Conjugation of 4-aminosalicylate with thiazolinones afforded non-cytotoxic potent in vitro and in vivo anti-inflammatory hybrids.
Eicosanoids like leukotrienes and prostaglandins that produced within the arachidonic acid cascade are involved in the pathogenesis of pain, acute and chronic inflammatory diseases. A promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Aiming to develop balanced COX/LOX inhibitors; 4-aminosalicylate based thiazolinones having different substituents at the 5th position of the 4-thiazolinone ring (2-22) were designed, synthesized, characterized and evaluated in vitro and in vivo for their anti-inflammatory activity. Most of the investigated compounds showed high COX-2 inhibitory potencies (IC50 39-200 nM) with selectivity indexes (30-84). Two compounds, 19 and 21, (IC50 = 41 and 44 nM), are equipotent to celecoxib (IC50 = 49 nM), while compound 22 (IC50 = 39 nM) was the most potent. For 15-LOX, compounds 5, 11, 19, 21 and 22 revealed higher potency (IC50 1.5-2.2 µM) than zileuton (IC50 15 µM). Thus, compounds 5, 11, 19, 21 and 22 are potent dual inhibitors of COX-2 and 15-LOX. In vivo anti-inflammatory testing of these compounds revealed that, compounds 5 and 21 had an anti-inflammatory activity similar to indomethacin and celecoxib (% inhibition of oedema = 60 ± 9) and higher than diclofenac potassium (% inhibition = 52 ± 29), while compound 22 (% inhibition = 63 ± 5) was more active than the reference drugs. The results showed that the activity is controlled by the bulkiness and lipophilicity of the substituent at the 5th position. The cytotoxicity results revealed that all compounds are not cytotoxic, additionally, in an experimental model of ulcerogenic effect, the most active compounds 21 and 22 showed better safety profile than indomethacin. Further, at the active sites of the COX-1, COX-2 and 15-LOX co-crystal, 19, 21, and 22 showed high binding forces in free binding energy study, which is consistent with in vitro and in vivo results. In conclusion, these compounds are good candidates for further biological investigation as potential anti-inflammatory drugs with dual balanced inhibition of COX and 15-LOX and good safety profile.


Variation of favism-inducing factors (vicine, convicine and L-DOPA) during pod development in Vicia faba L.
Changes in the concentrations of vicine, convicine and L-DOPA in two cultivars of Vicia faba L. seeds in different stages of pod development were determined by high performance liquid chromatography (HPLC). The vicine and convicine content was highest in fresh green cotyledons (moisture content about 80%) and gradually declined until a constant level was reached when seed dry matter percentage was around 40%. A similar pattern of variation in glucoside concentration was observed for the seed coat. The pods contained neither vicine nor convicine but they were particularly rich in L-DOPA. These compounds were not homogeneously distributed in the seeds.


Castanospermine blocks the hyperglycemic response to carbohydrates in vivo: a result of intestinal disaccharidase inhibition.
Castanospermine is a potent inhibitor of rat intestinal glycohydrolases in vitro and prevents the hyperglycemic response to an oral sucrose challenge in vivo. Among the glycohydrolases tested, castanospermine was most effective against sucrase with an IC50 of 1.1 x 10(-7) M. In vivo, a significant effect was seen at doses less than 1 mg/kg in both normal and streptozotocin-treated rats. Castanospermine has a prolonged duration of activity in vivo with significant activity when administered 4 hours before sucrose.


Microsystem for in vitro primary and secondary immunization of channel catfish (Ictalurus punctatus) leukocytes with hapten-carrier conjugates.
Methods are described for the in vitro generation and detection of antibody-secreting cells (PFC) from channel catfish. Hapten-specific PFC can readily be enumerated by an indirect plaque assay employing rabbit antiserum to catfish Ig and guinea pig complement. A modified Mishell-Dutton-type culture system was developed for effectively generating significant in vitro anti-hapten PFC responses with catfish leukocytes at 27 degrees C. The classical hapten-carrier effect and primary responses to both TI and TD antigens were demonstrable with catfish cells. Variables found to be important with catfish cells included the serum supplement, cell densities and, to a lesser extent, antigen form. Optimistically these methods will prove useful in attempts to delineate the functional roles of different lymphocyte subpopulations in fish.


Management of abdominal aortic aneurysm.
A series of 245 patients was operated upon for abdominal aortic aneurysm during the years 1969-77, of whom 162 were elective cases while in 83 the aneurysm was leaking or had ruptured. The hospital mortality for the latter group fell from 77 per cent at the beginning of the study period to 30 per cent at the end. For elective operations, hospital mortality averaged 9.3 per cent, though during the last 2 years there were no deaths in the 51 consecutive cases. Operative methods and postoperative treatment changed during the years of the study, with few excision-replacement grafts and greater use of the inlay technique, most of the latter being simple unbranched Dacron tubes. Early graft infection, the most important and serious surgical complication, caused 9 deaths, an overall incidence of 3.7 per cent, of which 8 were in patients who received no perioperative antibiotics and only 1 among the patients who did receive them. All deaths were in the inlay group. The reasons for this are discussed. Since July 1976 perioperative antibiotic treatment has been routine for all arterial prosthetic graft patients in our hospital.


cAMP signaling pathway in depressed patients with psychotic features.
Abnormalities in protein kinase A (PKA) and Rap1 have recently been reported in depressed patients. The aim of the present study was to investigate the levels of these proteins in platelets from untreated unipolar and bipolar depressed patients with psychotic features. The levels PKA and Rap1 were assessed by Western blot analysis and immunostaining in 37 drug-free patients and 29 healthy subjects. Both unipolar and bipolar patients with psychotic depression have significantly lower levels of platelet regulatory type I and higher levels of catalytic subunits of PKA than controls, whereas the levels of regulatory type II were higher only in psychotic unipolar patients. No significant differences were found in the immunolabeling of both Rap1 and actin among groups. These findings support the idea that besides nonpsychotic depression, abnormalities of PKA could be linked, albeit in a somewhat different way, with psychotic depression.


Proliferative response of human venous endothelial cells to medium conditioned by human tumour cells.
Serum-free medium conditioned by the prior cultivation of cells of the IPT line (derived from a poorly differentiated carcinoma of the lung) contained material of a high MW which stimulated proliferation in cultures of endothelial cells from human umbilical vein. A response was shown by cells seeded on plastic, gelatin or collagen of type I or type IV, at densities of 25 to 200/mm2, and in media with serum concentrations ranging from 0.5 to 20% v/v. Cells plated on biological substrata showed a greater response than those on plastic.


Correlation of bone and cartilage markers in the synovial fluid with the degree of osteoarthritis.
In recent years, many biochemical markers were tested with the aim of developing a tool for the early detection and monitoring of osteoarthritis (OA). Apart from chondral markers, we also evaluated osseous markers from the synovial fluid to obtain more comprehensive information, and we compared the levels in relation to the severity of OA. In this prospective, cross-sectional study, synovial fluid samples were obtained from 73 patients with OA of the knee joint prior to operation and after the joint was flushed with 50 ml of normal saline. All patients underwent surgery and were classified in accordance with the Outerbridge and the Noyes classification. The measured biochemical markers included pyridinoline (PD), deoxypyridinoline (DPD), N-telopeptide (NTx), carboxyterminal propeptide of collagen-1 (PICP), matrix metalloproteinases (MMP-1 and MMP-3), and tissue inhibitor of MMPs (TIMP-1). The marker levels were normalized against the total protein content and were compared with the Outerbridge and the Noyes classification. For the majority of markers, the correlation coefficient was below r=0.3, with large 95% confidence intervals. The highest correlation coefficients were obtained from DPD and TIMP-1. In relation to the Outerbridge classification, DPD revealed high values only in stage IV. The overall results indicate that the majority of the tested markers are unspecific with regard to the different stages of OA. The two markers with the highest correlation coefficients showed no major sensitivity to detect OA at an initial stage. However, they might give additional information to clinical and radiological findings with regard to the severity of the disease.


External Drainage Alone Versus External Drainage With Vitrectomy in Advanced Coats Disease.
To evaluate the efficacy of transscleral drainage of subretinal fluid (TDSRF) with and without pars plana vitrectomy (PPV), which are performed as an adjunct to ablative therapies in advanced Coats disease. Retrospective, comparative case series. A total of 31 eyes from 31 consecutive patients with advanced Coats disease at an average age of 47.8 ± 34.2 (2-156) months at the time of the surgery, who underwent TDSRF alone or in combination with PPV. Main outcome measurements were LogMAR visual acuity values, anterior and posterior segment findings, need for further surgery, laser photocoagulation, and anti-vascular endothelial growth factor (anti-VEGF) treatment. Anatomical success was defined as the maintenance of retinal reattachment without any further surgery during follow-up. Sixteen patients underwent TDSRF alone, and 15 patients underwent combined TDSRF and PPV. Mean follow-up time was 34.8 ± 32.9 months (6-128). Anatomical success rate of combined TDSRF and PPV was higher than that of TDSRF alone (93.8% vs 75%, respectively). The incidence of epiretinal membrane formation, number of laser photocoagulation procedures, and anti-VEGF treatments were statistically significantly higher in the group that underwent TDSRF alone than in those who had combined TDSRF and PPV in the long term. There was an improvement in vision in only 4 eyes (12.9%) (all >3 years old at presentation) during the follow-up. Combined TDSRF and PPV appears to be more effective in controlling the disease than TDSRF alone, as an adjunct to ablative procedures for the treatment of advanced Coats disease. The need for additional treatment is much less with the addition of PPV.


MicroRNA-mediated breast cancer metastasis: from primary site to distant organs.
The recent upsurge of interest in microRNA (miRNA) is partly attributed to the discovery of the novel roles of miRNAs in many physiological and pathological processes, including tumor development. Research on breast cancer metastasis has also focused on the concept of miRNA, which can act either as promoters or as suppressors of metastases. This review will focus on a series of recent studies that demonstrate the involvement of miRNAs in breast cancer metastasis and will briefly describe various pathways of miRNA-regulated metastasis. Finally, future prospects will be discussed for the potential role of miRNAs as predictive markers and therapeutic agents for patients with breast cancer metastases.


A comparative bronchodilator study of salbutamol and salbutamol sulphate that were administered by metered-dose inhalers.
Twenty-one patients with mild-to-moderately-severe asthma participated in a placebo-controlled, double-blind, cross-over, randomized bronchodilator study of 200 micrograms of salbutamol (Glaxo) and 200 micrograms of salbutamol in the form of salbutamol sulphate (Riker; 50-microL and 25-microL valves) that were administered by metered-dose inhalers. The mean baseline forced expired volumes in one second (FEV1) were similar for the four separate study days. The three active treatments caused a significantly-greater FEV1 response than did placebo for four hours (P less than 0.05) and no difference was found between the treatments (P greater than 0.05). The power of the study was 75% with a clinically-significant difference in the FEV1 response of 25%. The administration of 200 micrograms of salbutamol (Glaxo) caused the same FEV1 response as did that of 400 micrograms of salbutamol at the end of that study day (P greater than 0.05), but both 200-micrograms doses of salbutamol sulphate (Riker) caused a smaller FEV1 response than did the 400 micrograms of salbutamol sulphate (P less than 0.05). These observations indicate that no clinically-significant difference occurs between the bronchodilator effects of salbutamol and those of salbutamol sulphate which is administered as 200 micrograms of salbutamol equivalent, with different propellant mixtures, dispersal agents and valvular systems.


Low Utilization of External Beam Radiation Therapy for Patients With Unresectable Hepatocellular Carcinoma: An Analysis of the United Network for Organ Sharing Database.
External beam radiation therapy (EBRT) is a safe and emerging bridging liver-directed therapy (LDT) to liver transplant (LT) for patients with hepatocellular carcinoma (HCC). The prevalence and clinical characteristics of patients receiving EBRT as an LDT for LT have not been evaluated. Our aim was to describe the utilization of EBRT in patients with HCC evaluated for LT in the United States. We analyzed United Network for Organ Sharing data from October 2013 to June 2020 and identified patients with HCC who applied for model for end-stage liver disease (MELD) exceptions for LT wait list prioritization. The primary outcome was the period prevalence of EBRT. We examined associations between clinical variables and EBRT and fit survival models with EBRT as a time-varying predictor. We identified 18,543 patients with HCC with MELD exception applications. EBRT was used in 658 patients (3.5%) either alone (1.2%) or combined with other LDT (2.3%). Transarterial chemoembolization was the most used LDT (59.3%), followed by thermal ablation (27.9%) and radioembolization (15.2%). EBRT prevalence rose by an average of 12.2% per year (P = .001). Use of EBRT differed by geographic region, ranging from 2% to 8% (P < .001). EBRT and no EBRT groups had similar initial MELD score, portal vein thrombosis, tumor diameter, number of tumors, bilirubin, and α-fetoprotein (P > .05). Median time-to-transplant from wait list registration for EBRT versus no EBRT groups was 10 months (95% confidence interval, 9.4-10.9) versus 11.9 months (95% confidence interval, 11.7-12.2; P < .001). Evaluated as a time-varying predictor, EBRT increased the risk of LT by 30% (sub-hazard ratio, 1.30; P < .001), while the effect of EBRT on the risk of wait list removal due to clinical deterioration or death (sub-hazard ratio, 1.07; P = .489) was nonsignificant. In the United States, EBRT is rarely used compared with other LDTs and exhibits geographic variation. Low EBRT utilization highlights a gap in the treatment armamentarium for HCC.


Effect of sonographically guided cerebral glioma surgery on survival time.
We investigated the value of intraoperative sonography in improving the prevalence of total tumor resection and the survival time of patients who underwent resection of cerebral gliomas. One hundred thirty-seven patients who underwent sonographically guided surgery were followed for 6 to 60 months. In addition, 60 randomly selected patients (30 with low-grade gliomas and 30 with high-grade gliomas) who had surgery in our hospital without sonographic guidance served as the control group. Follow-up included the survival time, and the difference in the survival time between the study and control groups was statistically analyzed. Total removal of the lesion was achieved in 77 cases (69%), and partial removal was achieved in 35 (31%). In the control low-grade glioma group, 6-month survival was 96.7%; 1-year survival was 73.3%; and 2-year survival was 53.3%. In the study low-grade glioma group, survival rates at 6 months, 1 year, and 2 years were 98.0%, 96.1%, and 88.2%, respectively. In the control and study high-grade glioma groups, survival rates at 6 months, 1 year, and 2 years were 83.3% and 93.4%, 43.3% and 59.2%, and 13.3% and 32.8%. When comparing survival at 6 months, 1 year, and 2 years between the control and study groups, there was no significant difference at 6 months (P > .05), but survival at 1 and 2 years was significantly different (P < .05). Sonographically guided resection of cerebral gliomas helps the surgeon understand the relationship between the lesion and the surrounding structures. It is of value in improving the prevalence of total tumor resection and the patient's survival time.


The Association Between Sleep Duration and Sleep Timing and Insulin Resistance Among Adolescents in Mexico City.
Emerging evidence suggests that short sleep duration and delayed sleep timing may be independently related to insulin resistance (IR), although findings are mixed. Our aim was to investigate associations between sleep duration and timing with insulin resistance among adolescents. The analytic sample included 384 Mexican adolescents from a birth cohort study who took part in a follow-up study beginning in 2015. Insulin and glucose were measured in fasting serum, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated (marker of insulin resistance; [insulin x glucose]/22.5). Sleep duration and midpoint were measured by actigraphy for 7 days after the visit and for analysis were separated by weekdays and weekends. In full and sex-stratified regression analysis, sleep duration and midpoint were exposures, and the log HOMA-IR was the outcome, adjusting for age. The mean age of the sample was 13.8 ± 1.93 with 51% female. Shorter sleep duration on weekdays was associated with higher log HOMA-IR (β = -.049, 95% confidence interval [CI] -.097 to -.0009). Later midpoints on weekdays and the weekend were independently associated with higher log HOMA-IR (β = .0408, 95% CI -.0049 to .087, and β = .0486, 95% CI .0042 to .093, respectively). Girls showed stronger associations than boys for both sleep duration and timing with HOMA-IR. Sleep duration and sleep timing were independently associated with insulin resistance, and associations were more pronounced among girls.


Estrogen induced expression of the C-jun proto-oncogene in the immature and mature rat uterus.
The expression of the proto-oncogene c-jun in response to estradiol treatment in immature and mature rat uterine tissue was measured using a cDNA encoding the mouse c-jun proto-oncogene. This probe hybridized to a major RNA band of 2.7 kb and a minor 3.2 kb band. In Northern blots of total RNA from both immature and mature rat uteri, estradiol treatment resulted in at least a 3 fold increase in expression of the 2.7 kb band over control levels by 3 hr post injection. By 12 hr post injection, expression of c-jun mRNA had returned to control levels. A strong induction (greater than 5 fold) of c-jun mRNA expression was also observed in stroma-myometrial tissue isolated from mature rats approximately 3 hours after treatment with estradiol. The similar kinetics of induction of c-fos and c-jun emphasizes the functional significance of the fos/jun heterodimer in control of uterine cell proliferation.


A signal process method for DNA segments separation in micro-channel electrophoresis.
This paper presents a signal process method for DNA segments separation in micro-channel electrophoresis. It is developed and optimized by using a laser induced fluorescence (LIF) based detection system. In this detection system, signal is sampled and processed through a novel signal process module. The results show that this signal process method provides good signal-to-noise ratios and lower limit of detection (LOD).


Crossed radio-immunoisoelectric focusing as a method of identifying isoallergens: identification of isoallergens in rat urine extracts.
A method of 2-dimensional radio-immunoelectrophoresis to detect directly the presence of 'isoallergens' in complex allergenic (skin test) extracts is described. This procedure, in which the components are separated by isoelectric focusing in agarose gel in the first dimension is therefore basically similar to that of crossed radio-immunoelectrophoresis, and hence has been termed crossed radio-immunoisoelectric focusing. The method has been applied to the allergens present in rat urine and has verified the presence of the cross-reacting alpha 2-euglobulin and prealbumin components in (at least) 3 and 2 isoallergenic forms respectively.


Evaluation of milk yield and composition, feed intake, chewing activities, and clinical variables in dairy cows under hot-humid climate of tropical zone.
Dairy cows increase heat loads when the temperature-humidity index (THI) value is elevated in the ambient environments. This condition often occurs in the tropical areas due to a higher THI rate throughout seasons. The major objective of the study was to investigate the different responses in milk yield and composition, chewing activities, and health parameters in dairy cows under the dry and wet seasons of tropical climate zone in Indonesia. Twenty mid-lactating Indonesian Holstein-Friesian cows (139.3 ± 24.63 DIM; 10 primiparous and 10 multiparous; 441 ± 21.5 kg BW) were randomly subjected to 2 groups, dairy cows under dry (n = 10) and wet season (n = 10). Both groups received the same diets throughout the experiment. To determine the heat stress condition, the THI values were recorded daily. Overall, a higher number of THI was more pronounced in wet season. A lower dry matter intake (DMI) and milk yield were observed in wet season group. A tendency towards higher milk protein contents was found in dairy cows under dry season compared to cows under wet season. The other milk compositions such as fat, lactose, and SNF remained unchanged in both dry and wet season groups. The comparison between both groups at several time points of eating and ruminating time revealed significantly higher in cows under dry season. Overall, a higher chewing per bolus was observed in cows under dry season than their counterparts. Furthermore, a tendential greater extent rectal temperature pointed in the wet season group compared to the dry season group relatively. Data suggest that a stronger heat stress condition in wet season was more pronounced compared to dry season, with adversely affecting stronger declined DMI, milk yield, and chewing activities of dairy cows.


Coagglutination for detection and serotyping of bacterial antigens: usefulness in acute pneumonias.
Staphylococcal coagglutination was evaluated for detection of Streptococcus pneumoniae and Haemophilus influenzae antigens in vitro and in the clinical setting of acute pneumonia. Coagglutination testing was performed with Phadebact reagents and with polyvalent and type-specific reagents for pneumococci prepared in the laboratory. Purified capsular antigens of 10 of 14 pneumococcal serotypes (included in the current pneumococcal vaccine formulation) were detected by coagglutination in the range of 0.5-62 ng/ml; serotype 6 was detected at 125 ng/ml, and serotypes 12, 23, and 25 were detected only at 500 ng/ml or more. Haemophilus influenzae type b antigen was detected at 100 ng/ml. Sputum, blood, and urine specimens of 36 consecutive patients admitted with pneumonia were evaluated prospectively by coagglutination. Nonspecific reactions were eliminated by pretreatment with ethylenediaminetetra-acetic acid and heating and with staphylococcal protein A. Eight of nine patients with sputum cultures positive for pneumococci had positive sputum coagglutination (sensitivity of 89%); 24 of 27 patients with cultures negative for pneumococci had negative sputum coagglutination (specificity of 89%). Serum or urine coagglutination was positive in five patients with pneumococcal pneumonia, including the only bacteremic case, the only fatality, and another patient who had a protracted clinical course. In conclusion, coagglutination is a simple, rapid, sensitive, and specific test for antigen detection in patients with acute pneumonia.


Simultaneous analysis of miRNA-mRNA in human meningiomas by integrating transcriptome: A relationship between PTX3 and miR-29c.
Although meningioma is a common disease, there is a lack of understanding of the underlying molecular mechanisms behind its initiation and progression. We used combined miRNA-mRNA transcriptome analysis to discover dysregulated genes and networks in meningiomas. Fourteen fresh-frozen meningioma samples and one human meningeal cell line were analyzed by using miRNA and whole transcriptome microarray chips. Data was filtered and analyzed. Candidate miRNAs and mRNAs were selected for validation in fifty-eight patient samples. miRNA and target mRNA relationships were assessed by inhibiting miRNA in meningioma cells. Apoptosis and viability assays were also used as functional tests. With the whole transcriptome microarray, 3753 genes were found to be dysregulated, and 891 miRNAs were found to be dysregulated as a result of miRNA microarray. Results were combined and analyzed with bioinformatics tools. Top differential pathways included those of inflammation, cancer, and cellular growth and survival. The oncosupressor PTX3 was constitutively low in meningioma samples. Moreover, PTX3 negatively correlated with miR-29c in our samples. Inhibiting miR-29c upregulated the PTX3 level, induced apoptosis of meningioma cells, and decreased cell viability. CABIN1, miR-29c, TMOD1, PTX3, RPL22, SPARCL1 and RELA were correlated with clinicopathological features in patient samples. Our results present the first integrated mRNA-miRNA analysis in meningiomas. miR-29c-3p and PTX3 are inversely correlated in tissues and meningioma cells, hinting that PTX3 can be regulated by miR-29c-3p. Furthermore, we determined potential clinicopathological markers.


Computer model analysis of the radial artery pressure waveform.
Simultaneous measurements of aortic and radial artery pressures are reviewed, and a model of the cardiovascular system is presented. The model is based on resonant networks for the aorta and axillo-brachial-radial arterial system. The model chosen is a simple one, in order to make interpretation of the observed relationships clear. Despite its simplicity, the model produces realistic aortic and radial artery pressure waveforms. It demonstrates that the resonant properties of the arterial wall significantly alter the pressure waveform as it is propagated from the aorta to the radial artery. Although the mean and end-diastolic radial pressures are usually accurate estimates of the corresponding aortic pressures, the systolic pressure at the radial artery is often much higher than that of the aorta due to overshoot caused by the resonant behavior of the radial artery. The radial artery dicrotic notch is predominantly dependent on the axillo-brachial-radial arterial wall properties, rather than on the aortic valve or peripheral resistance. Hence the use of the radial artery dicrotic notch as an estimate of end systole is unreliable. The rate of systolic upstroke, dP/dt, of the radial artery waveform is a function of many factors, making it difficult to interpret. The radial artery waveform usually provides accurate estimates for mean and diastolic aortic pressures; for all other measurements it is an inadequate substitute for the aortic pressure waveform. In the presence of low forearm peripheral resistance the mean radial artery pressure may significantly underestimate the mean aortic pressure, as explained by a voltage divider model.


Antiparkinsonian activity and dopamine receptor binding studies of imidazolone derivatives.
Mannich bases and styryl derivatives of imidazolones were evaluated for their antiparkinsonian activity. Two compounds showed potent antiparkinsonian activity. These active compounds also showed binding with dopamine receptors in striatal membrane preparation of rat brain.


Artificial Intelligence and Big Data.
Medical images play an important role in ophthalmology and radiology. Medical image analysis has greatly benefited from the application of "deep learning" techniques in clinical and experimental radiology. Clinical applications and their relevance for radiological imaging in ophthalmology are presented.


Caruncle lesions: the use of histological evaluation in determining a definitive diagnosis.
Caruncle tumors are rare and difficult to definitively diagnose using standard clinical examination techniques. Because some of these lesions may be cancerous, eventually leading to local invasion of tissue, metastasis, and even death, biopsy with histologic evaluation may be indicated. A brief discussion of caruncle tumors and a case report is presented.


Effectiveness of oestrogen pretreatment in patients with expected poor ovarian response (POSEIDON groups 3 and 4) undergoing GnRH antagonist protocol: study protocol for a randomised controlled trial.
Women characterised by diminished ovarian reserve are considered to have poor ovarian response (POR) according to Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria. Patients in this population often have a poor prognosis for treatment with assisted reproductive technology. In previous studies, oestrogen pretreatment before ovarian stimulation has been shown to have a beneficial effect. However, recent studies presented conflicting conclusions. This study aims to evaluate the effectiveness of oestrogen pretreatment in patients with expected POR (POSEIDON groups 3 and 4) undergoing gonadotrophin releasing hormone antagonist (GnRH-ant) protocol. A prospective superiority randomised parallel controlled trial will be conducted at a tertiary university-affiliated hospital. A total of 316 patients will be randomly divided into two groups at a ratio of 1:1. In the intervention group, oral oestrogen pretreatment will be administered from day 7 after ovulation until day 2 of the next menstrual cycle. Afterwards, a flexible GnRH-ant protocol will be initiated. The control group will receive no additional intervention beyond routine ovarian stimulation. The primary outcome is the number of oocytes retrieved. Secondary outcomes include the total number of retrieved metaphase II oocytes, average daily dose of gonadotropin, total gonadotropin dose and duration of ovarian stimulation, cycle cancellation rate, top quality embryos rate, blastocyst formation rate, embryo implantation rate, clinical pregnancy rate, early miscarriage rate and endometrial thickness on trigger day. All data will be analysed according to the intention-to-treat and per-protocol principles. The ethical approval has been confirmed by the reproductive ethics committee of the affiliated hospital of Shandong University of Traditional Chinese Medicine (SDUTCM/2022.9.20). In addition, written informed consent will be obtained from all the participants before the study. The results will be disseminated via publications. ChiCTR2200064812.


Linkages between aerosol pollution and planetary boundary layer structure in China.
China suffers from high levels of PM2.5 pollution, which is often exacerbated by unfavorable planetary boundary layer (PBL) structures. Partly due to a lack of appropriate observations, the PBL-aerosol linkages in China are not clearly understood. Thus, we investigated these linkages from a national perspective using sounding data collected from 2014 to 2017. Correlation analyses revealed a significant anti-correlation between monthly boundary layer height (BLH) and aerosol pollution that was ubiquitous across China, indicating the important role of the PBL in regulating the seasonal variations of pollution in China. Besides, the day-to-day variations in pollution were modulated by the daily variabilities in the PBL structure. During winter, highly polluted days in most of the Chinese cities studied were associated with a low BLH, strong thermal stability, and weak PBL winds. In the North China Plain and Northeast China, the wintertime heavy pollution was often related to southerly winds and moister PBL. This study has important implications for understanding the crucial role that the PBL plays in modulating aerosol pollution in China.


Education and Training in Hemostasis: Perspectives of the Early Practitioner and Expert Practitioner.
Hemorrhagic emergencies in otolaryngology can present significant challenges to the early practitioner. The development of procedural skills, clinical decision making, effective communication strategies, and leadership remain critical to ensuring positive patient outcomes. Procedural task trainers and simulation-based complex scenarios provide safe and effective learning environments for young practitioners to build confidence and develop such skills. This article reviews the principles of managing epistaxis and postoperative neck hematoma geared toward early learners by providing a road map for educators to use in simulation-based curriculums.


T(2) relaxation time mapping reveals age- and species-related diversity of collagen network architecture in articular cartilage.
The magnetic resonance imaging (MRI) parameter T(2) relaxation time has been shown to be sensitive to the collagen network architecture of articular cartilage. The aim of the study was to investigate the agreement of T(2) relaxation time mapping and polarized light microscopy (PLM) for the determination of histological properties (i.e., zone and fibril organization) of articular cartilage. T(2) relaxation time was determined at 9.4 T field strength in healthy adult human, juvenile bovine and juvenile porcine patellar cartilage, and related to collagen anisotropy and fibril angle as measured by quantitative PLM. Both T(2) and PLM revealed a mutually consistent but varying number of collagen-associated laminae (3, 3-5 or 3-7 laminae in human, porcine and bovine cartilage, respectively). Up to 44% of the depth-wise variation in T(2) was accounted for by the changing anisotropy of collagen fibrils, confirming that T(2) contrast of articular cartilage is strongly affected by the collagen fibril anisotropy. A good correspondence was observed between the thickness of T(2)-laminae and collagenous zones as determined from PLM anisotropy measurements (r=0.91, r=0.95 and r=0.91 for human, bovine and porcine specimens, respectively). According to the present results, T(2) mapping is capable of detecting histological differences in cartilage collagen architecture among species, likely to be strongly related to the differences in maturation of the tissue. This diversity in the MRI appearance of healthy articular cartilage should also be recognized when using juvenile animal tissue as a model for mature human cartilage in experimental studies.


Comparison of captopril (0.5%) cream with diltiazem (2%) cream for chronic anal fissure: a prospective randomized double-blind two-centre clinical trial.
This study compared the efficacy of topical captopril with topical diltiazem in the treatment of chronic anal fissure (CAF). Fifty patients aged between 15 and 75 years with CAF were included in a prospective randomized, double-blind clinical trial. They were randomly allocated to either captopril (0.5%) cream or diltiazem (2%) cream in a dose of 2 cm of cream on the perianal skin every 12 h for 8 weeks. The intensity of pain upon defaecation was evaluated every 10 days using a visual analogue scale. Bleeding on defaecation, pruritus and the presence of perianal irritation were also recorded before and during the trial. The average pain scores were lower in the diltiazem group on the 20th and 30th days. From day 40 to the end of the trial the average pain scores of the two groups did not differ significantly. There were no significant differences in bleeding or perianal irritation between the groups, but the incidence of pruritus was considerably higher in the captopril group, and at the end of the trial 45.8% of the patients in this group still suffered from pruritus. Topical captopril and diltiazem were found to be equally effective in the management of pain, bleeding and perianal irritation due to CAF, but due to the high incidence of pruritus observed with topical captopril this medication is not recommended for the treatment of CAF.


Neoadjuvant chemotherapy, interval debulking surgery or primary surgery in ovarian carcinoma FIGO stage IV?
The aim of this study was to investigate the impact of surgical approach, the extent of surgery and chemotherapy on overall survival in patients with ovarian carcinoma (OC) stage IV. We retrospectively collected population-based data from the Norwegian Radium Hospital code registry on the diagnosis and surgery of 238 patients diagnosed with OC stage IV from 1996-2005. All patients received platinum-based chemotherapy. Surgical approach was registered as primary debulking surgery (PDS), interval debulking surgery (IDS) and delayed primary surgery (DPS). Surgery level was classified as radical surgery (RS), standard surgery (SS) or suboptimal surgery (SUBS). Univariate and multivariate analyses identified prognostic factors in PDS, IDS and DPS groups and subgroups. There were no differences in overall survival between the PDS, IDS and DPS groups. Surgery level was significantly associated with overall survival in the whole cohort (p<0.001), the PDS and IDS groups, but not in the DPS group. More patients with RS achieved no residual tumour (RT), but overall survival was not superior compared to no RT in the SS group. In 66 patients with no RT there were no differences in overall survival between those who underwent PDS, IDS and DPS. Chemotherapy with platinum/paclitaxel tended to improve survival. RT, World Health Organisation (WHO) performance status and histology were prognostic factors for overall survival in the whole cohort. No RT remains the objective, whether PDS, IDS or DPS is performed, and no differences in overall survival were found in the three treatment groups.


Pharmaceutical residues in water and sediment of Msunduzi River, KwaZulu-Natal, South Africa.
The little data about pharmaceutical residue contamination in African water bodies motivated our study on the occurrence of pharmaceutical residues in the water and sediment of Msunduzi River in the KwaZulu-Natal province of South Africa; and in the Darvill wastewater treatment plant found in Msunduzi catchment. Samples collected along the River and wastewater treatment plant were extracted and analysed for pharmaceutical residues selected based on statistics of drug usage in South Africa i.e. antipyretics, antibiotics, caffeine, an antiepileptic and an antipsychotic drug were determined using HPLC-MS/MS. In all the matrices investigated, the antipyretic ibuprofen had the highest concentration of up to 117 μg L(-1), 84.60 μg L(-1) and 659 ng g(-1) in wastewater, surface water and sediment respectively. Antibiotics were detected in generally low concentrations of<10 μg L(-1) in surface water samples and up to 34.50 μg L(-1) in wastewater; moreover they were not completely removed during wastewater treatment. The percentage removal efficiency of the studied group was 6.55-98.00% for antipyretics, 73.33-98.90% for antibiotics, 48.80% for the anti-epileptic drug and 86.40% for Caffeine. Clozapine exhibited a negative removal. In surface water, Henley dam exhibited a high concentration of the pharmaceutical residues and the highest concentration of metronidazole in sediment (up to 1253.50 ng g(-1)) detected. Metronidazole was only detected in sediment and bio-solids.


Prevalence and Correlates of Intracranial Atherosclerotic Disease Among Community-Dwelling Older Adults of Amerindian Ancestry. The Three Villages Study.
Knowledge on the prevalence and correlates of intracranial atherosclerotic disease (ICAD) is limited. We aimed to assess prevalence, clinical and neuroimaging correlates of ICAD in a cohort of older adults of Amerindian ancestry. The study included 581 community-dwellers aged ≥60 years (mean age 71 ± 8.4 years; 57% women) living in rural Ecuadorian villages. ICAD was identified by means of CT determinations of carotid siphon calcifications (CSC) or MRA findings of significant stenosis of intracranial arteries. Fully-adjusted logistic regression models were fitted with biomarkers of ICAD as the dependent variables. A total of 205 (35%) of 581 participants had ICAD, including 185 with high calcium content in the carotid siphons and 40 with significant stenosis of at least one intracranial artery (20 subjects had both biomarkers). Increasing age, high fasting blood glucose, >10 enlarged basal ganglia-perivascular spaces and non-lacunar strokes were associated with high calcium content in the carotid siphons. In contrast, male gender, moderate-to-severe white matter hyperintensities, lacunar and non-lacunar strokes were associated with significant stenosis of intracranial arteries. Stroke was more common among subjects with any biomarker of ICAD than in those with no biomarkers (29% versus 9%, p < 0.001). Significant stenosis of intracranial arteries was more often associated with stroke than high calcium content in the carotid siphons, suggesting that CSC are more likely an ICAD biomarker than causally related to stroke. ICAD prevalence in Amerindians is high, and is significantly associated with stroke. CSC and significant stenosis of intracranial arteries may represent different phenotypes of ICAD.


Neurite outgrowth of spinal neurons on tissue sections of embryonic muscle is largely integrin dependent.
Embryonic chick spinal neurons have been cultured over sections of human foetal muscle to determine which cell adhesion molecules present in embryonic muscle are important in promoting neurite outgrowth. Using blocking antibodies against the major cell adhesion molecules, neural cell adhesion molecule (NCAM), N-cadherin and the beta 1 subunit of the integrins, neurite outgrowth was significantly blocked only by anti-integrin antibodies. In addition other agents that block neurite outgrowth stimulated by NCAM, N-cadherin and L1, such as the calcium channel antagonists verapamil and omega-conotoxin and pertussis toxin which inactivates G-proteins also had no effect. This suggests that in this culture system integrins are able to promote neurite outgrowth whereas NCAM and N-cadherin are not.


Reactions of the fauna on the bark of trees to the frequency of fires in a North American savanna.
The arthropod communities living on the bark of the oak species Quercus macrocarpa and Q. ellipsoidalis were investigated in a North American oak savanna. Differences were found in the community structure of the arthropods living on the bark of these two tree species, although they have the same fissured bark type. In the North American oak savanna ecosystem the most important disturbance factor is fire, which maintains species richness. Highest numbers of species and specimens were found at moderately disturbed sites. Three main ecological groups of arthropods living on the bark of trees can be distinguished in relation to the degree of disturbance: (1) Inhabitants of bark of trees restricted to undisturbed sites: they do not occur in fire-disturbed areas; (2) Inhabitants of bark of trees adapted to a moderate degree of disturbance: many species occur in high numbers only in moderately disturbed areas; and (3) Specialist inhabitants of bark of trees in heavily disturbed areas. The number of specimens of these species increases per trunk with the frequency of disturbance.


Identification of the Fosl1/AMPK/autophagy axis involved in apoptotic and inflammatory effects following spinal cord injury.
Strategies for reducing spinal cord injury (SCI) have become a research focus because an effective treatment of SCI is unavailable. The objective of this study was to explore the underlying mechanisms of Fosl1 following SCI. Based on the analysis of the Gene Expression Omnibus (GEO) database, Fosl1 was found to be highly enhanced in SCI. This result was confirmed in our animal model, and Fosl1 was found to be obviously expressed in neurons. Next, we treated PC-12 cells with H2O2 to mimic injured neurons and further verified that Fosl1 silencing upregulated AMPK expression, promoted autophagy and inhibited inflammation and apoptosis. Subsequently, a special inhibitor of AMPK was used to examine the role of AMPK, and we learned that the inhibition of AMPK suppressed autophagy and promoted inflammation and apoptosis following Fosl1 silencing. These changes completely reversed the beneficial effects of Fosl1 silencing on injured PC-12 cells. Moreover, treatment with an AMPK activator resulted in effects that were opposite those of the inhibitor. Finally, rats were injected intrathecally with si-Fosl1 to detect its role in vivo. The results showed that si-Fosl1 improved neurological function and decreased apoptosis and inflammation at 14 d postoperation, and the activator further benefited the rats of si-Fosl1 treatment. In conclusion, Fosl1 inhibits autophagy and promotes inflammation and apoptosis through the AMPK signaling pathway following SCI in vivo and in vitro.


[Polysomnographic studies on sleep in adult borderline personality disorder].
Borderline personality disorder (BPD) represents 2% of the general population, 10% of outpatient psychiatry facilities, 20% of inpatients and nearly 41% of patients seen in Emergency Room for attempted suicide. Also, 10% complete suicide and 64-66% have comorbid substance dependence. In addition, several studies report sleep subjective complaints in patients with BPD, and research has explored objective sleep disturbances. To examine the results of previous studies in polysomnography in BPD to better characterize the objective sleep disturbances in this population. A review of the literature on MedLine and PsycINFO using the term "borderline personality disorder", "sleep" and "polysomnography" allowed the review of 15 original articles on sleep assessed by PSG in subjects adults with BPD, published between 1980 and may 2010. Compared with healthy subjects, a decreased onset delay of rapid eye movements (REM) sleep and an increased REM density have been observed in BPD. In addition BPD shares with major depression the following disturbances: increase in onset latency, decreased total sleep time and efficiency. Differences between studies regarding sex, age, mood state at the time of the study and psychiatric comorbidity influence the results, which explains the disparity in findings. There are objective disturbances associated with BPD according to polysomnographic studies.


Radiation protection measures during endourological therapies.
The objective of this narrative review was to search the existing literature for studies reporting measures to minimize radiation use during endoscopic management of stone disease and present ways of reducing the exposure of both patients and operating room staff. A literature review in PubMed was performed to identify studies describing protocols or measures to reduce radiation received during endourological procedures from January 1970 to August 2022. Eligible studies were those that reported outcomes for ureteroscopy or percutaneous nephrolithotripsy regarding measures to minimize radiation doses used intraoperatively, performed either in real-life theatres or using phantoms. Both comparative and non-comparative studies were deemed eligible. Protection can be achieved initially at the level of diagnosis and follow-up of patients, which should be done following an algorithm and choice of more conservative imaging methods. Certain protocols, which follow principles for minimized fluoroscopy use should be implemented and urologists as well as operating room staff should be continuously trained regarding radiation damage and protection measures. Wearing protective lead equipment remains a cornerstone for personnel protection, while configuration of the operating room and adjusting X-ray machine settings can also significantly reduce radiation energy. There are specific measures, which can be implemented to reduce radiation exposure. These include avoiding excessive use of computed tomography scans and X-rays during diagnosis and follow-up of urolithiasis patients. Intraoperative protocols with minimal fluoroscopy use can be employed. Staff training regarding dangers of radiation plays also a major role. Use and maintenance of protective equipment and setting up the operating room properly also serve towards this goal. Machine settings can be customized appropriately and finally continuously monitoring of exposure with dosimeters can be adopted.


Identification and localization of gonadotropin-inhibitory hormone (GnIH) orthologs in the hypothalamus of the red-eared slider turtle, Trachemys scripta elegans.
Gonadotropin-inhibitory hormone (GnIH) was discovered in 2000 as a novel hypothalamic neuropeptide that inhibited gonadotropin release in the Japanese quail. GnIH and its orthologs have a common C-terminal LPXRFamide (X=L or Q) motif, and have been identified in vertebrates from agnathans to humans, apart from reptiles. In the present study, we characterized a cDNA encoding GnIH orthologs in the brain of the red-eared slider turtle. The deduced precursor protein consisted of 205 amino-acid residues, encoding three putative peptide sequences that included the LPXRFamide motif at their C-termini. In addition, the precursor sequence was most similar to those of avian species. Immunoaffinity purification combined with mass spectrometry confirmed that three mature peptides were produced in the brain. In situ hybridization and immunohistochemistry showed that turtle GnIH-containing cells were restricted to the periventricular hypothalamic nucleus. Immunoreactive fibers were densely distributed in the median eminence. Thus, GnIH and related peptides may act on the pituitary to regulate pituitary hormone release in turtles as well as other vertebrates.


Interleukin-1β enhances cell migration through AP-1 and NF-κB pathway-dependent FGF2 expression in human corneal endothelial cells.
Interleukin (IL)-1β is a major pro-inflammatory cytokine that plays a crucial role in the regulation of inflammation and wound healing in the cornea. Elucidation of IL-1β signalling may help identify therapeutic targets for corneal wound healing; however, mechanisms such as cell migration, a component of IL-1β-induced wound healing response in human corneal endothelial cells (CEC), have not been well characterised. Stimulation of human CEC with IL-1β activated expression of fibroblast growth factor 2 (FGF2) and resulted in enhanced cell migration. This, in turn, was abolished by treatment with either IL-1 receptor antagonist or SU-5402, a pan-fibroblast growth factor signalling inhibitor. Phosphatidyl inositol (PI) 3-kinase or IL receptor-associated kinase 1/4 antagonists demonstrated that IL receptor-associated kinase 1/4 activates PI 3-kinase, which in turn phosphorylates p38 and inhibitor κB kinase α/β, leading to FGF2 expression through activation of activator protein 1 (AP-1) and nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) in human CEC. Treatment of IL-1β-stimulated human CEC with either AP-1 or NF-κB antagonists decreased FGF2 expression and resulted in reduced IL-1β-enhanced cell migration. Co-treatment of IL-1β-stimulated human CEC with both inhibitors completely blocked FGF2 expression and IL-1β-enhanced cell migration. Chromatin immunoprecipitation assays demonstrated that AP-1 and NF-κB directly bind to the FGF2 promoter following IL-1β stimulation. The results show that binding of IL-1β to its receptor in human CEC leads to parallel activation of AP-1 and NF-κB pathways, leading, in turn, to FGF2 expression and enhanced cell migration.


Exercise and the immune response.
A growing number of reports have become available which implicate infectious disease with reduced performance in athletes. The immune system consists of both nonspecific and specific components geared to control infections. Adaptive immunity functions through both antibody-mediated and cell-mediated compartments to establish and maintain long term immunity to infectious agents. Evidence is accumulating to support the view that physical exercise can lead to modification of the cells of the immune system. However, studies have often not been well designed to control exercise protocols when examining the effects of exercise on the immune system. Large numbers of peripheral blood lymphocytes are mobilised with exercise and in vitro tests indicate that temporarily these cells may not be capable of responding normally to mitogens. These reactions appear to be influenced by hormones to some degree and there are reports that the cells of the immune system are extremely active biochemically and may depend on products from muscles to maintain their activity. Specific populations within the circulating leucocyte pool vary significantly with exercise and there is some evidence that the T4/T8 lymphocyte ratio may become significantly reduced. This reduction in ratio may be related to the variable responses to T and B cell mitogens recorded in vitro which overall suggests that a temporary immune suppression may exist following certain training or performance schedules. It is argued that this may lead to a temporary susceptibility to infection and could result from overtraining.


Remnant cholesterol and the risk of cardiovascular disease in type 2 diabetes: a nationwide longitudinal cohort study.
Elevated remnant cholesterol (remnant-C) is considered a risk factor for cardiovascular disease (CVD); however, whether this notion applies to the East Asian population with type 2 diabetes (T2D) has not been established. This study investigated the association between remnant-C concentrations and the risk of CVD in Korean patients with T2D. By using the Korean National Health Insurance Service database, 1,956,452 patients with T2D and without atherosclerotic CVD who underwent regular health checks between 2009 and 2012 were included. Cox regression analyses were conducted to assess the association between remnant-C concentrations and incident CVD comprising myocardial infarction (MI) and ischemic stroke. In total, 50,120 (2.56%) cases of MI and 73,231 (3.74%) cases of ischemic strokes occurred during a median follow-up of 8.1 years. The adjusted hazard ratios for MI and stroke in the highest remnant-C quartile were 1.281 (95% confidence interval [CIs], 1.249-1.314) for MI and 1.22 (1.195-1.247) for ischemic stroke, compared to those in the lowest quartiles. The results were similar, based on stratified analysis by age, sex, use of statin or fibrate, and levels of other cholesterol. The increased risk of CVD in the highest remnant-C quartile was profound in patients who had a longer T2D duration. A remnant-C concentration ≥ 30 mg/dL differentiated patients who were at a higher risk of CVD, compared to patients with a lower concentrations, regardless of whether LDL-C levels were or were not on target at ≤ 100 mg/dL. In Korean patients with T2D, remnant-C was associated with CVD, independent of the LDL-C level or other conventional CVD risk factors. Our finding confirmed evidence of the causal role of remnant-C on CVD, as a residual risk of CVD, in East Asian patients with T2D.


Identification and functional analysis of a chemosensory protein from Bactrocera minax (Diptera: Tephritidae).
Olfaction has an indispensable role in insect behavior, enabling location of suitable host plants and oviposition sites, finding mates and evasion of natural enemies. Chemosensory proteins (CSPs) function to screen external odorants and transport them to olfactory receptor neurons, thereby increasing the sensitivity of the olfactory system. At present, CSP genes have been identified in many insect species, but there are relatively few studies on the function of CSP, especially in Tephritidae. In this study, we sequenced and analyzed 12 transcriptomes of Bactrocera minax and identified five CSP genes. The results of polymerase chain reactions with reverse transcription showed that BminCSP3 was highly expressed only in antennae. Results from competitive binding experiments showed that BminCSP3 has good binding ability to citral compared with 23 other volatile organic compounds. The docking model with citral showed hydrogen bond formation with residues (ARG97); however, no hydrogen bonds were formed in the docking of five other ligands (furfuryl alcohol, linalool, cis-3-hexenyl acetate, (R)-(+)-limonene and (+)-carvone). Electroantennogram (EAG) analyses revealed that citral was active in B. minax at the antennal level, and the EAG response value of female adults was significantly higher than that of male adults. Furthermore, the results of behavioral bioassays showed that females were significantly attracted to citral. Our results suggest that BminCSP3 plays an important role in the recognition of citral by B. minax adults. © 2022 Society of Chemical Industry.


Transneuronal uptake of horseradish peroxidase in the central nervous system of dipterous insects.
Horseradish peroxidase (HRP) applied to lesioned neurons in the retina and thoracic ganglia of the flies Musca, Calliphora and Drosophila labeled axons terminals, dendrites and perikarya of the severed neurons after anterograde or retrograde passage. In addition, HRP reaction product secondarily labeled intact neurons that are contiguous with injured nerve cells. In many cases labeling of optic lobe neurons remote from primarily filled ones was also seen (here called "tertiary" labeling). HRP labeling was extensive and both primarily and transneuronally filled neurons could be resolved in almost as much detail as Golgi-impregnated or cobalt-silver-labeled cells. Electron microscopy showed that in both primarily and secondarily filled neurons, reaction product was distributed diffusely in the cytoplasm. Transneuronal uptake of HRP was specific to certain types of neurons in the brain and thus displayed certain pathways. The pathways resolved by transneuronal labeling with HRP extend from the optic lobes to the thoracic ganglia and include visual neurons previously identified electrophysiologically and anatomically. Transneuronal HRP uptake, although believed to occur in vivo, could not be shown to be dependent on synaptic activity. Three other heme peptides tested were taken up by injured neurons, but showed no transneuronal labeling: lactoperoxidase, cytochrome c, and microperoxidase.


Phase separation drives the self-assembly of mitochondrial nucleoids for transcriptional modulation.
Mitochondria, the only semiautonomous organelles in mammalian cells, possess a circular, double-stranded genome termed mitochondrial DNA (mtDNA). While nuclear genomic DNA compaction, chromatin compartmentalization and transcription are known to be regulated by phase separation, how the mitochondrial nucleoid, a highly compacted spherical suborganelle, is assembled and functions is unknown. Here we assembled mitochondrial nucleoids in vitro and show that mitochondrial transcription factor A (TFAM) undergoes phase separation with mtDNA to drive nucleoid self-assembly. Moreover, nucleoid droplet formation promotes recruitment of the transcription machinery via a special, co-phase separation that concentrates transcription initiation, elongation and termination factors, and retains substrates to facilitate mtDNA transcription. We propose a model of mitochondrial nucleoid self-assembly driven by phase separation, and a pattern of co-phase separation involved in mitochondrial transcriptional regulation, which orchestrates the roles of TFAM in both mitochondrial nucleoid organization and transcription.


Anticonvulsant and behavioral effects observed in mice following treatment with an ester derivative of ferulic acid: Isopentyl ferulate.
The objective of this study was to evaluate the potential anticonvulsant effect of isopentyl ferulate, a new ester derived from ferulic acid in mice (Mus musculus) subjected to two models of induced seizures. According to the results obtained, the IF at doses of 25, 50 and 75 mg/kg (i.p.) showed protective effect against induced seizures by pilocarpine (400 mg/kg, i.p.) and pentylenetetrazole (70 mg/kg, i.p.). In the two animal models of seizures, the pretreatment of the IF (25, 50 and 75 mg/kg) with flumazenil blocked the anticonvulsant effect, suggesting that the mechanism of action of this ester derived of ferulic acid may be related to activity in the benzodiazepine-binding site of the GABAA receptor (γ-aminobutyric acid, type A). In addition to the anticonvulsant effect, behavioral changes as neurotoxicity indication were assessed by using the rota rod and open field tests. The results obtained showed that the IF (25, 50 and 75 mg/kg) does not induce significant changes in locomotor activity and motor coordination when compared with the control group, unlike the results presented by diazepam. Thus, these results demonstrate a new pharmacological knowledge of IF with potential application against epileptic seizures. However, further studies are needed to elucidate other neurobiological mechanisms underlying epilepsy.


Brazilin inhibits the Zn2+-mediated aggregation of amyloid β-protein and alleviates cytotoxicity.
Interactions of Zn2+ with amyloid β-protein (Aβ) and the subsequent induction of Aβ aggregation have been implicated in the pathogenesis of Alzheimer's disease (AD). The development of small-compound inhibitors against Zn2+-mediated Aβ aggregation is therefore greatly desired. In this study, brazilin was used to inhibit Zn2+-mediated Aβ aggregation and alleviate its cytotoxicity. The binding properties of brazilin and Zn2+ were first probed using Fourier transform infrared (FTIR) spectroscopy and isothermal titration calorimetry (ITC) assays. Both the FTIR and ITC results have shown that brazilin is able to bind Zn2+ in a physiologically suitable range of concentrations. The dissociation constant (Kd) between brazilin and Zn2+ was about 46.0±6.8μM, which makes brazilin a potential drug model for the chelation of free Zn2+. Moreover, the higher affinity of brazilin for Aβ42 (Kd=2.5±1.6μM) than that of Zn2+ (Kd=6.2±0. 9μM), enables brazilin to sequester Zn2+ from the Aβ42-Zn2+ complex. In addition, the inhibitory effects of brazilin on Zn2+-mediated Aβ aggregation were examined using the Thioflavin T fluorescence assay, transmission electron microscopy and cytotoxicity assays. It was found that brazilin showed remarkable inhibitory capability against Zn2+-induced aggregation of Aβ42. Furthermore, the Zn2+-mediated cytotoxicity of Aβ42 was also largely mitigated under the influence of brazilin. This study therefore provides further insights into the role of Zn2+ in the Aβ42 aggregation pathway, indicating potential new strategies for the design of small compounds with therapeutic potential for AD.


Bone marrow influences quantitative ultrasound measurements in human cancellous bone.
Quantitative ultrasound (QUS) transmission and backscatter measurements were made in 46 human cancellous bone specimens from the calcaneus. All QUS measurements were made at 35 degrees C, initially with marrow filling the pores and then repeated after substituting water for marrow. Bone mineral density (BMD) was determined using x-ray absorptiometry. Marrow significantly decreased ultrasound (US) velocity, but increased attenuation, attenuation slope and backscatter (p < 0.001 for all) compared to the water-saturated state. The impact of marrow on QUS measurements was greater at lower BMD values (p < 0.05), and was greater in women than in men (p < 0.05). QUS measurements in marrow-saturated specimens correlated less strongly with BMD than did corresponding measurements in water-saturated specimens (p < 0.05), consistent with interspecimen marrow heterogeneity. These data indicate that the potential impact of marrow should be considered when interpreting clinical QUS measurements. Understanding and exploiting these effects could lead to novel approaches for ultrasonic characterisation of both bone and marrow.


Characterization of Bacterial Communities in Deep-Sea Hydrothermal Vents from Three Oceanic Regions.
Deep-sea hydrothermal vents are considered to be one of the most spectacular ecosystems on Earth. Microorganisms form the basis of the food chain in vents controlling the vent communities. However, the diversity of bacterial communities in deep-sea hydrothermal vents from different oceans remains largely unknown. In this study, the pyrosequencing of 16S rRNA gene was used to characterize the bacterial communities of the venting sulfide, seawater, and tubeworm trophosome from East Pacific Rise, South Atlantic Ridge, and Southwest Indian Ridge, respectively. A total of 23,767 operational taxonomic units (OTUs) were assigned into 42 different phyla. Although Proteobacteria, Actinobacteria, and Bacteroidetes were the predominant phyla in all vents, differences of bacterial diversity were observed among different vents from three oceanic regions. The sulfides of East Pacific Rise possessed the most diverse bacterial communities. The bacterial diversities of venting seawater were much lower than those of vent sulfides. The symbiotic bacteria of tubeworm Ridgeia piscesae were included in the bacterial community of vent sulfides, suggesting their significant ecological functions as the primary producers in the deep-sea hydrothermal vent ecosystems. Therefore, our study presented a comprehensive view of bacterial communities in deep-sea hydrothermal vents from different oceans.


Religion, spirituality and improved glycemic control among people with type 2 diabetes: A systematic review.
This systematic review investigates the association between measures of religiosity or spirituality (R/S) and glycemic control in patients with type 2 diabetes. A systematic literature review was conducted for all English language articles published between 1966 and August 2022 in six relevant databases: PubMed, PSYCHinfo, CINAHL, ATLA, Scopus, Sociological Abstracts, and the Cochrane Central Register of Controlled Clinical Trials. Search terms for religious variables included, "religion", "religiosity", "spirituality", "religious attendance". Search terms for diabetes outcomes included, "diabetes", "hemoglobin A1c", "blood glucose", "glycemic control." The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO). A total of 758 studies examining correlations between R/S and glycemic control were screened from relevant databases. Forty studies were evaluated for eligibility and inclusion. Eight studies were selected and analyzed. Three studies showed positive associations, two studies showed positive and neutral associations, two studies showed positive and negative associations, and one study showed a neutral association. Limitations included small sample sizes and heterogeneity of study designs. Involvement in religious and spiritual practices may be associated with improved glycemic control in patients with type 2 diabetes. Specific mechanisms for associations may be partially explained by more effective self-management practices, increased positive social contacts, and regular community support. Further research is needed to clarify these associations.


Analysis of acylcarnitine levels by tandem mass spectrometry in epileptic children receiving valproate and oxcarbazepine.
This prospective study was designed to investigate whether or not monotherapy with sodium valproate (VPA) or oxcarbazepine (OXC) affects plasma levels of fatty acylcarnitine esters in children with epilepsy. A total of 56 children with idiopathic partial or generalised epilepsy were included in the study. Patients were assigned to receive either VPA or OXC monotherapy. Free carnitine (C0) and acylcarnitine profiles of the patients were investigated using tandem mass spectrometry at baseline and at six and 18 months after commencement of therapy. For patients receiving VPA or OXC monotherapy, there were no significant differences in plasma levels of C0, compared with baseline, at six and 18 months (p>0.05). Treatment with VPA for six and 18 months correlated with a significant increase in 3-hydroxy-isovalerylcarnitine (C5-OH) (six months: +23%; 18 months: +73%), and significant decreases in the following acylcarnitines: C6-acylcarnitine (six months: -60%; 18 months: -66%), C14-acylcarnitine (six months: -25%; 18 months: -38%), C16-acylcarnitine (six months: -73%; 18 months: -73%), and C18:1-OH-acylcarnitine (six months: -60%; 18 months: -70%), compared with baseline (p<0.05). In patients receiving OXC monotherapy, on the other hand, plasma concentrations (μmol/L) of acylcarnitines (from C2 to C18:1-OH) fell within the normal reference range. The results of this study indicate that there are significant biochemical changes in acylcarnitines in ambulatory children on VPA monotherapy but these are not clinically significant. OXC monotherapy had no effect on acylcarnitine metabolism in ambulatory children.


The renin-angiotensin-aldosterone system (RAAS) and cardiac arrhythmias.
The role of the renin-angiotensin-aldosterone system (RAAS) in many cardiovascular disorders, including hypertension, cardiac hypertrophy, and atherosclerosis, is well established, whereas its relationship with cardiac arrhythmias is a new area of investigation. Atrial fibrillation and malignant ventricular tachyarrhythmias, especially in the setting of cardiac hypertrophy or failure, seem to be examples of RAAS-related arrhythmias because treatment with RAAS modulators, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor blockers, reduces the incidence of these arrhythmias. RAAS has a multitude of electrophysiological effects and can potentially cause arrhythmia through a variety of mechanisms. We review new experimental results that suggest that RAAS has proarrhythmic effects on membrane and sarcoplasmic reticulum ion channels and that increased oxidative stress is likely contributing to the increased arrhythmic incidence. A summary of ongoing clinical trials that will address the clinical usefulness of RAAS modulators for prevention or treatment of arrhythmias is presented.


Ezrin immunoreactivity in relation to survival in serous ovarian carcinoma patients.
Ezrin is a membrane-cytoskeleton linker protein, which regulates cell polarity and signaling. Increased ezrin expression in astrocytomas and uveal melanomas is correlated with unfavorable prognostic factors and reduced patient survival. We investigated ezrin IR in normal ovarian surface epithelium and serous ovarian carcinomas, and its relation with clinical parameters and patient outcome. Tissue microarray blocks were constructed of all serous ovarian carcinoma tissue samples removed at a primary operation in Helsinki University Central Hospital between 1964 and 1999 and of healthy ovarian tissue samples. Ezrin expression was assessed by indirect immunohistochemistry using a monoclonal 3C12 ezrin antibody. Tissue samples (n = 440) were scored for the intensity of ezrin immunoreactivity, and the scores were compared with patient age, the stage and grade of disease, and disease outcome. Healthy ovarian epithelium showed strong polarized ezrin immunoreactivity. In serous ovarian carcinoma, the reactivity varied from strong (15.0% of samples) to moderate (57.3%) or weak/negative (27.7%) and the subcellular distribution was typically diffuse. Weak or negative expression of ezrin was associated with shorter survival (P = 0.027) but also with an advanced age of the patients (P = 0.0001), and a higher histological grade of the disease (P = 0.032). In Cox multivariate survival analysis, ezrin immunoreactivity had no independent effect on survival, when controlling for the stage and grade of the disease, and patient age. In contrast with astrocytomas and uveal melanomas, negative or weak ezrin immunoreactivity in serous ovarian carcinoma correlates with poor patient outcome.


Using high-resolution radar images to determine vegetation cover for soil erosion assessments.
Healthy soils are crucial for human well-being. Because soils are threatened worldwide, politicians recognize the need for soil protection. For example, the European Commission has launched the Thematic Strategy for Soil Protection, which requests the European member states to identify high risk areas for soil degradation. Most states use the Universal Soil Loss Equation (USLE) to assess soil erosion risk at the national scale. The USLE includes different factors, one of them is the vegetation cover and management factor (C factor). Modern satellite-based radar sensors now provide highly accurate vegetation cover data, enabling opportunities to improve the accuracy of the C factor. The presented study proves the suitability for C factor determination based on a multi-temporal classification of high-resolution radar images. Further USLE factors were derived from existing data sources (meteorological data, soil maps, digital elevation model) to conduct an USLE-based soil erosion assessment. The resulting map illustrates a qualitative assessment for soil erosion risk within a plot of about 7*12 km in an agricultural region in Poland that is very susceptible to soil erosion processes. A high erosion risk of more than 10 tonnes per ha and year was assessed to occur on 13.6% (646 ha) of the agricultural areas within the investigated plot. Further 7.8% (372 ha) of agricultural land is threaten by a medium risk of 5-10 tonnes per ha and year. Such a spatial information about areas of high or medium soil erosion risk are crucial for the development of strategies for the protection of soils.


Determination of moxifloxacin anaerobic susceptibility breakpoints according to the Clinical and Laboratory Standards Institute guidelines.
A summary of the key data presented to Clinical and Laboratory Standards Institute (CLSI, formerly National Committee for Clinical and Laboratory Standards) in determination of moxifloxacin anaerobic breakpoints is presented. The breakpoint analysis required review of a variety of data, including bacteriologic and clinical outcomes by MIC of anaerobic isolates from prospective clinical trials in patients with complicated intra-abdominal infections, human and animal pharmacokinetic/pharmacodynamic (PK/PD) information and in vitro models, MIC distributions of indicated organisms, and animal model efficacy data for strains with MIC values around prospective breakpoints. The compilation of the various components of this breakpoint analysis supports the US Food and Drug Administration (FDA) and CLSI moxifloxacin anaerobic breakpoints of < or =2 mg/L (susceptible), 4 mg/L (intermediate), and > or =8 mg/L (resistant), and provides information to European investigators for interpretation of MICs prior to establishment of the European Committee on Antimicrobial Susceptibility Testing breakpoints.


Modelling and Prevention of Acute Kidney Injury through Ischemia and Reperfusion in a Combined Human Renal Proximal Tubule/Blood Vessel-on-a-Chip.
Renal ischemia/reperfusion injury (rIRI) is one of the major causes of AKI. Although animal models are suitable for investigating systemic symptoms of AKI, they are limited in translatability. Human in vitro models are crucial in giving mechanistic insights into rIRI; however, they miss out on crucial aspects such as reperfusion injury and the multitissue aspect of AKI. We advanced the current renal proximal tubule-on-a-chip model to a coculture model with a perfused endothelial vessel separated by an extracellular matrix. The coculture was characterized for its three-dimensional structure, protein expression, and response to nephrotoxins. Then, rIRI was captured through control of oxygen levels, nutrient availability, and perfusion flow settings. Injury was quantified through morphologic assessment, caspase-3/7 activation, and cell viability. The combination of low oxygen, reduced glucose, and interrupted flow was potent to disturb the proximal tubules. This effect was strongly amplified upon reperfusion. Endothelial vessels were less sensitive to the ischemia-reperfusion parameters. Adenosine treatment showed a protective effect on the disruption of the epithelium and on the caspase-3/7 activation. A human in vitro rIRI model was developed using a coculture of a proximal tubule and blood vessel on-a-chip, which was used to characterize the renoprotective effect of adenosine. The robustness of the model and assays in combination with the throughput of the platform make it ideal to advance pathophysiological research and enable the development of novel therapeutic modalities.


Aberrant somatosensory-evoked responses imply GABAergic dysfunction in Angelman syndrome.
A role for gamma-aminobutyric acid (GABA)ergic inhibition in cortical sensory processing is one of the principle concerns of brain research. Angelman syndrome (AS) is thought to be one of the few neurodevelopmental disorders with GABAergic-related genetic involvement. AS results from a functional deficit of the imprinted UBE3A gene, located at 15q11-q13, resulting mainly from a 4-Mb deletion that includes GABA(A) receptor subunit genes. These genes are believed to affect the GABAergic system and modulate the clinical severity of AS. To understand the underlying cortical dysfunction, we have investigated the primary somatosensory-evoked responses in AS patients. Subjects included eleven AS patients with a 15q11-q13 deletion (AS Del), two AS patients without a 15q11-q13 deletion, but with a UBE3A mutation (AS non-Del), six epilepsy patients (non-AS) and eleven normal control subjects. Somatosensory-evoked fields (SEFs) in response to median nerve stimulation were measured by magnetoencephalography. The N1m peak latency in AS Del patients was significantly longer (34.6+/-4.8 ms) than in non-AS patients (19.5+/-1.2 ms, P<0.001) or normal control subjects (18.4+/-1.8 ms, P<0.001). The next component, P1m, was prolonged and ambiguous and was only detected in patients taking clonazepam. In contrast, SEF waveforms of AS non-Del patients were similar to those of control individuals, rather than to AS Del patients. Thus, GABAergic dysfunction in AS Del patients is likely due to hemizygosity of GABA(A) receptor subunit genes, suggesting that GABAergic inhibition plays an important role in synchronous activity of human sensory systems.


A 9-year retrospective study of poisoning-related deaths in Southwest China (Sichuan).
Poisoning is an increasing and significant burden that causes morbidity and mortality worldwide. In this retrospective study, poisoning-related cases that occurred in 19 cities and prefectures in Sichuan, Southwest China, between 2010 and 2018 were collected from the West China Forensic Medical Center of Sichuan and Public Security Bureaus. A total of 782 poisoning-related deaths were recorded, and their demographic characteristics, season of death, type of poison, and manner and cause of death were analysed. Of these cases, the victims were predominantly male (65.3%), and the 21∼50-year-old age group included the most victims (63.2%). The rural incidence was 71%. The most common poisoning agent was pesticide (40%), followed by toxic gases (32%), and there were cases of poisoning by poisonous animals and plants that are not common in other regions of China. The predominant manner of poisoning death was accident (50%), followed by suicide (38.3%) and homicide (5.0%). In this study, relevant information on poisoning-related cases was collected and compared with the poisoning data from other areas of China and foreign countries to provide guidance for the formulation of public health policies in Sichuan, Southwest China.


Plasmon-controlled shaping of gold nanostar photothermal therapy agents.
Tunable gold nanostars were synthesized through the reduction of gold salt by an aminosugar, N-methyl-D-glucamine, in a seed-less route. The nanoparticle morphology and size were facilely tuned through adjustments in reaction pH and LED light-mediated synthesis. The materials demonstrated low inherent cytotoxicity and high potential for photothermal therapy.


Using elderly donors in liver transplantation.
Elderly donors are half of the grafts available in our center for liver transplantation. We retrospectively investigated their characteristics, outcomes, and variables related to graft failure. From 1996 to 2003, 540 (46.4%) of 1163 donors were older than 60 years of age and 236 grafts (43.4%) were transplanted, whereas the others were refused. The clinical investigated variables were examined among this cohort. The median age of donors increased from 37 to 62 years. Donors older than 60 years of age were more often refused than younger ones (66% vs 44%); HCV-positive (9.9% vs 5.4%); HbcAb-positive (18.6% vs 12.6%), and steatotic (35.7% vs 13.9%; P < .01). Among donors older than 60 years, the main parameter to refuse the graft was the grade of steatosis. The variables related to the graft loss from donors older than 60 years were as follows: model for end stage liver disease (MELD) recipient >15 (65% vs 39%), cold ischemia time >10 hours (25% vs 13%), high blood losses (3987 +/- 4764 vs 2664 +/- 2043 mL), and year of liver transplantation after 2000 (26% vs 46%; P < .01). The 1-, 3-, and 5-year graft survival rates were significantly lower among donors older than 60 years than other donors: 75%, 65%, and 62% versus 85%, 83%, and 78%, respectively (P < .001). Donors older than 60 years of age provided liver transplants to half of our recipients. The graft survival rate of these organs was lower than that of younger donors and to improve it the other risk variables for poor outcome should be reduced, including MELD score of the recipient and prolonged cold ischemia time.


Differences in effect of copper and ProgestasertR IUDS on fibrinolytic activity of the endometrium in the rabbit.
Rabbits, which have two separate uteri, were used to assess intraindividual differences in the endometrial fibrinolytic activity in the two uteri, one containing a copper IUD and the other a progesterone-releasing IUD (ProgestasertR). A higher activity was demonstrated in the uterus containing the copper-IUD. Enhanced fibrinolytic activity in the endometrium has been held responsible for the increased menstrual blood loss in women using different IUDs. Thus, the present experimental study supports the clinical observation that women using ProgestasertR-IUD have less bleeding complaints than those using copper-IUD.


Ornithodoros peruvianus Kohls, Clifford & Jones (Ixodoidea: Argasidae) in Chile: a tentative diagnosis.
Three argasid tick larvae were collected on April 2, 2010, from a common vampire bat, Desmodus rotundus, captured in the Parque Nacional Pan de Azúcar (26°09' S, 70°41' W), Region of Atacama, Chile. The larvae were diagnosed as Ornithodoros, and further comparative analysis showed them to be Ornithodoros peruvianus Kohls, Clifford & Jones or a species close to it. Phylogenetic analysis based on 16S mitochondrial rRNA gene sequences of Ornithodoros species plus four Argas species was carried out to clarify the taxonomic position of the larvae. This is the first finding of ticks parasitizing D. rotundus in Chile.


Preoperative spinal cord arteriography in aneurysmal disease of the descending thoracic and thoracoabdominal aorta: preliminary results in 45 patients.
Between 1985 and 1988 45 patients with descending thoracic or thoracoabdominal aortic aneurysms underwent selective arteriography of the intercostal and lumbar arteries to delineate preoperatively the artery of Adamkiewicz and the thoracic radicular artery. Identification of these vessels failed in five patients (11%), was considered complete in 31 patients (69%) and incomplete in nine (20%). Selective arteriography classified these patients into four groups: groups A and B--the artery of Adamkiewicz arose respectively above and below the zone of operation; group C--the artery arose directly from the segment to be operated; and group D--origin could not be determined. All 30 patients in group C underwent a spinal cord revascularization procedure (complete in 20 cases, incomplete in 10). Spinal cord complications occurred in 9/45 patients (20%). No spinal cord complications occurred in groups A and B; their incidence was 5% in group C when revascularization was complete, and 50% when revascularization was incomplete; and 60% had complications in group D (p less than 0.01). Spinal cord complications were more frequent (p less than 0.05) when the artery of Adamkiewicz arose from an intercostal or lumbar artery obliterated at its aortic origin but filled through collaterals or when spinal cord circulation was interrupted for more than 45 minutes. This study confirms the importance of preserving arterial supply to the spinal cord during repair of descending thoracic and thoracoabdominal aneurysms. The information obtained from spinal cord arteriography allows the prediction of complications and informs the choice of the appropriate surgical technique.


Predictors of quality of life in oncology outpatients with pain from bone metastasis.
The relationship between pain and quality of life (QOL) in cancer patients is complex due to the number and the diversity of factors that can influence pain and QOL. The aims of this study of oncology outpatients with pain from bone metastasis were: 1) to determine the extent to which pain characteristics (i.e., severity, duration, meaning of pain, and perceived availability and efficacy of pain relief), psychological distress (i.e., depression), physical functioning, social functioning and QOL are intercorrelated, and 2) to determine which of these variables are important predictors of QOL. A total of 157 oncology outpatients completed questionnaires that evaluated pain, QOL, depression, physical functioning, and social functioning at the time of enrollment into a randomized clinical trial that evaluated the effectiveness of a psychoeducational intervention to improve cancer pain management. Pearson product moment correlation coefficients were calculated to examine the relationships among the study variables. A blockwise, hierarchical multiple regression analysis was performed to determine which variables were the most important predictors of QOL. Meaning of pain was significantly correlated with all the other variables, in particular pain intensity and duration. The most important factors that predicted QOL were depression, social functioning, and physical functioning. Depression proved to be the most important predictor of QOL.


Psychopathology and temperament in parents and offspring: results of a family study.
Although research on the association between temperament and psychopathology has received renewed interest, few investigations have addressed the issues of psychiatric comorbidity or the role of temperament across the life span. The present investigation employed a family study/high-risk design to examine the specificity of associations between temperamental traits and psychiatric disorders in both children and adults. The sample was composed of 244 probands and 82 children (ages 7-17) from the Yale Family Study of Comorbidity of Substance Abuse and Anxiety. Psychiatric disorders were assessed using structured diagnostic interviews administered by clinicians, and temperament was measured using the Dimensions of Temperament Survey. In both adults and children, anxiety and depression were generally associated with low scores on adaptability and approach/withdrawal, while externalizing or substance use disorders were associated with low attention scores and higher activity. However, psychiatric comorbidity was associated with the manifestation of both clusters of temperamental traits and far greater impairment and clinical severity. Some temperamental characteristics in children also demonstrated specificity of association with parental psychiatric disorder. This investigation was limited to the analysis of cross-sectional data and was unable to separate genetic from other familial risk factors. The results suggest that temperament remains associated with psychopathology across the life span and may reflect diverse familial influences. Clinical intervention and prevention efforts may benefit from focusing on individuals at higher risk for psychiatric disorder through parental psychopathology or the expression of temperament problems in childhood.


The application of artificial intelligence to accelerate G protein-coupled receptor drug discovery.
The application of artificial intelligence (AI) approaches to drug discovery for G protein-coupled receptors (GPCRs) is a rapidly expanding area. Artificial intelligence can be used at multiple stages during the drug discovery process, from aiding our understanding of the fundamental actions of GPCRs to the discovery of new ligand-GPCR interactions or the prediction of clinical responses. Here, we provide an overview of the concepts behind artificial intelligence, including the subfields of machine learning and deep learning. We summarise the published applications of artificial intelligence to different stages of the GPCR drug discovery process. Finally, we reflect on the benefits and limitations of artificial intelligence and share our vision for the exciting potential for further development of applications to aid GPCR drug discovery. In addition to making the drug discovery process "faster, smarter and cheaper," we anticipate that the application of artificial intelligence will create exciting new opportunities for GPCR drug discovery.


A review on production and application of activated carbon from discarded plastics in the context of 'waste treats waste'.
In the post-COVID scenario, the annual increase in plastic waste has taken an upsurge due to the disposal of plastic masks, gloves and other protective equipment. To reduce the plastic load ending up in landfills and oceans or dumped at roadsides, the potential of using plastic polymers in different sectors has been investigated over the years leading to their potential application in pavement laying, concrete industry, fuel generation and production of carbon-based compounds among which activated carbons (AC) is a prime example. As one of the most recommended adsorbents for removing contaminants from water and adsorbing greenhouse gases, AC creates a potential sector for using discarded plastic to further treat pollutants and approach closer to a circular economy for plastics. This paper analyses the production process, the effect of production parameters on AC characteristics and properties that aid in adsorption. The interdependence of these factors determines the surface area, porosity, relative micropore and mesopore volume, thereby defining the utility for removing contaminant molecules of a particular size. Furthermore, this work discusses the application of AC along with a summary of the earlier works leading to the existing gaps in the research area. Production costs, formation of by-products including toxic substances and adsorbate selectivity are the major issues that have restricted the commercial application of this process towards its practical use. Research aimed at valorization of plastic waste into ACs would minimize the solid waste burden, along with treating other pollutants.


Remission induction and remission maintenance in adult acute nonlymphocytic leukemia employing a modified cytostatic (COAP) regimen.
Thirty adult patients suffering from acute nonlymphocytic leukemia (ANLL) were treated according to a modified COAP regimen. Vincristine, cyclophosphamide, and prednisone were given by push injection, while cytosine arabinoside was infused over periods of 8 h. Nineteen patients (63%) achieved complete remission. Remission maintenance therapy consisted of 6-mercaptopurine daily and methotrexate twice weekly. Later in the study, COAP consolidation and reinduction was added, which improved the median duration of complete remission from 7 to 24 months. Comparison of the results with the literature shows that the modified COAP regimen is one of the most effective treatment schedules for adult ANLL.


The comprehensive complication index is more sensitive than the Clavien-Dindo classification for grading complications in elderly patients after radical cystectomy and pelvic lymph node dissection: Implementing the European Association of Urology guideline.
Lack of assessment of 90-d perioperative morbidity in elderly patients after radical cystectomy and pelvic lymph node dissection (PLND) using a standard reporting methodology, and the Clavien-Dindo classification (CDC) does not accurately reflect the burden of complications. We aim to report the 90-d complications of elderly patients after radical cystectomy, and to compare the validity of the Comprehensive Complication Index (CCI) and CDC. Retrospective review of 280 patients aged ≥75 years who received radical cystectomy between 2006 and 2021. The 90-d complications of elderly patients after radical cystectomy were reported by implementing the EAU criteria. The CDC and CCI were both used for grading complications. The Spearman rank correlation coefficient was used to estimate the correlation between postoperative stay and CDC/CCI. Logistic regression was used to identify the risk factors for major complications. The sample size for a fictive superiority trial was calculated for different endpoints. A total of 225 (80.36%) patients suffered from 528 complications. The cumulative CCI had a more accurate prediction of postoperative stay than the CDC (r = 0.378, p < 0.001 vs. r = 0.349, p < 0.001). The need for sample size could decrease when CCI was used for the primary endpoint. More risk factors for major complications were identified when CCI ≥33.7 was defined as the endpoint of major complications. CCI is better than CDC for grading the severity of complications in elderly patients after radical cystectomy and PLND.


Magnetic resonance imaging findings of bilateral thalamic involvement in severe paroxysmal sympathetic hyperactivity: a pediatric case series.
Paroxysmal sympathetic hyperactivity is a complication of brain injury that has mainly been described in the adult brain injury literature. We present a case series of three pediatric patients that developed paroxysmal sympathetic hyperactivity of varying severity following hypoxic brain injury. Comparison of brain magnetic resonance imaging revealed bilateral and symmetric global ischemic changes in all three cases. However, the thalamus was not affected in the patient with the mild case of paroxysmal sympathetic hyperactivity. In contrast, bilateral and symmetric damage to the thalamus was observed in the two severe cases. Our case series suggests that in hypoxic brain injury, evidence of bilateral ischemic injury to the thalamus on magnetic resonance imaging may be an important early predictor of severity and length of paroxysmal sympathetic hyperactivity. While this is an interesting observation, definite proof of our hypothesis requires further research including analysis of larger numbers of patients and comparison of MRI findings in children with hypoxic brain injury that do not develop paroxysmal sympathetic hyperactivity.


Embolic aspergillus endophthalmitis in an immunocompetent patient from aortic root aspergillus endocarditis.
We report the first case of endogenous aspergillus endophthalmitis in an immunocompetent person with systemic aortic root aspergillus endocarditis.


Pediatric intraocular knife.
An intraocular knife was developed that is of fine sharpness and small size to permit easy use in the eyes of young children.


The protection of bioenergetic functions in mitochondria by new synthetic chromanols.
alpha-Tocopherol is the most important lipophilic antioxidant of the chromanol type protecting biomembranes from lipid peroxidation (LPO). Therefore, alpha-tocopherol and its derivatives are frequently used in the therapy or prevention of oxygen radical-derived diseases. In the present study, novel chromanol-type antioxidants (twin-chromanol, cis- and trans-oxachromanol) as well as the well-known short-chain analogue of alpha-tocopherol, pentamethyl-chromanol, were tested for their antioxidative potency in rat heart mitochondria (RHM). Our experiments revealed that the bioenergetic parameters of mitochondria were not deteriorated in the presence of chromanols (up to 50 nmol/mg protein). Exposure of RHM to cumene hydroperoxide and Fe2+ (final concentrations 50 microM each), inducing LPO, significantly affected their bioenergetic parameters which were determined in the presence of glutamate and malate (substrates of mitochondrial complex I). Alterations of the bioenergetic parameters were partially prevented in a concentration-dependent manner by preincubating RHM with antioxidants before adding the radical-generating system. In the lower concentration range, twin-chromanol turned out to be more efficient than pentamethyl-chromanol, both being far more protective than cis- and trans-oxachromanol. Measurement of protein-bound SH groups and thiobarbituric acid-reactive substances revealed that this protective effect was due to their antioxidative action. Furthermore, HPLC measurements of alpha-tocopherol and alpha-tocopheryl quinone in rat liver mitochondria demonstrated an alpha-tocopherol-sparing effect of twin-chromanol. In conclusion, new chromanol-type antioxidants, especially twin-chromanol, were able to improve bioenergetic and biochemical parameters of mitochondria exposed to oxidative stress.


A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team.
Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesized that amitriptyline or mexiletine would improve the pain symptoms. A randomized, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit. The improvement in amitriptyline group (0.31+/-0.31 units [mean+/-SD]) and mexiletine group (0.23+/-0.41) was not significantly different from placebo (0.20+/-0.30). Both interventions were generally well tolerated. Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.