Base and conformational specificity of an amine modification of DNA.
We have investigated the site and conformational preference of the reaction of a formaldehyde/amine reagent with DNA. Previous investigations of this laboratory have established that this reagent will react with native DNA, placing a positively charged amine moiety on the duplex that will survive exhaustive dialysis. The resulting adduct is duplex and base stacked in character, possessing B backbone geometry with a higher average winding angle and exhibiting remarkable stability with respect to the A-form, Z-form, or the single-strand denaturated species. In this current investigation, we have found that the stability of the adduct is dramatically reduced if the DNA is converted to mononucleotides, thus obviating the usual approach of nuclease digestion and chromatography for the identification of the modified nucleotides. Using indirect approaches, we have established that the reactive site that survives removal of the equilibrium concentrations of CH2O and amine is the exocyclic amino group of the guanine bases. This conclusion is based on (1) the positive correlation between GC content and the extent of adduct formation under standard reaction conditions (27 degrees C, 0.63M CH2O, 0.007M n-butylamine, pH 7); (2) decreases in the level of substitution of amine in DNA, which has this site blocked by trinitrobenzene modification; and (3) failure of poly(dI-dC) to retain amine upon dialysis. Raman spectra of the derivatized poly(dG-dC) show enhanced 2'-endo B character, with no marked shifts in the position of any of the lines, indicating the absence of any ring structures involving the N7 and the 06 of G. In standard reaction mixtures, other sites may react but this phenomenon appears to be minimal under conditions that do not favor fluctuational opening of base pairs. In the latter case, excess loading of amine on high GC content polymers produces a CD spectrum that is similar to one produced by poly(dA-dT) in the "X"-form [M. Vorlickova, E. Minyat, and J. Kypr (1984) Biopolymers 23, 1-4]. This conformation is lost, however, upon removal of excess reagents by dialysis and cannot be reestablished, in the absence of unbound amine and formaldehyde. The reaction is specific for the B-form of polynucleotides as demonstrated by the failure of poly(dG-m5dC) in the stable Z-form to exhibit substantial reaction. The B-form of this polymer will react readily with the retention of 0.23 moles amine/mole nucleotide under our standard reaction conditions.(ABSTRACT TRUNCATED AT 400 WORDS)


Outcomes of pediatric community-acquired pneumonia before and after national pneumococcal immunization in Taiwan.
In Taiwan, the incidence of invasive pneumococcal disease (IPD) in children declined after the catch-up primary vaccination programs and the full national immunization program (NIP) with PCV13. The objective of the study was to investigate the clinical outcomes of pediatric community-acquired pneumonia (CAP) before and after the NIP. The study included patients aged 3 months to 17 years who were diagnosed with CAP and treated at the National Taiwan University Hospital between 2007 and 2019. Patients were assigned to three birth cohorts according to their birth years and vaccination eligibility: non-NIP, catch-up, and full NIP. We compared the rates of severe outcomes, including case fatality and pathogens. A total of 6557 patients who met the CAP criteria were enrolled during the study period. The case-fatality rate decreased from 3.2% (94/2984) in the non-NIP cohort to 0.3% (7/2176) in the catch-up cohort and 0.8% (11/1397) in the full NIP cohort (p < 0.001). Furthermore, there was a significant decrease in invasive ventilation from the non-NIP (17.9%) to both catch-up (6.8%) and full NIP cohorts (9.1%). The rate of IPD declined from the non-NIP cohort to the catch-up cohort (1.8% vs. 0.6%, p < 0.001) and from the catch-up to the full NIP cohort (0.6% vs. 0.07%, p = 0.014). In contrast, the rates of infections with other pathogens increased after NIP. The introduction of PCV13 showed significant reduction in case-fatality and IPD rates. The increasing rates of other pathogens warrant further surveillance for their clinical significance.


Differential effects of cefmetazole sodium on the reproductive system of infant and pubertal male rats.
The effects of cefmetazole (CMZ), a cephem antibiotic which contains the N-methyltetrazolethiol (NMTT) side-chain moiety, were compared in infant (6-42 days of age) and pubertal (6-10 weeks of age) male Sprague-Dawley rats. High doses of either CMZ or free NMTT caused reductions in testicular weight and delayed maturation of spermatogenic germ cells in the testes of infant rats, implicating NMTT as the active component in causing these effects. Pubertal rats expressed neither of these effects, even when treated with doses of CMZ far in excess of those used in infant rats. The effects of CMZ and NMTT on testicular weights and histologic features of testes of rats treated as infants were mainly reversed when these animals were examined 35 and 70 days after cessation of treatment. All reproductive functional parameters were normal in mating studies using male rats which had been treated with CMZ or NMTT as infants and allowed to recover. Because of the species differences in rates of sexual maturation and the greater rate at which rats metabolize CMZ to NMTT, the relevance to humans of the testicular effects of CMZ in infant rats is unknown.


Correction to: The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants.
In the original article, the reference 4 has been published and cited incorrectly.


Effects of high hydrostatic pressure and thermal processing on anthocyanin content, polyphenol oxidase and β-glucosidase activities, color, and antioxidant activities of blueberry (Vaccinium Spp.) puree.
Thermal processing (TP) and high hydrostatic pressure (HHP) are two important puree processing methods. In this study, the polyphenol oxidase (PPO) and β-glucosidase activities, chromatic values, peroxide radical scavenging capacities (PSCs), cellular antioxidant activities (CAAs), and anthocyanin profiles were evaluated in blueberry puree following TP and HHP treatments. Nine anthocyanins were identified and cyanidin glycosides were the most abundant compounds in the blueberry puree sample. Petunidin-3-O-arabinoside, malvidin-3-O-galactoside, and malvidin-3-O-glucoside concentrations increased at temperatures of 70-90 °C (TP) and a pressure of 300 MPa (HHP). The highest total anthocyanin concentration (503.5 μg/mL) and PSC (13.45 µg VCE/mL) were observed following the TP (90 °C) treatment. Furthermore, a positive correlation was observed between the anthocyanin content and PSC (R2 = 0.655, P < 0.05). Finally, HHP treatment resulted in better puree color retention than TP treatment. The results of this study could provide valuable information for optimizing the processing methods for anthocyanin-rich products.


Associations between dogs that were serologically positive for Rickettsia conorii relative to the residences of two human cases of Mediterranean spotted fever in Piemonte (Italy).
A geographic information system and K-function analysis were used to evaluate the spatial association of canine serological results for Rickettsia conorii, the causative agent of Mediterranean spotted fever (MSF), and clinical cases of MSF in humans in Piemonte, northwest Italy. The residences of dog owners were clustered in two rural villages in the province of Cuneo, where two human cases of MSF occurred in 1997 and 1998. Eighteen out of 116 dogs examined were positive by indirect immunofluorescent assay (IFA+, titre > or =1:160) for MSF. K-functions were compared for IFA+ dogs and for all dogs sampled. Monte Carlo and bootstrap simulations demonstrated that clustering of IFA+ dogs was significantly greater than clustering of all dogs, at distances of less than 0.6 km from human cases of MSF. Logistic regression analysis indicated that the risk of being IFA+ was highest for dogs residing within the first quartile of distance (0.7 km) from human cases of the disease, and for dogs that were not confined. However, year and season of blood collection were not associated with IFA status. It was concluded that a relatively high dog population density along with a rural or semi-rural environment favours the occurrence of emergent foci of MSF in the province of Cuneo.


Transplacental transmission of Cryptococcus neoformans to an HIV-exposed premature neonate.
Cryptococcosis during pregnancy is well documented, but transmission of infection to the fetus is rare. We describe a premature neonate born to a mother with congenitally acquired human immunodeficiency virus (HIV) and active cryptococcosis. Histological examination of the placenta revealed Cryptococcus neoformans within the maternal intervillous space with focal invasion into the chorionic villi. A positive serum cryptococcal antigen (1:2) was detected on days 1 and 5 of life. The neonate had no evidence of central nervous system disease and was treated with fluconazole with resolution of antigenemia. This case highlights both the potential for transplacental transmission of C. neoformans infection and the complexities of caring for pregnant mothers who themselves are congenitally infected with HIV.


Deferral of first review after uneventful phacoemulsification cataract surgery until 2 weeks: randomized controlled study.
To investigate the safety of deferring the ophthalmic review after uneventful phacoemulsification cataract surgery until 2 weeks after the procedure. Waterford Regional Hospital, Waterford, Ireland. After uneventful cataract surgery, 233 patients were randomized to have ophthalmic review 2 hours after the procedure and 2 weeks postoperatively (Group 1) or to forego any ophthalmic review before the 2-week postoperative visit in the outpatient department (Group 2). Of the 115 patients randomized to Group 1, 25 (21.7%) had intraocular pressure (IOP) spikes of 30 mm Hg or greater and 2 (1.7%) had a corneal abrasion in the immediate postoperative period. Group 1 and Group 2 were statistically similar in terms of problems encountered in the first 2 postoperative weeks and anterior segment findings and visual acuity at the 2-week postoperative visit. The results of this randomized controlled study indicate that the first ophthalmic review after uneventful cataract surgery can be safely deferred until 2 weeks postoperatively in patients in whom a transient IOP spike would not be deemed clinically deleterious. Such a policy will enhance the efficiency of day-surgery units.


Temperature might increase the hospital admission risk for rheumatoid arthritis patients in Anqing, China: a time-series study.
Temperature has been studied in relation to many health outcomes. However, few studies have explored its effect on the risk of hospital admission for rheumatoid arthritis (RA). A distributed lag non-linear model (DLNM) was used to analyze associations between mean temperature, diurnal temperature range (DTR), temperature change between neighboring days (TCN), and daily admissions for RA from 2015 to 2019 in Anqing, China. Subgroup analyses based on age, gender, rheumatoid factors, and admission route were performed. In total, 1456 patients with RA were hospitalized. Regarding the cumulative-lag effects of extreme cold temperature (5th percentile = 3℃), the risks of admissions for RA were increased and highest at lag 0-11 (RR = 2.68, 95% CI: 1.23-5.86). Exposing to low (5th percentile = 1.9℃) and high (95th percentile = 14.2℃) DTRs both had increased risks of RA admission, with highest RRs of 1.40 (95% CI: 1.03-1.91) and 1.24 (95% CI: 1.0-1.53) at lag 0 day, respectively. As for TCN, the marginal risk of admission in RA patients was found when exposed to high TCN (95th percentile = 2.9℃) with the largest single-day effect at lag 10 (RR = 1.11, 95% CI: 1.01-1.23). In subgroup analyses, females were more susceptible to extreme cold temperature, low and high DTRs, and high TCN. In regard to extreme cold temperature, significant risk of hospital admission in females only appeared at lag 2 (RR = 1.48, 95% CI: 1.02-2.15) and lag 0-2 (RR = 2.35, 95% CI: 1.11-4.95). It is clear that RA patients exposed to changing temperature may increase risks of admission.


Trends in Strategic Napping in Surgical Residents by Gender, Postgraduate Year, Work Schedule, and Clinical Rotation.
To identify surgical resident and clinical rotation attributes which predict on-shift napping through objectively measured sleep patterns and work schedules over a 2-month period. In a cross-sectional study, participants provided schedules, completed the Epworth Sleepiness Scale (ESS), and wore sleep-tracking devices (Zulu watch) continuously for 8 weeks. Multiple linear regression predicted percent days with on-shift napping from resident and rotation characteristics. Greater Washington, DC area hospitals. Twenty-two (n = 22) surgical residents rotating in at least 1 of 5 different clinical rotation categories. Residents slept 6 hours within a 24-hour period (370 ± 129 minutes) with normal sleep efficiency (sleep efficiency (SE): 87.13% ± 7.55%). Resident ESS scores indicated excessive daytime sleepiness (11.64 ± 4.03). Ninety-five percent (n = 21) of residents napped on-shift. Residents napped on-shift approximately 32% of their working days and were most likely to nap when working between 23:00 and 05:00 hours. Earlier shift start times predicted less on-shift napping (B = -0.08, SE = 0.04, β = -2.40, t = -2.09, p = 0.05) while working more night shifts (B = 1.55, SE = 0.44, β = 4.12, t = 3.52, p = 0.003) and shifts over 24 hours (B = 1.45, SE = 0.55, β = 1.96, t = 2.63, p = 0.01) predicted more frequent on-shift napping. Residents are taking advantage of opportunities to nap on-shift. Working at night seems to drive on-shift napping. However, residents still exhibit insufficient sleep and daytime sleepiness which could reduce competency and represent a safety risk to themselves and/or patients. These findings will help inform intervention strategies which are tailored to surgical residents using a biomathematical model of fatigue.


Selective quantification of lacosamide in human plasma using UPLC-MS/MS: Application to pharmacokinetic study in healthy subjects with different doses.
A practical, sensitive, and robust UPLC-MS/MS method was developed and validated to quantify lacosamide in human plasma. A simple one-step protein precipitation was used to extract lacosamide and labeled lacosamide-13C, D3 as an internal standard (IS) from 150-μL plasma. The extracts were analyzed on an Eclipse Plus C18 column (50 × 2.1 mm, 1.8 μm) using 0.1% formic acid in water and methanol:acetonitrile (50:50, v/v) under gradient conditions. The extracts were quantified on LCMS-8040 using electrospray ionization source operated in positive ionization and multiple reaction monitoring modes. The method showed good linearity from 0.02 to 20 μg/mL, which was adequate to cover lacosamide concentration assayed in formulations with different strengths. The bioanalytical assay was fully validated as per current regulatory guidelines. The intra-batch and inter-batch precision values of lacosamide were less than 4.6%. Lacosamide was found to be stable at different storage conditions. The extraction recoveries and IS-normalized matrix factors for lacosamide ranged from 97.17 to 99.68% and from 0.973 to 1.012, respectively. The validated method was successfully applied to a pharmacokinetic study with three lacosamide formulations (50, 100, and 200 mg) in 36 healthy subjects. The assay reliability was determined by reanalysis of 81 subject samples.


Differential growth regulation of human bladder tumor cells (J82) in culture by normal bladder cells from different aged human donors.
This study used an agarose gel culture system to study growth regulatory interactions between normal and neoplastic human bladder cells. The effects of normal human fibroblasts on tumor cell cloning efficiency in agarose was studied using 2 experimental protocols. In 1 system, the fibroblasts proliferated as anchored cells beneath the agarose, and in the other the fibroblasts were nongrowing cells embedded within the agarose as nonanchored cells. In contrast to the largely inhibitory effects of anchored fetal fibroblasts on tumor cell growth, their nonanchored counterparts were exclusively stimulatory. Similar experiments with normal fibroblasts derived from the bladders of increasingly older donors showed a progressive decline in their capacity to inhibit tumor cell growth in agarose. Further experiments modulating the growth rate of neonatal fibroblasts with fetal bovine serum have indicated that the diverse tumor responses elicited by anchored versus nonanchored cells, as well as those observed for the aged bladder fibroblasts, were a function of fibroblast growth rate. We concluded that there was an inverse regulatory relationship between the growth of normal and tumor cells; rapidly growing fibroblasts were inhibitory whereas nongrowing fibroblasts stimulated tumor cell growth in agarose culture.


Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass in adult patients undergoing cardiac surgery.
The aims of the present study were to establish a population pharmacokinetic (PPK) model of cefazolin for adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to assess the probability of target attainment (PTA) for the prophylaxis of surgical site infection (SSI) using cefazolin. Adult patients who underwent cardiac surgery with CPB were enrolled in the prospective study. Blood samples for plasma cefazolin assay were collected, and total and unbound drug concentrations were measured and analysed using the nonlinear mixed-effects modelling (NONMEM) software considering saturable plasma protein binding. Using the PPK model, plasma unbound cefazolin concentration-time courses with current prophylaxis protocols were simulated, and the PTA for common SSI pathogens was estimated. A total of 199 blood samples were obtained from 27 patients. A one-compartment model with first-order elimination plus an on/off CPB compartment best described the data. The population mean for systemic drug clearance (CL) was reduced and that for the volume of distribution (V) was increased during CPB compared with the pre-CPB values. CPB-induced hypoalbuminemia was associated with reduced maximum protein binding (Bmax). The simulation studies suggested that the current dosing protocols are insufficient for attaining PTA > 0.9 throughout surgery against pathogens with minimum inhibitory concentrations (MICs) >8 mg/L. A new dosing protocol that achieves a PTA > 0.9 for pathogens with a MIC of 16 mg/L was proposed. PPK modelling with simulation may be valuable for devising a cefazolin prophylaxis protocol for patients undergoing cardiac surgery with CPB.


A practical overview of considerations for penile prosthesis placement.
Penile prostheses have remained the gold-standard therapy for medically refractory erectile dysfunction (ED) since their popularization. Advances in device design and surgical techniques have yielded improved rates of infection, satisfaction, and mechanical survival of devices. Operative techniques in penile prosthesis surgery include the use of adjunctive procedures (such as ventral phalloplasty and release of the suspensory ligament), management of penile fibrosis, and manoeuvres to correct Peyronie's-disease-related curvature. Complications include urethral and corporal perforation, crossover, infection, impending erosion, and/or supersonic transporter deformity. Long-term data regarding mechanical, overall, and infection-free survival demonstrate excellent results, and, given the consistently high satisfaction rates and limited alternatives for medically refractory ED, penile prostheses are likely to remain a relevant and important treatment strategy for the foreseeable future.


Human coronavirus OC43 3CL protease and the potential of ML188 as a broad-spectrum lead compound: homology modelling and molecular dynamic studies.
The coronavirus 3 chymotrypsin-like protease (3CL(pro)) is a validated target in the design of potential anticoronavirus inhibitors. The high degree of homology within the protease's active site and substrate conservation supports the identification of broad spectrum lead compounds. A previous study identified the compound ML188, also termed 16R, as an inhibitor of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) 3CL(pro). This study will detail the generation of a homology model of the 3CL(pro) of the human coronavirus OC43 and determine the potential of 16R to form a broad-spectrum lead compound. MODELLER was used to generate a suitable three-dimensional model of the OC43 3CL(pro) and the Prime module of Schrӧdinger predicted the binding conformation and free energy of binding of 16R within the 3CL(pro) active site. Molecular dynamics further confirmed ligand stability and hydrogen bonding networks. A high quality homology model of the OC43 3CL(pro) was successfully generated in an active conformation. Further studies reproduced the binding pose of 16R within the active site of the generated model, where its free energy of binding was shown to equal that of the 3CL(pro) of SARS-CoV, a receptor it is experimentally proven to inhibit. The stability of the ligand was subsequently confirmed by molecular dynamics. The lead compound 16R may represent a broad-spectrum inhibitor of the 3CL(pro) of OC43 and potentially other coronaviruses. This study provides an atomistic structure of the 3CL(pro) of OC43 and supports further experimental validation of the inhibitory effects of 16R. These findings further confirm that the 3CL(pro) of coronaviruses can be inhibited by broad spectrum lead compounds.


Epidemiologic study of 230 cases of testicular/paratesticular tumors or masses: 15-year experience of a single center.
This study retrospectively investigated the cases of testicular tumors/masses treated in our center from 2002 to 2017 and analyzed their epidemiologic features. Data were collected by searching our center's database using "testicular tumor" or "testicular mass" as keywords. Patients not operated in our hospital were excluded. Preoperative serum alpha-fetoprotein (AFP) levels were reviewed in germ cell tumor (GCT) cases and analyzed to predict malignancy in various age groups. In total, 230 cases were identified: 151 were benign (78 in the left, 72 in the right, and 1 bilateral) with 3.63years mean age during the operation, and 79 were malignant (42 in the left, 36 in the right, and 1 bilateral) with 2.21years mean age during the operation. Main pathological diagnoses were mature teratoma (92, 40.00%), yolk sac tumor (53, 23.04%), dermoid cyst (23, 10.00%), embryonic carcinoma (15, 6.53%), immature teratoma (14, 6.09%), benign cyst (8, 3.48%), Leydig cell tumor (6, 2.61%), and paratesticular rhabdomyosarcoma (5, 2.17%). All GCT cases with AFP >1000ng/ml, >100ng/ml, >20ng/ml were malignant in <7-, 7-9-, and ≥10-month-old groups, respectively. Radical inguinal orchiectomy without biopsy is suggested in 7-9- and ≥10-month-old cases with AFP >100ng/ml and >20ng/ml, respectively. Retrospective Study. Level III-IV.


Determination of hexoestrol residues in animal tissues based on enzyme-linked immunosorbent assay and comparison with liquid chromatography-tandem mass spectrometry.
A competitive enzyme-linked immunosorbent assay (ELISA) was developed for the quantitative detection of the hexoestrol (HES). Polyclonal rabbit antisera, raised against protein conjugate hexoestrol-mono-carboxyl-propyl-ethyl-bovine-serum-albumin (HES-MCPE-BSA), were utilized in immobilized antibody-based and competitive immunoassays. Assay conditions, including concentrations of antisera and Horseradish peroxidase (HRP)-HES were optimized. The effect of incubation time, surfactant concentration, ionic strength and pH of the medium were also investigated. The typical calibration curve gave an average IC50 value of 2.4 ng/ml, calibration range from 0.2 ng/ml to 30.5 ng/ml and a detection limit of 0.07 ng/ml. The specificity of the assay was tested against HES structurally related compounds, and the assay proved highly selective for HES. Assay performance was validated by using spiked pork and liver tissues samples. Moreover, it was compared with liquid chromatography-tandem mass spectrometry. The ion pair for quantification of HES was 269.4/134, and linear equation of HES was Y=0.2148X-0.0374 (r=0.9993). The two analytical methods can be applied to monitor HES and other steroid residues in edible foods.


Endocrine and clinical effects of spironolactone in female hyperandrogenism.
In a double-blind cross-over study, 24 hyperandrogenic women were treated for three months at a time with either spironolactone 100 mg or placebo daily from the 5th to the 21st days of the menstrual cycle. Spironolactone had a slight but statistically insignificant effect on hirsutism when compared with placebo. Slightly more regular menstruation and better follicular growth was noted during spironolactone treatment. Ovulation (defined as a day 21 serum progesterone level of more than 10 nmol/l) occurred in only 12% of spironolactone cycles, as against 28% of placebo cycles. Spotting occurred in one-third of the spironolactone cycles. No significant differences were found between spironolactone and placebo cycles in serum levels of LH, FSH, prolactin, estradiol, progesterone, androstenedione, total testosterone, sex-hormone binding globulin (SHBG), unbound testosterone, dehydroepiandrosterone sulphate (DHEAS), cortisol, potassium and sodium. The average ovarian volume was 13.0 (5.7-21.8) cm3, and no significant differences were found between treatment and placebo cycles. No significant effect of spironolactone could be demonstrated on androgen secretion and the incidence of ovulation.


Ovarian carcinoma: improved survival following abdominopelvic irradiation in patients with a completed pelvic operation.
A prospective, stratified, randomized study of 190 postoperative ovarian patients with Stages IB, II, and III (asymptomatic) presentations is reported. The median time of follow-up was 52 months. Patients in whom bilateral salpingo-oophorectomy and hysterectomy (BSOH) could not be completed because of extensive pelvic tumor had a poor prognosis which did not differ for any of the therapied tested. When BSOH was completed, pelvic plus abdominopelvic irradiation (P + AB) with no diaphragmatic shielding significnatly improved patient survival rate and long-term control of occult upper abdominal disease in approximately 25% more patients than pelvic irradiation alone or followed by adjuvant daily chlorambucil therapy. The effectiveness of P + AB in BSOH-completed patients was independent of stage or tumor grade and was most clearly appreciated in patients with all gross tumor removed. Chlorambucil added to pelvic irradiation delayed the time to treatment failure without reducing the number of treatment failures.


Donepezil restores GH secretion in old rats without affecting the sleep/wake cycle.
A chronic treatment with a cholinesterase inhibitor, donepezil (0.085 mg/kg/h for 30 days) increases significantly the number and amplitude of growth hormone (GH) pulses in 3- and 24-month-old rats without modifying nadir GH values. This treatment does not reduce age-related alterations in sleep/wake cycle but it increases immobility-related high-voltage spindles (HVS) in old animals. These data suggest that cholinergic mechanisms involved in age-related alterations in GH and sleep regulation are different.


Differences in the prevalence of childhood adversity by geography in the 2017-18 National Survey of Children's Health.
Previous efforts to examine differences in adverse childhood experiences (ACEs) exposure by geography have yielded mixed results, and have not distinguished between urban, suburban, and rural areas. Additionally, few studies to date have considered the potentially moderating role of geography on the relationship between ACEs and health outcomes. To examine differences in exposure to ACEs by geography, and determine whether geography moderates the relationship between ACE exposure and health outcomes (overall health, asthma, attention deficit hyperactivity disorder (ADHD), and special health care needs). The cross-sectional 2017-18 National Survey of Children's Health (NSCH). Distributions of individual and cumulative ACEs by geography (urban, suburban, rural) were compared using chi-squared tests. Logistic regression was used to determine the association between geography and exposure to 4 + ACEs, and to explore whether the relationship between ACEs and health outcomes varied by geography, adjusting for sociodemographic covariates. Adjusting for covariates, rural residency was associated with 1.29 times increased odds of exposure to 4 + ACEs (95 % CI: 1.00, 1.66) compared to suburban residency. Statistically significant evidence for an interaction between geography and ACE exposure on overall health was not observed, but urban status was observed to increase the association between ACEs and asthma. This analysis demonstrates a higher ACE burden in rural compared to suburban children. These findings underscore the importance of ACE screening and suggest investment of healthcare resources in the historically underserved rural population.


Effect of Protein Supplementation on Physical Performance in Older People With Sarcopenia-A Randomized Controlled Trial.
To test the long-term effects of whey-enriched protein supplementation on muscle and physical performance. A 12-month randomized controlled double blind trial with a 43-month of post-trial follow-up. Porvoo, Finland. A total of 218 older (>74 years of age) community-dwelling people with sarcopenia. (1) Control with no supplementation; (2) isocaloric placebo; and (3) 20 g × 2 whey-enriched protein supplementation. All participants were given instructions on home-based exercise, dietary protein, and vitamin D supplementation of 20 μg/d. Physical performance was assessed by short physical performance battery and continuous summary physical performance scores. Hand grip strength and calf intracellular resistance based skeletal muscle index were measured by bioimpedance spectroscopy. The measurements were performed at 0, 6, and 12 months. The post-trial follow-up was performed by a postal questionnaire and national census record data. The participants were older (75-96 years of age) and mostly women (68%). The test supplements had no significant effects on physical performance; the 12-month changes for short physical performance battery were -0.55, -.05, and 0.03 points in control, isocaloric, and protein groups (P = .17), respectively. The changes in continuous summary physical performance scores were similar between the intervention groups (P = .76). The hand grip strength decreased significantly in all intervention groups, and the 12-month changes in calf intracellular resistance-based skeletal muscle index were minor and there were no differences between the intervention groups. One-half of the patients (56%) in both supplement groups reported mild gastrointestinal adverse effects. Differences were found neither in the all-cause mortality nor physical functioning in the post-trial follow-up. The whey-enriched protein supplementation in combination with low intensity home-based physical exercise did not attenuate the deterioration of muscle and physical performance in community-dwelling older people with sarcopenia.


"Stopping for knowledge": The sense of beauty in the perception-action cycle.
According to a millennial-old philosophical debate, aesthetic emotions have been connected to knowledge acquisition. Recent scientific evidence, collected across different disciplinary domains, confirms this link, but also reveals that motor inhibition plays a crucial role in the process. In this review, we discuss multidisciplinary results and propose an original account of aesthetic appreciation (the stopping for knowledge hypothesis) framed within the predictive coding theory. We discuss evidence showing that aesthetic emotions emerge in correspondence with an inhibition of motor behavior (i.e., minimizing action), promoting a simultaneous perceptual processing enhancement, at the level of sensory cortices (i.e., optimizing learning). Accordingly, we suggest that aesthetic appreciation may represent a hedonic feedback over learning progresses, motivating the individual to inhibit motor routines to seek further knowledge acquisition. Furthermore, the neuroimaging and neuropsychological studies we review reveal the presence of a strong association between aesthetic appreciation and the activation of the dopaminergic reward-related circuits. Finally, we propose a number of possible applications of the stopping for knowledge hypothesis in the clinical and education domains.


Femoral nerve status during the anterolateral approach for total hip arthroplasty: Motor-evoked potential analysis and an influencing factor.
Femoral nerve palsy is an uncommon but serious complication during the anterolateral approach for total hip arthroplasty. One of the reported reasons for femoral nerve palsy is retractor-induced intraoperative damage after retractor placement on the anterior wall of the acetabulum. The present study aimed to clarify the femoral nerve status during anterolateral approach total hip arthroplasty using motor-evoked potential analysis and to identify risk factors influencing the nerve status. From June 2019 to September 2020, 32 hips in 31 patients underwent primary total hip arthroplasty via the anterolateral approach. The integrity of the femoral nerve was tested by the motor-evoked potential at three time points: preoperatively as a control (first period), immediately after retractor placement on the anterior wall of the acetabulum (second period), and after the procedure (third period). In the second period, the hips were divided into the following two groups: a <50% femoral nerve amplitude group and a ≥50% group. The iliopsoas muscle volume was evaluated by measuring the muscle cross-sectional area on preoperative computed tomography images, and compared between the two groups. The mean amplitude of the femoral nerve was significantly reduced from 100% in the first period to 35% in the second period (p < 0.01), but then significantly recovered to 54% in the third period (p < 0.01). In 26 (81%) hips, the femoral nerve amplitude was <50% in the second period. The muscle cross-sectional area of the iliopsoas muscle in the <50% group was significantly smaller than that in the ≥50% group (p < 0.05). The mean amplitude of the femoral nerve was significantly reduced to 35% in the second period, and the iliopsoas muscle volume was considered to influence this femoral nerve status.


Color Stability of Teeth Restored with Biodentine: A 6-month In Vitro Study.
White mineral trioxide aggregate (WMTA) has been reported to cause dental discoloration. A previous study on the color stability of 5 calcium silicate-based materials investigated the color stability of Biodentine (Septodont, Saint-Maur-des-Fossés, France) in different experimental environments; however, no data are available on the color stability of teeth restored with Biodentine. In this study, we assessed the color stability under artificial light of ex vivo human teeth restored coronally with WMTA or Biodentine. Cavities were prepared on coronal tooth specimens and restored with WMTA + composite (n = 16), Biodentine + composite (n = 16), or composite alone (control, n = 3). Color was assessed spectrophotometrically at 6 time points (initial, 1 week, 2 weeks, 1 month, 3 months, and 6 months), and color difference values were calculated. Statistical analysis was performed using analysis of variance and the Fisher least significant difference test for which P < .05 was considered statistically significant. The WMTA group showed discoloration at 1 week, which increased over time. The Biodentine and control groups showed color stability and were not significantly different from one another. Teeth treated with WMTA exhibited discoloration, whereas those treated with Biodentine maintained color stability throughout the study. However, further in vivo studies are necessary to corroborate these results.


Evaluation of equilibrium constants for antigen-antibody interactions by solid-phase immunoassay: the binding of paraquat to its elicited mouse monoclonal antibody.
A procedure is devised for simple graphical evaluation of the association constant for antibody-antigen interactions from data obtained by conventional solid-phase immunoassay for antigen. Application of the method to situations involving a univalent antigen is illustrated by means of ELISA data for the interactions of paraquat with its elicited murine monoclonal antibody, and the Fab fragment derived therefrom. Although the completely general situation with both antibody and antigen multivalent is not amenable to study by the present procedure, the quantitative expression is readily modified to accommodate antigen multivalency provided that the univalent Fab fragment may be substituted for the multivalent antibody (IgG or IgM) as partitioning species in the solid-phase immunoassay.


Prognostic features of cervical dysplasia associated with specific types of HPV DNA and cytologic features characteristic of HPV infection in dysplasia.
To study a possible etiologic relationship between the prognosis of uterine cervical dysplasia, association of type-specific human papillomavirus (HPV) DNA and cytologic features characteristic of HPV infection. Two hundred thirteen cases of uterine cervical dysplasia were selected in which follow-up survey for more than two years was possible. Frequency of the presence of HPV DNA in the DNA samples was determined by polymerase chain reaction. The cervical scrapings were also examined microscopically for the frequencies of cells with cytologic features characteristic of HPV infection. HPV was positive in 98 cases (46.0%). The high-risk type of HPV was detected at almost the same frequencies in both progressive and regressive states of dysplasia. Cytologic features were more evident in cells infected with the low-risk type of HPV. Involvement of an as-yet-unknown factor or factors coupled with infection with the high-risk type of HPV is implicated in the progression of uterine cervical dysplasia. Cytologic features characteristic of HPV infection may serve as a diagnostic marker for a favorable prognosis in dysplasia.


Argyrophil cell carcinoma of the uterine cervix with ectopic production of ACTH, beta-MSH, serotonin, histamine, and amylase.
The case of a 38-year-old female with primary argyrophil cell carcinoma of the uterine cervix is reported. Two years after operation the patient developed widespread metastases with typical Cushing's syndrome. Microscopically, the tumor consisted of solid anaplastic cells, adenocarcinoma, and squamous cells. The plasma levels of ACTH and cortisol were elevated. Many cells of both the primary and metastatic tumors showed argyrophilia. Almost all the cells of the metastases contained numerous round secretory granules measuring about 117 micrometers in diameter. Small rod-shaped or larger round secretory granules, measuring 250 and 430 micrometers respectively, were also found in a few of these cells. The tumors in the right lung, pancreas, and kidney contained high levels of ACTH, beta-MSH, serotonin, histamine, and amylase. This is the first report of ectopic production of these five substances from argyrophil cell carcinoma of the uterine cervix.


Activation of glucocorticoid-type II receptor complexes in brain cytosol leads to an increase in surface hydrophobicity as determined by hydrophobic interaction chromatography.
Hydrophobic interaction chromatography has been used to demonstrate an increase in the surface hydrophobicity of [3H]triamcinolone acetonide ([3H]TA)-labeled type II receptors in mouse brain cytosol following transformation of these receptor complexes to the activated DNA-binding form. After removing unbound [3H]TA and molybdate (which prevents activation) by gel filtration, [3H]TA-type II receptors were activated by incubation at 22 degrees C for 20 min. Gel filtration was then used to remove newly dissociated steroid and to readjust the molybdate and/or KCl concentration. Unactivated and activated receptors were then added to propyl, butyl, pentyl, hexyl, octyl, decyl, and dodecyl alkyl agarose, phenyl agarose, or unmodified agarose columns equilibrated and eluted with buffers of various molybdate and KCl concentrations and/or other additions, including glycerol, ethylene glycol, and urea. Under high-salt conditions, activated receptors were retained longer than unactivated receptors run on butyl, pentyl, hexyl, and phenyl agaroses. With the longer alkyl chain columns, essentially none of the [3H]TA was eluted in association with receptor macromolecules. Removal of the remaining steroid required receptor denaturation with urea. Under low-salt conditions, both receptor forms were retained more avidly on all alkyl agarose columns; however, on phenyl agarose only activated receptors displayed this increased retention. Further studies revealed that optimal separation and subsequent recovery of unactivated and activated [3H]TA-type II receptor complexes were achieved on pentyl agarose columns equilibrated and eluted with buffers containing 50 mM molybdate and 600-1,200 mM KCl.(ABSTRACT TRUNCATED AT 250 WORDS)


Autonomous growth fluctuations of the methane oxidizing bacterial strain M 102 in batch and continuous culture.
The growth rates of the methane oxidizing strain M 102 were unstable. In unlimited batch cultures they ranged from 0 to 1.4 d-1 with most frequent values around 0.25 d-1. The yield coefficients were between 0.1 and 1.6 mg dry weight per mg methane and varied from 1.1 to 0.4 even in a continuous culture with the limiting substrate in the gas phase. It was possible to prove intermittent release and uptake of organic compounds by the definition of a "net" yield coefficient and its theoretical boundaries. The response of the fluctuations to varying dilution frequencies and culture volumes showed analogies to controlled systems. The simultaneous variations in the age distribution and in the excretion pattern revealed the dependence of the dividing stages on a product of the young cells. The mathematical description of the findings suggests that the young cells favor division at their own disadvantage. The consequent autonomous synchronisations are the reason for the unstable growth rates of strain M 102.


ICS educational module: Cystometry in children.
To introduce the standard procedure of cystometry and interpretation of the results in children. The literature on cystometry in children in PubMed for the last 20 years was reviewed. The updated knowledge regarding indication, preparation, technique, and interpretation of cystometry in children were summarized. Filling cystometry is the core content of a paediatric urodynamic study. In this section, the technique for performing cystometry is introduced in details. Emphasis is placed on correctly setting up the equipment according to ICS and ICCS guidelines, using appropriate terminology, providing indications for its performance with specific considerations for children, and proper interpretation of results. Cystometry can be used in children including newborn to evaluate lower urinary tract dysfunction.


Polymeric biomolecules based nanomaterials: Production strategies and pollutant mitigation as an emerging tool for environmental application.
The ever-exploding global population coupled with its anthropogenic impact has imparted unparalleled detrimental effects on the environment and mitigating them has emerged as the prime challenge and focus of the current century. The niche of nanotechnology empowered by composites of biopolymers in the handling of xenobiotics and environmental clean-up has an unlimited scope. The appositeness of biopolymer-nanoparticles (Bp-NPs) for environmental contaminant mitigation has received unique consideration due to its exclusive combination of physicochemical characteristics and other attributes. The current review furnishes exhaustive scrutiny of the current accomplishments in the development of Bp-NPs and biopolymer nanomaterials (Bp-NMs) from various polymeric biomolecules. Special attention was provided for polymeric biomolecules such as cellulose, lignin, starch, chitin, and chitosan, whereas limited consideration on gelatin, alginate, and gum for the development of Bp-NPs and Bp-NMs; together with coverage of literature. Promising applications of tailored biopolymer hybrids such as Bp-NPs and Bp-NMs on environmentally hazardous xenobiotics handling and pollution management are discussed as to their notable environmental applications.


28-Homobrassinolide mitigates boron induced toxicity through enhanced antioxidant system in Vigna radiata plants.
The objective of this study was to establish relationship between boron induced oxidative stress and antioxidant system in Vigna radiata plants and also to investigate whether brassinosteroids will enhance the level of antioxidant system that could confer tolerance to the plants from the boron induced oxidative stress. The mung bean (V. radiata cv. T-44) plants were administered with 0.50, 1.0 and 2.0 mM boron at 6 d stage for 7 d along with nutrient solution. At 13 d stage, the seedlings were sprayed with deionized water (control) or 10(-8) M of 28-homobrassinolide and plants were harvested at 21 d stage to assess growth, leaf gas-exchange traits and biochemical parameters. The boron treatments diminished growth, water relations and photosynthetic attributes along with nitrate reductase and carbonic anhydrase activity in the concentration dependent manner whereas, it enhanced lipid peroxidation, electrolyte leakage, accumulation of H(2)O(2) as well as proline, and various antioxidant enzymes in the leaves of mung bean which were more pronounced at higher concentrations of boron. However, the follow-up application of 28-homobrassinolide to the boron stressed plants improved growth, water relations and photosynthesis and further enhanced the various antioxidant enzymes viz. catalase, peroxidase and superoxide dismutase and content of proline. The elevated level of antioxidant enzymes as well as proline could have conferred tolerance to the B-stressed plants resulting in improved growth, water relations and photosynthetic attributes.


Developmental incompetence to stand trial in juvenile courts.
Juveniles' competency to participate in delinquency proceedings has received increased attention in recent years. Developmental incompetence, whereby juveniles' incompetency is based upon their immaturity, as opposed to a mental disorder or developmental disability, is an evolving and important aspect of this area of law. The following paper reviews theories used to support the notion of developmental incompetence, as well as the extant empirical research on juveniles' competency-related abilities. Using a LexisNexis search, statutory and case laws pertaining to juvenile competency were identified across the 50 states and the District of Columbia. Only six states clearly allow developmental incompetence, whereas 17 have laws that do not include developmental immaturity as an acceptable basis of incompetence in juvenile courts. Developmental incompetence is likely to affect a relatively small proportion of juvenile cases, but has important implications for juvenile forensic practice. Recommendations are offered for forensic practitioners conducting this type of evaluation.


ZLY032, the first-in-class dual FFA1/PPARδ agonist, improves glucolipid metabolism and alleviates hepatic fibrosis.
The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) are considered as anti-diabetic targets based on their role in improving insulin secretion and resistance. Based on their synergetic mechanisms, we have previously identified the first-in-class dual FFA1/PPARδ agonist ZLY032. After long-term treatment, ZLY032 significantly improved glucolipid metabolism and alleviated fatty liver in ob/ob mice and methionine choline-deficient diet-fed db/db mice, mainly by regulating triglyceride metabolism, fatty acid β-oxidation, lipid synthesis, inflammation, oxidative stress and mitochondrial function. Notably, ZLY032 exhibited greater advantages on lipid metabolism, insulin sensitivity and pancreatic β-cell function than TAK-875, the most advanced candidate of FFA1 agonists. Moreover, ZLY032 prevented CCl4-induced liver fibrosis by reducing the expressions of genes involved in inflammation and fibrosis development. These results suggest that the dual FFA1/PPARδ agonists such as ZLY032 may be useful for the treatment of metabolic disorders.


The road to implementation of pharmacokinetic-guided dosing of factor replacement therapy in hemophilia and allied bleeding disorders. Identifying knowledge gaps by mapping barriers and facilitators.
Clinical guidelines and expert groups recommend the use of pharmacokinetic (PK)-guided dosing of factor replacement therapy for the treatment of bleeding disorders, especially for patients with hemophilia. Although PK-guided dosing is increasingly applied, it is generally not considered standard clinical practice. The aim of this scoping review is to map barriers and facilitators for the implementation of PK-guided dosing in clinical practice and to identify knowledge gaps. A literature search was performed and 110 articles were included that describe PK-guided dosing in patients with bleeding disorders, mostly hemophilia A. We defined two overarching themes, efficacy and feasibility, and discuss five topics within each theme. For each topic, barriers, facilitators and knowledge gaps were described. Although consensus was found with regard to some topics, contradicting reports were found for others, especially with respect to the efficacy of PK-guided dosing. These contradictions highlight the need for future research to elucidate current ambiguities.


Oxidising agents and its effect on human dentine fluorescence diagnostic measurements.
The ability to determine the effectiveness of root canal disinfection in real-time prior to the final root filling could significantly influence the management and treatment outcomes of root canal therapy. Laser fluorescence devices can detect bacterial fluorescence in real-time, however since quenching of fluorescence is a possible confounding factor, this study explored the effects of oxidising endodontic irrigants on laser fluorescence in dentine. A total of 78 transverse 2 mm thick sections were prepared from the crowns of sterilised extracted non-functional third molars that had been embedded in acrylic resin. The dentine sections where then treated with different concentrations of sodium hypochlorite and hydrogen peroxide, with or without further rinsing with distilled water wash. Fluorescence values were recorded over 24 h using the DIAGNOdent laser fluorescence device. Both sodium hypochlorite and hydrogen peroxide cause quenching of fluorescence readings of human dentine, with reductions of 30-60% in fluorescence readings. The quenching effect occurred quickly, and recovery to baseline readings took from 1 h to 24 h. Rinsing with water reduced but did not eliminate the quenching effect. The use of laser fluorescence to reliably detect root canal bacteria porphyrins in real-time could significantly influence the management of teeth needing root canal therapy. This study highlighted the quenching effects of some root canal irrigants on human teeth root dentine, a variable that should be considered and controlled prior to using lasers to assist in assessing root canal sterility.


Roles of adenine methylation in the physiology of Lacticaseibacillus paracasei.
Lacticaseibacillus paracasei is an economically important bacterial species, used in the food industry and as a probiotic. Here, we investigate the roles of N6-methyladenine (6mA) modification in L. paracasei using multi-omics and high-throughput chromosome conformation capture (Hi-C) analyses. The distribution of 6mA-modified sites varies across the genomes of 28 strains, and appears to be enriched near genes involved in carbohydrate metabolism. A pglX mutant, defective in 6mA modification, shows transcriptomic alterations but only modest changes in growth and genomic spatial organization.


Joint Universal Modular Plasmids: A Flexible Platform for Golden Gate Assembly in Any Microbial Host.
Modular cloning standards based on Golden Gate DNA assembly allow for construction of complex DNA constructs over several rounds of assembly. Despite being reliable and automation-friendly, each standard uses a specific set of vectors, requiring researchers to generate new tool kits for novel hosts and cloning applications. JUMP vectors (Valenzuela-Ortega and French, bioRxiv 799585, 2019) combine the robustness of modular cloning standards with the Standard European Vector Architecture and a flexible design that allows researchers to easily modify the vector backbone via secondary cloning sites. This flexibility allows for JUMP vectors to be used in a wide variety of applications and hosts.


Design and Application of a High Sensitivity Piezoresistive Pressure Sensor for Low Pressure Conditions.
In this paper, a pressure sensor for low pressure detection (0.5 kPa-40 kPa) is proposed. In one structure (No. 1), the silicon membrane is partly etched to form a crossed beam on its top for stress concentration. An aluminum layer is also deposited as part of the beam. Four piezoresistors are fabricated. Two are located at the two ends of the beam. The other two are located at the membrane periphery. Four piezoresistors connect into a Wheatstone bridge. To demonstrate the stress concentrate effect of this structure, two other structures were designed and fabricated. One is a flat membrane structure (No. 2), the other is a structure with the aluminum beam, but without etched silicon (No. 3). The measurement results of these three structures show that the No.1 structure has the highest sensitivity, which is about 3.8 times that of the No. 2 structure and 2.7 times that of the No. 3 structure. They also show that the residual stress in the beam has some backside effect on the sensor performance.


Cyclosporin A prevents the anti-murine antibody response to a monoclonal anti-tumour antibody in rabbits.
Repeated therapy of cancer with mouse monoclonal antibodies frequently produces antibodies directed against the administered antibody. We have investigated the ability of cyclosporin A (CsA) and the use of ultracentrifuged antibody to prevent the formation of anti-antibodies in rabbits. Courses of CsA, 20 mgkg-1 day-1, were given intramuscularly for 6 days to rabbits and a mouse monoclonal anti-human chorionic gonadotrophin antibody was given intravenously on day 2 with or without ultracentrifugation to remove microaggregates. The whole course was repeated after an interval of two weeks. Rabbit anti-mouse antibody production was prevented in all 8 animals that were given CsA and ultracentrifuged preparation (non UC-W14). Anti-mouse antibody was produced by all the animals that were not given CsA. A further dose of mouse antibody eight weeks after CsA demonstrated that immunological recovery had occurred in all four animals re-challenged with non UC-W14 but only 3/7 animals given an UC-W14 preparation. This suggests that CsA and ultracentrifugation facilitate the induction of immunological tolerance. The complete suppression of antibody production which could be achieved justifies a clinical trial of CsA and ultracentrifugation of antibody.


Fabrication of three-dimensional poly(ε-caprolactone) scaffolds with hierarchical pore structures for tissue engineering.
The physical properties of tissue engineering scaffolds such as microstructures play important roles in controlling cellular behaviors and neotissue formation. Among them, the pore size stands out as a key determinant factor. In the present study, we aimed to fabricate porous scaffolds with pre-defined hierarchical pore sizes, followed by examining cell growth in these scaffolds. This hierarchical porous microstructure was implemented via integrating different pore-generating methodologies, including salt leaching and thermal induced phase separation (TIPS). Specifically, large (L, 200-300 μm), medium (M, 40-50 μm) and small (S, <10 μm) pores were able to be generated. As such, three kinds of porous scaffolds with a similar porosity of ~90% creating pores of either two (LS or MS) or three (LMS) different sizes were successfully prepared. The number fractions of different pores in these scaffolds were determined to confirm the hierarchical organization of pores. It was found that the interconnectivity varied due to the different pore structures. Besides, these scaffolds demonstrated similar compressive moduli under dry and hydrated states. The adhesion, proliferation, and spatial distribution of human fibroblasts within the scaffolds during a 14-day culture were evaluated with MTT assay and fluorescence microscopy. While all three scaffolds well supported the cell attachment and proliferation, the best cell spatial distribution inside scaffolds was achieved with LMS, implicating that such a controlled hierarchical microstructure would be advantageous in tissue engineering applications.


An automatic monitoring system for epithelial cell height.
This paper describes an automatic method to measure cell height (h) of epithelia grown as monolayers on transparent filter supports. Tissues are mounted in an Ussing-type chamber enabling solution exchange on both sides. The apical and basal side of the epithelial cells are marked with fluorescent beads. The image of the fluospheres is captured with a video camera and processed by a computer-based video imaging system. One basal reference bead in a gelatin layer on the filter support and up to three beads attached at the apical surface are used to monitor changes in cell height of three cells simultaneously. The focusing of the microbeads is done automatically by moving the objective with a piezoelectric device mounted on the nosepiece of the microscope. The algorithm for locating the bead is based on the changes in fluorescent light intensity emitted by the fluospheres. The method has an accuracy higher than 0.1 micron and a time resolution as low as 6 s if measurements are restricted to one bead at the apical side. The method was tested on artificial model systems and used to measure volume changes in renal cultured epithelia (A6) after exposing the serosal surface to hypotonic solutions and replacing cell-impermeable sucrose by an organic compound (glycerol) with a smaller reflection coefficient. Serosal hypotonicity elicited a rapid volume increase followed by regulatory volume decrease, whereas the organic compound replacement caused a steady increase in cell volume.


Impact of hypoxia-related tumor acidosis on cytotoxicity of different chemotherapeutic drugs in vitro and in vivo.
Extracellular acidosis in tumors leads to an activation of the p-glycoprotein (Pgp) drug transporter. In the present study the cytotoxicity of different chemotherapeutic drugs and its dependence on the Pgp activity during acidosis were analyzed in vitro and in vivo. Treating R3327-AT1, Pgp-positive tumor cells at pH 7.4 with daunorubicin, cisplatin or docetaxel led to marked apoptosis induction and cell death. Under acidic (pH 6.6) conditions cytotoxicity of daunorubicin or docetaxel was significantly reduced whereas cisplatin-induced cell death was almost pH-independent. Inhibiting Pgp with verapamil reversed the acidosis-induced chemoresistance against daunorubicin and docetaxel. The Pgp expression was unaffected by pH. In vivo the cytotoxicity of daunorubicin and docetaxel was also pH dependent. When acidifying the tumors by forcing glycolytic metabolism, apoptosis induction decreased significantly indicating a reduced chemosensitivity. The cytotoxic effect of cisplatin in vivo was unaffected by the tumor pH. Since daunorubicin and docetaxel (but not cisplatin) are substrates of the Pgp, these results underline the influence of the tumor acidosis on the Pgp-mediated chemoresistance which can be counteracted by inhibition of the drug transporter.


Chemical ligation of oligodeoxynucleotides by X-irradiation and its application to regulation of G-quadruplex formation.
We demonstrated radiolytic ligation of oligodeoxynucleotides (ODNs) possessing disulfide bond and its application to regulation of DNA quadruplex formation. G-rich hexamer ODNs had poor ability to form quadruplex, while X-irradiation of the ODNs induced interstrand exchange reaction at disulfide bond to form ligated 12 mer ODNs, leading to the ready formation of quadruplex due to the entropic effect. Since complexation of the ligated ODNs with hemin in the presence of K(+) showed strong soret band absorption and also catalyzed the H(2)O(2)-mediated oxidation of luminol, it appears that the quadruplex formed from ligated ODNs showed a function similar to native DNA quadruplex.


Design, synthesis, and biological activity evaluation of campthothecin-HAA-Norcantharidin conjugates as antitumor agents in vitro.
Three components of Camptothecin, hydroxyacetic acid, and functionalized norcantharidins were constructed together to form a novel series of camptothecin derivatives in a good yield. The synthesized campthothecin-HAA-norcantharidin conjugate pro-drugs could suppress cancer cell growth in vitro. These conjugated pro-drug molecules possess therapeutic potential as novel bi-functional conjugates platforms for cancer treatment.


Chest stab wound-related coronary artery pseudoaneurysm sealed with a polytetrafluoroethylene-covered stent.
We describe a case in which a polytetrafluoroethylene (PTFE)-covered stent was implanted to treat impending rupture of a coronary artery pseudoaneurysm related to a chest stab wound. In this case, transthoracic echocardiography was used to verify the characteristics of the pseudoaneurysm, and we concluded that a PTFE-covered stent may prevent rupture in post-traumatic pseudoaneurysm.


Early healing processes of free tendon grafts within bone tunnels is bone-specific: a morphological study in a rabbit model.
In order to function as effective ligament replacements, free tendon grafts must become firmly healed into bone tunnels as soon as possible. We hypothesized that graft incorporation would be bone-specific. Free semitendinosus tendon grafts were inserted into drill holes in a lapine medial collateral ligament reconstruction model; thus, creating tibial and femoral bone-specific incorporation sites. Femur-semitendinosus tendon-tibia complexes were harvested from 26 rabbits for histological analysis at various healing times: 0, 6, 12, or 24 weeks post-surgery. Incorporation and remodeling of the graft in the chondral callus was much more extensive at the cancellous-filled femoral insertion than within the marrow-dominated tibial insertion, suggesting that tendon graft healing may depend on the cancellous bone architecture at the graft site.


Intravenous NAB 365 (clenbuterol) and terbutaline in exercise-induced bronchospasm (EIB).
In a single-blind, placebo-controlled, cross-over study, the effects of intravenous 20 micrograms NAB 365 (clenbuterol) and intravenous 250 microgram terbutaline were compared in nine asthmatic patients with bronchospasm induced by exercise. The exercise consisted of treadmill running. The two beta-adrenergic bronchodilator drugs effectively prevented post-exercise bronchospasm in eight of the nine patients. The effects were superior to those in the untreated group and in the placebo-treated group. Six of the patients treated with terbutaline complained of adverse reactions (tremor, palpitation, tachycardia). No adverse reactions were observed after clenbuterol.


Mechanisms of pathogenic effects of eosinophil cationic protein and eosinophil-derived neurotoxin on human keratinocytes.
Cutaneous deposition of eosinophil degranulation proteins is a major feature of eosinophil-rich cutaneous diseases including bullous pemphigoid (BP). We sought to better understand the effect of two of these proteins - eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN), on human keratinocytes using the Het-1A cell line. To evaluate expression of key cytokines and chemokines observed in BP as well as metal metalloprotease 9 (MMP9), we performed qPCR and in-cell Western assays on cells treated with either ECP or EDN. We further evaluated the effect of ECP and EDN on keratinocyte survival, generation of reactive oxygen species (ROS) and apoptosis. Lastly, we assessed ECP and EDN's ability to induce keratinocyte detachment from provisional matrix. Treatment of keratinocytes with ECP and EDN resulted in significant increases in IL-5, eotaxin-1 and CCL5 (RANTES) expression at both mRNA and protein levels, but not IL-17 or IL-31. ECP and EDN also upregulate MMP9 production. Inhibiting MMP9, we confirmed that keratinocyte expression of IL-5, eotaxin-1 and RANTES was independent from MMP9. Both ECP and EDN were cytotoxic to keratinocytes, inducing ROS formation and apoptosis through a mitochondrion-dependent pathway as evidenced by results of terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) and cytochrome c release assays, respectively. ECP but not EDN led to significant keratinocyte detachment from provisional matrix. These findings demonstrate that the pathogenic effects of ECP and EDN in BP may result from their direct action on keratinocytes, and as such may became a target for future therapies in eosinophil-rich cutaneous diseases.


A national analysis of vascular surgery resident operative experience in peripheral artery disease.
Endovascular and hybrid interventions have played an increasingly prominent role in the treatment of peripheral arterial disease (PAD) in the past decade. This shift has prompted concerns about the adequacy of open surgical training for current surgical residents. Moreover, the recent Best Surgical Therapy in Patients With Critical Limb Ischemia trial has further emphasized the importance of open surgical techniques in the treatment of peripheral arterial disease. The purpose of this study was to examine national temporal trends in peripheral operative volume among integrated vascular surgery residents. Data was obtained from the Accreditation Council for Graduate Medical Education national data reports for integrated vascular surgery residents. Case volumes for surgeon chief or surgeon junior cases were collected from academic years 2012 to 2013 and 2021 to 2022. Trends in case-mix and volume were evaluated using linear regression analysis. The mean total vascular operative volume increased from 851.2 to 914.3 cases among graduating chief residents, with an annual growth of 8.5 ± 1.7 cases/year (R2 = 0.77; P < .0001). Major vascular case volume also increased at a rate of 5.7 ± 1.2 cases/year (R2 = 0.74; P < .001). Among operative categories, peripheral cases were the most frequent (n = 232.2 [26.6%]) and demonstrated the greatest annual growth (+8.0 ± 0.8 cases/year, R2 = 0.93; P < .001). No changes were seen in volume of open peripheral cases, including suprainguinal bypass (+0.1 ± 0.2 cases/year; R2 = 0.08; P = .40) or femoropopliteal bypass procedures (-0.1 ± 0.2 cases/year; R2 = 0.17; P = .20). Infrapopliteal bypass (+0.4 ± 0.1 cases/year; R2 = 0.48; P = .006), iliac/femoral endarterectomy (+1.3 ± 0.2 cases/year; R2 = 0.82; P < .001), and leg thromboembolectomy (+0.4 ± 0.1 cases/year; R2 = 0.64; P < .001) all demonstrated annual growth. For endovascular peripheral cases, aortoiliac revascularization (+3.4 ± 0.3 cases/year; R2 = 0.94; P < .001), femoropopliteal revascularization (+5.4 ± 0.2 cases/year; R2 = 0.98; P < .001), and tibioperoneal revascularization (+2.0 ± 0.2 cases/year; R2 = 0.92; P < .001) all increased in volume. Lower extremity amputations, including above-knee amputation (+0.6 ± 0.2 cases/year; R2 = 0.65; P < .001) and below-knee amputation (+0.9 ± 0.2 cases/year; R2 = 0.72; P < .001) also demonstrated an increase in volume. Current graduating residents have higher open and endovascular case volumes for peripheral artery disease on a national level, despite the increasing popularity of endovascular techniques. Further studies are needed to identify how these trends may impact current vascular surgery milestones. These trends may also influence the rising interest in competency-based training programs.


Acute toxicity and chemical evaluation of coking wastewater under biological and advanced physicochemical treatment processes.
This study investigated the changes of toxic compounds in coking wastewater with biological treatment (anaerobic reactor, anoxic reactor and aerobic-membrane bioreactor, A1/A2/O-MBR) and advanced physicochemical treatment (Fenton oxidation and activated carbon adsorption) stages. As the biological treatment stages preceding, the inhibition effect of coking wastewater on the luminescence of Vibrio qinghaiensis sp. Nov. Q67 decreased. Toxic units (TU) of coking wastewater were removed by A1/A2/O-MBR treatment process, however approximately 30 % TU remained in the biologically treated effluent. There is a tendency that fewer and fewer residual organic compounds could exert equal acute toxicity during the biological treatment stages. Activated carbon adsorption further removed toxic pollutants of biologically treated effluent but the Fenton effluent increased acute toxicity. The composition of coking wastewater during the treatment was evaluated using the three-dimensional fluorescence spectra, gas chromatography-mass spectrometry (GC-MS). The organic compounds with high polarity were the main cause of acute toxicity in the coking wastewater. Aromatic protein-like matters in the coking wastewater with low biodegradability and high toxicity contributed mostly to the remaining acute toxicity of the biologically treated effluents. Chlorine generated from the oxidation process was responsible for the acute toxicity increase after Fenton oxidation. Therefore, the incorporation of appropriate advanced physicochemical treatment process, e.g., activated carbon adsorption, should be implemented following biological treatment processes to meet the stricter discharge standards and be safer to the environment.


Factors associated with viremia in people living with HIV on antiretroviral therapy in Guatemala.
Viral suppression prevents HIV transmission and disease progression, but socio-economic and clinical factors can hinder the goal of suppression. We evaluated factors associated with viral non suppression (VNS) and persistent viremia (PV) in people living with HIV (PLHIV) receiving antiretroviral therapy (ART) in Guatemala. We conducted a cross sectional analysis using data from an ongoing cohort of PLHIV attending the largest HIV clinic in Guatemala. Univariable and multivariable analyses were conducted between PLHIV with viral suppression and detectable viremia. VNS was defined as most recent HIV RNA ≥ 200 copies/ml and PV as two consecutive HIV RNA ≥ 200 copies/ml. Of 664 participants, 13.3% had VNS and 7.1% had PV. In univariable analysis disaggregated by gender, low income, poor education, perceived difficulty attending healthcare, and alcohol use were associated with VNS in men while low CD4 at diagnosis, multiple prior ART regimens and treatment interruptions were significant in both genders. Multiple prior ART regimens (adjusted Odds Ratio (aOR) 2.82, [95% confidence interval (CI) 1.59, 4.99], p < 0.01), treatment interruptions (aOR 4.51, [95% CI 2.13, 9.58], p < 0.01), excessive alcohol consumption (aOR 2.56, [95% CI 1.18, 5.54], p < 0.05) perceived difficulty attending healthcare (aOR 2.07, [ 95% CI 1.25, 3.42], p < 0.01) and low CD4 at diagnosis (aOR 2.34, 95% [CI 1.30, 4.20], p < 0.01) were independently associated with VNS on multivariable regression. We conclude that socio-economic and clinical factors influence viral suppression in our cohort and vary between men and women. Gender specific approaches are necessary to achieve the 90% suppression goal.


The immune response of white shrimp Litopenaeus vannamei following Vibrio alginolyticus injection.
White shrimp Litopenaeus vannamei injected with saline, and injected with tryptic soy broth (TSB)-grown Vibrio alginolyticus at 1.0 x 10(5) and 1.8 x 10(5) colony-forming units (cfu) shrimp(-1) were examined for hyaline cell (HC) counts, granular cell (GC) counts, total haemocyte counts (THCs), phenoloxidase (PO) activity, respiratory burst (RB) and superoxide dismutase (SOD) activity after 1-168 h. Shrimp that received no injection served as the control. The shrimps which received V. alginolyticus at both doses showed significant decreases in these parameters after 6-96 h. The values for HC and SOD activity decreased earlier and then RB. The time to cause maximum depletion of haemocytes (haemocytopenia), PO activity, RB, and SOD activity were 12, 72, 48, and 24 h post-injection, respectively. The HC, GC, and RB returned to the original values earlier at 72 h, followed by SOD activity at 96 h, and then PO activity at 168 h post-infection. It was concluded that an injection of V. alginolyticus rapidly reduced the shrimp's immunity by decreasing HC, GC, SOD activity, RB, and PO activity within 3-24 h, followed by a slow recovery during 72-168 h post-injection. Furthermore, white shrimp L. vannamei which received V. alginolyticus showed a 6-9 h later response in PO activity, and a 72-96 h later recovery of PO activity, compared to the responses in RB and SOD activity indicating their roles in shrimp defence and immunity.


Dissipation of pesticides during composting and anaerobic digestion of source-separated organic waste at full-scale plants.
In the present study, concentration levels and dissipation of modern pesticides during composting and digestion at full-scale plants were followed. Of the 271 pesticides analyzed, 28 were detected. Within the three windrows studied, total concentrations were between 36 and 101microg per kg of dry matter (d.m.) in input materials and between 8 and 20microg kg d.m.(-1) in composts after 112 days of treatment. Fungicides and among them triazoles clearly dominated over other pesticides. More than two-thirds of all pesticides detected in the input materials showed dissipation rates higher than 50% during composting, whilst levels of most triazoles decreased slightly or remained unchanged. The investigation on semi-dry thermophilic anaerobic digestion suggests that pesticides preferentially end up in presswater after solid-liquid separation.


Fireworks ocular injury in Saudi children: profile and management outcomes.
To explore the demographic profiling, causes, types, complications, management outcomes, and severity of fireworks-inflicted ocular injuries in children in KSA. This is a retrospective study of 115 cases with eye injuries managed at the Emergency Department, of our institution between 2003 and 2019. Demography, clinical features at presentation, mode of management and the Best-corrected visual acuity (BCVA) were evaluated at the last follow up. The study included 117 eyes of 115 children [median age: 9 years; 96 (83.5%) boys;19 (16.5%) girls]. Fifty-six (48.7%) participants were bystanders. The injuries were caused mainly due to bangers (n = 47; 40.9%), rockets in bottle (n = 28; 24.3%), firecrackers (n = 27; 23.5%), and nonspecific reasons (n = 13; 11.3%). The children had presented with various severity levels: corneal abrasion (n = 52; 44.4%); cataract (n = 47;40.2%); penetrating injury (n = 40; 34.2%); secondary glaucoma (n = 22;18.8%); subluxated lens (n = 19;16.2%); limbal stem cell deficiency (n = 14;12.0%); Iridodialysis (n = 12;10.3%), and vitreous hemorrhage (n = 11;9.4%). Management interventions of the eyes under study included: penetrating injury repair (n = 40; 34.2%), lens removal plus intraocular lens implantation (n = 26; 22.2%), removal of foreign body (n = 9; 7.7%). The BCVA after six months was 20/20 to 20/60 in 49 (41%) cases; 20/70 to 20/200 in 27 (23.1%) cases; < 20/200 to 20/400 in 7 (6%) cases, and < 20/400 in 34 (29.1%) of the cases. Out of 51.3% eyes with < 20/200 before management, only 35% recorded severe visual impairment. Fireworks-related eye injuries were mainly observed in boys primarily due to the use of bangers. Visual disability remained in one-third of the managed cases.


The versatility of the posterior lumbotomy approach in infants.
The versatility of the posterior lumbotomy approach to the upper urinary tract in infants is reviewed. A total of 32 procedures in 25 patients was performed. Nine different types of operations were performed ranging from upper pole heminephrectomy to ureterolysis. Surgical techniques and outcome are reviewed.


Late life cognition among men: a life course perspective on psychosocial experience.
This report assesses associations between trajectories of psychosocial experience over the life course and cognitive function in late life men. Survey data from the National Longitudinal Study of Older Men, a community sample of 1835 United States men aged 45-59 years in 1966, are used to explore the cognitive effects of personality (locus of control) and emotion (affect) as these attributes evolve from middle age to late life. Locus of control is very stable over time, whereas negative and positive affect fluctuate. Inverse relationships are found between cognitive function and external locus of control, enduring negative affect, and the absence of positive affect. Levels of education also moderate these effects. Low educational attainment appears to intensify the risk for poor cognitive function associated with mixed internal-external locus of control and poor emotional state over time. The connection between education, usually completed early in the life course, and late life cognitive outcomes emphasizes the importance of promoting educational attainment among young people. Among older men with low educational attainment, the identification of mood disorders and personality attributes that negatively impact cognition may lead to the development of appropriate interventions.


Use of deep artificial neural networks to identify stroke during triage via subtle changes in circulating cell counts.
The development of tools that could help emergency department clinicians recognize stroke during triage could reduce treatment delays and improve patient outcomes. Growing evidence suggests that stroke is associated with several changes in circulating cell counts. The aim of this study was to determine whether machine-learning can be used to identify stroke in the emergency department using data available from a routine complete blood count with differential. Red blood cell, platelet, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts were assessed in admission blood samples collected from 160 stroke patients and 116 stroke mimics recruited from three geographically distinct clinical sites, and an ensemble artificial neural network model was developed and tested for its ability to discriminate between groups. Several modest but statistically significant differences were observed in cell counts between stroke patients and stroke mimics. The counts of no single cell population alone were adequate to discriminate between groups with high levels of accuracy; however, combined classification using the neural network model resulted in a dramatic and statistically significant improvement in diagnostic performance according to receiver-operating characteristic analysis. Furthermore, the neural network model displayed superior performance as a triage decision making tool compared to symptom-based tools such as the Cincinnati Prehospital Stroke Scale (CPSS) and the National Institutes of Health Stroke Scale (NIHSS) when assessed using decision curve analysis. Our results suggest that algorithmic analysis of commonly collected hematology data using machine-learning could potentially be used to help emergency department clinicians make better-informed triage decisions in situations where advanced imaging techniques or neurological expertise are not immediately available, or even to electronically flag patients in which stroke should be considered as a diagnosis as part of an automated stroke alert system.


Elevation of soluble interleukin-2 receptor in patients with non-small cell lung cancer treated with gefitinib.
We previously reported that plasma thromboxan B(2), soluble P-selectin, and serum regulated on activation, normal T-cell expressed and secreted (RANTES) were elevated after gefitinib treatment. We hypothesized that gefitinib could activate T-lymphocytes via activated platelets, and so we measured serum levels of soluble interleukin-2 receptor (sIL-2R) in patients medicated with gefitinib. Twenty-one patients with non-small cell lung cancer (NSCLC) were entered into this study. All patients received gefitinib over 2 weeks without severe adverse effects. Blood samples were withdrawn from all patients before and after the administration of gefitinib and plasma soluble P-selectin, serum RANTES, and serum sIL-2R were measured by enzyme-linked immunosolvent assay. In addition, we carried out the basic study of the interleukin-2 receptor (IL-2R) expression on CD4(+) lymphocytes by RANTES. Plasma soluble P-selectin, serum RANTES, and serum sIL-2R levels increased significantly in patients receiving gefitinib treatment for 1 and 2 weeks. RANTES did not induce the expression of IL-2R on CD4(+) lymphocyte. However, the anti-CD3 monoclonal antibody-induced expression of IL-2R was enhanced by the addition of RANTES. Our finding indicated that lymphocytes were activated by gefitinib treatment. We think that sIL-2R elevation after gefitinib administration may be a factor positively effecting patients with NSCLC. It is deemed possible that the effect of gefitinib is induced not only by its blocking of the tyrosine kinase of epidermal growth factor receptor but also by antitumor immunity via its activation of T-cells.


Modified aqueous drainage implants in the treatment of complicated glaucomas in eyes with pre-existing episcleral bands.
Control of intraocular pressure (IOP) after retinal surgery with scleral band placement may be problematic. In this study, outcome after silastic drainage implant placement is reviewed. A retrospective chart review of 11 eyes in 11 patients with severe glaucoma after multiple surgeries, including scleral buckle procedures. Patients received silastic drainage implant surgery, either a long Krupin Denver valved implant (7) or a trimmed Baerveldt seton (4). Vision, IOP, and need for further glaucoma medication or glaucoma surgery were measured. One- and 2-year life-table success rates (either complete or qualified success) were 82% and 73%, respectively, defining success as final IOP of 21 mmHg or less without need for further glaucoma surgery and no loss of visual acuity. Half of the successful eyes required antiglaucoma medication. Silastic drainage implants may be a viable option in the treatment of complicated glaucoma after retinal surgery.


CD147 promotes MTX resistance by immune cells through up-regulating ABCG2 expression and function.
Methotrexate (MTX) is a drug used to treat psoriasis due to inducing immune cell apoptosis. However, certain patients show MTX resistant. CD147, highly expressed by psoriatic PBMCs, is assumed to regulate MTX sensitivity. The underlining mechanism is still relatively understudied. To understand the mechanisms of that CD147 promotes MTX resistance in immune cells. The expression of CD147 and ABCG2 in PBMCs from psoriatic patients, cellular apoptosis and intracellular MTX amount were measured. We also checked the cellular drug sensitivity of CHO (Chinese Hamster Ovary) cell lines with introduced CD147 and Jurkat T cells depeleted CD147. By immunoprecipitation, we detected the interaction between CD147 and ABCG2. Both ABCG2 and CD147 are highly expressed in psoriatic PBMCs. Cultured in vitro, the PBMCs from psoriatic patients were more resistant to MTX-induced apoptosis comparing to PBMCs from healthy people. Further studies demonstrated that exogenous overexpression of CD147 in CHO cells increased ABCG2 protein level. After MTX treatment, CD147 overexpressing CHO cells showed lower apoptosis rate and lower intracellular MTX concentration. On the contrary, knockdown of CD147 by shRNA in Jurkat T cells decreased ABCG2 expression, as well as increased MTX-induced apoptosis and decreased MTX efflux. Immunoprecipitation experiment revealed that the trans-membrane domain of CD147 conferred its' interaction with ABCG2. Our study suggests a role of CD147 in regulating ABCG2 transportation of MTX in immune cells. Strategies involving targeting CD147 could be considered in clinical treatment of psoriatic patients resistant to MTX.


Comment on 'A conserved strategy for inducing appendage regeneration in moon jellyfish, Drosophila, and mice'.
Abrams et al. report that a simple dietary supplement is sufficient to induce appendage regeneration in jellyfish, fruit flies, and mice (Abrams et al., 2021). This conclusion is surprising because it was previously thought that flies and mice lack the capacity for regeneration after injury. We replicated the Drosophila experiments of Abrams et al. but did not observe any instances of leg regeneration. We also conclude that the "white blob" observed at the amputation site by Abrams et al. consists of bacteria and is not regenerated tissue.


Familial XX chromosomal maleness does not arise from a Y chromosomal translocation.
To determine the mechanism for the coexistence of XX chromosomal maleness and true hermaphroditism in the same family, we performed cytogenetic and molecular genetic analyses, using DNA probes from the short arm of the Y chromosome. These studies excluded the following possible mechanisms: (1) an inherited, mitotically unstable Y chromosome that results in chromosomal mosaicism, (2) an inherited Y-to-X or Y-autosomal translocation, (3) recurrent Y-to-X translocation, and (4) incomplete inactivation of the X chromosomal homolog for the testicular determining factor. We conclude that the disorder of sexual differentiation observed in this family can be best explained by a dominant autosomal gene with variable expressivity.


Alpha-adrenergic activity and urethral pressure in prostatic zone in benign prostatic hypertrophy.
In order to examine to what extent adrenergic mechanism contributes to the urethral pressure in patients with benign prostatic hypertrophy, changes in the intraurethral pressure in the prostatic zone were measured in vivo by both the urethral pressure profile technique and the balloon method before and after administration of alpha-adrenergic stimulants and an alpha-adrenergic blocker. The effect of spinal anesthesia on the urethral pressure was also investigated. It is suggested that 40 per cent of the total urethral pressure in patients with benign prostatic hypertrophy is due to alpha-adrenergic tone, and the remaining 53 per cent is due to static pressure resulting from the hypertrophied prostatic bulk. The in vitro study indicates that the increase in urethral pressure and contraction of the prostate, prostatic capsule and prostatic urethra.


Impaired thrombolysis: a novel cardiovascular risk factor in end-stage renal disease.
End-stage renal disease (ESRD) patients have an excess cardiovascular risk, above that predicted by traditional risk factor models. Prothrombotic status may contribute to this increased risk. Global thrombotic status assessment, including measurement of occlusion time (OT) and thrombolytic status, may identify vulnerable patients. Our aim was to assess overall thrombotic status in ESRD and relate this to cardiovascular risk. Thrombotic and thrombolytic status of ESRD patients (n = 216) on haemodialysis was assessed using the Global Thrombosis Test. This novel, near-patient test measures the time required to form (OT) and time required to lyse (lysis time, LT) an occlusive platelet thrombus. Patients were followed-up for 276 ± 166 days for major adverse cardiovascular events (MACE, composite of cardiovascular death, non-fatal MI, or stroke). Peripheral arterial or arterio-venous fistula thrombosis was a secondary endpoint. Occlusion time was reduced (491 ± 177 vs. 378 ± 96 s, P < 0.001) and endogenous thrombolysis was impaired (LT median 1820 vs.1053 s, P < 0.001) in ESRD compared with normal subjects. LT ≥ 3000 s occurred in 42% of ESRD patients, and none of the controls. Impaired endogenous thrombolysis (LT ≥ 3000 s) was strongly associated MACE (HR = 4.25, 95% CI = 1.58-11.46, P = 0.004), non-fatal MI and stroke (HR = 14.28, 95% CI = 1.86-109.90, P = 0.01), and peripheral thrombosis (HR = 9.08, 95% CI = 2.08-39.75, P = 0.003). No association was found between OT and MACE. Impaired endogenous thrombolysis is a novel risk factor in ESRD, strongly associated with cardiovascular events.


Giant megaureters presenting as a multicystic abdominal mass.
Megaureter is a developmental anomaly of the ureter, which is associated with significant morbidity in children and frequently requires surgical intervention. I am presenting here a case of massively dilated ureters in a child that occupied almost the entire abdomen and was wrongly misinterpreted as a cystic lymphangioma due to its unusual presentation.


[Effect of insulin on cartilage differentiation in vitro].
A consistent chondrogenesis takes place in high-density microcultures derived from bud mesenchymal cells of 4-day-old chicken embryos in a serum-supplemented medium. In serum-free medium DNA level and uronic acid content in the cultures were low, as well as the 35SO4 uptake and release, and only a small mass of cartilage was formed. With the addition of 0.025-10 micrograms/ml insulin to serum-free medium the uronic acid and DNA content in the cultures increased considerably in a dose-dependent way. The intensity of 35SO4 uptake and release exceeded the values measured in serum-containing medium, more cartilage tissue was formed in them also in a dose-dependent manner. With the use of 20-80 micrograms/ml insulin, the increment in DNA content proved to decrease, and with the use of 80 micrograms/ml insulin the uronic acid content and the cartilage mass decreased to a greater extent than in the case of lover doses.


Clinical patterns of corneal epithelial wound healing.
We studied the reepithelialization of corneal abrasions in 21 patients. All abrasions, irrespective of the nature of injury, followed a consistent pattern during reepithelialization. Three to six convex leading fronts of migrating epithelial sheets developed along the circumference of the defect and progressed toward the center. Neighboring fronts met along their sides, resulting in the formation of various geometric shapes. In the final stage of the healing process a contact line shaped like a "Y" or two "Y's" placed with their long axes end to end was seen where the advancing fronts of migrating epithelial sheets met. The rate of healing of the abrasions was determined by measuring the area of the abrasions at daily intervals from serial photographs. The area of the epithelial defects decreased exponentially with time, indicating a constant rate of epithelial cell migration.


Decreased Movement Path Tortuosity Is Associated With Improved Functional Status in Patients With Traumatic Brain Injury.
To determine if movement path tortuosity in everyday ambulation decreases in Veterans being treated in a residential setting for traumatic brain injury. Elevated path tortuosity is observed in assisted living facility residents with cognitive impairment and at risk for falls, and tortuosity may decrease over the course of cognitive rehabilitation received by the Veterans. If observed, decreased tortuosity may be linked to improved clinical outcomes. Longitudinal observational study without random assignment. Veterans Affairs Medical Center inpatient residential polytrauma treatment facility. Twenty-two Veterans enrolled in a postacute predischarge residential polytrauma treatment facility. None, observation-only. Mayo-Portland Adaptability Index-4, and movement path tortuosity measured by Fractal Dimension (Fractal D). Fractal D was obtained continuously from an indoor movement tracking system primarily used to provide machine-generated prompts and reminders to facilitate activities of daily living. Patients were deemed "responders" (N = 10) if a significant linear decline in Fractal D occurred over the course of treatment, or nonresponders (N = 12) if no significant decline was observed. Responders had lower discharge Mayo-Portland Adaptability Inventory scores (mean = 32.6, SD = 9.53) than non-responders (mean = 39.5, SD = 6.02) (F = 2.07, df = 20, P = .05). Responders and nonresponders did not differ on initial injury severity or other demographic measures. Fractal D, a relatively simple measure of movement path tortuosity can be linked to functional recovery from traumatic brain injury.


The role of reactive oxygen species in atherosclerosis.
Reactive oxygen species (ROS) are probably not only unintended, toxic side-products of oxygen metabolism in mammalian cells, they also have several important physiologic functions including antimicrobial killing, regulation of cellular proliferation and growth, and regulation of vascular tone. ROS are generated within the vessel wall by several mechanisms, including a vascular type of a NAD(P)H oxidase. ROS formation can be stimulated by mechanical stress, environmental factors, the peptide angiotensin II, cytokines, native low-density lipoproteins (LDL), and in the presence of catalytic metal ions. Their ability to modify LDL, react with endothelial-derived nitric oxide subsequently forming peroxynitrite, and amplify the expression of various genes important for leukocyte recruitment within the arterial wall are the basis of the oxidant injury theory of atherosclerosis. In animal studies, antioxidant therapy (probucol, butylated hydroxytoluene, N', N'-diphenylenediamide, vitamin E, superoxide dismutase) have been successfully used to prevent fatty streak formation, and to restore impaired nitric oxide-dependent vasorelaxation. In man, antioxidant therapy (e.g., supplementation with vitamin E) clearly increased the resistance of LDL to oxidative modification. Case-controlled and prospective clinical studies suggest a relation between baseline antioxidant plasma levels and/or antioxidant supplementation and risk of cardiovascular events. In one secondary prevention trial (randomized, blinded, placebo-controlled), vitamin E supplementation reduced significantly the risk for non-fatal myocardial infarctions. Before general recommendations can be made, results of further large-scale trials should be awaited.


Giant cell tumor of bone in the pediatric population: a retrospective study highlighting cases of metaphyseal only location and increased local recurrence rates in skeletally immature patients.
To describe the presentation of giant cell tumors (GCT) of the bone in the pediatric population to (1) improve the differential diagnosis of pediatric bone tumors and (2) identify the origin of GCT. Understanding the origin of bone tumors assists in establishing appropriate diagnoses and recommending treatment options. This is particularly important in children, where evaluating the need for invasive procedures is balanced with the desire to avoid overtreatment. GCT have historically been considered epiphyseal lesions with potential metaphyseal extension. Therefore, GCT may be inappropriately excluded from the differential diagnosis of metaphyseal lesions in the skeletally immature. We identified 14 patients from 1981 to 2021 at a single institution who had histologic confirmation of GCT and were less than 18 years old at diagnosis. Patient characteristics, tumor location, surgical treatment, and local recurrence rates were collected. Ten (71%) patients were female. Eleven (78.6%) were epiphysiometaphyseal (1 epiphyseal, 4 metaphyseal, 6 epiphysiometaphyseal). Five patients had an open adjacent physis, of which three (60%) had tumors confined solely to the metaphysis. Of the five patients with open physis, four (80%) developed local recurrence while only one patient (11%) with a closed physis had local recurrence (p value = 0.0023). Our results illustrate that for the skeletally immature, GCT can (and in our results more commonly did) occur in the metaphyseal location. These findings suggest that GCT should be included in the differential diagnosis of primary metaphyseal-only lesions in the skeletally immature.


A structural dissection of large protein-protein crystal packing contacts.
With the rapid increase in crystal structures of protein-protein complexes deposited in the Protein Data Bank (PDB), more and more crystal contacts have been shown to have similar or even larger interface areas than biological interfaces. However, little attention has been paid to these large crystal packing contacts and their structural principles remain unknown. To address this issue, we used a comparative feature analysis to analyze the geometric and physicochemical properties of large crystal packing contacts by comparing two types of specific protein-protein interactions (PPIs), weak transient complexes and permanent homodimers. Our results show that although large crystal packing contacts have a similar interface area and contact size as permanent homodimers, they tend to be more planar, loosely packed and less hydrophobic than permanent homodimers and cannot form a central core region that is fully buried during interaction. However, the properties of large crystal packing contacts, except for the interface area and contact size, more closely resemble those of weak transient complexes. The large overlap between biological and large crystal packing contacts indicates that interface properties are not efficient indicators for classification of biological interfaces from large crystal packing contacts and finding other specific features urgently needed.


Three-metal-center spin interactions through the intercalation of metal azaporphines and porphines into an organic pillared coordination box.
Discrete homo Cu-Cu-Cu and hetero Cu-Pd-Cu or Cu-Co-Cu metal arrays are prepared within an organic-pillared coordination box by inserting M(ii)-azaporphine/porphine cartridges (M = Cu(ii), Pd(ii) or Co(ii)), where the metal arrays show unique spin interactions in ESR: in particular, Deltam(s) = 3 for the Cu-Cu-Cu array.