Prostate-specific antigen to predict outcome of external beam radiation for prostate cancer: Walter Reed Army Medical Center experience, 1988-1995.
To assess the ability of pretreatment and post-treatment prostate-specific antigen (PSA) measurements, clinical tumor stage, tumor grade, Gleason sum, race, age, and radiation dose to predict the recurrence of prostate cancer following external beam radiation therapy (XRT) since the introduction of PSA as a tumor marker at one tertiary care center. The recurrence of prostate cancer among 371 evaluable patients of 389 patients treated with XRT at Walter Reed Army Medical Center was analyzed using Kaplan-Meier survival methodology and Cox multivariable regression models. Serologic (PSA) recurrence was determined using three consecutive rises in PSA after a nadir value. Clinical recurrence was defined as local recurrence (palpable or positive biopsy) and/or distant (radiographically evident) recurrence. Mean and median follow-up is 40.2 and 39.4 months, respectively (range 3.0 to 89.5), and minimum follow-up is 18 months for patients who were alive at the time of analysis. No patient received adjuvant hormonal therapy. Potential prognostic factors evaluated are pretreatment PSA, PSA nadir, age, race, clinical tumor stage, tumor grade, Gleason sum, and radiation dose. Of the 371 evaluable patients, 125 had disease recurrence. The Kaplan-Meier 5-year disease-free survival (DFS) rates for significant pretreatment variables in univariate analyses are as follows: pretreatment PSA less than 4 (79%), 4.1 to 10 (67%), 10.1 to 20 (57%), 20.1 to 50 (27%), and more than 50 (0%); for clinical tumor Stage T1a-T1c (84%), T2a-T2c (51 %), and T3-T4 (29%); for tumor grade well (58%), moderate (58%), and poor (30%). Four-year DFS rates for Gleason sum are 2 to 4 (82%), 5 (72%), 6 (56%), and 7 to 10 (48%). In multivariable Cox regression analysis with backward elimination of nonsignificant variables, age, race, tumor grade, and radiation dose were eliminated, leaving pretreatment PSA, clinical tumor stage, and Gleason sum as significant prognostic factors. Analysis of a Cox model that included nadir PSA as a time-dependent variable showed it to be the strongest prognostic factor variable in the analysis. XRT remains a suitable treatment modality for patients with pretreatment PSA less than 20.0, clinical tumor Stages T1-T2, and Gleason sum 2 to 6 prostate cancer. Patients achieving a nadir value less than 0.5 have more durable treatment outcomes.


Microbiological N-deoxygenation and C-oxygenation of pioglitazone-N-oxide in a single fermentation.
Oxygenation of pioglitazone-N-oxide by a microorganism isolated from soil was accompanied by N-deoxygenation to produce the pioglitazone metabolites 5-[4-[2-[5-(1-hydroxyethyl)-2-pyridyl]ethoxy]benzyl]-2,4-thiazolidinedio ne and 5-[4-[2-(5-acetyl-2-pyridyl)ethoxy]benzyl]2,4-thiazolidinedione. The oxygenating/deoxygenating organism has been characterized as Streptomyces hygroscopicus strain 02179 (UC 11099). The culture has been deposited with Agricultural Research Service, USDA, with accession number NRRL 18975.


Induction of a late asthmatic response associated with airway inflammation in mice.
To investigate mechanisms underlying the late asthmatic response, we developed a murine model using repetitive intratracheal antigen challenge. BALB/c mice sensitized by i.p. injection with ovalbumin+alum were challenged with ovalbumin intratracheally 4 times. The 1st challenge induced early airway obstruction peaking at 30 min but without a late response; however, the 4th challenge caused not only early but also late airway obstruction at 2-8 h. Eosinophils, and CD4+ and CD8+ T lymphocytes were increased in the airway before the 4th but not before the 1st-3rd challenges. The numbers of IgE+/CD117+ (mast) cells were also increased in the lung before the 4th challenge. Levels of Th2 cytokines were also increased in the airway. Daily administration of dexamethasone during the challenge period suppressed all these inflammatory events. Thus, this experimental late asthmatic response is associated with Th2 cytokine production from inflammatory cells recruited as a consequence of the 1st-3rd challenges.


Nutritional status and performance capacity in internal medical patients.
The nutritional status (3 anthropometric records, serum albumin and delayed cutaneous hypersensitivity (DCH)), recent weight loss, dynamometric capacity and mood were assessed in 205 recently admitted non-cancer internal medical patients. 20% of the subjects were classified as malnourished (3 of the 5 nutritional variables below the reference range). The occurrence of malnutrition was higher (1/3) in multiple organ dysfunction or chronic respiratory disease. In order to reduce the risk of overestimating malnutrition, the data for serum albumin and DCH were omitted when they appeared to be influenced by non-nutritional factors. Disease duration >2 years, old age and multiple organ dysfunction were independently related to malnutrition. Serum albumin correlated more strongly with the acute phase reactant, serum acid glycoprotein (r = 0.33, P < 0.001) than with the anthropometric variables (r < 0.24). Recalled recent weight loss >5% was found in 34% of the malnourished subjects. Malnourished, in comparison to well nourished patients, exhibited reduced (p < 0.05) recordings for hand grip strength, peak expiratory flow and time of ambulation. Depressive tendencies were seen in malnourished women (p < 0.05).


Electron beam-induced current imaging with two-angstrom resolution.
An electron microscope's primary beam simultaneously ejects secondary electrons (SEs) from the sample and generates electron beam-induced currents (EBICs) in the sample. Both signals can be captured and digitized to produce images. The off-sample Everhart-Thornley detectors that are common in scanning electron microscopes (SEMs) can detect SEs with low noise and high bandwidth. However, the transimpedance amplifiers appropriate for detecting EBICs do not have such good performance, which makes accessing the benefits of EBIC imaging at high-resolution relatively more challenging. Here we report lattice-resolution imaging via detection of the EBIC produced by SE emission (SEEBIC). We use an aberration-corrected scanning transmission electron microscope (STEM), and image both microfabricated devices and standard calibration grids.


Mechanism of induction of cytochrome P-450ac (P-450j) in chemically induced and spontaneously diabetic rats.
Previous studies demonstrated that a microsomal high-affinity N-nitrosodimethylamine demethylase activity and cytochrome P-450ac (an acetone/ethanol-inducible form) were induced by streptozotocin-induced diabetes in rats. In the present work, the induction was studied in detail in two chemically induced (by streptozotocin and alloxan) diabetic rat models and one spontaneously (BB/Wor) diabetic rat model. All the diabetic conditions caused increases in three parameters: (a) microsomal N-nitrosodimethylamine demethylase activity which is known to be a good indicator of the level of P-450ac; (b) the levels of P-450ac as determined by immunoblot analysis; and (c) the levels of mRNA of P-450ac as determined by hybridization assays with a cDNA probe for this enzyme. These increases were abolished by treatment of the diabetic rats with insulin. The results suggest that the pathophysiological condition of diabetes is responsible for the induction of P-450ac and elevation of mRNA is involved in all of the three diabetic models investigated.


[Electrocardiograms: derived derivations!]
Simple and non-invasive, the electrocardiogram is a basic examination for studying how the cardiac muscle functions. Very commonly used, it nonetheless requires great rigour when applying the electrodes to avoid false results that can be harmful to appropriate care for the patient. A reminder of good practices.


Selective emigration of suppressor T cells from Peyer's patches.
The emigration of Peyer's patch lymphocytes to mesenteric lymph nodes was studied by injecting fluorescein isothiocyanate (FITC) directly into Peyer's patches. Using double immunofluorescence it was demonstrated that at 2 and 4 hr after FITC injection 70% of the labeled cells that migrated to mesenteric lymph nodes were T lymphocytes, although rat Peyer's patches contain only 15-20% T lymphocytes. At later time points after FITC injection this percentage of T cells derived from Peyer's patches gradually declined, most likely caused by selective interaction and/or retention inside the mesenteric lymph node. Determination of helper and suppressor T-cell subsets within this emigrating population showed an increased number of T suppressor cells migrating into mesenteric lymph nodes. The putative role of suppressor T cells in inducing systemic tolerance after oral antigen administration was discussed.


Neuromuscular scoliosis.
Scoliosis is a common deformity in many types of neuromuscular disease. Severe spinal curvature can cause difficulty in sitting. Conservative and surgical treatment of neuromuscular scoliosis differs from idiopathic scoliosis, being more complex and with a higher complications rate. Non-surgical measures rarely fully control progressive scoliosis, but aim to prevent spinal deformities secondary to muscular hypotonia or contracture. Twenty-four hour bracing should be adjusted throughout growth, and may induce functional impairment and loss of independence. Corrective surgery requires multidisciplinary management and perioperative screening. Pelvic obliquity is commonly associated with neuromuscular scoliosis, making sitting difficult: correction needs to be considered during surgical planning. The goal of surgical correction is to obtain and maintain a well-balanced spine above a well-positioned pelvis. Preoperative multidisciplinary assessment enables potential problems of terrain to be anticipated. Respiratory function investigation will guide possible non-invasive perioperative ventilation. Nutritional and psychosocial assessment should also be incorporated in this preparation, as should overall postoperative care. Implementing this overall strategic planning can achieve a good surgical and functional result in the vast majority of cases.


Systematic evaluation of candidate ligands regulating ectodomain shedding of amyloid precursor protein.
Despite intense interest in the proteolysis of the β-Amyloid Precursor Protein (APP) in Alzheimer's disease, how the normal processing of this type I receptor-like glycoprotein is physiologically regulated remains ill-defined. In recent years, several candidate protein ligands for APP, including F-spondin, Reelin, β1 Integrin, Contactins, Lingo-1, and Pancortin, have been reported. However, a cognate ligand for APP that regulates its processing by α- or β-secretase has yet to be widely confirmed in multiple laboratories. Here, we developed new assays in an effort to confirm a role for one or more of these candidate ligands in regulating APP ectodomain shedding in a biologically relevant context. A comprehensive quantification of APPsα and APPsβ, the immediate products of secretase processing, in both non-neuronal cell lines and primary neuronal cultures expressing endogenous APP yielded no evidence that any of these published candidate ligands stimulate ectodomain shedding. Rather, Reelin, Lingo-1, and Pancortin-1 emerged as the most consistent ligands for significantly inhibiting ectodomain shedding. These findings led us to conduct further detailed analyses of the interactions of Reelin and Lingo-1 with APP.


An informatics approach to integrating genetic and neurological data in speech and language neuroscience.
A number of heritable disorders impair the normal development of speech and language processes and occur in large numbers within the general population. While candidate genes and loci have been identified, the gap between genotype and phenotype is vast, limiting current understanding of the biology of normal and disordered processes. This gap exists not only in our scientific knowledge, but also in our research communities, where genetics researchers and speech, language, and cognitive scientists tend to operate independently. Here we describe a web-based, domain-specific, curated database that represents information about genotype-phenotype relations specific to speech and language disorders, as well as neuroimaging results demonstrating focal brain differences in relevant patients versus controls. Bringing these two distinct data types into a common database ( http://neurospeech.org/sldb ) is a first step toward bringing molecular level information into cognitive and computational theories of speech and language function. One bridge between these data types is provided by densely sampled profiles of gene expression in the brain, such as those provided by the Allen Brain Atlases. Here we present results from exploratory analyses of human brain gene expression profiles for genes implicated in speech and language disorders, which are annotated in our database. We then discuss how such datasets can be useful in the development of computational models that bridge levels of analysis, necessary to provide a mechanistic understanding of heritable language disorders. We further describe our general approach to information integration, discuss important caveats and considerations, and offer a specific but speculative example based on genes implicated in stuttering and basal ganglia function in speech motor control.


Comparison of the averaged evoked cisterna cerebellomedullaris potential, cortical potential, and neurologic examination in the diagnosis of spinal cord injury of the dog.
Average cerebrocortical potentials (ECP) and cisterna cerebellomedullaris potentials (ECMP), evoked by ulnar and sciatic nerve stimulation, were compared with neurologic examination to evaluate their accuracy in the diagnosis of the degree of experimental spinal injury in 24 Beagles. The dogs were divided into 2 equal groups. Various impact forces were applied to the spinal cord at L1 of 1 group of dogs and various degrees of compression forces were applied to the spinal cord at L1 of the other group of dogs. The degrees of functional loss in both groups of dogs extended from mild to complete. The dogs were untreated and monitored for 30 days after injury. A short-acting barbiturate was compared with a long-acting barbiturate as the means of anesthesia; both were found to permit similar production of ECP and ECMP. The ECMP was found to be a more sensitive, more easily interpreted, and more consistent means of evaluating the degree of spinal injury than the ECP or the neurologic examination.


Nobiletin protects against murine l-arginine-induced acute pancreatitis in association with downregulating p38MAPK and AKT.
Acute pancreatitis (AP) is an inflammatory disease characterized by acinar cell damage, oxidative stress, and inflammation of the pancreas. Nobiletin (3',4',5,6,7,8-hexamethoxyflavone), a major polymethoxy flavone, has shown health-promoting properties in previous studies. Therefore, in this study, we investigated whether nobiletin protects against experimental AP induced with l-arginine. C57BL/6 mice were treated with 25 or 50mg/kg nobiletin by intraperitoneal injection once daily for 14 consecutive days. AP was then induced in the mice with two intraperitoneal injections of l-arginine (4g/kg). The nobiletin treatment significantly reduced the plasma amylase levels, pancreatic myeloperoxidase activity, percentage of pancreatic necrosis, plasma proinflammatory factors, the generation of reactive oxygen species, cell apoptosis, tissue damage, and the expression of phosphorylated p38MAPK (p-p38MAPK) and p-AKT. These results suggest that nobiletin is a new therapeutic method for l-arginine-induced AP in mice.


Cerebral infarction associated with moyamoya disease: histogram-based quantitative analysis of diffusion tensor imaging -- a preliminary study.
Moyamoya disease (MMD) is a rare disorder of unknown etiology in which terminal portions of the internal carotid arteries become steno-occlusive, with fine collateral "moyamoya vessels" formed secondarily, resulting in serial ischemic strokes throughout its clinical course. Whole-brain histogram (WBH) of diffusion tensor imaging (WBH-DTI) is an analytical tool whose feasibility has been ascertained in various pathologies. To elucidate whether WBH-DTI could detect any difference between ischemic MMD and normal controls, we examined 27 consecutive MMD patients without hemorrhage and 48 normal controls in this prospective study using a 3.0-T magnetic resonance scanner. WBHs of fractional anisotropy (FA) (WBH-FA) and mean diffusivity (MD) (WBH-MD) were compared among three groups: Group 1, MMD patients with infarct (n=15); Group 2, MMD patients without infarct (n=12); and Group 3, normal controls (n=48). Group 1 showed significantly higher peak height and significantly lower mean value on WBH-FA, as well as significantly lower peak height and significantly higher mean value on WBH-MD, compared with Groups 2 and 3. No significant difference was seen in parameters at either WBH-FA or WBH-MD between Groups 2 and 3. These results might reflect the pathological severity of each group, and WBH-DTI could feasibly detect differences between ischemic MMD with infarction and MMD without infarction and normal controls.


Human footprint is associated with shifts in the assemblages of major vector-borne diseases.
Predicting how increasing intensity of human-environment interactions affects pathogen transmission is essential to anticipate changing disease risks and identify appropriate mitigation strategies. Vector-borne diseases (VBDs) are highly responsive to environmental changes, but such responses are notoriously difficult to isolate because pathogen transmission depends on a suite of ecological and social responses in vectors and hosts that may differ across species. Here we use the emerging tools of cumulative pressure mapping and machine learning to better understand how the occurrence of six medically important VBDs, differing in ecology from sylvatic to urban, respond to multidimensional effects of human pressure. We find that not only is human footprint-an index of human pressure, incorporating built environments, energy and transportation infrastructure, agricultural lands and human population density-an important predictor of VBD occurrence, but there are clear thresholds governing the occurrence of different VBDs. Across a spectrum of human pressure, diseases associated with lower human pressure, including malaria, cutaneous leishmaniasis and visceral leishmaniasis, give way to diseases associated with high human pressure, such as dengue, chikungunya and Zika. These heterogeneous responses of VBDs to human pressure highlight thresholds of land-use transitions that may lead to abrupt shifts in infectious disease burdens and public health needs.


Does macroprudential policy alleviate the adverse impact of COVID-19 on the resilience of banks?
This paper examines the resilience of banks as perceived by market participants during the COVID-19 crisis. We analyse how bank stock returns during January-March 2020 relate to the pre-crisis activation of macroprudential policy across 52 countries in a cross-sectional dimension. We find that, overall, a tighter macroprudential policy stance is beneficial for bank systemic risk, as assessed by equity market investors. A robust finding is that a perceived decrease in bank risk stems primarily from the use of credit growth limits, reserve requirements, and dynamic provisioning. By contrast, a pre-crisis build-up of capital surcharges on systemically important financial institutions seems to lower bank stock returns. Alternative bank risk indicators suggest that the latter is likely to be driven by concerns about profits rather than the probability of default.


The first glycosides isolated from propolis: diterpene rhamnosides.
Two diterpene glycosides, ent-8(17)-labden-15-O-alpha-L-rhamnoside and ent-8(17)-labden-15-O-(3'-O-acetyl)-alpha-L-rhamnoside (new natural compounds) were isolated from propolis from El Salvador. The compounds showed significant antibacterial activity and moderate toxicity to Artemia salina nauplii. These are the first glycosides reported in bee glue.


[Surgical management of supraglottic laryngeal carcinoma in 182 patients with special emphasis on functional preservation].
To explore the surgical methods and evaluate the long-term result of laryngectomy in patients with supraglottic laryngeal cancer. 182 patients with supraglottic laryngeal carcinoma underwent operation from 1979 to 1999, with stage I 11, stage II 45, stage III 49 and stage IV 77 lesions. The choice of surgical procedure was decided with the disease condition of the larynx. The surgical procedures proposed by TD Wang were adhered to as: minor partial laryngectomy 36, major partial laryngectomy 85, subtotal partial laryngectomy with laryngoplasty 22 and total laryngectomy 39. The ultimate rate of larynx preservation was 78.6% (143/182) with 69.8% (88/126) in stage III and IV diseases. The decannulation rate was 81.8% in cases with preservation of laryngeal function. The overall 3- and 5-year survival rates were 82.9% and 67.3%, with 76.88% and 57.4% in the advanced (stage III and IV) cases who survived with preserved laryngeal function. They were 82.5% and 67.0% in similar advanced cases who were treated by total laryngectomy. The difference in the survival rates between these two groups was not statistically significant. It is suggested that preservation of the laryngeal function be possible for advanced supraglottic laryngeal carcinoma without compromising the remote survival rate. To improve the rate of larynx preservation, one should follow the surgical methods suggested.


Ambulatory Activity and Risk of Premature Mortality Among Young and Middle-aged American Indian Individuals.
To our knowledge, no published studies have investigated the association of ambulatory activity with risk of death among young and middle-aged American Indian individuals. The burden of chronic disease and risk of premature death is higher among American Indian individuals than among the general US population, so better understanding of the association of ambulatory activity with risk of death is needed to inform public health messaging in tribal communities. To examine the association of objectively measured ambulatory activity (ie, steps per day) with risk of death among young and middle-aged American Indian individuals. The ongoing longitudinal Strong Heart Family Study (SHFS) is being conducted with participants aged 14 to 65 years in 12 rural American Indian communities in Arizona, North Dakota, South Dakota, and Oklahoma and includes up to 20 years of follow-up (February 26, 2001, to December 31, 2020). This cohort study included SHFS participants who had available pedometer data at baseline. Data analysis was performed on June 9, 2022. Objectively measured ambulatory activity at baseline. Outcomes of interest were total and cardiovascular-related mortality. Mixed-effects Cox proportional hazards regression was used to estimate hazard ratios for risk of death, with entry at the time of the pedometer assessment and time at risk until death or the latest adjudicated date of follow-up. A total of 2204 participants were included in this study. Their mean (SD) age was 41.0 (16.8) years; 1321 (59.9%) were female and 883 (40.1%) were male. During a mean follow-up of 17.0 years (range, 0-19.9 years), 449 deaths occurred. Compared with participants in the lowest quartile of steps per day (<3126 steps), individuals in the upper 3 quartiles of steps per day had lower risk of mortality, with hazard ratios of0.72 (95% CI, 0.54-0.95) for the first quartile, 0.66 (95% CI, 0.47-0.93) for the second quartile, and 0.65 (95% CI, 0.44-0.95) for the third quartile after adjustment for age, sex, study site, education, smoking status, alcohol use, diet quality, body mass index, systolic blood pressure, prevalent diabetes, prevalent cardiovascular disease, biomarker levels (fibrinogen, low-density lipoprotein cholesterol, and triglycerides), medication use (hypertensive or lipid-lowering agents), and self-reported health status. The magnitude of the hazard ratios was similar for cardiovascular mortality. In this cohort study, American Indian individuals who took at least 3126 steps/d had a lower risk of death compared with participants who accumulated fewer steps per day. These findings suggest that step counters are an inexpensive tool that offers an opportunity to encourage activity and improve long-term health outcomes.


The epidemiology of knee injuries in children and adolescents.
Injuries in childhood and adolescence are frequent and the knee is one of the most common sites of injuries. This study aimed to analyze the epidemiology, gender distribution, age, and circumstances of knee injuries in childhood at a Level I Trauma Center in Austria. All pediatric and adolescent trauma patients who presented in a 2-year period were recorded. Children managed with knee injuries were selected prospectively. Patients were divided into five age groups: infants (younger than 1 year); pre-school aged children (1-6 years); pre-pubertal school-aged children (7-10 years); early adolescent patients (11-14 years); and late adolescent patients (15-18 years). Five diagnosis-related groups were formed: extraarticular soft tissue injuries, intraarticular soft tissue injuries, patella disorders, fractures, and overload injuries. The study included 23,832 patients up to the age of 18 years, who presented with 1,199 knee injuries. There was a male predominance (m:f = 58,6%:41.4%). Boys had a lower mean age at presentation (11.9 years) as girls (12.3 years). The most common accident sites were outdoors (34.8%) and sports facilities (32.8%). Leading injury mechanisms were falls on level surfaces (58.1%) and traffic accidents (13.4%). The number of knee injuries and its severity increased with age. Knee injuries did not occur in infants. In general, extraarticular soft-tissue injuries were most common and fractures were rare. Knee injuries in children and adolescents are rare and extraarticular soft-tissue injury is the most frequent type of knee trauma. The number of knee injuries and its severity increases with age with a male predominance. Sports facilities and traffic injuries are important scenes of knee trauma. Mechanisms and patterns evaluated in this study can serve as the basis for knee-injury prevention efforts in children and adolescents and may be used for necessary precautions. IV.


Prerequisites of language acquisition in the newborn brain.
Learning to decode and produce speech is one of the most demanding tasks faced by infants. Nevertheless, infants typically utter their first words within a year, and phrases soon follow. Here we review cognitive abilities of newborn infants that promote language acquisition, focusing primarily on studies tapping neural activity. The results of these studies indicate that infants possess core adult auditory abilities already at birth, including statistical learning and rule extraction from variable speech input. Thus, the neonatal brain is ready to categorize sounds, detect word boundaries, learn words, and separate speech streams: in short, to acquire language quickly and efficiently from everyday linguistic input.


Associations between e-cigarette pack size and vaping frequency among U.S. adults.
Little research exists on the association between e-cigarette pack quantity and use. We examined whether using e-cigarettes every day or somedays was associated with purchasing e-cigarettes by the box/pack or as singles. Data are from the 2018-2019 Tobacco Use Supplement to the Current Population Survey, analyzed in 2020. The sample included adults who reported current e-cigarette use (N=2,413). We conducted multivariable logistic regression models to examine the association between purchasing e-cigarettes by the box/pack or as singles and using e-cigarettes every day or somedays. Models controlled for demographic characteristics, flavored e-cigarette use, and other tobacco use, and were stratified by sex and device type. Of the 2,413 respondents, 63.1% reported purchasing e-cigarettes as singles, while 36.9% reported buying by the box or pack. Among those who purchased by the box and singles, approximately 56% and 50% used e-cigarettes every day, respectively. Those who reported purchasing by the box/pack had greater odds of every day e-cigarette use compared to some day use (Adjusted Odds Ratio: 1.36, 95% CI: 1.09, 1.68). This finding held for both males, females, and all device types. These findings present a first step in determining the relationship between e-cigarette pack size and use behavior.


Does surgery reduce knee osteoarthritis, meniscal injury and subsequent complications compared with non-surgery after ACL rupture with at least 10 years follow-up? A systematic review and meta-analysis.
We compared long-term follow-up from surgical versus non-surgical treatment of ACL rupture regarding radiographic knee osteoarthritis (OA), secondary surgery, laxity and patient-reported outcome measures (PROMs). Systematic review and meta-analysis. Embase, MEDLINE, CINAHL and the Cochrane Library databases. Studies directly comparing the minimally invasive surgical (arthroscopy or miniarthrotomy) and non-surgical treatment of ACL rupture with at least 10 years of follow-up in adult patients were included. Five studies met the eligibility criteria. A meta-analysis revealed a higher risk of radiographic knee OA and a lower risk of secondary meniscal surgery for patients in the surgical group. The risk of graft rupture/secondary ACL revision and secondary ACL reconstruction was equal in the surgical and non-surgical groups. Knee laxity was lower among patients in the surgical group in four studies. No difference was found in the PROMs (ie, International Knee Documentation Committee, Tegner, Knee Injury and Osteoarthritis Outcome, and Lysholm scores). The risk of radiographic knee OA was higher, but the risk of secondary meniscal injury was lower 10 years after surgical treatment of ACL rupture. The risk of graft rupture/secondary ACL revision or secondary reconstruction was unrelated to treatment type. The degree of knee laxity was reduced after surgical treatment in comparison with non-surgical treatment, while PROMs were similar. However, due to the methodological challenges highlighted in this systematic review, these findings must be interpreted with caution. CRD42019119468.


Basis-independent spectral methods for non-linear optical response in arbitrary tight-binding models.
In this paper, we developed a basis-independent perturbative method for calculating the non-linear optical response of arbitrary non-interacting tight-binding models. Our method is based on the non-equilibrium Keldysh formalism and allows an efficient numerical implementation within the framework of the kernel polynomial method for systems which are not required to be translation-invariant. Some proof-of-concept results of the second-order optical conductivity are presented for the special case of gapped graphene with vacancies and an on-site Anderson disordered potential.


Observations on the morphology of axons and somata of slowly conducting dorsal root ganglion cells in the cat.
In anaesthetized cats, the somata of cervical dorsal root ganglion (DRG) cells were impaled with glass micropipettes containing horseradish peroxidase. Slowly conducting afferent units were first classified by the conduction velocity of the peripheral axon (group IV: less than 2.5 m/s, group III: 2.5-30 m/s) and then injected iontophoretically with horseradish peroxidase in order to visualize the perikaryon and the axons close to the ganglion. All units classified as group IV had non-myelinated peripheral and central axons. DRG cells classified as group III were morphologically heterogeneous. Units conducting in the lower group III range had non-myelinated axons on both sides of the bifurcation; in those having an intermediate conduction velocity only the peripheral axon was myelinated, and in the fastest conducting group III units both the peripheral and central axons were myelinated. One out of the 36 stained cells gave rise to 3 processes, namely 1 central axon and 2 peripheral branches. The latter ones left the ganglion at its distal pole. Within the ganglion a significant tapering of the peripheral axon of group IV afferent units was observed. In the frequency distribution histogram of cell sizes, the cross-sectional areas of group IV somata were not restricted to the lower extreme of the distribution, but showed a great overlap with the somata of group III and even group II and I units.


Effect of modified no-touch laparoscopic radical hysterectomy on outcomes of early stage cervical cancer: A retrospective cohort study.
We aimed to compare the prognosis of modified no-touch laparoscopic radical hysterectomy (MLRH) and laparoscopic radical hysterectomy (LRH) on survival in patients with early stage cervical cancer. The clinicopathological data of patients with stage IB1 and IIA1 cervical cancer, who underwent radical surgery between 2014 and 2019, were retrospectively reviewed. The 5-year disease-free survival (DFS) and overall survival (OS) were compared between the MLRH and LRH groups using the Kaplan-Meier method. Independent prognostic factors for 5-year DFS and OS were identified using multivariate, forward, stepwise Cox proportional hazards regression models. A total of 223 patients with stage IB1 and IIA1 cervical cancer were included. Kaplan-Meier analysis revealed that the 5-year DFS and OS rates in the MLRH (n = 81) group were significantly higher than those in the LRH group (n = 142) (DFS, 94.5% vs. 78.8%, p = 0.007; OS, 96.7% vs. 87.6%, p = 0.033). No significant differences were identified between the two groups in terms of operative time, blood loss, transfusion requirement, and intraoperative or postoperative complications. MLRH was an independent prognostic factor associated with increased 5-year DFS (adjusted hazard ratio [HR], 0.202; 95% confidence interval [CI], 0.069-0.594; p = 0.004) and 5-year OS (adjusted HR, 0.163; 95% CI, 0.035-0.748; p = 0.020). The oncologic outcomes were superior with MLRH than with LRH in patients with stage IB1 and IIA1 cervical cancer. Contact of cervical tumor cells with the pelvic cavity likely explains the worse prognosis associated with LRH.


Biophysical investigation of the dual binding surfaces of human transcription factors FOXO4 and p53.
Cellular senescence is protective against external oncogenic stress, but its accumulation causes aging-related diseases. Forkhead box O4 (FOXO4) and p53 are human transcription factors known to promote senescence by interacting with each other and activating p21 transcription. Inhibition of the interaction is a strategy for inducing apoptosis of senescent cells, but the binding surfaces that mediate the FOXO4-p53 interaction remain elusive. Here, we investigated two binding sites involved in the interaction between FOXO4 and p53 by NMR spectroscopy. NMR chemical shift perturbation analysis showed that the binding between FOXO4's forkhead domain (FHD) and p53's transactivation domain (TAD), and between FOXO4's C-terminal transactivation domain (CR3) and p53's DNA-binding domain (DBD), mediate the FOXO4-p53 interaction. Isothermal titration calorimetry data showed that both interactions have micromolar Kd values, and FOXO4 FHD-p53 TAD interaction has a higher binding affinity. We also showed that the intramolecular CR3-binding surface of FOXO4 FHD interacts with p53 TAD2, and FOXO4 CR3 interacts with the DNA/p53 TAD-binding surface of p53 DBD, suggesting a network of potentially competitive and/or coordinated interactions. Based on these results, we propose that a network of intramolecular and intermolecular interactions contributes to the two transcription factors' proper localisation on the p21 promoter and consequently promotes p21 transcription and cell senescence. This work provides structural information at the molecular level that is key to understanding the interplay of two proteins responsible for cellular senescence.


A qPCR method to quantify bioavailable phosphorus using indigenous aquatic species.
Bioavailable phosphorus (BAP) represents the sum of phosphorus that is readily available for algae growth and is useful to indicate the severity of eutrophication in aquatic environments. Here, a quantitative real-time PCR (qPCR)-based bioassay was developed to quantify BAP using the indigenous cyanobacterium species Anabaena sp. of Lake Tai, a large and shallow eutrophic lake in the Yangtze Valley, China. Primers were designed to quantify the gene expression of alkaline phosphatase (phoA/phoA-like) and phosphate transporter (pst1) genes of Anabaena. The specificity and efficiency of the primer sets were evaluated by gel electrophoresis and real-time PCR. The results showed that the primers developed here could successfully be used to measure BAP in the water. The linear range of BAP measurements by the pst1 gene after 2 h incubation was 0.125-2.00 mg/L. Then, the qPCR-based bioassay was applied to analyze water samples from Tai Lake, which had BAP levels in the range of 0.239-0.459 mg/L. The qPCR-based bioassay represents a promising biomonitoring tool that can quantify phosphorus bioavailability in aquatic environments.


Posttranscriptional regulation of SOD1 gene expression under oxidative stress: Potential role of ELAV proteins in sporadic ALS.
Increased levels of SOD1 mRNA have been observed in sporadic ALS patients (SALS) compared to controls. Hence, the understanding of the mechanisms by which SOD1 gene expression is modulated may shed new light on SOD1 involvement in ALS. Of interest, some adenine/uracil-rich elements (AREs) in SOD1 3'-untranslated region have been identified. These sequences represent the docking sites for several RNA-binding proteins such as ELAV proteins (ELAVs), positive regulators of gene expression. We first investigated in SH-SY5Y cells whether SOD1 mRNA represents a target of ELAVs. Results from RNA Electrophoretic Mobility Shift and RNA-immunoprecipitation assays showed a molecular interaction between ELAVs and SOD1 mRNA. We also observed that the treatment with H2O2 induced a significant increase of the amount of SOD1 mRNA bound by ELAVs and an up-regulation of SOD1 protein levels. We found a specific increase in ELAV/HuR phosphorylation, suggesting activation of this protein, in peripheral blood mononuclear cells from SALS patients compared to controls. Finally, we found increased levels of ELAV proteins in the motor cortex and spinal cord from SALS patients compared to controls, in parallel with SOD1 up-regulation in the same areas. This study suggests, for the first time, that ELAVs are involved in the regulation of SOD1 gene expression at post-transcriptional level and that these proteins are more activated in ALS pathology. The link between ELAVs and SOD1 may open novel perspectives for ALS research, paving the way for new therapeutic options.


Expression of the beacon gene in endocrine glands of the rat.
Beacon gene has been recently identified in the rat hypothalamus, and reported to be overexpressed in obese animals. This pattern of expression suggests that beacon may be involved in the functional regulation of neuroendocrine axes. Hence, we have investigated the expression of beacon in the endocrine system of the rat. Reverse transcription-polymerase chain reaction showed the expression of beacon mRNA in the hypothalamus, adenohypophysis, thyroid gland, adrenal gland, testis, ovary and pancreatic islets. Immunocytochemistry demonstrated the presence of the beacon immunoreactivity in all tissues studied, the staining being very intense in the neurons of paraventricular and supraoptic nuclei, the basophils of adenohypophysis, the parathyroid gland, adrenocortical cells, testis Leydig cells, ovary thecal, granulosa and lutein cells, and pancreatic islets. Due the fact that beacon has been included in the ubiquitin-like protein family, its widespread expression in rat endocrine tissues is not astonishing. The in vivo administration of beacon[47-73] (3.5 nmol/100 body weight) elicited within 60 min a marked decrease in the plasma concentration of ACTH, aldosterone and corticosterone, and a moderate lowering of the blood levels of testosterone and estradiol. This finding suggests that beacon exerts a negative modulatory action on the pituitary-adrenal axis and gonad secretory activity, whose physiological relevance remains, however, to be established.


Decay of human immunodeficiency virus type 1 unintegrated DNA containing two long terminal repeats in infected individuals after 3 to 8 years of sustained control of viremia.
Covert human immunodeficiency virus (HIV) replication was ongoing during the first 3 years of aviremia in 22 patients, as determined by detection of DNA containing two long terminal repeats (2 LTR DNA). Although total HIV DNA was detected in 60 2 LTR DNA-negative samples, the absence of 2 LTR DNA in 90% of patients following 7 to 8 years of highly active antiretroviral therapy suggests suppression of cryptic viral replication.


Significant reduction in hospital admissions for acute exacerbation of chronic obstructive pulmonary disease in Hong Kong during coronavirus disease 2019 pandemic.
Chronic respiratory diseases are risk factors for severe disease in coronavirus disease 2019 (COVID-19). Respiratory tract infection is one of the commonest causes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). There has not been evidence suggesting the link between COVID-19 and AECOPD, especially in places with dramatic responses in infection control with universal masking and aggressive social distancing. This is a retrospective study to assess the number of admissions of AECOPD in the first three months of 2020 in Queen Mary Hospital with reference to the admissions in past five years. Log-linear model was used for statistical inference of covariates, including percentage of masking, air quality health index and air temperature. The number of admissions for AECOPD significantly decreased by 44.0% (95% CI 36.4%-52.8%, p < 0.001) in the first three months of 2020 compared with the monthly average admission in 2015-2019. Compare to same period of previous years, AECOPD decreased by 1.0% with each percent of increased masking (p < 0.001) and decreased by 3.0% with increase in 1 °C in temperature (p = 0.045). The numbers of admissions for control diagnoses (heart failure, intestinal obstruction and iron deficiency anaemia) in the same period in 2020 were not reduced. The number of admissions for AECOPD decreased in first three months of 2020, compared with previous years. This was observed with increased masking percentage and social distancing in Hong Kong. We postulated universal masking and social distancing during COVID-19 pandemics both contributed in preventing respiratory tract infections hence AECOPD.


Simultaneous determination of aminopyrine hydroxylation and aminopyrine N-demethylation in liver microsomes by high-performance liquid chromatography.
Aminopyrine and its metabolites, including 3-hydroxymethyl-2-methyl-4-dimethylamino-1-phenyl-3-pyrazoline-5-one which is a hydroxylated metabolite of aminopyrine, were separated on a reversed-phase (C8) Radial-Pak column using a mobile phase of methanol-triethylamine-water (30:1:69) adjusted to pH 5.40 with acetic acid. Detection of the peak was performed by an ultraviolet detector at 254 nm. By the rapid and simple method, aminopyrine hydroxylation as well as aminopyrine N-demethylation in liver microsomes can be examined simultaneously.


Routine Bedside Use of Obstetric Early Warning System in the Postnatal Ward to Identify Maternal Morbidity Among High-Risk Women.
Several authorities have recommended the use of an obstetric early warning system (OEWS) to prevent severe morbidity and mortality. Data on the accuracy of OEWS in different clinical settings and maternal populations are still scarce. Our aim was to validate OEWS to detect maternal morbidity among high-risk women in the postnatal ward. An OEWS was assigned to women with a body mass index >35 kg/m2, postpartum hemorrhage (PPH) >1500 mL, preeclampsia, concern over the maternal condition, chorioamnionitis, or type 1 diabetes. Morbidity was defined as worsening preeclampsia, action on hemorrhage, thromboembolia, diabetic ketoacidosis, puerperal infections, transfer to the intensive care unit, cardiopulmonary dysfunction, or death during the stay in the postnatal ward. The use of OEWS was implemented on November 1, 2016, and the study period ended on April 30, 2018. The study group included 827 women. The incidence of maternal morbidity was 29%. Women with PPH (odds ratio [OR], 6.4 [95% confidence interval, 3.5-11.6]) and preeclampsia (OR, 5.7 [3.5-9.6]) had the highest risk for morbidity. The sensitivity of OEWS for any morbidity was 42% (35%-48%), the specificity was 83% (80%-86%), the positive predictive value was 50% (44%-56%), and the negative predictive value was 78% (76%-80%). Systolic (OR, 6.8 [4.0-11.5]) and diastolic (OR, 3.3 [1.8-6.0]) blood pressure as well as pulse (OR, 2.1 [1.1-4.2]) predicted morbidity the most. In high-risk women, OEWS revealed one-half of the morbidity. Women with PPH and preeclampsia benefited most from it. Abnormal blood pressure and pulse had the strongest associations with morbidity.


Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours.
We recently showed that the 1.7 megabase multiple aberration region (MAR) on human chromosome 12q15 harbours recurrent breakpoints frequently found in a variety of benign solid tumours. We now report a candidate gene within MAR suspected to be of pathogenetical relevance. Using positional cloning, we have identified the high mobility group protein gene HMGI-C within a 175 kilobase segment of MAR and characterized its genomic organization. By FISH analysis, we show the majority of the breakpoints of eight different benign solid tumour types fall within this gene. By Southern blot and 3'-RACE analysis, we demonstrate consistent rearrangements in HMGI-C and/or expression of altered HMGI-C transcripts. These results suggest a link between a member of the HMG gene family and benign solid tumour development.


Patterns of clinical use of antipsychotics in hospitalized psychiatric patients.
The ways of using antipsychotic drugs have greatly changed over the last 10 years. The aim of this study was to evaluate such changes in psychiatric patients admitted to the Psychiatric Department of Milan's Ospedale Maggiore in 1989 (n=350), 1999 (n=718) and 2002 (n=628). The medical records of the hospitalized patients were evaluated by analyzing the anamnestic and clinical data with particular reference to age, gender, diagnosis and medication use. In 2002, atypical antipsychotics were more frequently prescribed as monotherapy upon discharge than typical antipsychotics (32.64% vs. 30.10%). Combinations of two or more antipsychotic drugs were prescribed upon discharge for 20.63% of the patients in 1989, 31.24% in 1999 and 23.09% in 2002. The combinations of one typical and one atypical drug increased from 4.04% in 1999 to 13.06% in 2002. The mean (+/-S.D.) daily antipsychotic drug dose (expressed in chlorpromazine equivalents) was significantly higher in 2002 than in 1999 and 1989. The results of this study confirm the trend to use combinations of one typical and one atypical antipsychotic, and higher doses.


Glioblastoma management in the temozolomide era: have we improved outcome?
Temozolomide (TMZ) during and after radiotherapy (RT) is recommended for patients with newly diagnosed glioblastoma (GBM). We analyzed the adoption of this new standard of care for GBM in an academic cancer centre in Canada and assessed its impact on survival. GBM patients registered with Cancer Care Ontario between 2004 and 2008 were identified. Those ≥ 16 years age, newly diagnosed, treated at our institution, had confirmed pathology and complete records were included. Demographics, treatments, toxicity and outcome were captured. For survival analysis patients were stratified by age, ECOG, and treatment modalities including total cycles of TMZ. Descriptive statistics were used for early progressors and long term survivors. Kaplan-Meier curves, log-rank test and Cox proportional hazards model were used for survival analyses. At a median follow-up of 28 months, we compared our outcome to updated EORTC-NCIC CE 3 results. Of 517 patients 433 were included for analysis. Majority were male (63 %), ECOG 0-1 (66 %), and ≤ 65 years (55 %). 44 % received CRT followed by TMZ, 13 % had CRT only, 30 % had RT only and 13 % had best supportive care. 10 % were early progressors and 9 % survived beyond 2 years. Comparison of our results to NCIC CTG CE.3 study data showed median survival was 15.8 versus 14.6 months, 2 year survival rate for CRT plus TMZ was 35 versus 26 %, and for RT alone 0 versus 10 %, respectively. <50 % of GBM patients complete CRT with TMZ in the real-world setting. Prognosis for most patients with GBM remains dismal particularly if they are not suitable for RT and CRT.


Glycine-rich analogues of Cucurbita maxima trypsin inhibitor (CMTI-III) substituted by valine in position 27 display relatively low antitrypsin activity.
Five new analogues of the trypsin inhibitor CMTI-III were synthesized by the solid-phase method. All analogues containing a valine residue in position 27 and glycine residues in some or all of the positions 9, 11, 14, 17, 19, 29 as well as in two cases a norleucine residue in position 8 displayed association equilibrium constants by 6-7 orders of magnitude lower than the native CMTI-III inhibitor.


Mitotic checkpoints.
Entry into mitosis is triggered by activation of maturation promoting factor and a complex of p34cdc2 kinase and cyclin B. Activation induces nuclear lamina breakdown, chromosome condensation and mitotic spindle assembly. Exit from mitosis is initiated by the degradation of cyclin B and the subsequent inactivation of maturation-promoting factor. A more thorough understanding of the checkpoints for initiation of and exit from mitosis has evolved during the past few years.


A review of nonvalidated and complementary therapies for cluster headache.
Cluster headache is arguably the most disabling form of primary headache. There is a great deal of information available about alternative therapy for migraine, but very little regarding alternative therapy for cluster headaches. This article reviews the popular and scientific print and electronic sources of information about alternative and complementary treatments for cluster headache dietary supplements, herbal modalities, folk remedies, physical and manual therapies, and unlabeled use of prescription drugs such as botulinum toxin, baclofen, and methylphenidate.


The inhibitory effect of diphenyltin on gap junctional intercellular communication in HEK-293 cells is reduced by thioredoxin reductase 1.
Organotins display high biological activity and are toxic to animals and humans. Besides carcinogenic effects, they have been shown to have highly immunotoxic and/or neurotoxic activity; however, the molecular mechanism of their toxicity is not fully understood. The ability of chemicals to inhibit communication via gap junctions has been associated with their toxicological properties. The aim of this study was to determine whether diphenyltin (DPhT) affects the gap junctional intercellular communication (GJIC) and whether thioredoxin reductase (TrxR1) is involved in the regulation of this process. We found that DPhT inhibits GJIC in HEK-293 cells. The inhibition of GJIC depends on the activation of PKC delta and is associated with the induction of Cx43 phosphorylation at Ser262. Moreover, we found that GJIC inhibited by DPhT in HEK-293 cells is fully re-established as a result of TrxR1 overexpression.


Evaluation of stromal metalloproteinases and vascular endothelial growth factors in a spontaneous metastasis model.
This study aims to investigate MMP2 and MT1-MMP protein as well as VEGF-C and VEGF-D mRNA expression in tumor cells and distant organs considered to be targets for metastasis in a tumor spontaneous metastasis model previously described. Cultured tumor cells, able to express pro-MMP2, MMP2, pro-MMP9, and MT1-MMP, develop tumor growth and metastasis, mainly in the liver and spleen, when they are injected in the mammary pad gland of Wistar rats. Immunohistochemical studies of tumor masses showed small groups of tumor cells staining for MT1-MMP but not for MMP2. In the liver, tumor metastatic foci and a stromal positive staining for both MMP2 and MT1-MMP were shown. The spleen and lymph nodes, with only scattered metastatic cells, did not show MMPs immunostaining. Using RT-PCR, a significantly higher VEGF-C and VEGF-D gene expression was shown in the liver of tumor-bearing rats respect to normal rats, whereas spleen and lymph nodes did not show significant differences in mRNA VEGF-C/D levels. Taken together, our results suggest that the stroma microenvironment of target organs for metastasis has the ability to produce MMPs and VEGFs that facilitate the anchorage of tumor cells and promote tumor cell growth and angiogenesis.


Role of immune processes in peripheral opioid analgesia.
The experimental data clearly demonstrate that opioids (alkaloids as well as peptides) are able to inhibit nociception arising from inflamed tissue by a local peripheral action. mu- and delta- as well as kappa-opioid receptor ligands are effective by interaction with the respective opioid receptors presumably located in the terminal region of the sensory nerves. Similar effects are obtained when endogenous opioid peptides are released under stress conditions from immune cells present in the inflamed tissue. Immunoreactive beta-EP and enkephalins, processed in these cells, seem to be the relevant peptides in this respect. Although the mechanism of stress-induced release of opioid peptides from the immunocytes is presently not clear, there is indication that this process involves cytokines and CRF. Apart from immunological processes, inflammation-induced changes also take place at the level of the opioid receptors and are of significance in the manifestation of peripheral opioid antinociception; in particular the "activation" of these receptors apparently occurs at the early stages of inflammation when the infiltration of the tissue with immunocompetent cells is just beginning. There is increasing evidence for a therapeutic relevance of opioid-induced analgesia at peripheral sites of inflammation.


Synergistic anti-tumor effect of combined inhibition of EGFR and JAK/STAT3 pathways in human ovarian cancer.
The EGFR signaling pathway is frequently activated in human ovarian cancer and associated with poor prognosis. However, inhibition of EGFR signaling in patients with recurrent ovarian cancer has been disappointing. It remains to be addressed whether ovarian cancer patients could benefit from targeting EGFR signaling. Here we investigated the mechanisms underlying the resistance to EGFR inhibition in ovarian cancer and developed a strategy to overcome it. We found that treatment of human ovarian cancer cells with an EGFR inhibitor, gefitinib, resulted in increased STAT3 phosphorylation in a dose- and time-dependent manner. Inhibiting STAT3 activation with a small molecule inhibitor of JAK, an upstream kinase that phosphorylates and activates STAT3, synergistically increased the anti-tumor activity of gefitinib in vitro. Similar results were obtained when STAT3 or JAK1 expression was knocked down. In contrast, inhibiting other signaling pathways, such as AKT/mTOR, MEK or SRC, was relatively less effective. The combined treatment resulted in simultaneous attenuation of multiple survival pathways and increased inhibition of ERK pathway. In addition, the dual inhibition showed a stronger suppression of xenograft tumor growth than either single inhibition. Our findings demonstrate that feedback activation of STAT3 pathway might contribute to the resistance to EGFR inhibition. Combined blockade of both pathways appears to be more effective against human ovarian cancer than inhibition of each pathway alone both in vitro and in vivo. This study may provide a strategy to improve clinical benefit of targeting EGFR pathway in ovarian cancer patients.


Brain-imaging studies of treatment-resistant schizophrenia: a systematic review.
Around 30% of patients with schizophrenia show an inadequate response to antipsychotics-ie, treatment resistance. Neuroimaging studies can help to uncover the underlying neurobiological reasons for such resistance and identify these patients earlier. Additionally, studies examining the effect of clozapine on the brain can help to identify aspects of clozapine that make it uniquely effective in patients with treatment resistance. We did a systematic search of PubMed between Jan 1, 1980, and April 13, 2015, to identify all neuroimaging studies that examined treatment-resistant patients or longitudinally assessed the effects of clozapine treatment. We identified 330 articles, of which 61 met the inclusion criteria. Replicated differences between treatment-resistant and treatment-responsive patients include reductions in grey matter and perfusion of frontotemporal regions, and increases in white matter and basal ganglia perfusion, with effect sizes ranging from 0·4 to greater than 1. Clozapine treatment led to reductions in caudate nucleus volume in three separate studies. The available evidence supports the hypothesis that some of the neurobiological changes seen in treatment-resistant schizophrenia lie along a continuum with treatment-responsive schizophrenia, whereas other differences are categorical in nature and have potential to be used as biomarkers. However, further replication is needed, and for neuroimaging findings to be clinically translatable, future studies need to focus on a-priori hypotheses and be adequately powered.


Effects of ouabain on NIH/3T3 cells transformed with retroviral oncogenes and on human tumor cell lines.
Both murine and human cell lines transformed by the v-Ki-ras gene have been shown to be much more sensitive to the toxic effects of the cardiac glycoside ouabain than their respective controls. This differential toxicity has previously been used in the isolation of flat revertant clones from populations of Kirsten murine sarcoma virus transformed NIH/3T3 cells. Here, we have undertaken a further characterization of this phenomenon in murine and human tumor cells. Two different techniques, a 51Cr-release assay and a quantitative Crystal violet elution assay, have been employed to compare the sensitivities to ouabain of normal and v-Ki-ras-transformed NIH/3T3 cells. In each assay, ras-transformed NIH/3T3 cell lines displayed an increased sensitivity to ouabain as compared to the parental NIH/3T3 cell line, both in dose-response and in time-course experiments. In a separate study, ouabain was also able to inhibit the growth in semi-solid medium of 2 v-Ki-ras-transformed NIH/3T3 cell lines (DT and K-NIH) in a dose-dependent fashion. The same concentrations of ouabain were effective in both the 51Cr-release and Crystal violet assays. To address the question of whether increased sensitivity to ouabain is a specific result of transformation with the ras oncogene or is a common event which accompanies transformation by other oncogenes, we have screened a variety of transformed NIH/3T3 derivatives. All of these lines displayed an increased sensitivity to ouabain when compared to the parental NIH/3T3 cell line.


Antischistosomal vaccines: beyond the laboratory.
In the effort to develop vaccines against schistosomiasis, insufficient attention has been given to the field evaluation of their safety and efficacy, and to conditions of routine use. Evaluation demands a clear case definition and precise diagnostic tools to determine the number, condition, and pathological effects of the schistosomes present in each subject. These are difficult to achieve for schistosomiasis. The trial should also assess the reduction in community transmission attributable to immunization. Ethical problems in efficacy trials include the need for subjects to be exposed to infection when means are available to minimize it, and the need to define the point at which chemotherapy must be given to subjects found to be infected. The epidemiological and economic consequences of vaccine use must be compared with alternative methods of control and with natural low-level transmission in the community. The characteristics of a desirable vaccine should be defined in advance by modelling and/or a consensus development process to provide guidance to bench researchers and to identify those candidate vaccines that should advance to field trials.


Inhibition of FKBP10 Attenuates Hypertrophic Scarring through Suppressing Fibroblast Activity and Extracellular Matrix Deposition.
Hypertrophic scar is a pathogenic form of scar formation with no recognized treatment to date. Its molecular mechanism is related to the abnormal proliferation and transition of fibroblasts and overproduction of extracellular matrix. FKBP10 is a molecular chaperone able to regulate α-smooth muscle actin expression and pro-collagen maturation in fibroblasts. However, to our knowledge, no research has investigated the biological function of FKBP10 in scar formation to date. In this study, we aim to assess the expression and function of FKBP10 in hypertrophic scarring. Through microarray analysis, real-time reverse transcriptase-PCR and immunohistochemistry, we discovered that FKBP10 is up-regulated in human and mouse hypertrophic scars. Then we evaluated hypertrophic scar formation in mouse models treated with FKBP10 small interfering RNA and found that knockdown of FKBP10 could attenuate hypertrophic scar formation in vivo. To further explore the underlying mechanism, FKBP10 was knocked down in human hypertrophic scar fibroblasts. The in vitro results showed that FKBP10 siRNA could inhibit fibroblast activity, reduce the expression of α-smooth muscle actin and extracellular matrix components, and attenuate transforming growth factor-β1 expression and the activation of the Smad signaling pathway. In conclusion, FKBP10 plays a crucial role in hypertrophic scar formation and might be a therapeutic target for hypertrophic scars.


Tetra-μ-acetato-κ8 O:O'-bis-[(3-chloro-pyridine-κN)ruthenium(II,III)](Ru-Ru) hexa-fluorido-phosphate 1,2-di-chloro-ethane monosolvate.
The title compound, [Ru2(μ-O2CCH3)4(C5H4ClN)2]PF6·C2H4Cl2, was obtained via a rapid substitution reaction of 3-chloro-pyridine for water in [Ru2(μ-O2CCH3)4(H2O)2]PF6 in 2-propanol and subsequent crystallization from a di-chloro-ethane solution. The cationic diruthenium(II,III) tetra-acetate core lies on a crystallographic inversion center with Ru-Ru and Ru-N bond lengths of 2.2738 (3) and 2.2920 (17) Å, respectively. The Ru-Ru-N bond angle is close to linear at 176.48 (4)°, and a significant π-stacking inter-action of 3.5649 (16) Å is seen between overlapping pyridine rings of adjacent cations.


A method for characterizing short-range molecular order in amorphous starch.
This study presents a new method for characterizing short-range molecular order in amorphous starch using Raman spectroscopy and wide-angle X-ray diffraction (XRD). Amorphous wheat and potato starch samples with different degrees of short-range molecular order were prepared by heating starch:water mixtures ranging from 1:1 to 1:19 at 100 °C for 10 min. The XRD and 13C CP/MAS NMR spectroscopy analyses showed that all starch samples had lost their long-range crystallinity and from that perspective were considered to be gelatinized. The peak area and intensity of the Raman bands at 480, 1131 and 1080 cm-1 and the full width at half maximum (FWHM) of XRD peaks at 16.7 and 20.7° (2θ) were correlated strongly to the degree of short-range molecular order in amorphous starch. On the basis of these relationships, we propose a method to analyze the short-range molecular order in amorphous starch, and thereby better characterize its properties.


Ulcerative colitis.
Ulcerative colitis is a chronic inflammatory disease of the rectum and colon. Results from many studies in people and animals of intestinal inflammation suggest that ulcerative colitis results from environmental factors triggering a loss of tolerance for normal intestinal flora in genetically susceptible individuals. Although progress has been made in the overall management of the disease, no innovative treatment has been developed. By contrast with Crohn's disease, there are few clinical data on biological agents. Probiotics seem the most promising of several experimental and traditional agents that have been investigated in controlled clinical trials.


Evidence for cerebellar-frontal subsystem changes in children treated with intrathecal chemotherapy for leukemia: enhanced data analysis using an effect size model.
Following brain insult in early childhood, the later maturing neocerebellum and frontal lobes frequently show abnormalities. To investigate the morphologic characteristics and function of a proposed cerebellar-frontal subsystem in children treated for acute lymphoblastic leukemia (ALL) with intrathecal methotrexate using quantitative magnetic resonance imaging, neuropsychological measures, nonlinear multiple regression analysis, and a statistical effect size model that augments interpretive validity of nonsignificant statistical findings, particularly from small sample size studies. Comparison and relationship of magnetic resonance imaging morphometry of cerebellar lobuli I-V and VI-VII and prefrontal cortices, and performance on 5 neuropsychological tests assessing visual-spatial attention, short-term memory, and visuomotor organization and coordination between childhood survivors of ALL and a matched control group. Ten childhood survivors of ALL treated between 1982 and 1989 with standard 3-year intrathecal chemotherapy, and matched control subjects. Morphometric results of cerebellar lobuli I-V and VI-VII and prefrontal cortices, and results of Trail-Making Tests, Rey-Osterreith Complex Figure Test, WISC-III Coding. Significant effect size model values for outcome measures in the ALL group support deficits in lobuli VI-VII and prefrontal cortices, and neuropsychological performance. Multiple regression analysis results were consistent with hypothesized involvement of a cerebellar-frontal brain subsystem. Treatment of children with ALL with intrathecal methotrexate before 5 years of age has structural and functional effects on the developing neocerebellar-frontal subsystem.


Co-benefits assessment of integrated livestock and cropland system based on emergy, carbon footprint and economic return.
The rapid specialization of livestock production contributes to spatially decoupled crop and livestock production. Relinking croplands and livestock to promote wastes and by-products exchange has been suggested to provide opportunities for sustainable intensification of agriculture systems. However, the environmental and economic performances of such crop-livestock systems remain highly context specific and unclear. This study proposed an emergy-LCA-based framework to study the GHG mitigation and ecological and economic benefits of the integrated crop planting and livestock feeding systems, by taking wheat maize rotation-swine systems (WMRS), tea-swine systems (TS) and citrus alfalfa intercropping-swine systems (CAIS) as the empirical cases. The results showed the three case modes can generally promote GHG mitigation and ecological and economic benefits. CAIS had the lowest carbon footprint per kcal product (0.12 g CO2-eq kcal-1), followed by TS (0.61 g CO2-eq kcal-1) and MWRS (0.66 g CO2-eq kcal-1). The significant difference in this indicator can be attributed to their different upstream input and manure management. Due to the lower dependence on purchased resources, CAIS also had the best performance on emergy-based sustainability and economic benefits. Based on our results, the policy implications, including promoting wastes and by-products exchange, choosing reasonable manure treatment mode and conducting systematic planning have been suggested to provide opportunities for GHG mitigation and sustainable intensification of agro-systems.


Reliability of the methods applied to assess age minority in living subjects around 18 years old. A survey on a Moroccan origin population.
We present a review of a population of 114 immigrant Moroccan males for which an age estimation was requested. The subjects' real chronological age was confirmed by the Moroccan Embassy in Spain. The confirmed age range was between 13 and 25, with an average age of 18.1 years and a standard deviation of 2.03. The following tests were performed to arrive at the forensic estimation of age: general physical examination, carpus X-ray (Greulich and Pyle method) and dental orthopantomography to determine the degree of maturity of the third inferior molars (Demirjian's method). Carpus X-ray (skeletal age) was the most useful method, followed by Demirjian's method (dental age), as prediction factors of a chronological age of over or under 18. The combination of skeletal and dental age variables represented a significant improvement in the prediction of the chronological age of the subjects in this population, reducing the number of ethically unacceptable test errors to a minimum.


Segregation of the E1j gene for plasma cholinesterase in family studies.
Four families are reported in which the E1j gene is segregating. Two E1jE1k and one E1jE1f genotypes have been recognised by genetic analysis. The biochemical characteristics of several E1j genotypes are presented.


Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways cooperate in mediating cytokine-induced proliferation of a leukemic cell line.
Granulocyte colony-stimulating factor (G-CSF) and fetal liver tyrosine kinase-3 (Flt3) ligand (FL) act in synergy to induce expansion and mobilization of hematopoietic progenitor cells. Regulation of mitogen activated protein (MAP) kinase pathways and gene transcription, induced by these cytokines were examined using the OCI-AML5 cell line. For this purpose, FL and G-CSF were used either alone, or in combination as the co-addition of FL and G-CSF (FL+G-CSF), or a chimeric molecule, progenipoietin-1 (ProGP-1). Both G-CSF and FL induced phosphorylation of extracellular signal-regulated kinases (ERKs) while p38 mitogen activated protein (MAP) kinase was phosphorylated only in response to G-CSF but not FL. Studies using specific kinase inhibitors suggested that both ERK and p38 MAP kinase pathways were required for the optimal cell proliferation in response to both G-CSF and FL. The magnitude of activation of the ERK pathway and induction of genes involved in cell cycle progression by G-CSF and FL exhibited a strong correlation with the degree of cell proliferation. These data suggest that OCI-AML5 cells proliferate at least in part, due to the activation of both ERK and p38 MAP kinase pathways in response to G-CSF and FL. This study represents the first report of the specific cell cycle genes induced by FL.


Differential protection of chlorophyllin against clastogenic effects of chromium and chlordane in mouse bone marrow in vivo.
The anticlastogenic activity of sodium-copper-chlorophyllin was tested against two known clastogens, chromium(VI) oxide and the pesticide chlordane, both of which occur as environmental toxicants. The chemicals were administered to male Swiss albino mice by gavage and chromosomes were studied from bone marrow cells 24 h after the exposure, following colchicine-air drying-Giemsa preparation. The end-points screened were the frequencies of chromosomal aberrations and damaged cells. The clastogenic effects induced by chromium in aqueous solution (20 mg/kg body weight) were reduced to a significant level by chlorophyllin (1.5 mg/kg body weight), when administered both before and simultaneously with the toxicant. The effects of chlordane in olive oil (10 mg/kg body weight) were, however, not reduced by the administration of chlorophyllin (1.5 and 3 mg/kg body weight).


Polymorphism of -765G > C COX-2 is a risk factor for gastric adenocarcinoma and peptic ulcer disease in addition to H pylori infection: a study from northern India.
To investigate -765G > C COX-2 polymorphism and H pylori infection in patients with gastric adenocarcinoma, peptic ulcer disease (PUD) and non-ulcer dyspepsia (NUD). We enrolled 348 adult patients (62 gastric adenocarcinoma, 45 PUD and 241 NUD) undergoing upper gastrointestinal endoscopy at two referral centers between September, 2002 and May, 2007. H pylori infection was diagnosed when any of the four tests (RUT, culture, histopathology and PCR) were positive. Genotyping for -765G > C polymorphism of COX-2 was performed by PCR-RFLP analysis. Frequency of C carrier had significant association with gastric adenocarcinoma as compared to NUD [77.4% vs 29%, P < 0.001, odds ratio (OR) 8.20; 95% confidence interval (95% CI), 4.08-16.47] and PUD (77.4% vs 31.1%, P < 0.001; OR 8.04; 95% CI, 3.25-19.90). Risk of gastric adenocarcinoma was significantly higher in patients having C carrier with (OR 7.83; 95% CI 3.09-19.85) and without H pylori infection (OR 7.06; 95% CI, 2.61-19.09). Patients with C carrier and H pylori infection had significant risk for the development of PUD (P < 0.001; OR 5.65; 95% CI, 2.07-15.34). -765G > C COX-2 polymorphism with or without H pylori could be a marker for genetic susceptibility to gastric adenocarcinoma. COX-2 polymorphism in presence of H pylori infection might be useful in predicting the risk of PUD.


Monoclonal antibody-directed phenotyping of cytochrome P-450-dependent aryl hydrocarbon hydroxylase and 7-ethoxycoumarin deethylase in mammalian tissues.
The distribution of cytochromes P-450 that catalyze aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase were studied with monoclonal antibody (MAb) 1-7-1 which completely inhibits these activities of a purified 3-methylcholanthrene-induced rat liver cytochrome P-450. The degree of inhibition by MAb 1-7-1 quantitatively assesses the contribution of different cytochromes P-450 in the liver, lung, and kidney microsomes from untreated, 3-methylcholanthrene- and phenobarbital (PB)-treated rats, mice, guinea pigs, and hamsters. Enzyme sensitivity to MAb 1-7-1 inhibition defines two types of cytochrome P-450 contributing to aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase. The MAb 1-7-1-sensitive cytochrome P-450 is a major contributor to aryl hydrocarbon hydroxylase in rat liver, lung, and kidney of 3-methylcholanthrene-treated rats, C57BL/6 mice, guinea pigs, and hamsters; this type is also present in lesser amounts in the extrahepatic tissues of the control and PB-treated animals, and in the lungs of the relatively "noninducible" DBA/2 mice treated with 3-methylcholanthrene. This form however makes little or no contribution to liver aryl hydrocarbon hydroxylase of control or PB-treated animals. 7-Ethoxycoumarin O-deethylase is also a function of both the MAb 1-7-1-sensitive and insensitive classes of cytochrome P-450. The ratio of the classes contributing to aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase differs in the various tissues and species and after inducer treatment. All of the 7-ethoxycoumarin O-deethylase activity in guinea pigs and hamsters is a function of cytochromes P-450 different than the MAb 1-7-1-sensitive cytochrome P-450 responsible for aryl hydrocarbon hydroxylase activity. Thus, the MAb 1-7-1 antigenically defines the type of cytochromes P-450 contributing to each reaction. Cytochromes P-450 can be viewed as paradigmatic for enzyme systems in which the nature and amount of product is regulated by multiple isoenzymic forms. Analyses using monoclonal antibodies to specific isoenzymes may thus have broad application to a variety of other complex systems which are composed of multiple isoenzymes.


Source apportionment of PM2.5 in Seoul, South Korea and Beijing, China using dispersion normalized PMF.
East Asian countries experience severe air pollution owing to their rapid development and urbanization induced by substantial economic activities. South Korea and China are among the most polluted East Asian countries with high mass concentrations of PM2.5. Although the occurrence of transboundary air pollution among neighboring countries has been recognized for a long time, studies involving simultaneous ground-based PM2.5 monitoring and source apportionment in South Korea and China have not been conducted to date. This study performed simultaneous daily ground-based monitoring of PM2.5 in Seoul and Beijing from January to December 2019. The mass concentrations of PM2.5 and its major chemical components were analyzed simultaneously during 2019. Positive matrix factorization (PMF) as well as dispersion normalized PMF (DN-PMF) were utilized for the source apportionment of ambient PM2.5 at the two sites. 23 h average ventilation coefficients were applied for daily PM2.5 chemical constituents' data. Nine sources were identified at both sites. While secondary nitrate, secondary sulfate, mobile, oil combustion, biomass burning, soil, and aged sea salt were commonly found at both sites, industry/coal combustion and incinerator were identified only at Seoul and incinerator/industry and coal combustion were identified only at Beijing. Reduction of the meteorological influences were found in DN-PMF compare to C-PMF but the effects of DN on mobile source were reduced by averaging over the 23 h sampling period. The DN-PMF results showed that Secondary nitrate (Seoul: 25.5%; Beijing: 31.7%) and secondary sulfate (Seoul: 20.5%; Beijing: 17.6%) were most dominant contributors to PM2.5 at both sites. Decreasing secondary sulfate contributions and increasing secondary nitrate contributions were observed at both sites.


The superior approach to the mitral valve--is it worthwhile?
The mitral valve was approached through a modified incision in the roof of the left atrium in 100 consecutive patients to study exposure of the valve, complications of the method and the incidence of dysrhythmia. There were five deaths: one related to difficult atrial closure and another to breakdown of the atrial suture line. Two major and two minor non-fatal haemorrhagic complications occurred. Exposure of the valve was found to be superior to that of conventional atrial incisions in the great majority of cases. When comparing the incidence of perioperative dysrhythmia in our 100 patients with that of 56 patients approached through the conventional atrial incisions, no significant differences were found even though the sinus node artery is likely to be divided when incising the roof of the left atrium.


Evaluation of the effect of 2-(2,4-dihydroxyphenyl)-4H-benzofuro[3,2-d][1,3]thiazin-4-one on colon cells and its anticancer potential.
In this paper, we present the biological effect of the newly synthesized 2-(2,4-dihydroxyphenyl)-4H-benzofuro[3,2-d][1,3]thiazin-4-one (DPBT) on human colon adenocarcinoma cell lines (HT-29 and LS180). Additionally, DPBT cytotoxicity was examined in human colon epithelial cells (CCD 841 CoTr) and human skin fibroblasts (HSF). The studies revealed a significant decrease in the proliferation of cancer cells after exposure to DPBT at concentrations in the range of 10-100 µM. Additionally, DPBT was not toxic to normal CCD 841 CoTr and HSF cells at concentrations that induced inhibition of cancer cell proliferation. The nature of the anti-proliferative action of DPBT in the cell cycle progression in colon cancer cells and the expression of proteins involved in this process were examined by flow cytometry and western blotting, respectively. The investigations demonstrated higher sensitivity of LS180 than HT-29 to the DPBT treatment. The anti-proliferative action of DPBT in LS180 was attributed to cell cycle arrest in the G1 phase via up-regulation of p27KIP1 and down-regulation of cyclin D1 and CDK4 proteins.


The use of the human erythrocyte as a model for studying the action of diuretics on sodium and chloride transport.
1. The Na+ and Cl- transport systems of human erythrocytes have been compared for their sensitivities to diuretics known to act in the ascending limb of Henle's loop. In addition, chemical analogues of 'loop' compounds and also diuretics which act in other areas of the nephron have been examined. 2. The Na+ transport system lacks specificity with respect to inhibition by 'loop' diuretics and also a related chemical analogue studied at equivalent concentrations. 3. The Cl- transport system is inhibited, at low concentrations, by diuretics known to act in the ascending limb of Henle's loop. 4. Erythrocyte Cl- transport offers a useful model with which to study the biochemical action of diuretics.


Nasopharyngeal carcinoma with orbital invasion.
To review the clinical profiles of patients having nasopharyngeal carcinoma (NPC) with orbital invasion, which occurs more frequently in patients with Chinese and south-east Asian racial backgrounds. Although this disease frequently spreads superiorly to the skull base and intracranium, it rarely invades the orbit and we wish to examine some cases in which it has. In this observational case series, we examined 406 patients, who were diagnosed with orbital tumour at Taipei Veterans General Hospital between January 1974 and December 2001. In all, 13 of the patients (11 males, two females) were found to have NPC with orbital invasion. Neuroimaging studies, pathologic reports, and clinical courses of these 13 patients were then reviewed retrospectively and survival analysis was carried out using a Kaplan-Meier estimate. One patient presented with eyelid tumour and three other patients presented with proptosis as the initial manifestation of NPC. The other nine cases, already diagnosed to have NPC, visited our department with a variety of ocular symptoms and signs, such as proptosis, diplopia, visual impairment, and orbital pain. Palliative treatment with radiotherapy alone or in combination with chemotherapy was given in 12 cases. During the follow-up period ranging from 4 to 64 months, six patients died, one was lost during follow-up, and six were still alive. Although orbital invasion in NPC is rare, we found a 5-year survival rate of 28% in our patients, indicating that orbital invasion with NPC confers a particularly poor prognosis.


Effect of topically applied beta-aminopropionitrile on granuloma tissue biochemistry.
The effects of the percutaneous transport of vehicles and the transport of beta-amino-propionitrile (beta APN) in vehicles were studied in rats. The bioavailability of topically administered beta APN was determined by measuring the degree of collagen cross-linking inhibition in the underlying granuloma tissue. Granulomas were induced by subcutaneous implantation of polyvinylalcohol sponges. From the 4th to 12th days postimplantation, a 20 mg/cm2 dose of beta APN fumarate was applied. Vehicles employed included dimethylsulfoxide (DMSO), urea, and occlusion. DMSO significantly enhanced the effect of beta APN in reducing the cross-linking of collagen. beta APN administered onto urea-pretreated skin and followed by occlusion in the granuloma tissue was more effective than beta APN in 30% DMSO, but only in the parameter reflecting extractibility of collagen into urea or thiocyanate solutions. The results suggest that beta APN administered topically in an appropriate vehicle penetrates the granuloma tissue and affects collagen polymerization. Though beta APN was topically administered, a systemic effect from the drug was evident, as documented by lower body weight of treated rats.


Crystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2.
The Eph receptors, which bind a group of cell-membrane-anchored ligands known as ephrins, represent the largest subfamily of receptor tyrosine kinases (RTKs). They are predominantly expressed in the developing and adult nervous system and are important in contact-mediated axon guidance, axon fasciculation and cell migration. Eph receptors are unique among other RTKs in that they fall into two subclasses with distinct ligand specificities, and in that they can themselves function as ligands to activate bidirectional cell-cell signalling. We report here the crystal structure at 2.9 A resolution of the amino-terminal ligand-binding domain of the EphB2 receptor (also known as Nuk). The domain folds into a compact jellyroll beta-sandwich composed of 11 antiparallel beta-strands. Using structure-based mutagenesis, we have identified an extended loop that is important for ligand binding and class specificity. This loop, which is conserved within but not between Eph RTK subclasses, packs against the concave beta-sandwich surface near positions at which missense mutations cause signalling defects, localizing the ligand-binding region on the surface of the receptor.


Effects of different stocking densities on organ development, blood biochemical indices, and antioxidative status of breeder pigeons during the rearing period.
The present experiment was conducted to investigate the effect of different stocking densities on the organ development, blood biochemical indices, and antioxidative status of breeder pigeons during the rearing period. A total of 280 (half male and half female) 40-day-old young pigeons were allocated into 4 groups, including 3 experimental groups (in compartments of the flying room): the high stocking density (HSD) (0.308 m3/bird), standard stocking density (SD) (0.616 m3/bird), and low stocking density (LSD) (1.232 m3/bird) and a caged control (0.04125 m3/bird). The results showed that the contents of corticosterone and heat shock protein 70 in males and the corticosterone content in females were higher in the control than in the other groups. The relative weight of liver, lung, and gizzard in males of the HSD group was the highest among the 4 treatments, whereas the abdominal fat index in the control group was higher than those in the other 3 treatments. Body weight and the relative weight of liver and abdominal fat in female pigeons in HSD group increased significantly. The levels of serum urea nitrogen and uric acid in pigeons of LSD group increased significantly, while the concentration of total cholesterol and the activity of alanine aminotransferase were higher in the control group. Ion (K+, Ca2+, and Na+) concentrations in female pigeon serum were also elevated in the control. The activity of antioxidant enzymes, including the total antioxidant capacity, superoxide dismutase, and glutathione peroxidase in pigeon breast muscle and liver had different degrees of inhibition when the space room was crowded. Moreover, the level of malondialdehyde in the liver of male caged pigeons was higher than that in the other treatments. In summary, rearing in cages or at a high density caused stress responses in the breeder pigeons. The stocking density of breeder pigeons during the rearing period should be ranged from 0.616 m3/bird to 1.232 m3/bird.


Effects of Soil Properties and Land Use Types on the Bioaccessibility of Cd, Pb, Cr, and Cu in Dongguan City, China.
In order to determine the potential heavy metal contamination in soil across Dongguan City, 124 soil samples from seven land use types were collected, four heavy metals (Cd, Pb, Cr, and Cu) were analyzed. Total Cd, Cr, and Cu contents were significantly higher than the background values for Guangdong Province. Lead bioaccessibility in urban green land was lower than that in industrial and abandoned districts. The bioaccessibility of heavy metals was affected by total metal concentrations, soil properties, and land use types. The results showed that there was a negative correlation between the bioaccessibility of heavy metals (except for Cu) and their total concentrations. Soil pH and organic matter were the main factors affecting the bioaccessibility of Cd, Cr, Pb, and Cu in most land use types. Furthermore, sand, P, and clay also affected Pb, Cr, and Cu bioaccessibility. With the exception of the industrial zone periphery and urban green land, the bioaccessibility of heavy metals was mainly affected by clay.


Skin test reactivity to histamine from infancy to old age.
The skin test reactivity to allergen and histamine differs according to the age of the patients, but complete data from infancy to old age are still lacking. Three hundred sixty-five subjects (1 to 85 years of age, 33.9% atopic, and 50.1% male patients) were prick tested with threefold dilutions of histamine hydrochloride (1 to 243 mg/ml). There was a significant (p less than 0.0001; F test) main effect of age on the skin reactivity to histamine. Age groups were defined and statistical analysis were performed by means of parallel line bioassay. All dose-response curves were linear and parallel. There is a significant increase in the mean wheal size between 4 to 5 and 6 to 9 years of age, 10 to 14 and 15 to 20 years. There was almost no difference between 15 to 20 and 21 to 50 years. No difference was observed between 21 to 30, 31 to 40, and 41 to 50 years, and then, the mean wheal sizes decreased significantly to reach a plateau after the age of 60 years. There was no sex difference, and skin tests with histamine were similar in atopic and nonatopic individuals.


[Head injuries (author's transl)].
The majority of mortalities after car accidents are due to head injuries. These are followed by injuries to the thorax, abdomen, and extremities. Correctly used seat belts may prevent up to 70% of the head injuries and decrease the effects of other injuries as well. At least half of those who are killed in car accidents would be alive today if they had worn a seat belt.


Atypical 22q11.2 deletion in a patient with DGS/VCFS spectrum.
Deletions in region 22q11.2 usually occur between two low copy repeat regions (LCRs), which are preferred chromosome sites for rearrangements. Most of the deletions encompass the same approximately 3 or approximately 1.5 Mb region, with breakpoints at LCR A and D or at LCR A and B, respectively. We report on a patient with clinical features of the 22q deletion syndrome who presents a novel, atypical deletion, smaller than 1.5 Mb, with distal breakpoint in LCR B and proximal breakpoint within no known LCR site.


Human pluripotent stem cell-derived cardiomyocytes for heart regeneration, drug discovery and disease modeling: from the genetic, epigenetic, and tissue modeling perspectives.
Heart diseases remain a major cause of mortality and morbidity worldwide. However, terminally differentiated human adult cardiomyocytes (CMs) possess a very limited innate ability to regenerate. Directed differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into CMs has enabled clinicians and researchers to pursue the novel therapeutic paradigm of cell-based cardiac regeneration. In addition to tissue engineering and transplantation studies, the need for functional CMs has also prompted researchers to explore molecular pathways and develop strategies to improve the quality, purity and quantity of hESC-derived and iPSC-derived CMs. In this review, we describe various approaches in directed CM differentiation and driven maturation, and discuss potential limitations associated with hESCs and iPSCs, with an emphasis on the role of epigenetic regulation and chromatin remodeling, in the context of the potential and challenges of using hESC-CMs and iPSC-CMs for drug discovery and toxicity screening, disease modeling, and clinical applications.


A prospective study of injury patterns in high school pole vaulters.
The pole vault is a track and field event that has witnessed a large increase in participants during the past 5 years. Currently there are no prospective studies that have evaluated injury patterns in pole vaulters. To determine the injury rate and to describe injury patterns in high school pole vaulters. Descriptive epidemiological study. This was a prospective cohort study of 140 Wisconsin high school athletes who participated in pole vaulting during the 2005 and 2006 track and field seasons. Baseline athlete information was obtained at the beginning of each season. When an injury occurred, an injury report form was completed to document diagnosis and circumstances of the incident. Injury rates were expressed as injuries per 100 athletes per season as well as injuries per 1000 athletic exposures. Risk factors were analyzed by calculating relative risks for baseline athlete variables. The injury rates were 26.4 injuries per 100 athletes per season (95% confidence interval, 18.6-36.4) and 7.1 injuries per 1000 athletic exposures (95% confidence interval, 5.0-9.8). Trauma to the lower extremities accounted for 71.5% of injuries. The most common injury types were ligament sprains (31.6%). Landing incorrectly was the most frequent mechanism of injury (26.3%). A history of pole-vault injury was associated with increased risk of injury (relative risk, 2.4; 95% confidence interval, 1.4-4.1). Injuries are common in young vaulters. Injury mechanisms indicate that many could be avoided by using proper technique, particularly during the landing phase. Coaches should focus on vaulters with prior injuries to identify risky behavior and to help correct poor technique.


Towards a target label-free suboptimum oligonucleotide displacement-based detection system.
A novel method for the future development of label-free DNA sensors is proposed here. The approach is based on the displacement of a labelled suboptimum mutated oligonucleotide hybridised with the immobilised biotin-capture probe. The target fully complementary to the biotin-capture probe can displace the labelled oligonucleotide causing a subsequent decrease of the signal that verifies the presence of the target. The decrease of signal was demonstrated to be proportional to the target concentration. A study of the hybridisation of mutated and complementary labelled oligonucleotides with an immobilised biotin-capture probe was carried out. Different kinetic and thermodynamic behaviour was observed for heterogeneous hybridisation of biotin-capture probe with complementary or suboptimum oligonucleotides. The displacement method evaluated colourimetrically achieved the objective of decreasing the response time from 1 h for direct hybridisation of 19-mer oligonucleotides in the direct enzyme-linked oligonucleotide assay (ELONA) to 5 min in the case of displacement detection in the micromolar concentration range.


Chronic mild stress in mice decreases peripheral cytokine and increases central cytokine expression independently of IL-10 regulation of the cytokine network.
Accumulating evidence indicates that stress leads to an increased expression of pro-inflammatory cytokines such as interleukin (IL)-6. The production and action of pro-inflammatory cytokines are down-regulated by anti-inflammatory cytokines such as IL-10. This makes IL-10-deficient mice a potentially useful model to assess the effects of stress on cytokine production. In the present study, IL-10-deficient mice were compared to wild-type mice in their behavioural and cytokine response to a chronic mild stress procedure. The 3-week chronic mild stress decreased body weight gain and sucrose consumption. It also resulted in a decreased expression of peripheral IL-1beta and IL-6 and an increased expression of brain IL-6. This last change in IL-6 was correlated to body weight loss in stressed mice. However, IL-10-deficient mice did not differ from wild-type mice in their response to the chronic mild stress procedure, despite substantial differences in functioning of the cytokine network. These results are interpreted in the context of the relationship between cytokines and behaviour.


Mimicking titration experiments with MD simulations: A protocol for the investigation of pH-dependent effects on proteins.
Protein structure and function are highly dependent on the environmental pH. However, the temporal or spatial resolution of experimental approaches hampers direct observation of pH-induced conformational changes at the atomic level. Molecular dynamics (MD) simulation strategies (e.g. constant pH MD) have been developed to bridge this gap. However, one frequent problem is the sampling of unrealistic conformations, which may also lead to poor pKa predictions. To address this problem, we have developed and benchmarked the pH-titration MD (pHtMD) approach, which is inspired by wet-lab titration experiments. We give several examples how the pHtMD protocol can be applied for pKa calculation including peptide systems, Staphylococcus nuclease (SNase), and the chaperone HdeA. For HdeA, pHtMD is also capable of monitoring pH-dependent dimer dissociation in accordance with experiments. We conclude that pHtMD represents a versatile tool for pKa value calculation and simulation of pH-dependent effects in proteins.


Association between allelic variants in the glucagon-like peptide 1 and cholecystokinin receptor genes with gastric emptying and glucose tolerance.
Nutrient-mediated release of cholecystokinin and glucagon-like peptide-1 (GLP-1) regulates gastric emptying (GE) via duodenogastric feedback mechanisms; GLP-1 also regulates postprandial insulin secretion. Some patients with functional upper gastrointestinal symptoms have impaired glucose tolerance during enteral dextrose infusion. Our hypothesis was that variants in CCK, GLP-1, and TCF7L2 (transcription factor 7-like 2 locus), which is associated with greatest genetic risk for development of type 2 diabetes mellitus, are associated with GE and independently with glucose tolerance. Our aims were to evaluate the associations between these GE, glucose tolerance, and these single nucleotide polymorphisms (SNPs). Genetic variants, scintigraphic GE of solids, plasma glucose, insulin, and GLP-1 during enteral dextrose infusion (75gm over 2 hours) were measured. GE and enteral dextrose infusion were, respectively, evaluated in 44 (27 controls and 17 patients with functional dyspepsia or nausea) and 42 (28 controls, 14 patients) participants; of these, 51 participants consented to assessment of SNPs. Four functional SNPs were studied: rs6923761 and rs1042044 at GLP-1 receptor, rs7903146 (TCF7L2), and rs1800857 (CCK receptor). Gastric emptying was normal in 38, rapid in 4, and delayed in two participants; 38 had normal, and four had impaired glucose tolerance. The T allele at rs7903146 (TCF7L2) was non-significantly associated (P = .14) with faster GE. The associations between SNPs and demographic variables, GE thalf , glucose tolerance and plasma GLP1 levels were not significant. There is a trend toward an association between faster GE and the diabetes-associated allele at rs7903146 in TCF7L2. However, these SNPs were not associated with plasma glucose or GLP1 concentrations during enteral dextrose infusion.