Immunohistochemistrical and clinicopathological characterization of chronic endometritis.
Chronic endometritis is an elusive entity that is often asymptomatic and undetectable by conventional endometrial biopsy and histological examination. Using immunohistochemistry for full-thickness endometrium, we sought for its clinicopathological features. Two hundred and thirty-four archival endometrial specimens obtained by hysterectomy were immunostained for the plasmacyte marker syndecan-1 to identify chronic endometritis. Endometrial morphology was dated by the standard criteria. The immunoreactive cells were enumerated in 10 non-overlapping endometrial stromal areas. The clinical parameters were obtained from the medical charts. Chronic endometritis was identified in 11.1% of the samples examined. Its occurrence was similar between the proliferative phase and secretory phase. A total of 23.1% of the cases were asymptomatic. Stromal plasmacyte infiltration and morphological delay were more prominent in symptomatic chronic endometritis than in asymptomatic counterpart. Chronic endometritis is a common gynecological pathological condition and more often asymptomatic than ever expected. There was no menstrual cycle-dependent fluctuation in its occurrence.


Reduced concentrations of collagen cross-links are associated with reduced strength of bone.
The known cross-links of bone collagen are derived from lysine and hydroxylysine. The first step in the enzymatic cross-linking process is a deamination by lysyl oxidase producing an aldehyde which then may condense with a lysyl or hydroxylysyl residue of a neighbouring collagen molecule. Some of the resulting divalent aldimine and oxo-imine cross-links may later on be incorporated in trivalent hydroxylysyl-pyridinoline and lysyl-pyridinoline cross-links. In bone collagen prepared from the cancellous bone of vertebral bodies of osteoporotic individuals we found a reduced stability towards acetic acid and pepsin, and a substantial reduction in the concentration of the divalent collagen cross-links compared with sex- and age-matched controls. To what extent do the collagen cross-links influence the mechanical properties of bone? beta-amino-propionitrile (BAPN) irreversibly inhibits the enzyme lysyl oxidase and therefore, the formation of cross-links between the collagen molecules. In the present study female rats, 70 days old, injected subcutaneously two times daily with BAPN (333 mg/kg/day) for 1 month and saline injected control rats were studied. The concentration of the hydroxypyridinium cross-links of femoral mid-diaphyseal cortical bone was determined by HPLC with fluorescence detection and the mechanical properties of the rat femoral diaphyses were analyzed by a materials testing machine. The BAPN injections resulted in a 45% reduction in the concentration of the hydroxypyridinium cross-links and a 31% decrease in the stability of the bone collagen towards acetic acid and pepsin compared with the control rats. No changes were found in ash or collagen concentrations of the cortical bone.(ABSTRACT TRUNCATED AT 250 WORDS)


Synthesis of the glycosylated polypeptide chain of an inducible costimulator on T-cells.
The glycoprotein AILIM/ICOS (Activation inducible lymphocyte immunomediately molecule/Inducible co-stimulator) on T-cells was identified in 1998 as a member of the CD28/CTLA4 family. The three-dimensional structure of the AILIM/ICOS extracellular domain has not been solved, and therefore we have examined the preparation of homogeneous glycosylated polypeptide chains of this domain having two homogeneous N-linked complex type oligosaccharides for use in folding experiments. To synthesize the glycosylated whole polypeptide chain of the AILIM/ICOS extracellular domain, the target polypeptide chain was divided into four segments, each containing a cysteine residue. Those peptide segments were synthesized by conventional SPPS, followed by thioesterification of the C-terminus. The oligosaccharide moiety, a biantennary complex type disialyloligosaccharide, was attached to the cysteine thiol in the peptide backbone using the haloacetamide method. These peptides, as well as a glycosylated peptide, were sequentially coupled by use of native chemical ligation. This process successfully afforded the desired polypeptide chain having homogeneous oligosaccharides.


Commensal E. coli rapidly transfer antibiotic resistance genes to human intestinal microbiota in the Mucosal Simulator of the Human Intestinal Microbial Ecosystem (M-SHIME).
Food-producing animals are indicated as a reservoir of antibiotic resistance genes and a potential vector for transmission of plasmid-encoded antibiotic resistance genes by conjugation to the human intestinal microbiota. In this study, transfer of an antibiotic resistance plasmid from a commensal E. coli originating from a broiler chicken towards the human intestinal microbiota was assessed by using a Mucosal Simulator of the Human Intestinal Microbial Ecosystem (M-SHIME). This in vitro model mimics the human intestinal ecosystem and received a single dose of 109E. coli MB6212, which harbors a plasmid known to confer resistance towards several antibiotics including tetracycline, sulfamethoxazole and cefotaxime. Since the degree of stress imposed by stomach pH and bile acids vary with the consumed meal size, the effect of meal size on E. coli donor survival and on plasmid transfer towards lumen and mucosal coliforms and anaerobes was determined. The administered commensal E. coli strain survived stomach acid and bile salt stress and was able to grow in the colon environment during the timeframe of the experiment (72 h). Transfer of antibiotic resistance was observed rapidly since cultivable transconjugant coliforms and anaerobes were already detected in the lumen and mucosa after 2 h in the simulated proximal colon. The presence of the resistance plasmid in the transconjugants was confirmed by PCR. Differences in meal size and adapted digestion had neither a detectable impact on antibiotic resistance transfer, nor on the survival of the E. coli donor strain, nor on short chain fatty acid profiles. The median number of resistant indigenous coliforms in the lumen of the inoculated colon vessels was 5.00 × 105 cfu/ml [min - max: 3.47 × 104-3.70 × 108 cfu/ml], and on the mucosa 1.44 × 107 cfu/g [min-max: 4.00 × 103-4.00 × 108 cfu/g]. Exact quantification of the anaerobic transconjugants was difficult, as (intrinsic) resistant anaerobic background microbiota were present. QPCR data supported the observation of plasmid transfer in the simulated colon. Moreover, inoculation of E. coli MB6212 had no significant impact on the microbial diversity in the lumen as determined by 16 S ribosomal gene based next generation sequencing on lumen samples. This study demonstrates that a commensal, antibiotic resistant E. coli strain present in food can transfer its antibiotic resistance plasmid relatively quickly to intestinal microbiota in the M-SHIME. The spread and persistence of antibiotic resistance genes and resistant bacteria in our intestinal system is an alarming scenario which might present clinical challenges, since it implies a potential reservoir for dissemination to pathogenic bacteria.


[Clinical observations in electric stimulation of the ear (author's transl)].
For 20 years direct electrical stimulation has been used in cases of severe bilateral hearing loss or complete deafness to mediate acoustic percepts. The relevant literature is reviewed. While these attempts were initially thought to be unphysiological and unsuited for transferring speech, acoustic sensations were successfully conveyed even with the very simple unichannel electrodes through percutaneous signal transfer. Patients fitted with such simple systems were able to hear and distinguish environmental noise and speech, their lip reading as well as their speech improved. Speech discrimination was, however, impossible with such simple implants both on theoretical grounds and in practical terms, because frequency analysis is exclusively based on periodicity (up to 400 Hz). Designing bipolar multichannel electrodes which, when introduced into the scala tympani or the modiolus, produce discrete stimulation of several circumscribed groups of nerve fibers, was the logical consequence of earlier attempts along these lines, Implantation of these systems can be done along the transmeatal, meato-mastoidal or mastoidal approach. The electrodes can be implanted in bundles through the round window or into the modiolus; they can, however, also be introduced individually through several drill holes in the promontory for placement in the scala tympani and vestibuli. This produces a far more differentiated stimulation simulating a tonotopic pattern of stimuli. In addition to periodicity, the place principle can thus be utilized for frequency coding. While their dynamic range is rather poor (15 to 30 dB at best), multichannel systems, in theory, offer substantially more favorable conditions for speech intelligibility. Since current knowledge of speech coding is, however, inadequate, the degree of intelligibility obtainable is still insufficient for everyday life. Inspite of this flaw, such implants as are available today substantially benefit the patients, who are able to establish acoustic communications with their environment by distinguishing environmental noise from speech, to discriminate between male and female voices, to recognize musical rhythms and even to understand a few words. Indications for the implantation of prostheses, the requisite conditions and postoperative training programs are discussed. While cochlear implants are still experimental, they appear to be reasonably justified in selected cases, since they have been well tolerated by all patients treated sofar without causing any complications and since many of the data obtainable can only be collected in humans. It is, however, essential that experimental implantation be exclusively dealt with by specialized teams, which should evaluate such data as are available and translate them into practice as soon as possible. A routine impantation of hearing prostheses is currently unwarranted.


Effect of dexamethasone and testosterone propionate on LH response to gonadoliberin (LRH) in young post-pubertal bulls.
LH and testosterone responses to gonadoliberin (LRH) were studied after previous dexamethasone and testosterone propionate combined treatment (treated group) compared with a single dexamethasone previous treatment (control group) in 12 Montbéliarde bulls aged 15 months. This experiment was performed on two occaisions 6 months apart according to the same schedule. They included each time 6 bulls, treated with intramuscular injections of 400 mg testosterone propionate and 6 hours later 0.25 mg gonadoliberin together with the other 3 bulls. Testosterone propionate did not influence the mean LH response to gonadoliberin although mean testosterone levels before gonadoliberin injection was very low in the controls. These data suggest that (1) the previously reported depressing effect of dexamethasone on LH is not mediated by the low peripheral testosterone level and (2) under the conditions of this study, there is no short term effect of testosterone at the pituitary level.


IAP Guideline on Practicing Safely During COVID-19 Era: Clinics and Small Establishments.
The unprecedented COVID-19 pandemic has had a formidable impact on Indian health care. With no sight of its end as yet, various establishments including the smaller clinics and nursing homes are restarting full operations. Hence, there is the need for recommendations to allow safe practice ensuring the safety of both the heath care worker (HCW) and patients. Indian Academy of Pediatrics organized an online meeting of subject experts on 27 July, 2020. A committee was formed comprising of pediatricians, pediatric and neonatal intensivists, and hospital administrators. The committee held deliberations (online and via emails) and a final consensus was reached by November, 2020. To develop recommendations to provide a safe and practical healthcare facility at clinics and small establishments during COVID times. The key recommendation to practise safely in this setting are enumerated. Firstly, organizing the out-patient department (OPD). Secondly, appropriate personal protective equipment (PPE) to provide protection to the individual. Thirdly, decontamination/disinfection of various common surfaces and equipment to prevent transmission of infection from fomites. Next, maintaining the heating ventilation and air conditioning (HVAC) to provide a stress-free, comfortable, and safe environment for patients and HCWs. Finally, steps to effectively manage COVID-19 exposures in a non-COVID-19 facility. All these measures will ensure safe practice during these unprecedent times in clinics and smaller establishments.


Communication with patients' families in the intensive care unit: A point prevalence study.
We aimed to describe point of care communication encounters with patients' families in centers with open visitation practices. Cross-sectional one-day point prevalence study in 14 Canadian adult intensive care units (ICUs) located in 7 academic and 7 community hospitals with open family visitation policies. ICU bedside nurses working on a randomly selected weekday completed a survey reporting all observed communication between providers and patients' families. Family point of care communication encounters were measured for 146 of 159 patients (92%) admitted to the study ICUs. Most patients had family (98%) with the majority observed visiting on the study date (73%). Of patients with family (n = 143), direct in-person communication occurred 71% of the time, either via participation in rounds (23%), family meetings (24%), and/or informal updates (71%). 43% (n = 62) of families had direct communication with a physician or nurse practitioner. Nurses provided the largest portion of informal bedside updates (83%, n = 85) and supplemented family communication with phone calls (22%, n = 31). There was no communication contact for 13% (n = 19) of families. ICUs adopt multiple ways of communicating with family members of critically ill patients. Significant interactions occur outside of traditional family meetings, in a less formal and more frequent fashion. Our study supports development of tools to support best practices within contemporary communication paradigms to support provider, patients and family needs.


Quality of life and mental health status in patients with lichen planopilaris based on Dermatology Life Quality Index and General Health Questionnaire-28 questionnaires.
Lichen planopilaris (LPP) is a relatively uncommon inflammatory skin condition that causes permanent hair loss. Irreversible hair loss can have a significant psychosocial and psychological impact on patients' lives. Limited studies have assessed the psychological status of patients suffering from LPP, and to our knowledge, none have evaluated patients with LPP as a separate group in this regard. This study aimed to assess the quality of life (QoL) and general health of patients with LPP using the Dermatology Life Quality Index (DLQI) questionnaire and General Health Questionnaire-28 (GHQ-28), respectively. Our study employed a cross-sectional design. In total, 41 patients with LPP attending the follow-up skin clinic at the Razi Hospital in Tehran, Iran were asked to complete the DLQI and GHQ-28. Furthermore, selected demographic information was obtained from patients to evaluate their association with general health and QoL. Forty-one patients (14 men and 27 women) with a mean age of 44.02 ± 10.8 years completed both questionnaires. QoL was affected moderately to extremely in 70.7% of patients. Also, 26 patients (63.4%) were at risk for psychological disorders. Lower QoL was reported by patients age <45 years (p < .05). Both QoL and general health had a negative relation with the disease activity index (p < .05), but were not affected by sex, marital status, education level, treatment type, presence of mucous lesions, and disease duration. LPP significantly affects patients' QoL and general health. Dermatologists should address these issues in patients with LPP alongside treating physical symptoms.


Lyophilized ophthalmologic patches as novel corneal drug formulations using a semi-solid extrusion 3D printer.
3D printing technology is a novel and practical approach for producing unique and complex industrial and medical objects. In the pharmaceutical field, the approval of 3D printed tablets by the US Food and Drug Administration has led to other 3D printed drug formulations and dosage forms being proposed and investigated. Here, we report novel ophthalmologic patches for controlled drug release fabricated using a semi-solid material extrusion-type 3D printer. The patch-shaped objects were 3D printed using hydrogel-based printer inks composed of hypromellose (HPMC), sugar alcohols (mannitol, xylitol), and drugs, then freeze-dried. The viscous properties of the printer inks and patches were dependent on the HPMC and sugar alcohol concentrations. Then, the physical properties, surface structure, water uptake, antimicrobial activity, and drug release profile of lyophilized patches were characterized. Lyophilized ophthalmologic patches with different dosages and patterns were fabricated as models of personalized treatments prepared in hospitals. Then, ophthalmologic patches containing multiple drugs were fabricated using commercially available eye drop formulations. The current study indicates that 3D printing is applicable to producing novel dosage forms because its high flexibility allows the preparation of patient-tailored dosages in a clinical setting.


CD209 (DC-SIGN) -336A>G promoter polymorphism and severe acute respiratory syndrome in Hong Kong Chinese.
CD209 (DC-SIGN) is an important C-type lectin which acts a receptor of many pathogens. The single nucleotide polymorphism (SNP) -336A>G in the CD209 promoter has been demonstrated to regulate promoter activity and to be associated with several important infectious diseases, such as human immunodeficiency virus-1 (HIV-1), Mycobacterium tuberculosis, and Dengue fever. CD209 facilitates severe acute respiratory syndrome (SARS)-coronavirus spike protein-bearing pseudotype driven infection of permissive cells in vitro. In keeping with previously published findings, our in vitro studies confirmed that this SNP modulates gene promoter activity. Genetic association analysis of this SNP with clinico-pathologic outcomes in 824 serologic confirmed SARS patients showed that the -336AG/GG genotype SARS patients was associated with lower standardized lactate-dehydrogenase (LDH) levels compared with the -336AA patients (p = 0.014, odds ratio = 0.40). High LDH levels are known to be an independent predictor for poor clinical outcome, probably related to tissue destruction from immune hyperactivity. Hence, SARS patients with the CD209 -336 AA genotype carry a 60% chance of having a poorer prognosis. This association is in keeping with the role of CD209 in modulating immune response to viral infection. The relevance of these findings for other infectious diseases and inflammatory conditions would be worth investigating.


Regenerative therapy in experimental parkinsonism: mixed population of differentiated mouse embryonic stem cells, rather than magnetically sorted and enriched dopaminergic cells provide neuroprotection.
The objective of the study was to develop regenerative therapy by transplanting varied populations of dopaminergic neurons, differentiated from mouse embryonic stem cells (mES) in the striatum for correcting experimental parkinsonism in rats. mES differentiated by default for 7 days in serum-free media (7D), or by enhanced differentiation of 7D in retinoic acid (7R), or dopaminergic neurons enriched by manual magnetic sorting from 7D (SSEA-) were characterized and transplanted in the ipsilateral striatum of 6-hydroxydopamine-induced hemiparkinsonian rats. Neurochemical, neuronal, glial and neurobehavioral recoveries were examined. 7R and SSEA- contained significantly reduced NANOG and high MAP2 mRNA and protein levels as revealed, respectively, by reverse transcriptase-PCR and immunocytochemistry, compared with 7D. Striatal engraftment of 7D resulted in a significantly better behavioral and neurochemical recovery, as compared to the animals that received either 7R or SSEA-. The 7R transplanted animals showed improvement neither in behavior nor in striatal dopamine level. The grafted striatum revealed increased GFAP staining intensity in 7D and SSEA-, but not in 7R cells transplanted group, suggesting a vital role played by glial cells in the recovery. Substantia nigra ipsilateral to the side of the striatum, which received transplants showed more tyrosine hydroxylase immunostained neurons, as compared to 6-hydroxydopamine-infused animals. These results demonstrate that default differentiated mixed population of cells are better than sorted, enriched dopaminergic cells, or cells containing more mature neurons for transplantation recovery in hemiparkinsonian rats.


Suppression of human lymphocyte mitogen response by retroviruses of type D. II. Non-activity of Mason-Pfizer monkey virus versus activity of human cell line derived virus PMFV.
In contrast to the human cell line derived type D retrovirus PMFV, the Mason-Pfizer monkey virus (MPMV) does not suppress the mitogen response of normal human lymphocytes. Both viruses have been propagated on the same cell lines and purified by the same methods. MPMV did not contain a factor able to abolish PMFV-induced suppression of the mitogen response. Neither could MPMV suppress the mitogen response of lymphocytes from rhesus monkeys or baboons. PMFV however inhibited their reactivity.


The Ca2+/Mg2+ sites of troponin C modulate crossbridge-mediated thin filament activation in cardiac myofibrils.
The Ca(2+)/Mg(2+) sites (III and IV) located in the C-terminal domain of cardiac troponin C (cTnC) have been generally considered to play a purely structural role in keeping the cTnC bound to the thin filament. However, several lines of evidence, including the discovery of cardiomyopathy-associated mutations in the C-domain, have raised the possibility that these sites may have a more complex role in contractile regulation. To explore this possibility, the ATPase activity of rat cardiac myofibrils was assayed under conditions in which no Ca(2+) was bound to the N-terminal regulatory Ca(2+)-binding site (site II). Myosin-S1 was treated with N-ethylmaleimide to create strong-binding myosin heads (NEM-S1), which could activate the cardiac thin filament in the absence of Ca(2+). NEM-S1 activation was assayed at pCa 8.0 to 6.5 and in the presence of either 1mM or 30 μM free Mg(2+). ATPase activity was maximal when sites III and IV were occupied by Mg(2+) and it steadily declined as Ca(2+) displaced Mg(2+). The data suggest that in the absence of Ca(2+) at site II strong-binding myosin crossbridges cause the opening of more active sites on the thin filament if the C-domain is occupied by Mg(2+) rather than Ca(2+). This finding could be relevant to the contraction-relaxation kinetics of cardiac muscle. As Ca(2+) dissociates from site II of cTnC during the early relaxing phase of the cardiac cycle, residual Ca(2+) bound at sites III and IV might facilitate the switching off of the thin filament and the detachment of crossbridges from actin.


Bacterial vaginosis and intraamniotic infection.
We sought to determine the predictors of intraamniotic infection with use of the presence or absence of vaginal microbes and clinical variables. Vaginal fluid was collected and analyzed on 936 of 2711 (35%) consecutive patients who were delivered over a 7-month period. Subjects were followed up prospectively for the development of intraamniotic infection. Intraamniotic infection was defined as an intrapartum fever > 37.8 degrees C plus at least two of the five following variables: maternal or fetal tachycardia, leukocytosis, tender uterus, or foul-smelling amniotic fluid. Bacterial vaginosis score and the presence or absence of aerobic vaginal organisms were independent microbial variables. Demographic, maternal, labor, and delivery characteristics were independent clinical variables. Stepwise logistic regression analysis was used to develop adjusted odds ratios for predicting intraamniotic infection (expressed as odds ratio [95% confidence interval]). Selection bias and microbiologic reliability were measured. A bacterial vaginosis score of 7 to 10 (odds ratio 1.7, [95% confidence interval 1.0 to 3.9]), nulliparity (2.1 [1.3 to 3.4]), each hour of internal fetal electrode (1.2 [1.0-1.3]); and, each vaginal examination (1.7 [1.0-3.9]) were predictors of intraamniotic infection. Selected aerobic vaginal organisms such as group B streptococci or gram-negative rods were not predictive. Reanalysis with a bacterial vaginosis score > or = 4 revealed similar predictors of intraamniotic infection. Bacterial vaginosis had an adjusted odds ratio of 1.85 (1.16 to 2.9). Selected higher risk populations, vaginal examinations > or = 6 (n = 365), or rupture of membranes > or = 7 hours (n = 421) did not change the risk of a bacterial vaginosis score > or = 4 (adjusted odds ratio 1.87 and 1.98, respectively). Abnormal vaginal flora combines with clinical variables to increase the risk of intraamniotic infection.


Liver microsomal levels of cytochrome P450IA1 as biomarker for exposure and bioavailability of soil-bound polycyclic aromatic hydrocarbons.
The bioavailability of soil-bound polycyclic aromatic hydrocarbons (PAHs) for mammalian species was studied with rats fed with a diet containing contaminated soil preparations. The extent of cytochrome P450IA1 (CYP1A1) induction in the liver correlated with the amount of 5- and 6-ring PAHs in the soil samples but not with the total PAH content. Other cytochromes P450 were much less affected by the soil-contaminants. The highest induction of CYP1A1 was obtained with a sample containing 274 mg 5- and 6-ring PAH/kg soil, resulting in a nearly 360-fold increase in the ethoxyresorufin deethylase (EROD) activity. In a semilogarithmic plot, a linear correlation was found between the 5- and 6-ring PAH concentration in the soil and the microsomal CYP1A1 content. As a model for the action of intestinal fluids, soil samples were extracted by bile acid solution. In these experiments, the selectivity in the solubilization of individual PAHs parallels that of toluene extraction, although the yield is lower than the latter and varies with the soil sample. The bioavailability of PAHs for microorganisms, but not for mammals, was shown to be considerably reduced in the presence of high total organic carbon (TOC) values of the soil samples. This may have implications for decontamination strategies, diminishing the effectiveness of biological decontamination in cases with high TOC values. The data suggest that CYP1A1 induction in rats is a parameter that may be useful in risk assessments of contaminated soils for mammalian species.


Laparoscopic uterovaginal anastomosis in patients with congenital cervicovaginal atresia: An institutional experience with 23 patients.
To introduce our experience of laparoscopic uterovaginal anastomosis and operative outcomes following this technique and update the clinical management of congenital cervicovaginal atresia. Between March 2015 and January 2019, twenty-three patients with congenital cervicovaginal atresia underwent laparoscopic uterovaginal anastomosis and Luohu procedure. Their clinical characteristics, surgical outcomes and follow-up data were retrospectively reviewed. The mean ± SD age of the cases was 16.4 ± 4.0 (11-26) years. All patients had a history of primary amenorrhea and cyclical abdominal pain, and the average delay in diagnosis from first symptoms was 33.5 ± 38 (1-156) months. Most of the patients had 1-3 cm long vaginal pouch. The operative procedure lasted 125 ± 32 (80-190) min. The average vaginal length at 1 month was 7.9 ± 1.3 (range 6-9) cm. All patients showed resumption of menstruation. The patients were followed for a mean of 27 ± 13 (12-56) months. During the follow-up, cervical stenosis did not occur in any of the cases. Laparoscopic uterovaginal anastomosis with Luohu procedure provided a minimally invasive, safe, and effective surgical option for the patients with congenital cervicovaginal atresia. The technique is uncomplicated, easy to learn and perform, and provides a functional and anatomic satisfactory result. No special surgical instruments are required with this technique.


Epilepsy across the spectrum: promoting health and understanding. A summary of the Institute of Medicine report.
Approximately 1 in 26 people will develop epilepsy at some point in their lives. Although epilepsy is one of the nation's most common neurological disorders, public understanding is limited. A complex spectrum of disorders, epilepsy affects an estimated 2.2 million people in the United States. Living with epilepsy is about more than just seizures; it is often defined in practical terms, such as challenges, uncertainties, and limitations in school, social situations, employment, driving, and independent living. People with epilepsy are also faced with health and community services that are fragmented, uncoordinated, and difficult to obtain. The Institute of Medicine's report (2012) [1], Epilepsy across the spectrum: promoting health and understanding, examines the public health dimensions of epilepsy with a focus on (a) public health surveillance and data collection and integration; (b) population and public health research; (c) health policy, health care, and human services; and (d) education for providers, people with epilepsy and their families, and the public. The report's recommendations range from the expansion of collaborative epilepsy surveillance efforts to the independent accreditation of epilepsy centers, to the coordination of public awareness efforts, and to the engagement of people with epilepsy and their families in education, dissemination, and advocacy activities. Given the current gaps in epilepsy knowledge, care, and education, there is an urgent need to take action-across multiple dimensions-to improve the lives of people with epilepsy and their families. The realistic, feasible, and action-oriented recommendations in this report can help enable short- and long-term improvements for people with epilepsy.


Novel diagnostic approach for amoebic liver abscess using cell free (cf) DNA: a prospective study.
Amoebic liver abscess (ALA) is commonly seen in tropical countries and diagnosis of ALA relies mainly on non-specific serological and imaging techniques as well as PCR from pus. This study evaluated the potential of using cell free DNA (cfDNA) from serum and urine for diagnosing ALA. We prospectively evaluated quantitative PCR (qPCR) for detection of cf DNA in serum and urine sample in all liver abscess patients. The samples were collected from patients reporting to emergency ward of Postgraduate Institute of Medical Education and Research, Chandigarh, India with symptoms suggestive of liver abscess. Real time PCR was done to detect cf DNA in serum and urine by targeting 99-bp unit of small subunit rRNA of Entamoeba histolytica and conventional PCR for pus. A total 113 samples (serum and urine) and 100 pus samples were analysed. A total of 62 ALA patients were confirmed; with maximum 57 patients detected by qPCR for cfDNA in the serum, 55 patients by PCR on pus aspirate and 50 ALA patients by qPCR for cfDNA in urine sample. Therefore, the sensitivity of qPCR for detection of cf DNA in serum was 91.94% and for urine was 80.65%. A total of 11.2% of ALA patients were diagnosed only through detection of E. histolytica cf DNA in their serum and urine. Detection of cfDNA from serum, urine of ALA has a potential role in future especially for developing countries as it is a rapid, sensitive and patient friendly diagnostic approach.


Localization of cells producting thyroid stimulating hormone in the pituitary gland of the domestic drake.
Cells binding anti-bovine TASH beta serum were found exclusively in the rostral lobe of the adenohypophysis of the drake using the peroxidase-antiperoxidase complex unlabelled antibody method. The specificity of the binding of the anti-serum to TSH cells was established by relating the morphology and relative abundance of immunochemically stained cells to the TSH content of the adenohypophysis after experimentally altering the activity of the pituitary-thyroid axis. The TSH activity of the adenohypophysis was assessed indirectly, by the weight of the thyroid glands, and directly, by bioassay. As determined by bioassay, the TSH content of the rostral lobe of the adenohypophysis was much greater than that of the caudal lobe. Compared with control drakes, immunochemically stained cells in birds fed a goitrogen, methimazole, seemed to be enlarged and were closer together, while the stained cells in drakes injected with thyroxine were shrunken and less intensely stained. The TSH content of the adenohypophysis was increased in drakes fed methimazole. Castration did not alter the TSH content of the adenohypophysis or change the morphology of immunochemically stained cells. These observations suggest that in the drake: 1) anti-bovine TSH beta serum binds specifically to TSH cells; 2) the TSH cells occur in the rostral and not in the caudal lobe of the adenohypophysis; and 3) the activity of TSH cells is not inhibited by the feedback effects of gonadal steroids.


Tax on sugary drinks and trends in daily soda consumption by family affluence: an international repeated cross-sectional survey among European adolescents.
The WHO recommends soda taxes to reduce sugar consumption, but the effect across socioeconomic groups is unclear. We assessed 16-y trends in daily soda consumption among adolescents in 4 European countries with a soda tax and 5 comparison countries, by family affluence. Five rounds of the international "Health Behaviour in School-Aged Children" school-based survey were used (school years 2001/2002 to 2017/2018, repeated cross-sectional design). Finland, France, Belgium, and Portugal introduced or updated a soda tax during this period. For comparison, we selected 5 neighboring countries without such a tax. Nationally representative samples of adolescents aged 13 and 15 y (n = 165,521; 51.2% girls) completed a standardized questionnaire, including a question on soda consumption frequency. Using the family affluence scale (FAS), we categorized adolescents into lower-, middle- or higher-affluent groups. Changes in daily soda consumption were assessed in each country independently. Before taxation, daily soda consumption was more likely among lower-affluent adolescents in France and Belgium (P < 0.001, socioeconomic inequalities) and was similar across FAS groups in Finland and Portugal (no inequalities). After the tax, daily soda consumption was reduced across all FAS groups in Finland, Belgium, and Portugal (Pinteractions ≥ 0.33). In France, a posttax decrease was observed only among lower-affluent adolescents (ORlower, 0.76; 95% CI: 0.60, 0.96; reduced inequalities). During the same periods, socioeconomic patterns remained stable in 3 comparison countries (Pinteractions ≥ 0.38), and larger reductions in daily soda consumption were observed among middle- or higher-affluent adolescents compared with lower-affluent adolescents in the remaining 2 comparison countries (Pinteractions ≤ 0.08, increased inequalities). Socioeconomic patterns did not change after the tax implementation in 3 out of 4 countries, and socioeconomic inequalities were reduced in France. Taxing sodas might be an effective measure to attenuate, or at least not exacerbate, socioeconomic inequalities in adolescent daily soda consumption. Am J Clin Nutr 20XX;xx:xx-xx.


Limb movements of another pedestrian affect crossing distance but not path planning during virtual over ground circumvention.
Circumventing another pedestrian is a frequent daily activity. The literature has provided a better understanding about anticipatory locomotor adjustments based on global (whole body) movement, but how local limb movements of another pedestrian affect one's circumvention is not well known. The purpose of this study was to understand how local limb movements of another pedestrian affect the planning and execution to circumvent them. Ten healthy young adults (24.5 ± 3.0 years) were immersed in a virtual environment representing a shopping mall. Participants walked to a shop located directly in front of them while circumventing a virtual agent which, when present, approached from straight ahead with one of four different locomotor patterns: 1-Normal locomotor movements; 2- No arm movements; 3- No leg movements; 4- No arm and leg movements (gliding to them). Circumvention trajectory, minimum clearance and coordination of head and trunk rotations along with center of mass lateral displacement were examined. Nonparametric Analysis of Longitudinal Data was used to compare variables across the different conditions. Minimum clearance was smaller for normal locomotor movements compared to all other conditions, but coordination of body movements and onset of circumvention trajectory deviations remained unchanged. These results suggest that global body movement is sufficient to plan circumvention trajectories in a predictable avoidance task, but clearance safety margins are influenced by the local limb movements of another pedestrian.


Preliminary Results in 173 Breast Cancer Patients Treated with Post-Lumpectomy MammoSite Single-Lumen Brachytherapy or Multi-Catheter Brachytherapy.
The objective of this study was to report our single-institution results with MammoSite and multi-catheter brachytherapy. Between February 2003 and January 2009, 173 women with unifocal pathological Tis, T1, or T2 (up to 30 mm), N0 or N1 carcinomas of the breast were treated with post-lumpectomy brachytherapy to 34 Gy in 10 fractions over 5-10 days. We treated 137 patients with MammoSite single-lumen balloon brachytherapy, and 36 patients with multi-catheter brachytherapy. Patients with small and/or nonspherical lumpectomy cavities were usually treated with multi-catheter brachytherapy using 4-12 interstitial catheters. Median follow-up was 33 months. Three-year ipsilateral breast tumor control, disease-free, and overall survival rates for MammoSite brachytherapy were 100%, 100%, and 99%, respectively. Similar rates were obtained with multi-catheter brachytherapy. Minimum distances from the planning target volume for plan evaluation to a rib were 10 ± 8 mm (mean ± standard deviation) and 8 ± 4 mm (mean ± standard deviation) for MammoSite brachytherapy and multi-catheter brachytherapy, respectively (p = 0.48). Maximum rib doses were 101 ± 14% (mean ± standard deviation) and 74 ± 10% (mean ± standard deviation) of the prescribed dose for MammoSite brachytherapy and multi-catheter brachytherapy, respectively (p = 0.001). Multi-catheter brachytherapy results in more conformal radiation dose delivery and a significantly lower rib dose than MammoSite single-lumen brachytherapy. Long-term follow-up is needed to determine if the delivery of a lower radiation dose to the ribs will translate into a lower incidence of rib pain and fractures.


Microphotometric determination of enzymes in brain sections. III. Glutamate dehydrogenase.
An incubation medium was established for the microphotometric demonstration of glutamate dehydrogenase (Gldh) in cryostat sections of the rat hippocampus which served as an exemplary brain region. The final incubation medium consisted of 100 mM L-glutamic acid monosodium salt, 5 mM NAD, 10 mM sodium azide (NaN3), 5 mM ADP, 20 mM sodium chloride, 0.15 mM phenazine methosulfate (PMS), 5 mM nitroblue tetrazolium chloride and 22% polyvinyl alcohol (PVA) in 0.05 M Hepes buffer; the final pH was 7.5. The study showed that in the histochemical demonstration of Gldh the use of relatively high PVA concentrations were necessary to avoid diffusion artefacts because Gldh seems to be only loosely bound to the mitochondrial matrix. The use of NaN3 as a blocker of the respiratory chain was indispensible, because without NaN3 most reduction equivalents were lost through the respiratory chain. With PMS as an exogenous electron carrier, the demonstrable Gldh activities increased significantly indicating that, in the case of Gldh, the endogenous NADH tetrazolium reductase was not sufficiently effective. Furthermore, it was shown that Gldh was affected by many small molecules (e.g. activation by sodium ions, inhibition by magnesium and calcium ions) so that minor variations of the incubation conditions may cause major differences in demonstrable activities.


Not all Whipple procedures are equal: Proposal for a classification of pancreatoduodenectomies.
Pancreatoduodenectomy is the standard treatment for pathologies of the pancreatic head and is performed routinely worldwide. The aim of the study was to analyze this procedure in terms of extent of surgery, technical difficulty, and clinical outcomes and thereby provide a standardized surgical categorization of pancreatoduodenectomies for future reference. For this cohort study, all patients who underwent pancreatoduodenectomy at a single center within an 18-year period (October 2001 to December 2019) were identified in a prospectively maintained database. Based on technical difficulty and extent of surgery, 4 pancreatoduodenectomy types were proposed: (1) standard pancreatoduodenectomy; (2) pancreatoduodenectomy with portal vein/superior mesenteric vein resection; (3) pancreatoduodenectomy with multivisceral resection; and (4) pancreatoduodenectomy with arterial resection. Patient characteristics, surgical parameters, and perioperative morbidity and mortality were analyzed. The 4 types were compared with regard to their surgical outcomes. A total of 3,953 pancreatoduodenectomies were performed in the study period. Standard pancreatoduodenectomy (type 1) was the most frequent procedure (n = 2,931, 74.1%), followed by pancreatoduodenectomy with portal vein/superior mesenteric vein resection (type 2: n = 568, 14.4%), pancreatoduodenectomy with multivisceral resection (type 3: n = 415, 10.5%), and pancreatoduodenectomy with arterial resection (type 4: n = 39, 1.0%). Demographic baseline characteristics were clinically comparable among pancreatoduodenectomy types. Mortality within 90-days correlated with the type of pancreatoduodenectomy (type 1: 2.9%; type 2: 4.2%; type 3: 6.3%; type 4: 10.3%; P = .0007). Overall surgical morbidity was 41.7% (type 1), 40.8% (type 2), 52.5% (type 3), and 59.0% (type 4) (P < .0001), including postoperative pancreatic fistula type B/C (type 1: 11.9%; type 2: 7.7%; type 3: 14.7%; type 4: 15.4; P = .0031) and delayed gastric emptying (type 1: 19.4%; type 2: 22.5%; type 3: 22.0%; type 4: 25.6%; P = .187) as the most frequent complications. Relaparotomies were more frequent in type 4 (20.5%) and type 3 (20.6%) than in type 2 (12.0%) or type 1 (10.4%) pancreatoduodenectomy (P < .0001). Intensive care unit stay ≥2 days was more frequent in type 4 (48.7%) compared with type 3 (25.7%) or type 2 (27.1%) and type 1 (18.6%) (P < .0001). The results show different clinical outcomes for the 4 types of pancreatoduodenectomy. Morbidity and mortality correlate with pancreatoduodenectomy type. The proposed pancreatoduodenectomy classification is useful for reporting pancreatoduodenectomy procedures, enhances the comparability of future studies, may be used for training purposes, and may guide intra and postoperative decision-making.


Joint epitope selection and spacer design for string-of-beads vaccines.
Conceptually, epitope-based vaccine design poses two distinct problems: (i) selecting the best epitopes to elicit the strongest possible immune response and (ii) arranging and linking them through short spacer sequences to string-of-beads vaccines, so that their recovery likelihood during antigen processing is maximized. Current state-of-the-art approaches solve this design problem sequentially. Consequently, such approaches are unable to capture the inter-dependencies between the two design steps, usually emphasizing theoretical immunogenicity over correct vaccine processing, thus resulting in vaccines with less effective immunogenicity in vivo. In this work, we present a computational approach based on linear programming, called JessEV, that solves both design steps simultaneously, allowing to weigh the selection of a set of epitopes that have great immunogenic potential against their assembly into a string-of-beads construct that provides a high chance of recovery. We conducted Monte Carlo cleavage simulations to show that a fixed set of epitopes often cannot be assembled adequately, whereas selecting epitopes to accommodate proper cleavage requirements substantially improves their recovery probability and thus the effective immunogenicity, pathogen and population coverage of the resulting vaccines by at least 2-fold. The software and the data analyzed are available at https://github.com/SchubertLab/JessEV. Supplementary data are available at Bioinformatics online.


Large-Area Crystalline Zeolitic Imidazolate Framework Thin Films.
We report that continuous MOF films with highly controlled thickness (from 44 to 5100 nm) can be deposited over length scales greater than 80 centimeters by a facile, fast, and cost-effective spray-coating method. Such success relies on our discovery of unprecedented perfectly dispersed colloidal solutions consisting of amorphous MOF nanoparticles, which we adopted as precursors that readily converted to the crystalline films upon low-temperature in situ heating. The colloidal solutions allow for the fabrication of compact and uniform MOF films on a great deal of substrates such as fluorine-doped tin oxide, glass, SiO2 , Al2 O3 , Si, Cu, and even flexible polycarbonate, widening their technological applications where substrates are essential. Despite the present work focuses on the fabrication of uniform cobalt-(2-methylimidazole)2 and zinc-(2-methylimidazole)2 films, our findings mark a great possibility in producing other high-quality MOF thin films on a large scale.


Kinetics of extracellular ATP from goldfish hepatocytes: a lesson from mathematical modeling.
In goldfish hepatocytes, hypotonic exposure leads to cell swelling, followed by a compensatory shrinkage termed RVD. It has been previously shown that ATP is accumulated in the extracellular medium of swollen cells in a non-linear fashion, and that extracellular ATP (ATPe) is an essential intermediate to trigger RVD. Thus, to understand how RVD proceeds in goldfish hepatocytes, we developed two mathematical models accounting for the experimental ATPe kinetics reported recently by Pafundo et al. in Am. J. Physiol. 294, R220-R233, 2008. Four different equations for ATPe fluxes were built to account for the release of ATP by lytic (J(L)) and nonlytic mechanisms (J(NL)), ATPe diffusion (J(D)), and ATPe consumption by ectonucleotidases (J(V)). Particular focus was given to J(NL), defined as the product of a time function (J(R)) and a positive feedback mechanism whereby ATPe amplifies J(NL). Several J (R) functions (Constant, Step, Impulse, Gaussian, and Lognormal) were studied. Models were tested without (model 1) or with (model 2) diffusion of ATPe. Mathematical analysis allowed us to get a general expression for each of the models. Subsequently, by using model dependent fit (simulations) as well as model analysis at infinite time, we observed that: - use of J(D) does not lead to improvements of the models. - Constant and Step time functions are only applicable when J(R)=0 (and thus, J(NL)=0), so that the only source of ATPe would be J(L), a result incompatible with experimental data. - use of impulse, Gaussian, and lognormal J(R)s in the models led to reasonable good fits to experimental data, with the lognormal function in model 1 providing the best option. Finally, the predictive nature of model 1 loaded with a lognormal J(R) was tested by simulating different putative in vivo scenarios where J(V) and J(NL) were varied over ample ranges.


Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole versus voriconazole after allogeneic hematopoietic cell transplantation.
Aspergillus infections pose the toughest infectious challenges to the clinician caring for hematopoietic cell transplant recipients. About 15% of patients become infected, with a case fatality rate of approximately 65%. To date, no effective prophylactic strategies have been developed. Voriconazole, a recently licensed extended-spectrum azole, with demonstrated efficacy against aspergillus, is currently being tested as a potential prophylactic agent against aspergillus and other invasive fungal infections. Logistic issues--such as patient selection, choice of comparator, blinding of study drugs, duration of study drug administration, and how to handle empirical amphotericin B for possible invasive fungal infections--and analytic concerns, including choice and definition of the primary end point and the potential confounding effect of informative censoring (as a result of noninfectious events), were considered in the design of the clinical trial. The trial is now under way, with a projected 3-year enrollment period. Each design decision shaped the trial in a way that permitted certain questions to be answered while not allowing others to be addressed. Once completed, the trial's results must be interpreted in light of these design details.


The comparative effectiveness and cost-effectiveness of ranibizumab for neovascular macular degeneration revisited.
To compare a near decade of follow-up, newer control cohort data, use of both the societal and third party insurer cost perspectives, and integration of unilateral/bilateral therapy on the comparative effectiveness and cost-effectiveness of intravitreal ranibizumab therapy for neovascular, age-related macular degeneration (AMD). Value-Based Medicine®, 12-year, combined-eye model, cost-utility analysis employing MARINA and HORIZON clinical trial data. Preference-based comparative effectiveness outcomes were quantified in (1) QALY (quality-adjusted life-year) gain, and (2) percent improvement in quality-of-life, while cost-effectiveness outcomes were quantified in (3) the cost-utility ratio (CUR) and financial return-on-investment (ROI) to society. Using MARINA and HORIZON trial data and a meta-analysis control cohort after 24 months, ranibizumab therapy conferred a combined-eye patient value (quality-of-life) gain of 16.3%, versus 10.4% found in 2006. The two-year direct ophthalmic medical cost for ranibizumab therapy was $46,450, a 33.8% real dollar decrease from 2006. The societal cost perspective CUR was -$242,920/QALY, indicating a $282,517 financial return-on-investment (ROI), or 12.3%/year to society for direct ophthalmic medical costs expended. The 3rd party insurer CUR ranged from $21,199/QALY utilizing all direct, medical costs, to $69,591/QALY using direct ophthalmic medical costs. Ranibizumab therapy for neovascular AMD in 2015, considering treatment of both eyes, conferred greater patient value gain (comparative effectiveness) and improved cost-effectiveness than in 2006, as well as a large monetary return-on-investment to the Gross Domestic Product and nation's wealth. The model herein integrates important novel features for neovascular age-related macular degeneration, vitreoretinal cost effectiveness analyses, including: (1) treatment of both eyes, (2) a long-term, untreated control cohort, and (3) the use of societal costs.


Redundant Nerve Roots of the Cauda Equina, MRI Findings and Postoperative Clinical Outcome: Emphasizing an Overlooked Entity.
Retrospective study. To describe the MRI findings of RNRs in patients with low back pain, and observe the imaging findings and the clinical outcome post decompression surgery. The lumbar spine MRI of 202 patients (122 females) with proven RNRs were retrospectively reviewed. The morphology and the location of the RNRs in relation to the level of stenosis were described. The level(s), grade and cause of lumbar canal stenosis were recorded. The persistence of symptoms and the imaging findings on follow up post decompression surgery were recorded. The imaging findings were correlated among each other and with patients' demographics. Two distinctive morphological appearance of the RNRs were noted: loop (56.4%), and serpentine-shaped. In the majority of the cases the RNRs were located above the level of stenosis (79.7%). Eighteen patients underwent decompression surgery, only 4 patients remained symptomatic post decompression surgery. The RNRs changed in shape and location after decompression surgery. Age was a strong predictor value in the location of the RNRs. There was no correlation between the shape and location of the RNRs, or with the gender of the patients. RNRs is not an uncommon finding on lumbar spine MRI with lumbar canal stenosis. Its importance remains a controversy. A common language between the radiologists and the clinicians is mandatory to aid in the management planning.


The relationship between renal impairment and left ventricular structure, function, and ventricular-arterial interaction in hypertension.
Our objective was to define the relationship between renal dysfunction--both albuminuria and reduced estimated glomerular filtration rate (eGFR)--and cardiac structure and diastolic dysfunction among patients with chronic hypertension. Both albuminuria and eGFR were measured in 540 asymptomatic patients with hypertension and diastolic dysfunction assessed by reduced early mitral annular relaxation velocity (E'). The majority of patients were white, mean age was 60 ± 10 years, mean SBP was 149 ± 18 mmHg, and there was a low prevalence comorbid conditions. Albuminuria was undetectable in 148 (27%), within the normal to low range [urine albumin-to-creatinine ratio (UACR) 1-25 mg/g for men, 1-17 mg/g for women] in 292 (54%), and high or very high (UACR >25 mg/g for men, >17 mg/g for women) in 100 (19%). Estimated GFR was 60 ml/min per 1.73 m² or less in 75 (14%), 61-90 ml/min per 1.73 m² in 244 (45%), and more than 90 ml/min per 1.73 m² in 221 (41%). Albuminuria, even within the normal range, was associated with greater left ventricular wall thickness (P = 0.01), higher relative wall thickness (P = 0.004), worse diastolic function reflected in lower E' (P = 0.01), greater arterial and left ventricular end-systolic stiffness (P < 0.0001 and P = 0.003, respectively), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) level (P = 0.0025), even after adjustment for differences in baseline characteristics. In contrast, no independent relationship was observed between eGFR and parameters of cardiac structure or function. Among asymptomatic hypertensive patients with evidence of diastolic dysfunction, the presence of albuminuria, even within the normal range, is associated with greater concentric remodeling, greater left ventricular end-systolic stiffness, and worse diastolic function.


Performance of antegrade double-balloon enteroscopy: comparison with push enteroscopy.
Double-balloon enteroscopy (DBE) is a novel procedure for the diagnosis of small-bowel pathology. The aim of this retrospective study was to compare the performance and the diagnostic value of antegrade DBE with those of push enteroscopy (PE). We reviewed endoscopic and histologic findings in 118 patients examined by PE or antegrade DBE during a period 1980 to 2004. The maximal length of insertion under plain radiograph was compared between patients examined by PE and those examined by antegrade DBE. Diagnostic yield was compared among patients stratified by indication for enteroscopy and the duodenal pathology. Ninety-one patients were examined by PE and 27 patients by antegrade DBE. Length of insertion from the ligament of Treitz was significantly greater in antegrade DBE (median, 92 cm; range, 40-144 cm) than in PE (median, 22 cm; range, 0-98 cm; p < 0.0001). In 90 nonbleeding patients with inflammatory or miscellaneous diseases or polyposis, the diagnostic yield was not different between PE and antegrade DBE (64% vs. 82%, p = 0.13). However, it was higher in antegrade DBE (79%) than in PE (31%, p = 0.012) in nonbleeding patients without duodenal pathology. In bleeding patients, the diagnostic yield was 40% in antegrade DBE and 36% in PE (p = 0.61). Antegrade DBE is superior to PE in exploration of the small intestine and in diagnostic yield for small-intestinal pathology.


Role of ethno-phytomedicine knowledge in healthcare of COVID-19: advances in traditional phytomedicine perspective.
Since the outbreak of the COVID-19 virus, ethnomedicinal plants have been used in diverse geographical locations for their purported prophylactic and pharmacological effects. Medicinal plants have been relied on by people around the globe for centuries, as 80% of the world's population rely on herbal medicines for some aspect of their primary health care needs, according to the World Health Organization. This review portrays advances in traditional phytomedicine by bridging the knowledge of ethno-phytomedicine and COVID-19 healthcare. Ethnomedicinal plants have been used for symptoms related to COVID-19 as antiviral, anti-infective, anti-inflammatory, anti-oxidant, antipyretic, and lung-gut immune boosters. Traditionally used medicinal plants have the ability to inhibit virus entry and viral assembly, bind to spike proteins, membrane proteins, and block viral replications and enzymes. The efficacy of traditional medicinal plants in the terms of COVID-19 management can be evaluated by in vitro, in vivo as well as different in silico techniques (molecular docking, molecular dynamics simulations, machine learning, etc.) which have been applied extensively to the quest and design of effective biotherapeutics rapidly. Other advances in traditional phytomedicines against COVID-19 are controlled clinical trials, and notably the roles in the gut microbiome. Targeting the gut microbiome via medicinal plants as prebiotics is also found to be an alternative and potential strategy in the search for a COVID-19 combat strategy. Since medicinal plants are the sources of modern biotherapeutics development, it is essential to build collaborations among ethnobotanists, scientists, and technologists toward developing the most efficient and the safest adjuvant therapeutics against the pandemic of the twenty-first century, COVID-19.


Atrioventricular node functional remodeling induced by atrial fibrillation.
The atrioventricular node (AVN) plays a vital role in determining the ventricular rate during atrial fibrillation (AF). AF results in profound electrophysiological and structural remodeling in the atria as well as the sinus node. However, it is unknown whether AVN undergoes remodeling during AF. To determine whether AVN undergoes functional remodeling during AF. AVN conduction properties were studied in vitro in 9 rabbits with AF and 10 normal controls. A previously validated index of AVN dual-pathway electrophysiology, His-electrogram alternans, was used to monitor fast-pathway or slow-pathway (SP) AVN conduction in these experiments. AVN conduction properties were further studied in vivo in 7 dogs with chronic AF and 8 controls. Compared with the control rabbits, the rabbits with AF had a longer AVN conduction time (83 ± 16 ms vs 68 ± 7 ms; P <.01), longer AVN effective refractory period (141 ± 27 ms vs 100 ± 9 ms; P <.01), an earlier transition from fast-pathway to SP conduction (at a longer prematurity, 249 ± 60 ms vs 171 ± 24 ms; P <.01), and a slower ventricular rate during simulated AF (RR interval 249 ± 42 ms vs 202 ± 12 ms; P <.01). Notably, a larger proportion of conducted beats utilized the SP in AF preparations (92% ± 12% vs 63% ± 32%; P <.05). Long-term AF in dogs resulted in a longer atrioventricular conduction time and AVN effective refractory period and a slower ventricular rate during AF compared with the controls. Pronounced AVN functional electrophysiological remodeling occurs after long-term AF, which could lead to a spontaneous slowing of the ventricular rate. Furthermore, the SP dominance during AF underscores the effectiveness of its modification by ablation for ventricular rate control during AF.


Mechanisms of enhancer action: the known and the unknown.
Differential gene expression mechanisms ensure cellular differentiation and plasticity to shape ontogenetic and phylogenetic diversity of cell types. A key regulator of differential gene expression programs are the enhancers, the gene-distal cis-regulatory sequences that govern spatiotemporal and quantitative expression dynamics of target genes. Enhancers are widely believed to physically contact the target promoters to effect transcriptional activation. However, our understanding of the full complement of regulatory proteins and the definitive mechanics of enhancer action is incomplete. Here, we review recent findings to present some emerging concepts on enhancer action and also outline a set of outstanding questions.


The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on molar and mandible traits in congenic mice: a test of the role of the Ahr locus.
2,3,7,8-Tetracholorodibenzo-p-dioxin is a highly toxic substance that can cause a variety of adverse effects on organisms. While it has been shown that TCDD acts mainly through the aryl-hydrocarbon receptor (AHR), the mechanism of toxicity is not completely clear. To test the role of the AHR in mediating the effects of TCDD, we exposed two congenic strains of mice differing only at the Ahr locus (Ahr(b)/Ahr(b) and Ahr(d)/Ahr(d)) to TCDD (0, 0.01, 0, or 1 microg/kg body weight) in utero on gestation day 13 and examined the developmental effects on mandible and mandibular tooth row size and shape. Our hypothesis was that TCDD would significantly affect one or more of these endpoints in Ahr(b)/Ahr(b) mice, previously shown to be sensitive to the effects of TCDD, while causing little or no effect in mice carrying the less sensitive Ahr(d) allele. At the doses used in this study, TCDD did not alter the size of mandibles or molars in either Ahr(b)/Ahr(b) or Ahr(d)/Ahr(d) mice. However, we did find that the highest dose of TCDD altered mandible shape, but only in Ahr(b)/Ahr(b) (not Ahr(d)/Ahr(d)) male mice. Similarly, the highest dose of TCDD significantly altered molar shape in Ahr(b)/Ahr(b) but not Ahr(d)/Ahr(d) male mice, although females in both congenic strains were affected. These results suggest that the effects of TCDD on molar and mandible shape are influenced by the Ahr genotype but that males and females differ in sensitivity to both of these effects.


Occurrence of D-aspartic acid in human seminal plasma and spermatozoa: possible role in reproduction.
To determine D-aspartic acid (D-Asp) in human seminal plasma and spermatozoa in fertile and infertile donors. Prospective observation study. Department of Pathophysiology for Human Reproduction, Hospital "S. Luca," Salerno, Italy, and Department of Neurobiology and Comparative Physiology, Zoological Station "A. Dohrn," Naples, Italy. Ten normospermic, 10 oligoasthenoteratospermic, and 10 azoospermic (nonobstructive) men. D-aspartic acid was determined by a specific enzymatic high-performance liquid chromatography method on purified seminal plasma and on isolated spermatozoa and by an immunohistochemical method using light and electronic microscopic techniques. Concentration of D-Asp in seminal plasma and in isolated spermatozoa; subcellular localization of D-Asp in the acrosome and nucleus. The concentration of D-Asp in seminal plasma and in spermatozoa was significantly reduced in oligoasthenoteratospermic donors. In the seminal fluid of normospermic donors, D-Asp occurs at a concentration of 80 +/- 12 nmol/mL semen (10.4 +/- 1.5 microg/mL), whereas 26 +/- 6 nmol/mL semen were found in oligoasthenoteratospermic donors, and 12 +/- 1.5 nmol/mL semen were found in azoospermic donors. In spermatozoa from normospermic donors, D-Asp occurred at a concentration of 130 +/-15 fmol per spermatozoa (17.0 +/- 1.96 ng per spermatozoa), vs. 60.5 +/- 5.0 fmol per spermatozoa from oligoasthenoteratospermic subjects. Other D-amino acids analyzed were not present in seminal plasma or in spermatozoa in a significant concentration compared with D-Asp. D-aspartic acid occurs in human seminal plasma and spermatozoa and is implicated in male fertility.


Transanal endoscopic microsurgery--lessons from a single UK centre series.
Transanal endoscopic microsurgery (TEM), a minimally invasive technique has been employed in the excision of benign and selected malignant rectal tumours since 1983. We present a single surgeon's series of 102 procedures. A retrospective case note review of 102 procedures performed over a 6-year period between 1996 and 2001. One hundred and two TEM procedures were performed on 100 patients. 68 for adenomas, 19 potentially curative excisions for carcinoma, 13 palliative procedures for advanced carcinoma and 2 for solitary rectal ulcer syndrome (SRUS). Four adenomas recurred and were successfully treated by various procedures. None went on to develop malignancy, or a further recurrence. Of the cancers, six T1 and 10 T2 were excised with curative intent. Three T3 cancers were excised before endorectal ultrasound was available in the unit and went on to have definitive procedures. One T1 and two T2 carcinomas were not completely histologically excised. These patients were offered definitive procedure and there have been no recurrences. 11 patients underwent palliative TEM procedures, 2 went on to have a recurrence of symptoms. Both underwent a successful second TEM procedure. Although longer term follow up is still required, TEM appears to be an effective method of excising benign tumours and T1 carcinomas of the rectum. The role of TEM in the treatment of T2 carcinomas is, as yet, unclear and needs further evaluation although the results of our series and others are encouraging.


Ureteropyelostomy and ureteroneocystostomy in renal transplantation: postoperative urological complications.
Ureteropyelostomy offers a suitable alternative to ureteroneocystostomy as a primary method of urinary reconstruction after renal transplantation. In a total of 108 such procedures 12 urological complications occurred. Only 1 patient had graft loss directly attributable to these complications.


Rare Giant Angiokeratoma of the Vulva: A Case Report.
Angiokeratoma of fordyce occurring over on the vulva is a rare condition. Fordyce angiokeratoma is observed more frequently among men than women. In women, it is generally observed in later life, and appears as multiple dark purple papules, measuring 2-4 mm, on the vulva. We present the case of a 17-year-old white teenage girl with giant Fordyce angiokeratoma on the right vulva. The angiokeratoma was removed and a V-Y advancement flap was made. In the literature, this is the first childhood case reported in which a reconstruction of the vulva was performed.


Genetic influences of angiotensin-converting enzyme inhibitor response: an opportunity for personalizing therapy?
The angiotensin-converting enzyme (ACE) inhibitors are a cornerstone drug therapy in the current treatment of patients with hypertension, stable coronary artery disease and heart failure. Individualizing therapy of ACE inhibitors with clinical risk factors in low-risk patients with stable coronary artery disease is not feasible. The concept of pharmacogenetics, by studying patient factors more individually, offers a first glimpse in the quest for the 'holy grail' of personalized medicine. As such, genetic targets in the direct pharmacodynamic pathway of ACE inhibitors, the renin-angiotensin-aldosterone system, is a plausible candidate for such an approach. In the past few decades, results of pharmacogenetic studies were scarce and inconsistent. However, recently the first reports of larger pharmacogenetic studies are now confirming that the 'pharmacogenetic approach' might be feasible in the future. The current review focuses on the recent developments in pharmacogenetic research in response to ACE inhibitors in patients with stable coronary artery disease.


Application of neuromuscular electrical stimulation on the support limb during reactive balance control in persons with stroke: a pilot study.
The aim of the present study was to investigate the effect of the application of neuromuscular electrical stimulation to the quadriceps muscle of the paretic limb during externally induced stance perturbations on reactive balance control and on fall outcomes in people with chronic stroke. Ten participants experienced 12 stance treadmill perturbation trails, 6 forward balance perturbation trials and 6 backward balance perturbation trials. For each perturbation condition, three perturbation trials were delivered synchronized with neuromuscular electrical stimulation applied to the quadriceps of the paretic limb and three perturbation trials were delivered without stimulation. Behavioral outcome measures, such as incidence of laboratory falls and number of compensatory steps, kinematic outcome measures, such as margin of stability and minimum hip high values after the perturbation, step initiation time, step execution time and step length of the stepping leg were analyzed. The application of neuromuscular electrical stimulation on the paretic quadriceps between the range of 50 and 500 ms after stance forward and backward perturbations reduced the laboratory falls incidence (p < 0.05), improved stability values (p < 0.05) and reduced the hip height descent (p < 0.05) compared to the experimental condition in which participants were exposed to stance perturbations without neuromuscular electrical stimulation. Additionally, step initiation time of the recovery step was lower in neuromuscular electrical stimulation condition during the forward balance perturbation protocol. Our results showed that the application of neuromuscular electrical stimulation on the knee extensor muscles of the paretic limb reduces the incidence of laboratory falls, enhances reactive stability control and reduces vertical limb collapse after stance forward and backward perturbations in people with chronic stroke.


The direct cost of acute hip fracture care in care home residents in the UK.
Data on the true acute care costs of hip fractures for patients admitted from care homes are limited. Detailed costing analysis was undertaken for 100 patients. Median cost was £9,429 [<euro>10,896], increasing to £14,435 [<euro>16,681], for those requiring an upgrade from residential to nursing home care. Seventy-six percent of costs were attributable to hospital bed days, and therefore, interventions targeted at reducing hospital stay may be cost effective. Previous studies have estimated the costs associated with hip fracture, although these vary widely, and for patients admitted from care homes, who represent a significant fracture burden, there are limited data. The primary aim of this study was to perform a detailed assessment of the direct medical costs incurred and secondly compare this to the actual remuneration received by the hospital. One hundred patients presenting from a care home in 2006 were randomly selected and a detailed case-note costing analysis was undertaken. This cost was then compared to the actual remuneration received by the hospital. Median cost per patient episode was £9,429 [<euro>10,896] (all patients) range £4,292-162,324 [<euro>4,960-187,582] (subdivided into hospital bed day costs £7,129 [<euro>8,238], operative costs £1,323 [<euro>1,529] and investigation costs £977 [<euro>1,129]). Twenty-two percent of the patients admitted from a residential home required upgrading to a nursing home. In this group, the median length of stay was 31 days (mean 38, range 10-88) median cost £14,435 [<euro>16,681]. Average remuneration received equated to £6,222 [<euro>7,190] per patient. This represents a mean loss in income, compared to actual calculated costs of £3,207 [<euro>3,706] per patient. The median cost was £9,429 [<euro>10,896], increasing to £14,435 [<euro>16,681], for those requiring an upgrade from residential to nursing home care at discharge. Significant cost differences were seen comparing the actual cost to remuneration received. Interventions targeted at reducing length of stay may be cost effective.


Human rotavirus strain Wa downregulates NHE1 and NHE6 expressions in rotavirus-infected Caco-2 cells.
Rotavirus (RV) is the most common cause of severe gastroenteritis and fatal dehydration in human infants and neonates of different species. However, the pathogenesis of rotavirus-induced diarrhea is poorly understood. Secretory diarrhea caused by rotavirus may lead to a combination of excessive secretion of fluid and electrolytes into the intestinal lumen. Fluid absorption in the small intestine is driven by Na+-coupled transport mechanisms at the luminal membrane, including Na+/H+ exchanger (NHE). Here, we performed qRT-PCR to detect the transcription of NHEs. Western blotting was employed for protein detection. Furthermore, immunocytochemistry was used to validate the NHE's protein expression. Finally, intracellular Ca2+ concentration was detected by confocal laser scanning microscopy. The results demonstrated that the NHE6 mRNA and protein expressed in the human colon adenocarcinoma cell line (Caco-2). Furthermore, RV-Wa induced decreased expression of the NHE1 and NHE6 in Caco-2 cell in a time-dependent manner. In addition, intracellular Ca2+ concentration in RV-Wa-infected Caco-2 cells was higher than that in the mock-infected cells. Furthermore, RV-Wa also can downregulate the expression of calmodulin (CaM) and calmodulin kinase II (CaMKII) in Caco-2 cells. These findings provides important insights into the mechanisms of rotavirus-induced diarrhea. Further studies on the underlying pathophysiological mechanisms that downregulate NHEs in RV-induced diarrhea are required.


Disruption of Endoplasmic Reticulum Proteostasis in Age-Related Nervous System Disorders.
Endoplasmic reticulum (ER) stress is a prominent cellular alteration of diseases impacting the nervous system that are associated to the accumulation of misfolded and aggregated protein species during aging. The unfolded protein response (UPR) is the main pathway mediating adaptation to ER stress, but it can also trigger deleterious cascades of inflammation and cell death leading to cell dysfunction and neurodegeneration. Genetic and pharmacological studies in experimental models shed light into molecular pathways possibly contributing to ER stress and the UPR activation in human neuropathies. Most of experimental models are, however, based on the overexpression of mutant proteins causing familial forms of these diseases or the administration of neurotoxins that induce pathology in young animals. Whether the mechanisms uncovered in these models are relevant for the etiology of the vast majority of age-related sporadic forms of neurodegenerative diseases is an open question. Here, we provide a systematic analysis of the current evidence linking ER stress to human pathology and the main mechanisms elucidated in experimental models. Furthermore, we highlight the recent association of metabolic syndrome to increased risk to undergo neurodegeneration, where ER stress arises as a common denominator in the pathogenic crosstalk between peripheral organs and the nervous system.


Fine structure of flight muscles in different Notch mutants of Drosophila melanogaster reared at different temperatures.
The fine structure of the indirect flight muscles was studied by electron microscopy in the following Notch locus mutants of Drosophila melanogaster reared at 18° C or 29° C for 6 days after eclosion: Ax 16172/Ax16172, Ax28/ Ax28, l(1)Nts1/l(1)Nts1,l(1)Nts1/Y and in wild-type controls. The flies were raised up to eclosion at 25° C or 18° C. It was observed that the l(1)Nts1 flies gradually became flightless within a few days if reared at 29° C as adults, and gross changes in the fine structure of the flight muscles were also observed in flies of this genotype. Peripheral myofilaments of myofibrils were disarranged and the mitochondria diminutive. At 18° C the flight muscles remained normal. In all of the Abruptex (Ax) combinations the flight muscles remained similar to the wild-type controls at both 18° C and 29° C, i.e. they were normal. The results suggest that the Notch gene is active in adult flies in addition to its activity during embryonic, larval and pupal stages, and is directly or indirectly involved in the adult development of the muscle tissue.


Renal contribution to thoracic duct lymph in dogs.
1. The renal contribution to thoracic duct lymph was measured in seventeen anaesthetized fasting dogs by measurement of thoracic duct flow before and after renal arterial occlusion.2. In eight experiments it was shown that thoracic duct flow and glomerular filtration rate were not significantly affected by the operation to expose the renal artery.3. In three experiments occlusion of the renal vein, after release of arterial occlusion, resulted in a sudden increase in thoracic duct flow.4. In animals infused with isotonic saline or dextrose (approximately 1 ml./min) the average values obtained for control thoracic duct flow, left renal flow and right renal flow were approximately 2.0, 0.7 and 0.3 ml./hr/kg body wt.: in non-infused animals these values were 1.4, 0.4 and 0.35 ml./hr/kg body wt. respectively.5. Possible reasons for the apparently smaller lymph flow from the right than the left kidney, and the relationship between the renal contribution to thoracic duct flow and actual renal lymph flow are discussed.6. Close correlation was found between control thoracic duct flow and body weight and between renal lymph flow and control thoracic duct flow.


Questionnaire-based survey to determine an at-risk group for coeliac disease among school children in Moscow, Russia.
Coeliac disease (CD) is a chronic digestive disorder which presents in diverse ways and is under-diagnosed. The purpose of this study was to provide insights into suspected CD among Russian schoolchildren, through defining the percentage of participants in an 'at-risk' group for CD in a paediatric cohort, by means of a questionnaire as a primary screening tool. Russian school children of both sexes age 7-18 years were enrolled in a population-based study to identify individuals affected by CD. Each participant was presented with a structured questionnaire based on criteria that can be used to reveal symptomatic signs of CD. Following on, we developed a case-finding strategy for the 'at-risk' group, based on serological and genetic testing and, where possible, endoscopic examination of participants. 10.2% of questionnaire respondents (312/3070) were classified as an at-risk group. Pathobiological CD analysis of this group returned positive test results for 13.5% of participants (42/312), and 0.6% of them (2/312) had CD confirmed by biopsy sample analysis. Our findings suggest that at-risk groups among children with symptomatic or some oligosymptomatic CD presentations can be identified through adopting a questionnaire as part of a population-based screening survey, if generally accepted screening programs are inaccessible.


Cell-mediated immunity in interstitial nephritis. IV. Anti-tubular basement membrane antibodies can function in antibody-dependent cellular cytotoxicity reactions: observations on a nephritogenic effector mechanism acting as an informational bridge between the humoral and cellular immune response.
Anti-tubular basement membrane antibodies (alpha TBMA) were tested in vitro in an antibody-dependent cellular cytotoxicity (ADCC) reaction utilizing tubular antigen-coated targets. A selected subpopulation of normal guinea pig spleen cells induced significantly more target cell lysis in the presence of sera containing alpha TBMA than in the presence of control sera. this ADCC reaction using alpha TBMA exhibited a characteristic dose responsiveness and the alpha TBMA binding was specific for species-independent tubular antigens. The spleen effector cells used in this assay were characterized as nonadherent, non-T cells bearing Fc-receptors similar to other previously described natural killer cells found in guinea pigs. These studies suggest that natural surveillance systems may be able to use alpha TBMA as an informational bridge to tubular antigens. Such a potential nephritogenic effector mechanism has not been previously described.


Transesophageal bronchoscopic ultrasound-guided fine-needle aspiration for diagnosis of peripheral lung cancer.
Peripheral lung cancer is still a diagnostic challenge. The transbronchial approach with bronchoscopy or the transthoracic approach with radiologic imaging has been used extensively for the pathologic diagnosis of peripheral lung cancer. However, the explorability or feasibility with these modalities depends on the lesion location or patient's respiratory function. Herein, we report a case with severe pulmonary emphysema and lung cancer located at a parenchymal region difficult to access through an airway with a bronchoscope. Successful diagnosis was obtained by a transesophageal ultrasound-guided needle aspiration using an endobronchial ultrasound bronchoscope. This technique is accurate and less invasive in the primary diagnosis of lung cancer adjoining the esophagus.


Electro- and Photocatalytic Oxidative Upgrading of Bio-based 5-Hydroxymethylfurfural.
Conversion of biomass into biofuels and high value-added chemicals is a promising strategy to solve the increasingly deteriorating environmental problems caused by fossil energy consumption. The development of efficient technologies and methods is the premise and guarantee to realize the high-value conversion of biomass. 5-Hydroxymethylfurfural (HMF), as a versatile biomass platform compound, is generated via dehydration of hexoses (e. g., fructose and glucose) derived from cellulosic biomass. This Review gives an overview of the advances and challenges of electro- and photocatalytic oxidation of biomass-derived HMF to high-value chemicals such as 2,5-formylfuran (DFF) and 2,5-furandicarboxylic acid (FDCA). These strategies and methods for the preparation of high-value chemicals by electro- and photocatalytic oxidation of HMF, coupled with, for example, hydrogen evolution reaction, organic substrate reduction, CO2 reduction reaction, or N2 reduction reaction, were summarized and discussed. Moreover, the catalytic efficiency and mechanism of different types of catalysts were also introduced in these conversion systems.


[Advances in the Study of Invasive Non-mucinous Adenocarcinoma with Different Pathological Subtypes].
Lung cancer is the leading cause of cancer death in the world today, and adenocarcinoma is the most common histopathological type of lung cancer. In May 2021, World Health Organization (WHO) released the 5th edition of the WHO classification of thoracic tumors, which classifies invasive non-mucinous adenocarcinoma (INMA) into lepidic adenocarcinoma, acinar adenocarcinoma, papillary adenocarcinoma, solid adenocarcinoma, and micropapillary adenocarcinoma based on its histological characteristics. These five pathological subtypes differ in clinical features, treatment and prognosis. A complete understanding of the characteristics of these subtypes is essential for the clinical diagnosis, treatment options, and prognosis predictions of patients with lung adenocarcinoma, including recurrence and progression. This article will review the grading system, morphology, imaging prediction, lymph node metastasis, surgery, chemotherapy, targeted therapy and immunotherapy of different pathological subtypes of INMA. .


Response and resistance to cladribine in patients with advanced systemic mastocytosis: a registry-based analysis.
We sought to evaluate the efficacy of the purine analogue cladribine in 79 patients with advanced systemic mastocytosis (AdvSM) using data from the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)'. The overall response rate according to modified Valent criteria (46 evaluable patients) for first- (1L) and second-line (2L) cladribine treatment was 41% (12/29) and 35% (6/17, P = 0.690), respectively, and the median overall survival (OS, all patients evaluable) was 1.9 years (n = 48) and 1.2 years (n = 31; P = 0.311). Univariate and multivariable analyses of baseline and on-treatment parameters identified diagnosis of mast cell leukemia (hazard ratio [HR] 3.5, 95% confidence interval [CI, 1.3-9.1], P = 0.012), eosinophilia ≥ 1.5 × 109/L (HR 2.9 [CI 1.4-6.2], P = 0.006) and < 3 cycles of cladribine (HR 0.4 [CI 0.2-0.8], P = 0.008) as independent adverse prognostic parameters for OS. There was no impact of other laboratory (anemia, thrombocytopenia, serum tryptase) or genetic markers (mutations in SRSF2, ASXL1 or RUNX1) on OS. In consequence, none of the recently established prognostic scoring systems (MARS, IPSM, MAPS or GPSM) was predictive for OS. Modified Valent criteria were superior to a single factor-based response assessment (HR 2.9 [CI 1.3-6.6], P = 0.026). In conclusion, cladribine is effective in 1L and 2L treatment of AdvSM. Mast cell leukemia, eosinophilia, application of < 3 cycles and a lack of response are adverse prognostic markers.


Effects of acute ammonia exposure and recovery on the antioxidant response and expression of genes in the Nrf2-Keap1 signaling pathway in the juvenile golden pompano (Trachinotus ovatus).
Continuous exposure to high levels of ammonia can cause oxidative damage to fish tissues and organs. To date, the mechanism by which juvenile golden pompano (Trachinotus ovatus) are poisoned by ammonia exposure has not been thoroughly elucidated. although the mechanisms of ammonia toxicity are not well described for the pompano, many other studies presented these effects to other fish species. So an overview would be given. First, an acute ammonia nitrogen toxicity experiment on juvenile golden pompano obtained a 96-h half-lethal concentration (96 h LC50) of 26.9 mg/L. In the ammonia exposure experiment, fish were sampled at 0 h, 6 h, 12 h, 24 h, 48 h, 72 h and 96 h after exposure to ammonia water (26.93 mg/L). The results showed that with the prolonged ammonia nitrogen exposure, plasma cortisol (COR), total cholesterol (TC), glutamic-pyruvic transaminase (ALT), glutamic oxalacetic transaminase (AST) and malonaldehyde (MDA) levels continued to rise, while glucose (GLU) levels first increased and later gradually decreased after 12 h. The activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) in the liver and the mRNA expression levels of antioxidant genes (SOD, CAT, and GPX) first increased and subsequently decreased with increasing exposure time. Through microscopic observation, it was found that the degree of liver damage increased with increasing stress time and was most serious at 96 h. In the post-poison recovery experiment, the fish exposed to ammonia were transferred to clean water, and samples were taken at 24 h, 48 h, 72 h and 96 h after recovery. The results showed that with the increasing recovery time, each index recovered to the initial level to varying degrees, but the recovery time of 96 h was not enough for the fish to return to the normal level. We also examined the regulation of the Nrf2-Keap1 signaling pathway by the molecular mechanism of the antioxidant defense system. The results of this analysis showed that there was a positive correlation between Nrf2 and liver antioxidant gene expression levels, while there was a negative correlation between Keap1 and liver antioxidant gene expression levels, which may be observed because Nrf2 plays a key role in inducing antioxidant genes, and Keap1 may hinder the response to Nrf2. These results may provide a deeper and more comprehensive understanding of the impact of ammonia exposure on fish and help to provide a foundation for managing the healthy reproduction of juvenile fish.


Acquired port-wine stains in six pediatric patients.
Port-wine stains, also known as capillary malformations, are due to dermal vascular ectasia and dilation and are most commonly congenital; however, acquired port-wine stains (APWS) developing later in life have been noted in the literature, most commonly in the context of trauma. This case series presents 6 pediatric patients with APWS who first developed lesions between ages 3 and 11 years in the absence of a traumatic or other etiologic trigger. The epidemiology, clinical features, and treatment response of these patients are compared to what has been previously described in other cases in the literature.


Pulmonary Artery Aneurysm Diagnosed by Dynamic Digital Chest Radiography.
Pulmonary artery aneurysms (PAAs) are rare but clinically important because their rupture can cause sudden death. This report describes a case of an asymptomatic patient with an unruptured PAA that was successfully diagnosed by dynamic digital chest radiography (DDCR) and was treated surgically. DDCR is an advanced, temporally resolved radiographic technique that offers high-quality fluoroscopy-like images at a low radiation dose. Although noncontrast chest computed tomography revealed only a nonspecific nodule, DDCR delineated this lesion as a pulsatile nodule synchronized with cardiac pulsations, thereby establishing the diagnosis of PAA. This diagnosis was confirmed by computed tomographic pulmonary angiography and surgery.


Still New Chronic Q Fever Cases Diagnosed 8 Years After a Large Q Fever Outbreak.
Chronic Q fever usually develops within 2 years after primary infection with Coxiella burnetii. We determined the interval between acute Q fever and diagnosis of chronic infection, assessed what factors contribute to a longer interval, and evaluated the long-term follow-up. From 2007 to 2018, patients with chronic Q fever were included from 45 participating hospitals. The interval between acute and chronic infection was calculated in patients with a known day of first symptoms and/or serological confirmation of acute Q fever. Chronic Q fever-related complications and mortality were assessed by 2 investigators based on predefined criteria. In total, 313 (60.3%) proven, 81 (15.6%) probable, and 125 (24.1%) possible chronic Q fever patients were identified. The date of acute Q fever was known in 200 patients: in 45 (22.5%), the interval was longer than 2 years, with the longest observed interval being 9.2 years. Patients in whom serological follow-up was performed after acute Q fever were diagnosed less often after this 2-year interval (odds ratio, 0.26; 95% confidence interval, 0.12-0.54). Chronic Q fever-related complications occurred in 216 patients (41.6%). Chronic Q fever-related mortality occurred in 83 (26.5%) of proven and 3 (3.7%) of probable chronic Q fever patients. Chronic Q fever is still being diagnosed and mortality keeps occurring 8 years after a large outbreak. Intervals between acute Q fever and diagnosis of chronic infection can reach more than 9 years. We urge physicians to perform microbiological testing for chronic Q fever even many years after an outbreak or acute Q fever disease.


The contribution of lifestyle factors to socioeconomic differences in obesity in men and women--a population-based study in Sweden.
The objective was to investigate whether and to what extent the association between socioeconomic status and obesity can be explained by lifestyle factors. The relationship between socioeconomic status (SES) and obesity, and the role of lifestyle factors such as smoking, physical activity, heavy alcohol use, avoidance of dietary fat and propensity to eat fiber-rich food, was studied in a cross-sectional population-based study consisting of 6394 men and women aged 25-74 years in Värmland County in Sweden. Educational level was used for measuring SES. The contribution of the measured lifestyle factors was assessed using logistic regression models. 12% of men and 14% of women were obese. Subjects with high education were leaner than subjects with low education, except among elderly women (65-74 years). Although many lifestyle factors were related to obesity and SES in this study, only a part (18-29%) of the association between educational level and obesity could be explained by the measured lifestyle factors. Physical inactivity and heavy alcohol use were the main factors contributing to this association, whereas smoking and the measured dietary attitudes towards fat and fiber had little additional effect. The findings of this study are consistent with the view that socioeconomic differences in obesity and its consequences can only partly be reduced by changes in lifestyle. Longitudinal studies, a more detailed investigation of the role of dietary factors and more studies including elderly subjects are, however, recommended to further elucidate the association between SES and obesity.


Development of a Rapid Intraoperative Point-of-Care Method Using Tissue Suspension to Differentiate Parathyroid Tissue: A Possible Substitute for Frozen Sections.
We reported that aspartate aminotransferase (AST)/lactate dehydrogenase (LDH) ratio of a tissue suspension can precisely differentiate normal and hyperfunctioning parathyroid tissue (PT) from other tissues. However, in these studies, LDH and AST were measured using the standard method for blood samples, with a turnaround time of approximately 1 h, hampering clinical application. Here, we developed a rapid and robust method to differentiate PT instead of using frozen sections. Excised specimens from 28 patients (n = 69) who underwent thyroid or parathyroid surgery between October 2019 and April 2020 were analyzed. AST and LDH were measured in suspensions of PT or other tissues, using both the standard method in the in-facility laboratory and a point-of-care testing device (NX500, Fujifilm, Japan). A good correlation was found between the standard method and NX500 for AST and LDH levels >10 IU/L. In the analyses using 52 specimens with ≥ 10 IU/L of both AST and LDH measured using the NX500, PT was distinguished with 100% sensitivity and specificity using an optimal cutoff AST/LDH ratio of 0.48. The turnaround time was estimated to be less than 10 min. This method could be a cost- and labor-effective alternative to frozen sections to reduce the incidence of postoperative hypoparathyroidism and improve the outcome of primary hyperparathyroidism in low-resource areas.


[Build a bridge to the patient experiences psychosis in a context of coercion].
The nursepatient relationship is particularly challenging when the patient experiences psychosis and when he or she is placed in a context of coercion. Psychosis causes relational problems in the patient, which are further complicated in a context of coercion as this practice implies differences of understanding, status and power between the nurse and the patient. The Tidal Model, a care model focused on recovery, comprises ten principles of commitment for caregivers, which help to build a bridge between them and the person experiencing psychosis.


An update on targets for treating osteoarthritis pain: NGF and TRPV1.
a)Osteoarthritis (OA) is the most common form of arthritis, and pain is the primary symptom of the disease, yet analgesic options for treating OA pain remain limited. In this review, we aimed to give an update on the current clinical and preclinical studies targeting two pathways that are being investigated for treating OA pain: the nerve growth factor (NGF) pathway and the transient receptor potential vanilloid-1 (TRPV1) pathway. b)Antibodies against NGF, small molecule inhibitors of TrkA, TRPV1 agonists, and TRPV1 antagonists are all in different stages of clinical and pre-clinical testing for the treatment of OA pain. NGF antibodies have shown efficacy in the primary endpoints tested compared to placebo, however, rapidly progressive OA has been consistently observed in a subset of patients and the cause remains unclear. TRPV1 agonists have also demonstrated reduced pain with no serious adverse events - the most common adverse events include a burning or warming sensation upon administration. c)Targeting the NGF and TRPV1 pathways appear effective for reducing OA pain, but further work is needed to better understand which patients may benefit most from these treatments. The anti-NGF antibody tanezumab and the TRPV1 agonist CNTX-4975 have both received fast-track designation from the FDA for the treatment of OA pain.


SB 9200, a novel agonist of innate immunity, shows potent antiviral activity against resistant HCV variants.
SB 9200 is a novel, first-in-class oral modulator of innate immunity that is believed to act via the activation of the RIG-I and NOD2 pathways. SB 9200 has broad-spectrum antiviral activity against RNA viruses including hepatitis C virus (HCV), norovirus, respiratory syncytial virus, and influenza and has demonstrated activity against hepatitis B virus (HBV) in vitro and in vivo. In phase I clinical trials in chronically infected HCV patients, SB 9200 has been shown to reduce HCV RNA by up to 1.9 log10 . Here, we demonstrate the antiviral activity of SB 9200 against a HCV replicon system and patient derived virus. Using the HCV capture-fusion assay, we show that SB 9200 is active against diverse HCV genotypes and is also effective against HCV derived from patients who relapse following direct-acting antiviral treatment, including viruses containing known NS5A resistance-associated sequences. These data confirm the broad antiviral activity of SB 9200 and indicate that it may have clinical utility in HCV patients who have failed to respond to current antiviral regimens.


Binary and ternary salt gradients in hydrophobic-interaction chromatography of proteins.
Hydrophobic-interaction chromatography of mixtures of acidic and basic proteins having a wide range of molecular weights and hydrophobic character was carried out by using binary and ternary salt gradients. Chaotropic and antichaotropic salts as well as organic salts were incorporated in the eluents. The stationary phase consisted of macroporous silica with surface-bound polyether moieties. At constant eluent surface tension, gradient elution with two or three aqueous salt solutions was found to be superior to single-salt gradients in modulating hydrophobic-interaction chromatography retention and selectivity. The effect was attributed to the competitive salt-specific binding to the protein molecule and/or the stationary phase surface. Chaotropic/antichaotropic salt gradient systems exhibited vastly different selectivities upon changing the nature and concentrations of salts in the eluents. In general, the retention of basic proteins increased while that of acidic proteins either decreased or remained unchanged with the use of chaotropic salts. At the same surface tension of the eluent, KSCN and KC1O4 yielded different selectivities. The addition of organic salts, such as tetrabutylammonium bromide was found to be suitable for the separation of proteins having a wide range of isoelectric points.