Electrocardiographic abnormalities in apparently healthy men and the risk of sudden death.
Identification of individuals at increased risk of sudden cardiac death is an important but difficult problem, especially in persons without clinically apparent heart disease. The ability of the electrocardiogram (ECG) to predict sudden death was determined in a study of 3983 men who were 30.8 years of age (mean) at entry and who had been followed with regular examinations, including ECGs. During the 30-year observation period, 70 cases of sudden death occurred in men without previous clinical manifestations of heart disease. Electrocardiographic abnormalities were detected before sudden death in 71.4% of cases. The abnormalities were, in decreasing order of frequency, ST segment and T-wave abnormalities, ventricular extrasystoles, left ventricular hypertrophy, complete left bundle branch block, and pronounced left axis deviation. When these electrocardiographic findings in men without clinical manifestations of heart disease were related prospectively to the incidence of sudden death, ST segment and T-wave abnormalities, ventricular extra-systoles, left ventricular hypertrophy and complete left bundle branch block were significant predictors of sudden death, while left axis deviation and right bundle branch block were not significant predictors of sudden death. Increased severity of primary T-wave abnormalities and the association of ST segment and T-wave abnormalities with increased QRS voltage further increased the sudden death risk. The combination of ventricular extrasystoles with either ST-T abnormalities or left ventricular hypertrophy considerably increased the risk of sudden death. Thus, these data indicate that electrocardiographic abnormalities detected on routine examination in men without clinical evidence of heart disease identify men at an increased risk of sudden death.


Relationship of testosterone, sex hormone binding globulin, and calculated free testosterone to subsequent clinical progress in patients with carcinoma of the prostate treated with bilateral orchidectomy or estrogens.
The concentration in serum of testosterone, sex hormone binding globulin (SHBG), and albumin has been measured, and from these measurements free testosterone has been calculated in 75 patients with carcinoma of the prostate treated with either bilateral orchidectomy, stilbestrol, or estramustine phosphate (Estracyt). After exclusion of 3 noncompliant patients, total testosterone did not differ significantly between treatments, but free testosterone was lower in estrogen-treated patients (5.9 +/- 0.9 (SEM) pmol/l, n = 28) compared with the orchidectomized patients (23 +/- 1.4 pmol/l, n = 44) (P less than 0.001); all of the estrogen-treated patients falling in the lower third of the range of the orchidectomized patients. Free testosterone did not change systematically during several years of treatment and there was no evidence of a rise with clinical deterioration. In the 33 patients with metastatic cancer treated with orchidectomy, the third with the lowest free testosterone or total testosterone showed a better survival over 2 years than the two-thirds with higher free or total testosterone; thereafter, the advantage was lost.


Identification of two discrete ribonucleoprotein particles within the monomer population of rat liver nuclear RNPs.
30-50 S RNP particles (monoparticles) isolated from rat liver nuclei were submitted to electrophoresis in native 0.5% agarose gels. Two RNP fractions were thus separated, a minor one remaining closer to the top of the gel (MI) and a more abundant one migrating further into the gel (MII). SDS-polyacrylamide gel electrophoresis revealed that MII contains the major monoparticle (Mr 30 000-40 000 or 'core') polypeptides and higher molecular weight proteins, whereas MI contains several minor proteins of Mr greater than 40 000. Some proteins are common to both particle classes. Urea-acrylamide gel electrophoresis revealed that HnRNA is mainly present in MII, whereas snRNA is confined to the MI particle class.


How Did We Get Here: The Best Vaccines Ever Facing the Highest Public Hesitancy?
mRNA vaccine technology is the most interesting final product of decades of research. This new platform for public health is simple to transfer to low-income countries and can be used against diverse agents, including cancer. It is environmentally clean, relatively low-cost, and does not use animals for its production. Most importantly, mRNA vaccines have been highly efficacious in avoiding serious disease and death from COVID-19. Yet, at the highest point of the pandemic, many voices, including some from prominent positions, opposed their use. Similarly, the Human Papillomavirus (HPV) vaccines, which are highly effective, very safe, and probably confer long life protection against its HPV types, faced strong parents' hesitancy. Vaccine hesitancy has been the subject of extensive research, focusing primarily on factors associated with the public, the political environment, and messaging strategies. However, the issue of unfair worldwide access to the COVID-19 vaccines has recently sparked significant debate about the vaccine industry's role. Recent data demonstrated that the system's perceived unfairness with the masses is behind the growing populist anti-vaccine movements worldwide. The association between populism and antivaccine attitudes has been reported at country and individual levels. The anti-science attitudes behind vaccine hesitancy emerge when the scientist is not found credible due to the suspicion that they had monetary investments in pharmaceutical companies. Here, I argue that the obscurity of the vaccine market, but also its unfairness, are important factors contributing to vaccine hesitancy. The purpose of this commentary is to stimulate a review of current market regulations and to improve its transparency and fairness, particularly in the context of public health emergencies. By doing so, a new pandemic would find us better prepared. The general population and much of the healthcare community often ignore the years of dedicated work and substantial public funding that enabled the discovery and design of vaccines. Conversely, pharmaceutical companies often over-emphasize their investments in research and development. A decade ago, Marcia Angell provided a detailed breakdown of pharmaceutical expenses, revealing that marketing and administration costs were 2.5 times higher than research and development expenses; recently, Olivier Wouters confirmed the high expenditures of the pharmaceutical industry in lobbying and political campaign contributions. In this commentary, I will present the cases of HPV and COVID-19 vaccines as examples of when vaccines, instead of being public health goods, became market goods, creating large inequities and health costs. This failure is a structural cause behind more ideological vaccine hesitancy, less studied so far.


Variation in the definition of clinical target volumes for pelvic nodal conformal radiation therapy for prostate cancer.
We conducted a comparative study of clinical target volume (CTV) definition of pelvic lymph nodes by multiple genitourinary (GU) radiation oncologists looking at the levels of discrepancies amongst this group. Pelvic computed tomography (CT) scans from 2 men were distributed to 14 Radiation Therapy Oncology Group GU radiation oncologists with instructions to define CTVs for the iliac and presacral lymph nodes. The CT data with contours were then returned for analysis. In addition, a questionnaire was completed that described the physicians' method for target volume definition. Significant variation in the definition of the iliac and presacral CTVs was seen among the physicians. The minimum, maximum, mean (SD) iliac volumes (mL) were 81.8, 876.6, 337.6 +/- 203 for case 1 and 60.3, 627.7, 251.8 +/- 159.3 for case 2. The volume of 100% agreement was 30.6 and 17.4 for case 1 and 2 and the volume of the union of all contours was 1,012.0 and 807.4 for case 1 and 2, respectively. The overall agreement was judged to be moderate in both cases (kappa = 0.53 (p < 0.0001) and kappa = 0.48 (p < 0.0001). There was no volume of 100% agreement for either of the two presacral volumes. These variations were confirmed in the responses to the associated questionnaire. Significant disagreement exists in the definition of the CTV for pelvic nodal radiation therapy among GU radiation oncology specialists. A consensus needs to be developed so as to accurately assess the merit and safety of such treatment.


Doppler-guided hemorrhoid artery ligation with Recto-Anal-Repair modification: functional evaluation and safety assessment of a new minimally invasive method of treatment of advanced hemorrhoidal disease.
We present 12-month followup results of functional evaluation and safety assessment of a modification of hemorrhoidal artery ligation (DGHAL) called Recto-Anal-Repair (RAR) in treatment of advanced hemorrhoidal disease (HD). Patients with grade III and IV HD underwent the RAR procedure (DGHAL combined with restoration of prolapsed hemorrhoids to their anatomical position with longitudinal sutures). Each patient had rectal examination, anorectal manometry, and QoL questionnaire performed before 3 months, and 12 months after RAR procedure. 20 patients completed 12-month followup. There were no major complications. 3 months after RAR, 5 cases of residual mucosal prolapse were detected (25%), while only 3 patients (15%) reported persistence of symptoms. 12 months after RAR, another 3 HD recurrences were detected, to a total of 8 patients (40%) with HD recurrence. Anal pressures after RAR were significantly lower than before (P < 0.05), and the effect was persistent 12 months after RAR. One patient (5%) reported occasional soiling 3 months after RAR. RAR seems to be a safe method of treatment of advanced HD with no major complications. The procedure has a significant influence on anal pressures, with no evidence of risk of fecal incontinence after the operation.


Two-dimensional Fibonacci grating for far-field super-resolution imaging.
A two-dimensional (2D) Fibonacci grating is used to transform evanescent waves into propagating waves for far-field super-resolution imaging. By detecting far-field intensity distributions of light field through objects in front of the 2D Fibonacci grating in free space at once, we can retrieve the image of objects with beyond λ/7 spatial resolution. We also find that the coherent illumination case can give a better resolution than incoherent illumination case by such 2D grating-assisted imaging system. The analytical results are verified by numerical simulation.


Evaluation of three pumpkin species: correlation with physicochemical, antioxidant properties and classification using SPME-GC-MS and E-nose methods.
To ascertain the most discriminant variables for three pumpkin species principal component analysis (PCA) was performed. Twenty-four parameters (pH, conductivity, sucrose, glucose, total soluble solids, L*, a*, b*, individual weight, edible rate, firmness, citric acid, fumaric acid, l-ascorbic acid, malic acid, PPO activity, POD activity, total flavonoids, vitamin E, total phenolics, DPPH, FRAP, β-carotene, and aroma) were considered. The studied pumpkin species were Cucurbita maxima, Cucurbita moschata, and Cucurbita pepo. Three pumpkin species were classified by PCA based on aroma, physicochemical and antioxidant properties because the sum of PC1 and PC2 were both greater than 85% (85.06 and 93.64% respectively). Results were validated by the PCA and showed that PPO activity, total flavonoid, sucrose, glucose, TSS, a*, pH, malic acid, vitamin E, DPPH, FRAP and β-carotene, and aroma are highly useful parameters to classify pumpkin species.


Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate.
Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.


Application of a factorial design to the study of specific parameters of a Carbopol ETD 2020 gel. Part I. Viscoelastic parameters.
This work studies the application of a 2(3) factorial design to a cosmetic gel with the aim of simplifying the analysis of the influence of the concentration of Carbopol ETD 2020 (cb), of ethanol (et) and of glycerin (gl) on the viscoelastic parameters: equilibrium modulus (Gn), critical molecular weight (Mc), degree of structuring (logG'/lognu) and viscous modulus (G"). We have obtained high linear polynomial correlations among the components and the response factors determined. The results obtained evidence the usefulness of this type of technique in detecting interactions among the components that would be difficult to foresee otherwise. Mc, logG'/lognu and G" depend on the interaction cb-et. Gn depends on the interaction of cb-et-gl. That is, an increase in gl can increase or decrease the elasticity (Gn) of the gels, depending on the concentrations of cb and et.


Expression of multiple type 1 phosphoprotein phosphatases in Arabidopsis thaliana.
Type 1 phosphoprotein Ser/Thr phosphatases (PP1) are highly conserved enzymes found in all eukaryotes. These enzymes have multiple functions in fungal and animal cells but little is known of their function and regulation in plants. Previous studies in our laboratory indicated that maize and Arabidopsis contain a family of PP1 genes and/or pseudogenes. In this study, we report the isolation of five distinct Arabidopsis cDNA clones (TOPP1, TOPP2, TOPP3, TOPP4 and TOPP5) which encode the catalytic subunit (PP1c) of type 1 protein phosphatases. Genomic Southern blot analyses indicate that these clones are the products of five distinct genes and that an additional 2-3 PP1c genes and/or pseudogenes may be present in the Arabidopsis genome. The derived amino acid sequences of the TOPP clones are very similar to published sequences of PP1c from animals, fungi and plants. Four of the TOPP amino acid sequences show unique structural features not observed in other PP1c sequences from fungi or animals. All of the TOPP genes are expressed in Arabidopsis roots, rosettes and flowers, although TOPP1, TOPP2 and TOPP3 appear to be expressed at higher levels in these tissues than TOPP4 and TOPP5.


Oocyte vitrification offers more space for a tailored surgical management of endometriosis.
Oocyte vitrification is an attractive and efficient option in the long-term management of endometriosis patients. Which women would benefit from banked oocytes when pregnancy is attempted, and whether oocyte vitrification should be carried out before or after the surgical management of endometriosis, is still debated. On the basis of recent data, and in the absence of cost-effective modelling, a personalized strategy should assess crucial variables, such as type of surgery, effect on oocyte yield and the huge heterogeneity of the clinical scenarios possibly requiring surgery. Research into a more tailored approach to maximize the result of each available intervention, e.g. hormones, surgery, assisted reproductive technology or their combination to prevent infertility and reduce the actual burden of personal and societal cost of the disease, is recommended.


Impact of severe mental illnesses on health-related quality of life among patients attending the Institute of Psychiatry, Rawalpindi from 2019 to 2021: A cross-sectional study.
Severe mental illnesses have huge impact on health-related quality of life. They contribute to significant morbidity in terms of number of number of years of life lost in form DALYS (disability adjusted life years) and shorter life expectancy and early mortality. There is limited evidence on their burden in low- and middle-income countries like Pakistan. To determine the health-related quality of life in patients suffering from severe mental illness (schizophrenia, depression, and bipolar affective disorder) and demographic factors associated with poor health related quality of life in these patients. This was descriptive cross sectional, using retrospective record view of data. Study was done under IMPACT (Improving Mental And Physical health Together) Program, which conducted a multi-morbidity survey conducted at institute of psychiatry, Benazir Bhutto hospital, Rawalpindi, using EQ 5d 5l (EURO QOL 5D5L) questionnaire having both subjective (EQVAS) and objective domains. The study included 922 SMI patients, of whom 555 participants (60.2%) were males and 367(39.69%) were females. The participants suffered from major depressive disorder (422;45.8%), followed by bipolar affective disorder (392; 42.51%) and schizophrenia (108;11.7%). Most participants were in a younger age group with (80%) of population being below 50 years old and had education level below secondary education (57.4%). In the analysis of association between EQ-VAS (subjective quality of life scale) and demographic factors, a significant association was found for marital status(p<0.001), gender (p< 0.001) and education (p< 0.001). Women had lower EQ-VAS scores (M = 49.43±SD = 27.72) as compared to males (M = 58.81±SD = 27.1) and individuals with lower educational status also had lower mean scores. Additionally, participants who were single, divorced or widowed also had lower mean EQVAS scores. When health related quality of life was analyzed across SMI, it was lower in all SMI, but was significantly lower for depression in both subjective and objective domains of health related of quality-of-life instrument. Health related quality of life is an important outcome measure and regular assessment of both subjective and objective aspects should be incorporated in management plans of patients suffering from severe mental illnesses.


Antiproliferative activities of interferons against human bladder carcinoma cell lines in vitro.
The antiproliferative effect of interferons against 5 human bladder carcinoma cell lines, RT112, T24, RT4, 647V and HT1197, was determined in vitro. Each of these human bladder carcinoma cell lines except 647V was sensitive to human interferons in liquid media. The antiproliferative effect of interferons was observed only upon continuous exposure, not after 1 hour. Partially purified, naturally produced interferon beta was more inhibitory of cell growth than naturally produced interferon alpha. Interferon alpha 54, 76, 61, 6L and 1 purified to homogeneity were as effective as naturally produced, partially pure interferon alpha. Although interferon beta, produced by recombinant DNA technology and purified to homogeneity, was not equivalent in effectiveness to naturally produced interferon beta, its antiproliferative activity was greater than interferon alpha 54 for 3 of 4 cell lines tested. Antimitotic effects may underlie, at least in part, the potential therapeutic activity of interferons for bladder carcinoma.


Growth stimulating activity produced by human bladder cancer cells.
Growth promoting properties have been identified in the conditioned serum-free medium from cultures of the human transitional cell carcinoma cell line 647V. This activity appears to reside in a molecule of more than 5000 MW. The factor responsible for 647V growth is distinguished from epidermal growth factor, since it fails to inhibit the specific binding of epidermal growth factor by 647V cells, and 647V cells are not stimulated to grow by epidermal growth factor. It also does not appear to be an insulin-like growth factor-like molecule since it fails to competitively bind with human insulin-like growth factor-carrier protein.


Synergistic effect of residual sugar on freeze-thaw stability of high internal phase emulsions using glycosylated cod protein as interface stabilizer.
Nowadays, glycosylated protein seems to be one of the most effective stabilizers for preparing freeze-thaw stabile emulsion; nevertheless, few papers mentioned the relationship between the residual free sugars after the glycosylation reaction and the freeze-thaw stability of high internal phase emulsions (HIPEs). Herein, glucose was used to prepare glycosylated cod proteins (GCPs). The synergistic effect was related to the grafting degree of GCP, and the amount of glucose added to prepare freeze-thaw stable HIPEs was reduced from 20% to 4% when the grafting degree of GCP increased from 0% to 31.58% (i.e. 12% GCP). This might be due to fewer ice crystals forming in water phase or less destruction of emulsion droplets by ice crystals. The obtained results in this study will allow developing freeze-thaw stable HIPEs or new frozen ingredients.


An introduction to stomas: reasons for their formation.
The word 'stoma' comes from the Greek word meaning 'mouth' or 'opening'. Three types of stoma are discussed in this article: colostomy, ileostomy and ileal conduit. All are involved in the elimination of either faeces or urine.


Results of Baha® implantation using a small horizontal incision.
Techniques for Baha® implantation continue to evolve. The Weber technique, utilizing a 1.5 cm horizontal incision for Baha® implantation is evaluated. Retrospective review of patients undergoing Baha® implantation by a single surgeon over three years. 33 Baha®s implanted in 30 patients. Fourteen used an Inverted J (IJ) incision with an anteriorly-based skin-flap, 13 with the Weber technique (W). Five were not included as other techniques were used. Demographics and weeks to activation (14.58 vs 13.4, p = 0.12) were similar. There were no differences in the number of patients with minor complications (5 vs 2, p = 0.22) or number of minor complications (20 vs 4, p = 0.09). One patient in the IJ Group required operative revision for overgrowth. There were no infections in the IJ Group, and one requiring oral antibiotics in the W Group. Follow-up was longer in the IJ Group (41 vs 13 weeks, p = 0.016), no complications occurred after 14 weeks post-op. Mean operative times were similar (43 vs 39 min, p = 0.59). There were no cases of skin flap necrosis in either group. A small incision for Baha® implantation proved as effective, without increased complications as a skin-flap based technique.


How to Understand and Treat Laryngopharyngeal Reflux.
Laryngopharyngeal reflux (LPR) is frustrating, as symptoms are nonspecific and diagnosis is often unclear. Two main approaches to diagnosis are empiric treatment trials and objective reflux testing. Initial empiric trial of Proton pump inhibitors (PPI) twice daily for 2-3 months is convenient, but risks overtreatment and delayed diagnosis if patient complaints are not from LPR. Dietary modifications, H2-antagonists, alginates, and fundoplication are other possible LPR treatments. If objective diagnosis is desired or patients' symptoms are refractory to empiric treatment, pH testing with/without impedance should be considered. Additionally, evaluation for non-reflux etiologies of complaints should be performed, including laryngoscopy or videostroboscopy.


Tactile, acoustic and vestibular systems sum to elicit the startle reflex.
The startle reflex is elicited by intense tactile, acoustic or vestibular stimuli. Fast mechanoreceptors in each modality can respond to skin or head displacement. In each modality, stimulation of cranial nerves or primary sensory nuclei evokes startle-like responses. The most sensitive sites in rats are found in the ventral spinal trigeminal pathway, corresponding to inputs from the dorsal face. Cross-modal summation is stronger than intramodal temporal summation, suggesting that the convergence of acoustic, vestibular and tactile information is important for eliciting startle. This summation declines sharply if the cross-modal stimuli are not synchronous. Head impact stimuli activate trigeminal, acoustic and vestibular systems together, suggesting that the startle response protects the body from impact stimuli. In each primary sensory nucleus, large, second-order neurons project to pontine reticular formation giant neurons critical for the acoustic startle reflex. In vestibular nucleus sites, startle-like responses appear to be mediated mainly via the vestibulospinal tract, not the reticulospinal tract. Summation between vestibulospinal and reticulospinal pathways mediating startle is proposed to occur in the ventral spinal cord.


Hydroxynonenal, toxic carbonyls, and Alzheimer disease.
Cytoskeletal disruption is one of the distinguishing characteristics of the vulnerable neurons in Alzheimer disease (AD). It has been suggested that these cytoskeletal changes occur secondarily to covalent modifications of the protein components. Despite the abundance and probable importance of these changes, there has been very little data regarding the identity of the modified proteins or the precise chemistry of the modifications. Here we review a specific type of modification, namely carbonylation of proteins, which has been shown to be a common result of cellular oxidative stress. Hopefully, the following discussion will help elucidate the relationship between oxidative stress, protein modification and the pathogenesis of AD.


The 12-lead electrocardiogram in midseptal, anteroseptal, posteroseptal and right free wall accessory pathways.
The 12-lead electrocardiograms of 50 patients with 1 anterogradely conducting accessory pathway were analyzed to obtain characteristics of electrocardiographic findings in the midseptal, anteroseptal, true posteroseptal and right free wall accessory pathway locations. Locations were confirmed by surgery (33 patients) or radiofrequency catheter ablation (17 patients). This study analyzed (1) QRS in the frontal plane, (2) delta wave axis in the frontal plane, (3) the angle between QRS and delta wave axes, (4) the R/S ratio in lead III, (5) negativity of delta wave in inferior leads, and (6) the R/S ratio in precordial leads.(ABSTRACT TRUNCATED AT 250 WORDS)


Does Alcohol Contribute to College Men's Sexual Assault Perpetration? Between- and Within-Person Effects Over Five Semesters.
The current longitudinal study was designed to consider the time-varying effects of men's heavy episodic drinking (HED) and drinking setting attendance on college sexual assault perpetration. Freshman men (N = 992) were recruited in their first semester and completed online measures at the end of their first five semesters. Using multilevel models, we examined whether men with higher frequency HED (or party or bar attendance) were more likely to perpetrate sexual assault (between-person, Level 2 effect) and whether sexual assault perpetration was more likely in semesters in which HED (or party or bar attendance) was higher than each individual's average (within-person, Level 1 effect). The between-person effect of HED on sexual assault was not significant after accounting for the between-person effects of antisocial behavior, impersonal sex orientation, and low self-control. The within-person effect of HED on sexual assault perpetration was not significant. However, models substituting frequency of party attendance or bar attendance revealed both between- and within-person effects. The odds of sexual assault were increased for men with higher bar and party attendance than the sample as a whole, and in semesters in which party or bar attendance was higher than their own average. Supplemental analyses suggested that these drinking setting effects were explained by hookups, with sexual assault perpetration more likely in semesters in which the number of hookups exceeded one's own average. Findings point toward the importance of drinking contexts, rather than drinking per se, as predictors of college men's sexual assault perpetration.


Resection of an unusually large goitre.
This paper reports the resection of a benign non-toxic goitre measuring 75 X 60 X 45 cm in a patient aged 48 who was unable to walk or sit because of the size of the goitre. The tumour proved to arise from the right half of the thyroid. A right-sided hemistrumectomy was performed under local anaesthesia with the patient prone. A temporary tracheostomy was established. The postoperative course was uneventful apart from slight necrosis of the wound edge. The patient was discharged in good health on the twentieth postoperative day.


Variations in trace metal levels in rat hippocampus during ontogenetic development.
The variations in trace metal (zinc, iron, copper and manganese) levels in rat hippocampus were followed by atomic absorption spectrophotometry from the 17th embryonic day to the 100th postnatal day. In agreement with histochemical observations, it was found that the greatest relative increase in the hippocampal zinc level occurs during the 11th-20th postnatal days, simultaneously with the morphological maturation of the mossy fibre terminals. The iron level falls dramatically from the 17th embryonic day to the 3rd postnatal day. Beginning from the 11th postnatal day, the iron level, similarly to the copper level, continuously increases with age. The manganese level rises up to the 20th postnatal day, and subsequently progressively decreases. It is suggested that all of these elements are indispensable for the normal development and functioning of the hippocampus and the mossy fibre terminals.


Prognostic significance of steroid hormone receptors and histopathological characterization of human breast cancer.
Since breast cancer is a heterogeneous disease, evaluation of prognosis is an obvious problem. The prognostic significance of several pathological criteria including tumor grading according to WHO, steroid hormone receptor status, histological tumor type, tumor size, and axillary lymph node involvement have been investigated. The single parameters with the strongest prognostic significance were axillary lymph node status, tumor grading, and estrogen receptor status. A significant direct correlation exists between tumor grading and steroid hormone receptors, but nevertheless on stratified analysis both factors independently affected the risk of death. Tumor size had weak prognostic importance and histological tumor types failed to show any statistically significant differences with regard to survival.


Tumor necrosis factor-alpha receptor 1 (p55) knockout only transiently decreases the activation of c-Jun and does not affect the survival of axotomized dopaminergic nigral neurons.
The activation of the c-Jun N-terminal kinases and their substrate transcription factor c-Jun is central to the death of dopaminergic neurons of the substantia nigra pars compacta (SNC) but the underlying signal cascades are poorly understood. We have studied the impact of the p55 tumor necrosis factor-alpha receptor (TNF-R) 1 on the N-terminal phosphorylation of c-Jun and the survival of the dopaminergic SNC neurons after transection of the medial forebrain bundle. The axotomy raised the immunoreactivities of tumor necrosis factor-alpha, p75 TNF-R2 and ED1 (ectodysplasin A) in the substantia nigra equally in wildtype and knockout (ko) mice and of TNF-R1 in wildtype mice. Importantly, TNF-R1 ko significantly reduced the early phosphorylation of c-Jun between 18 h and 3 d post-axotomy but the functional deficiency of TNF-R1 did not affect the survival of the dopaminergic neurons up to day 30. These findings demonstrate that: (i) TNF-R1 is involved in the early cell body response after axon transection; (ii) TNF-R1 operates upstream of c-Jun N-terminal kinase/c-Jun, the central signal system of nerve fiber injury, and (iii) the failure of persistent reduction of activated c-Jun is linked to the failure of protection of dopaminergic SNC neurons by TNF-R1 ko.


Multiple fractures, pain, and severe disability in a patient with adult-onset hypophosphatasia.
Hypophosphatasia (HPP) is a rare, inherited metabolic bone disease resulting from mutations in the gene encoding tissue non-specific alkaline phosphatase. The biochemical hallmark and key diagnostic indicator is low alkaline phosphatase activity, which leads to a variety of clinical manifestations across all ages. The diagnosis is easily missed in adults, who frequently present with nonspecific clinical manifestations such as fractures, osteomalacia, and pain. Here, the pathway to diagnosis and disease course is described in an adult patient presenting with pain. Low serum alkaline phosphatase activity went unnoticed for 2 years until osteomalacia was suspected, during which time he experienced multiple fractures and progressing pain. Currently, accumulated morbidity has rendered the patient unable to work, and treatment is focused on pain management. This case highlights the importance of low alkaline phosphatase in the differential diagnosis of patients with musculoskeletal pain.


Metal Complexes of 1,3,4-Thiadiazole-2,5-Disulfonamide are Strong Dual Carbonic Anhydrase Inhibitors, although the Ligand Possesses very Weak such Properties.
Coordination compounds of Co(II), Ni(II), Cu(II), Zn(II), and Cd(II) with 1,3,4-thiadiazole-2,5-disulfonamide as ligand were synthesized and characterized by IR and UV spectroscopy, conductimetry and thermogravimetry. The parent ligand is a very weak carbonic anhydrase (CA) inhibitor, although it constituted the lead for developing important classes of diuretics. The complex derivatives behave as much stronger CA inhibitors, with IC(50) values around 10(-8)M against isozyme CA II, and 10(-7) M against isozyme CAI.


Three methods of capillary electrophoresis compared with high-resolution agarose gel electrophoresis for serum protein electrophoresis.
We assessed the BioFocus 2000 capillary electrophoresis instrument for use in a routine clinical laboratory. We examined 210 serum samples received for serum protein electrophoresis by four methods: (1) The Bio-Rad HR015EC high-resolution serum protein kit on the BioFocus; (2) the Jenkins-Guerin (JG) method on the Applied Biosystems 270A HT Capillary Electrophoresis System (JG-ABI); (3) the Jenkins-Guerin method using the BioFocus (JG-BF); and (4) the quantitation of monoclonal bands found in 76 of the 210 samples was assayed by Helena Titan Hi-Res agarose gel electrophoresis (HRAGE). The correlation coefficient between the three sets of capillary electrophoresis monoclonal band results and the Helena quantitation was 0.92 or better. Although the quantitative comparison of monoclonal bands by HR015EC was very good, the lack of sharpness of monoclonal bands using the HR015EC kit meant our preference was to use the JG method on either the ABI or on the Biofocus.


Cell proliferation following extrahepatic biliary obstruction. Evaluation by immunohistochemical methods.
The aim of the present investigation was to conduct an immunohistochemical study using bromodeoxyuridine (BrdU) incorporation as a marker of S-phase cells and cytokeratins as markers of biliary epithelial cells, in bile-duct-ligated rats at intervals of 1, 3, 7, 14 and 21 days after total biliary obstruction. Data obtained using only BrdU incorporation by S-phase nuclei were compared with those obtained by the simultaneous demonstration of S-phase nuclei and cytoplasmic cytokeratins. The labelling index of parenchymal liver cells and of biliary epithelial cells was evaluated as an index of the cellular growth pattern after total biliary obstruction. Our data show that following total biliary obstruction: (a) cell proliferation follows a similar pattern for biliary epithelial cells hepatocytes with a peak on the 3rd day; (b) the labelling index is significantly higher in biliary epithelial cells than in hepatocytes; and (c) sequential immunohistochemical staining using cytokeratin as a marker allows better identification of biliary epithelial cells, especially when the ductular lumen is not clearly outlined, or in isolated biliary cells which appear as components of the wall of the ducts of Hering.


A historical perspective on sleep disorders medicine.
The recent development of sleep disorders medicine traces its origins to the increased understanding of basic human sleep physiology gained over the past 30 years. The primary tool for diagnosis and management is the long-term polygraphic recording of multiple physiologic variables (polysomnography). A "style" of practice is emerging that is multidisciplinary and often institutionally-based in sleep disorders centers. High patient and physician satisfaction in this field indicate that rapid growth will continue.


Temafloxacin does not potentiate the anticoagulant effect of warfarin in healthy subjects.
The potential for drug interaction between temafloxacin, a new fluorinated quinolone antibiotic, and low-intensity warfarin was studied in 10 healthy male volunteers. Warfarin was administered orally at titrated dosages to maintain the International Normalised Ratio between 1.3 and 1.7, and was kept constant during the last 4 days of the 16-day trial, when temafloxacin 600mg twice daily was coadministered. Prothrombin times during temafloxacin and warfarin administration were similar to those during warfarin alone. Thus, temafloxacin did not potentiate the anticoagulant effect of warfarin 1.5 to 5.5mg daily in healthy volunteers.


Substance use, harm reduction attitudes and behaviors among attendees of nature rave parties in Israel.
Few studies have analyzed harm reduction behaviors and attitudes among rave party attendees. Since the late 1980s, there has been a large Israeli rave scene, also known as 'Nature Parties'. However, only a few studies have been conducted among nature party attendees and almost all of them are from a qualitative perspective. This study's aim was to fill the gap and conduct quantitative research to investigate the patterns of substance use, harm reduction attitudes and behaviors among Israeli nature rave party attendees. A cross-sectional online survey recruited 1,206 people who reported having attended nature rave parties. All of the participants were aged 18-60 years (M = 29.9; SD = 7.4), and 770 (64%) were male. The most common illicit substances used at Israeli nature rave parties in the past year were cannabis (62.2%), followed by LSD (41.4%), MDMA (31.7%), mushrooms/psilocybin (23.9%), ketamine (19.6%) and cocaine (17.2%). A significant but weak association was found between harm reduction behaviors and attitudes toward harm reduction interventions (r = .26, p < .001) and attitudes toward drug testing kits (r = .33, p < .001). It seems that although we found higher positive harm reduction attitudes, it is harder to implement harm reduction behaviors. Logistic regressions demonstrated stronger associations with high harm reduction behaviors and higher levels of positive attitudes toward drug testing kits (OR = 4.53; CI 2.97-6.90; p < .001), higher levels of positive attitudes toward harm reduction interventions (OR = 4.06; CI 2.62-6.29; p < .001), marital status of widower/divorced (OR = 2.22; CI 1.49-3.32; p < .001), using MDMA (OR = 1.63; CI 1.19-2.23; p < = .01) and using LSD (OR = 1.41; CI 1.03-1.94; p < = .05). Formal harm reduction policies and interventions are needed for Israeli nature rave parties in addition to prevention and information programs, which are also very rare. Future studies should examine the subjects of harm reduction attitudes and behaviors among the public, policy makers and professionals.


The effect of capsaicin on circulating biomarkers, soluble tumor necrosis factor and soluble tumor necrosis factor-receptor-1 and -2 levels in vivo using lipopolysaccharide-treated mice.
The circulating soluble tumor necrosis factor (sTNF) and sTNF-receptor (R) 1 and -R2 have known as septic biomarker. The pungent component of capsicum, capsaicin (Cap), has several associated physiological activities, including anti-oxidant, anti-bacterial and anti-inflammatory effects. The aim of this study was to elucidate the effect of Cap on circulating sTNF and sTNF-R1 and -R2 in vivo using lipopolysaccharide (LPS)-treated mice. LPS (20 mg/kg, ip)-treated group was significantly increased circulating sTNF, sTNF-R1, and -R2 and TNF-α mRNA expression levels compared to the vehicle group. Treatment with LPS (20 mg/kg, ip) + Cap (4 mg/kg, sc)-treated group was significantly decreased both circulating sTNF levels (after 1 h only) and TNF-α mRNA expression (after 6 h) compared to the LPS-treated group. There is an early increase in circulating sTNF, sTNR-R1, and -R2 observed in the LPS-treated mice. Since Cap inhibits this initial increase as biomarkers, circulating sTNF, it is considered a potent treatment option for TNF-α-related diseases, such as septicemia. In conclusion, Cap interferes with TNF-α mRNA transcription and exerts an inhibiting effect on TNF-α release from macrophages in the early phase after LPS stimulation. Thus, Cap is considered a potent agent for the treatment of TNF-α-related diseases, such as septicemia.


Effect of photodynamic therapy on anti-tumor immune defenses: comparison of the photosensitizers hematoporphyrin derivative and chloro-aluminum sulfonated phthalocyanine.
The effects of the two photosensitizers chloroaluminum sulfonated phthalocyanine (ClAlSPc) and hematoporphyrin derivative (HpD) on the functional activities of macrophages and natural killer (NK) cells, two immunocyte populations implicated in the control of tumor development and spread, have been investigated. Murine peritoneal macrophages treated in vivo with ClAlSPc or HpD at 10 mg/kg body weight showed no impairment of Fc-mediated phagocytic capacity and only minor disturbances of in vitro tumoricidal/tumoristatic function. The NK cell activity of splenocytes obtained from photosensitizer-treated mice, assayed 24 or 48 h after i.v. injection of ClAlSPc or HpD at 10 mg/kg was unaffected compared to controls. However significant inhibition of NK activity was observed when splenocytes obtained from mice with or without subcutaneous Colo 26 tumors, treated with ClAlSPc plus laser therapy (675 nm) were used as effector cells. The results show that impairment of some anti-tumor activity can be observed in phthalocyanine treated or phthalocyanine + laser-treated animals but this relatively minor impairment may augur well for the use of systemic phthalocyanine administration in photodynamic therapy.


Chipping away at the embryonic stem cell network.
Critical transcription factors, notably OCT4, SOX2, and NANOG, are necessary to maintain self-renewal and pluripotency, two properties characteristic of embryonic stem (ES) cells. By analyzing the genome-wide localization of these factors at promoter regions in human ES cells, Boyer et al. (2005) demonstrate frequent promoter co-occupancy at numerous target genes. As they discuss in this issue of Cell, their findings indicate the presence of a complex network of autoregulatory and feedforward loops in human ES cells.


Effects of hunger state on flavour pleasantness conditioning at home: flavour-nutrient learning vs. flavour-flavour learning.
This study examined acquired liking of flavour preferences through flavour-flavour and flavour-nutrient learning under hungry or sated conditions in a naturalistic setting. Each participant consumed one of three versions of a test drink at home either before lunch or after lunch: minimally sweetened ( 3% sucrose, 40 kcal), artificially sweetened (3% sucrose 40 kcal plus artificial sweeteners ASPARTAME) and sucrose-sweetened (SUCROSE: 9.9% sugar, 132 kcal). The test drink was an uncarbonated peach-flavoured iced tea served in visually identical drink cans (330 ml). Participants preselected as "sweet likers" evaluated the minimally sweetened flavoured drink (conditioned stimulus, CS) in the same state (hungry or sated) in which they consumed the test drink at home. Overall, liking for the CS flavour increased in participants who consumed the SUCROSE drink, however, this increase in liking was significantly larger when tested and trained hungry than sated, consistent with a flavour-nutrient model. Overall increases in pleasantness for the CS flavour in participants who consumed the SUCROSE drink when sated or the ASPARTAME drink independent of hunger state, suggest that flavour-flavour learning also occurred. These results are discussed in light of current learning models of flavour preference.


Problem children's adult adjustment predicted from teachers' ratings.
Teacher ratings of 187 children seen at a guidance clinic are compared to interview-based ratings of social adjustment nine to fifteen years later. Children described as failing to get along with others are seen to be relatively disturbed at follow-up, and differences are found between teacher-rated behavior patterns relating to later social adjustment for boys and those for girls. It is concluded that teacher ratings can be useful predictors of adjustment, especially if focused on the child's peer relationships.


Skin lightening effect of natural extracts coming from Senegal botanical biodiversity.
Skin depigmentation is increasingly oriented toward plant extracts because of harmfulness of depigmenting active ingredients used in cosmetics and dermatology. Reconstructed human pigmented epidermis (RHPE) is the closest in vitro model to human skin and offers the possibility to test the global depigmenting effect of a plant extract. These co-cultures of keratinocytes and melanocytes are the most advanced and newest models for testing depigmentation, and until now very few studies have been done with these cultures. We investigated the cytotoxicity and the inhibitory effect on tyrosinase and melanogenesis of four extracts from Combretum micranthum (G. Don) leaves, Anacardium occidentale (L.) fruits, Moringa oleifera (Lam.) seeds, and Adansonia digitata (L.) seeds. The vegetal extracts were obtained by ultrasound-assisted extraction and the vegetal oils by maceration. Anti-tyrosinase properties of two aqueous extracts were evaluated. Then, the cytotoxicity and depigmenting effects of these plant extracts were tested in vitro with RHPE model delivered by SkinEthic® . Antityrosinase activities were found to be 84.58% and 31.02% for C. micranthum and A. occidentale, respectively. All extracts, except A. occidentale, showed to be nontoxic. C. micranthum, M. oleifera, A. digitata, and mixture of M. oleifera and A. digitata extracts have shown, for the first time, an in vitro depigmenting activity equivalent or even more important than kojic acid. These natural extracts coming from Senegal botanical biodiversity could be used in cosmetic and dermatology as alternative agents to achieve skin depigmentation. Further study should be focused on the mechanism of action of these plant extracts.


Diagnosis of malignant breast disease by axillary lymphoscintigraphy: a preliminary report.
The ability of regional lymph nodes to take up 99Tcm-labelled antimony sulphide colloid from the breast tissue was studied in 50 patients with mammary symptoms by gamma-camera scanning. Thirteen out of 14 patients with histologically confirmed carcinoma of the breast had a depressed uptake of labelled colloid in ipsilateral nodes, i.e. a positive scan. Twenty-nine out of 32 patients with benign breast disease had a negative scan. The method promises to aid both the precise diagnosis of breast disease and the definition of the extent of mammary cancer.


Rice-gall midge interactions: Battle for survival.
Gall midges are insects specialized in maneuvering plant growth, metabolic and defense pathways for their benefit. The Asian rice gall midge and rice share such an intimate relationship that there is a constant battle for survival by either partner. Diverse responses by the rice host against the midge include necrotic hypersensitive resistance reaction, non-hypersensitive resistance reaction and gall-forming compatible interaction. Genetic studies have revealed that major R (resistance) genes confer resistance to gall midge in rice. Eleven gall midge R genes have been characterized so far in different rice varieties in India. In addition, no single R gene confers resistance against all the seven biotypes of the Asian rice gall midge, and none of the biotypes is virulent against all the resistance genes. Further, the interaction of the plant resistance gene with the insect avirulence gene is on a gene-for-gene basis. Our recent investigations involving suppressive subtraction hybridization cDNA libraries, microarray analyses, gene expression assays and metabolic profiling have revealed several molecular mechanisms, metabolite markers and pathways that are induced, down-regulated or altered in the rice host during incompatible or compatible interactions with the pest. This is also true for some of the pathways studied in the gall midge. Next generation sequencing technology, gene expression studies and conventional screening of gall midge cDNA libraries highlighted molecular approaches adopted by the insect to feed, survive and reproduce. This constant struggle by the midge to overcome the host defenses and the host to resist the pest has provided us with an opportunity to observe this battle for survival at the molecular level.


Transitioning to age inclusive early intervention for psychosis.
Early Intervention in psychosis Services (EIS) have previously restricted access based on age. However, there is now a move to age inclusive service. We aimed to examine differences between early and late onset (>35 years) psychosis to see if a threshold was valid. We also investigated the potential of a statistical modelling method to identify group characteristics which may be missed using a descriptive approach. Routine clinical data (n = 343), from an EIS, comprising socio-demographic, clinical, physical and treatment variables, were examined using descriptive and classification and regression tree (CART) analysis. The findings suggest that age differences were best explained by social factors. There was no emerging evidence that the differences exhibited had a fundamental impact on the clinical outcomes of the clients in terms of support beyond EIS (ie, hospitalization and home treatment team involvement) and pharmacological and psychological interventions. CART analysis revealed distinct service user characteristics associated with the clinical outcomes. There was no evidence to support a clinical cut off based on age providing support for age inclusive services. However, in the transition to age inclusive service delivery, EIS need to consider social/life stage variables, adapting provision where service delivery may operate a youth focused model. Routine analysis of clinical data should employ methods to identify groups of service users who may require adjusted service provision.


Impact of age group on bloodstream infection risk evaluation in immunosuppressed patients: a retrospective, single-centre, 5-year cohort study.
Elderly patients in immunosuppressive status may have an increased occurrence of illness and risk of poor prognosis. It is a generally overlooked population that we should pay more attention to their risk factors of sickness and mortality. Eight hundred and nine patients who were diagnosed with bloodstream infection in immunosuppressive states during accepting treatment in our hospital were selected from 2015 to 2019.The demographic data, underlying diseases, comorbidity, inducement, complications, pathogen sources, etiologies, and the antibiotics therapy were analyzed between ages > 65 years groups and ages < 65 years groups. The clinical characteristics of totally 809 immunosuppressed people diagnosed with bloodstream infection were analyzed, and among those people about 371 were ages > 65 years. By univariate logistic regression analysis and multivariate logistic regression analysis, we found that hypertension (OR: 2.864, 95% CI 2.024-4.051, P < 0.0001), cerebral Infarction (OR: 4.687, 95% CI 2.056-10.686, P < 0.0001), coronary heart disease (OR: 1.942, 95% CI 1.168-3.230, P = 0.011), acute pancreatitis (OR: 3.964, 95% CI 2.059-7.632, P < 0.0001), infective endocarditis (OR: 6.846, 95% CI 1.828-25.644, P = 0.004), aortic dissection (OR: 9.131, 95% CI 3.190-26.085, P < 0.0001), chemotherapy (OR: 3.462, 95% CI 1.815-6.603, P < 0.0001), transplant status (OR: 20.031, 95% CI 4.193-95.697, P < 0.0001), and respiratory tract infection (OR: 2.096, 95% CI 1.269-3.461, P = 0.004) were significantly different between ages > 65 years groups and ages < 65 years groups. Hypertension, cerebral Infarction, coronary heart disease, acute pancreatitis, infective endocarditis, aortic dissection, chemotherapy, transplant status, and pathogen source of respiratory tract were the independent risk factors of ages > 65 years in immunosuppressed patients, which would have the benefit to discriminate the prognostic factors in immunosuppressive elderly people with bloodstream infection.


Comparison of amniotic fluid lung maturity profiles in paired vaginal and amniocentesis specimens.
Amniotic fluid was obtained by transvaginal amniocentesis from 27 pregnant women in the third trimester. Subsequent to amniocentesis, membranes were ruptured and vaginal pool amniotic fluid was taken by bulb aspiration. The samples were analyzed for lung maturity profile, consisting of the lecithin/sphingomyelin (L/S) ratio and the percentages of phosphatidylinositol and phosphatidylglycerol. The L/S ratio was higher in the vaginal pool than in the amniotic sac in 22% of the paired samples. Similarly, the percentage of phosphatidylinositol was greater in the vaginal pool than in the amniotic sac in 48%. Phosphatidylglycerol, however, is invariably present in the amniotic sac when it is detected in the vaginal pool. The possible usefulness of these results in the management of patients with premature rupture of membranes is discussed.


Distance dependence and salt sensitivity of pairwise, coulombic interactions in a protein.
Histidine pK(a) values were measured in charge-reversal (K78E, K97E, K127E, and K97E/K127E) and charge-neutralization (E10A, E101A, and R35A) mutants of staphylococcal nuclease (SNase) by (1)H-NMR spectroscopy. Energies of interaction between pairs of charges (DeltaG(ij)) were obtained from the shifts in pK(a) values relative to wild-type values. The data describe the distance dependence and salt sensitivity of pairwise coulombic interactions. Calculations with a continuum electrostatics method captured the experimental DeltaG(ij) when static structures were used and when the protein interior was treated empirically with a dielectric constant of 20. The DeltaG(ij) when r(ij) < or = 10 A were exaggerated slightly in the calculations. Coulomb's law with a dielectric constant near 80 and a Debye-Hückel term to account for screening by the ionic strength reproduced the salt sensitivity and distance dependence of DeltaG(ij) as well as the structure-based method. In their interactions with each other, surface charges behave as if immersed in water; the Debye length describes realistically the distance where interactions become negligible at a given ionic strength. On average, charges separated by distances (r(ij)) approximately 5 A interacted with DeltaG(ij) approximately 0.6 kcal/mole in 0.01 M KCl, but DeltaG(ij) decayed to < or =0.10 kcal/mole when r(ij) = 20 A. In 0.10 M KCl, DeltaG(ij) approximately 0.10 kcal/mole when r(ij) = 10 A. In 1.5 M KCl, only short-range interactions with r(ij) < or = 5 A persisted. Although at physiological ionic strengths the interactions between charges separated by more than 10 A are extremely weak, in situations where charge imbalance exists many weak interactions can cumulatively produce substantial effects.


Integrated computer-aided formulation design: A case study of andrographolide/ cyclodextrin ternary formulation.
Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists, which is time-consuming, high cost and waste materials. This research aims to integrate various computational tools, including machine learning, molecular dynamic simulation and physiologically based absorption modeling (PBAM), to enhance andrographolide (AG) /cyclodextrins (CDs) formulation design. The lightGBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy. AG/γ-CD inclusion complexes showed the strongest binding affinity, which was experimentally validated by the phase solubility study. The molecular dynamic simulation was used to investigate the inclusion mechanism between AG and γ-CD, which was experimentally characterized by DSC, FTIR and NMR techniques. PBAM was applied to simulate the in vivo behavior of the formulations, which were validated by cell and animal experiments. Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate (TPGS) significantly increased the intracellular uptake of AG in MDCK-MDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers. The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills, respectively. In conclusion, this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility, dissolution rate and bioavailability. The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.


Recurrence of varicose veins after endovenous ablation of the great saphenous vein in randomized trials.
Recurrence of varicose veins after surgery (REVAS) for saphenous incompetence has been well described after ligation and stripping (L&S) but not after the now most frequently performed method of saphenous ablation, endovenous ablation (EVA). The purpose of this study was to define the overall incidence of REVAS as well as both the sites of reflux and the causes of REVAS through a systematic review and meta-analysis of randomized controlled trials (RCTs) for EVA. These studies have the advantage of prospectively collected data and a uniform duplex follow-up. We searched databases (January 1, 2000 through July 1, 2014) for published RCTs evaluating EVA treatment of great saphenous vein (GSV) incompetence that employed endovenous laser ablation or radiofrequency ablation. RCTs were eliminated that (1) did not have follow-up of at least 2 years, (2) did not obtain postoperative duplex scans, (3) did not clearly report the incidence of recurrent varicosities after GSV ablation, and (4) treated the small saphenous or anterior accessory saphenous veins. Of the 68 studies screened, 20 RCTs that employed EVA of the GSV were identified. Eight had a follow-up of at least 2 years, but one was eliminated because of lack of information on both the site and cause of REVAS. The resultant seven RCTs provided eight comparisons (one study compared both types of EVA to a comparator arm): three used radiofrequency ablation, and five employed endovenous laser ablation. Overall recurrent varicose veins developed in 125 limbs after EVA (22%), with no difference in the incidence vs the L&S group (22%) based on the number of limbs available at the time of the development of recurrence for both groups, but this incidence is dependent on the length of follow-up after the initial treatment. The two studies with serial follow-up showed an approximate doubling of REVAS over time for both EVA and L&S. By contrast, the cause of REVAS was different between the two methods. Neovascularization occurred in only two limbs (2%) after EVA vs 18 (18%) in the L&S group. Recanalization was the most common cause of REVAS for EVA (32%; 40 of 125 limbs), followed by the development of anterior accessory saphenous vein incompetence (19%; 23 of 125 limbs). In contrast to other reports, incompetent calf perforating veins were an infrequent cause of REVAS (7%; eight of 125). There is no difference in the incidence of REVAS for EVA vs L&S, but the causes of REVAS are different with L&S, which has important implications for treatment.


Construct validity of the miniclinical evaluation exercise (miniCEX).
To investigate the construct validity of the miniclinical evaluation exercise (miniCEX). Forty faculty participants from 16 internal medicine residency programs enrolled in a randomized, controlled trial of faculty development. Using a standard nine-point miniCEX rating form, participants watched and rated performances of standardized residents on nine scripted clinical videotapes depicting three levels of performance (unsatisfactory, marginal/satisfactory, and high satisfactory/superior). The nine-point rating scale was 1-3 = unsatisfactory, 4-6 = marginal/satisfactory, and 7-9 = superior. The performances were rated for three clinical skills, history taking, physical examination, and counseling. For each of the three clinical skills, the faculty participants were able to successfully discriminate among the three levels of performance using the miniCEX scale. Differences among ratings of the three performance levels were statistically significant; however, the range in ratings among the participants for each videotape was wide. The authors believe this to be the first study to document the construct validity of the miniCEX. Although the miniCEX appears to have reliability and construct validity, further research is needed to improve individual faculty observation skills and reduce interrater variability.


Recovery of active anti TNF-α ScFv through matrix-assisted refolding of bacterial inclusion bodies using CIM monolithic support.
Anti TNF-α molecules are important as therapeutic agents for many of the autoimmune diseases in chronic stage. Here we report the expression and purification of a recombinant single chain variable fragment (ScFv) specific to TNF-α from inclusion bodies. In contrast to the conventional on column refolding using the soft gel supports, an efficient methodology using monolithic matrix has been employed. Nickel (II) coupled to convective interaction media (CIM) support was utilized for this purpose with 6M guanidine hydrochloride (GuHCl) as the chaotropic agent. The protein purified after solubilization and refolding proved to be biologically active with an IC₅₀ value of 15 μg. To the best of our knowledge, this is the first report showing the application of methacrylate based chromatographic supports for matrix-assisted refolding and purification of Escherichia coli inclusion bodies. The results are promising to elaborate the methodology further to exploit the potential positive features of monoliths in protein refolding science.


Phenolic content, chemical composition and anti-/pro-oxidant activity of Gold Milenium and Papierowka apple peel extracts.
In this study the peels of ecologically grown apple (Malus domestica) cultivars: Gold Milenium (a new scab-resistant variety) and Papierowka (Papirovka; an old, sensitive to apple scab variety) were examined for their composition (phenolic compounds, triterpenoids, simple organic acids, macro-, microelements, reducing sugars, L-ascorbic acid), pro- and antioxidant properties as well as their application in reduction of the oxidative stress in cultured human skin fibroblast. The higher content of phenolic compounds correlated with the greater pro- and antioxidant activity of the peels of Papierowka compared to Gold Milenium in DPPH·, ABTS+, FRAP and CUPRAC assays as well as an ability to inhibition of lipid peroxidation. The quantity of the compounds strongly depended on the type of extraction. The extract of Papierowka peels possessed much higher amount of phenolic compounds compared to Gold Milenium (Papierowka: 3.68 ± 0.20 mg/g peel ultrasound assisted extraction (u.a.e); 2.02 ± 0.13 mg/g peel conventional extraction (c.e.); Gold Milenium: 1.46 ± 0.19 mg/g peel u.a.e; 1.15 ± 0.04 mg/g peel c.e. according the HPLC measurement). The pro-oxidant activity of the extract from Papierowka peels can be correlated with the content of phenolic compounds and metal ions as well. The apple peel extract is promising agent reducing the oxidative stress in skin fibroblast.


The calcified eggshell matrix proteome of a songbird, the zebra finch (Taeniopygia guttata).
The proteins of avian eggshell organic matrices are thought to control the mineralization of the eggshell in the shell gland (uterus). Proteomic analysis of such matrices identified many candidates for such a role. However, all matrices analyzed to date come from species of one avian family, the Phasianidae. To analyze the conservation of such proteins throughout the entire class Aves and to possibly identify a common protein toolkit enabling eggshell mineralization, it is important to analyze eggshell matrices from other avian families. Because mass spectrometry-based in-depth proteomic analysis still depends on sequence databases as comprehensive and accurate as possible, the obvious choice for a first such comparative study was the eggshell matrix of zebra finch, the genome sequence of which is the only songbird genome published to date. The zebra finch eggshell matrix comprised 475 accepted protein identifications. Most of these proteins (84 %) were previously identified in species of the Phasianidae family (chicken, turkey, quail). This also included most of the so-called eggshell-specific proteins, the ovocleidins and ovocalyxins. Ovocleidin-116 was the second most abundant protein in the zebra finch eggshell matrix. Major proteins also included ovocalyxin-32 and -36. The sequence of ovocleidin-17 was not contained in the sequence database, but a presumptive homolog was tentatively identified by N-terminal sequence analysis of a prominent 17 kDa band. The major proteins also included three proteins similar to ovalbumin, the most abundant of which was identified as ovalbumin with the aid of two characteristic phosphorylation sites. Several other proteins identified in Phasianidae eggshell matrices were not identified. When the zebra finch sequence database contained a sequence similar to a missing phasianid protein it may be assumed that the protein is missing from the matrix. This applied to ovocalyxin-21/gastrokine-1, a major protein of the chicken eggshell matrix, to EDIL3 and to lactadherin. In other cases failure to identify a particular protein may be due to the absence of this protein from the sequence database, highlighting the importance of better, more comprehensive sequence databases. The results indicate that ovocleidin-116, ovocleidin-17, ovocalyxin-36 and ovocalyxin-32 may be universal avian eggshell-mineralizing proteins. All the more important it is to elucidate the role of these proteins at the molecular level. This cannot be achieved by proteomic studies but will need application of other methods, such as atomic force microscopy or gene knockouts. However, it will also be important to analyze more eggshell matrices of different avian families to unequivocally identify other mineralization toolkit proteins apart from ovocleidins and ovocalyxins. Progress in this respect will depend critically on the availability of more, and more comprehensive, sequence databases. The development of faster and cheaper nucleotide sequencing methods has considerably accelerated genome and transcriptome sequencing, but this seems to concur with frequent publication of incomplete and fragmented sequence databases.


The completely mobilized remnant stomach: A new choice to reconstruct the esophagus in lower thoracic esophageal carcinoma with a history of distal gastrectomy.
It is a significant surgical challenge to reconstruct esophagus for the patients following distal gastrectomy (DGE). Remnant stomach seems to be a better choice compared with colon or jejunal. But many complicated surgical methods were performed because of limitation of feeding vessels. We found the remnant stomach remained viable when all the feeding vessels were dissected. We used the completely mobilized stomach to reconstruct esophagus successfully in 29 lower thoracic esophageal carcinoma patients with a history of DGE. The clinical data of 29 patients were retrospectively analyzed from August 2005 to March 2017 who accepted esophagoplasty by the completely mobilized remnant stomach. All the vessels of the remnant stomach were dissected including short gastric, posterior gastric, left gastric and left gastroepiploic vessels. The DGE included 2 Billroth I and 27 Billroth II. No perioperative death, no remnant stomach necrosis occurred. One Leakage was the iatrogenic injury on the remnant stomach. The other postoperative complications were the pulmonary infection(5) and arrhythmia(4). The completely mobilized remnant stomach was viable and functional after dissecting all the feeding vessels. Application of it was a new and feasible surgical method to perform esophagoplasty with the simpler procedure and less complication.


Structural and genome-wide analyses suggest that transposon-derived protein SETMAR alters transcription and splicing.
Extensive portions of the human genome have unknown function, including those derived from transposable elements. One such element, the DNA transposon Hsmar1, entered the primate lineage approximately 50 million years ago leaving behind terminal inverted repeat (TIR) sequences and a single intact copy of the Hsmar1 transposase, which retains its ancestral TIR-DNA-binding activity, and is fused with a lysine methyltransferase SET domain to constitute the chimeric SETMAR gene. Here, we provide a structural basis for recognition of TIRs by SETMAR and investigate the function of SETMAR through genome-wide approaches. As elucidated in our 2.37 Å crystal structure, SETMAR forms a dimeric complex with each DNA-binding domain bound specifically to TIR-DNA through the formation of 32 hydrogen bonds. We found that SETMAR recognizes primarily TIR sequences (∼5000 sites) within the human genome as assessed by chromatin immunoprecipitation sequencing analysis. In two SETMAR KO cell lines, we identified 163 shared differentially expressed genes and 233 shared alternative splicing events. Among these genes are several pre-mRNA-splicing factors, transcription factors, and genes associated with neuronal function, and one alternatively spliced primate-specific gene, TMEM14B, which has been identified as a marker for neocortex expansion associated with brain evolution. Taken together, our results suggest a model in which SETMAR impacts differential expression and alternative splicing of genes associated with transcription and neuronal function, potentially through both its TIR-specific DNA-binding and lysine methyltransferase activities, consistent with a role for SETMAR in simian primate development.


Value of Endoscopic Ultrasound-Guided Through-the-Needle Biopsy in Pancreatic Cystic Lesions. A Systematic Review and Meta-Analysis.
Endoscopic ultrasound-guided through-the-needle biopsy (EUS-TTNB) has been used over the past few years to increase diagnostic accuracy for pancreatic cystic lesions (PCLs). However, many concerns remain regarding its widespread use. This systematic review and meta-analysis aimed to pool the data from high-quality studies to evaluate the utility of EUS-TTNB in diagnosing PCLs. Electronic databases (PubMed, Embase, and Cochrane Library) from January 2010 through October 2022 were searched for publications addressing the diagnostic performance of EUS-TTNB in the diagnosis of pancreatic cystic lesions. Pooled proportions were calculated using fixed (inverse variance) and random-effects (DerSimonian-Laird) models. The initial search identified 635 studies, of which 35 relevant articles were reviewed. We extracted data from 11 studies that met the inclusion criterion, comprising a total of 575 patients. Mean patient age was 62.25 years ± 6.12 with females constituting 61.39% of the study population. Pooled sensitivity of EUS-TTNB in differentiating a PCL as neoplastic or non-neoplastic was 76.60% (95% CI = 72.60-80. 30). For the same indication, EUS TTNB had a pooled specificity of 98.90% (95% CI = 93.80-100.00). The positive likelihood ratio was 10.28 (95% CI = 4.77-22.15), and the negative likelihood ratio was 0.26 (95% CI = 0.22-0.31). The pooled diagnostic odds ratio for EUS-TTNB in diagnosing PCLs as malignant/pre-malignant vs. non-malignant was 41.34 (95% CI = 17.42-98.08). Pooled adverse event rates were 3.04% (95% CI = 1.83-4.54) for pancreatitis, 4.02% (95% CI = 2.61-5.72) for intra-cystic bleeding, 0.94% (95% CI = 0.33-1.86) for fever, and 1.73% (95% CI = 0.85-2.91) for other minor events. EUS-TTNB has good sensitivity with excellent specificity in accurately classifying PCLs as neoplastic or non-neoplastic. Adding EUS-TTNB to EUS-FNA increases the accuracy of EUS-guided approach in diagnosing PCLs. However, it could significantly increase the risk of post-procedural pancreatitis.


Prioritising Urological Surgery in the COVID-19 Era: A Global Reflection on Guidelines.
Determining whether members follow guidelines, including guidelines prepared to help direct practice management during the coronavirus disease 2019 (COVID-19) pandemic, is an important goal for medical associations. To determine whether practice of urologists is in line with guidelines for the management of common urological conditions during the COVID-19 pandemic produced by leading (inter)national urological associations. Self-selected urologists completed a voluntary survey available online from March 27 to April 11, 2020 and distributed globally by the Société Internationale d'Urologie. Responses to two survey questions on the (1) management of 14 common urological procedures and (2) priority scoring of 10 common urological procedures were evaluated by practice setting and geographical region using chi-square and one-way analysis of variance analyses, respectively. There were 2494 respondents from 76 countries. Oncological conditions were prioritised over benign conditions, and benign conditions were deferred when feasible and safe. Oncological conditions with the greatest malignant potential were prioritised over less aggressive cancers. Respondents from Europe were least likely to postpone and most likely to prioritise conditions identified by guidelines as being of the highest priority. Respondents' priority scoring of urological procedures closely matched the priorities assigned by guidelines. The main limitation of this study is that respondents were self-selected, and access to the survey was limited by language and technology barriers. Prioritisation and management of urological procedures during the COVID-19 pandemic are in line with current guidelines. The greatest agreement was reported in Europe. Observed differences may be related to limited resources in some settings. When deciding how best to treat patients during the coronavirus disease 2019 (COVID-19) pandemic, urologists are taking into account both expert recommendations and the availability of important local resources.


Does Use of Atoxigenic Biocontrol Products to Mitigate Aflatoxin in Maize Increase Fumonisin Content in Grains?
In the tropics and subtropics, maize (Zea mays) and other crops are frequently contaminated with aflatoxins by Aspergillus flavus. Treatment of crops with atoxigenic isolates of A. flavus formulated into biocontrol products can significantly reduce aflatoxin contamination. Treated crops contain up to 100% fewer aflatoxins compared with untreated crops. However, there is the notion that protecting crops from aflatoxin contamination may result in increased accumulation of other toxins, particularly fumonisins produced by a few Fusarium species. The objective of this study was to determine if treatment of maize with aflatoxin biocontrol products increased fumonisin concentration and fumonisin-producing fungi in grains. Over 200 maize samples from fields treated with atoxigenic biocontrol products in Nigeria and Ghana were examined for fumonisin content and contrasted with maize from untreated fields. Apart from low aflatoxin levels, most treated maize also harbored fumonisin levels considered safe by the European Union (<1 part per million; ppm). Most untreated maize also harbored equally low fumonisin levels but contained higher aflatoxin levels. In addition, during one year, we detected considerably lower Fusarium spp. densities in treated maize than in untreated maize. Our results do not support the hypothesis that treating crops with atoxigenic isolates of A. flavus used in biocontrol formulations results in higher grain fumonisin levels.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.


Extensible byssus of Pinctada fucata: Ca(2+)-stabilized nanocavities and a thrombospondin-1 protein.
The extensible byssus is produced by the foot of bivalve animals, including the pearl oyster Pinctada fucata, and enables them to attach to hard underwater surfaces. However, the mechanism of their extensibility is not well understood. To understand this mechanism, we analyzed the ultrastructure, composition and mechanical properties of the P. fucata byssus using electron microscopy, elemental analysis, proteomics and mechanical testing. In contrast to the microstructures of Mytilus sp. byssus, the P. fucata byssus has an exterior cuticle without granules and an inner core with nanocavities. The removal of Ca(2+) by ethylenediaminetetraacetic acid (EDTA) treatment expands the nanocavities and reduces the extensibility of the byssus, which is accompanied by a decrease in the β-sheet conformation of byssal proteins. Through proteomic methods, several proteins with antioxidant and anti-corrosive properties were identified as the main components of the distal byssus regions. Specifically, a protein containing thrombospondin-1 (TSP-1), which is highly expressed in the foot, is hypothesized to be responsible for byssus extensibility. Together, our findings demonstrate the importance of inorganic ions and multiple proteins for bivalve byssus extension, which could guide the future design of biomaterials for use in seawater.


Is Hypozincemia Related to Tinnitus?: A Population Study Using Data From the Korea National Health and Nutrition Examination Survey.
The aim of present study was to determine the relationship between serum zinc level and tinnitus using data from the Korea National Health and Nutrition Examination Survey (KNHANES). The present study examined the relationship between serum zinc level and tinnitus using data from the KNHANES. A total of 2,225 KNHANES participants responded to the tinnitus questionnaire and provided blood samples to measure serum zinc concentration. Based on questionnaire responses, participants were categorized into control, mild tinnitus, moderate tinnitus, and severe tinnitus subgroups. There were no significant differences between groups in serum zinc level after adjustment for sex, age, and hearing loss. It was concluded that hypozincemia is not related to tinnitus in a large population.


Performance comparison between MRI and CT for local staging of sigmoid and descending colon cancer.
To compare the diagnostic performance of MRI and CT for local staging of sigmoid and descending colon cancer, with pathological results as the reference standard. This retrospective study included 116 patients with sigmoid or descending colon cancer who underwent both MRI and CT before surgery. MRI and CT images were separately reviewed by two independent and blinded radiologists to assess the following features: T-stage, presence of extramural extension (T3-4 disease), lymph node metastases (N+), and extramural vascular invasion (EMVI+). Diagnostic performance with sensitivity and specificity for detecting positive status (T3-4, N+ or EMVI+) were assessed using receiver-operating-characteristic (ROC) curve, and compared between MRI and CT. MRI achieved correct T-stage in 81 of 116 patients (69.8 %) while CT in 66 (56.9 %). For detecting T3-4 disease, MRI showed better performance than CT with area under the curve (AUC) of 0.888 versus 0.712 (P = 0.002) and specificity of 81.82 % versus 54.6 % (P = 0.011). No significance was found in sensitivity between two modalities (89.2 % versus 83.1 %, P = 0.302). For detecting N+ disease, performance of MRI and CT were similar (AUC, 0.670 versus 0.650, P = 0.412). For detecting EMVI+, MRI showed better performance than CT (AUC, 0.780 versus 0.575, P = 0.012) with significantly higher sensitivity (68.6 % versus 40.0 %, P = 0.031) and similar specificity (both are 84.3 %). MRI may offer more superior diagnostic performance than CT for detecting T3-4 disease and EMVI, thereby supporting its alternative application to CT in local staging of colon cancer.


Self-assembly of methylene violet-conjugated perylene diimide with photodynamic/photothermal properties for DNA photocleavage and cancer treatment.
Near-infrared (NIR) light-activated phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), has gained considerable attention due to the advantages of high efficiency and minimally invasiveness. However, the development of a single component therapeutic agent with clear structure and molecular weight that achieve photodynamic/photothermal synergistic therapy is still challenging. Herein, we design and synthesize a new smart photosensitizer (PRX) by conjugation of perylene diimide (PDI) and methylene violet (RAX). The typical donor-acceptor (D-A) structure of RAX facilitates the red-shift of absorption to the near-infrared (NIR) region. The amphiphilic PRX could self-assemble into monodispersed nanoparticles (PRX NPs) with enhanced and broadened absorption. Under a single 808 nm laser irradiation, PRX NPs could generate efficient reactive oxygen species (ROS) and heat simultaneously with the photothermal conversion efficiency as high as 59%. PRX NPs displays strong interaction with DNA and can damage plasmid DNA upon light irradiation. The biocompatibility and high phototoxicity of PRX NPs against A549 cells are further confirmed through MTT assay. Therefore, the as-prepared PRX NPs could be served as a promising antitumor nanoagent through photothermal/photodynamic combination manner.


Pathology of human plaque vulnerability: mechanisms and consequences of intraplaque haemorrhages.
Atherothrombotic diseases are still major causes of inability and mortality and fighting atherothrombosis remains a public health priority. The involvement of repeated intraplaque haemorrhages (IPH) in the evolution of atherothrombotic lesions towards complications was proposed as early as 1936. This important topic has been recently revisited and reviewed. Histological observations have been corroborated by magnetic resonance imaging (MRI) of human carotid atheroma, identifying IPH as the main determinant of plaque evolution towards rupture. Beside the intimal integration of asymptomatic luminal coagulum, inward sprouting of neovessels from the adventitia towards the plaque, is one source of IPH in human atheroma. We recently described that directed neo-angiogenesis from the adventitia towards the plaque, across the media, is initiated by lipid mediators generated by the plaque on the luminal side, outwardly convected to the medial VSMCs. Subsequent stimulation of VSMC PPAR-γ receptors induces VEGF expression which causes centripetal sprouting of adventitial vessels. However, this neovascularization is considered to be immature and highly susceptible to leakage. The main cellular components of IPH are Red Blood Cells (RBCs), which with their haemoglobin content and their cell membrane components, particularly enriched in unesterified cholesterol, participate in both the oxidative process and cholesterol accumulation. The presence of iron, glycophorin A and ceroids provides evidence of RBCs. IPH also convey blood leukocytes and platelets and are sites prone to weak pathogen contamination. Therefore prevention and treatment of the biological consequences of IPH pave the way to innovative preventive strategies and improved therapeutic options in human atherothrombotic diseases.


[Tolerance and efficacy of lipomodelling as an element of breast symmetry in breast reconstruction].
Fat transfer significantly improved results in breast reconstruction. Final breast symmetry is very important in breast reconstruction, but sometimes, the result is not perfect with usual techniques. The aim of this study is to evaluate the tolerance and efficacy of lipomodelling as a complementary technique for breast symmetrisation. In this study, 150 patients had controlateral breast symmetrisation after breast reconstruction, using or completed with fat transfer. Patients were clinically evaluated one year after surgery. Age, BMI, harvested, purified and transferred fat volumes, and postoperatory complications were recorded. Morphological outcomes were evaluated by the surgeon as: very good, good, average or bad. Patients rated their degree of satisfaction as: very satisfying, satisfying, poor or bad. We found out that 98.6 % of morphological results were good or very good, and 86.6 % of the patients were satisfied or very satisfied with the result. Complications were rare (2 % of cytosteatonecrotic lesions). Lipomodelling in native breast symmetrisation after reconstruction is a powerful technique because it allows to increase volume of a hypoplastic controlateral breast, to ameliorate its shape, and to finally enhance mammoplasty result by correcting persisting localized volume defects. It definitively is a major therapeutic tool for enhancing breast reconstruction outcomes.


Adipocyte gene expression in obesity - insights gained and challenges ahead.
White adipocytes possess extraordinary plasticity with an unparalleled capacity to expand in size with nutritional overload. Several lines of evidence indicate that limitations to this plasticity, as found in both lipodystrophy and obesity, drive several of the comorbidities of these disease, thereby underscoring the need to understand the mechanisms of healthy and unhealthy adipose expansion. Recent single-cell technologies and studies of isolated adipocytes have allowed researchers to gain insight into the molecular mechanisms of adipocyte plasticity. Here, we review current insight into the effect of nutritional overload on white adipocyte gene expression and function. We review the role of adipocyte size and heterogeneity and discuss the challenges and future directions.


Abdominal abscess and Hafnia alvei septicemia occurring during the aplastic phase after autologous stem-cell transplantation in a patient with diffuse large B-cell lymphoma.
Hafnia alvei is a motile gram-negative bacterium that is rarely isolated from human specimens, but that sometimes can be found as part of the gastrointestinal flora. Here we report a rare case of Hafnia alvei septicemia with an abdominal abscess in a 60-year-old woman with diffuse large B-cell lymphoma involving the spleen, liver, and then lymph nodes. She initially received a splenectomy, and, over a 2-year period, four courses of chemotherapy. After achieving complete remission status, she underwent autologous peripheral blood stem-cell transplantation (PBSCT). During the aplastic phase following transplantation, the patient developed fever, diarrhea, and abdominal pain, with blood cultures positive for Hafnia alvei and an abscess in the splenic recess. Considering the high surgical risk, the infection was treated, successfully, with antibiotics (imipenem/cilastatin), without surgery or computed tomography (CT)-guided percutaneous drainage. Infections due to Hafnia alvei are rare, and this is the first reported case of Hafnia alvei septicemia in an adult hematologic patient undergoing a stem-cell transplantation procedure.


Presence and significance of minor antenna components in the energy transfer sequence of the green photosynthetic bacterium Chloroflexus aurantiacus.
Antenna components in the energy transfer processes of a green photosynthetic bacterium Chloroflexus aurantiacus were spectrally investigated by time-resolved fluorescence spectroscopy at -196 degrees C on intact cells. Besides major antenna components so far reported, three minor components were resolved; those were Bchl c located at 785 nm, the baseplate Bchl a at 819 nm and Bchl a in the B808-866 complex at 910 nm. The last component was assigned to a longer wavelength antenna closely associated with a reaction center. An additional Bchl c fluorescence component was kinetically suggested to be present, which can be an energy donor to a major Bchl c. Presence of these minor components was signified in terms of (1) increase in the spectral overlap integral and (2) adjustment of the direction of dipole moments in the energy transfer sequence of intact cells.


A coumarin analogue NFA from endophytic Aspergillus fumigatus improves drought resistance in rice as an antioxidant.
Drought and its resulting oxidative damage are the major yield limiting factors for crops in arid and semi-arid regions. Recent studies have found that endophytic fungi coexisting in plants can alleviate biotic or abiotic damage to plant growth and development. In order to screen for the endophytes associated with drought stress, 12 strains of endophytic fungi with high antioxidant activity isolated from riparian plants Myricaria laxiflora were evaluated for their effects in rice by the crude extracts. Of the 12 endophytic fungi, Aspergillus fumigatus SG-17 functioned most effectively, with the crude extract exhibiting relatively higher antioxidant capacity both in vivo and in vitro. The subsequent MS and NMR analysis showed that the primary substance responsible for the antioxidant activity in the extract was (Z)-N-(4-hydroxystyryl) formamide (NFA), an analogue of coumarin. Enzyme activity assay in nerve cells SH-SY5Y showed that NFA could maintain the membrane integrity and regulate the antioxidase activity under oxidative stress. In rice suffering drought stress, NFA effectively alleviated the harm by regulating the contents of NADPH oxidases, antioxidants and heat shock proteins, all of which are closely related with the reactive oxygen species pathway. These findings indicated that some endophytes from plants often subjected to flooding and oxidative stress could enhance drought resistance by producing compounds such as NFA to regulate the oxidative pathway.


Interleukin 10 inhibits oxidative stress-induced autophagosome formation in hepatic stellate cells by activating the mTOR-STAT3 pathway.
Autophagy is involved in the activation of hepatic stellate cells (HSCs) and liver fibrosis. Previous studies have shown that interleukin 10 (IL-10) has a marked therapeutic effect against liver fibrosis. However, few studies have evaluated the effect of IL-10 on autophagy in HSCs and fibrotic livers. The aim of this study was to assess the effect of IL-10 on the autophagy of HSCs in vitro and in vivo and then to explore the underlying pathway. In vitro, The results revealed that IL-10 had inhibitory effects on hydrogen peroxide (H2O2)-induced autophagy, as evidenced by the decreased LC3II/I ratio and Beclin1 expression, increased p62 expression, reduced numbers of autophagosomes, and blocked autophagy initiation in HSCs. Mechanistically, IL-10 significantly promoted the phosphorylation of the signal transducer and activator of transcription 3(STAT3) and mammalian target of rapamycin (mTOR), leading to the activation of STAT3 and mTOR, which in turn inhibited autophagy. In vivo, the increased expression of IL-10 in fibrotic livers inhibited significantly liver fibrosis and decreased the autophagic activity in fibrotic livers and HSCs. Overall, our results indicate that IL-10 suppressed H2O2-induced autophagy in HSCs by activating the STAT3-mTOR signaling pathway. Present study provides a new theoretical basis for the anti-fibrotic effects of IL-10.


Corticotropin-releasing hormone microinfusion in the central amygdala diminishes a cardiac parasympathetic outflow under stress-free conditions.
The central nucleus of the amygdala (CeA) is known to be involved in the regulation of autonomic, neuroendocrine and behavioural responses in stress situations. The CeA contains large numbers of corticotropin-releasing hormone (CRH) cell bodies. Neuroanatomical studies revealed that the majority of the CRH fibres from the CeA have direct connections with autonomic regulatory nuclei in the brainstem. In the present study, the effects of locally infused CRH (30 ng) into the CeA, in freely moving male Wistar rats under stress-free conditions, were examined. Heart rate, endocrine parameters and behavioural activity were repeatedly measured before, during and after local administration of CRH, pretreated with either artificial CSF or the CRH-receptor antagonist, alpha-helical CRH (alpha-hCRH). CRH infusion alone caused a long-lasting increase in heart rate without affecting plasma adrenaline and noradrenaline as indicators of sympathetic activity. This CRH-induced tachycardia was effectively blocked by pretreatment with a high dose (1 microgram) alpha-hCRH locally into the CeA, while the pretreatment with low dose (0.1 microgram) of the alpha-hCRH caused a minor blockade of the CRH-induced tachycardia. The results suggest that CRH mechanisms in the CeA regulate the autonomic changes probably only by affecting parasympathetic but not sympathetic output systems. Because CRH is given at the level of the cell body of the CRH neurons in the CeA, we suggest that the reduction of the parasympathetic output may be explained as an autoreceptor-mediated inhibition of CRH neurons from the CeA with parasympathetic-regulating brainstem nuclei.


Binding of specific ligand by D2- and NMDA-receptors of striatum cells in two rat strains predisposed and resistant to audiogenic seizures.
We studied parameters of specific receptor binding of D2-dopamine receptor ligand [(3)H]-sulpiride and NMDA-receptor ligand [(3)H]-MK-801 on the membranes of striatum cells in Krushinsky-Molodkina rats (predisposed to audiogenic seizures) and strain "0" selected for the absence of audiogenic seizures. No interstrain differences were observed in affinity (K(d)) of both D2- and NMDA-receptors to ligands. At the same time, significant interstrain differences in receptor density (B(max)) were found for both D2-receptors and NMDA-receptors. The reduced number of dopamine and glutamate receptors in the striatum can be associated with neurological peculiarities of Krushinsky-Molodkina rat strain (audiogenic seizures and postictal catalepsy).


Generation of offspring-producing 3D ovarian organoids derived from female germline stem cells and their application in toxicological detection.
In vitro production of oocytes capable of producing offspring has exciting potential applications in reproductive medicine. Here, we generated and characterized an ovarian organoid model derived from female germline stem cells using a three-dimensional culture system. We show that this model generated normal offspring and detected drug toxicity. The ovarian organoids could produce oocytes and exhibited endocrine functions. Single-cell analysis of ovarian organoids identified six ovarian cell lineages, such as germ, granulosa and theca cells, and produced gene-expression signatures for each cell type. Investigation of the expression patterns of genes related to meiosis and gene ontogeny analysis for germ cell clusters showed that a germ cell population was maintained in the ovarian organoids. Moreover, flow cytometric analysis confirmed that the population of germ cells could be maintained on the organoids and showed that ascorbic acid treatment had a beneficial effect of germ cell population maintenance on the organoids. Furthermore, we demonstrated the successful production of offspring from oocytes derived from ovarian organoids. Finally, we showed the ovarian organoids had the potential to drug toxicological detection. For example, we found that salinomycin impaired the formation of ovarian organoids and germ cell population maintenance by inducing apoptosis. These results indicate that the female germline stem cell-derived ovarian organoids represent a valuable model system for generating oocytes that can yield offspring, and provide a novel model for drug screening and toxicological detection.