Oral Isotretinoin Therapy in Recalcitrant Molluscum Contagiosum in an Immunocompromised Patient.
Molluscum contagiosum is a viral infection caused by the Poxvirus characterized by multiple umbilicated papules. It is common in children and can be present at any body site. Severe molluscum is common in immunocompromised patients. We report a 20-year-old HIV-positive individual with widespread molluscum contagiosum, recalcitrant to topical therapy, under antiretroviral therapy, who was treated with oral isotretinoin and had a dramatic outcome. Although studies are needed to confirm the effectiveness of oral isotretinoin therapy in molluscum contagiosum, its easy availability, cost, and excellent safety profile appear to offer a promising therapeutic option.


Metabolic evaluation of a 75% lipid/25% glucose high nitrogen solution for intravenous nutrition.
To compare the metabolic response to a 75% lipid/25% glucose regimen of intravenous feeding with that of a regimen of isocaloric isonitrogenous glucose alone. Randomised crossover study. University department of surgery. 14 Patients (of 18 consecutive) who did not develop infections after major upper gastrointestinal operations. Patients received five days of each of two regimens, both of which provided 0.38 g nitrogen and 0.155 MJ (37 kcal)/kg/day. Nitrogen balance, prealbumin and transferrin concentrations, and basal efflux of amino acids from the lower limb before and after a five day course of each regimen. Mean (SD) nitrogen balance increased from -11.4 (2.6) g/day to 1.7 (4.1) and 1.6 (5.5) g/day after lipid/glucose and glucose alone, respectively (p < 0.0001). Basal prealbumin and transferrin concentrations increased after both regimens, but significantly so only after lipid/glucose (p < 0.01 and < 0.02, respectively). Mean (SD) net basal efflux of total amino acids from the lower limb was significantly reduced after both regimens, (p < 0.0001 in each case). Net basal alanine efflux was significantly reduced only by glucose alone, and basal glutamine efflux only by lipid/glucose (p < 0.05 in each case). Plasma free fatty acids were increased only by glucose alone (p < 0.001), and glucose alone augmented tissue uptake of glucose significantly more than lipid/glucose (p < 0.01 and < 0.05, respectively). The solution high in lipids and nitrogen was well tolerated. There was no difference in improvements in nitrogen balance or amino acid flux across the lower limb, but lipid/glucose was associated with higher increases in visceral protein concentrations.


Familiar interacting object pairs are perceptually grouped.
Identification of objects in a scene may be influenced by functional relations among those objects. In this study, observers indicated whether a target object matched a label. Each target was presented with a distractor object, and these were sometimes arranged to interact (as if being used together) and sometimes not to interact. When the distractor was semantically related to the label, identification was more accurate for targets arranged to interact with that distractor. This effect depended on observers' ability to perceptually integrate the stimulus objects, suggesting that it was perceptual in nature. The effect was not attributable to attentional cuing and did not depend on expectation of certain object pairs. These data suggest that familiar functional groupings of objects are perceptually grouped.


Subclinical Hypothyroidism among Patients with COVID-19 Infection in a Tertiary Care Centre: A Descriptive Cross-sectional Study.
Hypothyroidism occurs as a consequence of chronic autoimmune inflammation of the thyroid gland, which occurs due to the reduced function in the secretion of thyroid hormones. The coronavirus disease infection has shown many complications in all organic systems, during the acute phase of infection and in the post-COVID-19 period. SARS-CoV-2 may induce thyroid dysfunction that is usually reversible, including subclinical and atypical thyroiditis. The aim of this study was to find out the prevalence of subclinical hypothyroidism among patients with COVID-19 infection in a tertiary care centre. A descriptive cross-sectional study was conducted in the Department of Internal Medicine of a tertiary care centre from 1 September 2022 to 28 February 2023 after obtaining ethical approval from the Research and Institutional Review Committee (Reference number: 15-079/080). Convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated. Among 38 patients with COVID-19, subclinical hypothyroidism was seen among 23 (60.53%) (44.99-76.07, 95% Confidence Interval). The prevalence of subclinical hypothyroidism among COVID-19 patients was found to be similar to other studies done in similar settings. COVID-19; hypothyroidism; thyroid gland.


"What makes you well?" Supports of well-being in bipolar disorder. A qualitative study.
Subjective experience of people living with bipolar disorder is gaining attention in the field of research. Improving well-being could be as important as symptom remission, but this constitutes a vague concept. This study aimed at exploring the boundaries and the determinants of the well-being of people living with bipolar disorder in a French context. Individual semi-structured interviews were conducted with 16 patients by three professionals. Interviews were transcribed and analysed using the thematic analysis method. Various dimensions emerged as contributing to well-being: daily routines, connectedness, regaining a positive identity, and self-awareness for self-management. In addition to those common to the general population, this study highlighted specific determinants of well-being: the construction of a positive identity through acceptance of the diagnosis, the importance of self-awareness and self-management. They are highly intertwined with those of personal recovery and could help caregivers design interventions that directly target these goals. This study aimed to identify specific components of well-being for people living with bipolar disorder. Understanding the determinants of well-being enable caregivers to design tailored interventions that directly target quality of life and help improve bipolar disorder outcomes.


Economic aspects of the detection of occlusal dentine caries.
To evaluate the cost of true-positive occlusal dentine caries detection in permanent molars assessed by: (I) visual-tactile examination, (II) visual-tactile examination combined with bitewing radiographs, and (III) selective radiographic examination of patients with lesions detected clinically. A second aim was to analyse the different strategies when the costs of the subsequent restorative care are considered. A model analysis was applied owing to the lack of original articles. Sensitivity and specificity were calculated from a systematic review and included in vitro and in vivo studies of medium and high quality. The direct costs for examinations and restorative care were extracted from the costs of the Public Dental Service in Sweden (2006). The diagnostic costs per true-positive finding were dependent on the occurrence of occlusal caries and increased with decreasing prevalence. The strategy by which radiographs were exposed selectively on the basis of findings from visual-tactile examination resulted in higher initial costs compared with the first and second strategies. When the costs of the subsequent restorative care were added, the selective strategy was most beneficial by up to 26% savings per true-positive diagnosis. However, with this selective strategy, more cases of true-positive dentine caries were assumed would remain undetected as compared with the combined strategy with visual-tactile examination and radiographs for all. The cost for a true-positive caries diagnosis was inversely related to caries occurrence, and different diagnostic strategies may display contrasting outcomes when subsequent restorative care is taken into account.


Amentoflavone attenuates cell proliferation and induces ferroptosis in human gastric cancer by miR-496/ATF2 axis.
Amentoflavone (AF) is a natural multifunctional biflavonoid that has been revealed to possess multiple biological activities, including anticancer activity. Here, this work focused on exploring the functions and mechanism of AF in gastric cancer (GC). Levels of genes and proteins were examined by quantitative real-time PCR and western blotting. Cell proliferation and cell death were analyzed using cell counting kit-8, colony formation, and lactate dehydrogenase (LDH) release assay, respectively. Cell ferroptosis was evaluated by detecting the levels of malondialdehyde (MDA), reduced glutathione (GSH), Fe2+ , and intracellular reactive oxygen species (ROS). The binding between miR-496 and activating transcription factor 2 (ATF2) was confirmed by using dual-luciferase reporter assay. Murine xenograft assay was conducted for in vivo experiments. The results showed that AF suppressed the proliferation and induced ferroptotic cell death in GC cells. MiR-496 expression was decreased in GC tissues and cells, and AF treatment increased miR-496 expression level in GC cells. Functionally, miR-496 inhibition reversed the inhibitory effects of AF on GC cell proliferation and promoting effects on ferroptotic cell death. Mechanistically, ATF2 was targeted by miR-496. ATF2 expression was increased in GC tissues and cells, which was decreased by AF treatment and subsequently rescued by miR-496 downregulation in GC cells. Moreover, miR-496 overexpression suppressed the proliferation and induced ferroptotic cell death in GC cells via targeting ATF2. In all, AF suppressed the proliferation and induced ferroptotic cell death in GC cells via miR-496/ATF2 axis, indicating a novel therapeutic approach for GC patients.


Lipegfilgrastim for the prophylaxis and treatment of chemotherapy-induced neutropenia.
Chemotherapy is frequently associated with hematologic toxicity. Neutropenia with or without fever is a relevant cause of morbidity, mortality and costs, compromising treatment administration and clinical outcomes. The development of granulocyte colony-stimulating factors has had a positive impact on the clinician's approach to neutropenia. Such agents, currently used for primary and secondary prophylaxis of chemotherapy-induced neutropenia and febrile neutropenia (FN), are effective in limiting hematologic toxicities and consequently allow the administration of intensive dose-dense regimens. Several biosimilar products of filgrastim have been developed over the years, showing effects similar to the originator drug. Until now, pegfilgrastim has been the only available long-acting factor, requiring just a single administration per chemotherapy cycle. The recent approval of the novel granulocyte colony-stimulating factors, lipegfilgrastim, offers interesting therapeutic alternatives. In fact, similar to pegfilgrastim, it has been demonstrated to reduce the duration of neutropenia and the occurrence of FN during chemotherapy safely.


A multicentre randomized controlled follow-up study of the effects of the underwater traction therapy in chronic low back pain.
Low back pain (LBP) is one of the most costly diseases in the developed world. This study aimed to investigate the effects of underwater traction therapy on chronic low back pain. The primary objective was to prove that underwater traction therapy has favorable effects on LBP. Our secondary objective was to evaluate whether it also leads to improvement in the quality of life. This is a prospective, multicenter, follow-up study. A total of 176 patients with more than 3 months of low back pain enrolled from outpatient clinics were randomized into three groups: underwater weight bath traction therapy and non-steroidal anti-inflammatory drugs (NSAIDs); weight bath; and only NSAIDs. The following parameters were measured before, right after, and 9 weeks after the 3-week therapy: levels of low back pain in rest and during activity were tested using the visual analogue scale (VAS), the Oswestry Low Back Disability Questionnaire, and the EuroQol-5D-5L Questionnaire.The VAS levels improved significantly (p < 0.05) in both underwater weight bath traction therapy groups by the end of the treatment, whereas the improvement in the third group was not statistically significant. Furthermore, the improvements measured in the groups receiving traction therapy were persistent during the follow-up period. There were no significant changes in the Oswestry Index or the EuroQol-5D-5L without VAS parameters in any of the groups.Based on our results, for patients suffering from LBP pain who underwent underwater weight bath traction therapy, there were favorable impacts on the pain levels at rest or during activity. Clinical trial registration ID: NCT03488498, April 5, 2018.


Acute Torsion of Appendicular Mucocele.
We present the case of an 81-year-old man with a known appendicular mucocele who presented to the emergency department with acute abdominal pain. A CT scan showed a change in orientation of the previously seen ovoid mass with surrounding fat stranding suggesting torsion. An emergency laparotomy with appendicectomy and resection of the caecal pole was performed. We discuss the findings and histopathology.


Oxidative stress and dermal toxicity of iron oxide nanoparticles in vitro.
A number of commercially available metal/metal oxide nanoparticles (NPs) such as superparamagnetic iron oxide (SPION) are utilized by the medical field for a wide variety of applications. These NPs may able to induce dermal toxicity via their physical nature and reactive surface properties. We hypothesize that SPION may be toxic to skin via the ability of particles to be internalized and thereby initiate oxidative stress, inducing redox-sensitive transcription factors affecting/leading to inflammation. Due to the skin's susceptibility to UV radiation, it is also of importance to address the combined effect of UVB and NPs co-exposure. To test this hypothesis, the effects of dextran-coated SPION of different sizes (15-50 nm) and manufacturers (MicroMod, Rostock-Warnemunde, Germany and KTH-Royal Institute of Technology, Stockholm, Sweden) were evaluated in two cell lines: normal human epidermal keratinocytes (HEK) and murine epidermal cells (JB6 P(+)). HEK cells exposed to 20 nm (KTH and MicroMod) had a decrease in viability, while the 15 and 50 nm particles were not cytotoxic. HEK cells were also capable of internalizing the KTH particles (15 and 20 nm) but not the MicroMod SPION (20 and 50 nm). IL-8 and IL-6 were also elevated in HEK cells following exposure to SPION. Exposure of JB6 P(+) cells to all SPIONs evaluated resulted in activation of AP-1. Exposure to SPION alone was not sufficient to induce NF-κB activation; however, co-exposure with UVB resulted in significant NF-κB induction in cells exposed to 15 and 20 nm KTH SPION and 50 nm MicroMod particles. Pre-exposure of JB6 P(+) cells to UVB followed by NPs induced a significant depletion of glutathione, release of cytokines, and cell damage as assessed by release of lactate dehydrogenase. Altogether, these data indicate that co-exposure to UVB and SPIONs was associated with induction of oxidative stress and release of inflammatory mediators. These results verify the need to thoroughly evaluate the adverse effects of UVB when evaluating dermal toxicity of engineered NPs on skin.


A hypothesis concerning the relationship of cellular pharmakokinetics to optimal scheduling of anti-cancer agents.
It is well recognized that the degree of toxicity, type of toxicity, and therapeutic to toxic ratio of most anti-cancer agents are dependent upon schedule. It is postulated that an optimal schedule is one that creates the largest possible difference in uptake of drug between neoplastic and normal cells, especially those cells that by their death limit the amount of drug that can be given to the patient. Specific pharmacokinetic parameters can be determined that optimize the relative distribution of drug between neoplastic tissues and dose-limiting normal tissues, and thus may permit optimization of schedule.


Sexual orientation and neurocognitive ability: A meta-analysis in men and women.
The cross-sex-shift hypothesis predicts that homosexual men and women will be similar in certain neurobehavioral traits to their opposite-sex counterparts. Accordingly, it predicts that homosexual men should perform in the direction of heterosexual women, and homosexual women in the direction of heterosexual men, on neurocognitive tests that show normative sex differences. We conducted a meta-analysis on the relationship between sexual orientation and cognitive performance, and tested the effects of potential moderating variables separately by sex. A total of 106 samples and 254,231 participants were included. The meta-analysis revealed that homosexual men performed like heterosexual women in both male-favouring (e.g., spatial cognition) and female-favouring (e.g., verbal fluency) cognitive tests, while homosexual women performed like heterosexual men only in male-favouring tests. The magnitude of the sexual orientation difference varied across cognitive domains (larger for spatial abilities). It was also larger in studies comparing exclusive heterosexuals with exclusive homosexuals compared to studies comparing exclusive heterosexuals with non-exclusive homosexuals for both sexes. The results may narrow down potential sites for sexual orientation-related neural differences.


Astilbin prevents bone loss in ovariectomized mice through the inhibition of RANKL-induced osteoclastogenesis.
Osteoporosis is the most common osteolytic disease characterized by excessive osteoclast formation and resultant bone loss, which afflicts millions of patients around the world. Astilbin, a traditional herb, is known to have anti-inflammatory, antioxidant and antihepatic properties, but its role in osteoporosis treatment has not yet been confirmed. In our study, astilbin was found to have an inhibitory effect on the RANKL-induced formation and function of OCs in a dose-dependent manner without cytotoxicity. These effects were attributed to its ability to suppress the activity of two transcription factors (NFATc1 and c-Fos) indispensable for osteoclast formation, followed by inhibition of the expression of bone resorption-related genes and proteins (Acp5/TRAcP, CTSK, V-ATPase-d2 and integrin β3). Furthermore, we examined the underlying mechanisms and found that astilbin repressed osteoclastogenesis by blocking Ca2+ oscillations and the NF-κB and MAPK pathways. In addition, the therapeutic effect of MA on preventing bone loss in vivo was further confirmed in an ovariectomized mouse model. Therefore, considering its ability to inhibit RANKL-mediated osteoclastogenesis and the underlying mechanisms, astilbin might be a potential candidate for treating osteolytic bone diseases.


Acute effects of the number of players and scoring method on physiological, physical, and technical performance in small-sided soccer games.
This study aims to examine the effect of differences in the number of players and scoring method on heart rate responses, time-motion characteristics, and technical/tactical performance during small-sided soccer games. Ten male amateur soccer players (26.4 ± 5.3 years old, 8.4 ± 3.2 years of practice, 179.3 ± 5.2 cm body height, 71.2 ± 7.1 kg body weight, 45.8 ± 2.6 ml.kg(-1)min(-1)VO2max) from the Portuguese regional league played nine different small-sided games (i.e., 3 formats × 3 scoring methods). The study used two-way MANOVA, two-away ANOVA, and one-way ANOVA, depending on the specific procedure for the analysis. Compared with other formats, 2v2 induced significantly greater values of technical/tactical indexes (p = 0.001), 3v3 induced significantly higher %HRreserve values (p = 0.001), and 4v4 led to significantly greater distance coverage and speed (p = 0.001). The study provided evidence for coaches to set different small-sided game conditions depending on the training purpose in terms of physiological, physical, and technical performance.


Bioabsorbable polyphosphazene matrices as systems for calcitonin controlled release.
To provide a suitable delivery system for the calcitonin controlled release 80 mg bioabsorbable polyphosphazene matrices were obtained with entrapped 50 or 250 micrograms calcitonin. The in vitro behaviour demonstrated a release burst for about 24 hours, followed by a period of slow release of the peptide lasting for weeks. Matrices containing 250 micrograms calcitonin were implanted under general anaesthesia in osteoporotic female rats, while a group of animals (control group) received unloaded matrices. After thirty days a second batch of matrices was implanted in both groups to prolong the period of treatment until two months. The explanted matrices were histologically evaluated together with the surrounding tissues, and the dosage of the residual calcitonin was also performed. Results demonstrated the good biocompatibility of the system and the complete release of the calcitonin from the matrices 30 days after implantation. The therapeutic effect, after sixty days of treatment was confirmed by the better densitometric values observed in the femoral bone of treated animals than in controls.


Development and preparation of a new serum protein reference material: feasibility studies and processing.
The availability of matrix reference materials is essential for the standardisation of (immuno)assays used to measure proteins. The reference material ERM-DA470 (previously called CRM470) certified in 1993 has led to a large degree of harmonisation of these assays. A new serum protein reference material has now been produced (ERM-DA470k). It is intended to replace ERM-DA470, and will additionally be certified for beta(2)-microglobulin (B2M). Serum from 390 healthy donors was pooled and processed so as to stabilise, delipidate and 'maturate' it. Purified C-reactive protein (CRP) and recombinant B2M were added. Pilot batches were produced to study the stability, homogeneity, and commutability of the material. On the basis of the results with the trial batches it was decided to proceed with the processing of the main batch of a candidate reference material. Two pilot batches were produced and the processed and spiked serum lyophilised after filling (1 mL). The B2M in the material was shown to be stable and commutable. For CRP, it was discovered that freeze-drying led to a decrease in measurable protein. The main batch of candidate reference material was produced and fulfilled the required criteria in terms of optical transparency, homogeneity and stability. A new serum protein reference material has been produced with the properties required for a serum protein reference material for 14 proteins. An apparent loss of CRP of approximately 20% was observed upon freeze-drying of the material.


Regulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS.
Microglial cells, the resident macrophages of the central nervous system (CNS), exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell-damaging factors, they get transformed into an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species, and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia have a number of important physiological functions in the CNS; for example, they shield small disruptions of the blood-brain barrier by their processes, dynamically interact with synaptic structures, and clear surplus synapses during development. In neurodegenerative illnesses, they aggravate the original disease by a microglia-based compulsory neuroinflammatory reaction. Therefore, the blockade of this reaction improves the outcome of Alzheimer's Disease, Parkinson's Disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. The function of microglia is regulated by a whole array of purinergic receptors classified as P2Y12, P2Y6, P2Y4, P2X4, P2X7, A2A, and A3, as targets of endogenous ATP, ADP, or adenosine. ATP is sequentially degraded by the ecto-nucleotidases and 5'-nucleotidase enzymes to the almost inactive inosine as an end product. The appropriate selective agonists/antagonists for purinergic receptors as well as the respective enzyme inhibitors may profoundly interfere with microglial functions and reconstitute the homeostasis of the CNS disturbed by neuroinflammation.


Potentiation of the primary humoral immune response in vitro by C5a anaphylatoxin.
The effect of the anaphylatoxin C5a on the primary humoral immune response to SRBC was studied in culture of spleen cells from C3H mice. The addition of human C5a to antigen-stimulated cultures resulted in a significant, dose-dependent augmentation of the primary PFC response to antigen. The specificity of this effect was affirmed by the ability of C5ades Arg, but not of the structurally analogous C3a anaphylatoxin, to act in a parallel fashion. Enhancement could be observed over a range of doses of antigen. Brief preincubation of macrophages, but not of lymphoid cells, with C5a was sufficient to cause subsequent enhancement of the primary humoral immune responses. The duration of preincubation required for this effect closely paralleled that for binding of C5a to peritoneal cells. Immunopotentiation by C5a appears to involve the function of C5a receptor-bearing, Ia- accessory cells as well as Ia+ antigen-presenting cells. Immunopotentiation could be observed when the addition of C5a was delayed for up to 24 hr after initiation of culture. Additionally, augmentation of tritiated thymidine uptake in mixed lymphocyte reactions was enhanced by the addition of C5a in a fashion parallel to that for the primary response to SRBC. These observations support a role for C5a as a modulator of cellular immunity in addition to its role in acute inflammation. Possible cellular mechanisms and implications for immunomodulation of immune responses are discussed.


Improving the Survival Time of Multiagents in Social Dilemmas through Neurotransmitter-Based Deep Q-Learning Model of Emotions.
In multiagent systems, social dilemmas often arise whenever there is a competition over the limited resources. The major challenge is to establish cooperation among intelligent virtual agents for solving the situations of social dilemmas. In humans, personality and emotions are the primary factors that lead them toward a cooperative environment. To make agents cooperate, they have to become more like humans, that is, believable. Therefore, we hypothesize that emotions according to the personality give birth to believability, and if believability is introduced into agents through emotions, it improves their survival rate in social dilemma situations. The existing researches have introduced different computational models to introduce emotions in virtual agents, but they lack emotions through neurotransmitters. We have proposed a neurotransmitters-based deep Q-learning computational model in multiagents that is a suitable choice for emotion modeling and, hence, believability. The proposed model regulates the agents' emotions by controlling the virtual neurotransmitters (dopamine and oxytocin) according to the agent's personality. The personality of the agent is introduced using OCEAN model. To evaluate the proposed system, we simulated a survival scenario with limited food resources in different experiments. These experiments vary the number of selfish agents (higher neuroticism personality trait) and the selfless agents (higher agreeableness personality trait). Experimental results show that by adding the selfless agents in the scenario, the agents develop cooperation, and their collective survival time increases. Thus, to resolve the social dilemma problems in virtual agents, we can make agents believable through the proposed neurotransmitter-based emotional model. This proposed work may help in developing nonplayer characters (NPCs) in games.


Hsa_circ_0031608: A Potential Modulator of VSMC Phenotype in the Rupture of Intracranial Aneurysms.
Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays an important role in the development of intracranial aneurysms (IAs). Growing evidence has demonstrated that circular RNAs (circRNAs) may serve as a potential modulator of VSMC phenotype in various vascular diseases. This study aimed to assess the potential function of circRNAs in the rupture of IAs and VSMC phenotypic modulation. Using surgically dissected human ruptured (n = 8) and unruptured (n = 8) IA lesions, differentially expressed circRNAs were screened by transcriptomic sequencing and verified using qRT-PCR. Based on the screened circRNA, we predicted and screened the combined miRNA and downstream mRNAs to construct circRNA-miRNA-mRNA networks. Further in vitro experiments were performed to investigate the relationship between the validated circRNA and the phenotypic switching of VSMCs. We found 1,373 differentially expressed genes in ruptured versus unruptured aneurysms. The top five dysregulated circRNAs were selected for qRT-PCR validation. We found hsa_circ_0031608 was both highly expressed in ruptured IAs and pro-inflammatory transformation of VSMCs. Then, a regulatory circRNA-miRNA-mRNA with one circRNA node, six miRNA nodes, and 84 mRNA nodes was constructed. GO analysis and KEGG pathway enrichment analysis were performed on mRNAs in the network. Then, a PPI network was built based on these mRNAs and five hub genes were identified (FOXO3, DICER1, CCND2, IGF1R, and TNRC6B) by the cytoHubba plugin in Cytoscape software. In vitro, overexpression of hsa_circ_0031608 influenced the expression of VSMC phenotypic markers validated by qPCR and Western blotting. Furthermore, hsa_circ_0031608 promoted the migration and proliferation capacity of VSMCs. hsa_circ_0031608 regulated the phenotypic modulation of VSMCs and played an important role in the rupture of IAs. The specific mechanism should be further studied and confirmed.


A Systematic Review of Endovascular Repair Outcomes in Atherosclerotic Chronic Mesenteric Ischaemia.
Chronic mesenteric ischaemia (CMI) treatment focuses on symptom relief and prevention of disease progression. Endovascular repair represents the main treatment modality, while data on the associated antiplatelet regimen are scarce. The aim of this meta-analysis was to assess the early and midterm outcomes of endovascular repair in patients with CMI. Randomised controlled trials and observational studies (1990 - 2022) reporting on early and midterm endovascular repair outcomes in patients with atherosclerotic CMI. The PRISMA guidelines and PICO model were followed. The protocol was registered to PROSPERO (CRD42023401685). Medline, Embase (via Ovid), and Cochrane databases were searched (end date 21 February 2023). The Newcastle-Ottawa Scale was used for risk of bias assessment, and GRADE for evidence quality assessment. Primary outcomes were technical success, 30 day mortality, and symptom relief, assessed using prevalence meta-analysis. The role of dual antiplatelet therapy (DAPT) was investigated using meta-regression analysis. Sixteen retrospective studies (1 224 patients; mean age 69.8 ± 10.6 years; 60.3% female) reporting on 1 368 target vessels (57.8% superior mesenteric arteries) were included. Technical success was 95.0% (95% CI 93 - 97%, p = .28, I2 19%, low certainty), the 30 day mortality rate was 2.0% (95% CI 2 - 4%, p = .93, I2 36%, low certainty), and immediate symptom relief was 87.0% (95% CI 80 - 92%, p < .010, I2 85%, very low certainty). At mean follow up of 28 months, the mortality rate was 15.0% (95% CI 9 - 25%, p = .010, I2 86%, very low certainty), symptom recurrence 25.0% (95% CI 21 - 31%, p < .010, I2 68%, very low certainty) and re-intervention rate 26.0% (95% CI 17 - 37%, p < .010, I2 92%, very low certainty). Single antiplatelet therapy (SAPT) and DAPT performed similarly in the investigated outcomes. Endovascular repair for CMI appears to be safe as first line treatment, with a low peri-operative mortality rate and acceptable immediate symptom relief. During midterm follow up, symptom recurrence and need for re-intervention are not uncommon. SAPT appears to be equal to DAPT in post-operative outcomes.


Two young Somalians with gastric outlet obstruction as a first manifestation of gastroduodenal tuberculosis.
Gastroduodenal tuberculosis (GDTB) is an uncommon condition which can mimic other gastrointestinal disorders. It usually occurs secondary to pulmonary tuberculosis. We describe two young Somalian patients who presented with abdominal pain and gastric outlet obstruction. GDTB was diagnosed in both patients and they were successfully treated with antituberculous drugs.


Evaluation of oral-motor movements and speech in patients with tetanus of a public service in Brazil.
The characterisation of oral-motor movements and speech of patients with tetanus were investigated to determine the existence of possible signs that are characteristic of this pathology. Thirteen patients clinically diagnosed with tetanus (10 with severe tetanus and three with very severe tetanus) and admitted to an intensive care unit underwent clinical evaluation of oral-motor movements and speech. Statistical analysis indicated significant between-group differences for speech motor functions, suggesting that individuals with very severe tetanus present rigidity as a characteristic interfering in articulatory precision (P = 0·035) and movement rate (P = 0·038). For lip closure, tongue movement, palatal elevation, gag reflex and voice quality, no between-group differences were identified for the specific abnormal characteristics. The observed abnormal results indicate that muscle strength and functional status of the oral-motor system presented by most of the participants of the study did not ensure the necessary integrity for satisfactory performance. The characterisation of the oral myofunctional aspects of patients with tetanus provides medical teams, patients and families with a wider and better description of the clinical situation, giving support to the diagnosis, prognostics and treatment.


Evolution of care during pregnancy and childbirth in the extreme south of Brazil.
To describe the evolution of care during pregnancy and childbirth among postpartum women living in the municipality of Rio Grande, Southern Brazil, using data from surveys carried out every three years between 2007 and 2019. Within 48 hours after delivery, a single, standardized questionnaire was applied to all mothers who had children in local hospitals and met the inclusion criteria. Demographic and reproductive characteristics, lifestyle habits, socioeconomic level of the family, and care received during pregnancy and childbirth were investigated. In the analysis, the chi-square test for linear trend was used to assess the distribution of indicators per survey. A total of 12,645 parturients were interviewed (98% of the women eligible to participate in the surveys). In the period evaluated, the proportion of births fell 35% among adolescents and increased 25% among women aged 35 years and over. Mothers gained, on average, two years of schooling, and their families experienced an important economic improvement, followed by loss of income in the last survey. Maternal smoking, before and during pregnancy, fell by half. The rate of mothers who started prenatal care in the first trimester and the number of consultations and laboratory tests increased. Almost 60% of prenatal consultations and 80% of births took place in the Brazilian Unified Health System. In 2019, vaginal delivery was once again the most common. The rates of low birth weight (9%) and prematurity (17%) virtually remained unchanged. We found an important change in the reproductive profile and increased coverage of various prenatal care and delivery services. Children continue to be born well, but low birth weight and prematurity remain endemic.


Depletion of β-arrestin-1 in macrophages enhances atherosclerosis in ApoE-/- mice.
Autophagy in atherosclerotic plaque macrophage contributes to the alleviation of atherosclerosis through the promotion of lipid metabolism. β-arrestins are multifunctional proteins participating various kinds of cellular signaling pathways. Here we aimed to determine the role of β-arrestin-1, an important member of β-arrestin family, in atherosclerosis, and whether autophagy was involved in this process. ApoE-/-β-arrestin-1fl/flLysM-Cre mice were created through bone marrow transplantation for the atherosclerosis model with conditional myeloid knocking out β-arrestin-1. Bone marrow-derived macrophages (BMDMs) were used for the in vitro studies. Oil red O staining was used to detect the lesional area. F4/80, Masson trichrome and picro-Sirius red staining were applied for the determination of plaque stability. Real-time PCR was used for the detection of levels of lipid metabolism-related receptors. Electron microscopy and tandem fluorescent mRFP-GFP-LC3 plasmid was applied to test autophagy level. We found that β-arrestin-1 was highly increased in expression in plaque macrophage on the occurrence of atherosclerosis. Conditional myeloid knocking out β-arrestin-1 largely promotes plaque formation and vulnerability. In murine macrophage with lipid loading, knocking down β-arrestin-1 enhanced foam cell formation and levels of plasma and cellular cholesterol, while overexpressing β-arrestin-1 led to the opposite effects. The alleviative effects induced by macrophage β-arrestin-1 in atherosclerosis were involved in autophagy, based on the reduction of autophagy level with the knocking down of macrophage β-arrestin-1 and administration of autophagy inhibitors which largely attenuated the decreasing effect on foam cell formation. Our results demonstrated for the first time that macrophage β-arrestin-1 protected against atherosclerosis through the induction of autophagy.


Post-Translational Modifications of Proteins: Novel Insights in the Autoimmune Response in Rheumatoid Arthritis.
Post-translational modifications (PTM) are chemical changes mostly catalyzed by enzymes that recognize specific target sequences in specific proteins. These modifications play a key role in regulating the folding of proteins, their targeting to specific subcellular compartments, their interaction with ligands or other proteins, and eventually their immunogenic properties. Citrullination is the best characterized PTM in the field of rheumatology, with antibodies anticyclic citrullinated peptides being the gold standard for the diagnosis of rheumatoid arthritis (RA). In recent years, growing evidence supports not only that a wide range of proteins are subject to citrullination and can trigger an autoimmune response in RA, but also that several other PTMs such as carbamylation and acetylation occur in patients with this disease. This induces a wide spectrum of autoantibodies, as biomarkers, with different sensitivity and specificity for diagnosis, which may be linked to peculiar clinical manifestations and/or response to treatment. The purpose of this review article is to critically summarize the available literature on antibodies against post-translationally modified proteins, in particular antibodies against citrullinated proteins (ACPA) and antibodies against modified proteins (AMPA), and outline their diagnostic and prognostic role to be implemented in clinical practice for RA patients.


[Hereditary hypokaliaemic periodic paralysis in a 13-year-old boy].
Hypokaliaemic periodic paralysis is a rare hereditary neuro-muscular disease caused by an error in the ion-canals in muscle cells resulting in decreased excitabiliy. It presents itself in the late childhood or teenage years with a periodic paralysis without involving respiratory and heart muscles. Our patient was a 13-year-old boy, who woke up with decreased strength in arms and legs after excessive physical activity and a high carbo-hydrate intake. Tests showed a low P-potassium level. The patient had full remission of his symptoms within 24 hours.


Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease.
The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population. 906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case-control analysis and detailed genotype-phenotype analysis were performed. The Leu1007finsC variant was associated with susceptibility to CD by case-control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5-14.7]). These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.


Total lymphocyte count and hemoglobin combined to predict CD4 lymphocyte counts of less than 200 cells/mm(3) in HIV/AIDS.
to obtain the sensitivity and specificity of combining total lymphocyte count and hemoglobin to predict the CD4 lymphocyte count below 200 cells/m3. this is a cross sectional study. Subject characteristics were patient with HIV/AIDS who have not been initiated ARV therapy, the age above 15 years, have a CD4 lymphocyte count data. A total of 72 patients were recruited from clinic of Edelweis or hospitalized patients at Dr. Sardjito Hospital Yogyakarta in March 2002 - March 2007. Independent t test and Mann-Whitney test was used to find out the differences of continue variable. P < or = 0.05 was considered significant. a total of 72 patients were studied. Of these,50 patients (69.4%) were male, 22 patients (30.6%) were female. 53 patients with CD4 below 200 cells/mm3 and 19 patients with CD4 above 200 cells/mm3. Mean of TLCin HIV/AIDS patients with CD4 below 200 cells/mm3 were: 1013.24+/- 96.06 and CD4 above 200 cells/mm3 were 2161.36 +/- 214.66. Mean of Hb in HIV/AIDS patients with CD4 below 200 cells/mm3 were: 11.61+/- 0.30 and CD4 above 200 cells/mm3 were 12.47 +/- 0.59.Sensitivity of combined TLC+Hb man (algorithms a,b) were 80.95%, 88.09% Vs TLC 66.66%; Sensitivity of combined TLC+Hb woman (algorithms a, b) were 54.54%,54.54% Vs TLC 54.54%; Specificity of combined TLC+Hbman (algorithms a, b) were 87.50%, 87.50% Vs TLC 87.50%; Specificity of combined TLC+Hb woman (algorithms a, b)were 63.63%, 54.54% Vs TLC 90.90%. adding hemoglobin to TLC (algorithms aand b in man) increased sensitivity, there by reducing the risk of false-negative results.


BAK1 plays contrasting roles in regulating abscisic acid-induced stomatal closure and abscisic acid-inhibited primary root growth in Arabidopsis.
The mechanisms that balance plant growth and stress responses are poorly understood, but they appear to involve abscisic acid (ABA) signaling mediated by protein kinases. Here, to explore these mechanisms, we examined the responses of Arabidopsis thaliana protein kinase mutants to ABA treatment. We found that mutants of BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1 (BAK1) were hypersensitive to the effects of ABA on both seed germination and primary root growth. The kinase OPEN STOMATA 1 (OST1) was more highly activated by ABA in bak1 mutant than the wild type. BAK1 was not activated by ABA treatment in the dominant negative mutant abi1-1 or the pyr1 pyl4 pyl5 pyl8 quadruple mutant, but it was more highly activated by this treatment in the abi1-2 abi2-2 hab1-1 loss-of-function triple mutant than the wild type. BAK1 phosphorylates OST1 T146 and inhibits its activity. Genetic analyses suggested that BAK1 acts at or upstream of core components in the ABA signaling pathway, including PYLs, PP2Cs, and SnRK2s, during seed germination and primary root growth. Although the upstream brassinosteroid (BR) signaling components BAK1 and BR INSENSITIVE 1 (BRI1) positively regulate ABA-induced stomatal closure, mutations affecting downstream components of BR signaling, including BRASSINOSTEROID-SIGNALING KINASEs (BSKs) and BRASSINOSTEROID-INSENSITIVE 2 (BIN2), did not affect ABA-mediated stomatal movement. Thus, our study uncovered an important role of BAK1 in negatively regulating ABA signaling during seed germination and primary root growth, but positively modulating ABA-induced stomatal closure, thus optimizing the plant growth under drought stress.


Evaluation of antidepressant-like activity of aqueous and ethanolic extracts of Terminalia bellirica Roxb. fruits in mice.
The present study was undertaken to investigate the effect of aqueous and ethanolic extracts of T. bellirica on depression in mice using forced swim test (FST) and tail suspension test (TST). The extracts were administered orally for 10 successive days in separate groups of Swiss young male albino mice. Aqueous extract (50, 100 and 200 mg/kg) in a dose-dependent manner and ethanolic extract (100 mg/kg) significantly reduced the immobility time of mice in both FST and TST. The extracts were without any significant effect on locomotor activity of mice. The efficacies of aqueous extract (200 mg/kg) and ethanolic extract (100 mg/kg) were found to be similar to that of imipramine (15 mg/kg, po) and fluoxetine (20 mg/kg, po) administered for 10 successive days. Both extracts reversed reserpine-induced extension of immobility period of mice in FST and TST. Prazosin (62.5 microg/kg, ip; an alpha1-adrenoceptor antagonist), sulpiride (50 mg/kg, ip; a selective D2 receptor antagonist) and p-chlorophenylalanine (100 mg/kg, ip; an inhibitor of serotonin synthesis) significantly attenuated the aqueous and ethanolic extract-induced antidepressant-like effect in TST. Thus, both the aqueous and ethanolic extracts of T. bellirica elicited a significant antidepressant-like effect in mice by interaction with adrenergic, dopaminergic and serotonergic systems.


Ventral Tegmental Area GABA Neurons Are Resistant to GABA(A) Receptor-Mediated Inhibition During Ethanol Withdrawal.
The neural mechanisms underlying alcohol dependence are not well-understood. GABAergic neurons in the ventral tegmental area (VTA) are a relevant target for ethanol. They are inhibited by ethanol at physiologically-relevant levels in vivo and display marked hyperexcitability during withdrawal. In the present study, we examined the effects of the GABA(A) receptor agonist muscimol on VTA neurons ex vivo following withdrawal from acute and chronic ethanol exposure. We used standard cell-attached mode electrophysiology in the slice preparation to evaluate the effects of muscimol on VTA GABA neuron firing rate following exposure to acute and chronic ethanol in male CD-1 GAD-67 GFP mice. In the acute condition, the effect of muscimol on VTA neurons was evaluated 24 h and 7 days after a single in vivo dose of saline or ethanol. In the chronic condition, the effect of muscimol on VTA neurons was evaluated 24 h and 7 days after either 2 weeks of twice-daily IP ethanol or saline or following exposure to chronic intermittent ethanol (CIE) vapor or air for 3 weeks. VTA GABA neuron firing rate was more sensitive to muscimol than DA neuron firing rate. VTA GABA neurons, but not DA neurons, were resistant to the inhibitory effects of muscimol recorded 24 h after a single ethanol injection or chronic ethanol exposure. Administration of the NMDA receptor antagonist MK-801 before ethanol injection restored the sensitivity of VTA GABA neurons to muscimol inhibition. Seven days after ethanol exposure, VTA GABA neuron firing rate was again susceptible to muscimol's inhibitory effects in the acute condition, but the resistance persisted in the chronic condition. These findings suggest that VTA GABA neurons exclusively undergo a shift in GABA(A) receptor function following acute and chronic exposure. There appears to be transient GABA(A) receptor-mediated plasticity after a single exposure to ethanol that is mediated by NMDA glutamate receptors. In addition, the resistance to muscimol inhibition in VTA GABA neurons persists in the dependent condition, which may contribute to the the hyperexcitability of VTA GABA neurons and inhibition of VTA DA neurons during withdrawal as well as the motivation to seek alcohol.


Subglottic secretion viscosity and evacuation efficiency.
Ventilator-associated pneumonia (VAP) is a common nosocomial pneumonia that occurs in critically ill patients and results in mortality rates as high as 71%. Subglottic secretions (SSs) are a known risk factor. Several clinical trials have shown that continuous aspiration of subglottic secretions (CASS) reduces the risk of VAP by nearly half. Optimal suction pressure levels needed to efficiently evacuate viscous SSs are unknown. The purpose of this study was to describe SSs and the effective suction pressure (20 mmHg, 30 mmHg, 40 mmHg, and 50 mmHg) needed to maximize evacuation efficiency based on SS volume (2 ml, 4 ml, and 6 ml) and viscosity (watery, thick, and gel-like). A laboratory model was designed to replicate a human trachea. Thick secretions had the highest percentage of mean recovery representative of evacuation efficiency of SSs (mean recovery of 86%). The suction pressure of 30 mmHg had the highest overall mean of secretion recovery (83%) across all viscosity types and amounts. This study demonstrated that higher viscosity secretions were easier to evacuate than lower viscosity secretions when 30-mmHg suction pressure was applied. Management of secretion viscosity may assist in secretion removal and delay VAP development. With increased understanding of the molecular structure of SSs, there is the potential that clinicians will be able to manipulate secretion viscoelastic properties to maximize evacuation efficiency of the secretions. Further research is needed to identify safe suction pressures for optimal evacuation of SSs in human subjects.


Outcome prediction after penetrating craniocerebral injury in a civilian population: aggressive surgical management in patients with admission Glasgow Coma Scale scores of 3, 4, or 5.
In an attempt to evaluate the response of patients who have low admission Glasgow Coma Scale scores (GCS) after a penetrating craniocerebral injury to aggressive management, we evaluated a series of 190 patients with penetrating injuries who presented with a GCS score of 3, 4, or 5 during a 6-year period. Entrance criteria required replicable neurological examinations that were not altered by the presence of hypotension, drugs/toxins, or systemic injury. The surgical patients included 21 patients with an admission GCS score of 3, 24 with an admission GCS score of 4, and 15 with an admission GCS score of 5. All patients underwent surgical intervention and aggressive perioperative management in the neurosurgical intensive care, including resuscitative protocols. Five of the patients with a GCS score of 3 survived, all with poor outcomes. Seven of the patients with a GCS score of 4 survived, although only one had a good outcome. Eleven of the patients with a GCS score of 5 survived. Five had a Glasgow Outcome Score of 2, five had a Glasgow Outcome Score of 3, and one had a Glasgow Outcome Score of 4. We have devised a prospective model of outcome based on our series in an attempt to predict nonsurvivors at admission (while overpredicting for survivors). The variables most predictive of mortality include admission GCS score and subarachnoid hemorrhage in one model and admission GCS score and pupillary changes in a second, when pupillary response was definitive at admission (P < or = 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)


mmnet: An R Package for Metagenomics Systems Biology Analysis.
The human microbiome plays important roles in human health and disease. Previous microbiome studies focused mainly on single pure species function and overlooked the interactions in the complex communities on system-level. A metagenomic approach introduced recently integrates metagenomic data with community-level metabolic network modeling, but no comprehensive tool was available for such kind of approaches. To facilitate these kinds of studies, we developed an R package, mmnet, to implement community-level metabolic network reconstruction. The package also implements a set of functions for automatic analysis pipeline construction including functional annotation of metagenomic reads, abundance estimation of enzymatic genes, community-level metabolic network reconstruction, and integrated network analysis. The result can be represented in an intuitive way and sent to Cytoscape for further exploration. The package has substantial potentials in metagenomic studies that focus on identifying system-level variations of human microbiome associated with disease.


Cloning of a novel Apaf-1-interacting protein: a potent suppressor of apoptosis and ischemic neuronal cell death.
Cytochrome c-initiated activation of apoptotic protease activating factor-1 (Apaf-1) is a key step in the mitochondrial-signaling pathway for the activation of death-executing caspases in apoptosis. This signaling pathway has been implicated in the pathophysiology of various neurological disorders, including ischemic brain injury. In this study, we have cloned a novel rat gene product, designated as Apaf-1-interacting protein (AIP), which functions as a dominant-negative inhibitor of the Apaf-1-caspase-9 pathway. AIP is constitutively expressed in the brain, but at substantially lower levels than Apaf-1 and caspase-9. AIP can directly bind to Apaf-1 in vitro through its N-terminal caspase-recruiting domain, and this protein interaction was increased in cells undergoing apoptosis. Cytosolic extracts from cells overexpressing AIP were highly resistant to cytochrome c- dATP-induced activation of caspase-9 and caspase-3. Gene transfection of AIP into cell lines, including the neuronal-differentiated PC12 cells, potently suppressed apoptosis induced by various pro-apoptotic stimuli. To further investigate the functional role of AIP in primary neurons and in the brain, an adeno-associated virus (AAV) vector carrying the AIP cDNA was constructed. AAV-mediated overexpression of AIP in primary cortical- hippocampal neurons markedly reduced cell death and caspase-3 activation triggered by protein kinase C inhibition, DNA damage, or oxygen- glucose deprivation. Moreover, intracerebral infusion of the AAV vector resulted in robust AIP expression in the hippocampus and significantly promoted CA1 neuronal survival after transient global cerebral ischemia. These results suggest that molecular targeting of the Apaf-1-caspase-9 signaling pathway may be a feasible neuroprotective strategy to enhance the endogenous threshold for caspase activation and prevent neuronal loss in stroke and related disorders.


Pharmacogenomics and tailored polypharmacy: an 80-year-old lady with rosuvastatin-associated rhabdomyolysis and maprotiline-related Ogilvie's syndrome .
What is known and objectives: Multiple adverse drug reactions (ADRs) are expected, and thus should be prevented in the elderly comorbid patient on polypharmacy. Rosuvastatin is commonly prescribed for the treatment and prevention of atherosclerotic diseases, and in rare cases, is associated with rhabdomyolysis. Maprotiline is a tetracyclic antidepressant, infrequently used in the United States, but seemingly more broadly in European countries. Acute colonic pseudo-obstruction (Ogilvie's syndrome) caused by maprotiline has thus far, to our knowledge, not yet been described in the literature. We present a unique case of synchronous rhabdomyolysis and Ogilvie's syndrome in an 80-year-old lung cancer survivor following a recent ischemic stroke for which she was prescribed clopidogrel and rosuvastatin for secondary prevention, and maprotiline for post-stroke, new-onset insomnia and anxiety. The ADRs resolved on removal of the offending agents and initiation of conservative treatment. Retrospective pharmacogenetic testing of the patient's drug-metabolizing enzymes and transporters was performed to guide further management and prevent future potential drug interactions and ADRs. What is novel and conclusions: This is an interesting, albeit unfortunate, complex case that depicts the risk of rare adverse effects to medications and their potential relationship to pharmacogenetics. The impact of anticholinergic side effects of antidepressants on gastrointestinal motility, risk of myopathies with statins, increased susceptibility to ADRs caused by drug-drug interactions, and the utility of pharmacogenomic testing are discussed. The question whether commercially available pharmacogenomic tools are relevant for everyday use to direct patient care and reduce harmful drug-drug interactions is addressed and warrants further research. .


[Congenital jejunoileal and colonic atresia].
Jejunoileal and colonic atresias are a common cause of neonatal intestinal obstruction. Authors present the aetiology, types of atresias, clinical symptoms, diagnostics, surgical treatment, problems of postoperative management and prognosis in the newborns with congenital intestinal atresia. In the years 1992-2000, in the Department of Paediatric Surgery and in the Department of Pathology and Intensive Care of Newborn at the National Research Institute of Mother and Child in Warsaw, 539 newborns were surgically treated (congenital anomalies of gastrointestinal tract, genito-urinary system, central nervous system, defects of abdominal wall and diaphragm). In 21 patients jejunoileal or colonic atresia were confirmed. On the base of the course of treatment the authors analyse prognostic factors: prematurity, certain types of atresia, additional pathology accompanying intestinal defect, necessesity of re-section of the long part of the bowel or multiple anastomosis. Diagnostic and treatment problems in three patients with short bowel syndrome needed additional discussion.


Contribution of Histopathologic Tissue Composition to Quantitative MR Spectroscopy and Diffusion-weighted Imaging of the Prostate.
To determine associations of metabolite levels derived from magnetic resonance (MR) spectroscopic imaging (ie, hydrogen 1 [(1)H] MR spectroscopic imaging) and apparent diffusion coefficients (ADCs) from diffusion-weighted imaging with prostate tissue composition assessed by digital image analysis of histologic sections. Institutional ethical review board approved this retrospective study and waived informed consent. Fifty-seven prostate cancer patients underwent an MR examination followed by prostatectomy. One hematoxylin and eosin-stained section of the resected prostate per patient was digitized and computationally segmented into nuclei, lumen, and combination of epithelial cytoplasm and stroma. On each stained section, regions of interest (ROIs) were chosen and matched to the corresponding ADC map and (1)H MR spectroscopic imaging voxels. ADC and two metabolite ratios (citrate [Cit], spermine [Spm], and creatine [Cr] to choline [Cho] and Cho to Cr plus Spm) were correlated with percentage areas of nuclei, lumen, and cytoplasm and stroma for peripheral zone (PZ), transition zone (TZ), and tumor tissue in both zones of the prostate by using a linear mixed-effect model and Spearman correlation coefficient (ρ). ADC and (Cit + Spm + Cr)/Cho ratio showed positive correlation with percentage area of lumen (ρ = 0.43 and 0.50, respectively) and negative correlation with percentage area of nuclei (ρ = -0.29 and -0.26, respectively). The Cho/(Cr + Spm) ratio showed negative association with percentage area of lumen (ρ = -0.40) and positive association with area of nuclei (ρ = 0.26). Percentage areas of lumen and nuclei, (Cit + Spm + Cr)/Cho ratio, and ADC were significantly different (P < .001) between benign PZ (23.7 and 7.7, 8.83, and 1.58 × 10(-3) mm(2)/sec, respectively) and tumor PZ tissue (11.4 and 12.5, 5.13, and 1.20 × 10(-3) mm(2)/sec, respectively). These parameters were also significantly different between benign TZ (20.0 and 8.2, 6.50, and 1.26 × 10(-3) mm(2)/sec, respectively) and tumor TZ tissue (9.8 and 11.2, 4.36, and 1.03 × 10(-3) mm(2)/sec, respectively). The observed correlation of (Cit + Spm + Cr)/Cho ratio and ADC of the prostate with its tissue composition indicates that components of this composition, such as percentage luminal area, contribute to the value of these MR parameters.


[Clinical analysis of pregnancy in second and third trimesters complicated severe acute respiratory syndrome].
To explore and analyze the clinical manifestation, diagnosis, management and maternal-perinatal prognosis of severe acute respiratory syndrome (SARS)-complicated pregnancy in second and third trimesters. Clinical data of 5 inpatients with SARS-complicated pregnancy in second and third trimesters from 4(th) February to 17(th) March 2003 were analyzed retrospectively. Five patients were all primigravida (including 2 twins). Two were infected in second trimester while the other 3 in third trimester with 2 hospital-acquired infections and 3 community-acquired infections. All patients had fever (5/5), 3 chills or rigor, 4 cough; 2 with decreased lymphocyte, 2 decreased platelet, 3 elevated alanine aminotransferase (ALT), 4 hypoalbuminemia, 5 abnormal chest radiographs. All 5 patients were cured with 1 requiring intensive care. 5 neonates including 1 twins have been followed up without evidence of SARS infections up to now. In a twin-pregnancy 1 fetus was lost while the pregnant's situation is stable. Common diagnostic criteria were Suitable for SARS-complicated pregnancy in second and third trimesters, but attention should be paid to the interaction between SARS and special pathological changes during pregnancy. Patients should be isolated and monitored intensively with timely cesarean section in severe cases, which could significantly decrease the maternal-perinatal mortality. The use of corticosteroids and psychological supports need further study.


Formation of Environmentally Persistent Free Radicals on Microplastics under Light Irradiation.
Microplastics (MPs) are presumed to be inert during aging under ambient conditions. In this study, four types of virgin MPs, including polystyrene (PS), phenol-formaldehyde resin (PF), polyethylene (PE), and polyvinyl chloride (PVC), were aged under simulated solar light irradiation. Surprisingly, several environmentally persistent free radicals (EPFRs), which are considered to be a type of emerging contaminant, were detected on the irradiated PS and PF, rather than PE and PVC, by electron paramagnetic resonance (EPR) spectroscopy. Depending on the photoaging duration time, the characteristic g-factors of the EPFRs produced on PS and PF were 2.0044-2.0049 and 2.0043-2.0044, respectively. The generated EPFRs on PS and PF decayed rapidly at the initial stage and then slowly disappeared with the elapsed aging time. Analyses by attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), nuclear magnetic resonance (NMR), and gel permeation chromatography (GPC) suggested that MPs might experience chemical chain scission, O2/H2O addition, and EPFR formation under the light irradiation. Accompanying with the formation of EPFRs, reactive oxygen species, such as O2•- and •OH, were also observed. The findings provide a novel insight to evaluate the potential hazards of MPs to organisms and ecosystems.


A maternal diet high in saturated fat impairs offspring hippocampal function in a sex-specific manner.
While a maternal diet high in saturated fat is likely to affect foetal brain development, whether the effects are the same for male and female offspring is unclear. As a result, we randomly assigned female, Sprague-Dawley rats to either a control, or high-fat diet (HFD; 45% of calories from saturated fat) for 10 weeks. A range of biometrics were collected, and hippocampal function was assessed at both the tissue level (by measuring synaptic plasticity) and at the behavioural level (using the Morris water maze; MWM). Subsequently, a subset of animals was bred and remained on their respective diets throughout gestation and lactation. On post-natal day 21, offspring were weaned and placed onto the control diet; biometrics and spatial learning and memory were then assessed at both adolescence and young adulthood. Although the HFD led to changes in the maternal generation consistent with an obese phenotype, no impairments were noted at the level of hippocampal synaptic plasticity, or MWM performance. Unexpectedly, among the offspring, a sexually dimorphic effect upon MWM performance became apparent. In particular, adolescent male offspring displayed a greater latency to reach the platform during training trials and spent less time in the target quadrant during the probe test; notably, when re-examined during young adulthood, the performance deficit was no longer present. Overall, our work suggests the existence of sexual dimorphism with regard to how a maternal HFD affects hippocampal-dependent function in the offspring brain.


Penetrating Keratoplasty at a Tertiary Referral Center in Ethiopia: Indications and Outcomes.
To describe the indications, visual acuity outcomes, and graft survival after penetrating keratoplasty (PKP) in Addis Ababa, Ethiopia. The medical records of patients who underwent PKP at Menelik II Hospital between September 2000 and September 2013 were retrospectively reviewed. The prespecified outcomes were graft survival, visual acuity, and complication rates. A total of 321 patients underwent PKP during the study period and were included in the analysis. Indications for surgery were trachoma or leukoma in 141 (44%), keratoconus in 45 (14%), corneal dystrophy in 46 (14%), pseudophakic or aphakic bullous keratopathy in 28 (9%), trauma in 27 (8%), previous graft failure in 18 (6%), active ulcer, burn, or perforation in 9 (3%), and others in 7 (2%). The graft survival rate was 80% overall at 2 years but varied considerably depending on the indication for surgery. Uncorrected visual acuity improved from baseline mean logarithm of the minimum angle of resolution 2.09 (SD 0.67) to mean logarithm of the minimum angle of resolution of 1.53 (SD 1.03) at 2 years. A number of factors affected the visual acuity outcomes. Patients were not routinely refracted, and only 18% (N = 60) of patients had access to corrective spectacles or contact lenses postoperatively. Complication rates were high with infectious keratitis being the most common. PKP is becoming a viable treatment for corneal opacity in developing countries. However, the high burden of disease and lack of corrective lenses remain significant obstacles to overcome.


Aberration analysis of optimized Alvarez-Lohmann lenses.
In this paper aberrations in Alvarez-Lohmann lenses are analyzed, and a semi-analytical strategy for compensation is derived. An x-y polynomial model is used to describe the aberrations and classify them into static and dynamic components. The lenses are enhanced by higher-order polynomials, and a numerical optimization process is used to determine the most influential coefficients. Two simulations of corrected systems are presented. The first one is optimized for on-axis imaging. The second system is optimized for multiple field points and shows the limitations of a single Alvarez-Lohmann lens. Two systems overcoming these limitations by introducing additional optical surfaces are presented, and their performance is analyzed in simulations.


A Case of Lower Respiratory Tract Infection with Canine-associated Pasteurella canis in a Patient with Chronic Obstructive Pulmonary Disease.
This is the report of lower respiratory tract infection with Pasteurella canis in a chronic obstructive pulmonary disease (COPD) patient with history of casual exposure to cats. Pasteurella species are part of the oral and gastrointestinal flora in the canine animals. These organisms are usually implicated in wound infection following animal bites, but can also be associated with a variety of infections including respiratory tract infections.


A new variant of "subjective" delusional misidentification associated with aggression.
Delusional misidentification syndromes are psychotic conditions in which the affected individual experiences delusions of radical change concerning the identity of others and/or of the self. These syndromes may lead to aggression, including serious violence toward others. In this article, we describe and analyze in detail an aggressive individual who suffered from a delusion that physical and psychological replicas of himself existed. We specifically analyze the link between the patient's subjective misidentification delusion and his resulting aggression. Both the roles of phenomenology and biology of delusional misidentification are evaluated as potential contributors of aggression.


Advances in the treatment of gastric cancer.
To review the recent literature regarding treatment of gastric cancer. Addition of postoperative radiation therapy to perioperative chemotherapy offers no survival benefit. Fluoropyrimidines, in particular 5-fluorouracil (5-FU), are the backbone for gastric cancer chemotherapy. S-1, an oral prodrug of 5-FU, has become the mainstay for gastric cancer chemotherapy in Japan. In a Japanese adjuvant chemotherapy trial, addition of docetaxel to standard S-1 chemotherapy improved disease-free survival; this regimen will become their new standard for adjuvant therapy. Microsatellite instability (MSI) high status is emerging as a favorable prognostic marker in resected gastric cancer and may indicate a group of patients who do not gain additional benefit from treatment with adjuvant chemotherapy. In metastatic gastric cancer, the addition of ramucirumab, an antivascular endothelial growth factor receptor 2-targeted antibody, to first-line chemotherapy did not improve survival over chemotherapy alone. Trifluridine/tipiracil treatment in chemotherapy-refractory gastric cancer improved survival compared to placebo and will emerge as a late-line therapy option. Phase II and III trials indicate activity for the immune checkpoint inhibitors pembrolizumab and nivolumab in chemotherapy-refractory gastric cancer and have led to US regulatory approval for pembrolizumab in chemotherapy-refractory programmed death ligand 1-positive or MSI-high gastric cancer, and approval in Japan for nivolumab in chemotherapy-refractory gastric cancer. However, a phase III trial in advanced gastric cancer failed to show a survival benefit for pembrolizumab over conventional paclitaxel. The poly ADP ribose polymerase inhibitor, olaparib, added to second-line paclitaxel in advanced gastric cancer failed to improve overall survival compared with paclitaxel alone. Perioperative or postoperative adjuvant chemotherapy without radiation therapy remains the standard of care in gastric cancer. Addition of docetaxel to adjuvant S-1 will likely emerge as a new care standard. Pembrolizumab and nivolumab improve survival and now are treatment options in chemotherapy-refractory gastric cancer, especially for programmed death ligand 1-positive or MSI-high cancers.


Cross-validation and out-of-sample testing of physical activity intensity predictions with a wrist-worn accelerometer.
Wrist-worn accelerometers are gaining popularity for measurement of physical activity. However, few methods for predicting physical activity intensity from wrist-worn accelerometer data have been tested on data not used to create the methods (out-of-sample data). This study utilized two previously collected data sets [Ball State University (BSU) and Michigan State University (MSU)] in which participants wore a GENEActiv accelerometer on the left wrist while performing sedentary, lifestyle, ambulatory, and exercise activities in simulated free-living settings. Activity intensity was determined via direct observation. Four machine learning models (plus 2 combination methods) and six feature sets were used to predict activity intensity (30-s intervals) with the accelerometer data. Leave-one-out cross-validation and out-of-sample testing were performed to evaluate accuracy in activity intensity prediction, and classification accuracies were used to determine differences among feature sets and machine learning models. In out-of-sample testing, the random forest model (77.3-78.5%) had higher accuracy than other machine learning models (70.9-76.4%) and accuracy similar to combination methods (77.0-77.9%). Feature sets utilizing frequency-domain features had improved accuracy over other feature sets in leave-one-out cross-validation (92.6-92.8% vs. 87.8-91.9% in MSU data set; 79.3-80.2% vs. 76.7-78.4% in BSU data set) but similar or worse accuracy in out-of-sample testing (74.0-77.4% vs. 74.1-79.1% in MSU data set; 76.1-77.0% vs. 75.5-77.3% in BSU data set). All machine learning models outperformed the euclidean norm minus one/GGIR method in out-of-sample testing (69.5-78.5% vs. 53.6-70.6%). From these results, we recommend out-of-sample testing to confirm generalizability of machine learning models. Additionally, random forest models and feature sets with only time-domain features provided the best accuracy for activity intensity prediction from a wrist-worn accelerometer. NEW & NOTEWORTHY This study includes in-sample and out-of-sample cross-validation of an alternate method for deriving meaningful physical activity outcomes from accelerometer data collected with a wrist-worn accelerometer. This method uses machine learning to directly predict activity intensity. By so doing, this study provides a classification model that may avoid high errors present with energy expenditure prediction while still allowing researchers to assess adherence to physical activity guidelines.


Primary pulmonary lymphoma: report of three cases and a brief review of the literature.
We report three patients with primary pulmonary non-Hodgkin's lymphoma which is a rare extranodal lymphoid neoplasm. In these patients, both the history and physical findings were vague and minimal. The laboratory findings were normal apart from chest radiographic abnormalities and serum gammopathy in two cases. All three patients underwent several diagnostic procedures before conclusive results were obtained from thoracotomy specimens. Histology revealed small lymphocytic infiltrate of the pulmonary parenchyma with nodal involvement in all three cases. All three patients had surgical resection and two received adjuvant chemotherapy. They are all alive and symptom-free at 92, 51 and 12 months, respectively, after diagnosis.


Impact of concomitant medications on the efficacy of immune checkpoint inhibitors: an umbrella review.
Cancer is a major global health concern, and immune checkpoint inhibitors (ICIs) offer a promising treatment option for cancer patients. However, the efficacy of ICIs can be influenced by various factors, including the use of concomitant medications. We searched databases (PubMed, Embase, Cochrane Library, Web of Science) for systematic reviews and meta-analyses for systematic reviews and meta-analyses on the impact of concomitant medications on ICIs efficacy, published from inception to January 1, 2023. We evaluated the methodological quality of the included meta-analyses, and re-synthesized data using a random-effects model and evidence stratification. We included 23 publications, comprising 11 concomitant medications and 112 associations. Class II-IV evidence suggested that antibiotics have a negative impact on ICIs efficacy. However, ICIs efficacy against melanoma, hepatocellular carcinoma, and esophageal squamous cell carcinoma was not affected, this effect was related to the exposure window (class IV). Class III evidence suggested that proton pump inhibitors have a negative impact on ICIs efficacy; nevertheless, the efficacy against melanoma and renal cell carcinoma was not affected, and the effect was related to exposure before the initiation of ICIs therapy (class II). Although class II/III evidence suggested that steroids have a negative impact, this effect was not observed when used for non-cancer indications and immune-related adverse events (class IV). Class IV evidence suggested that opioids reduce ICIs efficacy, whereas statins and probiotics may improve ICIs efficacy. ICIs efficacy was not affected by histamine 2 receptor antagonists, aspirin, metformin, β-blockers, and nonsteroidal anti-inflammatory agents. Current evidence suggests that the use of antibiotics, PPIs, steroids, and opioids has a negative impact on the efficacy of ICIs. However, this effect may vary depending on the type of tumor, the timing of exposure, and the intended application. Weak evidence suggests that statins and probiotics may enhance the efficacy of ICIs. Aspirin, metformin, β-blockers, and NSAIDs do not appear to affect the efficacy of ICIs. However, caution is advised in interpreting these results due to methodological limitations. https://www.crd.york.ac.uk/PROSPERO,identifier, CRD42022328681.


Assessment of the effect of grape seed cake inclusion in the diet of healthy fattening-finishing pigs.
Modulatory capacity of bioactive compounds from different wastes has been scarcely investigated in pigs. This study aimed to evaluate the effects of dietary inclusion of grape seed cakes (GS diet) on performance and plasma biochemistry parameters as health indicators, as well as on several markers related to inflammation and antioxidant defence in the liver of fattening-finishing pigs. Twelve cross-bred pigs (TOPIG) were randomly assigned to one of two experimental diets: control and 5% grape seed cake diet during finishing period (24 days). No effect of GS diet on pig performance and blood biochemistry was observed. However, GS diet decreased significantly (-9.05%, p < .05) the cholesterol concentration (85.71 ± 0.94 mg/dl vs 94.24 ± 2.16 mg/dl) and increased IgA level (+49.90%, p < .05) in plasma (5.04 ± 0.5 mg/ml vs 3.36 ± 0.7 mg/ml). GS cakes decreased the inflammatory response in the liver of pigs fed with GS diet by lowering the Gene expression and protein concentration of pro-inflammatory cytokines (IL-1β, IL-8, TNF-α and IFN-γ) as well as the mRNA abundances of NF-κB signalling molecules. The antioxidant status was not increased by GS diet. The gene expression and activity of catalase decreased significantly. The gene expression of Nrf2, superoxide dismutase, glutathione peroxidase and heat-shock protein decreased, and no effect on their activity was observed with the exception of catalase activity which decreased. However, TBARS was reduced significantly. GS diet showed a modulatory effect on antioxidative status as well as anti-inflammatory and hypocholesterolic properties without effect on pig performance.


Estrogen signaling, through estrogen receptor β, regulates DNA methylation and its machinery in male germ line in adult rats.
Estrogen, through its receptors, regulates various aspects of spermatogenesis and male fertility. To understand the roles of estrogen receptors (ERα and ERβ) in male fertility, we have developed in vivo selective ER agonist administration models. Treatment of adult male rats with ERα or ERβ agonist for 60 d decreases fertility and litter size mainly due to increased pre- and post-implantation embryo loss. Since epigenetic mechanisms like DNA methylation play a crucial role in male fertility, we investigated the effects of the ER agonists on DNA methylation in spermatozoa. Treatment with ERβ agonist causes a significant decrease in DNA methylation both at the global level and at the H19 differentially methylated region (DMR). This could be due to decrease in DNA methyltransferases in the testis upon ERβ agonist treatment. The hypomethylation observed at the H19 DMR corroborates with aberrant expression of Igf2 and H19 imprinted genes in the resorbed embryos sired by ERβ agonist-treated males. Thus, our study demonstrates that ERβ regulates DNA methylation and methylating enzymes during adult rat spermatogenesis. Activation of estrogen signaling through ERβ could therefore cause DNA methylation defects leading to impaired male fertility. These results define a role for estrogen in epigenetic regulation of male germ line, suggesting that epigenetic insults by exposure to environmental estrogens could potentially affect male fertility.


Short-term effect of combined drug therapy and cognitive stimulation therapy on the cognitive function of Alzheimer's disease.
Acetylcholinesterase inhibitors (i.e. donepezil) are known to benefit Alzheimer's disease (AD) patients. However, the combined effects of acetylcholinesterase and cognitive stimulation therapy (CST) are still debated. The present study examined their combined effects on the progression of cognitive decline in AD. The present study was a non-randomized controlled study and included two groups of patients with AD (i.e. CST group and control group). The CST group consisted of 31 patients with AD who received donepezil and weekly, 30-min CST sessions over the course of 7 weeks. The control group consisted of 18 patients who received only donepezil. Changes in cognitive abilities were assessed with Hasegawa's Dementia Scale-Revised (HDS-R) and were statistically analyzed by repeated-measure analysis of variance (anova). ANOVA showed a significant group × time interaction effect on the HDS-R score. HDS-R scores for the CST group increased significantly during the intervention period, whereas the scores for the control group did not increase. Differences between the means of pre- and post-test HDS-R scores were significantly different between the groups; scores were significantly higher for the CST group than the control group. The groups differed significantly in the proportion of subjects whose score increased by more than four points on the HDS-R (Fisher's exact test, P < 0.05; 8 patients (25.8%) in the CST group and none (0.0%) in the control group). These results suggest that CST is one of the important non-pharmacological treatment strategies for patients with AD.


Relative contribution of nervous system and hormones to hyperglycemia induced by thyrotropin-releasing hormone in fed rats.
In a continuation of our studies on the mechanism of central nervous system induced hyperglycemia in the rat, we evaluated the relative contribution of a direct neural effect on the liver and of certain hormones to the hyperglycemia induced by administration of thyrotropin-releasing hormone (TRH). The findings were compared with those of a previous investigation using neostigmine or 2-deoxy-D-glucose. In the present study TRH was injected into the third cerebral ventricle of rats, and the concentrations of hepatic venous plasma glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine, were measured. Four groups of animals were evaluated: (1) intact rats; (2) rats receiving an infusion of somatostatin with insulin via the femoral vein to inhibit glucagon secretion and to maintain the basal insulin level; (3) rats bilaterally adrenalectomized (ADX) to prevent epinephrine secretion, and (4) ADX rats administered an infusion of somatostatin and insulin. Evaluation of the areas under the glucose curves for the rats receiving somatostatin with insulin, ADX rats, and ADX rats receiving somatostatin with insulin showed values 202, 50, and 79% of those observed in intact animals. These observations suggest that TRH-induced hyperglycemia results from at least two effects: a direct neural effect on the liver including a suppressive effect of epinephrine on insulin secretion (contributing about 79% to the total hyperglycemic effect) and a direct effect of epinephrine on the liver (contributing about 21% to the total hyperglycemic effect).(ABSTRACT TRUNCATED AT 250 WORDS)


Generalized vasculopathy and finger blood flow abnormalities in rheumatoid arthritis.
Resting blood flow, spontaneous variations of resting blood flow and postischemic peak flow of the fingers, measured by venous occlusion plethysmography, were reduced in patients with rheumatoid arthritis (n = 39) as compared to normals (n = 18). Resting blood flow and postischemic peak flow were reduced only in patients without skin vessel wall immune complex (IC) deposits, whereas spontaneous variations of resting blood flow were found to be reduced in patients with IC deposits. However, after inducing sympathicolysis, postischemic peak flow was reduced in both groups. These findings were consistent with the presence of organic lesions of the finger arteries in both groups associated with additional functional vasospasm in patients without complex deposits, that in the other group may have been counteracted by the presence of IC deposits.


Identification of novel AR-targeted microRNAs mediating androgen signalling through critical pathways to regulate cell viability in prostate cancer.
MicroRNAs (miRNAs) have been recognized as significantly involved in prostate cancer (PCa). Since androgen receptor (AR) plays a central role in PCa carcinogenesis and progression, it is imperative to systematically elucidate the causal association between AR and miRNAs, focusing on the molecular mechanisms by which miRNAs mediate AR signalling. In this study, we performed a series of time-course microarrays to observe the dynamic genome-wide expressions of mRNAs and miRNAs in parallel in hormone-sensitive prostate cancer LNCaP cells stimulated by androgen. Accordingly, we introduced Response Score to identify AR target miRNAs, as well as Modulation Score to identify miRNA target mRNAs. Based on theoretical identification and experimental validation, novel mechanisms addressing cell viability in PCa were unravelled for 3 miRNAs newly recognized as AR targets. (1) miR-19a is directly up-regulated by AR, and represses SUZ12, RAB13, SC4MOL, PSAP and ABCA1, respectively. (2) miR-27a is directly up-regulated by AR, and represses ABCA1 and PDS5B. (3) miR-133b is directly up-regulated by AR, and represses CDC2L5, PTPRK, RB1CC1, and CPNE3, respectively. Moreover, we found miR-133b is essential to PCa cell survival. Our study gives certain clues on miRNAs mediated AR signalling to cell viability by influencing critical pathways, especially by breaking through androgen's growth restriction effect on normal prostate tissue.


Bicolor electroluminescent pixels from single active molecular material.
We report on the fabrication of the first bicolor micropixelated OLED from a single molecular material using a single-step bottom up procedure. The implementation of a deposition technique, based on a spatial-switch and conformational-sensitive STD surface-tension-driven lithography, has allowed us to exploit the spontaneous supramolecular properties and the conformational flexibility of a conjugated thiophene-based material, 6-bis-(50-hexyl-[2, 20]bithiophen-5-yl)-3, 5-dimethyl-dithieno[3, 2-b; 20, 30-d]thiophene (DTT7Me). The existence of two regularly alternating emitting regions on a micrometer scale allows obtaining electroluminescent emission at two different wavelengths from a single material.


Coffee consumption and risk of fatal cancers.
In 1960, the coffee consumption habits and other lifestyle characteristics of 23,912 white Seventh-day Adventists were assessed by questionnaire. Between 1960 and 1980, deaths due to cancer were identified. There were positive associations between coffee consumption and fatal colon and bladder cancer. The group consuming two or more cups of coffee per day had an estimated relative risk (RR) of 1.7 for fatal colon cancer and 2.0 for fatal bladder cancer, compared to the group that consumed less than one cup per day (RR = 1.0). These positive associations were apparently not confounded by age, sex, cigarette smoking, or meat consumption habits. In this study, there were no significant or suggestive associations between coffee consumption and fatal pancreatic, breast, and ovarian cancer, or a combined group of all other cancer sites.


Discovery and Development of Monoamine Transporter Ligands.
Monoamine transporters (MATs) are targets of a wide range of compounds that have been developed as therapeutic treatments for various neuropsychiatric and neurodegenerative disorders such as depression, ADHD, neuropathic pain, anxiety disorders, stimulant use disorders, epilepsy, and Parkinson's disease. The MAT family is comprised of three main members - the dopamine transporter (DAT), the norepinephrine transporter (NET), and the serotonin transporter (SERT). These transporters are through reuptake responsible for the clearance of their respective monoamine substrates from the extracellular space. The determination of X-ray crystal structures of MATs and their homologues bound with various substrates and ligands has resulted in a surge of structure-function-based studies of MATs to understand the molecular basis of transport function and the mechanism of various ligands that ultimately result in their behavioral effects. This review focusses on recent examples of ligand-based structure-activity relationship studies trying to overcome some of the challenges associated with previously developed MAT inhibitors. These studies have led to the discovery of unique and novel structurally diverse MAT ligands including allosteric modulators. These novel molecular scaffolds serve as leads for designing more effective therapeutic interventions by modulating the activities of MATs and ultimately their associated neurotransmission and behavioral effects.


Clinicopathologic and prognostic factors in short- and long-term surviving dogs with protein-losing enteropathy.
The aim of the present study was to investigate the differences in the characteristics of short- and long-term surviving dogs with protein-losing enteropathy (PLE) and to identify factors that predict its outcome. We retrospectively reviewed the medical records of 59 client- owned dogs with PLE diagnosed at three different hospitals between January 2009 and November 2013. The dogs were classified as either short-term (= 6 months; STs) or long-term (> 6 months; LTs) survivors. Clinical and clinicopathological variables were investigated between the groups and receiver operating characteristic (ROC) curve analysis was performed. Nineteen dogs were classified as STs and 40 as LTs. Body weight and blood urea nitrogen concentrations were significantly higher in the STs at diagnosis (P < 0.05). At 1 month after initiation of immunosuppressive therapy (data- driven cut-off, T1), chronic canine enteropathy clinical activity index (CCECAI) scores were higher (P < 0.01) and albumin, serum total protein and total cholesterol concentrations were lower (P < 0.01) in the STs. ROC curve analysis showed that CCECAI > 5 evaluated at T1 was the best predictor of poor outcome. Although the severity of clinical signs and the majority of clinicopathological findings at diagnosis did not influence the outcome, survival time was shorter in the dogs with high CCECAI scores at T1 and which did not respond to therapy.


An optimal polymerization process for low mean molecular weight HBOC with lower dimer.
The new research tried to improve the distribution of molecular weight of Hb-based oxygen carriers (HBOC), a bottleneck of glutaraldehyde (GDA)-polymerization process. The orthogonal experiments were done on the basis of the early study of human placenta Hemoglobin (Hb)-crosslinked-GDA and three factors were selected including the molar ratio of GDA and Hb, Hb concentration, and the rate of the feeding GDA. The optimal match condition of polymerization process prepared for the purpose of lower mean molecular weight, content of super-weight molecule, and the content of dimer. The results showed that the molar ratio of GDA and Hb was the greatest influencing factor on the molecular weight distribution of polymerized-Hb, followed by the Hb concentration, and the last is the rate of feeding GDA. The optimum matching conditions had reached the objective that the mean molecular weight with 155.54 ± 5.79, the content of dimer with 17.23 ± 3.71, and content of super-weight molecule with 0.17 ± 0.09, and the results can be repeated in the 30 times expansion experiments.


The frataxin-encoding operon of Caenorhabditis elegans shows complex structure and regulation.
The genome of the nematode Caenorhabditis elegans is unusual among eukaryotes, in that it contains operons. Approximately 15% of genes in the worm are clustered into groups of between two and eight genes, which are under the control of shared regulatory sequences. Polycistronic transcripts from such operons are trans-spliced, during transcription, to produce mature monocistronic messengers. The C. elegans frataxin gene, frh-1, is encoded in the operon CEOP2232. This is one of the largest operons identified thus far in the C. elegans genome. Here we describe in detail the structure of all of the coding units within this operon. The operon is composed of eight genes of a diverse nature, organized in a complex structure. We have produced transgenic strains carrying fusions between gfp and a number of genes from the operon. These constructs show complex differential expression patterns that suggest the presence of internal promoters and regulatory sequences in the operon. This organization would permit both coordinated expression and differential expression of the components of the CEOP2232 operon. The heterogeneity of the genes, and their complex expression patterns, suggests that the clustering of CEOP2232 is not due to a need for synchronized expression of genes involved in the same physiological pathway.


Effects of forskolin on pancreatic exocrine secretion and cyclic nucleotide concentrations of the dog pancreas.
The effects of forskolin on the secretion of pancreatic juice and on the intracellular levels of cyclic nucleotides were investigated in preparations of the isolated and blood-perfused dog pancreas. Forskolin (3-100 micrograms) injected intra-arterially caused a dose-dependent increase in the secretion of pancreatic juice. The concentration of bicarbonate in the pancreatic juice induced by forskolin was increased. However, protein concentration was decreased. Forskolin-induced secretion was not modified by pretreatment with atropine, phentolamine, propranolol, cimetidine, sulpiride and verapamil. Forskolin (10-30 micrograms) significantly increased cyclic AMP concentration in the pancreatic tissue before the onset of the pancreatic secretion. On the other hand, cyclic GMP concentration was not influenced significantly throughout 30 min after the administration of forskolin. From these results, it is concluded that forskolin may produce an increase in pancreatic secretion mediated through an increase of intracellular cyclic AMP concentration.


Transition-metal complexes as enzyme-like reagents for protein cleavage: complex cis-[Pt(en)(H2O)2]2+ as a new methionine-specific protease.
Complex cis-[Pt(en)(H(2)O)(2)](2+) promotes selective hydrolytic cleavage of two proteins, horse cytochrome c and bovine beta-casein. The cleavage is completed in 24 h under relatively mild conditions, at about pH 2.5, and a temperature as low as 40 degrees C. The results of HPLC and TSDS PAGE separations, MALDI mass spectrometry, and Edman sequencing showed that cleavage occurred exclusively at the peptide bond involving the C-terminus of each methionine residue, both such residues in cytochrome c and all six such residues in beta-casein. While having the same selectivity as cyanogen bromide (CNBr), the most common chemical protease, cis-[Pt(en)(H(2)O)(2)](2+) has several advantages. It is nonvolatile, easy to handle, and recyclable. Its cleavage is residue-selective, the rest of the polypeptide backbone remains intact, and the other side chains remain unmodified. It is applied in approximately equimolar amounts with respect to methionine residues, creates free amino and carboxylic groups, and cleaves even the Met-Pro bond, which is resistant to CNBr and most proteolytic enzymes. Finally the complex also works in the presence of the denaturing reagent sodium dodecyl sulfate. Experiments with the synthetic peptides, AcAla-Lys-Tyr-Gly-Gly-Met-Ala-Ala-Arg-Ala (termed Met-peptide) and AcVal-Lys-Gly-Gly-His-Ala-Lys-Tyr-Gly-Gly-Met-Ala-Ala-Arg-Ala (termed HisMet-peptide) as substrates, revealed structural and mechanistic features of the proteolytic reactions. We explain why two similar complexes with similar metal ions, cis-[Pt(en)(H(2)O)(2)](2+) and cis-[Pd(en)(H(2)O)(2)](2+), differ in selectivity as proteolytic reagents. The selectivity of cleavage is governed by the selectivity of the cis-[Pt(en)(H(2)O)(2)](2+) binding to the methionine side chain. The proteolytic activity is governed by the modes of coordination, which control the approach of the anchored Pt(II) ion to the scissile peptide bond. The cleavage occurs with a small, but significant, catalytic turnover of more than 18 after 7 days. The ability of cis-[Pt(en)(H(2)O)(2)](2+) to cleave proteins at relatively few sites, with explicable selectivity and catalytic turnover, bodes well for its use in biochemical practice.