Cell surface markers in human embryonic stem cells.
The pluripotent nature of human embryonic stem cells (hESCs) is based on their potential to form every cell type in the body. Prior to use in directed differentiation strategies, these cells need to be thoroughly characterized. The large number of glycoproteins and carbohydrates that exist on the cell surface provide an excellent opportunity for characterizing hESCs and a means to delineate pluripotent and differentiated cell types. A panel of 14 lectins, based on their specificity for a variety of carbohydrates and carbohydrate linkages, along with stage-specific embryonic antigen-4 (SSEA-4), have been chosen to examine hESCs for other potential pluripotent markers. These studies have been achieved by binding quantitation by flow cytometry and binding localization in adherent colonies by immunocytochemistry. We have shown that certain lectins may be used as markers that are associated with the pluripotent state of hESCs because binding percentages and binding localization of these lectins are similar to those of SSEA-4. This presents options for systematic classification of pluripotent hESCs and for distinguishing differentiated hESC types based on glycan presentation that accompanies differentiation.


Benzo(ghi)perylene (BgP) a black tattoo ingredient induced skin toxicity via direct and indirect mode of DNA damage under UVA irradiation.
Tattooing is a very common fashion trend across all the ages and gender of the society worldwide. Although skin inflammatory diseases are very frequent among tattoo users because of the active chemical ingredients used in tattoo ink, yet no ingredient-specific toxicity study has been performed. Benzo(ghi)perylene (BgP) is one of the PAHs and an important ingredient of black tattoo ink that shows strong absorption in UVA and UVB radiation of sunlight. Therefore, understanding the hazardous potential of BgP especially under UVA exposure is important for the safety of skin of tattoo users by considering the fact that penetration of UVA is in the dermis region where tattoo ingredients reside. To evaluate the hazardous potential of BgP on human skin under UVA exposure, different experimental tools i.e., in-chemico, in-silico and in-vitro were utilized. Our results illustrated that BgP photosensitized under UVA (1.5 mW/cm2) irradiation shows a degradation pattern till 4 h exposure. Photosensitized BgP reduced significant cell viability (%) at 1 μg/ml concentration. However, the pretreatment of singlet and hydroxyl radical quenchers, restoration of cell viability observed, confirmed the role of type-I and type-II photodynamic reactions in phototoxicity of BgP. Further, intracellular uptake of BgP in HaCaT cells was estimated and confirmed by UHPLC analysis. Molecular docking of BgP with DNA and formation of γ-H2AX foci demonstrated the DNA intercalation and double-stranded DNA damaging potential of BgP. Furthermore, acridine orange and ethidium bromide (AO/EB) dual staining showed apoptotic cell death via photosensitized BgP under UVA irradiation. The above findings suggest that BgP reached the human skin cell and induced dermal toxicity via direct and indirect mode of DNA damage under UVA exposure finally promoting the skin cell death. Thus, BgP-containing tattoo ink may be hazardous and may induce skin damage and diseases, especially in presence of UVA radiation of sunlight. To minimize the risk of skin diseases from synthetic ingredients in tattoo ink, the study highlights the importance of developing eco-friendly and skin-friendly tattoo ingredients by companies.


Treatment of established spinal injury-induced gastric erosions in rats with cimetidine and 16,16-dimethyl prostaglandin E2.
Most research on the beneficial effects of pharmacologic agents on stress-induced acute gastric erosions in animals is directed at prevention. It is only the rare study that has been concerned with treatment of established erosions. A treatment model has been created using cervical cord-injured male Sprague-Dawley rats which consistently developed extensive linear erosions of the glandular portions of the stomach within 12 hr. A group of spinal rats was sacrificed after 12 hr to serve as a base of pretreatment ulcer severity. Treatment of established erosions with cimetidine 25 mg/kg every 2 hr in one group and 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2) 5 micrograms/kg every 2 hr in a second group was compared to saline-treated controls. All drugs were administered by intraperitoneal route. Treatment began 12 hr after the cord transection and continued for another 12 hr at which time the rats were sacrificed. Both cimetidine and 16,16-dmPGE2 significantly inhibited the degree of erosion progression after 12 hr compared to saline controls (P less than 0.05). Acid output studies were carried out on a second set of rats subjected to the same experimental conditions with the addition of pyloric ligation 6 hr prior to sacrifice. A significant decrease in acid output (P less than 0.05) occurred only in the cimetidine group compared to control. It is concluded that both cimetidine and 16,16-dmPGE2 can arrest the progression of erosive changes in the stomach after cervical cord injury in rats. This is likely related to acid reduction by cimetidine and cytoprotection by prostaglandin.


Outcomes With Deferred Versus Performed Revascularization of Coronary Lesions With Gray-Zone Fractional Flow Reserve Values.
Management of coronary lesions with fractional flow reserve values in the gray zone (0.75-0.80) remains controversial due to conflicting data on the performance versus deferral of revascularization. We performed a systematic review and meta-analysis of 7 observational studies including 2683 patients that compared the outcomes of deferred versus performed revascularization of coronary lesions with gray-zone fractional flow reserve values. During a mean follow-up of 31±9 months, the incidence of major adverse cardiovascular events (12.54 % versus 11.25%; odds ratio [OR], 1.64 [95% CI, 0.78-3.44]; P=0.19, I2=84%), cardiac mortality (1.25% versus 0.72%; OR, 1.78 [95% CI, 0.58-5.46]; P=0.31, I2=18%), and myocardial infarction (1.28% versus 2.66%; OR, 0.79 [95% CI, 0.22-2.79]; P=0.71, I2=65%) was similar with deferral versus performance of revascularization in coronary lesions with gray-zone fractional flow reserve. Deferral of revascularization was associated with a higher incidence of target vessel revascularization (9.12% versus 5.78%; OR, 1.85 [95% CI, 1.03-3.33]; P=0.04, I2=62%). When the analysis was limited only to studies that used percutaneous coronary intervention for revascularization, deferred revascularization remained associated with a higher risk of target vessel revascularization (18% versus 7.3%; OR, 3.04 [95% CI, 1.53-6.02]; P<0.001) and was associated with a higher risk of major adverse cardiovascular event (23.2% versus 13.4%; OR, 3.38 [95% CI, 1.92-5.95]; P<0.001). In lesions with gray-zone fractional flow reserve, revascularization was associated with a similar incidence of major adverse cardiovascular event but a lower incidence of target vessel revascularization over a mean follow-up of approximately 2.5 years. URL: https://www.crd.york.ac.uk/prospero/. Unique identifier: CRD42019128076.


Bacterial profile and antibiotic selection for pediatric appendicitis: A retrospective cohort study.
The objective of this study was to identify the predominant bacteria cultured from the surface of removed appendices in pediatric patients with acute appendicitis and determine the appropriate choice of antibiotics for preoperative and postoperative management. A 2-year retrospective cohort study was conducted at Mediclinic Parkview Hospital, Dubai, UAE. Patients under 14 years of age with diagnosed acute appendicitis who underwent laparoscopic appendectomy were included. Swab cultures, along with demographic, laboratory, and pathology data, were analyzed. Out of the 56 enrolled patients, 27 (48 %) exhibited bacterial growth on swab cultures, while 29 (52 %) showed no bacterial growth. Escherichia coli (E. coli) was the predominant isolated bacteria, present in 23/27 patients (85 %). Seven patients had co-infections involving E. coli and other bacteria, with Pseudomonas being the second most common bacteria identified in 7/27 patients (25 %). Antibiotic sensitivity testing indicated that 85 % of the isolated bacteria were sensitive to Gentamicin, 63 % to Amoxicillin/Clavulanic acid, 59 % to Trimethoprim + Sulfamethoxazole, and 27 % to Cefazolin. E. coli was the most prevalent bacteria identified on swabs taken from inflamed appendices in pediatric patients. Amoxicillin/Clavulanic acid was determined to be an appropriate choice for preoperative prophylaxis. This study provides valuable insights for guiding the management of pediatric appendicitis and facilitating the appropriate and judicious use of antibiotics.


Development of the muographic tephra deposit monitoring system.
Measurements of volcanic tephra fallout deposits provide useful information about the magnitude and intensity of explosive volcanic eruptions and potential for remobilization of deposits as dangerous volcanic flows. However, gathering information in the vicinity of erupting craters is extremely dangerous, and moreover, it is often quite difficult to determine deposit thickness proximal to volcanic craters because the thickness of the deposit is too great to easily measure; thus, airborne remote sensing technologies have generally been utilized during the intermission between eruptions. As an alternative tool, a muographic tephra deposit monitoring system was developed in this work. Here we report the performance of this system by applying the muographic data acquired at Sakurajima volcano, Japan as an example. By assuming the average density of the deposit was 2.0 g cm-3, the deposit thicknesses measured with muography were in agreement with the airborne results, indicating that volcanic fallout built up within the upper river basin, showed its potential for monitoring the episodic tephra fallouts even during eruptions.


Competitive and non-competitive antagonism exhibited by 'selective' antagonists at atrial and ileal muscarinic receptor subtypes.
The affinity of a number of 'selective' agonists and antagonists has been assessed at atrial or ileal muscarinic receptors by use of in vitro functional analysis. The most selective compound for ileal muscarinic receptors was silabenzhexol (approx. 50 fold), and to a lesser extent benzhexol (approx. 5 fold). Conversely, the most selective compound for the atrial muscarinic receptors was AF-DX 116 (approx. 6 fold). The novel M1-receptor antagonist, telenzepine and other antagonists such as propantheline and isopropamide did not distinguish between atrial and ileal receptors. Dicyclomine, adiphenine, hexahydroadiphenine and oxyphenonium exhibited competitive antagonism at atrial receptors but non-competitive antagonism at ileal receptors. No conclusions could, therefore, be drawn with regard to their selectivity. The agonists, arecaidine propargyl ester (APE), ethoxyethyltriethylammonium (EOE) and carbachol, exhibited some selectivity in potency but little difference in affinity. It is concluded that the study supports the existence of ileal and atrial muscarinic receptor subtypes. However, the use of dicyclomine and related compounds in receptor classification is limited.


Small Round Blue Cell Tumours of the Sinonasal Area: Our 5 year Experience in a Tertiary Care Centre in India.
Purpose: The main purpose of this study is to understand the characteristics and management of sinonasal small round blue cell tumors and also to emphasise the role of immunohistochemistry in their diagnosis and on the outcomes after endoscopic/open excision in these patients. Methods: This is a retrospective study conducted at a tertiary care referral centre in India which included 38 patients with sino nasal for a period of 5 years. All the patients were evaluated clinically and radiologically. All cases were confirmed diagnostically with histopathological examination and immunohistochemistry following surgical excision either by endoscopic or open approach. Some of the cases underwent post operative radiotherapy. Results: In our study, among 176 cases diagnosed with Sino nasal malignancies, 38 (21.6%) cases were diagnosed with sinonasal small round blue cell tumors with male to female ratio 1.4:1. Most common histopathological type among all the sinonasal small round blue cell tumors that presented to us was esthesioneuroblastoma i.e., 8 (21%) patients followed by pituitary macroadenoma in 7(8.4%) patients. Other types are undifferentiated squamous cell carcinoma 10(13.1%), craniopharyngioma 8(10.5%), lymphoma 3(7.9%), synovial/spindle cell sarcoma, malignant melanoma and adenocarcinoma 1(2.6%) each. Schwannoma, rhabdomyosarcoma, neuroendocrine carcinoma and neurofibroma 2 (5.2%) each. Conclusion: Sinonasal small round blue cell tumors are extremely rare tumours. Histopathological diagnosis with immunohistochemistry is characteristic of various tumors and is conclusive for diagnosis. Knowledge of these tumor entity is essential as early diagnosis helps in further management in preventing spread to vital structures and improving outcome. Most of the tumors have a multimodality treatment approach which includes surgical excision, radiotherapy and chemotherapy.


Factors associated with weight loss by age among community-dwelling older people.
Factors associated with weight loss in community-dwelling older people have been reported in several studies, but few studies have examined factors associated with weight loss by age groups. The purpose of this study was to clarify factors associated with weight loss by age in community-dwelling older people through a longitudinal study. Participants in the SONIC study (Longitudinal Epidemiological Study of the Elderly) were community-dwelling people aged 70 or older. The participants were divided into two groups: 5% weight loss and maintenance groups, and compared. In addition, we examined factors affecting weight loss by age. The analysis method used was the χ2 test, and the t-test was used for comparison of the two groups. Factors associated with 5% weight loss at 3 years were examined using logistic regression analysis with sex, age, married couple, cognitive function, grip strength, and the serum albumin level as explanatory variables. Of the 1157 subjects, the proportions showing 5% weight loss after 3 years among all subjects, those aged 70 years, 80 years, and 90 years, were 20.5, 13.8, 26.8, and 30.5%, respectively. In logistic regression analysis, factors associated with 5% weight loss at 3 years by age were influenced by BMI of 25 or higher (OR = 1.90, 95%CI = 1.08-3.34, p = 0.026), a married couple (OR = 0.49, 95% = 0.28-0.86, p = 0.013), serum albumin level below 3.8 g/dL (OR = 10.75, 95% = 1.90-60.73, p = 0.007) at age 70, and the grip strength at age 90 (OR = 1.24, 95%CI = 1.02-1.51, p = 0.034), respectively. The results suggest that factors associated with weight loss by age in community-dwelling older people through a longitudinal study differ by age. In the future, this study will be useful to propose effective interventions to prevent factors associated with weight loss by age in community-dwelling older people.


Properties of immobilized MAS1-H108A lipase and its application in the efficient synthesis of n-3 PUFA-rich triacylglycerols.
This study reports the properties of immobilized MAS1-H108A lipase from marine Streptomyces sp. strain W007 on XAD1180 resin and its application in the synthesis of n-3 polyunsaturated fatty acids (PUFA)-rich triacylglycerols (TAG) for the first time. It was found that the optimal temperature and pH for both immobilized MAS1-H108A lipase and free lipase MAS1-H108A were 70 °C and 7.0, respectively. However, immobilized MAS1-H108A lipase exhibited higher thermostability when compared with free lipase MAS1-H108A. It was also interesting that both immobilized MAS1-H108A lipase and free lipase MAS1-H108A showed no regiospecificity in the hydrolysis of triolein. Subsequently, immobilized MAS1-H108A lipase and free lipase MAS1-H108A were employed to catalyze glycerolysis of n-3 PUFA-rich ethyl esters (EE) and esterification of n-3 PUFA with glycerol under vacuum in the solvent-free system. The results showed that n-3 PUFA-rich TAG were synthesized efficiently by non-regiospecific immobilized MAS1-H108A lipase and TAG contents separately reached 92.07% and 76.13% during the esterification and glycerolysis reactions, which were significantly higher than those (71.82% and 39.62%, respectively) obtained by free lipase MAS1-H108A. Besides, TAG exhibited similar n-3 PUFA composition to the substrate. These findings indicated that non-regiospecific immobilized MAS1-H108A lipase is a promising and efficient biocatalyst for the industrial synthesis of n-3 PUFA-rich TAG.


Characteristics and spatiotemporal distribution of microplastics in sediments from a typical mariculture pond area in Qingduizi Bay, North Yellow Sea, China.
Microplastics (MPs) in mariculture environments may have an impact on mariculture and ecosystems. This study sampled the sediments in mariculture ponds and offshore areas in Qingduizi Bay during winter and summer. The abundance, characteristics, spatiotemporal distribution and pollution risk of microplastics were analyzed. The results showed that the abundance of MPs in the mariculture pond and offshore area was 49.2 ± 35.9 items·kg-1 d.w. and 17.1 ± 9.9 items·kg-1 d.w.; the MPs were mainly composed of transparent fibers of thickness 2000-5000 μm, with the main polymers being polyethylene terephthalate (PET) and cellophane (CP). The spatial distribution showed a downward trend from the inside to the outside, but the difference was not significant when comparing different seasons. The pollution load index (PLI) risk assessment showed that all sampling sites were at Hazard Level I. This study can provide valuable information for the risk assessment of microplastic pollution in mariculture areas.


Redox potential affects the measured heat resistance of Escherichia coli O157:H7 independently of oxygen concentration.
Cells of Escherichia coli O157:H7 were heat-treated at 59 degrees C and enumerated in (i) anaerobic medium with a low redox potential, (ii) anaerobic media with the oxidizing agents potassium ferricyanide or 2,6-dichloroindophenol (DPIP) added to raise the redox potential, (iii) aerobic medium with a high redox potential and (iv) aerobic medium with the reducing agent dithiothreitol added to lower the redox potential. The measured heat-resistance was greatest when the enumeration medium was highly anaerobic due to the absence of oxygen and the presence of hydrogen and cysteine HCl. Measured heat resistance was influenced by the redox potential of the enumeration medium independently of the chemical used to adjust it and therefore, independently of the presence of oxygen. Sub-lethally heat-damaged cells regained their ability to grow in media of high redox potential at a similar rate whether the redox potential was increased by the addition of potassium ferricyanide, DPIP or oxygen.


Feasibility of neurobehavioral screening following diagnosis of pediatric cancer.
Neurobehavioral deficits will affect up to 50% of pediatric cancer survivors treated with central nervous system (CNS)-directed therapies. Guidelines suggest assessment of neurobehavioral skills at diagnosis be extended from patients with brain tumors to include all patients requiring CNS-directed therapies. However, comprehensive neuropsychological assessment at diagnosis is difficult to implement and resource intensive. A screening assessment targeted at the neurobehavioral domains known to be impacted by cancer treatments may be more feasible. This study aimed to assess the feasibility of implementing baseline neurobehavioral screening following childhood cancer diagnosis. A consecutive sample of 59 recently diagnosed patients requiring CNS-directed therapies, and 49 healthy controls were assessed using a targeted neurobehavioral screen, which included measures of developmental, cognitive, academic, behavioral, and psychosocial functioning. Feasibility was assessed using a formal feasibility framework, with criteria of brevity, simplicity, relevance, acceptability, and value. Neurobehavioral assessment was compared to standard care to determine the quality of information acquired from the screen. Mean time from diagnosis to assessment was 5.17 weeks. Assessments were completed within 1 hour for 87% of patients. Participant and researcher evaluation indicated the screen was acceptable across a range of criteria, with no differences between clinical and control groups. Compared to standard medical record documentation, the screen provided significant additional information on developmental and neurobehavioral status of patients at diagnosis. A brief neurobehavioral screen in the early period following cancer diagnosis is feasible and provides valuable baseline data for children at risk of neurobehavioral late-effects of cancer treatments.


Dopaminergic reduction of intracellular calcium: the role of calcium influx.
The effects of dopamine (DA) on 45Ca2+ ion movement and prolactin release in dispersed female rat anterior pituitary cells were studied to elucidate the mechanism for DA reduction of intracellular calcium levels. In 45Ca2+ prelabeled cells, DA inhibited fractional calcium efflux and prolactin release simultaneously and continuously in a concentration-dependent manner (IC50 20 nM DA). We then studied unidirectional calcium influx and observed haloperidol-reversible, concentration-dependent DA suppression of calcium influx into unlabeled cells. These data complement and extend reported fluorescent dye studies and suggest that dopamine primarily inhibits calcium influx, thereby reducing intracellular calcium levels, which leads to suppression of prolactin release and is manifest secondarily as a reduction in fractional 45Ca2+ efflux.


Treatment advances in psoriatic arthritis.
Treatment of psoriatic arthritis, like the treatment of rheumatoid arthritis, now commonly includes the use of inhibitors of tumor necrosis factor in addition to traditional synthetic disease-modifying antirheumatic drugs. This paper examines the most recent data from therapeutic trials in psoriatic arthritis, with particular emphasis on the effectiveness of the tumor necrosis factor inhibitors. Recent data on potential future therapies is discussed as well, along with data on the mechanisms of current therapies that may have relevance for future treatment approaches.


Ageing, oxidative stress and cancer: paradigms in parallax.
Two paradigms central to geroscience research are that aging is associated with increased oxidative stress and increased cancer risk. Therefore, it could be deduced that cancers arising with ageing will show evidence of increased oxidative stress. Recent studies of gene expression in age-controlled breast cancer cases indicate that this deduction is false, posing parallax views of these two paradigms, and highlighting the unanswered question: does ageing cause or simply permit cancer development?


Suppression of rabbit lymphocyte functions by antibodies specific for allotypic membrane determinants.
Regulation of immunoglobulin synthesis and secretion was analyzed by exposing spleen cells of b4b4 rabbits to anti-b4 for 24 hr in culture. As noted previously, no lymphocytes with membrane-bound b4 were found immediately after pulse treatment, but substantial regeneration of membrane Ig (mIg) occurred on further culture in antibody-free medium. Splenocytes cultured either in the presence or absence of anti-b4 showed a marked loss of Ig-secreting cells (ISC) after 24 hr in culture but recovered and exhibited peak numbers of ISC on Day 2. However, ISC formation in cultures of antibody-treated cells was significantly suppressed and thereafter declined at a more rapid rate than in control cultures. Polyclonal B cell activators from Nocardia and from gram-negative bacteria stimulated ISC formation in cultures of normal spleen cells, but responsiveness to these activators was depressed following antibody treatment. Antibody-induced suppression of Ig synthesis was attributed to interference with differentiation of B lymphocytes to the secretory stage.


Synthesis and preliminary biological evaluation of a compound library of triazolylcyclitols.
A small library of compounds was prepared by a combination of toluene dioxygenase (TDO)-catalyzed enzymatic dihydroxylation and copper(I)-catalyzed Hüisgen cycloaddition. Some compounds were obtained by coupling an alkyne and a conduritol derivative, while more complex structures were obtained by a double Hüisgen reaction of a dialkyne and two molecules of the cyclitol. The compounds were fully characterized and subjected to preliminary biological screening.


Decrypting the potency of anti-cancer therapeutics by using mass spectrometry to quantify post-translational modifications.
In a recent issue of Science, Zecha et al.1 present decryptM, an approach aimed at defining the mechanisms of action of anti-cancer therapeutics through systems-level analysis of protein post-translational modifications (PTMs). By using a broad range of concentrations, decryptM generates drug response curves for each detected PTM, enabling identification of drug effects at different therapeutic doses.


Evaluating the crash and citation rates of Utah drivers licensed with medical conditions, 1992-1996.
Medical problems may affect the ability to drive motor vehicles, and programs that control the issuing of driver licenses to individuals with medical conditions exist in most states. The main activity of these programs is the imposition of restrictions upon the driving privileges of individuals with medical conditions that are deemed to pose some risk to public safety. However, little is known about the effectiveness of these licensing programs. The objective of this study was to compare the rates of adverse driving events (crash, at-fault crash and citations) experienced by drivers licensed with medical conditions to those of age-, sex- and location-matched controls. Separate comparisons were made for drivers reporting medical conditions licensed with full driving privileges, and those with restricted driving privileges (e.g. speed, area and time of day). Retrospective case-control. The study population was all drivers licensed in the state of Utah who reported a medical condition on their driver license application, over the 5-year period 1992-1996. Drivers enter the program by self-reporting their medical problems. Control drivers were chosen from the entire population of drivers licensed in Utah for the same period. Information on driver license status, participation in the medical conditions program, citations, involvement in crashes, and death certificate data was obtained from the relevant state agencies. Probabilistic linkage methodology was used to link the records in these disparate databases for eventual analysis. Rates of citation, crashes and at-fault crashes, expressed as events per 10000 license days, were calculated separately for program drivers and their corresponding control groups for each medical condition category and restriction status. These data were used to determine an estimate of relative risk (RR) and 95% confidence intervals. As a group, medical conditions drivers had modestly elevated rates of adverse driving events compared with control drivers (RR 1.09-1.74). Rates in the largest medical category, 'cardiovascular conditions', were not higher than controls. Rates were higher than control for some conditions, such as 'alcohol' and 'learning and memory', for some adverse events (RR 2.2 -5.75). Drivers with more than one medical condition appeared comparable to the general group of medical conditions program drivers. Drivers in Utah medical conditions program had modestly elevated rates of adverse driving events compared to matched controls. Possible underreporting of medical conditions and accurate assessment of exposure rates are potential weaknesses in the program.


The accuracy of endometrial cytology in the diagnosis of endometrial adenocarcinoma.
We have examined 62,234 cytological samples of endometrium to establish the accuracy and false-positive rate for the diagnosis of endometrial adenocarcinoma. The patients were either attending the gynaecological out-patients clinic with symptoms or were asymptomatic women attending for routine population screening as part of our cancer detection programme, the numbers from these two sources being equal. Out of 138 cases identified as endometrial adenocarcinoma by cytology 126 (91.3%) were confirmed histologically in our hospital. Twelve cases (8.7%) were shown to be false-positives. Reexamination of these led to the same false-positive diagnosis in all 12 cases. This was attributable to similarities of nucleo-cytoplasmic ratio, irregular arrangement of nuclei, variation in nuclear shape and in the numbers of nucleoli in repair cells and hyperplastic cells compared with the carcinoma cases. Most of the false-negative reports were due to insufficient material, pale staining in malignant cells or diagnostic error. Refraction measurement of the density of nuclei of cancer cells using equipment for which the patent is pending enabled objective measurement of nuclear density which indicated that the nuclei were not stained darkly enough in false-negative cases.


Trends in Cumulative Disenrollment in the Medicare Advantage Program, 2011-2020.
The Medicare Advantage (MA) program is rapidly growing. While previous work has found that beneficiaries with substantial health needs disenroll from plans at higher rates, the long-term frequency of disenrollment is not well understood. To compare cumulative disenrollment trends in the MA program by beneficiary and plan characteristics. This retrospective, serial cross-sectional study included beneficiaries with any MA enrollment from January 1, 2011, to December 31, 2020. Data analysis took place from September 2022 to March 2023. Beneficiary characteristics, including race and ethnicity, length of Medicare enrollment, dual eligibility, and comorbidity burden, and contract characteristics, including vertical integration status, premium, and MA star rating. The main outcome was disenrollment from an MA contract within 5 years. Rates of cumulative disenrollment by beneficiary and contract characteristics were compared. Pearson correlation coefficients were calculated to assess the correlation between a contract's 1-year disenrollment and the contract's disenrollment over a longer period. The sample included 82 377 917 beneficiaries (524 442 225 beneficiary-year observations; 56.7% female; mean [SD] age, 71.9 [10.3] years). After 1 year, 13.2% of nondually enrolled and 15.9% of dually enrolled beneficiaries had left their contract, increasing to 48.3% and 53.4%, respectively, after 5 years. Black enrollees disenrolled at the highest rates among race and ethnicity categories, with 14.8% disenrolling after 1 year and 52.6% disenrolling after 5 years. Contracts had a median disenrollment rate of 9.8% (IQR, 4.5%-19.0%) after 1 year and 56.1% (IQR, 23.1%-79.0%) after 5 years. Contracts rated 5 stars had substantially lower 5-year disenrollment rates (23.0% after 5 years compared with 41.2% for 4- to 4.5-star contracts and 67.2% for 3- to 3.5-star contracts). Disenrollment from a contract after 1 year was not well correlated with disenrollment after 5 years (r, 0.46). This cross-sectional study found substantial cumulative rates of disenrollment from MA plans within 5 years between 2011 and 2020, with wide variation in 5-year disenrollment by contract. The findings suggest that evaluating long-term disenrollment rates in MA performance measures may capture different outcomes than single-year disenrollment alone.


Influence of dithiocarb on the biliary excretion of paracetamol and bilirubin in rats.
In bile-fistula rats, the biliary elimination of conjugated paracetamol and conjugated bilirubin is diminished by simultaneous administration of dithiocarb. This dithiocarb effect could be the result of the interference with the glucuronidation of the compounds.


Application of intraoperative radiotherapy for malignant glioma.
Malignant glioma is characterized by rapid tumor cell proliferation and high recurrence risk. In terms of its treatment, the therapeutic effects of maximum resection and postoperative radiotherapy with adjuvant chemotherapy as well as many other new therapeutic techniques such as antiangiogenic therapy and immunotherapy remain poor. Glioma recurrence, especially local recurrence, is an important reason of glioma treatment failure. Intraoperative radiotherapy (IORT) enables exclusion of radiation-sensitive normal tissue from the radiation field in operation and then the application of a single high-dose precision irradiation to the residual tumor or tumor bed. IORT has great application potential in the control of local recurrence of malignant tumors. This paper thus aims to review the current status and prospects of IORT's application in malignant glioma treatment.


Conversion from twice-daily to once-daily tacrolimus in stable liver transplant patients: effectiveness in a real-world setting.
The prolonged-release once-daily (QD) tacrolimus is a formulation developed to improve adherence to immunosuppressant (IS) regimen, reducing the frequency of dosing, and to increase safety, avoiding toxic peak concentrations. We evaluated efficiency and quality of conversion from twice-daily (BID) to QD tacrolimus formulation in stable liver transplant (LT) recipients in the real-setting of a gastrohepatology team peripheral to LT centers. Thirty-four LT recipients (median age 60 years, range 33-69) were switched from BID tacrolimus to QD tacrolimus (1:1 dose) at a median of 38 months (range 8-211) after transplantation. Tacrolimus levels and laboratory analyses were recorded before and postconversion. Adherence to IS treatment was measured by a modified "Basel Assessment of Adherence Scale to Immunosuppressives." Median postconversion follow-up was 21 months (range 6-35, at least 12 months in 30 patients). Mean total tacrolimus daily dose and mean tacrolimus trough level were not significantly different before and after the switch (3.1 ± 2.3 preconversion versus 3.1 ± 2.5 and 3.0 ± 2.5 mg at 6 and 12 months postconversion, respectively; and 5.3 ± 1.8 preconversion versus 4.6 ± 1.4 and 4.5 ± 1.8 ng/mL at 6 and 12 months postconversion, respectively). All patients maintained stable liver and metabolic parameters. Renal function by glomerular filtration rate increased (67 ± 17 preconversion versus 73 ± 19 and 73 ± 20 mL/min at 6 and 12 months postconversion, respectively; P = .003). No acute rejection episode or major severe adverse events occurred postconversion. Patient-reported outcome showed a reduction of missed IS doses. We observed that in a real-world setting far from LT centers, the switch from BID tacrolimus to QD tacrolimus in stable LT recipients is efficient (safe and effective) to improve quality of medical care, with possibly better IS adherence and improvement of renal function.


[Organisation of cancer care during the COVID-19 pandemic : experience from CHU Liège].
The COVID-19 pandemic has had a major impact in the world of Oncology. Surprised by the rapidity of the extension of the pandemic, the oncological department had to be reorganised in a very short time period in a hospital which had the primary objective to treat infected patients. The author describes how with the help of an international network and local research projects all efforts have been done to offer the best patient's care in a secure environment.


Trends in prenatal diagnosis: An analysis of 40 years of Medical Subject Heading (MeSH) terms in publications.
To understand the evolution of the field of prenatal diagnosis over the past four decades. We analyzed the publications in the journal Prenatal Diagnosis from its inception in 1980 to 2019 using Medical Subject Headings (MeSH) to examine the major research topics and trends. The results were analyzed by 10-year intervals. Publications on prenatal cytogenetics, congenital anomalies and fetal imaging predominated during the first three decades, with a steady increase in molecular genetics over time. Publications on NIPT did not appear until the most recent decade and are likely under-counted because there was no MeSH term for NIPT until 2020. The topics covered in Prenatal Diagnosis articles have evolved considerably over the past four decades and reflect a response to advances in technology and widespread incorporation of prenatal screening and diagnosis into standard obstetric care. The strengths of this analysis are its objective nature, its use of the standard MeSH terms used for coding, and application of a novel cluster analysis to visualize trends. The analysis also pointed out the fact that MeSH terms in this sub-specialty area are often inconsistent due to manually coding based on individual subject matter expertise.


Effect of oxytocin on plasma testosterone levels in the male macaques (Macaca fascicularis).
The effect of oxytocin on testicular function was examined in the adult male long-tailed macaques (Macaca fascicularis). The monkeys were either infused with increasing concentrations of synthetic oxytocin (16-128 m.i.u./min for 3 h) or injected daily for a week with the same hormone (20 i.u., i.v.) and the plasma testosterone levels measured. The results of the present study show that acute infusion or chronic injection of oxytocin does not significantly affect the plasma testosterone levels, suggesting that systemic control of testicular endocrine function by oxytocin may be unimportant.


The Tromsø Study: body height, body mass index and fractures.
Tall persons suffer more hip fractures than shorter persons, and high body mass index is associated with fewer hip and forearm fractures. We have studied the association between body height, body mass index and all non-vertebral fractures in a large, prospective, population-based study. The middle-aged population of Tromsø, Norway, was invited to surveys in 1979/80, 1986/87 and 1994/95 (The Tromsø Study). Of 16,676 invited to the first two surveys, 12,270 attended both times (74%). Height and weight were measured without shoes at the surveys, and all non-vertebral fractures in the period 1988-1995 were registered (922 persons with fractures) and verified by radiography. The risk of a low-energy fracture was found to be positively associated with increasing body height and with decreasing body mass index. Furthermore, men who had gained weight had a lower risk of hip fractures, and women who had gained weight had a lower risk of fractures in the lower extremities. High body height is thus a risk factor for fractures, and 1 in 4 low-energy fractures among women today might be ascribed to the increase in average stature since the turn of the century. Low body mass index is associated with a higher risk of fractures, but the association is probably too weak to have any clinical relevance in this age category.


Perioperative care of the patient with hip fracture.
Primary care physicians can intervene to reduce perioperative complications due to comorbid medical illness in patients hospitalized with hip fracture. We review the role of the primary care physician in the treatment and prevention of perioperative morbidity and mortality.


T cell immune profiling of respiratory syncytial virus for the development of a targeted immunotherapy.
Respiratory syncytial virus (RSV)-associated viral infections are a major public health problem affecting the immunologically naïve/compromised populations. Given the RSV-associated morbidity and the limited treatment options, we sought to characterize the cellular immune response to RSV to develop a targeted T cell therapy for off-the-shelf administration to immunocompromised individuals. Here we report on the immunological profiling, as well as manufacturing, characterization and antiviral properties of these RSV-targeted T cells. A randomized, phase 1/2 clinical trial evaluating their safety and activity in haematopoietic stem cell transplant recipients as an off-the-shelf multi-respiratory virus-directed product is currently underway (NCT04933968, https://clinicaltrials.gov).


Machine Learning-Guided Adjuvant Treatment of Head and Neck Cancer.
Postoperative chemoradiation is the standard of care for cancers with positive margins or extracapsular extension, but the benefit of chemotherapy is unclear for patients with other intermediate risk features. To evaluate whether machine learning models could identify patients with intermediate-risk head and neck squamous cell carcinoma who would benefit from chemoradiation. This cohort study included patients diagnosed with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx from January 1, 2004, through December 31, 2016. Patients had resected disease and underwent adjuvant radiotherapy. Analysis was performed from October 1, 2019, through September 1, 2020. Patients were selected from the National Cancer Database, a hospital-based registry that captures data from more than 70% of newly diagnosed cancers in the United States. Three machine learning survival models were trained using 80% of the cohort, with the remaining 20% used to assess model performance. Receipt of adjuvant chemoradiation or radiation alone. Patients who received treatment recommended by machine learning models were compared with those who did not. Overall survival for treatment according to model recommendations was the primary outcome. Secondary outcomes included frequency of recommendation for chemotherapy and chemotherapy benefit in patients recommended for chemoradiation vs radiation alone. A total of 33 527 patients (24 189 [72%] men; 28 036 [84%] aged ≤70 years) met the inclusion criteria. Median follow-up in the validation data set was 43.2 (interquartile range, 19.8-65.5) months. DeepSurv, neural multitask logistic regression, and survival forest models recommended chemoradiation for 17 589 (52%), 15 917 (47%), and 14 912 patients (44%), respectively. Treatment according to model recommendations was associated with a survival benefit, with a hazard ratio of 0.79 (95% CI, 0.72-0.85; P < .001) for DeepSurv, 0.83 (95% CI, 0.77-0.90; P < .001) for neural multitask logistic regression, and 0.90 (95% CI, 0.83-0.98; P = .01) for random survival forest models. No survival benefit for chemotherapy was seen for patients recommended to receive radiotherapy alone. These findings suggest that machine learning models may identify patients with intermediate risk who could benefit from chemoradiation. These models predicted that approximately half of such patients have no added benefit from chemotherapy.


Testing Leggett's inequality using Aharonov-Casher effect.
Bell's inequality is established based on local realism. The violation of Bell's inequality by quantum mechanics implies either locality or realism or both are untenable. Leggett's inequality is derived based on nonlocal realism. The violation of Leggett's inequality implies that quantum mechanics is neither local realistic nor nonlocal realistic. The incompatibility of nonlocal realism and quantum mechanics has been currently confirmed by photon experiments. In our work, we propose to test Leggett's inequality using the Aharonov-Casher effect. In our scheme, four entangled particles emitted from two sources manifest a two-qubit-typed correlation that may result in the violation of the Leggett inequality, while satisfying the no-signaling condition for spacelike separation. Our scheme is tolerant to some local inaccuracies due to the topological nature of the Aharonov-Casher phase. The experimental implementation of our scheme can be possibly realized by a calcium atomic polarization interferometer experiment.


Characterization of ciprofloxacin binding to the linear single- and double-stranded DNA.
The binding of ciprofloxacin to natural and synthetic polymeric DNAs was investigated at different solvent conditions using a combination of spectroscopic and hydrodynamic techniques. In 10 mM cacodylate buffer (pH 7.0) containing 108.6 mM Na(+), no sequence preferences in the interaction of ciprofloxacin with DNA was detected, while in 2 mM cacodylate buffer (pH 7.0) containing only 1.7 mM Na(+), a significant binding of ciprofloxacin to natural and synthetic linear double-stranded DNA was observed. At low ionic strength of solution, ciprofloxacin binding to DNA duplex containing alternating AT base pairs is accompanied by the largest enhancement in thermal stability (e.g. DeltaT(m) approximately 10 degrees C for poly[d(AT)].poly[d(AT)]), and the most pronounced red shift in the position of the maximum of the fluorescence emission spectrum (lambda(max)). Similar red shift in the position of lambda(max) is also observed for ciprofloxacin binding to dodecameric duplex containing five successive alternating AT base pairs in the row. On the other hand, ciprofloxacin binding to poly[d(GC)].poly[d(GC)], calf thymus DNA and dodecameric duplex containing a mixed sequence is accompanied by the largest fluorescence intensity quenching. Addition of NaCl does not completely displace ciprofloxacin bound to DNA, indicating the binding is not entirely electrostatic in origin. The intrinsic viscosity data suggest some degree of ciprofloxacin intercalation into duplex.


Retrospective Evaluation of Periradicular Biopsies: An 18-Year Study.
Radiographic findings in periradicular areas are repeatedly associated with infected root canal systems. Although non-odontogenic lesions in teeth are reported to be low, they often mimic periapical pathoses, and consequently, histopathologic examinations after surgical revisions are nurtured. Biopsies submitted to the College of Dentistry between 2003 and 2021 were reviewed. Clinicopathologic characteristics were collected, including age, sex, medical history, location, sensibility tests, and clinic impressions from each specimen. Histopathologic diagnosis and gross description were also part of our database. A total of 72,055 pathology reports were reviewed, of which 10,031 lesions (13.9%) met the criterion of being intraosseous lesions at the periradicular area. Among those 10,031 lesions, 7.94% (n = 796) were of non-endodontic origin, 7153 were documented as non-vital, and 2.36% (n = 169) of these non-vital teeth were diagnosed with a non-endodontic origin. A total of 5707 lesions were obtained from surgeries within the periapical tissues, primarily performed by endodontists (94.02%). Non-endodontic lesions were reported in 1.09% of the cases. Odontogenic keratocyst was the most common non-endodontic diagnosis, followed by nasopalatine duct cyst and benign fibro-osseous lesion, respectively. Pathologic findings of the periradicular tissues are not always from endodontic origin. The probability of encountering non-endodontic lesions is almost 8%. Even in clinically reported teeth with pulp necrosis, 1%-3% of biopsies were confirmed as non-endodontic lesions.


Macroscopic expression of the chirality of amino alcohols by a double amplification mechanism in liquid crystalline media.
The central chirality of simple amino alcohols was amplified by binding to a dynamically axially chiral biphenol receptor and expressed as supramolecular chirality by effecting a change from a nematic to a cholesteric liquid crystalline phase.


[Condylomata acuminata and HIV infection--an epidemiologic study].
Within a period of 15 months, 134 patients suffering from condylomata acuminata were investigated with regard to simultaneous infection with HIV. 3 of these patients--2 showing warts in the anal region, 1 on the glans penis--were found positive for anti-HIV antibodies.


Genomic structure of the human TATA-box-binding protein (TBP).
The gene encoding the human TATA-box-binding protein (hTBP) is contained within a 20-kb DNA fragment and is split into eight exons. The coding sequence is interrupted by six introns and the 5'-untranslated region (5'-UTR) of the gene by a 2.5-kb intron. A comparison of the hTBP exon/intron organization with the various TBP cloned to date is presented.


Percolation thresholds in square-lattice Kauffman model.
In Kauffman's random Boolean network model for genetics, each gene is either on or off, depending in a fixed random way on whether K neighbor genes are on or off. Our computer simulation puts these genes on the sites of a square lattice and asks if the "off" genes, the "on" genes, the "oscillating" genes and the non-oscillating "stable" genes are percolating, i.e. form one connected network of neighboring sites. The percolation thresholds for stable and for oscillating genes are found to coincide numerically with the transition to chaos at p = 0.29. Up to one million sweeps through the lattice were made to find that agreement.


Who are Clive's friends? Latent sociality in the emergency department.
In the absence of social services and robust social networks, staff working at social service institutions serve as a significant element of sociality in the lives of a segment of people experiencing homelessness. Relationships forged within these institutions prove to be avenues of emotional support and material resources that facilitate the survival of some homeless people. To illustrate this point, this article draws on data collected over the course of 18 months between July 2014 and December 2016. I present an ethnographic case study of an elderly homeless man, Clive, who was labeled a "super-utilizer" of an Emergency Department (ED) in Atlanta, Georgia. This article explores how Clive's relationships with ED staff transcended professional obligations and enabled his survival during his estrangement from friends and family. I demonstrate that the ED, and hospitals in general, are better understood as human infrastructures that perform functions in excess of providing biomedical services. This sociality, I argue, is key to understanding how the most vulnerable individuals survive in the context of increasing social abandonment.


Sensitization to isothiazolinones in the Spanish Contact Dermatitis Registry (REIDAC): 2019-2021 epidemiological situation.
Current frequency and risk factors for sensitization to methylisothiazolinone (MI), methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), benzisothiazolinone (BIT) and octylisothiazolinone (OIT) in Spain are not well known. To study the frequency of sensitization, risk factors and simultaneous sensitization between the four isothiazolinones. We analysed all 2019-2021 consecutive patients patch-tested with MI (0.2% aq.), MCI/MI (0.02% aq.), BIT (0.1% pet.) and OIT (0.1% pet) within the Spanish Contact Dermatitis Registry (REIDAC). A total of 2511 patients were analysed. Frequencies of sensitization were: any isothiazolinone 15.7%, MI 6.8%, MCI/MI 4.8%, BIT 3.5% and OIT 0.5%. MI and MCI/MI sensitization was associated with being occupationally active, hand dermatitis, detergents and age over 40. BIT sensitization was associated with leg dermatitis and age over 40. About one in nine MI-positive patients were positive to BIT, whereas one in five BIT-positive patients were positive to MI. Sensitization to MI, MCI/MI and BIT is still common in Spain, while sensitization to OIT is rare. Currently, sensitization to MI and MCI/MI seems to be occupationally related. Although its origin is unknown, sensitization to BIT is more frequent in patients aged over 40 years. Simultaneous sensitization between MI and BIT is uncommon.


Evidence that molecular changes in cells occur before morphological alterations during the progression of breast ductal carcinoma.
Ductal carcinoma in situ (DCIS) of the breast includes a heterogeneous group of preinvasive tumors with uncertain evolution. Definition of the molecular factors necessary for progression to invasive disease is crucial to determining which lesions are likely to become invasive. To obtain insight into the molecular basis of DCIS, we compared the gene expression pattern of cells from the following samples: non-neoplastic, pure DCIS, in situ component of lesions with co-existing invasive ductal carcinoma, and invasive ductal carcinoma. Forty-one samples were evaluated: four non-neoplastic, five pure DCIS, 22 in situ component of lesions with co-existing invasive ductal carcinoma, and 10 invasive ductal carcinoma. Pure cell populations were isolated using laser microdissection. Total RNA was purified, DNase treated, and amplified using the T7-based method. Microarray analysis was conducted using a customized cDNA platform. The concept of molecular divergence was applied to classify the sample groups using analysis of variance followed by Tukey's test. Among the tumor sample groups, cells from pure DCIS exhibited the most divergent molecular profile, consequently identifying cells from in situ component of lesions with co-existing invasive ductal carcinoma as very similar to cells from invasive lesions. Additionally, we identified 147 genes that were differentially expressed between pure DCIS and in situ component of lesions with co-existing invasive ductal carcinoma, which can discriminate samples representative of in situ component of lesions with co-existing invasive ductal carcinoma from 60% of pure DCIS samples. A gene subset was evaluated using quantitative RT-PCR, which confirmed differential expression for 62.5% and 60.0% of them using initial and partial independent sample groups, respectively. Among these genes, LOX and SULF-1 exhibited features that identify them as potential participants in the malignant process of DCIS. We identified new genes that are potentially involved in the malignant transformation of DCIS, and our findings strongly suggest that cells from the in situ component of lesions with co-existing invasive ductal carcinoma exhibit molecular alterations that enable them to invade the surrounding tissue before morphological changes in the lesion become apparent.


Fibrinolytic activity in patients with acute tonsillitis.
Three parameters in blood fibrinolysis, viz, the levels of fibrinogen, plasminogen, and fibrinogen and/or fibrin degradation products (FDP), were measured in patients with acute tonsillitis and the results were compared with those for healthy adults. The fibrinogen content in acute tonsillitis increased significantly (P less than .001), that of plasminogen decreased significantly (P less than .005), while FDP showed a higher value (P less than .01). The significance of the fibrinolytic system in acute tonsillitis is discussed.


Perifollicular, perisinusal and trabecular myofibroblasts in the human fetal spleen.
Electron microscopic studies of the human fetal spleen were performed on 22 embryos and fetuses from 31 days to 32 weeks of age. In the course of splenic development myofibroblasts were frequently observed in the perifollicular and perisinusal regions and within the trabeculae. The perifollicular cells were flattened and markedly elongated in shape and had distinct bundles of microfilaments in their cytoplasm. The perisinusal cells under the sinal basement membrane had microfilaments found in particular beneath the plasmalemma. They were attached to each other and constituted a cellular network throughout the splenic cords. The trabecular myofibroblasts, embedded among the abundant collagen fibers, had elongated and often indented nuclei. The cytoplasm contained well developed Golgi apparatus, abundant rough surfaced ER cisternae and massive bundles of myofilaments. These cells showed cell-to-cell and cell-to-stroma connections and were assumed to play a role in the excretion of lymphocytes from the follicles and in pumping blood from the sinuses by their contraction.


Development and verification of a predictive nomogram to evaluate the risk of complicating ventricular tachyarrhythmia after acute myocardial infarction during hospitalization: A retrospective analysis.
The purpose of this study was to establish a nomogram to predict the risk of complicating ventricular tachyarrhythmia (VTA) in patients with acute myocardial infarction (AMI) during hospitalization and to verify the accuracy of the model. The authors enrolled the information of 503 patients who were diagnosed as AMI from January 2017 to December 2019. The cohort was randomly divided into a training set and a testing set at a ratio of 70%:30%. A total of 13 clinical indicators were screened by the least absolute shrinkage and selection operator (LASSO) regression and Boruta arithmetic independently in order to figure out the optimal feature variables. Multivariable logistic regression analysis was applied to establish the prediction model represented by a nomogram incorporating the selected feature variables. The performance of the nomogram was assessed by discrimination, calibration and clinical usefulness. C-Statistics with the area under the receiver operating characteristic curve (AUC), calibration curve and decision curve analysis were used to evaluate the identification ability, calibration and clinical practicability respectively. The prediction model was verified on the testing set to ensure its accuracy. Five feature variables as percutaneous coronary intervention (PCI) timing after hospitalization, ejection fraction (EF), high-sensitive troponin T (hsTnT) score, infection and estimated glomerular filtration rate (eGFR) were selected by both LASSO regression and Boruta arithmetic. C-statistics with AUC was 0.764 (95% confidence interval: 0.690-0.838) in the training set while a slight increasing to 0.804 (95% confidence interval: 0.673-0.935) in the testing set. Calibration curve illustrated that the predicted and actually diagnosis of VTA probabilities were satisfactory on both training set and testing validation. Decision curve analysis indicated that the nomogram can be used in clinical settings as it has a threshold of between 4% to 90% along with a net benefit. The nomogram with five variables is practical to clinicians in estimating the risk of complicating VTA after AMI during hospitalization.


Open Subpectoral Tenodesis of the Proximal Biceps.
This article summarizes both the various techniques for an open subpectoral biceps tenodesis as well as the biomechanics associated with these procedures. It provides information regarding the indications and contraindications to support the surgeon's decision. Furthermore, a postoperative protocol as well as an outcome overview is presented to address postoperative care. A short summary of the recent literature regarding potential complications is included to provide further insight on this technique. The open subpectoral tenodesis of the long head of the biceps is a safe and reproducible technique with a low complication rate for patients with pathologies of the proximal biceps.


Manufacturing uncertainty: contested science and the protection of the public's health and environment.
Opponents of public health and environmental regulations often try to "manufacture uncertainty" by questioning the validity of scientific evidence on which the regulations are based. Though most identified with the tobacco industry, this strategy has also been used by producers of other hazardous products. Its proponents use the label "junk science" to ridicule research that threatens powerful interests. This strategy of manufacturing uncertainty is antithetical to the public health principle that decisions be made using the best evidence available. The public health system must ensure that scientific evidence is evaluated in a manner that assures the public's health and environment will be adequately protected.


Low level of urinary cotinine in pregnant women also matters: variability, exposure characteristics, and association with oxidative stress markers.
China has relatively high indoor contamination of nicotine, according to recent publications. Therefore, nicotine exposure risks for sensitive populations such as pregnant women in China are of concern. The variability of its internal exposure levels across three trimesters among pregnant women is not well documented. Factors related with nicotine exposure across pregnancy and its associations with oxidative stress markers are also understudied. Based on a birth cohort, we measured concentrations of cotinine (a major metabolite of nicotine) and oxidative stress markers including 8-OHdG, 8-OHG, and HNE-MA in urine samples collected at three trimesters from 1,155 pregnant women enrolled between January 2014 and June 2017 in Wuhan, China. The variability of urinary cotinine across the trimesters, potential factors associated with it, as well as the relationships between urinary cotinine and oxidative stress markers were assessed in pregnant women with cotinine concentrations of < 50 ng/mL (the cutoff value to distinguish smokers and non-smokers). Urinary specific gravity adjusted median concentrations of cotinine (ng/mL) in the entire pregnancy, first, second, and third trimester were 3.04, 3.32, 3.36, and 2.50, respectively, which exhibited fair reliability (intraclass correlation coefficient: 0.47) across pregnancy. Most participants had an estimated daily intake of nicotine higher than the acceptable value (100 ng/kg-bw/day) recommended by the UK and the USA. Maternal age, education level, pre-pregnancy body mass index, and sampling seasons were related to urinary concentrations of cotinine. After adjusting for confounding factors, significant positive relationships (β; 95% confidence interval) were observed between urinary cotinine concentrations and 8-OHdG (0.28; 0.25, 0.30), 8-OHG (0.27; 0.25, 0.29), and HNE-MA (0.27; 0.21, 0.32), respectively (p < 0.01). These results lend insight into the major factors associated with nicotine exposure of pregnant women at environmentally relevant levels and its potential effect on oxidative stress with a large sample size, and warrant the necessity of reducing the exposure in sensitive populations.


3-(2,2-Dioxo-3,4-di-hydro-benzo[e][1,2,3]oxa-thiazin-4-yl)-3-fluoro-1-phenyl-indolin-2-one.
The title compound, C21H15FN2O4S, contains two chiral carbon centres, but crystal symmetry generates a racemic mixture. The crystal structure features N-H⋯O hydrogen bonding. The sulfonate group is disordered with an occupancy ratio of 0.933 (4):0.067 (4).


Recovering real-world images from single-scale boundaries with a novel filling-in architecture.
Filling-in models were successful in predicting psychophysical data for brightness perception. Nevertheless, their suitability for real-world image processing has never been examined. A unified architecture for both predicting psychophysical data and real-world image processing would constitute a powerful theory for early visual information processing. As a first contribution of the present paper, we identified three principal problems with current filling-in architectures, which hamper the goal of having such a unified architecture. To overcome these problems we propose an advance to filling-in theory, called BEATS filling-in, which is based on a novel nonlinear diffusion operator. BEATS filling-in furthermore introduces novel boundary structures. We compare, by means of simulation studies with real-world images, the performance of BEATS filling-in with the recently proposed confidence-based filling-in. As a second contribution we propose a novel mechanism for encoding luminance information in contrast responses ('multiplex contrasts'), which is based on recent neurophysiological findings. Again, by simulations, we show that 'multiplex contrasts' at a single, high-resolution filter scale are sufficient for recovering absolute luminance levels. Hence, 'multiplex contrasts' represent a novel theory addressing how the brain encodes and decodes luminance information.


The effects of cold therapy on postoperative pain in gynecologic patients: a prospective, randomized study.
The purpose of the study was to determine the effect of cold therapy on the subjective assessment of pain, analgesic requirements, and wound complications in female patients undergoing major abdominal surgery. Twenty-seven patients were entered in the study in a prospective, randomized fashion. The Hot/Ice Thermal Blanket was applied to 13 patients, and 12 patients were in the control group. All patients underwent exploratory laparotomy and received postoperative pain relief with intravenously self-administered morphine sulfate through a patient-controlled analgesic pump. Compared with the control group (0.363 +/- 0.118 mg/kg/day), the cold pack group used more morphine sulfate on the first postoperative day (0.529 +/- 0.236 mg/kg/day, p < 0.05). The mean amount of morphine sulfate used by both groups was similar on postoperative day 2. We conclude that the cold pack does not improve postoperative pain control in gynecologic patients undergoing exploratory laparotomy.


Pediatric trauma mortality in India and the United States: A comparison and risk-adjusted analysis.
There is a paucity of research comparing pediatric risk-adjusted trauma mortality between high-income and low- and middle-income countries. This limits identification of populations and injury patterns for targeted interventions. We aim to compare independent predictors of pediatric trauma mortality between India and the United States (US). A retrospective cohort study was conducted for pediatric patients (age <18 years) in India's Towards Improved Trauma Care Outcomes (TITCO) project database and the US National Trauma Data Bank (NTDB) from 2013 to 2015. Demographic, injury, physiologic, anatomic and outcome data were analyzed. Multivariable regressions were used to determine independent predictors of mortality. 126,678 pediatric trauma patients were included (India 3,373; US 123,305). Pediatric patients in India were on average significantly younger, with a higher median injury severity score (ISS), had lower systolic blood pressure, and suffered a higher case fatality rate (13.0% vs. 1.0%). When controlling for demographic, mechanism, physiologic, and anatomic injury characteristics, sustaining an injury in India was the strongest predictor of mortality (OR 22.70, 95% CI 18.70-27.56). On subgroup analysis, the highest relative odds of mortality in India was seen in children with lower injury and physiologic severity. Risk-adjusted pediatric trauma-related mortality is significantly higher in India compared to the US. The comparative odds of mortality are highest among children with lower injury and physiologic severity. This suggests that low-cost targeted interventions focused on standard timely trauma care, protocols, training and early imaging could improve pediatric injury mortality in India. Retrospective Prognosis Study LEVEL OF EVIDENCE: II.


A monoclonal antibody against erythrocyte spectrin reacts with both alpha- and beta-subunits and detects spectrin-like molecules in non-erythroid cells.
A panel of nine monoclonal antibodies against the characteristic erythrocyte membrane protein spectrin has been isolated. One antibody reacts with both the 240 000 and 220 000 D alpha- and beta-subunits of spectrin after denaturation. The same antibody reacts with a 240 000 D protein present in various hemopoietic and other cell lines, as well as some smaller polypeptides, as established by western blotting and immunoautoradiography. These results indicate that the alpha- and beta-subunits of spectrin, a polypeptide of 240 000, and some smaller polypeptides present in non-erythroid cell types possess a considerable region of sequence homology, but it is not yet clear just how extensively the spectrin-like molecules and other polypeptides are related.


Special techniques in diagnostic electron microscopy.
The power of electron microscopy as a diagnostic tool can be amplified considerably by the application of ancillary preparative and analytic methods. Subcellular chemistry and structure can be examined by various forms of microprobe analysis and by special staining methods, including cytochemical, immunocytochemical, and negative staining. Qualitative ultrastructural examination can be augmented by morphometric analysis. Correlative microscopic survey methods can be used as a means of targeting ultrastructural investigations. This article provides an overview of the use of these special techniques in the diagnosis and classification of tumors and other selected pathologic processes.


Crystal structure of pre-activated arrestin p44.
Arrestins interact with G-protein-coupled receptors (GPCRs) to block interaction with G proteins and initiate G-protein-independent signalling. Arrestins have a bi-lobed structure that is stabilized by a long carboxy-terminal tail (C-tail), and displacement of the C-tail by receptor-attached phosphates activates arrestins for binding active GPCRs. Structures of the inactive state of arrestin are available, but it is not known how C-tail displacement activates arrestin for receptor coupling. Here we present a 3.0 Å crystal structure of the bovine arrestin-1 splice variant p44, in which the activation step is mimicked by C-tail truncation. The structure of this pre-activated arrestin is profoundly different from the basal state and gives insight into the activation mechanism. p44 displays breakage of the central polar core and other interlobe hydrogen-bond networks, leading to a ∼21° rotation of the two lobes as compared to basal arrestin-1. Rearrangements in key receptor-binding loops in the central crest region include the finger loop, loop 139 (refs 8, 10, 11) and the sequence Asp 296-Asn 305 (or gate loop), here identified as controlling the polar core. We verified the role of these conformational alterations in arrestin activation and receptor binding by site-directed fluorescence spectroscopy. The data indicate a mechanism for arrestin activation in which C-tail displacement releases critical central-crest loops from restricted to extended receptor-interacting conformations. In parallel, increased flexibility between the two lobes facilitates a proper fitting of arrestin to the active receptor surface. Our results provide a snapshot of an arrestin ready to bind the active receptor, and give an insight into the role of naturally occurring truncated arrestins in the visual system.


Impact of the Coronavirus on Providing Oral Health Care in the Netherlands.
Transmission of SARS-CoV-2 during oral health care is potentially increased compared to regular social activities. Specific amendments to the Dutch national infection control guidelines were promulgated. This study aimed to map the impact of the coronavirus pandemic on providing oral health care during the first wave of the coronavirus pandemic in 2020 in the Netherlands. A cross-sectional web-based survey was sent via email to a representative sample of dental hygienists and dentists in the Netherlands. Of the 1700 oral health care practitioners approached, 440 (25.9%) responded to the survey. Patient access to oral health care was severely restricted during the lockdown in the spring of 2020. A total of 1.6% of the oral health care practitioners had laboratory-confirmed COVID-19 during the study period, although this is likely to be an underrepresentation due to limited access to testing at that time. Over half of the participants perceived an increased risk of virus transmission during aerosol-generating treatments in their practices. A large majority (65.0%-87.1%) of the oral health care practitioners followed the COVID-19-specific amendments to the national infection control guidelines. Compared to the pre-pandemic period, additional personal protective equipment and protocols were applied. Factors related with compliance with the additional recommendations were age, employment status, and occupation. The pandemic had a profound impact on both the accessibility and practice of oral health care. This survey study found that most Dutch oral health care practitioners paid extra attention to hygiene and infection control. Also, a low number of COVID-19 infections detected amongst Dutch oral health care practitioners was reported in the Netherlands. These overall outcomes suggest that safe oral health care can be provided when following the current infection control recommendations.


Response to DNA-damaging agents in cultured cells from patients with X-linked duchenne muscular dystrophy phenotype: male DMD, female DMD, possible carriers.
Using blood cultures the response to gamma (γ) radiation was examined in a male DMD and his mother, in a female DMD and her mother and in a normal control. In a series of experiments chromosome aberrations were determined after 3 separate γ-irradiation dose levels: 0, 150, 300 rads. The DMD patients showed a response to ionising radiations different from control, in fact the percentage of aberrations was lower than the control. In this preliminary study a slight difference between normal and possible carriers was also found.


Prevalence and clinical features of adverse food reactions in Portuguese adolescents.
The objective of the present study was to determine, for the first time, the prevalence and clinical features of food allergy in Portuguese adolescents. Cross-sectional study performed in various secondary schools in central Portugal. Randomly selected adolescents replied to a validated food allergy questionnaire. Those who reported an adverse food reaction were seen at participating hospitals, where clinical history was taken, skin prick (SPT) and prick-prick skin (SPPT) tests were performed, and food allergen-specific IgE levels (sIgE) were determined. An open oral challenge was performed in selected cases. Cases of positive clinical history of immediate (up to 2 h after ingestion) reaction in association with positive food sIgE levels and/or SPT were classified as IgE-associated probable food allergy and as confirmed IgE-mediated food allergy if food challenges were positive. Cases of positive clinical history of delayed (more than 2 h after ingestion) and negative food sIgE levels independently of positive SPT or SPPT results, were classified as non-IgE associated probable food allergy. The prevalence of probable food allergy in Portuguese adolescents was 1.41% (95% CI: 0.90-2.03%), with fresh fruits, shellfish, nuts, and peanut as the most frequently implicated foods. IgE-mediated probable food allergy occurred in 1.23% (95% CI: 0.67-1.72%) of cases, with fresh fruits, shellfish, and nuts mainly involved. Cutaneous symptoms were most frequently reported. The prevalence of probable food allergies in Portuguese adolescents is low, is mostly related to fresh fruits, shellfish, nuts, and peanut, and most frequently involves cutaneous symptoms.


Insomnia disorder in adolescence: Diagnosis, impact, and treatment.
Insomnia disorder is very common in adolescents; it is particularly manifest in older adolescents and girls, with a prevalence comparable to that of other major psychiatric disorders (e.g., depressive disorders). However, insomnia disorder in adolescence is poorly characterized, under-recognized, under-diagnosed, and under-treated, and the reason for the female preponderance for insomnia that emerges after puberty is largely unknown. Insomnia disorder goes beyond an individual complaint of poor sleep or a sleep state misperception, and there is emerging evidence supporting the association of insomnia symptoms in adolescents with alterations in several bio-systems including functional cortical alterations and systemic inflammation. Insomnia disorder is associated with depression and other psychiatric disorders, and is an independent risk factor for suicidality and substance use in adolescents, raising the possibility that treating insomnia symptoms in early adolescence may reduce risk for these adverse outcomes. Cognitive behavioral treatments have proven efficacy for adolescent insomnia and online methods seem to offer promising cost-effective options. Current evidence indicates that insomnia in adolescence is an independent entity that warrants attention as a public health concern in its own right.


C6-peptide serology as diagnostic tool in neuroborreliosis.
The aim of this study was to evaluate the usefulness of borrelia serology (Quick ELISA C6 Borrelia assay kit) as a diagnostic tool in cases of suspected neuroborreliosis. A retrospective patient material consisting of 124 paired serum and cerebrospinal fluid samples with a positive anti-borrelia antibody index (AI) using the IDEIA Lyme Neuroborreliosis test was compared with 124 AI-negative matched control subjects. The patients were divided into four groups based on presence of pleocytosis and age above or below 12 years. The presence of positive C6 serology in AI-positive patients with pleocytosis was 89% (83/93), significantly different (p<0.01) from in patients without pleocytosis (58%, 18/31). In AI-positive patients aged > or =12 years with pleocytosis, 94% (51/54) had a positive C6 serology. Of AI-positive patients with a symptom duration of more than 30 days, 93% (27/29) were positive by the C6 test. We conclude that the C6 serum test, together with clinical evaluation, is a powerful diagnostic tool in adult (> or =12 years) European patients with suspected neuroborreliosis with a symptom duration of more than 30 days. Patients with suspected neuroborreliosis and positive C6 results should be further investigated by lumbar puncture for definite diagnosis.


Percutaneous Ultrasound-Guided Release of the Lacertus Fibrosus for Median Nerve Entrapment at the Elbow.
The aim of this technical note is to present a microinvasive percutaneous ultrasound-guided release of the lacertus fibrosus of the biceps brachii for pronator syndrome, i.e., entrapment of the median nerve at the elbow. Fifteen consecutive patients were included. Patients showed isolated pronator syndrome including pain plus reduced strength of specific median nerve innervated muscles. The release was performed in a non-operating interventional room under wide-awake local anesthesia no tourniquet (WALANT). It was conducted superficial to the pronator teres with in-plane ultrasound guidance. The recovery of strength was first assessed peroperatively, and then systematic visits at postoperative weeks 1 and 4 included assessments of both strength and pain. Procedures were comfortably completed with no immediate surgical or anesthetic complication. Muscle strength returned immediately and persisted at postoperative visits. Visual analog scores for pain reduced from 6.2 to 2.5 and 0.6 at weeks 1 and 4, respectively. All working patients were able to perform in their professional activities at week 1. The millimetric skin incision healed with no hypertrophic scar tissue. A small hematoma occurred at week 1 and resorbed spontaneously. No other delayed complication was observed. The procedure appeared effective with improved invasiveness compared to existing techniques. Real-time monitoring with ultrasound may improve the safety. The technique could be regarded as a new ultrasound-guided alternative to surgery. Performed superficial to the pronator teres muscle under WALANT anesthesia, the microinvasive percutaneous ultrasound-guided release of the lacertus fibrosus may be an effective treatment of pronator syndrome.


Polysialic acid is associated with sodium channels and the neural cell adhesion molecule N-CAM in adult rat brain.
We have studied alpha 2,8-linked polysialic acid (polySia) and the neural cell adhesion molecule (N-CAM) in the adult rat brain by immunohistochemistry and Western blot analysis. Both molecules were widely distributed but not ubiquitous. Various brain regions showed colocalization of polySia and N-CAM. Strong immunoreactivity for polySia was seen in regions which were negative for N-CAM, such as the main and accessory olfactory bulbs. Immunohistochemical evidence for the heterogeneity of polySia expression in different brain regions was confirmed by immunoblotting. We present evidence that N-CAM is not the only polySia bearing protein in adult rat brain. Specifically, immunoprecipitation using the polySia-specific monoclonal antibody mAb 735 precipitated not only N-CAM isoforms carrying polySia, but also the sodium channel alpha subunit. Immunoblotting using sodium channel alpha subunit antibody (SP20) revealed a smear from 250 kDa upwards. PolySia removal using an endoneuraminidase specific for alpha 2,8-linked polysialic acid of 8 or more residues long, reduced this smear to a single band at 250 kDa. Thus both N-CAM and sodium channels carry homopolymers of alpha 2,8-linked polysialic acid in adult rat brain.


The cutaneous silent period in motor neuron disease.
To investigate the cutaneous silent period (CSP) by measuring its onset latency, duration and amount signal suppression in patients with motor neuron disease (MND) grouped according to the intensity of upper motor neuron involvement (UMN), and to test the effect of contralateral hand contraction. Painful stimulation was applied at the V finger, and contraction recorded from the abductor digiti minimi (ADM) muscle (baseline condition). Afterwards, CSP was studied during strong contralateral ADM contraction (test condition). 10-15 consecutive traces were recorded for each condition, signals were rectified, averaged, and analyzed offline. 46 patients were investigated, 15 with progressive muscular atrophy (PMA), 16 with typical amyotrophic lateral sclerosis (ALS), 15 with primary lateral sclerosis/predominant UMN-ALS (PLS+UMN-ALS), and 28 controls. In the baseline condition, all MND groups showed delayed onset latencies (p = 0.001). There was no significant difference in the CSP duration. Suppression was lower in the PLS + UMN-ALS group (p = 0.004). In the control group, contralateral contraction did not change CSP, but onset latency shortened significantly in the PMA group. CSP onset latency is delayed in all investigated groups of MND, including in PMA, indicating subclinical UMN involvement. Changes in CSP can indicate UMN lesion in MND. CSP should be explored to identify UMN involvement in MND.


Selective IgA deficiency: clinical and laboratory features of 118 children in Turkey.
Selective IgA deficiency (IgAD) is considered as the most common primary immunodeficiency. Although the vast majority of affected individuals are asymptomatic, symptomatic patients suffer from recurrent infections, allergies and autoimmune diseases. In the present study, we aimed to investigate the clinical and laboratory features of children with IgAD in a tertiary children's hospital in Turkey. The medical records of 118 patients (63 males, 55 females) aged 4-18 years (median: 7 years) seen from 2006 to 2011 were retrospectively reviewed. The most common clinical condition was infectious disease (99 patients, 83.9 %), followed by allergic (51 patients, 43.2 %) and autoimmune (20 patients, 17 %) disorders. Serum IgG, IgM and IgE levels were increased in 61 %, 22 % and 37.3 % of patients, respectively. Serum IgG subclasses were measured in 65 patients, and only 4 (6.2 %) patients had IgG2 subclass deficiency. Autoantibodies (ANA, anti-dsDNA, antigliadin IgA and IgG, tissue transglutaminase IgA and IgG, anti-TPO and anti-TG) were evaluated in 84 patients. Autoantibodies were detected in 26 (31 %) patients, only 10 had an autoimmune disorder. Sixty-one patients were followed for more than 6 months (mean: 2 years, range: 0.5-5 years), and none of them resolved during this period. Being the most comprehensive study conducted in Turkey, we believe it has importance in providing significant data on the clinical and laboratory characteristics of children with IgAD.


Enhancement of Production of D-Glucosamine in Escherichia coli by Blocking Three Pathways Involved in the Consumption of GlcN and GlcNAc.
D-Glucosamine is a commonly used dietary supplement that promotes cartilage health in humans. Metabolic flux analysis showed that D-glucosamine production could be increased by blocking three pathways involved in the consumption of glucosamine-6-phosphate and acetylglucosamine-6-phosphate. By homologous single-exchange, two key genes (nanE and murQ) of Escherichia coli BL21 were knocked out, respectively. The D-glucosamine yields of the engineered strains E. coli BL21ΔmurQ and E. coli BL21ΔnanE represented increases by factors of 2.14 and 1.79, respectively. Meanwhile, for bifunctional gene glmU, we only knocked out its glucosamine-1-phosphate acetyltransferase domain by 3D structural analysis to keep the engineered strain E. coli BL21glmU-Δgpa survival, which resulted in an increase in the production of D-glucosamine by a factor of 2.16. Moreover, for further increasing D-glucosamine production, two genes encoding rate-limiting enzymes, named glmS and gna1, were coexpressed by an RBS sequence in those engineered strains. The total concentrations of D-glucosamine in E. coli BL21 glmU-Δgpa', E. coli BL21ΔmurQ', and E. coli BL21ΔnanE' were 2.65 g/L, 1.73 g/L, and 1.38 g/L, which represented increases by factors of 8.83, 5.76, and 3.3, respectively.


[New insights into the molecular mechanisms of evolution: stress increases genetic diversity].
The mechanisms of stress-induced mutagenesis in prokaryotes and realization of reserved (preaccumulated) genetic variation in eukaryotes are considered. In prokaryotes, replication becomes error-prone in stress because of the induction of the SOS response and the inactivation of the mismatch repair system; stress also increases the transposition rate and the efficiency of interspecific gene transfer. In eukaryotes, chaperone HSP90, which restores the native folding of mutant proteins (e.g., signal transduction and morphogenetic proteins) in normal conditions, fails to do so in stress, which leads to abrupt expression of multiple mutations earlier reserved in the corresponding genes. The role of these mechanisms in the evolution of prokaryotes and eukaryotes is discussed.


Does anticoagulation in Eisenmenger syndrome impact long-term survival?
To determine the impact of anticoagulation on survival in Eisenmenger syndrome. The use of anticoagulation for primary prevention of adverse events in patients with Eisenmenger syndrome has been proposed but not studied. Strong arguments have been made both for and against anticoagulation based on the known risk of hemoptysis and pulmonary vascular thrombosis. Retrospective cohort study at a tertiary referral hospital. One hundred forty-four patients with established Eisenmenger physiology all underwent initial laboratory, echocardiographic, and catheterization evaluation after initial referral. We retrospectively identified patients who were started on anticoagulation (AC) and compared them to patients who did not receive anticoagulation therapy (non-AC). Baseline variables were compared between groups, as well as between survivors and nonsurvivors. Analyses of prognostic factors and survival were done using Cox and Kaplan-Meier methods. The primary outcome was death since time of baseline evaluation. We identified 48 anticoagulated and 44 non-anticoagulated patients with Eisenmenger physiology (oxygen saturation 82 ± 9%, PaO(2) 48 ± 8 mm Hg, hemoglobin 18.6 ± 4 g/dL). More atrial septal defect patients were in the AC group, but there were no other baseline differences in clinical, functional, or hemodynamic data. After mean follow-up of 7 ± 5.4 years (range 1-31), 11 patients died in the AC and 10 died in the non-AC group. There was no survival difference between groups (log rank test = 1.78; P is not significant). For the entire cohort, mortality was significantly associated with New York Heart Association class 3-4 (hazard ratio = 4.2), evidence of right heart failure (hazard ratio = 13.6), and a mean corpuscular volume <80 fL (hazard ratio = 3.8). Use of anticoagulation did not impact survival. Bleeding complications occurred in seven (16%) of AC patients, including two fatalities. Anticoagulation had no impact on long-term survival in this limited study. These data may be useful in considering future studies addressing this question.


Anticarcinogenic compounds of olive oil and related biomarkers.
Olive oil, one of the oldest vegetable oils consumed without any refining, is associated with a reduced risk of a number of common cancers. Minor constituents of virgin olive oil have been suggested to be among the major chemopreventive components. A brief overview is presented of recent findings concerning the bioavailability of certain important olive oil minor components including efficient antioxidant polyphenols, the triterpene hydrocarbon squalene and beta-sitosterol, considered as putative nutritional biomarkers, in relation to the incidence of cancer.


Transplantation of human cryopreserved adenomatous and hyperplastic parathyroid tissue to the hypocalcemic nude mouse.
Cryopreserved parathyroid glands from patients operated on for hyperparathyroidism were stored for further auto- or allografting. In an attempt to better use cryopreserved parathyroid glands in humans, we designed a study whose goal was to compare human parathormone (hPTH) secretion from cryopreserved parathyroid glands with regard to tissue histology (adenoma or hyperplasia), mass, and time of storage in hypocalcemic Nude mice and to be able to better use them in humans. A new hypocalcemic experimental model, using parathyroidectomized Nude mice was set up. Hypocalcemic mice received calibrated grafts from human parathyroid glands cryopreserved between 1982 and 1992 originating from 30 patients (15 adenomas, 15 hyperplasias). Each parathyroid was grafted into two mice under the ratio of one mass-unit (12 mg) and three mass-units (36 mg). The hPTH concentration was assessed by an immunoradiometric method 21 days after grafting. The mean cryopreservation time was 677 days (54-3187 days). The time of cryopreservation was identical in the two kinds of tissue (p = 0.88). The hPTH concentration in 59 living mice was 72.2 +/- 271.4 (SD) ng/ml (3-1936 ng/ml). This concentration was 7.1 +/- 4.3 ng/L for adenomas versus 139.4 +/- 378.6 ng/L for hyperplasias (p = 0.003) and 87.1 +/- 352.6 ng/L for one-unit-mass grafts versus 56.7 +/- 152.5 ng/L for three unit-mass grafts (p = 0.824). Hyperplastic glands showed more secretion, which was confirmed in both mass related groups (p = 0.02, p = 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)


Intracorporeal Versus Extracorporeal Neobladder After Robot-assisted Radical Cystectomy: Results From the International Robotic Cystectomy Consortium.
To compare perioperative and oncologic outcomes of intracorporeal (ICNB) and extracorporeal neobladder (ECNB) following robot assisted radical cystectomy (RARC) from a multi-institutional, prospectively maintained database, the International Robotic Cystectomy Consortium (IRCC). A retrospective review of IRCC database between 2003 and 2020 (3742 patients from 33 institutions across 14 countries) was performed (I-79606). The Cochran-Armitage trend test was used to assess utilization of ICNB over time. Multivariate logistic regression models were fit to evaluate variables associated with receiving ICNB, overall complications, high-grade complications, and readmissions after RARC. Kaplan Meier curves were used to depict recurrence-free, disease-specific, and overall survival. Four hundred eleven patients received neobladder, 64% underwent ICNB. ICNB utilization increased significantly over time (P <.01). Patients who received ICNB were readmitted and received neoadjuvant chemotherapy more frequently (36% vs 24%, P = .03, 35% vs 8%, P <.01, respectively). ICNB was associated with older age (OR 1.04, 95% CI 1.01-1.07, P = .001), receipt of neoadjuvant chemotherapy (OR 4.63, 95% CI 2.34-9.18, P <.01), and more recent RARC era (2016-2020) (OR 12.6, 95% CI 5.6-28.4, P <.01). On multivariate analysis, ICNB (OR 5.43, 95% CI 2.34-12.58, P <.01), positive surgical margin (OR 4.88, 95% CI 1.29-18.42, P = .019), longer operative times (OR 1.26, 95% CI 1.00-1.58, P = .048), and institutional annual RARC volume (OR 1.09, 95% CI 1.05-1.12, P <.01) were associated with readmissions. Utilization of ICNB increased significantly over time. Patients who underwent RARC and ICNB had shorter hospital stays and fewer 30-d reoperations but were readmitted more frequently compared to those who underwent ECNB.


Intrathecal cholecystokinin octapeptide attenuates the antinociception and release of immunoreactive Met-enkephalin induced by intraventricular beta-endorphin in the rat.
The effects of cholecystokinin octapeptide (CCK8s) given intrathecally (i.t.) on antinociception and the release of immunoreactive Met-enkephalin in the spinal perfusate induced by intraventricular (i.vt.) injection of beta-endorphin were studied in anesthetized rats. beta-Endorphin (5 micrograms) given i.vt. inhibited the tail-flick response. The inhibition of the tail-flick response induced by beta-endorphin was blocked dose-dependently by CCK8s (0.1-7 micrograms) given i.t. The antagonistic effect of CCK8s on beta-endorphin-induced inhibition was blocked dose dependently by co-intrathecal injection of proglumide (3 and 10 micrograms), a CCK8s receptor antagonist. beta-Endorphin (5 micrograms) given i.vt. elicited a release of immunoreactive Met-enkephalin in the spinal perfusate. Repeated injections of the same dose of beta-endorphin released about the same amount of the immunoreactive Met-enkephalin in the spinal perfusate. CCK8s at concentrations from 1 x 10(-9) to 1 x 10(-6) M added into the spinal perfusate decreased the release of Met-enkephalin induced by beta-endorphin given i.vt. in a dose-dependent manner. The results suggest that CCK8s may attenuate beta-endorphin-induced inhibition of the tail-flick response by inhibiting the release of Met-enkephalin from the spinal cord.


Hypertension exacerbates coronary artery disease in transgenic hyperlipidemic Dahl salt-sensitive hypertensive rats.
The mechanisms underlying the known interaction of two complex polygenic traits, hypertension and hyperlipidemia, resulting in exacerbation of coronary artery disease have not been elucidated. Identification of critical pathways underlying said exacerbation could identify mechanism-based targets for intervention and prevention. To investigate hypertension- atherosclerosis interaction, we studied the inbred transgenic atherosclerosis-polygenic hypertension Dahl salt-sensitive (S) rat model (Tg53), which over-expresses human cholesteryl ester transfer protein (hCETP) in the liver, and exhibits coronary artery disease and decreased survival compared with control non-transgenic Dahl S rats. Using serial-section histopathological and immunohistochemical analyses, we analyzed the coronary artery disease phenotype of Tg53 rats at end-stage marked by cardio-respiratory compromise as the experimental equivalent of acute coronary syndromes, and determined the effects of reduction of blood pressure through low salt diet (0.008% NaCl) on the coronary artery disease phenotype and survival. End-stage Tg53 rats exhibit coronary artery lesions in the proximal right coronary artery system which exhibit "culprit plaque" features such as plaque inflammation, matrix degradation, apoptosis, neovascularization, thrombosis and hemorrhage recapitulating said features and heterogeneity of human coronary "culprit plaques". Comparative analysis of 6 month vs end-stage lesions reveals distinct lesion development profiles of proximal coronary lesions which quickly progress from eccentric non-occlusive foam-cell rich lesions at 6 months to occlusive "culprit plaques", compared with more distal coronary lesions which exhibit occlusive thick-cap atheroma that remain relatively unchanged from 6 months to end stage. Reduction of hypertension through a low-salt (0.008% NaCl) diet increased survival (P < 0.0001) of Tg53 rats and significantly attenuated the coronary artery disease phenotype detected at 10 months of age marked by diminished apoptosis, neovascularization, matrix degradation compared with end-stage lesions detected at <8 months of age. End stage coronary lesions in the Tg53 rats recapitulate many, albeit not all, features of "culprit plaques" in humans supporting proposed paradigms of plaque vulnerability implicating lesion macrophage enrichment, apoptosis, matrix degradation and pathological neovascularization. Comparative time course analysis of coronary lesions reveals that plaques which develop into end-stage "culprit plaques" are distinct from "stable plaques" by location and early lesion morphology, suggesting distinct lesion development and progression pathways. The significant effects of low-salt diet-induced decrease in hypertension on right coronary disease phenotype provides compelling evidence that polygenic hypertension accelerates coronary plaque progression and complication independent of cardiac hypertrophy, and more importantly provides paradigmatic support for public health policy.


Rapid redistribution of thallium-201 post stress testing in a patient with variant angina.
Reperfusion of an ischemic area after stress scanning with 201TI can occur rapidly and early scanning post stress testing is emphasized.


Selectivity mechanism of GRK2/5 inhibition through in silico investigation.
As two representative isoforms of G protein-coupled receptor kinases family, the largest known membrane receptor family, GRK2 and GRK5 are ubiquitously distributed in human heart, brain, lung, kidney, skeletal muscle and other tissues. GRK2 and GRK5 have common functions implicated in the regulation of heart failure, though GRK5 has also been involved in diseases like hypertension, cancer, diabetes and Alzheimer's disease. Therefore, to clarify the selectivity mechanism towards GRK2 and GRK5 will be of great significance for the discovery of effective and selective inhibitors. To this end, the structures and chemical properties of key residues were analyzed among GRK2 and GRK5 derived from their respective protein crystal structures. Furthermore, a combination of multiple computational strategies, including sequence superposition, receptor-ligand docking, molecular dynamics, MM-GBSA calculation, QM/MM approach and pharmacological modeling, were integrated to validated and elucidate their unique binding modes towards highly selective inhibitors. In addition, the specific amino acid distribution within the GRK2/5 target site is also analyzed in this paper, which can guide future research and development of selective inhibitors in a more targeted manner. Overall, our study comprehensively clarifies the selectivity mechanism of GRK2/5 inhibition, thereby providing guidance for further rational design of selective inhibitors targeting GRK2/5.