[Expression of thymidylate synthase gene and recurrence of colorectal carcinoma: their relation and clinical significance].
To study the relationship between expression of thymidylate synthase (TS) gene and recurrence of colorectal carcinoma and its effect on clinical treatment. RT-PCR was used to detect the expression of TS gene in primary foci, para-tumoral intestine mucosa, local recurrence, abdominal-pelvic dissemination and hepatic metastasis in 68 cases of colorectal carcinoma, and TS protein was examined with western blot. In 68 cases of colorectal carcinoma, the expression of TS gene in primary foci was 22.1% (15/68); and the positive rates of TS gene expression in local recurrence, abdominal-pelvic dissemination and hepatic metastasis were 88.5% (23/26), 85.0% (17/20), 40.9% (9/20) respectively. The rates of TS protein expression in primary foci, local recurrence, abdominal-pelvic dissemination and hepatic metastasis were 22.1% (15/68), 84.6% (22/26), 80.0% (16/20), 36.4% (8/22) respectively. The negative expression of TS gene and TS protein was detected in paratumoral intestinal mucosa. The results of TS gene and TS protein expression were identical with those the two methods. The positive rates of TS gene and TS protein expression in diversified recurrence foci and metastasis were higher than those in primary foci (P < 0.01). The differences of TS gene and TS protein expression rates between recurrence and hepatic metastasis were significant (P < 0.01). The expression rates of TS gene and TS protein in local recurrence and abdominal-pelvic dissemination tissues were higher than those in hepatic metastasis. Overexpression of TS gene plays an important role in the process of local recurrence and abdominal-pelvic dissemination of colorectal carcinoma.


Role of isotope selection in long-term outcomes in patients with intermediate-risk prostate cancer treated with a combination of external beam radiotherapy and low-dose-rate interstitial brachytherapy.
To examine the rates of long-term biochemical recurrence-free survival (BRFS) with respect to isotope in intermediate-risk prostate cancer treated with external beam radiotherapy (EBRT) and brachytherapy. A total of 242 consecutive patients with intermediate-risk prostate cancer were treated with iodine-125 ((125)I) or palladium-103 ((103)Pd) implants after EBRT (range 45.0-50.4 Gy) from 1996 to 2002. Of the 242 patients, 119 (49.2%) were treated with (125)I and 123 (50.8%) with (103)Pd. Multivariate Cox regression analysis was used to analyze BRFS, defined according to the Phoenix definition (prostate-specific antigen nadir plus 2 ng/mL) with respect to Gleason score, stage, pretreatment prostate-specific antigen level, and source selection. Late genitourinary/gastrointestinal toxicities were assessed using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. At a median follow-up of 10 years, the BRFS rate was 77.3%. A statistically significant difference was found in the 10-year BRFS rate between the (125)I- and (103)Pd-treated groups (82.7% and 70.6%, respectively; P = .001). The addition of hormonal therapy did not improve the 10-year BRFS rate (77.6%) compared with RT alone (77.1%; P = .22). However, a statistically significant difference in the BRFS rate was found with the addition of hormonal therapy to (103)Pd, improving the 10-year BRFS rate for (73.8%) compared with (103)Pd alone (69.1%; P = .008). On multivariate analysis, isotope type ((103)Pd vs (125)I), pretreatment prostate-specific antigen level >10 ng/mL, and greater tumor stage increased the risk of recurrence by 2.6-fold (P = .007), 5.9-fold (P < .0001), and 1.7-fold (P = .14), respectively. (125)I renders a superior rate of BRFS compared with (103)Pd when used with EBRT. Hormonal therapy does not provide additional benefit in patients with intermediate-risk prostate cancer treated with a combination of EBRT and brachytherapy, except for the addition of hormonal therapy to (103)Pd.


Individual variability of amiodarone distribution in plasma and erythrocytes: implications for therapeutic monitoring.
The complexity of amiodarone disposition in blood and tissues gives rise to difficulty in determination of optimal therapeutic monitoring strategies. We have defined the within-patient variability of plasma and erythrocyte amiodarone and desethylamiodarone concentrations and electrocardiogram intervals [PR and corrected QT (QTc)] in 27 patients each sampled on three to four occasions during long-term stable amiodarone therapy. All individual repeated measurements were included in the concentration-effect analysis. The mean within-patient coefficients of variation for amiodarone and desethylamiodarone were significantly greater in erythrocytes, 46.0 and 24.5%, respectively, compared with plasma, 12.7 and 12.3%. Amiodarone and desethylamiodarone were significantly greater in erythrocytes, 46.0 and 24.5%, respectively, compared with plasma, 12.7 and 12.3%. Amiodarone and desethylamiodarone were strongly correlated (r = 0.29 p less than 0.004). There was a 10-fold variability in erythrocyte amiodarone for a given plasma level. These data emphasize the highly variable cellular distribution of amiodarone and desethylamiodarone in the same patient on stable dosage over time. Plasma amiodarone was significantly correlated with dosage (r = 0.98), and percent change in QTc, (r = 0.56, p less than 0.0001), but there was a fourfold variation in plasma amiodarone for a given QTc. Side-effect frequency was not related to plasma or erythrocyte amiodarone or desethylamiodarone concentrations. A clinically useful relationship between plasma concentration and effect could not be consistently demonstrated for amiodarone in the same individual during stable dosage.


Iridium-192 interstitial implant and external beam radiation therapy in the management of squamous cell carcinomas of the tonsil and soft palate.
To evaluate the results, techniques, indications and complications of interstitial brachytherapy in the management of squamous cell carcinomas of the tonsil and soft palate, we reviewed the Stanford University Medical School experience with this modality. Between May 1975 and January 1990, 37 patients with squamous cell carcinomas of the Tonsillo-Palatine region were treated with a combination of external beam irradiation and a removable Iridium-192 interstitial implant. The mean age of these patients was 56. Twenty-two were males and 15 were females. The stage distribution included four patients with Stage I, 5 with Stage II, 10 with Stage III, and 18 with Stage IV cancers. Thirty-two percent (12/37) of these patients had T3 or T4 lesions. Forty-nine percent (18/37) had stage N2 or N3 cervical lymphadenopathy. All 37 patients received initial external beam irradiation to the primary, bilateral necks, and supraclavicular region (mean dose: 5400 cGy, range 4000-6600). Eighteen patients (49%) also received neck dissections. All 37 patients received an interstitial Irridium-192 implant using a combination intraoral swage and external looping technique. The mean dose was 2700 cGy (range 2000-4000 cGy) to an average volume of 24 cc (range 5-81). Local control was obtained in 95% (35/37) of the patients. Eighty-seven percent (32/37) of the patients have remained disease-free in the neck. Nine patients have developed second primary lesions, and one developed pulmonary metastasis. Fifteen patients have died (6 succumbed to their cancers, 6 to second primaries, 2 to intercurrent disease, 1 from an unknown cause). The actuarial freedom from relapse is 75%, and overall survival is 64% at 5 years, with a mean follow up of 43 months (range 5-110). Complications were limited to one case of osteoradionecrosis of the mandible and one tonsillar ulcer. Functional and esthetic integrity was preserved in most of these patients. Iridium-192 interstitial implant boost combined with external beam radiation therapy is a safe and effective therapy in the management of locally advanced carcinomas of the tonsil and soft palate.


Defining Misinformation and Related Terms in Health-Related Literature: Scoping Review.
Misinformation poses a serious challenge to clinical and policy decision-making in the health field. The COVID-19 pandemic amplified interest in misinformation and related terms and witnessed a proliferation of definitions. We aim to assess the definitions of misinformation and related terms used in health-related literature. We conducted a scoping review of systematic reviews by searching Ovid MEDLINE, Embase, Cochrane, and Epistemonikos databases for articles published within the last 5 years up till March 2023. Eligible studies were systematic reviews that stated misinformation or related terms as part of their objectives, conducted a systematic search of at least one database, and reported at least 1 definition for misinformation or related terms. We extracted definitions for the terms misinformation, disinformation, fake news, infodemic, and malinformation. Within each definition, we identified concepts and mapped them across misinformation-related terms. We included 41 eligible systematic reviews, out of which 32 (78%) reviews addressed the topic of public health emergencies (including the COVID-19 pandemic) and contained 75 definitions for misinformation and related terms. The definitions consisted of 20 for misinformation, 19 for disinformation, 10 for fake news, 24 for infodemic, and 2 for malinformation. "False/inaccurate/incorrect" was mentioned in 15 of 20 definitions of misinformation, 13 of 19 definitions of disinformation, 5 of 10 definitions of fake news, 6 of 24 definitions of infodemic, and 0 of 2 definitions of malinformation. Infodemic had 19 of 24 definitions addressing "information overload" and malinformation had 2 of 2 definitions with "accurate" and 1 definition "used in the wrong context." Out of all the definitions, 56 (75%) were referenced from other sources. While the definitions of misinformation and related terms in the health field had inconstancies and variability, they were largely consistent. Inconstancies related to the intentionality in misinformation definitions (7 definitions mention "unintentional," while 5 definitions have "intentional"). They also related to the content of infodemic (9 definitions mention "valid and invalid info," while 6 definitions have "false/inaccurate/incorrect"). The inclusion of concepts such as "intentional" may be difficult to operationalize as it is difficult to ascertain one's intentions. This scoping review has the strength of using a systematic method for retrieving articles but does not cover all definitions in the extant literature outside the field of health. This scoping review of the health literature identified several definitions for misinformation and related terms, which showed variability and included concepts that are difficult to operationalize. Health practitioners need to exert caution before labeling a piece of information as misinformation or any other related term and only do so after ascertaining accurateness and sometimes intentionality. Additional efforts are needed to allow future consensus around clear and operational definitions.


Voluntary exercise attenuates nociceptive abnormalities with no significant alterations of social interaction deficits in the BTBR mouse model of autism.
Due to the financial burden and undesired side effects of treatment options, researchers have begun exploring alternative methods of treating autism spectrum disorder (ASD). Based on research suggesting impressive health benefits of engaging in physical activity, exercise treatment to alleviate symptoms could be a more cost effective alternative to pharmaceutical interventions. This study examined the effects of physical exercise on nociceptive responses and social interactions in an autism mouse model (BTBR T+ Itpr3tf/J). Subjects (n = 32) were separated into groups (BTBR vs B6 controls) based on the genetic strain and activity condition they were assigned. When compared to B6 controls, the BTBR mice demonstrated thermal hypoalgesia that normalized following 5 weeks of voluntary wheel running. However, exercise did not significantly attenuate social interaction deficits in BTBR mice, despite scores trending toward a positive direction. These results suggest that exercise could serve as a potential additive to other therapies for abnormal nociception in individuals with Autism Spectrum Disorder.


Direct monitoring of enzymatic glucan hydrolysis on a 27-MHz quartz-crystal microbalance.
By using a highly sensitive 27-MHz glucan-immobilized quartz-crystal microbalance, we could follow kinetically all processes (enzyme binding and release, kon and koff, and intramolecular hydrolysis rates, kcat) of glucan hydrolysis by glucoamylase by detecting directly the formation and decay of the enzyme-substrate complex as mass changes.


Synergetic delivery of artesunate and isosorbide 5-mononitrate with reduction-sensitive polymer nanoparticles for ovarian cancer chemotherapy.
Ovarian cancer is a highly fatal gynecologic malignancy worldwide. Chemotherapy remains the primary modality both for primary and maintenance treatments of ovarian cancer. However, the progress in developing chemotherapeutic agents for ovarian cancer has been slow in the past 20 years. Thus, new and effective chemotherapeutic drugs are urgently needed for ovarian cancer treatment. A reduction-responsive synergetic delivery strategy (PSSP@ART-ISMN) with co-delivery of artesunate and isosorbide 5-mononitrate was investigated in this research study. PSSP@ART-ISMN had various effects on tumor cells, such as (i) inducing the production of reactive oxygen species (ROS), which contributes to mitochondrial damage; (ii) providing nitric oxide and ROS for the tumor cells, which further react to generate highly toxic reactive nitrogen species (RNS) and cause DNA damage; and (iii) arresting cell cycle at the G0/G1 phase and inducing apoptosis. PSSP@ART-ISMN also demonstrated excellent antitumor activity with good biocompatibility in vivo. Taken together, the results of this work provide a potential delivery strategy for chemotherapy in ovarian cancer.


Novel Insight into How Nurses Working at PH Specialist Clinics in Sweden Perceive Their Work.
Outpatient pulmonary hypertension (PH) specialist centers have an important role in the optimal management of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The aim of the present study was to gain an understanding of the work facing nurses at the outpatient PH specialist centers in Sweden. All nurses (n = 14) working at the outpatient PH specialist centers in Sweden were included. Qualitative content analysis was employed to analyze the interviews, wherein an overarching theme emerged: "Build and maintain a relationship with the patient". Three categories described the nurses' experiences: "Ambiguous satisfaction regarding information and communication", "Acting as a coordinator" and "Professional and personal development". To provide good patient care, the nurses described the key components as the ability to give information on all aspects of the disease and their availability by phone for patients, their relatives, and other healthcare resources. This requires evidence-based, specialist knowledge about the disease, its care, and treatments as well as experience. In conclusion, working as a nurse at the outpatient PH specialist centers highlight the advantages, expectations, and difficulties in working with patients with a rare and life-threatening illness. The overall knowledge and skills were high, but the nurses expressed a need for in-depth and continued training.


Buffer system for the separation of neutral and charged small molecules using micellar electrokinetic chromatography with mass spectrometric detection.
An organic buffer system will be discussed that is suitable for the separation of neutral as well as charged molecules be means of micellar electrokinetic chromatography (MEKC). The buffers are based on the combination of a long chain alkyl acid, such as lauric acid with ammonium hydroxide or an organic base such as tris-hydroxymethylaminomethane (Tris). The resulting buffer system is able to separate neutral compounds based on its micellar properties. These buffers exhibit much reduced conductivity compared to traditional MEKC buffers, such as sodium dodecylsulfate (SDS), which contain inorganic salts. They also have inherent buffer capacity at high pH resulting from the basic buffer component, which in our studies had pK values from about 8-11. The separations that were observed showed high efficiency with plate counts in many cases above 500,000 plates per meter. The reduced conductivity allowed for the application of much higher electric fields, resulting in very fast analysis times. Alternatively, an increase in detection sensitivity could be achieved, as the reduced conductivity allowed for the use of capillaries with lager internal diameters. Combinations of different alkyl acids and organic bases provided for significant flexibility in selectivity tuning. Finally, the fact that the organic micellar buffer systems discussed here do not contain inorganic ions, allows for coupling with mass spectrometric (MS) detection. The possibility of MS detection combined with the high speed in analysis that can be obtained using these organic buffer systems, could make this approach an interesting option for high throughput analysis of combinatorial libraries.


Early diagnosis of iliofemoral venous thrombosis by Doppler examination.
The diagnosis of iliofemoral venous thrombosis prior to its progression to phlegmasia cerulea dolens can be difficult and, at times, confusing. The Doppler ultrasound examination in experienced hands can be extremely reliable and rapid in diagnosing the condition. During an 18 month period, we used the Doppler examination to diagnose iliofemoral venous thrombosis in 21 patients, 15 of whom had corroboration by venogram. The key to successful treatment and avoidance of significant complications was early and accurate diagnosis by the Doppler examination. No patient underwent operation or progressed to venous gangrene. Six were treated with streptokinase and the rest, with intravenous heparin, leg elevation, and stockings. We believe that iliofemoral venous thrombosis is a much more common disease than previously recognized and should be vigorously diagnosed and treated when a patient presents with a symptomatic extremity. The Doppler ultrasound examination represents a rapid, reliable alternative to the venogram in the early diagnosis of iliofemoral venous thrombosis.


Ultrastructural Mechanisms of Impaired Aldosterone Synthesis in Rats Exposed to DDT during Prenatal and Postnatal Development.
The study is aimed at elucidation of ultrastructural mechanisms underlying impaired aldosterone synthesis by glomerulosa cells in Wistar rats exposed to low doses of endocrine disrupter DDT during prenatal and postnatal development. Analysis of rat zona glomerulosa histology and function during the pubertal and postpubertal periods showed that exposure to endocrine disrupter DDT disturbs its development and reduced the production of aldosterone. Electron microscopy showed that changes in the aldosterone synthesis are related to impaired reorganization of the mitochondrial apparatus, one of the leading factors in the regulation of steroidogenesis, in glomerulosa cells in DDT-exposed rats during puberty.


Neural responses related to point-light walker perception: a magnetoencephalographic study.
The aim of this study is to extract magnetoencephalographic responses relating to the processing of point-light walker (PLW). To attenuate neural activities in the lower visual areas, we presented a scrambled-PLW as a first stimulus and then either an upright- or inverted-PLW/scrambled-PLW as a second stimulus. Each point of the scrambled-PLW stimulus had the same velocity vector as the points of the PLW stimulus, but points were interchanged randomly. The peak neuromagnetic response to the first stimulus was observed at around 250ms after stimulus onset, whereas the peak latency in response to second stimulus was around 350ms after stimulus onset. The peak amplitude induced by the PLW stimulus was significantly larger than that by the scrambled-PLW during the second stimulus. Moreover, the signal source of the responses to the PLW was estimated to lie in the occipitotemporal region, more anterior than the source of the response to the first stimulus. These findings indicate that the response to the first stimulus reflects general motion processing, while responses to the second stimuli are involved in PLW processing. This is the first evidence to specify a single neuromagnetic response to a PLW stimulus.


Regulation of biofilm components in Salmonella enterica serovar Typhimurium by lytic transglycosylases involved in cell wall turnover.
In Salmonella enterica serovar Typhimurium, a biofilm mode of growth known as the rdar morphotype is regulated by several networks which sense multiple environmental signals. The transcriptional regulator CsgD is the major target for these regulatory pathways. In this study, we show that two lytic transglycosylases of family I, MltE and MltC, in combination increase CsgD expression and rdar morphotype. MltE and MltC, which share a highly similar transglycosylase SLT domain, work redundantly to regulate CsgD at the transcriptional and posttranscriptional levels. The effect of MltE and MltC on CsgD levels was independent of the known regulatory pathways that sense cell envelope stress. These findings reveal, for the first time, a specific function of lytic transglycosylases in S. Typhimurium and suggest the existence of a new signaling pathway that links cell wall turnover to biofilm formation.


Structure-based design, synthesis and biological testing of piperazine-linked bis-epipodophyllotoxin etoposide analogs.
Drugs that target DNA topoisomerase II, such as the epipodophyllotoxin etoposide, are a clinically important class of anticancer agents. A recently published X-ray structure of a ternary complex of etoposide, cleaved DNA and topoisomerase IIβ showed that the two intercalated etoposide molecules in the complex were separated by four DNA base pairs. Thus, using a structure-based design approach, a series of bis-epipodophyllotoxin etoposide analogs with piperazine-containing linkers was designed to simultaneously bind to these two sites. It was hypothesized that two-site binding would produce a more stable cleavage complex, and a more potent anticancer drug. The most potent bis-epipodophyllotoxin, which was 10-fold more growth inhibitory toward human erythroleukemic K562 cells than etoposide, contained a linker with eight methylene groups. All of the mono- and bis-epipodophyllotoxins, in a variety of assays, showed strong evidence that they targeted topoisomerase II. COMPARE analysis of NCI 60-cell GI50 endpoint data was also consistent with these compounds targeting topoisomerase II.


Purification and regulatory properties of pigeon erythrocyte pyruvate kinase.
1. Pigeon erythrocyte pyruvate kinase (PK) was purified 22,000 fold by successive column chromatography on Sephadex DEAE A-50 and Red Agarose. The resulting enzyme preparation had a specific activity of 815.3 U/mg protein and an overall yield of 18.5%. 2. The molecular weight, as determined by gel filtration on Sephadex G-200 was 152,000. 3. Isoelectric focusing in the pH range of 3-10 showed that pigeon erythrocyte contained at least 3 PK isozymes with isoelectric points of 5, 5.7 and 6. 4. The variation of activity of PK at various ADP and phosphoenolpyruvate (PEP) concentrations was studied. The Km values for ADP and PEP were 0.40 and 0.46 mM respectively. 5. The enzyme was activated by FDP, and inhibited by ATP, highly phosphorylated inositol derivatives and 2,3-DPG: 6. It was activated by K+ and Mg2+ ions. 7. Phosphorylated hexoses and Pi stimulated the activity of PK. 8. The regulatory role of PK of pigeon erythrocytes, which lack the typical 2,3-DPG bypass, is discussed.


[Sporotrichoid cutaneous leishmaniasis in Tunisia: a clinical and histological study].
The sporotrichoid variety of cutaneous leishmaniasis is defined by the presence of dermal and hypodermal nodules along the lymphatic stream, and remote from the primary inoculation lesions. This clinical form is usually considered rare. The aim of our study was to investigate the epidemiological, clinical, histological and evolutionary particularities of sporotrichoid cutaneous leishmaniasis in the south of Tunisia. During a systematic study of all cases of cutaneous leishmaniasis from the south of Tunisia diagnosed in our hospital in 2002, sporotrichoid forms were diagnosed on the basis of clinical criteria. In all cases of sporotrichoid cutaneous leishmaniasis, the principal clinical characters were systematically specified. Cutaneous biopsies of subcutaneous nodules were performed in six cases. Of 102 patients with cutaneous leishmaniasis, 19 presented sporotrichoid cutaneous leishmaniasis, that is, a frequency of 19%. Between two and 20 painless subcutaneous nodules were arranged in linear strings on the upper leg in 79% of cases. Time to appearance varied between 12 days and one year after the primary lesions. Fourteen appeared without any preliminary treatment for cutaneous leishmaniasis and five appeared after Glucantime infiltration in the primary lesions. Biopsies of the nodules showed an inflammatory infiltrate composed of lymphocytes and histiocytes. This infiltrate was particularly dense and rich in plasmocytes at the level of the deep dermis. The biopsies were deep enough to involve the hypoderm in one case and the same type of infiltrate was noted at the level of interlobular septa. A small number amastigotes was seen in one deep biopsy sample. Outcome was favourable in all cases under treatment. Sporotrichoid cutaneous leishmaniasis appears to be common in the south of Tunisia, were cutaneous leishmaniasis is dominant because of Leishmania major. It is not associated with a poor prognosis.


Modulation of platelet aggregation by areca nut and betel leaf ingredients: roles of reactive oxygen species and cyclooxygenase.
There are 2 to 6 billion betel quid (BQ) chewers in the world. Areca nut (AN), a BQ component, modulates arachidonic acid (AA) metabolism, which is crucial for platelet function. AN extract (1 and 2 mg/ml) stimulated rabbit platelet aggregation, with induction of thromboxane B2 (TXB2) production. Contrastingly, Piper betle leaf (PBL) extract inhibited AA-, collagen-, and U46619-induced platelet aggregation, and TXB2 and prostaglandin-D2 (PGD2) production. PBL extract also inhibited platelet TXB2 and PGD2 production triggered by thrombin, platelet activating factor (PAF), and adenosine diphosphate (ADP), whereas little effect on platelet aggregation was noted. Moreover, PBL is a scavenger of O2(*-) and *OH, and inhibits xanthine oxidase activity and the (*)OH-induced PUC18 DNA breaks. Deferoxamine, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) and neomycin prevented AN-induced platelet aggregation and TXB2 production. Indomethacin, genistein, and PBL extract inhibited only TXB2 production, but not platelet aggregation. Catalase, superoxide dismutase, and dimethylthiourea (DMT) showed little effect on AN-induced platelet aggregation, whereas catalase and DMT inhibited the AN-induced TXB2 production. These results suggest that AN-induced platelet aggregation is associated with iron-mediated reactive oxygen species production, calcium mobilization, phospholipase C activation, and TXB2 production. PBL inhibited platelet aggregation via both its antioxidative effects and effects on TXB2 and PGD2 production. Effects of AN and PBL on platelet aggregation and AA metabolism is crucial for platelet activation in the oral mucosa and cardiovascular system in BQ chewers.


Cross-sectional associations between healthy eating index and thyroid function in U.S. male Adults, NHANES 2007-2012.
Little is known about whether diet quality is associated with thyroid function. We aimed to examine the relationship between diet quality and thyroid function. Data were from the National Health and Nutrition Examination Surveys, 2007-2012. A total of 3603 males who were at least 20 years old and had dietary recall data were included in the analysis. Thyroid function was assessed by eight indexes, including total and thyroglobulin antibodies, thyroid peroxidase antibodies, free T4 and T3, total T4 and T3, Tg, and thyroid-stimulating hormone. Multivariable linear regression, subgroup analyses, and interaction terms were employed to test the association between healthy eating index (HEI) and thyroid function. A total of 3603 male participants aged ≥20 years with an average age of 48.17 ± 0.51 years were enrolled. We found a negative association between HEI-2010 and total T3 (β = -3.41; p = .01) and free T3 (β = -0.06; p = .01). In subgroup analyses, HEI-2010 was negatively associated with TT3 in male participants aged <65 years old (β = -4.57; p < .01) and FT3 (β = -0.09; p < .001). Higher HEI-2010 was inversely associated with lower total T3 and free T3. More well-designed studies are still needed to validate the causal relationship between HEI and thyroid function.


Attention Problems Mediate the Association between Severity of Physical Abuse and Aggressive Behavior in a Sample of Maltreated Early Adolescents.
Empirical evidence has accumulated documenting an association between childhood physical abuse and aggressive behavior. Relatively fewer studies have explored possible mediating mechanisms that may explain this association. The purpose of the current study was to examine whether caregiver- and youth-reported attention problems mediate the association between physical abuse severity and aggressive behavior. A sample of 240 maltreated early adolescents (ages 9-11) and their caregivers were interviewed within 14 months of being removed from the home. Results from multiple regression analyses indicated that caregiver- and youth-reported attention problems were partial mediators of the association between physical abuse severity and aggressive behavior. These associations were significant even after controlling for children's intellectual functioning, sex, age, and severity of other maltreatment types. Possible explanations for the detrimental impact of physical abuse on behavior are discussed, along with the implications of the current study's results for interventions aimed at reducing early adolescent aggressive behavior.


Drug sensitivity studies on clonal cell lines isolated from heteroploid tumour cell populations. I. Dose response of clones growing in monolayer cultures.
Drug sensitivity of a heteroploid tumour cell line and three clones isolated from it was studied in tissue culture. Cells of the parent line P0, and of clone P1 were fibroblast-like and pseudo- and hypodiploid. Cones P3 and P4 consisted mostly of epithelial and round cells, respectively, and were hypotetraploid. In dose-response experiments, P1 and P4 clones were more sensitive to dianhydrodulcitol than tp0 or P3 clones. Adriamycin was more toxic to P3 than to the other three cell lines. P3 and P4 clones were more sensitive to vincristine than P0 or P1 clones. N-formyl-leurosine, a new derivative of the Vinca alkaloids, was least toxic to P4 cells, and the other three cell lines were equally sensitive. It was concluded that relative sensitivity of the clones depended on the particular drug. Presence of clones of lower sensitivity in heteroploid cell populations may have some bearing on regrowth of tumours after chemotherapy.


Implementation of an adhesive small bowel obstruction protocol using low-osmolar water soluble contrast and the impact on patient outcomes.
Small bowel obstruction (SBO) is a common condition leading to numerous hospital admissions and operations. Standardized care of adhesive SBO patients has not been widely implemented in hospital systems. A prospective cohort of SBO patients was compared to a historical cohort of SBO patients after implementation of a SBO protocol using evidence-based guidelines and Omnipaque, a low-osmolar water soluble contrast. Patients without a history of abdominal surgery were excluded and data was collected through chart review. Univariate analyses demonstrated a decrease in both LOS by 1.35 days and in the proportion of patients receiving surgery (37% vs 25%; p < 0.05). There was a decrease in time to surgery, rate of SBR, and rate of complications, yet an increase in readmission, although these findings were not statistically significant. Utilizing an evidence-based SBO protocol can lead to shorter LOS and may result in fewer operations for adhesive SBO patients.


Noninvasive Vascular Modulography Method for Imaging the Local Elasticity of Atherosclerotic Plaques: Simulation and In Vitro Vessel Phantom Study.
Mechanical and morphological characterization of atherosclerotic lesions in carotid arteries remains an essential step for the evaluation of rupture prone plaques and the prevention of strokes. In this paper, we propose a noninvasive vascular imaging modulography (NIV-iMod) method, which is capable of reconstructing a heterogeneous Young's modulus distribution of a carotid plaque from the Von Mises strain elastogram. Elastograms were computed with noninvasive ultrasound images using the Lagrangian speckle model estimator and a dynamic segmentation-optimization procedure to highlight mechanical heterogeneities. This methodology, based on continuum mechanics, was validated in silico with finite-element model strain fields and ultrasound simulations, and in vitro with polyvinyl alcohol cryogel phantoms based on magnetic resonance imaging geometries of carotid plaques. In silico, our results show that the NiV-iMod method: 1) successfully detected and quantified necrotic core inclusions with high positive predictive value (PPV) and sensitivity value (SV) of 81±10% and 91±6%; 2) quantified Young's moduli of necrotic cores, fibrous tissues, and calcium inclusions with mean values of 32±23, 515±30, and 3160±218 kPa (ground true values are 10, 600, and 5000 kPa); and 3) overestimated the cap thickness by . In vitro, the PPV and SV for detecting soft inclusions were 60±21% and 88±9%, and Young's modulus mean values of mimicking lipid, fibrosis, and calcium were 34±19, 193±14, and 649±118 kPa (ground true values are 25±3, 182±21, and 757±87 kPa).


Water quality assessment and pollution source apportionment in a highly regulated river of Northeast China.
Dams and sluices break down the river continuum, alter the river hydrological regime, and intercept the migration processes of nutrients and pollutants. The regulation of dams and sluices will have great impacts on water quality characteristics in the river basin. In this study, variable fuzzy pattern recognition model (VFPR), principal component analysis/factor analysis (PCA/FA), and the absolute principal component score-multiple linear regression (APCS-MLR) were used to assess the water quality and identify the potential pollution sources in a highly regulated river of Northeast China. A set of water quality variables at three stations were measured from January 2015 to August 2017. The water quality assessment results showed that there were spatial and temporal variations of water quality and the total nitrogen (TN) and fecal coliforms (F. coli) were the major pollution factors of the study river section. Four pollution sources, including industrial effluent source, domestic sewage source, meteorological factor and atmospheric deposition source, and agricultural non-point source, were identified in dry and wet seasons using the PCA/FA method. The APCS-MLR results showed that the industrial effluent source was the main pollution source in dry seasons and had a decrease in wet seasons. While the mean contribution of the domestic sewage source had an increase in wet seasons, influenced by the sewage overflow and the flushing of pollutants during the extreme precipitation, the construction of dams decreased the flow obviously in wet seasons and increased in dry seasons. The increase in pollutants caused by storm runoff and the reduction of dilution water in the river channel could be the main reason for the water quality degradation in wet seasons.


Lifestyle assessment in individuals with spinal cord injuries caused by accidents and disasters in qualitative studies published from 1990 to 2020: A meta-synthesis of qualitative study.
As a debilitating disorder, spinal cord injuries (SCIs) can bring about a range of physical, psychological, and social consequences in individuals and even have effects on their lifestyle indicators. The present study was thus to reflect on lifestyles among people with SCIs developing from accidents and disasters. Using a meta-synthesis of qualitative research, all articles recruiting qualitative methods to examine patients with SCIs, published from 1990 to 2020, were retrieved by the researchers, good at the Persian and English languages, from the databases of ScienceDirect, MD Consult, Pedro, ProQuest, PubMed, SID, MedLib, Magiran, Scopus, Google Scholar, Iranmedex, the Cochran Library, CINAHL, and Blackwell, tapping the keywords of "spinal cord injury, SCI, manmade disaster, natural disaster, content analysis, concept analysis, thematic analysis, lifestyle, quality of life, QoL, grounded theory, meta-synthesis, mixed-methods research, historical research, ethnography, and phenomenology" in both languages for their inclusion in this study and further analyses. With reference to the inclusion criteria, 18 articles were extracted, and after all 10 studies in line with the research topic were reviewed and analyzed. Ultimately, six main themes, namely, compromise, self-reliance, income-generating activities, mental status, inability, and issues of sexuality were extracted, demonstrating their importance to individuals suffering from SCIs. During the initial stages following SCIs, the abilities to engage in participatory practices and individual's power of decision-making diminish because of physical, social, psychological, and environmental constraints. It was accordingly recommended to have a holistic perspective and respect all aspects of life in individuals with SCIs.


Tracking Gut Motility in Organ and Cultures.
Gastrointestinal (GI) motility is a key component of digestive health, and it is complex, involving a multitude of cell types and mechanisms to drive both rhythmic and arrhythmic activity. Tracking GI motility in organ and tissue cultures across multiple temporal (seconds, minutes, hours, days) scales can provide valuable information regarding dysmotility and to evaluate treatment options. Here, the chapter describes a simple method to monitor GI motility in organotypic cultures, using a single video camera is placed perpendicularly to the surface of the tissue. A cross-correlational analysis is used to track the relative movements of tissues between subsequent frames and subsequent fitting procedures to fit finite element functions to the deformed tissue to calculate the strain fields. Additional motility index measures from the displacement information are used to further quantify the behaviors of the tissues that are maintained in organotypic culture over days. The protocols presented in this chapter can be adapted to study organotypic cultures from other organs.


Comparative studies of computed tomography and measurements of regional cerebral blood flow in stroke patients.
Comparative studies of computed tomography and of regional cerebral blood flow (rCBF) by means of the intracarotid xenon-133-clearance method were performed in 25 stroke patients. The relationships between an infarction in CT and disturbances of rCBF, between a normal CT in stroke cases and focal changes of CBF, and between the luxury perfusion syndrome in the rCBF study and contrast enhancement of an infarct in CT are demonstrated and discussed.


Cytochrome P450 dependent N-hydroxylation of a guanidine (debrisoquine), microsomal catalysed reduction and further oxidation of the N-hydroxy-guanidine metabolite to the urea derivative. Similarity with the oxidation of arginine to citrulline and nitric oxide.
The microsomal N-hydroxylation of the strongly basic guanidinium group (debrisoquine) to N-hydroxyguanidine (N-hydroxydebrisoquine) and the retroreduction of the N-hydroxyguanidine are demonstrated for the first time. The reduction of the N-hydroxyguanidine by liver homogenates and hepatocytes is catalysed by a microsomal NADH-dependent system that is strongly inhibited by hydroxylamine or N-methylhydroxylamine. In the presence of these alternate substrates for the reductase the microsomal catalysed N-hydroxylation of debrisoquine is readily characterized. The oxidation was inhibited by antibodies against NADPH cytochrome P450 reductase and the role of the P450 monooxygenase was further verified by studies with partially purified and purified P450 2C3 reconstituted systems. The transformation of N-hydroxydebrisoquine to the corresponding urea derivative was also detected in in vitro experiments with microsomal fractions and enriched P450 fractions as well as with flavin-containing monooxygenase (FMO). Experiments with catalase, superoxide dismutase and H2O2 have shown that the H2O2 or O2-, respectively, formed from the respective enzyme and the substrate, apparently participated in the reaction. Whereas the N-hydroxylation of the guanidine involves the usual monooxygenase activity of cytochrome P450 the resultant N-hydroxyguanidine decouples monooxygenases (cytochrome P450, FMO) and the H2O2 and, above all, O2- thus formed transform the N-hydroxyguanidine further to the corresponding urea derivative. The possibility for the N-hydroxylation of non-physiological guanidines to N-hydroxyguanidines and subsequent oxidative conversion to the respective urea is comparable to the physiological transformation of arginine to citrulline via N-hydroxyarginine with the liberation of nitric oxide (endothelial derived relaxing factor) and could, therefore, contribute to the efficacy of drugs containing guanidine and similar functional groups.


Proximal phocomelia and radial ray aplasia in fetal valproic syndrome.
We describe a child with multiple congenital anomalies born to a women treated with valproic acid (1000 mg/day) for post traumatic epilepsy. Defects included the typical dysmorphism of the "fetal valproic syndrome", bilateral radial ray aplasia, unilateral proximal phocomelia of the upper limb, kidney hypoplasia and brain atrophy. A direct teratogenic effect of valproic acid is suspected on an experimental basis, and validated by two previous reports of radial defects after valproic acid exposure.


Parturition pit: the bony imprint of vaginal birth.
To retrospectively evaluate for pits along the dorsum of the pubic body in females and compare the presence/absence of these pits to vaginal birth data. We retrospectively reviewed females with vaginal birth data who underwent pelvic CT. The presence of pits along the dorsum of the pubic body, pit grade (0 = not present; 1 = faintly imperceptible; 2 = present; 3 = prominent), and the presence of osteitis condensans ilii, preauricular sulcus, and sacroiliac joint vacuum phenomenon were assessed on imaging. Musculoskeletal radiologists who were blinded to the birth data evaluated the CTs. 48 males were also evaluated for the presence of pits. 482 female patients underwent CT pelvis and 171 were excluded due to lack of vaginal birth data. Of the 311 study patients, 262 had prior vaginal birth(s) and 194 had pits on CT. Only 7 of the 49 patients without prior vaginal birth had pits. There was a statistically significant association between vaginal birth and presence of pits (p < 0.0001). Patients with more prominent pits (grades 2/3) had a greater number of vaginal births. As vaginal deliveries increased, the odds of having parturition pits greatly increased, adjusting for age and race at CT (p < 0.0001). No males had pits. Our study indicates that parturition pits are associated with prior vaginal birth and should be considered a characteristic of the female pelvis. The lytic appearance of prominent pits on imaging can simulate disease and create a diagnostic dilemma for interpreting radiologists.


A comparative study of the typical toxic metals in serum by patients of schizophrenia and healthy controls in China.
Toxic metals are ubiquitous environmental pollutants, and their potential risks associated with the development of schizophrenia remain a subject of debate. In this study, we investigated the associations between six typical toxic metals (mercury, lead, chromium, silver, antimony, and uranium) in serum with the risk of schizophrenia using a case-control study design. In total, 109 patients with schizophrenia (cases) and 106 normal subjects (controls) from Shandong Province, China were recruited. Fasting blood samples were collected from all participants, as well as serum samples from the cases before and after medical treatment. The six metals were analyzed by inductively coupled plasma mass spectrometry. Only three metals (antimony, silver and uranium) had acceptable detection rates of >80%. The concentrations of antimony and uranium were significantly higher in the cases than in the controls, while no significant difference for silver. Moreover, the serum concentrations of antimony and uranium were significantly lower after medical treatment. Clear dose-response relationships between serum metal concentrations and the risk of schizophrenia were observed, even after adjusting for potential covariates. This suggests that higher levels of antimony and uranium may be one of the factors associated with an elevated risk of schizophrenia.


Enuresis and incontinence in children.
The terminology used to describe wetting children is defined. The etiologies of monosymptomatic nocturnal enuresis and nonneuropathic bladder-sphincter dysfunction are described. Treatment strategies and the results of recent large scale studies are presented.


Induction of cytotoxic lymphocyte subsets against leukemia by stimulation with AML blasts.
Although the application of interleukin-2 (IL-2) activated lymphocytes in immunotherapy of acute myelogenous leukemia (AML) is of therapeutic interest, the high resistance of AML blasts to lymphocyte lysis may represent an obstacle to this type of therapy. However, our data shows that the leukemia resistance can be conquered by concomitant culture of lymphocytes with IL-2 and AML blasts. This approach induces not only leukemia-directed cytotoxic cells, but also promotes their growth. Additionally, multiple cytotoxic lymphocyte populations with leukemia lytic activity are induced in AML/IL-2 cultures. These include natural killer (NK) cells and subsets of T cells with both the major histocompatibility complex (MHC)-restricted and MHC-nonrestricted cytotoxic function. Thus, this protocol, which is conducive to general stimulation of cellular immune responses against leukemia, may enhance the benefits of lymphocyte therapy.


Omalizumab for the treatment of patients with severe allergic asthma with immunoglobulin E levels above >1500 IU/mL.
Immunoglobulin E (IgE) plays a critical role in the allergen-initiated inflammatory pathway and thus serves as a viable therapeutic target in allergic or IgE-mediated diseases such as asthma. Omalizumab, an anti-IgE biologic, has been approved in the United States (US, 2003) and in the European Union (EU, 2005) as an add-on therapy in patients with moderate-to-severe persistent asthma and severe allergic asthma (SAA) aged 6 years and older. The dose and frequency of omalizumab are adjusted based on the patient's body weight and baseline IgE levels, as recommended by its dosing tables. Currently, these dosing recommendations are limited to patients with baseline IgE levels of up to 1500 IU/mL in the European Union and 700 IU/mL in the United States. However, many patients with SAA have IgE levels >1500 IU/mL, highlighting an unmet need. This review presents the current evidence on the treatment benefits of omalizumab in patients with IgE levels >1500 IU/mL. The findings from the reviewed studies which included >3000 patients support the efficacy and effectiveness of omalizumab in reducing exacerbations, and improving asthma control, lung function, and quality of life in patients with severe asthma having IgE levels beyond the current dosing range. Omalizumab was well-tolerated in these patients, with no new safety signals. In addition, high IgE levels (>1500 IU/mL) are also reported in several comorbidities of asthma (allergic rhinitis, atopic dermatitis, allergic bronchopulmonary aspergillosis [ABPA], food allergy, and nasal polyposis) and omalizumab has demonstrated efficacy and safety in these indications. These data suggest that omalizumab may be considered for administration in SAA patients, with high IgE levels outside the current dosing tables. A detailed assessment of patients with high IgE levels is needed before deciding on the optimal treatment approach. A management algorithm for SAA patients with IgE >1500 IU/mL is proposed in this review and a suggestion to follow the Delphi consensus is advised.


Tumour size is an important predictor for the outcome after liver transplantation for hepatocellular carcinoma.
Recently, there is a tendency to expand tumour sizes qualifying for OLT. The present study re-evaluates tumour size and histopathological features as selection criteria for OLT. Retrospective analysis of 93 adult HCC patients underwent OLT between June 1985 and December 2003. Median follow-up was 28 months (1-222 months). The Milan criteria were routinely applied since 1994. Five year survival rate of HCC patients was significantly lower than in patients transplanted for benign diseases, 41 and 71%, respectively (p<0.0001). Multivariate analysis revealed that the presence of vascular invasion represents the most significant predictor (p<0.001) affecting the survival rate. Survival was also significantly impaired when the tumour size was >5 cm (p<0.05), whereas the number of nodules had no significant effect on survival. Consequently, the survival rate for HCC fulfilling the Milan criteria histologically improved to 70% since 1994. Tumour size has been shown to be the most important pre-operatively detectable predictor for patient survival after OLT.


Endothelin-1 induces neutrophil-independent vascular injury in the rat gastric microcirculation.
Local intra-arterial infusion of picomole quantities of endothelin-1 induced gastric vascular leakage of radiolabelled albumin. This leakage was partially inhibited by the platelet activating factor (PAF) receptor antagonist WEB 2086 (0.5-2 mg kg-1), but was unaffected by the thromboxane synthase inhibitor OKY 1581 (5 mg kg-1) or by pretreatment with anti-neutrophil serum. These results indicate a partial role of PAF, but demonstrate that neutrophils are not involved in the gastric vascular dysfunction induced by locally administered endothelin-1.


The effect of UV-B on Arabidopsis leaves depends on light conditions after treatment.
Ultraviolet B (UV-B) irradiation can influence many cellular processes. Irradiation with high UV-B doses causes chlorophyll degradation, a decrease in the expression of genes associated with photosynthesis and its subsequent inhibition. On the other hand, sublethal doses of UV-B are used in post-harvest technology to prevent yellowing in storage. To address this inconsistency the effect of short, high-dose UV-B irradiation on detached Arabidopsis thaliana leaves was examined. Two different experimental models were used. After short treatment with a high dose of UV-B the Arabidopsis leaves were either put into darkness or exposed to constant light for up to 4 days. UV-B inhibited dark-induced chlorophyll degradation in Arabidopsis leaves in a dose-dependent manner. The expression of photosynthesis-related genes, chlorophyll content and photosynthetic efficiency were higher in UV-B -treated leaves left in darkness. UV-B treatment followed by constant light caused leaf yellowing and induced the expression of senescence-related genes. Irrespective of light treatment a high UV-B dose led to clearly visible cell death 3 days after irradiation. High doses of UV-B have opposing effects on leaves depending on their light status after UV treatment. In darkened leaves short UV-B treatment delays the appearance of senescence symptoms. When followed by light treatment, the same doses of UV-B result in chlorophyll degradation. This restricts the potential usability of UV treatment in postharvest technology to crops which are stored in darkness.


RNase E cleavage in the 5' leader of a tRNA precursor.
In this study, we have used various tRNA(Tyr)Su3 precursor (pSu3) derivatives that are processed less efficiently by RNase P to investigate if the 5' leader is a target for RNase E. We present data that suggest that RNase E cleaves the 5' leader of pSu3 both in vivo and in vitro. The site of cleavage in the 5' leader corresponds to the cleavage site for a previously identified endonuclease activity referred to as RNase P2/O. Thus, our findings suggest that RNase P2/O and RNase E activities are of the same origin. These data are in keeping with the suggestion that the structure of the 5' leader influences tRNA expression by affecting tRNA processing and indicate the involvement of RNase E in the regulation of cellular tRNA levels.


Shunt Failure-Risk Factors and Outcomes: An Analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database.
Systemic-to-pulmonary shunt failure is a potentially catastrophic complication. We analyzed a large multicenter clinical registry to describe the prevalence and evaluate risk factors. Infants (aged ≤365 days) undergoing shunt operations (systemic artery-to-pulmonary artery or systemic ventricle-to-pulmonary artery) in The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) from 2010 to 2015 were included. Multivariable logistic regression was used to evaluate risk factors for in-hospital shunt failure. Model covariates included patient characteristics, preoperative factors, procedural factors including shunt type, and center effects. Centers with more than 15% missing data for key covariates were excluded. Shunt operations were performed in 9,172 infants (118 centers). In-hospital shunt failure occurred in 674 (7.3%). In multivariable analysis, risk factors for in-hospital shunt failure included lower weight at operation (odds ratio [OR], 1.35; p = 0.001), preoperative hypercoagulable state (OR, 2.47; p = 0.031), and the presence of any other STS-CHSD preoperative risk factors (OR, 1.24; p = 0.038). Shunt failure was less likely with a systemic ventricle-to-pulmonary artery shunt than a systemic artery-to-pulmonary artery shunt (OR, 0.65; p = 0.020). Neither cardiopulmonary bypass nor single-ventricle diagnosis was a risk factor for shunt failure. Patients with in-hospital shunt failure had significantly higher rates of operative mortality (31.9% vs 11.1%, p < 0.001) and major morbidity (84.4% vs 29.4%, p < 0.001), and longer median postoperative length of stay among survivors (45 vs 22 days, p < 0.001). In-hospital shunt failure is common, and associated mortality risk is high. These data highlight at-risk patients and procedural cohorts that warrant expectant surveillance and may benefit from enhanced antithrombotic prophylaxis or other management strategies to reduce shunt failure. These findings may inform planning of future clinical trials.


Is it possible to repair the damaged prefrontal cortex by neural tissue transplantation?
The techniques are now well established for the viable transplantation of cortical and other neural tissues into the neonatal and adult cortex, at least in the laboratory rat. Under appropriate conditions such grafts survive well and can establish reciprocal connections with the host brain. On this basis, neural transplantation has become a powerful technique for the study of mechanisms involved in the development of the central nervous system and its capacity for regeneration after injury. Moreover, a variety of anatomical, electrophysiological and behavioural techniques suggest that grafted neural tissue may sustain functional interactions with the host brain. However, the extent and duration of recovery using present techniques is extremely limited. It remains undetermined whether such experimental observations may ever acquire therapeutic application.


Synthesis and biological evaluation of some nitrogen containing steroidal heterocycles.
epi-Androsterone 1 was converted into its hydrazone derivative through the reaction with hydrazine hydrate 80%. Hydrazonoandrostane derivative 2b reacted with hydrazonoyl halides in the presence of K(2)CO(3) forming the corresponding hydrazopyridazinoandrostane derivatives 6a-d. The 3β-acetyl-17-hydrazonoandrostane derivative 2b reacted with a halogen reagent, benzoyl chloride, to form the non-cyclic 16-benzoylated hydrazone 9. On the other hand, compound 2b produced the corresponding pyridazinoandrostane derivatives 11 and 12 via its reaction with phenacyl bromide and chloroacetone respectively. Reaction of the hydrazono derivative 2b with benzaldehyde in the presence of acetic acid drops led to the formation of the benzylidenehydrazonoandrostane derivative 13. The product 14, phosphinom-ethylenehydrazonoandrostane was obtained by the reaction of the derivative 13 with trisdimethylaminophosphine in the presence of dry benzene. The reaction of compound 2b with phenyl isothiocyanate followed by boiling in chloroacetic acid or thioglycolic acid produced the pyrazoloandrostane derivatives 17 and 18 respectively. The biological activity of compounds 6a, 6d, 11, 12, and 15 was evaluated as inhibitor of growth in a human liver carcinoma cell line and doxorubicine was used for comparison. Compounds 15 and 12 showed a higher potency than the other tested compounds.


Fibroblast growth factor 2 reduces endoplasmic reticulum stress and apoptosis in in-vitro Non-Alcoholic Fatty Liver Disease model.
Non-Alcoholic fatty liver disease is characterized by the accumulation of excess fat in the liver, chronic inflammation, and cell death, ranging from simple steatosis to fibrosis, and finally leads to cirrhosis and hepatocellular carcinoma. The effect of Fibroblast growth factor 2 on apoptosis and ER stress inhibition has been investigated in many studies. In this study, we aimed to investigate the effect of FGF2 on the NAFLD in-vitro model in the HepG2 cell line. The in-vitro NAFLD model was first induced on the HepG2 cell line using oleic acid and palmitic acid for 24 h and evaluated by ORO staining and Real-time PCR. The cell line was then treated with various concentrations of fibroblast growth factor 2 for 24 h, total RNA was extracted and cDNA was consequently synthesized. Real-time PCR and flow cytometry was applied to evaluate gene expression and apoptosis rate, respectively. It was shown that fibroblast growth factor 2 ameliorated apoptosis in the NAFLD in-vitro model by reducing the expression of genes involved in the intrinsic apoptosis pathway, including caspase 3 and 9. Moreover, endoplasmic reticulum stress was decreased following upregulating the protective ER-stress genes, including SOD1 and PPARα. FGF2 significantly reduced ER stress and intrinsic apoptosis pathway. Our data suggest that FGF2 treatment could be a potential therapeutic strategy for NAFLD.


UV-mediated genotoxicity of furanoquinoline and of certain tryptophan-derived alkaloids.
Certain furanoquinolines of the Rutaceae and a number of the widely distributed beta-carboline or harmane alkaloids are photosensitizers in near ultraviolet light (320-400 nm). These compounds have been shown to be phototoxic to yeasts and bacteria. In addition, two canthinones of the Rutaceae and the N-methylpyrolidine substituted harmane alkaloid, brevicolline (from Carex), display phototoxicity towards bacteria and fungi in near ultraviolet light. All of these alkaloids are phototoxic to Chinese hamster ovary cells, inhibiting mitosis and causing gross chromosomal changes. The target for their phototoxicity appears to be the cell nucleus.


An analytical quantification of mass fluxes and natural attenuation rate constants at a former gasworks site.
A new integral groundwater investigation approach was used for the first time to quantify natural attenuation rates at field scale. In this approach, pumping wells positioned along two control planes were operated at distances of 140 and 280 m downstream of a contaminant source zone at a former gasworks site polluted with BTEX- (benzene, toluene, ethyl-benzene, o-, p-xylene) and PAH- (polycyclic aromatic hydrocarbons) compounds. Based on the quantified changes in total contaminant mass fluxes between the control planes, first-order natural attenuation rate constants could be estimated. For BTEX-compounds, these ranged from 1.4e-02 to 1.3e-01 day(-1) whereas for PAH-compounds natural attenuation rate constants of 3.7e-04 to 3.1e-02 day(-1) were observed. Microbial degradation activity at the site was indicated by an increase in dissolved iron mass flux and a reduction in sulphate mass flux between the two investigated control planes. In addition to information about total contaminant mass fluxes and average concentrations, an analysis of the concentration-time series measured at the control planes also allowed to semi-quantitatively delineate the aquifer regions most likely contaminated by the BTEX- and PAH-compounds.


Serum S-100 beta protein during coronary artery bypass graft surgery with or without cardiopulmonary bypass.
Brain damage is a serious complication of cardiac anesthesia. The purpose of this study was to detect brain damage at different surgical stages during coronary artery bypass graft with or without cardiopulmonary bypass. We conducted a prospective, longitudinal study to evaluate serum S-100 beta protein, an early marker of brain injury, in patients electively undergoing off-pump (n = 30) or traditional coronary artery bypass graft (n = 60). Blood was sampled immediately before anesthesia, before and after cardiopulmonary bypass, and on the day after surgery. Serum S-100 beta protein was lowest immediately before induction of anesthesia and significantly increased before and after cardiopulmonary bypass, then declined by the first postoperative day in both groups. Peak values were highest in the traditional group directly after coronary artery bypass graft. On the day after surgery, S-100 beta protein levels were similar between groups, but were higher than baseline within each group. Significant increase in serum S-100 beta protein was also observed even before cardiopulmonary bypass in cardiopulmonary bypass patients, or before manipulation of the heart and aorta in off-pump patients. These reflect the possibility that brain damage may occur before major manipulation (cardiopulmonary bypass or manipulating heart and aorta). Moreover, S-100 beta levels did not return to normal on the day after the operation. This prospective study has shown that serum S-100 beta protein was not only higher than baseline both after cardiopulmonary bypass and on the day after surgery in both groups of patients but it was also significantly increased before cardiopulmonary bypass or manipulation of the heart or aorta. These findings may have implications for anesthesiologic care during the total course of cardiac surgery.


Cancer risk and survival according to body mass index in hepatobiliary malignancies: a nationwide registry-based cohort study.
The aim of this study was to explore the associations between BMI and cancer of the liver, bile ducts, and gallbladder. A registry-based cohort study was performed by linking data from several national registries in Norway. The cohort comprised 1 723 692 individuals including 4768 hepatobiliary cancer cases during 55 743 509 person-years of follow-up. In men, we found increased risk of cancer per 5 kg/m2 BMI increase for hepatocellular carcinoma and extrahepatic cholangiocarcinoma. In women there was increased risk of extrahepatic cholangiocarcinoma and gallbladder cancer. Women with high BMI in early adulthood had increased risk of intrahepatic cholangiocarcinoma. Reduced cancer-specific survival was found for all hepatobiliary malignancies in women with overweight and obesity. In men, reduced survival was observed in individuals with obesity for all hepatobiliary cancers, except gallbladder cancer. Increased risk of cancer-death per 5 kg/m2 BMI increase was found for hepatocellular carcinoma, intra-, and extrahepatic cholangiocarcinoma in women. For men, 5 kg/m2 BMI increase was positively associated with cancer-death from intrahepatic cholangiocarcinoma. This study supports the notion of an increased risk of hepatobiliary cancers with increasing BMI, with sex and age variations. The findings also suggest a higher risk of cancer-death with increasing BMI.


Treating the mother, protecting the unborn: the motherisk approach.
Pregnant women and their unborn babies are excluded from most pharmaceutical research. We have to convince regulatory agencies worldwide that, by not demanding research of drug safety and effectiveness in pregnancy from pharmaceutical agencies, we are orphaning pregnant women from progress in therapeutics and causing both themselves and their unborn babies tremendous unacceptable risks.


A new species of Tychobythinus Ganglbauer, 1896 (Coleoptera: Staphylinidae: Pselaphinae) from Turkey.
A new species of the genus Tychobythinus Ganglbauer, 1896, Tychobythinusoculatus sp. n., is described from near Köyceğiz, Muğla Province, in southwestern Turkey. The new species is morphologically closely related to Tychobythinusabnormipes Reitter, 1910, and Tychobythinuspauper Kiesenwetter, 1858, but can be readily distinguished from both by having very simplified internal armature of the aedeagus, and by the specific shape of the gular depression.


Clusterin transcript variants expression in thyroid tumor: a potential marker of malignancy?
Clusterin (CLU) is a ubiquitous multifunctional factor involved in neoplastic transformation. The CLU transcript variants and protein forms play a crucial role in balancing cells proliferation and death. We investigated the regulation of CLU transcript variants expression in an in vivo model system consisting of both neoplastic tissues and fine needle aspiration biopsy (FNAB) samples isolated from patients undergoing thyroidectomy. The immunohistochemical analyses showed an overall CLU up-regulation in papillary carcinoma. A specific CLU2 transcript variant increase was registered using qPCR in papillary carcinomas while CLU1 decreased. In addition, the analysis of CLU transcripts expression level showed an increase of the CLU2 transcript in the TIR 3 patients with histologically confirmed thyroid cancer. Our results suggest the existence of a specific alteration of CLU2:CLU1 ratio towards CLU2, thus providing the first circumstantial evidence for the potential use of CLU transcript variants as effective biomarkers for a more accurate assessment of the so called "indeterminate" thyroid nodules.


Decontamination assessment of Bacillus anthracis, Bacillus subtilis, and Geobacillus stearothermophilus spores on indoor surfaces using a hydrogen peroxide gas generator.
To evaluate the decontamination of Bacillus anthracis, Bacillus subtilis, and Geobacillus stearothermophilus spores on indoor surface materials using hydrogen peroxide gas. Bacillus anthracis, B. subtilis, and G. stearothermophilus spores were dried on seven types of indoor surfaces and exposed to > or =1000 ppm hydrogen peroxide gas for 20 min. Hydrogen peroxide exposure significantly decreased viable B. anthracis, B. subtilis, and G. stearothermophilus spores on all test materials except G. stearothermophilus on industrial carpet. Significant differences were observed when comparing the reduction in viable spores of B. anthracis with both surrogates. The effectiveness of gaseous hydrogen peroxide on the growth of biological indicators and spore strips was evaluated in parallel as a qualitative assessment of decontamination. At 1 and 7 days postexposure, decontaminated biological indicators and spore strips exhibited no growth, while the nondecontaminated samples displayed growth. Significant differences in decontamination efficacy of hydrogen peroxide gas on porous and nonporous surfaces were observed when comparing the mean log reduction in B. anthracis spores with B. subtilis and G. stearothermophilus spores. These results provide comparative information for the decontamination of B. anthracis spores with surrogates on indoor surfaces using hydrogen peroxide gas.


An oxygen-binding flavohemoprotein from Alcaligenes eutrophus.
A procedure is described for the purification of a soluble flavohemoprotein from the hydrogen bacterium Alcaligenes eutrophus. The isolated protein exists as a monomer with a molecular weight of approx. 43,000. The molecule contains two prosthetic groups, 1 mol each of noncovalently bound FAD and protoheme per monomer. The absorption spectra of the protein in its ferric, ferrous-deoxy and ferrous-carboxy forms are similar to those of hemoglobins, with the exception of the flavin contribution (absorption maxima--ferric form: 395, 456, 483, 645 nm; ferrous-deoxy form: 436, 560 nm; ferrour-CO form: 423, 539, 569 nm). The flavohemoprotein when reduced by NADH in aerobic solution is capable of binding oxygen reversibly. The stable oxygenated complex exhibits absorption maxima at 414, 541, and 576 nm. The protein catalyzes the reduction of various dyes and cytochrome c by NADH.


Lymphatic smooth muscle responses to leukotrienes, histamine and platelet activating factor.
Regional lymphatics regulate the accumulation of edema resulting from inflammation. The effects of mediators of inflammation on lymphatic smooth muscle, the primary determinant of lymph flow, are poorly understood. We studied mesenteric lymphatic vessels in 22 anesthetized rats with in vivo videomicroscopy following topical applications of histamine, leukotriene C4 or D4, or platelet-activating factor (PAF). Diameter, contractility, and contraction frequency were measured, and flow was calculated. Histamine caused increases in vessel diameter and contractility (174 and 218% of control, respectively; P less than 0.05), while contraction frequency was unaffected. Leukotrienes C4 and D4 caused an increase in frequency of contraction (348 and 392% of control, respectively; P less than 0.05), while having no significant influence on diameter or contractility. PAF caused smooth muscle relaxation, resulting in vasodilation and a decrease in contraction frequency (202 and 5% of control, respectively; P less than 0.05). Topical application of histamine and leukotrienes caused significant increases in calculated flow, while PAF decreased calculated flow. Mediators of inflammation have striking and diverse effects on lymphatic smooth muscle activity.


Hallucination-Specific structure-function associations in schizophrenia.
Combining structural (sMRI) and functional magnetic resonance imaging (fMRI) data in schizophrenia patients with and without auditory hallucinations (9 SZ_AVH, 12 SZ_nAVH), 18 patients with bipolar disorder, and 22 healthy controls, we examined whether cortical thinning was associated with abnormal activity in functional brain networks associated with auditory hallucinations. Language-task fMRI data were combined with mean cortical thickness values from 148 brain regions in a constrained principal component analysis (CPCA) to identify brain structure-function associations predictable from group differences. Two components emerged from the multimodal analysis. The "AVH component" highlighted an association of frontotemporal and cingulate thinning with altered brain activity characteristic of hallucinations among patients with AVH. In contrast, the "Bipolar component" distinguished bipolar patients from healthy controls and linked increased activity in the language network with cortical thinning in the left occipital-temporal lobe. Our findings add to a body of evidence of the biological underpinnings of hallucinations and illustrate a method for multimodal data analysis of structure-function associations in psychiatric illness.


Monodisperse microsphere-based immobilized metal affinity chromatography approach for preparing Antarctic krill phospholipids followed by HILIC-MS analysis.
Phospholipids enriched krill is a functional food beneficial in cardiovascular diseases. Herein, monodisperse microsphere-based immobilized metal affinity chromatographic material (MM-IMAC) was synthesized with Ti4+ incorporated to enrich phospholipids from krill by coordination with phosphate group. The extract was profiled by hydrophilic interaction chromatography-mass spectrometry (HILIC-MS) with 154 phospholipid molecular species detected. The parameters were loading solvent n-hexane/isopropanol (2:8, v/v), flow rate 0.8 mL·min-1, and eluting volume 1 mL. Besides, eicosapentaenoic and docosahexaenoic acids structured phospholipids were located, such as phosphatidylcholine (PC) 20:5/22:6, phosphatidylinositol (PI) 18:0/20:5, etc. Finally, this method was validated in linearity (R2 ≥ 0.9953), sensitivity (LOD ≤ 0.53 μg·mL-1 and LOQ ≤ 1.66 μg·mL-1), precision (RSDintraday ≤ 4.86% and RSDinterday ≤ 6.25%), and recovery (58-83%). It indicated that the MM-Ti4+-IMAC-HILIC-MS was reliable and efficient in specific study of phospholipids in food matrix.


Effect of calcium on the recovery and distribution of DNA polymerase alpha from cultured human cells.
It was recently reported (Lynch, W. E., Surrey, S., and Lieberman, I. (1975) J. Biol. Chem. 250, 8179-8183) that the extraction of regenerating rat liver in solutions of isotonic sucrose containing 4 mM CaCl2 leads to almost quantitative recovery of DNA polymerase alpha (Weissbach, A., Baltimore, D., Bollum, F., Gallo, R., and Korn, D. (1975) Science 190, 401--402) activity in the purified nuclear compartment. Our application of this method to the isolation of the DNA polymerase activities activities from cultured human epithelial and lymphoblastoid cells has led to substantially different results. We have observed that the inclusion of Ca2+ in either isotonic sucrose or hypotonic aqueous extraction media leads to the irreversible inactivation of the majority, cytoplasmic fraction of DNA polymerase alpha activity and is without quantitative effect on the recovery of the nuclear fraction of this activity.


Diagnostic and therapeutic challenges of childhood brucellosis in a nonendemic country.
We sought [corrected] to define the current epidemiology, clinical manifestations, and course of childhood brucellosis in the United States. A retrospective chart review was performed of 20 patients who received a diagnosis of brucellosis over a period of 13 years at a large, tertiary care children's hospital in Dallas, Texas. Diagnostic criteria, epidemiology, clinical presentations, and outcomes were recorded. Ninety-five percent of the patients had a recent history of either travel to Mexico or ingestion of unpasteurized milk products from Mexico. Fever was an initial complaint in 80% of the patients, and 50% of the patients presented with arthritis. Diagnosis was made via the identification of Brucella melitensis in the blood cultures of 18 patients. Five patients experienced relapse, and 3 experienced treatment failure. Childhood brucellosis in the United States is now an imported disease, primarily from Mexico. In the context of this epidemiologic link, the diagnosis should be entertained for a patient who presents with signs of systemic inflammation and arthritis. Therapeutic challenges remain.


Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics.
Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated. Here we assemble a workflow to discover and analyse pharmaceutical-related measurements from routine untargeted UHPLC-MS metabolomics datasets, derived from in vivo (rat plasma and cardiac tissue, and human plasma) and in vitro (human cardiomyocytes) studies that were principally designed to investigate endogenous metabolic responses to drug exposure. Our findings clearly demonstrate how untargeted metabolomics can discover extensive biotransformation maps, temporally-changing relative systemic exposure, and direct associations of endogenous biochemical responses to the internal dose.


Bilateral same-day endoscopic transcanal cartilage tympanoplasty: initial results.
Same-day closure of bilateral tympanic membrane perforations is a quick and more comfortable procedure for the patients. However, conventional bilateral same-day tympanoplasty or myringoplasty has been rarely performed because of the theoretical risk of postoperative complications. To evaluate the advantages and outcomes of bilateral simultaneous endoscopic cartilage tympanoplasty in patients with bilateral tympanic membrane perforations. From February 2012 to March 2013, patients with bilateral dry tympanic membrane perforations who had some degree of hearing loss corresponding to the size and location of the perforation entered the study. There was no suspicion to disrupted ossicular chain, mastoid involvement or other middle or inner ear pathology. Endoscopic transcanal cartilage tympanoplasty was done using the underlay (medial) technique. The graft was harvested from cymba cartilage in just one ear with preservation of perichondrium in one side. A 1.5cm×1.5cm cartilage seemed to be enough for tympanoplasty in both sides. Nine patients (4 males and 5 females) with the mean age of 37.9 years underwent bilateral transcanal cartilage tympanoplasty in a same-day surgery. The mean duration of follow up was 15.8 months. There were detected no complications including hearing loss, otorrhea and wound complication with no retraction pocket or displaced graft during follow-up period. The grafts take rate was 94.44% (only one case of unilateral incomplete closure). The mean of air-bone gap overall improved from 13.88dB preoperatively to 9.16dB postoperatively (p<0.05). Bilateral endoscopic transcanal cartilage tympanoplasty can be considered as a safe minimally invasive procedure that can be performed in a same-day surgery. It reduces the costs and operation time and is practical with a low rate of postoperative complications.


How has the effect of brand personality on customer-based brand equity changed over time? Longitudinal evidence from a panel data set spanning 18 years.
Using a panel data set (n = 49,626), this research tests opposing hypotheses about the influence of brand personality dimensions (BPDs) on customer-based brand equity (CBBE) and the evolution of this influence over an 18-year period. The results show that, on average, the BPDs of excitement, competence, and sincerity have more positive effects on CBBE than sophistication and ruggedness. Furthermore, the effects of sincerity, sophistication, and ruggedness on CBBE have declined over time while the effects of excitement and competence have grown more positive: A 1% change in excitement is associated with a .45% change in CBBE in 2001 and a .71% change in 2018 (a 58% increase), while a 1% change in competence is associated with a .42% change in CBBE in 2001 and a .60% change in 2018 (a 43% increase). How these effects vary between countries, industry sectors, and brand types is also explored. The online version contains supplementary material available at 10.1007/s11747-022-00895-2.


Isolation and anticancer activity of quercetin from Acalypha indica L. against breast cancer cell lines MCF-7 and MDA-MB-231.
In this study, the active components of the plant were carefully extracted and identified using three solvent systems. After extraction, we used solvent systems to further purify the main flavonoid chemical constituent. As a result of our analytical strategy, which included HPLC analysis, MS/MS spectroscopic analysis, and NMR data-based constructions, quercetin was determined to be the main chemical constituent. Our study suggests the potential therapeutic advantages of quercetin, a compound found in the leaves of Acalypha indica, for treating breast cancer cell lines MCF-7 and MDA-MB-231. Our comparison of Quercetin to the regularly prescribed medicine Doxorubicin shows that it has the capacity to inhibit MCF-7 and MDA-MB-231 cells. Measurements of apoptosis and cell cycle phase showed this to be the case. Furthermore, a ladder that formed as a result of cellular damage brought on by ROS provided further proof of the drug's impact on DNA integrity. Notably, pro-apoptotic proteins displayed increased apoptosis activity in cells treated with quercetin. Given that it is extracted from plants and has less adverse effects than other compounds, quercetin is a viable option for further clinical study. The objective is to fight breast cancer, one of the most prevalent diseases in the world and a main cause of death for women. Thus, our research makes a significant addition to the ongoing search for potent, plant-based breast cancer treatments. The online version contains supplementary material available at 10.1007/s13205-023-03705-w.


EEG Analysis of the Neurofeedback Training Effect in Algorithmic Thinking.
Although significant advances have been made in understanding several cognitive states, the algorithmic thinking ability is yet to be analyzed in terms of neuroscience and brain imaging techniques. Studies on the effects of neurofeedback on learning disabilities especially mathematics disorders are limited. The objective of the present study is to evaluate the brain activity and activation differences between neurofeedback trained participants and controls, during the overall EEG analysis during continuous algorithmic tasks performance. A study of 182 children of upper education is proposed to assess the efficacy of two protocols of neurofeedback training as means of algorithmic thinking ability evaluation. Results suggest statistical significant variation in the mean SD values in terms of several brain waves ratios during algorithmic task solving epochs.


A Quantitative Flow Cytometry-Based Method for Autophagy Detection Across the Cell Cycle.
Autophagy is deregulated in cancer cells and often activated as a cellular stress response to anticancer therapies. Flow cytometry-based assays enable detection and quantification of various cellular markers in live or fixed cells. Here, a flow cytometry-based assay to characterize autophagy across the cell cycle is described. This method is based on selective plasma membrane permeabilization with digitonin and extraction of membrane-unbound LC3 protein followed by staining of the autophagosome-bound LC3 protein with antibody and labeling of DNA with propidium iodide. Staining with the LC3 antibody described here can be also combined with the staining of other cellular markers, allowing to quantitatively assess autophagy in relation to different cellular processes by flow cytometry.


Endoscopic burr hole evacuation of an acute subdural hematoma.
Acute subdural hematoma evacuations frequently necessitate large craniotomies with extended operative times and high relative blood loss, which can lead to additional morbidity for the patient. While endoscopic minimally invasive approaches to chronic subdural collections have been successfully demonstrated, this technique has not previously been applied to acute subdural hematomas. The authors report their experience with an 87-year-old patient presenting with a large acute right-sided subdural hematoma successfully evacuated via an endoscopic minimally invasive technique. The operative approach is outlined, and the literature on endoscopic subdural collection evacuation reviewed.


Is the older perineum a safer perineum? Risk factors for obstetric anal sphincter injury.
Obstetric anal sphincter injury (OASI) is the most common cause of anal incontinence. Identifying risk factors may facilitate change in labour and delivery practice, potentially reducing the risk. The objective of this study is to identify maternal, foetal and intrapartum risk factors for OASI in a regional hospital. We conducted a retrospective analysis of vaginal deliveries over a 10-year period (2008-2017). Anal sphincter injury was diagnosed by an experienced clinician and classified according to RCOG recommendations. A multiple logistic regression model was created using the presence of OASI as the dependent variable. Coefficients were adjusted for relevant maternal, foetal and intrapartum risk factors. During the study period, there were 23,887 vaginal deliveries. Of these births, 18,550 were spontaneous (77.66%), 3746 vacuum-assisted (15.68%), 1196 forceps (5.01%) and 395 sequential instrumental deliveries (1.65%). The overall rate of OASI was 1.76%, with an upward trend seen in nulliparous mothers. Significant factors that increased the risk of OASI were nulliparity, Asian ethnicity, delivery by forceps or sequential instruments, and shoulder dystocia. Vacuum delivery did not significantly increase risk. Maternal age ≥ 35 years confers a protective effect after adjusting for parity, birth weight and mode of delivery. Given the context of an ageing reproductive population, additional research is required to investigate the impact of maternal age on anal sphincter injury.


Added value of systemic inflammation markers in predicting pulmonary infection in stroke patients: A retrospective study by machine learning analysis.
Exploring candidate markers to predict the clinical outcomes of pulmonary infection in stroke patients have a high unmet need. This study aimed to develop machine learning (ML)-based predictive models for pulmonary infection.Between January 2008 and April 2021, a retrospective analysis of 1397 stroke patients who had CT angiography from skull to diaphragm (including CT of the chest) within 24 hours of symptom onset. A total of 21 variables were included, and the prediction model of pulmonary infection was established by multiple ML-based algorithms. Risk factors for pulmonary infection were determined by the feature selection method. Area under the curve (AUC) and decision curve analysis were used to determine the model with the best resolution and to assess the net clinical benefits associated with the use of predictive models, respectively.A total of 889 cases were included in this study as a training group, while 508 cases were as a validation group. The feature selection indicated the top 6 predictors were procalcitonin, C-reactive protein, soluble interleukin-2 receptor, consciousness disorder, dysphagia, and invasive procedure. The AUCs of the 5 models ranged from 0.78 to 0.87 in the training cohort. When the ML-based models were applied to the validation set, the results also remained reconcilable, and the AUC was between 0.891 and 0.804. The decision curve analysis also showed performed better than positive line and negative line, indicating the favorable predictive performance and clinical values of the models.By incorporating clinical characteristics and systemic inflammation markers, it is feasible to develop ML-based models for the presence and consequences of signs of pulmonary infection in stroke patients, and the use of the model may be greatly beneficial to clinicians in risk stratification and management decisions.


Systematic review with meta-analysis: conditioned pain modulation in patients with the irritable bowel syndrome.
Irritable bowel syndrome (IBS) is common and is characterised by recurrent abdominal pain, which is a major contributor to healthcare seeking. The neurobiological basis of this pain is incompletely understood. Conditioned pain modulation is a neuromodulatory mechanism through which the brain inhibits the nociceptive afferent barrage through the descending pathways. Reduced conditioned pain modulation has been implicated in the pathophysiology of IBS, although to date only in studies with relatively small sample sizes. To clarify the relationship between conditioned pain modulation and IBS by undertaking a systemic review and meta-analysis METHODS: A systematic review of MEDLINE and Web of Science databases was searched (up to 10 May 2018). We included studies examining conditioned pain modulation in adults with IBS and healthy subjects. Data were pooled for meta-analysis to calculate the odds ratio and effect size of abnormal conditioned pain modulation in IBS, with 95% confidence intervals (CI). The search strategy identified 645 studies, of which 13 were relevant and 12 met the inclusion criteria. Conditioned pain modulation in IBS patients vs healthy subjects was significantly reduced, odds ratio 4.84 (95% CI: 2.19-10.71, P < 0.0001), Hedges' g effect size of 0.85 (95% CI: 0.42-1.28, P < 0.001). There was significant heterogeneity in effect sizes (Q-test χ2 = 52, P < 0.001, I2 = 78.8%) in the absence of publication bias. Conditioned pain modulation is significantly diminished in patients with IBS vs healthy controls. These data suggest that abnormal descending pathways may play an important pathophysiological role in IBS, which could represent an investigation and a therapeutic target in IBS.


Deficiency of Lactoferrin aggravates lipopolysaccharide-induced acute inflammation via recruitment macrophage in mice.
Lactoferrin (Lf), a multiple functional natural immune protein, is widely distributed in mammalian milk and glandular secretions (bile, saliva, tears and nasal mucosal secretions, etc.). In the previous study, we found that Lf plays an anti-inflammatory and anti-tumorigenesis role in AOM/DSS (azoxymethane/dextran sulfate sodium) induced mouse colitis-associated colon cancer model. Although we found that Lf has anti-inflammatory effects in chronic inflammation, its specific role and mechanisms in acute inflammation have not been clarified. Here, we reported that the expression levels of Lf were significantly increased when the organism was infected by Gram-negative bacteria. We then explored the role and potential mechanism of Lf in lipopolysaccharide (LPS)-induced acute inflammation. In the LPS-induced acute abdominal inflammation model, Lf deficiency aggravated inflammatory response and promoted macrophage chemotaxis to the inflammation site. Lf inhibited macrophage chemotaxis by suppressing the expression of macrophage-associated chemokines Ccl2 and Ccl5. Highly activated NF-κB signaling in Lf-/- mice was responsible for the high expression of Ccl2 and Ccl5. Our results suggested that the anti-inflammatory effect of Lf offers a new potential treatment for acute inflammatory diseases.


Alterations in semen parameters in men wıth epilepsy treated with valproate.
Besides the well-known adverse effects of valproate (VPA), disorders related to male reproductive functions have been reported. Furthermore, only a limited number of previous studies have reported the relationship between VPA dose and impairment of the hormonal axis and semen quality. A patient with reversible changes that occurred in the sperm parameters after a dose increment of VPA. A 34-year-old male patient who was diagnosed with juvenile myoclonic epilepsy almost 15 years ago was admitted to our clinic. His seizures responded well to high doses of VPA treatment. As the VPA dose was increased, consecutive semen analyses were performed and averaged for each dose; the results showed a remarkable decline in the sperm count and a manifest loss of sperm motility. VPA treatment was gradually diminished and stopped; meanwhile, treatment with another antiepileptic (lamotrigin) was initiated to control the patient's seizures. Nine months later, the patient's semen analysis was within normal ranges. After modification of the patient's treatment regimen, he and his wife had a healthy baby. We suggest that VPA-dependent impairments in the hormone and semen analysis parameters were reversible after the termination of medical treatment, and that the VPA treatment did not cause permanent hormonal deregulation and, these side effects are dose dependent.


Patients' perspective on the burden of migraine in Europe: a cross-sectional analysis of survey data in France, Germany, Italy, Spain, and the United Kingdom.
Migraine is a distinct neurological disease that imposes a significant burden on patients, society, and the healthcare system. This study aimed to characterize the incremental burden of migraine in individuals who suffer from ≥4 monthly headache days (MHDs) by examining health-related quality of life (HRQoL), impairments to work productivity and daily activities, and healthcare resource utilization (HRU) in the EU5 (France, Germany, Italy, Spain, United Kingdom). This retrospective cross-sectional study used data from the 2016 National Health and Wellness Survey (NHWS; N = 80,600). Short-Form 36-Item Health Survey, version 2 (SF-36v2) physical and mental component summary scores (PCS and MCS), Short-form-6D (SF-6D), and EuroQoL (EQ-5D), impairments to work productivity and daily activities (Work Productivity and Activity Impairment Questionnaire (WPAI), and HRU were compared between migraine respondents suffering from ≥4 MHDs (n = 218) and non-migraine controls (n = 218) by propensity score matching using sociodemographic characteristics. Chi-square, T-tests, and Mann-Whitney tests were performed to determine significant differences between the groups after propensity score matching. HRQoL was lower in migraine individuals suffering from ≥4 MHDs compared with non-migraine controls, with reduced SF-36v2 PCS (46.00 vs 50.51) and MCS (37.69 vs 44.82), SF-6D health state utility score (0.62 vs 0.71), and EQ-5D score (0.68 vs 0.81) (for all, p < 0.001). Respondents with migraine suffering from ≥4 MHDs also reported higher levels of absenteeism from work (14.43% vs 9.46%; p = 0.001), presenteeism (35.52% vs 20.97%), overall work impairment (38.70% vs 23.27%), and activity impairment (44.17% vs 27.75%) than non-migraine controls (for all, p < 0.001). Additionally, HRU was significantly higher for individuals with ≥4 MHDs compared to their matched controls. Consistently, migraine subgroups (4-7 MHDs, 8-14 MHDs and CM) had lower HRQoL, greater overall work and activity impairment, and higher HRU compared to non-migraine controls. Migraine of ≥4 MHDs was associated with poorer HRQoL, greater work productivity loss, and higher HRU compared with non-migraine controls. The findings of the study suggest that an unmet need exists among individuals suffering from ≥4 MHDs in the EU5 suggesting the need for effective prophylactic treatments to lessen the humanistic and economic burden of migraine.


Opposite roles of MRF4 and MyoD in cell proliferation and myogenic differentiation.
The basic helix-loop-helix myogenic regulatory factors play critical roles in skeletal myogenesis. Among the myogenic regulatory factors (MRFs), MRF4 shows a biphasic expression pattern during the formation of myotomes, although its function remains unclear. In this study, we used BEF (spontaneously immortalized bovine embryonic fibroblast that shows myogenic differentiation by overexpression of MyoD) and C2C12 cells to investigate the function of MRF4. Ectopic expressions of MRF4 did not stimulate myogenic differentiation in the BEF and C2C12 cells, but did show a marked increase of cell proliferation, upregulation of cyclin E, and downregulation of p21WAF1. Furthermore, MRF4 was found to induce degradation of the MyoD protein, which acts as a transcriptional activator for p21WAF1, and thus indicates that MRF4 accelerates cell proliferation by suppressing MyoD-dependent p21WAF1 expression. However, forced expression of MyoD in the MRF4-overexpressing cells inhibited cell proliferation and partially induced myogenic differentiation, which suggests that MyoD is a potential negative intercessor of MRF4 in the regulation of the cell cycle. Taken together, these results indicate that MRF4 and MyoD play competitive roles in myogenesis by stimulating cell proliferation and differentiation, respectively.


A comparison of renewal, spontaneous recovery, and reacquisition after punishment and extinction.
Punishment and extinction are both effective methods of reducing instrumental responding and may involve similar learning mechanisms. To characterize the similarities and differences between them, we examined three well-established recovery or "relapse" effects -renewal, spontaneous recovery, and reacquisition - following either punishment or extinction of an instrumental response. In Experiment 1a, both punished and extinguished responses renewed to similar degrees following a context change at test (ABA renewal). In Experiment 1b, responding spontaneously recovered to similar degrees following punishment or extinction. In Experiment 2, responding was rapidly reacquired when the response was reinforced again following extinction but not following punishment, as predicted by the idea that the reinforcer delivered in reacquisition is part of the context of punishment, but not extinction. The results collectively suggest that both punishment and extinction produce similar context-dependent retroactive interference effects. More broadly, they also suggest that punished and extinguished responses may be equally likely to return following a change of context despite the intuition that punishment might provide a more extreme and effective means of suppressing behavior. To our knowledge, this is the first direct behavioral comparison of response recovery after punishment and extinction within individual experiments.