Evolution of ageing.
An evolutionary view of ageing suggests that mortality may be due to an energy-saving strategy of reduced error regulation in somatic cells. This supports Orgel's 'error catastrophe' hypothesis and offers a new basis for the study of normal and abnormal ageing syndromes and of apparently immortal transformed cell lines.


Upper gastrointestinal endoscopy at four intensive care units in one hospital: frequency and indication.
To investigate the frequency, indication and results of upper gastrointestinal endoscopy (UGIE) at four different intensive care units (ICUs) in one hospital. Retrospective analysis. Rotterdam Erasmus University Hospital, The Netherlands. One hundred and ninety-nine male and 102 female patients; mean age, 58.3 years (range, 14-91 years). Four hundred and eleven UGIEs. UGIE was primarily diagnostic and therapeutic in 55% and 45% of patients, respectively. Seventy-three per cent of the diagnostic UGIEs were performed for localization of a haemorrhage and 70% of the therapeutic UGIEs for placement of feeding tubes. The causes of haemorrhage were varices, duodenal ulcer and oesophagitis in 26, 22 and 14% of cases, respectively. As co-incidental findings, oesophagitis, gastritis and gastric ulcer were seen in, respectively, 18, 8 and 7% of cases. The vast majority of UGIEs (81%) were performed at the surgical and medical ICUs. At the medical ICU, upper gastrointestinal haemorrhage (UGIH) usually was the ICU admission diagnosis, and usually concerned varices (56%). At the surgical ICU, UGIH was usually not the ICU admission diagnosis but a postoperative complication, and usually concerned oesophagitis (25%) or a duodenal or gastric ulcer (25 and 13%, respectively). Of all ICU patients, surgical patients were most prone to have co-incidental abnormalities of the digestive tract at UGIE (63%). UGIE is a frequent diagnostic and therapeutic procedure in patients admitted to the ICU, particularly at the surgical and medical ICU. Diagnostic and therapeutic endoscopy are most frequently performed for assessment of bleeding and placement of feeding tubes, respectively. Oesophagitis is a surprisingly common finding, both as a co-incidental diagnosis as well as the cause of bleeding, especially after surgery.


Modulation of activities and RNA level of the components of the plasminogen activation system during fusion of human myogenic satellite cells in vitro.
Primary cultures of human myogenic stem cells (satellite cells) mimic myogenic differentiation. During this process, the expression of the components of the plasminogen activation system underwent modulation. Activities and mRNA levels of tissue-type and urokinase-type plasminogen activator were increased in a reproducible pattern during differentiation. A modulation of the mRNA level of PAI-2 was also observed. Human satellite cells expressed a urokinase receptor and also the mRNA level of this component underwent modulation. With the exception of PAI-1 mRNA, the level of all mRNAs increased from Day 4 to Day 8, i.e., just before myoblasts fusion, and then remained high at later stages. The modulation of the plasminogen activating activity indicates that this system is directly involved in the fusion process of myogenic differentiation.


TOBMI: trans-omics block missing data imputation using a k-nearest neighbor weighted approach.
Stitching together trans-omics data is a powerful approach to assess the complex mechanisms of cancer occurrence, progression and treatment. However, the integration process suffers from the 'block missing' phenomena when part of individuals lacks some omics data. We proposed a k-nearest neighbor (kNN) weighted imputation method for trans-omics block missing data (TOBMIkNN) to handle gene-absence individuals in RNA-seq datasets using external information obtained from DNA methylation probe datasets. Referencing to multi-hot deck, mean imputation and missing cases deletion, we assess the relative error, absolute error, inter-omics correlation structure change and variable selection.The proposed method, TOBMIkNN reliably imputed RNA-seq data by borrowing information from DNA methylation data, and showed superiority over the other three methods in imputation error and stability of correlation structure. Our study indicates that TOBMIkNN can be used as an advisable method for trans-omics block missing data imputation. TOBMIkNN is freely available at https://github.com/XuesiDong/TOBMI. Supplementary data are available at Bioinformatics online.


Prospective outcome assessment of the therapeutic benefits of arthroscopy and arthrocentesis of the temporomandibular joint.
Patients who fail to respond to routine conservative measures to treat pain, restriction, and locking in the temporomandibular joint (TMJ) may have therapeutic arthroscopy or arthrocentesis, both of which are associated with symptomatic improvement in 86% of patients. To our knowledge there are no current data on improvements in mouth opening and lateral deviations after these procedures. This prospective audit includes 244 patients treated between 2005 and 2010 from one surgeon's practice, who were followed up at least once at 6 weeks after arthroscopy or arthrocentesis. They had various conditions but all had tender joints. Measurements of interincisal opening, left and right lateral excursions, and protrusion were taken before and during operation with callipers (mm). Opening and pain scores were also recorded on 10 cm analogue scales before operation and at 6 weeks. Pain scores improved with intervention from a mean score of 37.1-16.1 (range 0-100). The improvement in mouth opening ranged from 0 to 78% (as some patients had locking or pain with normal opening before operation), and 86% had improved enough to be discharged at 6 weeks. Temporary forehead weakness in two patients resolved within the timescale of the study. The study shows improvements in mouth opening, and confirms that pain scores can be improved after arthroscopy or arthrocentesis when conservative approaches have failed. In the hands of a skilled practitioner, arthroscopy can be a useful diagnostic and therapeutic adjunct, which can be used repeatedly with low morbidity.


Recommendations and Next Steps For Competency-Based Pharmacy Education.
In July 2021, the chairs of the American Association of Colleges of Pharmacy Council of Deans, Council of Faculties, and Council of Sections developed a task force to discuss potential ways to improve pharmacy education. The Competency-Based Education (CBE) Joint Task Force was created to explore the pros and cons of advancing a competency-based approach to pharmacy education (CBPE) and to determine ways to create more flexibility within pharmacy curricula to enable CBE. To achieve these goals, the Task Force systematically reviewed available resources and outlined the pros and cons of CBPE, best practices for implementation, strategies to minimize barriers, and recommendations on whether CBE should be implemented in pharmacy education. This commentary summarizes the Task Force's findings regarding whether CBPE is a suitable approach for pharmacy education and the next steps if implemented.


Cerebral evoked responses to skin warming recorded from human scalp.
Reponses evoked by warming the glabrous palmar skin were recorded maximally from a contralateral parietal scalp site that approximated the hand projection area of sensorimotor cortex. A smaller and later occurring response was also seen at the corresponding ipsilateral site. The temperature to which the skin was adapted was critical and was maintained at 35 degrees C rather at 30 degrees C as it was in an earlier study where no responses were seen. Peak latencies ranged from 280 msec to 356 msec for stimulus intensities of 8 degree C presented at a rate of 19 degrees C/sec. This warm evoked response appeared to have its origin in the specifically sensitive primary warm afferents. The presence of an evoked response when warming occurred from the 35 degrees C adapting temperature (AT) and its absence at the 30 degrees C AT coincide with the greater sensitivity of warm receptors at the higher AT. Comparison of these results with those for evoked responses to skin cooling and tactile tap suggest that the cortical organization of temperature (both warm and cool stimuli) in human is similar to that of touch.


Analysis of individual differences in neurofeedback training illuminates successful self-regulation of the dopaminergic midbrain.
The dopaminergic midbrain is associated with reinforcement learning, motivation and decision-making - functions often disturbed in neuropsychiatric disorders. Previous research has shown that dopaminergic midbrain activity can be endogenously modulated via neurofeedback. However, the robustness of endogenous modulation, a requirement for clinical translation, is unclear. Here, we examine whether the activation of particular brain regions associates with successful regulation transfer when feedback is no longer available. Moreover, to elucidate mechanisms underlying effective self-regulation, we study the relation of successful transfer with learning (temporal difference coding) outside the midbrain during neurofeedback training and with individual reward sensitivity in a monetary incentive delay (MID) task. Fifty-nine participants underwent neurofeedback training either in standard (Study 1 N = 15, Study 2 N = 28) or control feedback group (Study 1, N = 16). We find that successful self-regulation is associated with prefrontal reward sensitivity in the MID task (N = 25), with a decreasing relation between prefrontal activity and midbrain learning signals during neurofeedback training and with increased activity within cognitive control areas during transfer. The association between midbrain self-regulation and prefrontal temporal difference and reward sensitivity suggests that reinforcement learning contributes to successful self-regulation. Our findings provide insights in the control of midbrain activity and may facilitate individually tailoring neurofeedback training.


Developmental and cognitive troubles in Williams syndrome.
Williams syndrome (WS) is a neurodevelopmental genetic disorder with a prevalence of approximately 1 in 7500. It is caused by a hemizygous deletion of approximately 28 genes on the 7th chromosome (7q11.23), including the elastin allele. Individuals with WS have atypical facial characteristics, including medial eyebrow flair, epicanthal folds, upturned nose, elongated philtrum, and full lips. Infants typically experience constipation and colic. Cardiac and renal abnormalities, as well as hypertension, are common. Individuals with WS are at increased risk for hearing and vision difficulties. Gastrointestinal difficulties are common and include constipation and diverticulitis. Joint abnormalities are observed in both children and adults with WS. Individuals with WS are overly friendly yet can experience nonsocial anxieties. Cognitive skills are typically in the mild to moderately delayed range. Relative strengths have been demonstrated in some aspects of language and face processing, while visuospatial skills are significantly delayed.


Modulation of single-molecule magnet behaviour via photochemical [2+2] cycloaddition.
The first example of phototunable SMMs has been reported. Upon UV irradiation, variations of the coordination sphere around Dy(III) ions actually affect the magnetic behaviour of the compound via [2+2] cycloaddition reaction, leading to a magnetic transformation from the SMM behaviour to a field-induced slow relaxation.


Circulating concentrations of GLP-1 are associated with coronary atherosclerosis in humans.
GLP-1 is an incretine hormone which gets secreted from intestinal L-cells in response to nutritional stimuli leading to pancreatic insulin secretion and suppression of glucagon release. GLP-1 further inhibits gastric motility and reduces appetite which in conjunction improves postprandial glucose metabolism. Additional vasoprotective effects have been described for GLP-1 in experimental models. Despite these vasoprotective actions, associations between endogenous levels of GLP-1 and cardiovascular disease have yet not been investigated in humans which was the aim of the present study. GLP-1 serum levels were assessed in a cohort of 303 patients receiving coronary CT-angiography due to typical or atypical chest pain. GLP-1 was found to be positively associated with total coronary plaque burden in a fully adjusted model containing age, sex, BMI, hypertension, diabetes mellitus, smoking, triglycerides, LDL-C (low density lipoprotein cholesterol), hsCRP (high-sensitive C-reactive protein), and eGFR (estimated glomerular filtration rate) (OR: 2.53 (95% CI: 1.12 - 6.08; p = 0.03). Circulating GLP-1 was found to be positivity associated with coronary atherosclerosis in humans. The clinical relevance of this observation needs further investigations.


Engineering of Yarrowia lipolytica for terpenoid production.
Terpenoids are a group of chemicals of great importance for human health and prosperity. Terpenoids can be used for human and animal nutrition, treating diseases, enhancing agricultural output, biofuels, fragrances, cosmetics, and flavouring. However, due to the rapid depletion of global natural resources and manufacturing practices relying on unsustainable petrochemical synthesis, there is a need for economic alternatives to supply the world's demand for these essential chemicals. Microbial biosynthesis offers the means to develop scalable and sustainable bioprocesses for terpenoid production. In particular, the non-conventional yeast Yarrowia lipolytica demonstrates excellent potential as a chassis for terpenoid production due to its amenability to industrial production scale-up, genetic engineering, and high accumulation of terpenoid precursors. This review aims to illustrate the scientific progress in developing Y. lipolytica terpenoid cell factories, focusing on metabolic engineering approaches for strain improvement and cultivation optimization.


Adrenomedullin increased the short-circuit current in the pig oviduct through chloride channels via the CGRP receptor: mediation by cAMP and calcium ions but not by nitric oxide.
The oviduct serves as a site for the fertilization of the ovum and the transport of the conceptus down to the uterus for implantation. In this study, we investigated the presence of adrenomedullin (ADM) and its receptor component proteins in the pig oviduct. The effect of ADM on oviductal secretion, the specific receptor, and the mechanisms involved were also investigated. The presence of ADM and its receptor component proteins in the pig oviduct were confirmed using immunostaining. Short-circuit current (I(sc)) technique was employed to study chloride ion secretion in the oviductal epithelium. ADM increased I(sc) through cAMP- and calcium-activated chloride channels, and this effect could be inhibited by the CGRP receptor antagonist, hCGRP8-37. In contrast, the nitric oxide synthase inhibitor, L-NG-nitroarginine methyl ester (L-NAME), could not block the effect of ADM on I(sc). In summary, ADM may increase oviductal fluid secretion via chloride secretion independent of the nitric oxide pathway for the transport of sperm and the conceptus.


Effects of noise exposure and task demand on cardiovascular function.
Cardiovascular effects under various noise-exposure and task-demand conditions were studied among 40 senior highschool students. The subjects consisted of 20 males and 20 females with a mean age of 16.7 +/- 0.7 years. All subjects had equivalent abacus performance ratings. Each subject was tested with a random sequence of six sessions. The time limit set for each session was 33 min. Six experimental sessions were constructed by a random combination of noise exposure (60, 85 or 90 dB (A] white noise) and task demand (task presence or task absence) variables. Blood pressure measures were taken at the beginning and ending phases of each session. A task-demand variable was defined as a conjoint of mental arithmetic (3 min) and abacus arithmetic (30 min). The results from the present study show that the effect of noise exposure on task performance is remarkable. Only noise exposure tended to influence the performance of male students in abacus arithmetic. The effect of task demand on blood pressure was higher than that of noise exposure. No interaction effect (noise exposure x task demand) on blood pressure, was found via analyses of within-subjects two-way ANOVA.


Animal models of sugar and fat bingeing: relationship to food addiction and increased body weight.
Binge eating is a behavior that occurs in some eating disorders, as well as in obesity and in nonclinical populations. Both sugars and fats are readily consumed by human beings and are common components of binges. This chapter describes animal models of sugar and fat bingeing, which allow for a detailed analysis of these behaviors and their concomitant physiological effects. The model of sugar bingeing has been used successfully to elicit behavioral and neurochemical signs of dependence in rats; e.g., indices of opiate-like withdrawal, increased intake after abstinence, cross-sensitization with drugs of abuse, and the repeated release of dopamine in the nucleus accumbens following repeated bingeing. Studies using the model of fat bingeing suggest that it can produce some, but not all, of the signs of dependence that are seen with sugar binge eating, as well as increase body weight, potentially leading to obesity.


[Studies on chemical analysis of mycotoxin (XX). Chemical analysis of aflatoxins in corn and corn-products].
The investigation was carried out to analyze aflatoxins contaminated corn. 1) Methanol, chloroform and acetonitrile were used as the extraction solvents for aflatoxins added to corn. As the result, the method using acetonitrile was found to be effective to extract and detect aflatoxins. 2) The Rapid detection of aflatoxins was made possible by using the affinity column (containing monoclonal antibodies against aflatoxins bound onto agarose) and the mini-column. The detection-limit was 20 ppb of aflatoxins in samples.


Trehalose protects against spinal cord ischemia in rabbits.
This study tested to see if trehalose, a cytoprotective disaccharide, protects against spinal cord ischemia in a rabbit model. The infrarenal aorta was mobilized in four groups of 10 rabbits. In groups I, II, and III, it was clamped proximally and distally for 20 minutes. In group I, the clamped aorta was infused at 2.5 L/min for 2 hours with lactated Ringer's (LR) solution. In group II, the clamped aorta was infused with 5% trehalose in LR. LR was administered intravenously (2.0 mL/min) in groups I and II starting 30 minutes before clamping. In group III, 5% trehalose in LR was infused intravenously only. Group IV was a sham-operated control group without aortic clamping. At 8, 24, and 48 hours after reperfusion, hind limb function was scored using the Tarlov score (paralysis = 0, perceptible joint movement = 1, good joint movement but unable to stand = 2, able to walk = 3, normal = 4). Histologic analysis and electron microscopy were performed on anterior horn cells. The Tarlov scores in groups I, II, and III were, respectively, 1.1 ± 1.4, 3.5 ± 0.5, and 2.9 ± 0.9 at 8 hours; 0.8 ± 1.2, 3.9 ± 0.3, and 2.9 ± 0.9 at 24 hours; and 0.6 ± 0.7, 3.9 ± 0.3, and 2.7 ± 0.9 at 48 hours after reperfusion. Group IV scores were normal (4 ± 0) at all assessments. These scores were higher in groups II and III than in group I (P < .01) at all assessments. Scores at 24 and 48 hours were higher in group II than in group III (P < .05). In group III, delayed paraparesis developed in one rabbit at 24 hours and in two more at 48 hours. Histopathologic analysis showed the number of normal neurons was higher in groups II (P < .0001), III (P = .006), and IV (P < .0001) vs group I. Electron microscopy confirmed preserved neuronal cell ultrastructure in rabbits with normal limb function. Transaortic trehalose infusion was protective against paraplegia, whereas intravenous trehalose reduced spinal cord ischemia. This study was preliminary and further studies are needed.


Application and recent progress of inland water monitoring using remote sensing techniques.
Hyperspectral remote sensing, which retrieves the water quality parameters by direct high-resolution analysis of the electromagnetic spectrum reflected from the water surface, has been widely applied for inland water quality detection. Such a new approach provides an opportunity to generate real-time data from water with the noncontact method, largely improving working efficiency. By summarizing the development and current applications of hyperspectral remote sensing, we compare the relative merits of varying remote sensing platforms, popular inversion models, and the application of hyperspectral monitoring of chlorophyll-a (Chl-a), transparency, total suspended solids (TSS), colored dissolved organic matter (CDOM), phycocyanin (PC), total phosphorus (TP), and total nitrogen (TN) water quality parameters. Most studies have focused on spaceborne remote sensing, which is usually used to monitor large waterbodies for Chl-a and other water quality parameters with optical properties; semiempirical, bio-optical, and semianalytical models are frequently used. With the rapid development of aerospace technology and near-surface remote sensing, the spectral resolution of remote sensing imaging technology has been dramatically improved and has begun to be applied to small waterbodies. In the future, the multiplatform linkage monitoring approach may become a new research direction. Advanced computer technology has also enabled machine learning models to be applied to water quality parameter inversion, and machine learning models have higher robustness than the three commonly used models mentioned above. Although nitrogen and phosphorus, with nonoptical properties, have also received attention and research from some scholars in recent years, the uncertainty of their mechanisms makes it necessary to maintain a cautious attitude when treating such research.


Crude substance P from brain contains a cholecystokinin-like peptide.
The subfractions Fa, Fb, and Fc of crude substance P (SP) preparations made from human and bovine brains were analysed for SP and the COOH-terminal octapeptide of cholecystokinin (CCK-8). The methods were specific radioimmunoassays (RIAs) for SP and CCK-8, and bioassays on isolated organs of the guinea pig: the ileum, the gallbladder and the field-stimulated vas deferens. 1. In bioassays of synthetic peptides the vas deferens reacted specifically to SP and the gallbladder to CCK-8. 2. RIAs and bioassays revealed unequivocally that most of SP-like activity was present in Fb, while Fc contained mainly CCK-8-like activity. Varying results were obtained with Fa. 3. The pharmacologically active principle of Fc is CCK-8 or a closely related peptide. Earlier results concerning the pharmacological and neurochemical properties of Fc must be ascribed to this peptide.


[Comparative catamnestic studies of newly hospitalized patients with schizophrenia associated with alcoholism].
The authors analyze the destiny of 289 patients with associated schizophrenia and alcoholism. For the first time they were admitted to the psychiatric hospital in 1948-1951 (period I); 1959-1961 (period II); 1969-1971 (period III), and in 1979-1981 (period IV). The five-year catamnesis has demonstrated that schizophrenic patients abusing alcohol are often admitted to the hospital with paranoid symptomatology, retaining, however, a high enough level of social and labour adaptation, emotions, communicability for a long time. In the course of transition from the first to the fourth period, this group patients demonstrated an increase of the crime rate.


3,4-Di-hydro-1H-benzo[c]chromene-1,6(2H)-dione.
In the title compound, C13H10O3, the pyran-one and benzene rings are almost coplanar, making a dihedral angle of 1.9 (1)°. The cyclo-hexenone ring adopts an envelope conformation, with a methyl-ene C atom located at the flap and displaced by 0.639 (3) Å from the mean plane of the other five atoms. In the crystal, pairs of weak C-H⋯π inter-actions occur between inversion-related mol-ecules.


Problems and approaches in the surveillance and control of sexually transmitted diseases: the Cuban experience.
Cuba has a comprehensive National Health System which delivers primary and secondary health care to 100% of the population. Communicable disease control and preventive medicine programs are implemented through this System. The National Syphilis Control Program is described briefly as an example of a successful control program for sexually transmitted disease. Data defining the magnitude of the problems of gonorrhea and pelvic inflammatory disease are not complete. A program for improved gonorrhea surveillance and control is just beginning. Further improvements and refinements in this program are described.


Delicaflavone reactivates anti-tumor immune responses by abrogating monocytic myeloid cell-mediated immunosuppression.
Myeloid cell-mediated immunosuppression is a major obstacle to checkpoint blockade immunotherapy. We previously reported that total biflavonoids extract from Selaginella doederleinii (TBESD) and a flavone monomer isolated from TBESD, named Delicaflavone, have favorable anti-tumor activity. However, whether TBESD and Delicaflavone could affect the tumor microenvironment (TME) remains unclear. In this study, we focused on the TME to determine whether TBESD and Delicaflavone could restore anti-tumor immune response. 4T1 tumor-bearing immunocompetent BALB/c mice and T cell-deficient nude mice were used to examine the effect of TBESD on T cell-mediated immunity in vivo. Multi-parameter flow cytometry was conducted to evaluate the impacts of TBESD on TME. Primary cells, including murine CD8+ T cells, tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) were prepared to investigate the modulatory activities of TBESD on immune cells. It was further determined whether Delicaflavone or Amentoflavone, two typical functional biflavones from TBESD, mediated those effects of TBESD. Finally, the impacts of TBESD and Delicaflavone on Jak1/STAT6 signaling pathway were explored via western blot. We found that TBESD significantly reduced 4T1 tumor growth in immunocompetent BALB/c mice, but not in nude mice. This effect was associated with the regulation of TME, shown as an increase in functional T cells and M1 phenotype TAMs (M1-TAMs), and a decrease in M2 phenotype TAMs (M2-TAMs), monocytic-MDSCs (M-MDSCs) and regulatory T cells (Tregs) in TBESD-treated BALB/c mouse 4T1 tumors. It was found ex vivo that TBESD restrained the viability and immunosuppressive properties of M2-TAMs and M-MDSCs, especially for the loss of arginase-1 expression. Additionally, TBESD re-educated M2-TAMs to an M1 like phenotype. Further investigations determined that Delicaflavone predominantly mediated the immuno-modulatory activities of TBESD both ex vivo and in vivo. Finally, Delicaflavone and TBESD blocked Jak1/STAT6 signaling pathway in M2-TAMs and MDSCs. The present study suggests Delicaflavone as a potent natural inhibitor of M2-TAMs and MDSCs, which fills the gap in knowledge on the immuno-modulatory effects of TBESD and Delicaflavone, and could have translational implications to improve the efficacy of cancer immunotherapy.


In vivo functional characterisation of pheromone binding protein-1 in the silkmoth, Bombyx mori.
Male moths detect sex pheromones emitted by conspecific females with high sensitivity and specificity by the olfactory sensilla on their antennae. Pheromone binding proteins (PBPs) are highly enriched in the sensillum lymph of pheromone sensitive olfactory sensilla and are supposed to contribute to the sensitivity and selectivity of pheromone detection in moths. However, the functional role of PBPs in moth sex pheromone detection in vivo remains obscure. In the silkmoth, Bombyx mori, female moths emit bombykol as a single attractive sex pheromone component along with a small amount of bombykal that negatively modulates the behavioural responses to bombykol. A pair of olfactory receptor neurons, specifically tuned to bombykol or bombykal, co-localise in the trichodeum sensilla, the sensillum lymph of which contains a single PBP, namely, BmPBP1. We analysed the roles of BmPBP1 using BmPBP1-knockout silkmoth lines generated by transcription activator-like effector nuclease-mediated gene targeting. Electroantennogram analysis revealed that the peak response amplitudes of BmPBP1-knockout male antennae to bombykol and bombykal were significantly reduced by a similar percentage when compared with those of the wild-type males. Our results indicate that BmPBP1 plays a crucial role in enhancing the sensitivity, but not the selectivity, of sex pheromone detection in silkmoths.


Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP.
CSF1R mutations cause autosomal-dominant CSF1R-related leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) and autosomal-recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). The former is increasingly recognized, and disease-modifying therapy was introduced; however, literature is scarce on the latter. This review analyzes BANDDOS and discusses similarities and differences with CSF1R-ALSP.We systematically retrieved and analyzed the clinical, genetic, radiological, and pathological data on the previously reported and our cases with BANDDOS. We identified 19 patients with BANDDOS (literature search according to the PRISMA 2020 guidelines: n = 16, our material: n = 3). We found 11 CSF1R mutations, including splicing (n = 3), missense (n = 3), nonsense (n = 2), and intronic (n = 2) variants and one inframe deletion. All mutations disrupted the tyrosine kinase domain or resulted in nonsense-mediated mRNA decay. The material is heterogenous, and the presented information refers to the number of patients with sufficient data on specific symptoms, results, or performed procedures. The first symptoms occurred in the perinatal period (n = 5), infancy (n = 2), childhood (n = 5), and adulthood (n = 1). Dysmorphic features were present in 7/17 cases. Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia (n = 3/11), and optic nerve atrophy (n = 2/7). Skeletal deformities were observed in 13/17 cases and fell within the dysosteosclerosis - Pyle disease spectrum. Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10). Three patients died in infancy, two in childhood, and one case at unspecified age. A single brain autopsy evidenced multiple brain anomalies, absence of corpus callosum, absence of microglia, severe white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications.In conclusion, BANDDOS presents in the perinatal period or infancy and has a devastating course with congenital brain abnormalities, developmental delay, neurological deficits, osteopetrosis, and dysmorphic features. There is a significant overlap in the clinical, radiological, and neuropathological aspects between BANDDOS and CSF1R-ALSP. As both disorders are on the same continuum, there is a window of opportunity to apply available therapy in CSF1R-ALSP to BANDDOS.


Maternal interventions to prevent adverse fetal programming outcomes due to maternal malnutrition: Evidence in animal models.
Animal studies indicate that suboptimal conditions during pregnancy adversely impact both maternal health and offspring phenotype, predisposing offspring to development of later-life diseases including obesity, diabetes, cardiovascular diseases, and behavioral and reproductive dysfunction. Effective interventions during pregnancy and/or lactation are needed to improve both maternal and offspring health. This review addresses the relationship between adverse perinatal insults and its negative impact on offspring development and presents some maternal intervention studies in animal models, such as maternal nutrition (diet modification, antioxidants, omega-3-6 (n-3-6), probiotics) or physical activity, which can prevent or alleviate negative outcomes in both mother and offspring.


[Prognostic value on recovery rates for the application of sperm preparation techniques and their evaluation in sperm function].
To evaluate sperm recovery and total sperm motility in three different sperm preparation techniques (density gradient, simple washing and swim-up). A total of 290 subjects were randomly evaluated from November 2001 to March 2003. The density gradient method required Isolate (upper and lower layers). Centrifugation was performed at 400 g for 10 minutes and evaluation was done using the Makler counting chamber. The simple washing method included the use of HTF-M complemented with 7.5% of SSS, with centrifugation at 250 g, obtaining at the end 0.5 mL of the sperm sample. The swim-up method required HTF-M complemented with 7.5% of SSS, with an incubation period of 60 minutes at 37 degrees C. The demographic characteristics evaluated through their standard error, 95% ICC, and 50th percentile were similar. The application of multiple comparison tests and analysis of variance showed significant differences between the sperm preparations before and after capacitation. It was observed a superior recovery rate with the density gradient and swim-up methods; nevertheless, the samples used for the simple washing method showed a diminished sperm recovery from the original sample. Sperm preparation techniques have become very useful in male infertility treatments allowing higher sperm recovery and motility rates. The seminal parameters evaluated from the original sperm sample will determine the best sperm preparation technique in those patients who require it.


Expression Profile, Molecular Association, and Clinical Significance of POLD4 in Glioblastoma.
The POLD4 gene encodes a subunit (δ4) of DNA polymerase delta, which is a key enzyme involved in DNA replication and repair. Recent studies have suggested that POLD4 plays a crucial role in developing certain cancers. However, there is a lack of knowledge regarding the role of POLD4 in the context of glioblastoma (GBM). Therefore, in this study we have used various cancer bioinformatics tools to explore the role of POLD4 in glioblastoma. Data from various sources were accessed to analyze POLD4 gene expression and estimate tumor-infiltrating immune cells in glioblastoma. Methylation data were retrieved using the MEXPRESS web browser and analyzed. UALCAN webserver was used to analyze the protein expression of POLD4. Gene correlation and pathway enrichment analysis were performed using cBioPortal and GSEA software, respectively. Afterward, survival analysis was performed. POLD4 was significantly upregulated in glioblastoma at both gene and protein levels in GBM, and ROC curve analysis revealed it as a potential biomarker in glioblastoma. GSEA analysis of TCGA-GBM pan-cancer study exhibited that POLD4 expression was associated with critical pathways, such as interferon-gamma response, G2M checkpoint, inflammatory response, E2F targets, EMT transition, and KRAS signaling pathways. Furthermore, POLD4 expression was positively correlated with DNA methylation at 3 CpG sites, including Cg16509978, with a Pearson correlation coefficient value of 0.398 (p-value ≤ 0.01), while the promoter region had a positive correlation but was not significant. In addition, POLD4 is significantly linked with poor OS, PFS, and DFS. We also found association of POLD4 expression with altered immune cell infiltration. In conclusion, POLD4 is significantly upregulated in glioblastoma and may be used as a potential diagnostic or prognostic biomarker for GBM patients. However, to establish the same a large cohort study is needed. Using TCGA data and various cancer bioinformatics tools mentioned above we observed very high level of gene and protein expression of POLD4 in glioblastoma patients. The expression of POLD4 was significantly correlated with inflammatory and oncogenic pathways and it also has a significant correlation with adverse outcome in patients with glioblastoma.


Ventricular-Vascular Coupling at Rest and after Exercise Is Associated with Heart Failure Hospitalizations in Patients With Coronary Artery Disease.
The ventricular-vascular coupling ratio, defined as the ratio of arterial elastance (Ea) to left ventricular end-systolic elastance (Ees), has not been examined in populations with coronary artery disease (CAD), and its association with heart failure (HF) in this population is unknown. Ventricular-vascular coupling was measured at rest and after exercise using echocardiography and cuff blood pressure in 815 patients with stable CAD enrolled in the Heart and Soul Study. Adjusted Cox proportional-hazard models were used to evaluate the association between ventricular-vascular coupling and future HF hospitalizations. After a median of 8.9 years, 144 patients (18%) were hospitalized for HF. After multivariate adjustment, patients in the highest tertile of Ees (rest: hazard ratio [HR], 0.31 [95% CI, 0.17-0.57; P < .001]; exercise: HR, 0.26 [95% CI, 0.13-0.50; P < .001]) were at decreased risk for HF hospitalization, while patients in the highest tertile of the Ea/Ees ratio (rest: HR, 3.36 [95% CI, 1.91-5.93; P < .001]; exercise: HR, 4.09; [95% CI, 2.22-7.51; P < .001]) were at increased risk, compared with the lowest tertiles. Ea and the relative change observed in Ees and the Ea/Ees ratio with exercise were not associated with HF hospitalizations. The Ea/Ees ratio and Ees, at rest and after exercise, are strongly associated with future HF hospitalizations in patients with stable CAD and low rates of baseline HF. Ventricular-vascular coupling obtained from echocardiography shows promise as a risk assessment tool for HF in patients with CAD.


A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components.
Ultraviolet radiations (UV) serve as an environmental stress for human skin, and result in melanogenesis, with the pigment melanin having protective effects against UV induced damage. This involves a dynamic and complex regulation of various biological processes that results in the expression of melanin in the outer most layers of the epidermis, where it can exert its protective effect. A comprehensive understanding of the underlying cross talk among different signalling molecules and cell types is only possible through a systems perspective. Increasing incidences of both melanoma and non-melanoma skin cancers necessitate the need to better comprehend UV mediated effects on skin pigmentation at a systems level, so as to ultimately evolve knowledge-based strategies for efficient protection and prevention of skin diseases. A network model for UV-mediated skin pigmentation in the epidermis was constructed and subjected to shortest path analysis. Virtual knock-outs were carried out to identify essential signalling components. We describe a network model for UV-mediated skin pigmentation in the epidermis. The model consists of 265 components (nodes) and 429 directed interactions among them, capturing the manner in which one component influences the other and channels information. Through shortest path analysis, we identify novel signalling pathways relevant to pigmentation. Virtual knock-outs or perturbations of specific nodes in the network have led to the identification of alternate modes of signalling as well as enabled determining essential nodes in the process. The model presented provides a comprehensive picture of UV mediated signalling manifesting in human skin pigmentation. A systems perspective helps provide a holistic purview of interconnections and complexity in the processes leading to pigmentation. The model described here is extensive yet amenable to expansion as new data is gathered. Through this study, we provide a list of important proteins essential for pigmentation which can be further explored to better understand normal pigmentation as well as its pathologies including vitiligo and melanoma, and enable therapeutic intervention.


Characteristics of invasive aspergillosis in neutropenic haematology patients (Sousse, Tunisia).
Although scarce, available data suggest that the epidemiology of invasive aspergillosis (IA) in North Africa differs from northern countries, where more than 80 % is caused by Aspergillus fumigatus. This study aimed at describing the epidemiology of IA in the region of Sousse, Tunisia, and at assessing the usefulness of the available diagnostic tools. For 2 years, clinical and mycological data were prospectively collected from 175 neutropenia episodes of 91 patients hospitalised in the haematology department at the Farhat Hached hospital in Sousse (Tunisia). Screening for galactomannan antigen was positive in 40 % of neutropenia episodes; Aspergillus PCR was positive in 42 % of the tested sera. Nine patients were classified as probable and two as possible IA according to the EORTC/MSG criteria. Twelve patients who prematurely died, had no CT scan and could not be classified. Fifty-six Aspergillus spp. were isolated in 53 (6.5 %) sputa collected from 35 (20 %) patients. The following species were identified with MALDI-TOF mass spectrometry and DNA sequencing: A. niger, 35 %; A. flavus, 38 %; A. tubingensis, 19 %; A. fumigatus, 4 %; A. westerdijkiae, 2 % and A. ochraceus, 2 %. Our findings highlight the epidemiological features of IA in Tunisia, which is characterised by the predominance of Aspergillus spp. from sections Nigri and Flavi.


Airway stent placement for direct cricothyroid membrane puncture anesthesia with airway stricture or fistula.
Tracheal stent implantation with bronchoscope has become one of the main methods for the treatment of airway stenosis. Bronchoscopy is usually performed under local or general anesthesia. The aim of this study is to report our experience with direct cricothyroid membrane puncture anesthesia for airway stent placement. The medical records of 48 consecutive patients who underwent direct cricothyroid membrane puncture anesthesia for tracheal or bronchial stent placement were reviewed. The puncture site was chosen as the interspace between the thyroid cartilage and cricoid cartilage. Through the cricothyroid membrane, lidocaine was injected into the trachea to suppress the cough reflex. The airway stent was placed fluoroscopically at 48 patients at the trachea or bronchus. The success rate and complications of cricothyroid membrane puncture anesthesia were assessed. Anesthesia was successfully performed in all 48 patients. Six patients needed 2-4 mL supplementary lidocaine by injection from the catheter or stent delivery system. Technical success of the stent insertion was achieved in all 48 cases. Small asymptomatic subcutaneous hemorrhage occurred at the puncture site in two patients, which disappeared 1 or 2 days after stent placement. Direct cricothyroid membrane puncture anesthesia for airway metal stent insertion is safe and effective.


A Decision Support System for Diagnosing Diabetes Using Deep Neural Network.
According to the WHO, diabetes mellitus is a long-term condition marked by high blood sugar levels. The consequences might be far-reaching. According to current increases in mortality, diabetes has risen to number 10 among the leading causes of mortality worldwide. When used to predict diabetes using unbalanced datasets from testing, machine learning (ML) classifiers and established approaches for encoding categorical data have exhibited a broad variety of surprising outcomes. Early studies also made use of an artificial neural network to extract features without obtaining a grasp of the sequence information. This study offers a deep learning-based decision support system (DSS), utilizing bidirectional long/short-term memory (BiLSTM), to accurately predict diabetic illness from patient data. In order to predict diabetes, the BiLSTM hybrid model was used after balancing the data set. Unlike earlier studies, this proposed model's trial findings were promising, with an accuracy of 93.07%, 93% precision, 92% recall, and a 92% F1-score. Using a BILSTM model for classification outperforms current approaches in the diabetes detection domain.


DNA-SIP reveals an overlooked methanotroph, Crenothrix sp., involved in methane consumption in shallow lake sediments.
Methanotrophs are the main consumers of methane produced in lake sediments. In shallow lakes suffering from eutrophication, methanogenesis is accelerated by the excess organic carbon input, and thus methanotrophs play a key role in regulating this methane flux as well as carbon cycling. Here, we applied nucleic acid stable isotope probing (SIP) to investigate the active methanotrophic microbial community in sediments of several shallow lakes affected by eutrophication. Our results showed that an active methanotrophic community dominated by gamma-proteobacterial methanotrophs, as well as abundant beta-proteobacterial methanol-utilizers, was involved in methane-derived carbon assimilation. Crenothrix, a filamentous methanotroph, was found to be a key methane consumer in all studied lakes. The ecological role of Crenothrix in lacustrine ecosystems is so far poorly understood, with only limited information on its existence in the water column of stratified lakes. Our results provide a novel ecological insight into this group by revealing a wide distribution of Crenothrix in lake sediments. The active methane assimilation by Crenothrix also suggested that it might represent a so far overlooked but crucial biological sink of methane in shallow lakes.


Transfer standard for beta decay radionuclides in radiotherapy.
The measurement of the activity of therapeutic radiopharmaceuticals prior to the administration to patients is normally achieved via the use of radionuclide calibrators. An accurate measurement of the activity of pure beta-emitters is complex. Calibration problems can be solved by combining a primary calibration with a 90Y reference solution and a 90Sr/90Y transfer standard with a solid source, simulating geometric effects caused by high energetic beta radiation. The recent development of a 90Sr/90Y transfer standard for this purpose is reported.


Myelodysplastic syndrome with acquired hemoglobin H disease. Evolution through megakaryoblastic transformation into myelofibrosis.
A 64-year-old man was found to have a hemolytic anemia with a hematocrit of 0.28 (28%) during a routine evaluation. One month before this his hematocrit had been normal. Further studies revealed a myelodysplastic syndrome and acquired hemoglobin H disease. Eighteen months later this transformed into acute megakaryoblastic leukemia with disappearance of hemoglobin H, and shortly thereafter he had myelofibrosis develop. Acquired hemoglobin H disease, which is an alpha-thalassemia-like syndrome, results in the formation of an unstable hemoglobin composed of beta chain tetramers. This condition has been associated with preleukemia, sickle cell anemia, and hematologic malignancies. Although idiopathic myelofibrosis also has been described as a setting in which this thalassemic syndrome occurs, the present case is unusual in that the myelofibrosis was preceded by refractory anemia with leukemic transformation.


Selective extraction of metals from mixed oxide matrixes using choline-based ionic liquids.
The solubility of a range of metal oxides in a eutectic mixture of urea/choline chloride is quantified, and it is shown that the dissolved metals can be reclaimed from a mixed metal oxide matrix using electrodeposition.


Hormonal regulation of cAMP-independent protein phosphokinase activities: thyroxine and cortisol control of enzymes from rat liver cytosol.
Thyroxine control of cAMP-independent histone and casein phosphokinase activities was studied in thyroidectomized rats treated with thyroxine. All activities were evaluated in the presence of a thermostable inhibitor of cAMP-dependent enzymes. Cytosol enzymes can be resolved by sucrose gradient ultracentrifugation into three peaks of histone kinase activity (3.2S, 5S and 7.2S) and two peaks of casein kinases (3.6S and 7.1S). Neither thyroidectomy nor subsequent treatment of operated animals with thyroxine modifies the total histone kinase activity estimated, either in total cytosol or after its fractionation by the sucrose gradient ultracentrifugation. The activity ratios of different peaks were, however, changed. Casein kinase activity was significantly decreased after thyroidectomy (about 50%). Subsequent treatment with thyroxine restored this activity to its initial value. Sucrose gradient ultracentrifugation analysis showed that thyroxine action on the casein kinase activity is very specific. Only molecules that sediment in the 9S region were significantly stimulated by the hormone. Cortisol action on the casein kinase activity was studied in adrenalectomized animals treated with hormone for 24 h. Cortisol decreases the total casein kinase activity by about 30%. Sucrose gradient ultracentrifugation analysis showed that the population of molecules sedimenting at about 9S was the most sensitive to cortisol. The above data show that both thyroxine and cortisol control, in a selective way, the activities of cAMP-independent protein kinases. The same kinase molecules can be under double control by two different hormones that have opposite effects.


Mechanisms underlying the vasodilatory effects of canagliflozin in the rabbit thoracic aorta: Involvement of the SERCA pump and Kv channels.
Canagliflozin is an anti-diabetic agent and sodium glucose co-transporter-2 inhibitor. Despite numerous clinical trials demonstrating its beneficial effects on blood pressure, the cellular mechanisms underlying the effects of canagliflozin on vascular reactivity have yet to be clarified. We investigated the vasodilatory effect of canagliflozin on aortic rings isolated from rabbits. We used rabbit thoracic aortic rings and its arterial tone was tested by using wire myography system. Canagliflozin caused concentration-dependent vasodilation in aortic rings pre-constricted with phenylephrine or high K+. However, the degree of canagliflozin-induced vasodilation of the aortic rings pre-constricted with high K+ was less than that of rings pre-constricted with phenylephrine. Application of 4-aminopyridine, a voltage-dependent K+ (Kv) channel inhibitor, reduced canagliflozin-induced vasodilation. However, pre-incubation of an inwardly rectifying K+ channel inhibitor, a large-conductance Ca2+-activated K+ channel inhibitor, and an ATP-sensitive K+ inhibitor did not modulate the vasodilatory effects of canagliflozin. Indeed, canagliflozin increased Kv currents in aortic smooth muscle cells. Pre-treatment with thapsigargin or cyclopiazonic acid, a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors, reduced the vasodilatory effects of canagliflozin. Conversely, pre-treatment with a Ca2+ channel inhibitor, adenylyl cyclase/PKA inhibitors, and guanylyl cyclase/PKG inhibitors did not modulate the vasodilatory effects of canagliflozin. Endothelium removal, and pre-treatment with the nitric oxide synthase inhibitor L-NAME, and small- and intermediate-conductance Ca2+-activated K+ channel inhibitor apamin and TRAM-34, did not diminish the vasodilatory effects of canagliflozin. Our results indicate that canagliflozin induces vasodilation, which is dependent on the robust SERCA activity and Kv channel activation.


Value of Peak Expiratory Flow Rate in Evaluating Cough Ability in Patients Undergoing Lung Surgery.
Postoperative ineffective cough is easy to occur after thoracic surgery, and it is also a risk factor for postoperative pulmonary complications (PPCs). To explore the value of peak expiratory flow rate (PEF) in evaluating cough ability in patients undergoing lung surgery and evaluate the effectiveness of chest wall compression during the expiratory phase by PEF. From September 2020 to May 2021, the researchers collected the data of patients who underwent lung surgery. Eventually, 153 patients who met the criteria were included, 102 cases were included in the effective cough group and 51 cases were included in the ineffective cough group. The receiver working curve (ROC curve) was used to analyze whether PEF could evaluate cough ability. At the same time, the researchers collected the pulmonary function data of the first 30 patients of the ineffective cough group while compressing the chest wall during the expiratory phase to evaluate the effectiveness of chest wall compression. The area under the curve (AUC) of postoperative PEF to evaluate the postoperative cough ability was 0.955 (95% CI: 0.927-0.983, P < 0.001). The values of PEF (127.17 ± 34.72 L/min vs. 100.70 ± 29.98 L/min, P < 0.001, 95% CI: 18.34-34.59) and FEV1 (0.72 (0.68-0.97) L vs. 0.64 (0.56-0.82) L, P < 0.001) measured while compressing the chest wall were higher than those without compression. PEF can be used as a quantitative indicator of cough ability. Chest wall compression could improve cough ability for patients who have ineffective cough.


1H-1,2,4-Triazol-4-ium (3,4-dichloro-phen-yl)methane-sulfonate.
In the title molecular salt, C(2)H(4)N(3) (+)·C(7)H(5)Cl(2)O(3)S(-), C-C-S angle [112.25 (18)°] deviates slightly from that expected for ideal sp(3)-hybridization geometry. In the crystal, the components are linked by N-H⋯O and bifurcated N-H⋯(O,O) hydrogen bonds into chains parallel to [110].


Charge-transfer properties of lateral triphenylamine-dithienophosphole diads.
Installation of an exocyclic triphenylamine group at the phosphorus center provides access to dithienophosphole materials with lateral charge-transfer (CT) ability. The degree of CT can be significantly manipulated not only via oxidation of the P-center but also surprisingly by alkylation of the 2,6-position of the scaffold.


Improved Bioavailability of Poorly Water-Soluble Drug by Targeting Increased Absorption through Solubility Enhancement and Precipitation Inhibition.
Itraconazole (ITZ) is a class II drug according to the biopharmaceutical classification system. Its solubility is pH 3-dependent, and it is poorly water-soluble. Its pKa is 3.7, which makes it a weak base drug. The aim of this study was to prepare solid dispersion (SD) pellets to enhance the release of ITZ into the gastrointestinal environment using hot-melt extrusion (HME) technology and a pelletizer. The pellets were then filled into capsules and evaluated in vitro and in vivo. The ITZ changed from a crystalline state to an amorphous state during the HME process, as determined using DSC and PXRD. In addition, its release into the gastrointestinal tract was enhanced, as was the level of ITZ recrystallization, which was lower than the marketed drug (Sporanox®), as assessed using an in vitro method. In the in vivo study that was carried out in rats, the AUC0-48h of the commercial formulation, Sporanox®, was 1073.9 ± 314.7 ng·h·mL-1, and the bioavailability of the SD pellet (2969.7 ± 720.6 ng·h·mL-1) was three-fold higher than that of Sporanox® (*** p < 0.001). The results of the in vivo test in beagle dogs revealed that the AUC0-24h of the SD-1 pellet (which was designed to enhance drug release into gastric fluids) was 3.37 ± 3.28 μg·h·mL-1 and that of the SD-2 pellet (which was designed to enhance drug release in intestinal fluids) was 7.50 ± 4.50 μg·h·mL-1. The AUC of the SD-2 pellet was 2.2 times higher than that of the SD-1 pellet. Based on pharmacokinetic data, ITZ would exist in a supersaturated state in the area of drug absorption. These results indicated that the absorption area is critical for improving the bioavailability of ITZ. Consequently, the bioavailability of ITZ could be improved by inhibiting precipitation in the absorption area.


Up to 16 years follow-up of aortic valve reconstruction with pericardium: a stentless readily available cheap valve?
There is lack of information regarding the long-term behavior of aortic valve reconstruction with pericardium (AoR). A 16-year follow-up is reported here. Between 1988 and 1995, 92 consecutive patients had AoR with bovine (Group I, n=27) or glutaraldehyde-treated autologous pericardium (Group II, n=65). The mean age was 30 years (range 12-68). There were 65% males, 92% in sinus rhythm, 84% had rheumatic etiology and 36% had 'other valve' surgery. Mitral valve replacement with a mechanical prosthesis is a contraindication to the operation. Hospital mortality was 2%. The reconstructed aortic valve performed well with excellent hemodynamics. The mean follow-up interval was 10.5+/-4 years, range 9-16 years (longer for group I,12 versus 10 years) with 4% late deaths and seven patients lost to follow-up. Survival rate was 85+/-4%. There were no episodes of thromboembolism. Freedom from reoperation for the whole group was 68+/-5% at 10 years and 47+/-6% at 16 years. For group I, it was 68+/-9% at 10 years and 48+/-10% at 16 years, while for group II it was 72+/-6 and 45+/-8% at 10 and 15 years, respectively. Excluding endocarditis (one in group I and seven in group II) and 'other' reasons for reoperation (two in group I and three in group II), the freedom from structural valve degeneration (SVD) at 10 and 16 years was 78+/-1 and 55+/-10% for group I. For group II, it was 80+/-5% at 10 years and 58+/-9% at 15 years. The mean interval at which the valve degenerated was 8.8 years+/-3.6 and did not differ between the two groups. AoR is feasible with good hemodynamics, low mortality and thromboembolic rate. Its behavior at 10 years is comparable to that of stentless aortic valve bioprosthesis. It can be performed with either xenopericardium or glutaraldehyde-treated autologous pericardium, but the latter has the advantage of being inexpensive and readily available.


A Review on Caspases: Key Regulators of Biological Activities and Apoptosis.
Caspases are proteolytic enzymes that belong to the cysteine protease family and play a crucial role in homeostasis and programmed cell death. Caspases have been broadly classified by their known roles in apoptosis (caspase-3, caspase-6, caspase-7, caspase-8, and caspase-9 in mammals) and in inflammation (caspase-1, caspase-4, caspase-5, and caspase-12 in humans, and caspase-1, caspase-11, and caspase-12 in mice). Caspases involved in apoptosis have been subclassified by their mechanism of action as either initiator caspases (caspase-8 and caspase-9) or executioner caspases (caspase-3, caspase-6, and caspase-7). Caspases that participate in apoptosis are inhibited by proteins known as inhibitors of apoptosis (IAPs). In addition to apoptosis, caspases play a role in necroptosis, pyroptosis, and autophagy, which are non-apoptotic cell death processes. Dysregulation of caspases features prominently in many human diseases, including cancer, autoimmunity, and neurodegenerative disorders, and increasing evidence shows that altering caspase activity can confer therapeutic benefits. This review covers the different types of caspases, their functions, and their physiological and biological activities and roles in different organisms.


Improving blood pressure control and clinical outcomes through initial use of combination therapy in stage 2 hypertension.
Poor control of clinic and 24-h blood pressure (BP) is associated with enhanced risk of all cardiovascular disease events. Certain patient groups including the elderly, African-Americans, and those with hypertension and comorbid disease are difficult to control, as are patients with stage 2 hypertension (systolic BP>or=160 mmHg or diastolic BP>or=100 mmHg). It has been estimated that more than two-thirds of high-risk hypertensive patients with stage 2 hypertension and all hypertensive patients with diabetes mellitus or kidney disease will require two or more antihypertensive agents from different therapeutic classes to reach BP goals. Combining agents with distinct and complementary modes of action can address different pathophysiologic mechanisms involved in hypertension and may lead to more complete and prompt reductions in BP. Tolerability may also improve, as certain classes of antihypertensive agents ameliorate adverse effects associated with other agents. Patients may benefit from fixed-dose combinations of drugs as this simplifies the regimen and may improve adherence with therapy, control of BP, and ultimately lead to reductions in cardiovascular events. Recent data and treatment guidelines support the use of a combination strategy as 'initial' antihypertensive therapy in high-risk patients with stage 2 hypertension.


Time-dependent pharmacokinetics and drug metabolism of atovaquone plus proguanil (Malarone) when taken as chemoprophylaxis.
To determine the pharmacokinetic profiles of atovaquone (ATO), proguanil (PROG) and its active metabolite cycloguanil (CYCLO) with respect to possible accumulation and kinetic interaction upon repeated dosing with Malarone. Thirteen healthy volunteers first received a single dose and then after 1 week, repetitive daily doses of Malarone (one tablet) for 13 days. For analysis of plasma drug concentrations, blood samples were collected at regular intervals over 8 days after a single dose and over 12 days after the last day of multiple dosing. Single-dose and steady-state pharmacokinetic parameters were determined for each individual. Genotyping of the gene coding for CYP2C19, a major enzyme catalyzing PROG metabolism, was performed using polymerase chain reaction, and in vitro enzyme kinetic experiments were carried out to study the possible effect of ATO on the catalytic activities of CYP2C19 and 3A4 using fluorometric assays. For ATO, the ratio of the area under the concentration-time curve (AUC) during the last dose interval to the AUC after the single dose (AUC(0- tau)/AUC(0- infinity)) was found to be 0.90 [95% confidence interval (CI) 0.56, 1.24] indicating absence of undue accumulation. AUC(0- tau), and peak plasma concentration at steady state (C(max,ss)) values were, however, threefold lower than those reported in human immunodeficiency virus-infected subjects after 12 multiple daily doses of 250 mg ATO alone. Four volunteers, with mean CYCLO/PROG AUC(0-tau) of 0.03 (-0.23, 0.09) were classified as poor metaboliser (PM) phenotypes. There was a significant increase in the AUC of PROG at steady state with a PROG AUC(0-tau)/AUC(0-infinity) ratio of 1.38 (1.07, 1.69) in extensive metaboliser (EM) phenotypes. CYCLO/PROG AUC ratios were significantly lower 0.67 (0.54, 0.81) at steady state than that after the first single dose in EM phenotypes. The in vitro kinetic experiments on recombinant enzymes (CYP2C19 and CYP3A4) suggested a possible inhibition of catalytic activity of CYP3A4 by ATO. There was no unexpected accumulation of ATO following repeated administrations of the combination. In EM phenotypes, PROG elimination was reduced at steady state. Also, at steady state, either the elimination of CYCLO was increased or its formation clearance decreased the latter possibly by inhibition of CYP3A4 by ATO.


Femoral and pelvic osteotomies for severe hip displacement in nonambulatory children with cerebral palsy: a prospective population-based study of 31 patients with 7 years' follow-up.
Background and purpose - There is no consensus regarding the optimal treatment of hip displacement in children with cerebral palsy (CP). This prospective study assessed the outcome of femoral and pelvic osteotomies for severe hip displacement in nonambulatory children and analyzed prognostic factors for outcome.Patients and methods - 31 nonambulatory children (20 boys), recruited from a population-based screening program, consecutively underwent unilateral (23) or bilateral (8) osteotomies and bilateral soft-tissue releases at a mean age of 6.1 years (2.2-9.9). The procedures were femoral varus osteotomy alone (20 hips) and combined Dega-type pelvic osteotomy and femoral osteotomy (19 hips). Final outcome was termed good if the patient had not undergone further bony surgery and migration percentage (MP) was < 50%. The mean follow-up time was 7.1 years (3.8-11).Results - The mean preoperative MP was 69% (36-100). The outcome was good in 22 patients (29 hips) and poor in 9 patients (10 hips). Mean time to failure was 3.6 years (1.0-6.0). GMFCS level V and high MP 1-year postoperatively were statistically significant risk factors for poor final outcome. There was a higher rate of good outcome after combined osteotomies compared with isolated femoral osteotomy, but the difference was not statistically significant (p = 0.2).Interpretation - Better primary correction was obtained after combined femoral and pelvic osteotomies than after isolated femoral osteotomy, indicating that combined osteotomies are the preferred method in hips with the most severe degrees of displacement. Prophylactic femoral osteotomy of the contralateral non-subluxated hip is hardly indicated.


Epigenetics of Skeletal Muscle-Associated Genes in the ASB, LRRC, TMEM, and OSBPL Gene Families.
Much remains to be discovered about the intersection of tissue-specific transcription control and the epigenetics of skeletal muscle (SkM), a very complex and dynamic organ. From four gene families, Leucine-Rich Repeat Containing (LRRC), Oxysterol Binding Protein Like (OSBPL), Ankyrin Repeat and Socs Box (ASB), and Transmembrane Protein (TMEM), we chose 21 genes that are preferentially expressed in human SkM relative to 52 other tissue types and analyzed relationships between their tissue-specific epigenetics and expression. We also compared their genetics, proteomics, and descriptions in the literature. For this study, we identified genes with little or no previous descriptions of SkM functionality (ASB4, ASB8, ASB10, ASB12, ASB16, LRRC14B, LRRC20, LRRC30, TMEM52, TMEM233, OSBPL6/ORP6, and OSBPL11/ORP11) and included genes whose SkM functions had been previously addressed (ASB2, ASB5, ASB11, ASB15, LRRC2, LRRC38, LRRC39, TMEM38A/TRIC-A, and TMEM38B/TRIC-B). Some of these genes have associations with SkM or heart disease, cancer, bone disease, or other diseases. Among the transcription-related SkM epigenetic features that we identified were: super-enhancers, promoter DNA hypomethylation, lengthening of constitutive low-methylated promoter regions, and SkM-related enhancers for one gene embedded in a neighboring gene (e.g., ASB8-PFKM, LRRC39-DBT, and LRRC14B-PLEKHG4B gene-pairs). In addition, highly or lowly co-expressed long non-coding RNA (lncRNA) genes probably regulate several of these genes. Our findings give insights into tissue-specific epigenetic patterns and functionality of related genes in a gene family and can elucidate normal and disease-related regulation of gene expression in SkM.


Mating type genes in the genus Neofusicoccum: Mating strategies and usefulness in species delimitation.
The genus Neofusicoccum includes species with wide geographical and plant host distribution, some of them of economic importance. The genus currently comprises 27 species that are difficult to identify based on morphological features alone. Thus, species differentiation is based on phylogenetic species recognition using multigene genealogies. In this study, we characterised the mating type genes of Neofusicoccum species. Specific primers were designed to amplify and sequence MAT genes in several species and a PCR-based mating type diagnostic assay was developed. Homothallism was the predominant mating strategy among the species tested. Furthermore, the potential of mating type gene sequences for species delimitation was evaluated. Phylogenetic analyses were performed on both MAT genes and compared with multigene genealogies using sequences of the ribosomal internal transcribed spacer region, translation elongation factor 1-alpha and beta-tubulin. Phylogenies based on mating type genes could discriminate between the species analysed and are in concordance with the results obtained with the more conventional multilocus phylogenetic analysis approach. Thus, MAT genes represent a powerful tool to delimit cryptic species in the genus Neofusicoccum.


[Darier disease].
Darier disease (Darier-White disease, dyskeratosis follicularis) is a rare autosomal dominant genodermatosis with regional differences in prevalence. The responsible mutations have been identified on chromosome 12q23-24.1. The gene encodes a calcium-ATPase type 2 in the sarco-/endoplasmic reticulum (SERCA2), which belongs to the large family of P-type cation pumps. This pump couples ATP hydrolysis to the transport of cations across membranes and thus plays a significant role in intracellular calcium signaling. Neuropsychiatric disorders are often associated with Darier disease. However, these diseases are not due to mutations in the gene ATP2A2 but to a susceptibility locus in a 6.5 Mb region near this gene. Currently, the treatment is strictly limited to the relief of symptoms. In severe cases, oral retinoids (acitretin: initial 10-20 mg/Tag and isotretinoin: 0.5-1 mg/kg/day) lead to a response in 90% of cases. However, side effects often prevent long-term use of vitamin A derivatives.


Restoration of corticosteroid periodicity in obese rats by limited a.m. food access.
Absence of circadian periodicity of plasma corticosteroid levels has previously been reported to occur in animals maintained under constant light and in animals with suprachiasmatic nuclear lesions. Such animals also exhibit aperiodic rather than normal nocturnal eating. Restricted a.m. access to food (09.30--11.30 h) in such animals results in appearance of circadian corticosteroid periodicity (peak at 08.00 h) similar to that seen in normal animals on a similar food restriction regimen. The present study investigated the nature of adrenal circadian periodicity in obese rats who are reported to exhibit aperiodic feeding. Such aperiodic feeding occurred in obese male, but not in obese female, animals. These obese male animals manifested absent corticosteroid circadian periodicity. Restricted a.m. access to food was associated with the appearance of such periodicity similar to that described above in the two other experimental situations. These studies indicate differences in eating behavior and corticosteroid periodicity between obese male and obese female rats. They provide additional confirmation, in animals under normal light--dark conditions and in the absence of CNS lesions, of the role of periodic feeding in the generation of adrenal circadian periodicity.


Self-organization of a new fluorous porphyrin and C60 films on indium-tin-oxide electrode.
The highly fluorinated alkyl moieties of a new porphyrin drive the self-organization of thin films with C(60) on ITO electrodes.


The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part 1.
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.


ERK signaling pathways regulate the osteogenic differentiation of human mesenchymal stem cells on collagen I and vitronectin.
Adhesion to the extracellular matrix (ECM) proteins collagen I and vitronectin is sufficient to drive human mesenchymal stem cells (hMSCs) into an osteogenic differentiation pathway, but the mechanisms underlying this stimulation are not well understood. We found that addition of beta1 and alpha(v)beta3 integrin blocking antibodies inhibited ECM-induced ERK activation, while addition of the MEK inhibitor PD98059 blocked ERK activation, serine phosphorylation of the osteogenic transcription factor runx2/cbfa-1, osteogenic gene expression, and calcium deposition. These results suggest that ERK plays an important role in driving the ECM-induced osteogenic differentiation of hMSC.


Clinical and demographic parameters predict the progression from mild cognitive impairment to dementia in elderly patients.
To evaluate the possibility of predicting the risk of progression from mild cognitive impairment (MCI) to dementia using a combination of clinical/demographic parameters. A total of 462 MCI elderly patients (follow-up: 33 months). Variable measured included cognitive functions, age, gender, MCI type, education, comorbidities, clinical chemistry, and functional status. Amnestic type (aMCI) represented 63% of the sample, non-amnestic (naMCI) 37%; 190 subjects progressed to dementia, 49% among aMCI, and 28% among naMCI. At Cox multivariate regression analysis, only MMSE (one point increase HR 0.84; 95% CI 0.79-0.90), aMCI (HR 2.35; 95% CI 1.39-3.98), and age (1 year increase HR 1.05; 95% CI 1.01-1.10) were independently associated with progression to dementia. A score was created based on these dichotomized variables (score 0-3): age (≥ or < 78 years), MMSE score (≥ or < 25/30) and aMCI type. The conversion rate progressed from 6% in subjects with score 0 (negative predictive value: 0.94), to 31% in individuals with score 1, to 53% in subjects with score 2, to 72% in individuals with score 3 (positive predictive value: 0.72). ROC curve analysis showed an area under the curve of 0.72 (95% CI 0.66-0.75, p 0.0001). We have described a simple score, based on previously recognized predictors such as age, MMSE, and MCI type, which may be useful for an initial stratification of the risk of progression to dementia in patients affected by MCI. The score might help the clinicians to evaluate the need for more expansive/invasive examinations and for a closer follow-up in MCI patients.


Free orbital fat graft to prevent porous polyethylene orbital implant exposure in patients with retinoblastoma.
To determine if porous polyethylene orbital implant (Medpor) exposure can be prevented in retinoblastoma patients when the implant is placed in combination with a free orbital fat graft over the anterior surface of the implant. Free orbital fat grafts were performed after enucleation and Medpor implantation, and results were compared with patients who underwent conventional enucleation and Medpor implantation without an orbital fat graft. Although implant exposure occurred in 13 of 39 eyes (33.3%) that had conventional enucleation and Medpor implantation, exposure did not develop in any of the 38 eyes that had the combined procedure with a free orbital fat graft. These findings suggest that a free orbital fat graft is a simple, effective way to prevent orbital implant exposure in patients requiring enucleation and Medpor implantation.


Procalcitonin determined at emergency department as na early indicator of progression to septic shock in patient with sepsis associated with ureteral calculi.
To investigate the role of initial procalcitonin (PCT) level as an early predictor of septic shock for the patient with sepsis induced by acute pyelonephritis (APN) secondary to ureteral calculi. The data from 49 consecutive patients who met criteria of sepsis due to APN following ureteral stone were collected and divided into two groups: with (n=15) or without (n=34) septic shock. The clinical variables including PCT level for this outcome were retrospectively compared by univariate analysis, followed by multivariable logistic regression model. All subjects had hydronephrosis, and were hospitalized with the mean of 11.8 days (3-42 days). The mean size of the ureteral stones was 7.5mm (3-30mm), and 57% were located in upper ureter. At univariate analysis, patients with septic shock were significantly older, a higher proportion had hypertension, lower platelet count and serum albumin level, higher CRP and PCT level, and higher positive blood culture rate. Multivariate models indicated that lower platelet count and higher PCT level are independent risk factors (p=0.043 and 0.046, respectively). In ROC curve, the AUC was significantly wider in PCT (0.929), compared with the platelet count (0.822, p=0.004). At the cut-off of 0.52ng/mL, the sensitivity and specificity were 86.7% and 85.3%. Our study demonstrated elevated initial PCT levels as an early independente predictor to progress into septic shock in patients with sepsis associated with ureteral calculi.


Unveiling Photodegradation and Photosensitization Mechanisms of Unconjugated Pterins.
Invited for the cover of this issue are Enrique M. Arpa (Linköping University) and Inés Corral (Universidad Autónoma de Madrid). The image depicts two examples where pterin chemistry is relevant, the wing coloration of some butterflies and the cytotoxic action in vitiligo. Read the full text of the article at 10.1002/chem.202300519.


Countergradient variation in growth rate: compensation for length of the growing season among Atlantic silversides from different latitudes.
How do organisms adapt to the differences in temperature and length of the growing season that occur with latitude? Among Atlantic silversides (Menidia menidia) along the east coast of North America, the length of the first growing season declines by a factor of about 2.5 with increasing latitude. Yet body size at the end of the first growing season does not decline. High-latitude fish must, therefore, grow faster within the growing season than do low-latitude fish. This geographical pattern has a genetic basis. Laboratory experiments on fish from six different locations revealed a latitudinal gradient in the capacity for growth (i.e., maximum growth potential). In two subsequent experiments using fish from Nova Scotia (NS), New York (NY) and South Carolina (SC) that had been separately reared in a common environment for several generations, differences in growth rate among populations were highly significant. The rank order was NS>NY>SC, but the difference among populations depended on temperature. High-latitude fish outperformed those from low latitudes primarily at the high temperatures that low-latitude fish would be expected to experience most often in nature. These results suggest that instead of being adapted for growth at low temperatures, fish from high latitudes are adapted for rapid elevation of growth rate during the brief interval of the year when high temperatures occur. Selection on growth rate results from sizedependent winter mortality: the importance to winter survival of being large increases with latitude but the length of the growing season simultaneously decreases. The end result is countergradient variation in growth rate, a phenomenon that may be much more widespread than currently recognized.


TAK-220, a novel small-molecule CCR5 antagonist, has favorable anti-human immunodeficiency virus interactions with other antiretrovirals in vitro.
TAK-220 is a CCR5 antagonist, part of the new class of anti-human immunodeficiency virus type 1 (anti-HIV-1) entry inhibitors. We evaluated the anti-HIV-1 interactions between TAK-220 and various antiretrovirals in vitro. Synergy was observed with all drugs at the 90 and 95% inhibitory concentrations. The favorable drug interactions observed suggest that further clinical evaluation is warranted.


Spinal cord compression by vertebral hemangioma.
Asymptomatic vertebral hemangiomas occur frequently in adults but the discovery of a similar lesion in the pediatric are group is uncommon. A case which involves all the neural arch components with resultant spinal cord compression is rare and is reported with a review of pertinent literature.


Deubiquitination of phosphoribosyl-ubiquitin conjugates by phosphodiesterase-domain-containing Legionella effectors.
Posttranslational protein modification by ubiquitin (Ub) is a central eukaryotic mechanism that regulates a plethora of physiological processes. Recent studies unveiled an unconventional type of ubiquitination mediated by the SidE family of Legionella pneumophila effectors, such as SdeA, that catalyzes the conjugation of Ub to a serine residue of target proteins via a phosphoribosyl linker (hence named PR-ubiquitination). Comparable to the deubiquitinases in the canonical ubiquitination pathway, here we show that 2 paralogous Legionella effectors, Lpg2154 (DupA; deubiquitinase for PR-ubiquitination) and Lpg2509 (DupB), reverse PR-ubiquitination by specific removal of phosphoribosyl-Ub from substrates. Both DupA and DupB are fully capable of rescuing the Golgi fragmentation phenotype caused by exogenous expression of SdeA in mammalian cells. We further show that deletion of these 2 genes results in significant accumulation of PR-ubiquitinated species in host cells infected with Legionella In addition, we have identified a list of specific PR-ubiquitinated host targets and show that DupA and DupB play a role in modulating the association of PR-ubiquitinated host targets with Legionella-containing vacuoles. Together, our data establish a complete PR-ubiquitination and deubiquitination cycle and demonstrate the intricate control that Legionella has over this unusual Ub-dependent posttranslational modification.


Metabolic changes in the normal ageing brain: consistent findings from short and long echo time proton spectroscopy.
Sixty three healthy subjects were measured to assess dependence of brain metabolites on age using short- and long echo time spectroscopy in different brain regions. Younger and elderly humans were measured with long echo time (TE=135ms) 3D-MR-spectroscopic imaging (MRSI) (10 subjects) and with ultra-short echo (TE=11ms) time 2D-MRSI (7 subjects). In addition, results from single voxel (1)H-spectroscopy (TE=20ms) of two cohorts of 46 healthy subjects were retrospectively correlated with age. 3D-MR SI revealed reduced NAA/Cr in the older group in the frontal lobe (-22%; p<0.01), parietal lobe (-28%; p<0.01) and semiovale (-9%; p<0.01) compared to the younger group. Cho/Cr was elevated in the semiovale (+35%; p<0.01) and in the n. lentiformis (+42%; p<0.01) in the older group. NAA/Cho was reduced in all regions measured, except the thalamus, in the older group compared to the younger group (from -21 to -49%; p<0.01). 2D-MRSI revealed decreased total NAA (-3.1% per decade; p<0.01) and NAA/Cr (-3.8% per decade; p<0.01), increased total Cho (+3.6% per decade; p<0.01) and Cho/Cr (+4.6% per decade; p<0.01) and increased total myo-Inositol (mI, +4.7% per decade; p<0.01) and mI/Cr (+5.4% per decade; p<0.01) and decreased NAA/Cho (-8% per decade; p<0.01) in semiovale WM. Results from single voxel spectroscopy revealed a significantly negative correlation of NAA/Cho in frontal (-13% per decade; p<0.01) and in temporal lobe (-7.4% per decade; p<0.01) as well as increased total Cr (10% per decade; p<0.01) in frontal lobe. Other results from single voxel measurements were not significant, but trends were comparable to that from multivoxel spectroscopy. Age-related changes measured with long echo time and short echo time 1H-MRS were comparable and cannot, therefore, be caused by different T2 relaxation times in young and old subjects, as suggested previously.


One-pot sequential alcohol oxidation and asymmetric α-oxyamination in aqueous media using recyclable resin-supported peptide catalyst.
An efficient tandem reaction system was developed, in which primary alcohols were used for the oxidation to the corresponding aldehydes followed by an asymmetric α-oxyamination with a resin-supported peptide catalyst.


Problem-solving tools for analyzing system problems. The affinity map and the relationship diagram.
The author describes how to use two management tools, an affinity map and a relationship diagram, to define and analyze aspects of a complex problem in a system. The affinity map identifies the key influencing elements of the problem, whereas the relationship diagram helps to identify the area that is the most important element of the issue. Managers can use the tools to draw a map of problem drivers, graphically display the drivers in a diagram, and use the diagram to develop a cause-and-effect relationship.


The State of Racial and Gender Diversity in Cardiothoracic Surgery Training.
The field of cardiothoracic surgery has been striving to increase its gender and racial diversity. We sought to examine changes in gender and racial diversity in cardiothoracic fellowships and integrated residencies in the past decade. Accreditation Council for Graduate Medical Education data were obtained from 2011 to 2019. Linear trends were assessed for year-by-year data. Average percentages of women and underrepresented minorities were then calculated in 3-year intervals. Intervals were compared with Student's t test and χ2 tests. There was no statistically significant increase in percent female trainees in cardiothoracic fellowships (18.5% to 22.1%, P = .10) or integrated residencies (22.8% to 27.8%, P = .17), despite a significant increase in percent female applicants to fellowship (18.2% to 35.3%, P < .01) and integrated residency (8.9% to 33.0%, P < .01). Cardiothoracic fellowships had no increase in underrepresented minority trainees (8.3% to 9.4%, P = .48). Underrepresented minority trainees in integrated residencies increased from 2.7% to 6.9% (P = .03). Although there was no significant increase in underrepresented minority applicants to fellowships (10.2% to 11.3%, P = .66), the percent of underrepresented minority applicants to integrated residencies increased from 13.1% to 19.3% (P < .01). Cardiothoracic surgery training programs are attracting more female applicants, but that has not yet resulted in a higher percentage of female trainees. Although percentages of underrepresented minorities increased among integrated residency applicants and trainees, they remain low compared with other specialties. These data reflect positive changes but also highlight that much remains to be done to increase diversity in cardiothoracic surgery training.


Effect of thumb joint mobilization on pressure pain threshold in elderly patients with thumb carpometacarpal osteoarthritis.
This study evaluated the effects of Maitland's passive accessory mobilization on local hypoalgesia and strength in thumb carpometacarpal osteoarthritis (TCOA). Twenty-eight patients between 70 and 90 years old with secondary TCOA were randomized into glide mobilization and sham groups. This study was designed as a double-blind, randomized controlled trial. Therapy consisted of Maitland's passive accessory mobilization of the dominant hand during 4 sessions over 2 weeks. We measured pressure pain threshold (PPT) at the trapeziometacarpal joint (TMJ), the tubercle of the scaphoid bone, and the unciform apophysis of the hamate bone by algometry. The tip and tripod pinch strength was also measured. Grip strength was measured by a grip dynamometer. Measurements were taken before treatment and after 1 week (first follow-up [FU]) and 2 weeks (second FU). All values in sham group remained unchanged along the treatment period. In the treated group, the PPT in the TMJ was 3.85 ± 0.35 kg/cm(2), which increased after treatment to 3.99 ± 0.37 and was maintained at the same level during the first FU 3.94 ± 0.39 and second FU 4.74 ± 0.40. In contrast, we found no differences in PPT in the other studied structures after treatment. Similarly, tip, tripod pinch, and grip strength remained without change after treatment. Passive accessory mobilization increased PPT in the TMJ; however, it did not increase motor function in patients with TCOA.


A homogeneity study using NIR spectroscopy: tracking magnesium stearate in Bohle bin-blender.
A method was developed for studying mixing of cohesive pharmaceutical mixtures. A combination of accurate sampling and NIR spectroscopic analysis was developed as a suitable method to determine homogenization of magnesium stearate as a function of blending variables. A typical pharmaceutical blend containing a ratio 35:64:1 lactose, avicel, and magnesium stearate was used as a model system. The method accounted for variability of the concentration of magnesium stearate as well as variability of the excipients. Levels of magnesium stearate as low as 0.05% could be resolved by the method, and showed a predicting confidence interval above 98%.


Optimization of pH, time, temperature, variety and concentration of the added fatty acid and the initial count of added lactic acid Bacteria strains to improve microbial conjugated linoleic acid production in fermented ground beef.
The aim of the present study was to determine the optimum pH, time, temperature, variety and concentration of the added fatty acid and the initial count of added Lactobacillus plantarum AB20-961 and Lactobacillus plantarum DSM2601 for high conjugated linoleic acid (CLA) production in ground beef. The highest CLA production with using safflower fatty acids by L. plantarum AB20-961 and L. plantarum DSM2601 was 7.91 and 38.31 mg CLA/g fat, respectively (P < 0.05). Optimum conditions for both strains were 37 °C fermentation temperature, 5% added fatty acid in free form and 8 log CFU/g initial count. Additionally, the optimum pH and fermentation time were 7.94 pH and 78.78 h for L. plantarum AB20-961 and 7.68 and 72.57 h for L. plantarum DSM2601. The results indicated that both L. plantarum strains with optimum conditions determined in the present study may be applied in order to enrich CLA content in ground beef and satisfy consumer demands for the fermented meat products with functional components.


Travel patterns and advice-seeking behaviour of pregnant women in the Australian context: A multicentre cross-sectional analysis.
Travel poses risks to pregnant women, but little data exist describing the travel habits of women during pregnancy or pre-travel recommendations given. To examine travel patterns of pregnant women including frequency of pre-travel consultation, and advice recalled. Cross-sectional analysis of post-partum women admitted to five Victorian maternity hospitals between 21 May 2019 and 22 April 2020 in Australia. Forty-four percent (182/410) of women travelled during pregnancy, 32.9% (135/410) interstate and 19.5% (80/410) internationally. Fifty-five percent travelled for leisure (118/215) and 27% to visit friends/relatives (58/215). Overall, 68.1% (124/182) sought pre-travel advice, primarily from an obstetrician (60.5%, 75/124) or general practitioner (29.8%, 37/124). Only one woman attended a travel clinic. The most common reason for not seeking pre-travel advice was the belief that travel posed no risk (63.4%, 45/71). Pre-travel advice was sought least by those visiting friends/relatives (61.4%, 35/57). Women recalled recommendations regarding travel restrictions by gestational age and venous thromboembolism precautions, but not infectious disease prevention for those to whom it was relevant. Of international travellers, 48.8% (39/80) sought advice from the internet, one-third (13/39) as an alternative to seeing a healthcare provider. Travel is common during pregnancy and women seek pre-travel advice from the healthcare provider they see most often during pregnancy. All pregnant women should be provided with consistent, evidence-based pre-travel advice regardless of whom they consult. Further work is needed to educate and provide resources to maternity care providers to optimise pre-travel counselling.


Peripheral polymorphonuclear leukocyte activation as a systemic inflammatory response in ischemic stroke.
Stroke is one of the leading causes of mortality and morbidity in the world. The activation of polymorphonuclear leukocytes (PMNL) plays an important role in the inflammatory response after ischemic stroke. However, in the current literature, there are few studies discussing the process and role of peripheral PMNL activation. Here, we give a comprehensive description of peripheral PMNL activation after ischemic stroke and discuss their potential roles in the process of ischemic injury. Based on our analysis, peripheral PMNL activation is supposed to be attributed to systemic inflammatory response to cerebral ischemic insult, not reflecting the activity of PMNL in local ischemic brain. Inhibiting peripheral PMNL activation in stroke animals has been effective in reducing infarction and improving behavioral outcome; thus, the same approach of inhibiting peripheral PMNL activation is a promising therapeutic strategy for stroke patients.


SHP-1 suppresses endotoxin-induced uveitis by inhibiting the TAK1/JNK pathway.
We investigated how Src-homology 2-domain phosphatase-1 (SHP-1) regulates the inflammatory response in endotoxin-induced uveitis (EIU), and the signalling pathways involved. One week after intravitreal injection of short hairpin RNA targeting SHP-1 or SHP-1 overexpression lentivirus in rats, we induced ocular inflammation with an intravitreal injection of lipopolysaccharide (LPS). We then assessed the extent of inflammation and performed full-field electroretinography. The concentrations and retinal expression of various inflammatory mediators were examined with enzyme-linked immunosorbent assays and Western blotting, respectively. SHP-1 overexpression and knockdown were induced in Müller cells to study the role of SHP-1 in the LPS-induced inflammatory response in vitro. Retinal SHP-1 expression was up-regulated by LPS. SHP-1 knockdown exacerbated LPS-induced retinal dysfunction and increased the levels of proinflammatory mediators in the retina, which was abrogated by a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). SHP-1 overexpression had the opposite effects. In Müller cells, the LPS-induced inflammatory response was enhanced by SHP-1 knockdown and suppressed by SHP-1 overexpression. SHP-1 negatively regulated the activation of the transforming growth factor-β-activated kinase-1 (TAK1)/JNK pathway, but not the nuclear factor-κB pathway. These results indicate that SHP-1 represses EIU, at least in part, by inhibiting the TAK1/JNK pathway and suggest that SHP-1 is a potential therapeutic target for uveitis.


EphB4 as a therapeutic target in mesothelioma.
Malignant pleural mesothelioma (MPM) often develops decades following exposure to asbestos. Current best therapy produces a response in only half of patients, and the median survival with this therapy remains under a year. A search for novel targets and therapeutics is underway, and recently identified targets include VEGF, Notch, and EphB4-Ephrin-B2. Each of these targets has dual activity, promoting tumor cell growth as well as tumor angiogenesis. We investigated EphB4 expression in 39 human mesothelioma tissues by immunohistochemistry. Xenograft tumors established with human mesothelioma cells were treated with an EphB4 inhibitor (monomeric soluble EphB4 fused to human serum albumin, or sEphB4-HSA). The combinatorial effect of sEphB4-HSA and biologic agent was also studied. EphB4 was overexpressed in 72% of mesothelioma tissues evaluated, with 85% of epithelioid and 38% of sarcomatoid subtypes demonstrating overexpression. The EphB4 inhibitor sEphB4-HSA was highly active as a single agent to inhibit tumor growth, accompanied by tumor cell apoptosis and inhibition of PI3K and Src signaling. Combination of sEphB4-HSA and the anti-VEGF antibody (Bevacizumab) was superior to each agent alone and led to complete tumor regression. EphB4 is a potential therapeutic target in mesothelioma. Clinical investigation of sEphB4-HSA as a single agent and in combination with VEGF inhibitors is warranted.


Ontogeny of vasopressin and oxytocin in the fetal rat: early vasopressinergic innervation of the fetal brain.
The content and distribution of vasopressin and oxytocin were determined during fetal development in the rat brain and pituitary by means of radioimmunoassay and immunocytochemistry. The vasopressin content in the fetal brain showed a gradual rise from day 16 of pregnancy onwards, while pituitary vasopressin rapidly increased from fetal day 19 until birth. The oxytocin content in the fetal brain was considerably lower than the vasopressin content. A decrease in oxytocin content was seen between day 16 and day 18 while from day 18 of pregnancy onwards a slight increase was found. The pituitary oxytocin content starts to rise between day 17 and 18 of pregnancy, but at term the pituitary oxytocin content was only 1/20 of the vasopressin value. Immunocytochemistry revealed that vasopressin levels in the fetal rat brain were not only due to the presence of the classical hypothalamoneurohypophyseal system, but also to the early development of exohypothalamic fibers. Vasopressin containing cells were seen from fetal day 16 in the supraoptic nucleus, and from fetal day 18 in the paraventricular nucleus. The fiber outgrowth of these cells towards the pituitary and extrahypothalamic brain sites seems to be well synchronized, as on day 17 vasopressin containing fibers could be demonstrated in the olfactory bulb as well as in the median eminence. No positive staining for oxytocin could be obtained in the fetal rat, while during the entire fetal period no positive staining was found in cell bodies in the region of the suprachiasmatic nucleus. The early peptidergic innervation of the brain, which enabled the tracing of the source of some exohypothalamic fibers, might be related to several central processes among which brain development itself is included.