log-transformation) at baseline was significantly associated with an increased risk of CVD (HR: 1.88; P = 0.019) and stroke (HR: 3.19; P = 0.014). Analysis using categorical serum corin (in quartiles) showed that participants in the highest quartile had a 62% and 179% increased risk for CVD (HR: 1.62; P = 0.024) and stroke (HR: 2.79; P = 0.004), respectively, compared with those in the lowest quartile. We did not find a significant association between serum corin and coronary heart disease. A higher serum corin at baseline predicted a higher risk of CVD events and stroke, but not coronary heart disease, in Chinese adults, independent of conventional risk factors. Serum corin may be a predictor for stroke but the underlying mechanism needs further investigation.


Volcanic ash, victims, and tsunami debris from the Late Bronze Age Thera eruption discovered at Çeşme-Bağlararası (Turkey).
The Late Bronze Age Thera eruption was one of the largest natural disasters witnessed in human history. Its impact, consequences, and timing have dominated the discourse of ancient Mediterranean studies for nearly a century. Despite the eruption's high intensity (Volcanic Explosivity Index 7; Dense Rock Equivalent of 78 to 86 km) [T. H. Druitt, F. W. McCoy, G. E. Vougioukalakis, Elements 15, 185-190 (2019)] and tsunami-generating capabilities [K. Minoura et al., Geology 28, 59-62 (2000)], few tsunami deposits are reported. In contrast, descriptions of pumice, ash, and tephra deposits are widely published. This mismatch may be an artifact of interpretive capabilities, given how rapidly tsunami sedimentology has advanced in recent years. A well-preserved volcanic ash layer and chaotic destruction horizon were identified in stratified deposits at Çeşme-Bağlararası, a western Anatolian/Aegean coastal archaeological site. To interpret these deposits, archaeological and sedimentological analysis (X-ray fluorescence spectroscopy instrumental neutron activation analysis, granulometry, micropaleontology, and radiocarbon dating) were performed. According to the results, the archaeological site was hit by a series of strong tsunamis that caused damage and erosion, leaving behind a thick layer of debris, distinguishable by its physical, biological, and chemical signature. An articulated human and dog skeleton discovered within the tsunami debris are in situ victims related to the Late Bronze Age Thera eruption event. Calibrated radiocarbon ages from well-constrained, short-lived organics from within the tsunami deposit constrain the event to no earlier than 1612 BCE. The deposit provides a time capsule that demonstrates the nature, enormity, and expansive geographic extent of this catastrophic event.


Changes in the upper airway, hyoid bone and craniofacial morphology between patients treated with headgear activator and Herbst appliance: A retrospective study on lateral cephalometry.
The present study compared the treatment changes in the upper airway, hyoid bone position and craniofacial morphology between two groups of children with skeletal class II malocclusion treated with the headgear activator (HGA) and Herbst appliance (Herbst). Orthodontic population from the Faculty of Dentistry of the University of Hong Kong. Thirty-four skeletal class II patients treated with the HGA (17 patients, mean age 10.6 ± 1.5 years) and the Herbst (17 patients, mean age 11.0 ± 1.4 years) were matched for sex, age, overjet, skeletal class and mandibular divergence. The patients received lateral cephalometric radiographs (LCRs) at the beginning of treatment (T1 ), after treatment (T2 ) and at follow-up (T3 ). In the HGA group, patients underwent LCRs 7 months before the beginning of treatment (T0 ), which were used as growth reference for intra-group comparison. Paired Student's t tests were used for intra- and inter-group comparisons (α = .05). Treatment changes (T2 -T1 ) did not differ significantly between the groups. However, at follow-up (T3 -T1 ) the Herbst group showed a smaller increase than the HGA group in the vertical position of the hyoid bone relative to the Frankfort plane (P = .013) and mandibular plane (P = .013). There were no significant differences in the upper airway, hyoid bone position and craniofacial morphology between the groups at the end of treatment. However, the Herbst may provide better long-term control of the vertical position of the hyoid bone than the HGA in children with skeletal class II malocclusion.


[Effect of host cells on the course of chronic rabies virus infection in cell cultures].
Different patterns of rabies virus infection were observed in BHK-21/13S and HEp-2 cell cultures at late stages of persistent infections. The infection of BHK-21/13S cells was characterized by periodical increases and declines in the portion of the antigen-containing cells (from 100% to less than 1%) and low infectivity titers which did not correspond to fluctuations in the antigen production and occasional resistance to challenge with vesicular stomatitis virus. In contrast, persistently infected HEp-2 cell culture exhibited a more constant course of antigen production which never reached extreme points; the infectivity titers generally correlated with the portion of the antigen-containing cells. Cultivation in the presence of antirabies serum did not "cure" either of the cultures.


[Is there any evidence that the maternal HPL serum-concentration is of prognostic value in cases of threatened abortion? (author's transl)].
The mean values of the maternal HPL are significantly decreased in cases of threatened abortion from the 10th to the 16th week post menstruation. But the HPL concentration is only of prognostic value after the 13th week because only after that time the HPL concentration is significantly decreased in cases with following abortion. The common therapy with gestagens or with a combination of estrogens and gestagens has no influence of the mean HPL concentrations. For the first time it could be shown an influence of an exogen estrogen-gestagen combination on the individual values of HPL serum-concentrations.


Effect of prognostic classification on temsirolimus efficacy and safety in patients with relapsed or refractory mantle cell lymphoma: a retrospective analysis.
Temsirolimus, a selective inhibitor of the mammalian target of rapamycin, has demonstrated clinical benefit versus investigator's choice (INV) of therapy in patients with relapsed/refractory mantle cell lymphoma (MCL). This post hoc study retrospectively assigned simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) scores (ie, secondary MIPI) based on parameters at the time of randomization in patients with MCL (N = 162) who received temsirolimus 175 mg once weekly for 3 weeks followed by once-weekly 75 mg or 25 mg or the INV of active therapy. Outcomes were analyzed according to the low-, intermediate- or high-risk category. Patient distribution by MIPI risk category was 31%, 39%, and 30% in the low-, intermediate-, and high-risk groups, respectively. Among patients in all categories, objective response rate (complete response + partial response) was higher in patients in the temsirolimus 175/75-mg group versus the INV group, respectively: 42% versus 0% (low-risk); 33% versus 5% (intermediate-risk); 10% versus 0% (high-risk). Median progression-free survival was significantly longer with temsirolimus 175/75 mg versus INV, respectively, in patients with intermediate (4.3 vs 1.9 months; P = 0.035) or high (4.5 vs 1.6 months; P = 0.0025) risk, and a trend toward improvement was observed in patients with low risk (5.3 vs 2.6 months; P = 0.091). Improvement in median overall survival was observed with temsirolimus 175/75 mg versus INV in low-risk patients (18.0 vs 10.5 months, respectively; P = 0.069). This analysis suggests that, compared with INV, temsirolimus demonstrated benefit in all MIPI risk categories in patients with MCL. In all treatment groups, patients with high secondary MIPI scores at baseline faced a dismal prognosis. ClinicalTrials.gov NCT00117598.


Visual orienting response in goldfish: a multidisciplinary study.
The neural basis underlying the orienting response has been thoroughly studied in frontal-eyed mammals. However, in non-mammalian species, including fish, it remains almost unknown. Therefore, we studied the contribution of the optic tectum and the mesencephalic reticular formation to the performance of the orienting response in goldfish, using behavioural, physiological, and anatomical tracer techniques. The appearance of a visual stimulus (a pellet of food) in the environment of a goldfish evoked a turn of the body to reorient the line of sight. Left-tectal lobe ablation abolished the orienting turn response towards the contralateral hemifield. Electrical microstimulation of the optic tectum suggested the presence of a motor map, which is in correspondence with the overlying visual representation, as previously reported in other vertebrates. The tracer biotin-dextran amine was injected into different functionally identified tectal zones. The results showed that rostral and caudal poles of the mesencephalic reticular formation receive outflow mainly from the rostral and caudal tectal poles, respectively. This suggests that the tectal wiring with downstream structures is site-dependent. Furthermore, the electrical activation of rostral and caudal mesencephalic reticular formation revealed a different contribution to vertical and horizontal orienting eye movements. We conclude that the basic neural system coding the orienting response appears early in phylogenesis, although some specific characteristics are selected by adaptive pressure.


Levodopa Dose Equivalency in Parkinson's Disease: Updated Systematic Review and Proposals.
To compare drug regimens across clinical trials in Parkinson's disease (PD) conversion formulae between antiparkinsonian drugs have been developed. These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as 'levodopa equivalent dose' (LED). Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used. However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010. Therefore, consensus proposals for updated LED conversion formulae are needed. To update LED conversion formulae based on a systematic review. The MEDLINE, CENTRAL, and Embase databases were searched from January 2010 to July 2021. Additionally, in a standardized process according to the GRADE grid method, consensus proposals were issued for drugs with scarce data on levodopa dose equivalency. The systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review. Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon. The LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


[Effect of swimming on the uptake and content of taurine in the rat heart].
14C-taurine uptake and total taurine content increase during a 15-min period of swimming. Prolongation of this period leads to more active taurine metabolism (ISA formation) but the total taurine content does not change. Active accumulation against its concentration gradient and maintenance of the taurine content at the same level during the entire period of swimming suggest that the taurine uptake and its metabolism are interdependent and very important for heart activity.


Increased fluid intake and adequate dietary modification may be enough for the successful treatment of uric acid stone.
Uric acid stones are the most readily dissolvable of all types of urinary stones. The present paper describes two patients with uric acid stones in kidney and ureter, whom we have treated successfully only by a combination of increased fluid intake and adequate dietary modification.


Human fibrocyte-derived exosomes accelerate wound healing in genetically diabetic mice.
Diabetic ulcers represent a substantial societal and healthcare burden worldwide and scarcely respond to current treatment strategies. This study was addressed to evaluate the therapeutic potential of exosomes secreted by human circulating fibrocytes, a population of mesenchymal progenitors involved in normal wound healing via paracrine signaling. The exosomes released from cells sequentially stimulated with platelet-derived growth factor-BB and transforming growth factor-β1, in the presence of fibroblast growth factor 2, did not show potential immunogenicity. These exosomes exhibited in-vitro proangiogenic properties, activated diabetic dermal fibroblasts, induced the migration and proliferation of diabetic keratinocytes, and accelerated wound closure in diabetic mice in vivo. Important components of the exosomal cargo were heat shock protein-90α, total and activated signal transducer and activator of transcription 3, proangiogenic (miR-126, miR-130a, miR-132) and anti-inflammatory (miR124a, miR-125b) microRNAs, and a microRNA regulating collagen deposition (miR-21). This proof-of-concept study demonstrates the feasibility of the use of fibrocytes-derived exosomes for the treatment of diabetic ulcers.


Gene Therapy for the Treatment of Neurological Disorders: Amyotrophic Lateral Sclerosis.
Gene therapy is a powerful tool for treating diseases, including neurological disorder such at amyotrophic lateral sclerosis. When delivered to the CNS, gene therapy vectors can provide prosurvival signals to neurons, knock down the expression of toxic proteins, or restore lost function. How to best deliver this type of therapeutic depends on the nature of the disease and the expected function of the transgene. Here we describe a method for parenchymal injection into rodent models, allowing for localized delivery of gene therapy vectors and other therapeutic molecules. This technique has been a robust mechanism for proof-of-principle experiments.


Change of antibody levels to ferritin in the sera of foals after birth: possible passive transfer of maternal anti-ferritin autoantibody via colostrum and age-related anti-ferritin autoantibody production.
Antibody (immunoglobulin G (IgG), IgM or IgA) levels relative to ferritin in six foal sera (three male and three female) after birth (day 0 and 2, 6, 10, 20, 28, 36, 40, 52 and 56 weeks of age) were semi-quantitatively measured with normalization with antibody activity to ferritin in one adult horse serum. After addition of horse spleen ferritin to the serum sample, the complex formed between antibodies to ferritin in the serum and ferritin was co-immunoprecipitated using antibody to horse spleen ferritin. Antibody classes of the co-immnoprecipitate were detected with antibodies specific for horse IgG, IgM or IgA heavy chain. Six adult horse serum samples were found to have ferritin-binding activities in all immunoglobulin classes examined. Although ferritin antibody activities (IgG, IgM and IgA) were scant in the foal sera before sucking colostrum (day 0), their activities increased at 2 weeks of age. IgG antibodies showed a biphasic response and IgM antibody activity increased up to 40 weeks of age. Antibody (IgG, IgM and IgA) activities to ferritin in three colostrum samples were significantly higher than in adult horse serum samples. These results demonstrate that antibody to ferritin in foal serum is derived from colostrum after birth and is produced thereafter.


Protist communities are more sensitive to nitrogen fertilization than other microorganisms in diverse agricultural soils.
Agricultural food production is at the base of food and fodder, with fertilization having fundamentally and continuously increased crop yield over the last decades. The performance of crops is intimately tied to their microbiome as they together form holobionts. The importance of the microbiome for plant performance is, however, notoriously ignored in agricultural systems as fertilization disconnects the dependency of plants for often plant-beneficial microbial processes. Moreover, we lack a holistic understanding of how fertilization regimes affect the soil microbiome. Here, we examined the effect of a 2-year fertilization regime (no nitrogen fertilization control, nitrogen fertilization, and nitrogen fertilization plus straw amendment) on entire soil microbiomes (bacteria, fungi, and protist) in three common agricultural soil types cropped with maize in two seasons. We found that the application of nitrogen fertilizers more strongly affected protist than bacterial and fungal communities. Nitrogen fertilization indirectly reduced protist diversity through changing abiotic properties and bacterial and fungal communities which differed between soil types and sampling seasons. Nitrogen fertilizer plus straw amendment had greater effects on soil physicochemical properties and microbiome diversity than nitrogen addition alone. Moreover, nitrogen fertilization, even more together with straw, increased soil microbiome network complexity, suggesting that the application of nitrogen fertilizers tightened soil microbiomes interactions. Together, our results suggest that protists are the most susceptible microbiome component to the application of nitrogen fertilizers. As protist communities also exhibit the strongest seasonal dynamics, they serve as the most sensitive bioindicators of soil changes. Changes in protist communities might have long-term effects if some of the key protist hubs that govern microbiome complexities as top microbiome predators are altered. This study serves as the stepping stone to promote protists as promising agents in targeted microbiome engineering to help in reducing the dependency on exogenous unsustainably high fertilization and pesticide applications.


Differential expression of D(1A) and D(1B) dopamine receptor mRNAs in the developing avian retina.
In the chick retina, the D1 dopaminergic system differentiates very early, as shown by receptor-mediated increases in intracellular cyclic AMP concentration and the presence of [(3)H]SCH23390-specific binding sites. Here, we characterized, by RT-PCR, the expression of defined D1 receptor subtypes D(1A), D(1B), and D(1D) during the development of the chick retina. Total RNA was extracted from retinas of 6-day-old embryos (E6) to 1-day-old hatched chickens and reverse-transcribed. The resulting cDNA was amplified using D(1A)-, D(1B)-, or D(1D)-specific primers, and the PCR-amplified products were analyzed by electrophoresis. The fragment corresponding to D(1A) receptor was detected in developing retina as early as E7, whereas the fragment corresponding to D(1B) was observed starting around E10. No PCR product corresponding to D(1D) was observed in the retina, although it was detected in chick brain. As synaptogenesis in chick retina begins after E11 and [(3)H]SCH 23390 D1 binding sites increase after this stage, the present results show that expression of D(1B) receptor increases during synaptogenesis, whereas D(1A) is the receptor subtype associated with the D1-like actions of dopamine early in retina development.


Survival of elderly persons undergoing colonoscopy: implications for colorectal cancer screening and surveillance.
In the elderly, the increased prevalence of colorectal neoplasia and the protective effect of colonoscopy may be offset by advancing age and comorbidity. To describe and quantify the endoscopic findings, survival, and predictors of mortality of elderly persons after colonoscopy. Retrospective cohort study of persons aged>or=75 years who underwent colonoscopy in 1999 and 2000 at a U.S. Veterans Affairs facility and urban county hospital. Advanced neoplasms were defined as colorectal cancer (CRC), polyp with high-grade dysplasia, villous histologic features, or tubular adenoma>or=1 cm. Comorbidity was measured with the Charlson comorbidity index. Subjects were followed until death or study closure. Of 469 eligible subjects, 65 were excluded and 404 were included in the study. Fifty-nine of 404 (15%) had an advanced neoplasm, including 8 (2%) with CRC. There were 167 deaths (41%); the mean overall survival was 4.1+/-0.1 years (median 5.95 years). A symptomatic indication for colonoscopy was not predictive of death. Mortality was predicted by age (hazard ratio 1.16 for each year increase beyond age 75 years, 95% CI 1.07-1.3, P=.0003) and Charlson score (hazard ratio 8.3 for each point increase, 95% CI 1.4-48.5, P=.02). The median survival of patients aged 75 to 79 years was >5 years if the Charlson score was <or=4. Among patients aged>or=80 years, the median survival was <5 years regardless of Charlson score. Retrospective design. In this cohort of elders, age and comorbidity were predictors of death. The protective effect of younger age lessens as comorbidity increases. These findings may have important implications for CRC screening and surveillance in elders.


Effects of weaning on regulators of volatile fatty acid absorption and intracellular pH in Holstein calves.
This study examined the effects of changes in rumen fermentation during the weaning transition on abundance of transporters involved in volatile fatty acid (VFA) absorption or intracellular pH homeostasis. Holstein bull calves (n = 27) were assigned to 1 of 3 treatment groups in a randomized, complete block design: 2 preweaning groups [animals fed milk only (PRE-M) or milk, calf starter, and hay (PRE-S)] and 1 postweaning group (animals fed milk, starter, and hay with a 2-wk weaning transition; POST-S). Calves were euthanized at 42 d of age (PRE-M and PRE-S) or at 63 d of age (POST-S), and rumen epithelium and rumen fluid samples were collected. Rumen fluid was analyzed for VFA concentration, and rumen epithelium was analyzed for the abundance of VFA transporter monocarboxylate transporter isoform 1 (MCT1) and the intracellular pH regulators sodium bicarbonate co-transporter 1 (NBC1) and sodium-proton exchanger 3 (NHE3) protein. Preweaning, total VFA concentrations tended to increase and NBC1 abundance increased with starter intake. Between pre- and postweaning, total VFA concentrations increased but NHE3 protein abundance decreased. In calves, rumen epithelial development during the weaning transition appears to show more pronounced changes in intracellular pH homeostasis than in VFA transport capacity.