Topical ketorolac tromethamine 0.5% versus diclofenac sodium 0.1% to inhibit miosis during cataract surgery.
To compare the effect of topical ketorolac tromethamine 0.5% solution and topical diclofenac sodium 0.1% solution on the inhibition of surgically induced miosis. Tertiary care teaching hospital in South India. Fifty-one patients were prospectively randomized to receive ketorolac 0.5% or diclofenac 0.1% at 3 intervals preoperatively. Patients with diabetes mellitus, pseudoexfoliation, or local pupil abnormalities were excluded from the study. Mydriatics comprising homatropine 1% plus phenylephrine 10% were instilled in all patients 1 hour before the peribulbar block at 5 intervals. Horizontal pupil diameters were obtained at the beginning of surgery, after capsulotomy, after intraocular lens (IOL) implantation, and at the end of surgery. The mean horizontal pupil diameter was 7.40 mm at the start of surgery in both groups. The ketorolac group showed a consistent trend toward larger pupil diameters at subsequent surgical intervals. Changes from baseline also indicated more significant inhibition of miosis in the ketorolac group. Topical ketorolac was a more effective inhibitor of miosis than topical diclofenac during extracapsular cataract extraction and IOL implantation. It also provided a more stable mydriatic effect throughout surgery.


Sulcus deepening trochleoplasty for patellofemoral instability: A series of 34 cases after 15 years postoperative follow-up.
Trochlear dysplasia is one of the main elements of patellofemoral instability. Although correction by trochleoplasty seems logical, the long-term outcome of this procedure is unknown and the progression to osteoarthritis has not been clarified. Thus, we performed a retrospective study of a series of sulcus deepening trochleoplasties with a 15-year follow-up whose goal was to (1) evaluate the long-term clinical outcome and radiological rate of osteoarthritis, and (2) define the results in relation to the type of instability and the grade of dysplasia. Sulcus deepening trochleoplasty is an effective procedure to stabilize the patellofemoral joint that does not increase the risk of osteoarthritis. This retrospective study analyzed 34 sulcus deepening trochleoplasties based on clinical scores (IKS, Lille, Kujala and Oxford scores) and radiological results (stage of osteoarthritis according to the Iwano score) after a mean follow-up of 15 years (12-19 years). An Insall procedure was systematically associated with an anterior tibial tubercle transfer in 17 cases (7 prior tibial transfers). No recurrent objective instability was observed. Seven knees had additional surgery after a mean follow-up of 7 years (2-16): 7 underwent conversion to total knee arthroplasty because of progression of osteoarthritis and one knee had tibial tubercle transfer for pain and episodes of the knee giving way. The mean Lille, Kujala and IKS scores increased from 53.3 (30-92), 55 (13-75) and 127 (54-184) to 61.5 (25-93), 76 (51-94) and 152.4 (66-200) respectively between preoperative and follow-up assessment (P<0.05) (revisions included). Functional outcome was significantly better for dysplasia with supratrochlear spurs (IKS score 168 [127-200] versus 153 [98-198] and Kujula score 81.5 [51-98] versus 76 [51-94] [P<0.05]). Patients were satisfied in 65% of the cases and the total mean Oxford score was 24.1/60 (12-45 points). Occasional pain was present in 53% of the cases. The trochlear prominence decreased from 4.9 mm (3-9 mm) to -1.2mm (-7-4mm). Ten cases of preoperative patellofemoral osteoarthritis were identified, but none with>Iwano 2, while osteoarthritis was present in 33/34 cases at the final follow-up with 20 cases>Iwano 2 (65%). Sulcus deepening trochleoplasty corrects patellofemoral stability even in patients with severe dysplasia and the long-term functional outcome is better in this group. It does not prevent patellofemoral osteoarthritis. It should be limited to severe dysplasia with supratrochlear spurs and associated with procedures to realign the extensor apparatus.


A new method for the simultaneous estimation of phosphate efflux and influx during glucose stimulation of isolated pancreatic islets.
Isolated rat pancreatic islets were prelabeled with [33Pi] and then incubated with basal (2.8 mM) or stimulatory (16.7 mM) glucose in the presence of [32Pi]. Subsequent changes in islet [33P] and [32P] were utilized as respective indices of net efflux and influx. During the initial eight min, (the period usually spanning the first phase of stimulated insulin secretion) efflux was significantly greater with 16.7 than 2.8 mM glucose whereas the lesser amount of phosphate influx did not differ in the two systems. During the subsequent seven min (a time usually associated with the onset of the second phase of stimulated insulin secretion), efflux was dampened in the presence of 16.7 mM glucose and Pi influx significantly exceeded the 2.8 mM glucose values. Thus, acute stimulation with glucose effects an initial phosphate depletion in pancreatic islets as efflux exceeds influx and repletion occurs thereafter as efflux is attenuated and influx is enhanced. These oscillations in islet phosphate may contribute to the biphasic pattern of glucose-stimulated insulin release.


Development of a human interleukin-6 receptor antagonist.
Neutralizing monoclonal antibodies specific for human interleukin-6 (IL-6) bind two distinct sites on the IL-6 protein (sites I and II). Their interference with IL-6 receptor binding suggested that site I is a receptor-binding site of IL-6, whereas site II is important for signal transduction. Mutagenesis of site II could therefore result in the isolation of IL-6 receptor antagonists. To test this hypothesis, a panel of IL-6 mutant proteins was constructed that did not bind to a site II-specific monoclonal antibody. One such site II mutant protein (with double substitution of Gln-160 with Glu and Thr-163 with Pro) was found to be an antagonist of human IL-6. It was inactive on human CESS cells, weakly active on human HepG2 cells, but active on mouse B9 cells. It could specifically antagonize the activity of wild-type IL-6 on CESS and HepG2 cells. The binding affinity of this variant for the 80-kDa IL-6 receptor was similar to that of wild-type IL-6. High affinity binding to CESS cells, however, was abolished, suggesting that the mutant protein is inactive because the complex of the 80-kDa IL-6 receptor and the mutant protein cannot associate with the signal transducer gp130. The human IL-6 antagonist protein may be potentially useful as a therapeutic agent.


Reflex inhibition of heart rate and efferent cardiac sympathetic outflow induced by colorectal distension in anesthetized rats.
Colorectal distensions of 60 and 80 mmHg significantly reduced heart rate (HR) and cardiac sympathetic nerve activity in anesthetized rats. This bradycardiac response was not influenced by the intravenous administration of atropine, but was abolished by propranolol, suggesting that it was elicited by sympathetic but not vagal efferent nerves.


The effect of distance between holes on the structural stability of subchondral bone in microfracture surgery: a finite element model study.
Microfracture is a surgical technique that involves creating multiple holes of 3-4 mm depth in the subchondral bone to recruit stem cells in the bone marrow to the lesion, inducing fibrocartilage repair and knee cartilage regeneration. Recently, it has been reported that increasing the exposed area of the lower cartilaginous bone (drilling a lot of holes) increases the outflow of stem cells, which is expected to affect the physical properties of the subchondral bone when the exposed area is large. The purpose of this study was to analyse the effect of the distance between the holes in the microfracture procedure on the structural stability of the osteochondral bone using a finite element method. In this study, lateral aspects of the femoral knee, which were removed during total knee arthroplasty were photographed using microtomography. The model was implemented using a solitary walks program, which is a three-dimensional simplified geometric representation based on the basic microtomography data. A microfracture model was created by drilling 4 mm-deep holes at 1, 1.5, 2, 2.5, 3, 4, and 5 mm intervals in a simplified three-dimensional (3D) geometric femoral model. The structural stability of these models was analysed with the ABAQUS program. We compared the finite element model (FEM) based on the microtomography image and the simplified geometric finite element model. Von Mises stress of the subchondral bone plate barely increased, even when the distance between holes was set to 1 mm. Altering the distance between the holes had little impact on the structural stability of the subchondral bone plate. Safety factors were all below 1. Although we did not confirm an optimal distance between holes, this study does provide reference data and an epidemiological basis for determining the optimal distance between the holes used in the microfracture procedure.


Primary care physicians' attitudes and practices regarding cancer genetics: a comparison of 2001 with 1996 survey results.
To determine whether Texas primary care physicians' attitudes and practices regarding cancer genetics changed over a five-year period, a follow-up survey was conducted and the results obtained in 1996 were compared with those obtained in 2001. A survey was mailed in 2001 to a random sample of 350 primary care physicians in Texas. More primary care physicians in 2001 were discussing the subject of genetic screening with their patients and more physicians were referring their patients for genetic evaluations and testing for cancer risk, compared with 1996. Cost of genetic testing continues to be the most frequently cited barrier to using genetic testing for cancer susceptibility. Results suggest a continuing need for more educational programs for physicians regarding genetic testing for cancer susceptibility.


Assessment and treatment of major depression in older adults.
Late life depression is a significant public health problem as well as a burden on patients, their families, and caregivers. There are significant associations of late life depression with medical disorders and cognitive impairment, the latter due to effects of the depression itself or association with dementia. Diagnostic criteria and screening tests have continued to evolve and provide structure and guidelines for assessment. Accurate diagnosis and treatment are of utmost importance to improve quality of life, alleviate suffering, and prevent suicide. A number of effective antidepressant medications are available; combination therapy with these medications and cognitive behavioral therapy appear most efficacious, and maintenance therapy can decrease the chances of remission. A sequence for treatment of late life depression is provided, with strategies for treatment-resistant depression. The relationship of dementia to depression and the interaction of depression with mechanisms of aging are major foci of research.


Differences in the Development of Adverse Infusion Reactions to Rituximab in Patients With Systemic Lupus Erythematosus, Rheumatoid Arthritis and Non-Hodgkin's Lymphoma-Enigma Variations.
It has become clear that rituximab treatment is useful for both B-cell malignancies and autoimmune rheumatic diseases. However this treatment is associated with an increased risk of an allergic reaction. We have reviewed the frequency with which these reactions occur in these different conditions. They appear to be less frequent when rituximab is used to treat rheumatoid arthritis and systemic lupus perhaps because concomitant steroids are invariably given to these patients with the rituximab which is not necessarily the case with the treatment of B-cell malignancies.


Parent caregivers' preferences and satisfaction with currently provided childhood cancer survivorship care.
The aim of this study was to investigate the level of satisfaction of parent caregivers of childhood cancer survivors (CCSs) with currently provided survivorship care and their preferences for survivorship care provider. Study subjects were parent caregivers recruited at three hospitals in Korea. Study data were collected from self-administered questionnaires and medical records. We assessed parent caregivers' levels of satisfaction with specific survivorship care contents and preferred types of survivorship care provider among oncologists, primary care physicians (PCPs), and institutional general physicians (IGPs). Factors associated with parent caregivers' preferences for survivorship care provider were evaluated by multiple logistic regression analysis. 680 parent caregivers (mother 62.1% and father 37.9%) of 487 CCSs (mean age at diagnosis: 6.9 ± 5.1 years; mean time since treatment completion 5.4 ± 4.4 years) were included. Parent caregivers' dissatisfaction was the highest with screening for second primary cancer, followed by psychosocial problem management. Higher educational level of parent caregiver, parent caregiver's higher level of dissatisfaction with currently provided care, higher age of CCSs at cancer diagnosis, history of receiving hematopoietic stem cell transplant, and longer time lapse after cancer treatment were significantly associated with parent caregivers' higher preference for PCPs or IGPs than oncologists. Parent caregiver's multiple comorbidities and higher fear of cancer recurrence were associated with parent caregivers' higher preference for oncologists than PCPs or IGPs. Around 80% of parent caregivers recognized that a shared care system was helpful for promoting the health of CCSs. Parent caregivers were substantially dissatisfied with currently provided care, especially regarding the health issues not directly associated with the primary cancer. Parent caregivers' preferences for survivorship care provider is influenced by multiple factors, including age and survival time of CCSs, characteristics of parent caregivers, satisfaction level with care, and specific survivorship care contents. The findings of our study suggest that shared survivorship care for CCSs with consideration of specific care contents can complement the current oncologist-led survivorship care system.


Placement of loci for avenins and resistance to Puccinia coronata to a common linkage group in Avena strigosa.
Alcohol-soluble seed storage proteins of oat (avenins) were extracted from two diploid accessions representing the A genome and separated by high-resolution acid polyacrylamide gel electrophoresis. Polymorphisms were detected for three clearly resolved protein bands. Linkage analysis of 88 F2:3 families mapped the three bands to a single locus. Integration of avenin segregation data with an RFLP linkage map constructed from the same population, mapped the avenin locus to a linkage group containing a locus conferring resistance to nine isolates of Puccinia coronata. Linkage between genes encoding alcohol-soluble seed proteins and genes for resistance to Puccinia species was also observed for the homoeologous group 1 chromosomes of barley (1H), rye (1R), wheat (1A, 1B, 1D), and chromosomes 4 and 10 of maize.


Structural analysis of a simplified model reproducing SARS-CoV-2 S RBD/ACE2 binding site.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus identified as the cause of the coronavirus outbreak in December 2019 (COVID-19). Like all the RNA viruses, SARS-CoV-2 constantly evolves through mutations in its genome, accumulating 1-2 nucleotide changes every month, giving the virus a selective advantage through enhanced transmissibility, greater pathogenicity, and the possibility of circumventing immunity previously acquired by an individual either by natural infection or by vaccination. Several SARS-CoV-2 variants of concern (VoC) have been identified, among which we find Alpha (Lineage B.1.1.7), Beta (Lineage B.1.351), and Gamma (Lineage P.1) variants. Most of the mutations occur in the spike (S) protein, a surface glycoprotein that plays a crucial role in viral infection; the S protein binds the host cell receptor, the angiotensin-converting enzyme of type 2 (ACE2) via the receptor binding domain (RBD) and catalyzes the fusion of the viral membrane with the host cell. In this work, we present the development of a simplified system that would afford to study the change in the SARS-CoV-2 S RBD/ACE2 binding related to the frequent mutations. In particular, we synthesized and studied the structure of short amino acid sequences, mimicking the two proteins' critical portions. Variations in the residues were easily managed through the one-point alteration of the sequences. Nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopies provide insights into ACE2 and SARS-CoV-2 S RBD structure with its related three variants (Alpha, Beta, and Gamma). Spectroscopy data supported by molecular dynamics lead to the description of an ACE2/RBD binding model in which the effect of a single amino acid mutation in changing the binding of S protein to the ACE2 receptor is predictable.


Eosinophils: from low- to high-affinity immunoglobulin E receptors.
Several experimental approaches have been used to identify immunoglobulin (IgE) binding molecules expressed by human eosinophils. After the description that Fc epsilon RII/CD23 identified on eosinophils could participate in IgE binding and IgE-mediated cytotoxicity, Mac2/epsilon binding proteins belonging to the S-type lectin family were also detected on human eosinophils. Anti-Mac2 monoclonal antibodies inhibited eosinophil-dependent cytotoxicity towards parasitic targets. More recently, Fc epsilon RI was demonstrated on human eosinophils from hypereosinophilic patients. The 3 components of Fc epsilon RI, alpha, beta and gamma chains, were detected in eosinophils. The alpha chain of Fc epsilon RI was shown to be involved in IgE binding to eosinophils and in the selective release of eosinophil peroxidase. The participation of Fc epsilon RI-bearing eosinophils in a protective immune response against a parasitic infection indicates a so far unsuspected function of Fc epsilon RI. The interactions between the different types of IgE binding molecules are discussed.


Association and clinicopathologic significance of p38MAPK-ERK-JNK-CDC25C with polyploid giant cancer cell formation.
We previously showed that cobalt chloride (CoCl2) induction of polyploid giant cancer cells (PGCCs) was characterized by abnormal cell cycle-related protein expression and G2/M arrest. The role of the p38MAPK-ERK-JNK signaling pathway in cell cycle regulation has been reported, but the mechanism by which p38MAPK-ERK-JNK regulates PGCCs formation remains unclear. This study examined p38MAPK-ERK-JNK-CDC25C expression in PGCCs and their daughter and control cells and assessed the clinicopathological significance of p38MAPK, ERK, JNK, and CDC25C expression in human ovarian and breast cancers. CoCl2 was used to induce the formation of PGCCs in HEY and BT-549 cells. Western blotting and immunocytochemical staining were used to compare the expression and subcellular localization of p38MAPK, ERK, JNK, and CDC25C in the control group and CDC25C knockdown before and after CoCl2 treatment. The specific combination of p38MAPK and ERK with pCDC25C-Ser216 was detected by immunoprecipitation. In addition, p38MAPK, ERK, JNK, and CDC25C immunohistochemical staining were performed to compare the clinicopathologic significances in 81 cases of ovarian cancer tissue, including 20 cases of primary breast cancer with lymph node metastasis (group I), and their corresponding metastatic lymph nodes (group II), 31 cases of primary breast cancer without metastasis (group III), and 10 cases of benign breast tumors (group IV). Breast tumor tissue from 229 was divided into two groups: 167 cases of primary invasive breast cancer (group 1) and 62 cases of lymph node metastatic breast cancer (group 2). Compared to the control cells, p38MAPK and JNK expression were higher and CDC25C expression was lower in CoCl2-treated cells. Moreover, ERK displayed a trend of increased expression in HEY PGCCs and decreased expression in BT-549 PGCCs. p38MAPK and ERK regulated CDC25C by phosphorylating the CDC25C-Ser216 site and participated in the G2/M phase transition. Immunohistochemical (IHC) analysis of the ovarian tumor tissues showed significant positive staining rates of p38MAPK (P = 0.001), ERK (P = 0.002), JNK (P = 0.000), and CDC25C (P = 0.000) among the four groups. In breast tumor tissues, the overall expression in p38MAPK (P = 0.029), ERK (P = 0.002), JNK (P = 0.013), and CDC25C (P = 0.001) also differed significantly between the two groups. The p38MAPK-ERK-JNK signaling pathway was involved in cell cycle progression and the formation of PGCCs by regulation of CDC25C.


Endoplasmic reticulum stress and disturbed calcium homeostasis are involved in copper-induced alteration in hepatic lipid metabolism in yellow catfish Pelteobagrus fulvidraco.
The present study was conducted to investigate the effect of Cu exposure on ER stress and Ca(2+) homeostasis, and explore the underlying mechanism of the ER stress and disturbed Ca(2+) homeostasis in the regulation of hepatic lipid metabolism in yellow catfish Pelteobagrus fulvidraco. To this end, three experiments were conducted. In experiment 1, P. fulvidraco were exposed to three waterborne Cu concentrations for 56 days. Waterborne Cu exposure evoked ER stress and SREBP-1c activation and resulted in dysregulation of hepatic lipid metabolism in liver of P. fulvidraco in a time-dependent manner. In experiment 2, specific inhibitors 2-APB (IP3 receptor inhibitor) and dantrolene (RyR receptor inhibitor) were used to explore whether Ca(2+) release from ER was involved in the Cu-induced ER stress change. Dantrolene and 2-APB prevented Cu-induced intracellular Ca(2+) elevation, demonstrating that the release of Ca(2+) from the ER, mediated by both RyR and IP3R, contributed to dysregulation of lipid metabolism. In experiment 3, a chemical chaperone (PBA) was used to demonstrate whether Cu-induced alteration in lipid metabolism was suppressed through the attenuation of ER stress. PBA attenuated the Cu-induced elevation of mRNA expression of SREBP-1c, SCAP, ACC, FAS, GRP78/BiP, GRP94, CRT, eIF2α and XBP-1, and alleviated the Cu-induced downregulation of Insig-1. Based on these observations, these results reveal a link between ER stress and the change of lipid metabolism induced by Cu, which will help to understand the Cu-induced toxicity on cellular and molecular level, and provide some novel insights into the regulation of lipid metabolism in fish.


The Chromosome Conformation Capture (3C) in Drosophila melanogaster.
The discovery of the DNA double helix by Watson and Crick in 1953 was the first report showing that the genomic information is not contained in a stretched linear molecule. After that, a huge advance in the knowledge of the structure of the eukaryotic genome in the nuclear space has been made over the last decades, bringing us to the widely accepted concept that the genome is packaged into hierarchical levels of higher-order three-dimensional structures. The spatial organization of the eukaryotic genome has direct influence on fundamental nuclear processes that include transcription, replication, and DNA repair. The idea that structural alterations of chromosomes may cause disease goes back to the early nineteenth century. Big effort has been devoted to the study of the three-dimensional architecture of the genome and its functional implications. In this chapter, I will describe the chromosome conformation capture (3C), one of the first techniques used to detect and measure the frequency of interactions between genomic sequences that are kept in spatial proximity in the nucleus.


Mineral nutrient deficiency increases the sensitivity of photosynthesis to sulphur dioxide in needles of a coniferous tree, Abies nordmanniana.
Abies nordmanniana (Stev.) Spach was cultivated in rooting media either rich in nutrients (control) or low in magnesium (low Mg) or low in magnesium and nitrogen (low Mg-N), respectively. Intact, attached needles were exposed, in the light (460 μmol photons m-2 s-1), to an atmosphere containing 1 ppm SO2 for 5 h. Measurements of light- and CO2-saturated rates of photosynthetic O2 evolution, A max, were performed before and after SO2 treatments. In needles from well fertilized plants, A max was high (about 50 μmol m-2 s-1) and was not affected by SO2. Needles from low-Mg and low-Mg-N plants had lower photosynthetic rates and showed a marked decline in A max in response to the SO2 treatment. Stomatal conductance was similar in the three groups of plants during SO2 treatments.


Biliary Anomalies in Patients With HNF1B Diabetes.
The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined. To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP). Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype. Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia. Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant. Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.


Cancer incidence among spouses of patients with colorectal cancer.
The risk of colorectal cancer was examined among spouses of approximately 10,000 colorectal cancer patients. A total of 8,095 spouses were identified, and cancer cases in this cohort were sought in the Danish Cancer Registry. No excess risk was found for colorectal cancer as such. The data were also analyzed by subsite of the large bowel for the index cases and for the spouses, respectively. The estimated relative risks were in general close to unity, the only exception being the risk of right-sided colon cancer among husbands of index cases with left-sided colon cancer, RR = 2.17 (p less than 0.05). The absence of excess risk was noted regardless of the duration of marriage. The risk of other cancers with a presumed etiology similar to that of colorectal cancer (cancer of the uterine corpus, breast, prostate and biliary tract) was also close to expected values.


Protein Evaluation of Feedstuffs for Horses.
The German Society of Nutrition Physiology has proposed a new protein evaluation system for horse feeds to estimate pre-cecally digestible crude protein (pcdCP) and amino acids (pcdAA) from chemical properties. A total of 71 feeds for horses were chemically tested and evaluated according to the new protein evaluation system. A feeding trial with eight horses tested whether differences in estimated pcdAA and neutral detergent soluble CP (NDSCP) in the diet were reflected by post-prandial (ppr) kinetics of plasma lysine (Lys) by feeding a complementary feed (control = CTRL) with 1.02 g Lys/100 kg body weight (BW) as well as three diets with 3.02 g Lys/100 kg BW, as follows: (i) CTRL with synthetic AA (CTRL + synAA); (ii) CTRL with soybean meal (CTRL + SBM); and (iii) lucerne pellets (LUC). In comparison to CTRL, the areas of curves (AUCs) of ppr plasma Lys differed: CTRL < CTRL + SBM (p < 0.01) < CTRL + synAA (p < 0.05). For 71 feeds, the estimated pcdCP was correlated with the CP content (p < 0.001), NDSCP (p < 0.001), and ash-free neutral detergent fiber (p < 0.001). A mean neutral detergent insoluble CP content of at least 3-5% can be assumed in horse feed. It is speculated that the predicted availability of Lys from LUC seems to be underestimated by the new protein evaluating system. The influence of chewing and microbiota in vivo needs to be considered in horses.


The Intersection of Professional Identity Formation, Bias, and Marginalized Identities.
The objective of this integrative review is to call attention to the limited published literature on professional identity formation (PIF) in students who hold marginalized identities and to promote more inclusive PIF models. A person's identity is complicated and PIF is a dynamic and continuous lifelong process. A foundational component to PIF is for students to integrate their developing professional identity with their existing selves. Most PIF theoretical frameworks used in health education were created with a dominant culture lens and during a time when most professionals in practice were cisgendered, White, and/or male. These frameworks do not consider ways in which PIF may differ in learners who hold marginalized identities nor the influence that their marginalized identities may have on facilitators and barriers to their PIF journeys. PIF is a growing area of focus in pharmacy education and scholarship. To effectively support PIF for each member of a diverse student body, pharmacy educators must recognize the limitations of existing PIF theoretical frameworks owing to the historical exclusion of considerations of students' and practitioners' marginalized identities as a layer of professional identity, especially in the context of historical injustices. As members of the pharmacy Academy begin or continue to explore PIF in pharmacy education, they must be mindful and intentional about how they account for the impact that students' marginalized identities may have on their PIF.


Improved complete remission rates and survival for patients with large cell lymphoma treated with chemoimmunotherapy. A Southwest Oncology Group Study.
Between 1974 and 1977, 652 patients with non-Hodgkin's lymphoma without prior chemotherapy were randomized to 1 of 3 combination chemotherapy programs designed to induce complete remission (CR): COP-bleomycin (180 patients), CHOP-bleomycin (232 patients) or CHOP plus immunotherapy with Bacillus Calmette Guerin (BCG) (240 patients). With mature follow-up, the major effect of BCG immunotherapy was observed in patients with large cell lymphomas (diffuse or nodular "histiocytic") and not in other common lymphoma subtypes. CR rate for 65 patients with large cell lymphoma treated with CHOP-BCG was 68% compared to 48% in 61 patients treated with CHOP-bleomycin (P = 0.02) (two-tailed test) or 44% for 45 patients treated with COP-bleomycin (P = 0.02). CR duration for both CHOP-based regimens was similar and superior to that produced by COP-bleomycin (P = 0.03). Survival of patients with large cell lymphoma treated with CHOP-BCG was better than that observed with CHOP-bleomycin (P = 0.02) or COP-Bleomycin (P = 0.002). Although the explanation for the favorable effect of BCG remains unclear, further clinical trials to evaluate the combination of chemotherapy and other "biologic response modifiers" is warranted for patients with lymphoma.


Diphosphine sulfides derived from 2,2'-biphosphole: novel chiral S,S ligands for palladium-catalyzed asymmetric allylic substitution.
Diphosphine sulfides derived from 2,2'-biphosphole have been efficiently synthesized in an enantiomerically pure form by a four step synthetic sequence. These S,S-ligands were used for the first time in Pd-catalyzed asymmetric allylic alkylation. Good yields and enantiomeric excess up to 73% were obtained.


The gas-phase H/D exchange mechanism of protonated amino acids.
A mass spectrometry and Density Functional Theory study of gas-phase H/D exchange in protonated Ala, Cys, Ile, Leu, Met, and Val is reported. Site-specific rate constants were determined and results identify the alpha-amino group as the protonation site. Lack of exchange on the Cys thiol group is explained by the absence of strong intramolecular hydrogen bonding within the reaction complex. In aliphatic amino acids the presence of a methyl group at the beta-C atom was found to lower the site-specific H/D exchange rate for amino hydrogens. Study of the exchange mechanism showed that isotopic exchange occurs in two independent reactions: in one, only the carboxylic hydrogen is exchanged and in the other, both carboxylic and amino group hydrogens exchange. The proposed reaction mechanisms, calculated structures of various species, and a number of structural findings are consistent with experimental data.


Open-loop comparison of carotid sinus reflex respiratory and circulatory effects in cats.
Isolated control of pressure in the carotid sinus was exercised bilaterally by means of pump-driven autoperfusion in anaesthetized heparinized cats breathing 100% O2. In cats with vagus nerves intact, a rise of intrasinus pressure resulted in a non-adapting fall in arterial blood pressure and a short-lasting depression in tidal volume and frequency of breathing that adapted fully in the steady state. Vagotomy increased the steady-state gain of the intrasinus pressure-vasodepressor relationship and resulted sometimes in a measurable sustained inhibition of breathing, following its initial adaptation, at the upper levels of intrasinus pressure tested. Pharmacological stabilization of the blood pressure with the use of guanethidine plus phenylephrine did not detectably affect the adapting character of the sinus reflex respiratory response. Denervation of the carotid sinuses abolished all responses previously evoked by shifts of intrasinus pressure. It is concluded that the reflex effects of carotid sinus autoperfusion are produced by selective activation of the baroreceptors and that the respiratory adaptation results from signal processing in the central nervous system different from the processing involved in the non-adapting vasodepressor effect.


[Complications of deep anterior lamellar keratoplasty. Avoid, recognize and treat].
Deep anterior lamellar keratoplasty (DALK) offers tremendous advantages over penetrating keratoplasty (PK). Intraoperative safety is increased due to reduced opening of the eye interoperatively and the fact that no endothelial graft rejection can take place as the patient's own corneal endothelium is retained. Despite these advantages the number of DALK procedures performed each year in Germany remains constant at a low level. One reason could be that the DALK technique offers some complexity and at the same time intraoperative conversion to PK has to be performed in some cases due to rupture of Descemet's membrane. Moreover, interface-related and DALK-specific complications exist which can contribute to an unfavorable visual outcome. Most of these complications, such as incomplete attachment of Descemet's membrane or opacification within the interface between Descemet's membrane and the posterior corneal stoma can be resolved by adequate measures making PK for revision barely necessary. As visual acuity does not differ between PK and DALK, the benefits of DALK - lack of endothelial immune reaction and increased ocular stability during surgery - outweigh the risk of additional complications and DALK should therefore be performed whenever appropriate.


Sex-discrete role of depressive symptomatology on 10-year first and recurrent cardiovascular disease incidence: results from ATTICA and GREECS prospective studies.
The sex-specific effect of depressive symptomatology on 10-year first and recurrent cardiovascular disease (CVD) events was evaluated. The Greek samples from ATTICA (2002-2012, n = 845 free-of-CVD subjects) and GREECS (2004-2014, n = 2,172 subjects with acute coronary syndrome (ACS)) prospective epidemiological studies with baseline psychological assessments were used for the first and the recurrent event, respectively. Depressive symptomatology was assessed at baseline, through Zung Self-Rating Depression Scale in the ATTICA study, and through the Center for Epidemiological Studies-Depression scale in the GREECS study. ACS as well as free-of-CVD women scored significantly higher for depressive symptomatology. Men scored higher than women against first (19.7% vs. 11.7%) and subsequent CVD events (38.8% vs. 32.9%). In participants with depressive symptoms man-to-woman first and recurrent CVD event rate ratio was below 1, confirming that depressive women were more likely to have a CVD event than depressive men. Multiadjusted analysis revealed that depressive symptomatology had an independent aggravating effect on the first (hazard ratio (HR) = 2.72, 95% confidence interval (95% CI) 1.50, 9.12) and recurrent (HR = 1.31, 95% CI 1.01, 1.69) CVD events only in women. Mediation analysis in women revealed that 35% (23%, 44%) of excess first-CVD-event risk of depressive symptoms was attributed to conventional risk factors. The respective number for recurrent CVD events was 46% (23%, 53%); different patterns of ranking regarding the mediating effect corresponding to each adjustment factor were observed. The present work augments prior evidence that psychological stressors possess important drivers of CVD onset and progression mainly in women, while it gives rise to research toward unidentified paths behind this claim.


Nicotine paradoxically affects the facilitatory effect of ovarian hormones on the adenosine receptor-mediated renal vasodilation.
We tested the hypothesis that nitric oxide synthase (NOS) and/or heme oxygenase (HO) modulate the hormonally-dependent nicotine interaction with adenosine receptor-mediated renal vasodilations. Vasodilations caused by 5'-N-ethylcarboxamidoadenosine (NECA) in phenylephrine-preconstricted perfused kidneys were reduced in ovariectomized (OVX) rats and restored to sham levels after treatment with estrogen (E2), medroxyprogesterone acetate (MPA) or their combination. The facilitatory action of E2 or MPA was abolished after blockade of their respective receptors by ICI-182780 and mifepristone, or inhibition of NOS (N(ω)-nitro-L-arginine-methyl ester, L-NAME) but not HO (zinc protoporphyrin, ZnPP). NECA vasodilations were (i) decreased and increased by nicotine (1 mg/kg/day, 2 weeks) in OVX/MPA and OVX/E2 kidneys, respectively, and (ii) resistant to nicotine in females with deficient (OVX) or balanced (sham or E2/MPA-replaced OVX) hormonal milieu. The attenuation of NECA responses by nicotine in OVX/MPA kidneys disappeared after treatment with hemin (HO inducer) but not L-arginine (NOS substrate). Alternatively, nicotine enhancement of NECA responses in OVX/E2 kidneys was abolished following treatment with ICI 182780 or L-NAME. Overall, the NOS-coupled E2/progesterone receptor contributes to the enhancement of NECA vasodilations by ovarian hormones. Further, HO inhibition and NOS facilitation mediate the directionally opposite effects of nicotine on NECA responses in MPA- or E2-replaced OVX rats, respectively.


Retracted: Application of Accelerometer to Monitor Students' Exercise Load in 50 m Round Trip.
[This retracts the article DOI: 10.1155/2022/3142677.].


Analysis of energy and macronutrient balance in the postoperative infant.
The purpose of this study was to better define the energy and macronutrient balance of infants after major surgery. Forty studies were conducted in 29 full-term surgical infants (mean weight, 3.27 +/- 0.19 kg; mean days postsurgery, 8 +/- 1). Nineteen infants were receiving total parenteral nutrition, 13 were orally fed, and eight received a combination of intravenous and oral nutrition (mean caloric intake, 84 +/- 4 kcal/kg/d). Each study was comprised of a three-day nutritional balance measuring energy intake and energy losses in excreta. Metabolizable energy intake (MEI) was determined by subtracting losses from gross intake. Energy expenditure and macronutrient oxidation were determined on the second day of the balance using continuous open-circuit indirect calorimetry in combination with timed urinary nitrogen excretion. Energy and macronutrient storage were calculated by subtracting oxidation and losses from measured intake. The mean global energy expenditure was 57 +/- 1 kcal/kg/d. Linear regression analysis of the nutritional balance data allowed estimates of energy, fat, and protein storage at various MEI. The data suggest that in the surgical infant, protein balance is maintained, even during hypocaloric nutritional regimens. In infants receiving adequate calories to maintain energy balance, maintenance metabolism is supported by the oxidation of endogenous fat. Net fat deposition will predictably only occur at metabolizable intakes of greater than 71 kcal/kg/d.


Unique indications for internal joint stabilizer for elbow instability.
Treatment of elbow instability remains challenging despite advancements in surgical techniques. The objective of this study was to evaluate obesity, advanced age or frailty, and altered cognitive function (because of mental handicap, stroke, dementia, or traumatic brain injury) as unique indications for the use of the internal joint stabilizer (IJS) to augment surgical treatment of elbow instability. This was a retrospective review of all patients 18 years and older with elbow instability who were managed with an IJS along with standard measures of care for their specific injury, such as fracture fixation and collateral ligament reconstruction. Patients were excluded if they did not have a minimum follow-up of 3 months. All patients were treated by a single shoulder and elbow fellowship-trained orthopedic traumatologist at an urban university-based level 1 trauma center. Twenty-two patients were included in the study. Five patients were 60 years of age or older. Nine patients had a body mass index of 30 or greater. Five patients had a history of 1 or more cerebral insults or cognitive impairment. The majority of patients (21/22; 95%) regained elbow stability after the index surgery. At last follow-up, 14 of 22 patients (63%) regained a functional arc of motion, defined as at least 100° arc of motion, and 77% of patients had at least 90° of motion. Complications requiring revision surgery included culture-negative recurrent elbow instability (n = 1), deep infection (n = 1), and IJS failure without recurrent instability (n = 1). The IJS was removed in all 3 cases. Twelve patients underwent delayed IJS removal >2 months after the index surgery to grant additional time for bony and ligamentous healing and to permit secondary contracture release at the time of IJS removal. No complications were seen from delayed IJS removal. The IJS may be used to create elbow stability in complex patients, regardless of weight, frailty, cognitive function, neurologic insult, or other comorbidities. Unlike external fixation, the IJS does not require pin site care and is relatively light and low-profile. When augmenting surgical fixation for elbow instability, the IJS may be preferable for patients with complex comorbidities or social dynamics.


"Spontaneous" mediastinal pancreatic pseudocyst fistulization to the esophagus.
Transhiatal extension of pancreatic pseudocysts is an infrequent cause of symptomatic mass lesions in the posterior and middle mediastinum. Delayed recognition is common. An alcoholic patient with spontaneous fistulization between a mediastinal pseudocyst and distal esophagus is presented.


Percutaneous treatment of blunt hepatic and splenic trauma under contrast-enhanced ultrasound guidance.
The objective of this study was to evaluate the clinical application of hemostatic percutaneous therapy of liver and spleen trauma under contrast-enhanced ultrasound (CEUS) guidance. A total of 83 patients with 88 traumatic organ lesions were included in this study. Liver or spleen lesions were treated by percutaneous injection of haemocoagulase atrox and α-cyanoacrylate under CEUS guidance. The results showed that one treatment was sufficient to successfully control hemorrhaging in 86 of 88 traumatic organ lesions. In 2 of 88 traumas, a second percutaneous hemostatic treatment was necessary. Percutaneous treatment of blunt hemorrhagic trauma under CEUS guidance is a feasible and safe adjunct to observation in the nonoperative management.


Preliminary observations on transplacental infection of bluetongue virus in sheep-a possible overwintering mechanism.
Sheep infected mid-gestation with bluetongue virus type 4 and type 16 produced clinically normal lambs that were viraemic at birth. Viraemia persisted for two months in some lambs even though they received colostrum. It is suggested that transplacental infection of bluetongue virus in sheep may be an overwintering mechanism for the virus in some areas of the world.


Snake venom toxins--I. The primary structure of a long neurotoxin S4C6 from Aspidelaps scutatus (shield or shield-nose snake) venom.
1. Long neurotoxin S4C6 from Aspidelaps scutatus venom was purified by gel filtration and ion exchange chromatography (Joubert, 1987). 2. It contains 68 amino acids including 10 half-cystines. The toxicity of toxin S4C6 was determined and a LD50 of 0.13 +/- 0.04 micrograms/g mouse was found. 3. The complete primary structure of long neurotoxin S4C6 has been elucidated. In the toxin the 10 structurally invariant amino acids of the neurotoxins and cytoxins and the five functionally invariant amino acids of the neurotoxins are conserved.


Central nervous system abnormalities--contrasting patterns in early and late pregnancy.
A total of 509 specimens of spontaneous abortion were studied. Of 364 complete specimens, 15 (4.1%) had central nervous system (CNS) abnormalities. The defects which were seen were anencephaly, spina bifida, iniencephaly, encephalocele and anencephaly combined with complete rachischisis. A high proportion (five out of 15) had the more unusual defects of iniencephaly and encephalocele. All except one had ceased development at less than 12 weeks of gestation. Sex chromatin studies showed that males outnumbered females amount CNS defective fetuses. When the month of conception was calculated for these abnormal pregnancies, summer and winter peaks were detected. Only one of the 15 patients had a family history of neural tube defect (NTD). Histological examination of all small fetuses aborted spontaneously revealed two additional facts. First, in fetuses with a localised external CNS defect, the internal abnormality was more extensive. Second, the CNS was also abnormal in some fetuses with no visible external defect. The proportion of abnormality is much higher than at birth and is also higher than in other surveys of spontaneous abortion. We suggest that screening for serum alphafetoprotein should be undertaken and amniocentesis considered in pregnancies subsequent to an abortion of this type.


Chitosan activated with divinyl sulfone: a new heterofunctional support for enzyme immobilization. Application in the immobilization of lipase B from Candida antarctica.
A novel heterofunctional support for enzyme immobilization, chitosan-divinyl sulfone, was assessed in this study. The activation of chitosan with DVS was carried out at three different pHs (10.0, 12.5 and 14.0) and a Candida antarctica Lipase B (CALB) was selected as the model enzyme. After immobilization, the biocatalysts were incubated under alkaline conditions in a buffer to facilitate the multipoint covalent attachment, followed by incubation in ethylenediamine (EDA) aiming at blocking the remaining reactive groups. The highest thermal stability was obtained when pH 10.0 was used during support activation. These results were shown to be better than those obtained when using glutaraldehyde as the support-activating reagent. Subsequently, the immobilization pH was investigated (5.0, 7.0 and 10.0) prior to alkaline incubation, with the highest enzyme stability levels found at pH 10.0. Finally, the selected biocatalyst was used in the hydrolysis of ethyl hexanoate and presented an activity of 14,520.37 U/g of immobilized lipase at pH 5.0. These results show that chitosan activated with divinyl sulfone is a very promising support for enzyme immobilization and the proposed protocol is able to successfully improve enzyme stability.


Hypothesis: emergence of translation as a result of RNA helicase evolution.
The origin of translation and the genetic code is one of the major mysteries of evolution. The advantage of templated protein synthesis could have been achieved only when the translation apparatus had already become very complex. This means that the translation machinery, as we know it today, must have evolved towards some different essential function that subsequently sub-functionalised into templated protein synthesis. The hypothesis presented here proposes that translation originated as the result of evolution of a primordial RNA helicase, which has been essential for preventing dying out of the RNA organism in sterile double-stranded form. This hypothesis emerges because modern ribosome possesses RNA helicase activity that likely dates back to the RNA world. I hypothesise that codon-anticodon interactions of tRNAs with mRNA evolved as a mechanism used by RNA helicase, the predecessor of ribosomes, to melt RNA duplexes. In this scenario, peptide bond formation emerged to drive unidirectional movement of the helicase via a molecular ratchet mechanism powered by Brownian motion. I propose that protein synthesis appeared as a side product of helicase activity. The first templates for protein synthesis were functional RNAs (ribozymes) that were unwound by the helicase, and the first synthesised proteins were of random or non-sense sequence. I further suggest that genetic code emerged to avoid this randomness. The initial genetic code thus emerged as an assignment of amino acids to codons according to the sequences of the pre-existing RNAs to take advantage of the side products of RNA helicase function.


Genetic variants in interferon gamma (IFN-γ) gene are associated with resistance against ticks in Bos taurus and Bos indicus.
In tropical and subtropical regions of the world, parasitic diseases are major obstacle in the health and ultimately overall performance of animals. Cattle express heritable, contrasting phenotypes when exposed to ticks depicting genetic nature of trait. IFN-γ is one of the most reported genes critical for innate and adaptive immunity against viral and intracellular infections. To identify its role in resistance for ectoparasite especially tick, genetic characterization of this gene was done in resistant and susceptible animals of Sahiwal cattle (n = 95) and Friesian (n = 92). Nine Polymorphisms were identified, three of them were found in exonic region. One out of nine variants was being reported previously (ss82716193) and was confirmed in Pakistani Sahiwal cattle population as well. Single site analysis of each variant depicted their significance in tick resistant and tick susceptible groups (P < 0.05). The associations using haplotypes were more informative than for single markers. Eighteen different haplotypes resulting from nine polymorphic sites were used in construction of maximum parsimony tree which categorized resistant and susceptible animals in two clades. Genetic markers identified in this study can be useful in future breeding selection programs against tick resistance.


[Effect of steroid aromatase inhibitors on the catecholamine content of the hypothalamus of neonatally androgenized rats].
Administration of 50 micrograms of testosterone propionate to newborn female rats on the 5th day of life provoked a reliable increase in noradrenaline and dopamine concentrations in the hypothalamus of 10-day-old rats. Neonatal administration of aromatase inhibitors on the 5th and 7th days of life prevented testosterone-induced increase in catecholamine concentrations. The data obtained prove the integration of the processes of testosterone aromatization and catecholamine accumulation in androgen-dependent brain differentiation.


Sono-synthesis of core-shell nanocrystal (CdS/TiO2) without surfactant.
A core-shell nanocomposite (CdS/TiO(2)) was synthesized at relatively low temperature (70°C) with small particle sizes (~11 nm). First, CdS nanoparticles were prepared by a combination of ultrasound and new micro-emulsion (O/W) without surfactant. Then the synthesized CdS was easily combined with TiO(2) under sonication. The formation of uniform surface layer of TiO(2) with depths of 0.75-1.1 nm on the CdS led to an increase of particle size. Ultrasonic irradiation can control the hydrolysis and condensation of titanium tetra-isopropoxide (TTIP) and the formation of TiO(2) shell around the CdS core. This technique avoids some of the problems that exist in conventional microemulsion synthesis such as the presence of different additives and calcinations. It was found that nanocomposite particles extend the optical absorption spectrum into the visible region in comparison with pure TiO(2) and pure CdS. In addition, a larger depth of TiO(2) led to a red-shift of the absorption band in nanocomposite. The characterization of nanocomposites has been studied by HRTEM, TEM, XRD, EDAX, BET and, UV-vis.


N-Methylthio beta-lactam antibacterials: effects of the C3/C4 ring substituents on anti-MRSA activity.
N-Thiolated beta-lactams are a new family of antibacterials that inhibit the growth of Staphylococcus bacteria. Unlike other beta-lactam drugs, these compounds retain their full antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains and operate through a different mode of action. The structural features, which give these lactams their biological activity, have not yet been completely defined. Earlier efforts in our laboratory established that the N-organothio substituent is essential for antimicrobial activity while other groups at C(3) and C(4) on the lactam ring play a more subtle role. In this present study, we investigate these effects by varying the polar and steric nature of the ring substituents at these two centers. From the data presented herein, it appears that there is a need to balance the lipophilic character of the C(3)/C(4) groups to obtain an optimal anti-MRSA activity. The structure-bioactivity profiles more closely relate to the compound's ability to penetrate the bacterial cell membrane to sites of action within the cytoplasm rather than to any specific non-bonding interactions with a biological target. Based on these results, a model for the compounds' mode of action is presented.


Ex-vivo lung perfusion.
Ex-vivo lung perfusion (EVLP) has been developed to expand the donor pool for lung transplantation recipients. The role of EVLP in organ preservation, evaluation and potential reconditioning is reviewed. EVLP has been shown to significantly increase the utilization of donor lungs for transplantation. Evidence suggests that patient outcomes from EVLP lungs are comparable to standard procurement technique. Novel strategies are being developed to treat and recondition injured donor lungs. EVLP may also prove to be a tool for translational research of lung diseases. EVLP has been shown to be an effective system to expand donor pool for lung transplantation without detriment to recipients. Future potential ex-vivo developments may further improve patient outcomes as well as increasing availability of donor organs.


Hemodynamic evaluation of rectal varices by color Doppler ultrasonography: a case report.
A 69-year-old man with liver cirrhosis was admitted to our hospital with general fatigue. Colonoscopy revealed risky red color sign-positive enlarged tortuous rectal varices. Endoscopic injection sclerotherapy (EIS) was performed three times weekly using 5% ethanolamine oleate with iopamidol; the total amount of sclerosant was 7 ml. Images of rectal varices and the outflowing vessel from rectal varices were obtained via color Doppler ultrasonography before EIS, and fast Fourier transform analysis showed a continuous flow with a frequency shift of 276.6 Hz. We successfully performed EIS for this patient, having effective varicealography. After EIS, colonoscopy revealed shrinkage of the varices in the rectum, and color Doppler indicated an extreme decrease of blood flow in the rectal varices. In conclusion, color Doppler is a useful noninvasive modality for detecting rectal varices and for evaluating the therapeutic effects of EIS.


Cellular localization of orexin receptors in human adrenal gland, adrenocortical adenomas and pheochromocytomas.
Orexin-A and -B are hypothalamic peptides derived from a precursor called prepro-orexin and related with the regulation of the energy balance and arousal. They act on G protein receptors named orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). In the present study, we used immunohistochemical techniques to detect the distribution of OXR in normal human adrenal gland and adrenal tumours (adrenocortical adenomas and pheochromocytomas). OX1R was expressed in the cortex of the normal human adrenal gland (glomerulosa, fasciculata and reticular zones) and OX2R was located in the medulla (epinephrine and norepinephrine cells). By the double immunofluorescence techniques, we demonstrated that virtually all medullar cells (epinephrine and norepinephrine cells) expressed OX2R. As was expected, according to the results obtained in normal tissues, cortical tumours (adrenocortical adenomas) were positive for OX1R but not for OX2R and conversely, medullar tumours (pheochromocytomas) expressed only OX2R.


Quantitative Iron Neuroimaging Can Be Used to Assess the Effects of Minocycline in an Intracerebral Hemorrhage Minipig Model.
Iron-mediated toxicity is a key factor causing brain injury after intracerebral hemorrhage (ICH). This study was performed to investigate the noninvasive neuroimaging method for quantifying brain iron content using a minipig ICH model and assess the effects of minocycline treatment on ICH-induced iron overload and brain injury. The minipig ICH model was established by injecting 2 ml of autologous blood into the right basal ganglia, which were then subjected to the treatments of minocycline and vehicle. Furthermore, the quantitative susceptibility mapping (QSM) was used to quantify iron content, and diffusion tensor imaging (DTI) was performed to evaluate white matter tract. Additionally, we also performed immunohistochemistry, Western blot, iron assay, Perl's staining, brain water content, and neurological score to evaluate the iron overload and brain injury. Interestingly, we found that the ICH-induced iron overload could be accurately quantified by the QSM. Moreover, the minocycline was quite beneficial for protecting brain injury by reducing the lesion volume and brain edema, preventing brain iron accumulation, downsizing ventricle enlargement, and alleviating white matter injury and neurological deficits. In summary, we suggest that the QSM be an accurate and noninvasive method for quantifying brain iron level, and the minocycline may be a promising therapeutic agent for patients with ICH.


Hepatectomy is superior to thermal ablation for patients with a solitary colorectal liver metastasis.
Hepatic resection is the mainstay of treatment for solitary colorectal liver metastases (mCRC); however, some patients are not ideal candidates. The aim of this study was to compare outcomes for patients with solitary mCRC who underwent resection or ablation. A retrospective review of a hepatobiliary database identified patients with solitary mCRC. Patients who were treated with hepatectomy were compared to patients who underwent thermal ablation. The median follow-up time was 25.9 months. Ninety-four patients (67.1%) underwent resection whereas 46 patients (32.8%) underwent ablation. Of the resected patients, most (60%) required a major hepatectomy. Tumor ablation was a significant predictor of overall survival (p = 0.002, OR 3.75, 95% CI 1.696-8.284). Overall, the median disease-free survival was 55.2 months for patients undergoing resection vs. 42.6 months for ablated patients (p = 0.073). Median overall survival was 112.7 months for patients undergoing resection vs. 50.2 months for patients undergoing ablation (p = 0.005). Patients with solitary hepatic colorectal cancer metastases should be considered for hepatic resection as this provides superior survival when compared to thermal ablation.


Strategies to produce T-DNA free CRISPRed fruit trees via Agrobacterium tumefaciens stable gene transfer.
Genome editing via CRISPR/Cas9 is a powerful technology, which has been widely applied to improve traits in cereals, vegetables and even fruit trees. For the delivery of CRISPR/Cas9 components into dicotyledonous plants, Agrobacterium tumefaciens mediated gene transfer is still the prevalent method, although editing is often accompanied by the integration of the bacterial T-DNA into the host genome. We assessed two approaches in order to achieve T-DNA excision from the plant genome, minimizing the extent of foreign DNA left behind. The first is based on the Flp/FRT system and the second on Cas9 and synthetic cleavage target sites (CTS) close to T-DNA borders, which are recognized by the sgRNA. Several grapevine and apple lines, transformed with a panel of CRISPR/SpCas9 binary vectors, were regenerated and characterized for T-DNA copy number and for the rate of targeted editing. As detected by an optimized NGS-based sequencing method, trimming at T-DNA borders occurred in 100% of the lines, impairing in most cases the excision. Another observation was the leakage activity of Cas9 which produced pierced and therefore non-functional CTS. Deletions of genomic DNA and presence of filler DNA were also noticed at the junctions between T-DNA and genomic DNA. This study proved that many factors must be considered for designing efficient binary vectors capable of minimizing the presence of exogenous DNA in CRISPRed fruit trees.


Ancient helium and tungsten isotopic signatures preserved in mantle domains least modified by crustal recycling.
Rare high-3He/4He signatures in ocean island basalts (OIB) erupted at volcanic hotspots derive from deep-seated domains preserved in Earth's interior. Only high-3He/4He OIB exhibit anomalous 182W-an isotopic signature inherited during the earliest history of Earth-supporting an ancient origin of high 3He/4He. However, it is not understood why some OIB host anomalous 182W while others do not. We provide geochemical data for the highest-3He/4He lavas from Iceland (up to 42.9 times atmospheric) with anomalous 182W and examine how Sr-Nd-Hf-Pb isotopic variations-useful for tracing subducted, recycled crust-relate to high 3He/4He and anomalous 182W. These data, together with data on global OIB, show that the highest-3He/4He and the largest-magnitude 182W anomalies are found only in geochemically depleted mantle domains-with high 143Nd/144Nd and low 206Pb/204Pb-lacking strong signatures of recycled materials. In contrast, OIB with the strongest signatures associated with recycled materials have low 3He/4He and lack anomalous 182W. These observations provide important clues regarding the survival of the ancient He and W signatures in Earth's mantle. We show that high-3He/4He mantle domains with anomalous 182W have low W and 4He concentrations compared to recycled materials and are therefore highly susceptible to being overprinted with low 3He/4He and normal (not anomalous) 182W characteristic of subducted crust. Thus, high 3He/4He and anomalous 182W are preserved exclusively in mantle domains least modified by recycled crust. This model places the long-term preservation of ancient high 3He/4He and anomalous 182W in the geodynamic context of crustal subduction and recycling and informs on survival of other early-formed heterogeneities in Earth's interior.


De novo design of monomeric helical bundles for pH-controlled membrane lysis.
Targeted intracellular delivery via receptor-mediated endocytosis requires the delivered cargo to escape the endosome to prevent lysosomal degradation. This can in principle be achieved by membrane lysis tightly restricted to endosomal membranes upon internalization to avoid general membrane insertion and lysis. Here, we describe the design of small monomeric proteins with buried histidine containing pH-responsive hydrogen bond networks and membrane permeating amphipathic helices. Of the 30 designs that were experimentally tested, all expressed in Escherichia coli, 13 were monomeric with the expected secondary structure, and 4 designs disrupted artificial liposomes in a pH-dependent manner. Mutational analysis showed that the buried histidine hydrogen bond networks mediate pH-responsiveness and control lysis of model membranes within a very narrow range of pH (6.0-5.5) with almost no lysis occurring at neutral pH. These tightly controlled lytic monomers could help mediate endosomal escape in designed targeted delivery platforms.


Nursing Home Transfers for Behavioral Concerns: Findings from the OPTIMISTIC Demonstration Project.
To characterize pretransfer on-site nursing home (NH) management, transfer disposition, and hospital discharge diagnoses of long-stay residents transferred for behavioral concerns. This was a secondary data analysis of the Optimizing Patient Transfers, Impacting Medical Quality, Improving Symptoms: Transforming Institutional Care project, in which clinical staff employed in the NH setting conducted medical, transitional, and palliative care quality improvement initiatives and gathered data related to resident transfers to the emergency department/hospital setting. R software and Microsoft Excel were used to characterize a subset of transfers prompted by behavioral concerns. NHs in central Indiana were utilized (N = 19). This study included long-stay NH residents with behavioral concerns prompting transfer for acute emergency department/hospital evaluation (N = 355 transfers). The measures used in this study were symptoms prompting transfer, resident demographics and baseline characteristics (Minimum Data Set 3.0 variables including scores for the Cognitive Function Scale, ADL Functional Status, behavioral symptoms directed toward others, and preexisting psychiatric diagnoses), on-site management (e.g., medical evaluation in person or by phone, testing, and interventions), avoidability rating, transfer disposition (inpatient vs emergency department only), and hospital discharge diagnoses. Over half of the transfers, 56%, had a medical evaluation before transfer, and diagnostic testing was conducted before 31% of transfers. After transfer, 80% were admitted. The most common hospital discharge diagnoses were dementia-related behaviors (27%) and altered mental status (27%), followed by a number of medical diagnoses. Most transfers for behavioral concerns merited hospital admission, and medical discharge diagnoses were common. There remain significant opportunities to improve pretransfer management of NH transfers for behavioral concerns.


gmxapi: A GROMACS-native Python interface for molecular dynamics with ensemble and plugin support.
Gmxapi provides an integrated, native Python API for both standard and advanced molecular dynamics simulations in GROMACS. The Python interface permits multiple levels of integration with the core GROMACS libraries, and legacy support is provided via an interface that mimics the command-line syntax, so that all GROMACS commands are fully available. Gmxapi has been officially supported since the GROMACS 2019 release and is enabled by default in current versions of the software. Here we describe gmxapi 0.3 and later. Beyond simply wrapping GROMACS library operations, the API permits several advanced operations that are not feasible using the prior command-line interface. First, the API allows custom user plugin code within the molecular dynamics force calculations, so users can execute custom algorithms without modifying the GROMACS source. Second, the Python interface allows tasks to be dynamically defined, so high-level algorithms for molecular dynamics simulation and analysis can be coordinated with loop and conditional operations. Gmxapi makes GROMACS more accessible to custom Python scripting while also providing support for high-level data-flow simulation algorithms that were previously feasible only in external packages.


Quadriceps strength, quadriceps power, and gait speed in older U.S. adults with diabetes mellitus: results from the National Health and Nutrition Examination Survey, 1999-2002.
To examine the independent association between diabetes mellitus (and its duration and severity) and quadriceps strength, quadriceps power, and gait speed in a national population of older adults. Cross-sectional nationally representative survey. United States. Two thousand five hundred seventy-three adults aged 50 and older in the National Health and Nutrition Examination Survey 1999-2002 who had assessment of quadriceps strength. Diabetes mellitus was ascertained according to questionnaire. Measurement of isokinetic knee extensor (quadriceps) strength was performed at 60º/s. Gait speed was assessed using a 20-foot walk test. Multiple linear regression analyses were used to assess the association between diabetes mellitus status and outcomes, adjusting for potential confounders or mediators. Older U.S. adults with diabetes mellitus had significantly slower gait speed (0.96 ± 0.02 m/s) than those without (1.08 ± 0.01 m/s; P < .001). After adjusting for demographic characteristics, weight, and height, diabetes mellitus was also associated with significantly lower quadriceps strength (-4.6 ± 1.9 Nm; P = .02) and power (-4.9 ± 2.0 W; P = .02) and slower gait speed (-0.05 ± 0.02 m/s; P = .002). Associations remained significant after adjusting for physical activity and C-reactive protein. After accounting for comorbidities (cardiovascular disease, peripheral neuropathy, amputation, cancer, arthritis, fracture, chronic obstructive pulmonary disease), diabetes mellitus was independently associated only with gait speed (-0.04 ± 0.02 m/s; P = .02). Diabetes mellitus duration in men and women was negatively associated with age-adjusted quadriceps strength (-5.7 and -3.5 Nm/decade of diabetes mellitus, respectively) and power (-6.1 and -3.8 W/decade of diabetes mellitus, respectively) (all P ≤ .001, no significant interactions according to sex). Glycosylated hemoglobin was not associated with outcomes after accounting for body weight. Older U.S. adults with diabetes mellitus have lower quadriceps strength and quadriceps power that is related to the presence of comorbidities and walk slower than those without diabetes mellitus. Future studies should investigate the relationship between hyperglycemia and subsequent declines in leg muscle function.


Reproductive and developmental toxicity of dioxin in fish.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is a global environmental contaminant and the prototypical ligand for investigating aryl hydrocarbon receptor (AHR)-mediated toxicity. Environmental exposure to TCDD results in developmental and reproductive toxicity in fish, birds and mammals. To resolve the ecotoxicological relevance and human health risks posed by exposure to dioxin-like AHR agonists, a vertebrate model is needed that allows for toxicity studies at various levels of biological organization, assesses adverse reproductive and developmental effects and establishes appropriate integrative correlations between different levels of effects. Here we describe the reproductive and developmental toxicity of TCDD in feral fish species and summarize how using the zebrafish model to investigate TCDD toxicity has enabled us to characterize the AHR signaling in fish and to better understand how dioxin-like chemicals induce toxicity. We propose that such studies can be used to predict the risks that AHR ligands pose to feral fish populations and provide a platform for integrating risk assessments for both ecologically relevant organisms and humans.


Sound waves and antineoplastic drugs: The possibility of an enhanced combined anticancer therapy.
Kremkau wrote a historical review of the use of ultrasound in cancer therapy in 1979((1)) In 1990, Kondo and Kano published a Japanese review of the implications of the thermal and nonthermal effects of ultrasound in the treatment of cancer(2)). Again in 2000, Kondo et al reviewed the therapeutic applications of ultrasound and shock wave, emphasizing their thermal and cavitational effects(3)). Here we focus on the effects of ultrasound or shock waves in combination with anticancer agents, emphasizing their mechanisms of action and interaction. Most of the studies cited here reported promising results. Although the extent of the augmented combined effects in vivo is limited, synergism is the rule in vitro. In addition to the thermal effect of ultrasound, cavitational effects undoubtedly played a major role in both ultrasound and, more prominently, in shock wave therapy. Although the mechanism of the nonthermal noncavitational effects on biological processes is obscure, several factors, including temperature and the occurrence of cavitation and inertial cavitation, probably coexist and blend with these other effects. Magnification of anticancer activity results mainly from increased localization of drugs or other agents in vivo and increased intracellular permeabilisation both in vivo and in vitro. On the other hand, sublethal damage caused by ultrasound or shock waves may render cells more susceptible, to the effects of the agents, and both may act together, further amplifying these effects. We thus conclude that proper combination of an appropriate agent and ultrasound or shock wave should help improve cancer therapy by minimizing the side effects of drugs by lowering the effective dose and reducing the systemic concentration while increasing the efficiency of the therapy as a whole. Future studies should reveal specific conditions in this combined therapy that will lead to optimal outcome.


Estimation of exposure-specific rates from sparse case-control data.
Several methods for estimation of exposure-specific rates from case-control data have been developed, but none are practical for application to sparse stratifications, such as individually matched case-control data. This paper presents a method for estimating standardized exposure-specific rates that can be applied to sparse data, as well as other (non-sparse) stratifications. An application to a matched-pair case-control study of prostate cancer is given.


Effects of Hextend hemodilution on plasma coagulation kinetics in the rabbit: role of factor XIII-mediated fibrin polymer crosslinking.
Hydroxyethyl starch administration has been associated with decreases in hemostasis and has recently been demonstrated to decrease fibrinogen (FI)-thrombin-(FIIa)-Factor XIII (FXIII) interactions in vitro in human plasma. Thus, the purpose of the present study was to determine the effect of in vivo hemodilution with Hextend (6% hydroxyethyl starch, mean molecular weight 450 kDa) on plasma coagulation kinetics. Eight male, New Zealand White rabbits were intravenously administered with 20 ml/kg of Hextend. Citrated plasma was obtained before, 1 min after, and 1 h after hemodilution. Thrombelastographic analyses were performed, with clot initiation (R, sec), clot propagation (alpha, degrees), and clot strength (shear elastic modulus, G, dynes/cm(2)) determined over 20 min. Samples were celite-activated and had either with addition or without additions of FI, FIIa or activated FXIII (FXIIIa) to restore protein content to prediluted values. There was no significant difference in R values observed before (229 +/- 30), 1 min after (241 +/- 54), and 1 h after (214 +/- 42) hemodilution. Prediluted alpha values (75.2 +/- 1.9) were significantly decreased 1 min (53.3 +/- 5.9) and 1 h after hemodilution (56.1 +/- 10.2). Prediluted G values (1,992 +/- 434) were significantly reduced 1 min (532 +/- 195) and 1 h after (630 +/- 297) hemodilution. FI, FIIa, and FXIIIa addition significantly decreased R values after hemodilution. alpha and G values were significantly improved by FI and FXIIIa after hemodilution. FIIa addition did not significantly affect alpha or G. Hextend hemodilution in rabbits maintains clot initiation by diminishing both FIIa-FI and FXIIIa-fibrin interactions, whereas clot propagation and strength were reduced by diminished FXIIIa-fibrin interactions.


Avoiding Toxicity With Lung Radiation Therapy: An IASLC Perspective.
Toxicity concerns from thoracic radiation therapy in the treatment of lung cancers have changed substantially over the past few decades. Survival in the treatment of lung cancer has markedly improved and the introduction of advanced radiation and imaging techniques to treatment planning and delivery has made reducing toxicity possible. Phase 3 dose-escalation trials have revealed that excess dose to critical organs within the thorax can negatively impact overall survival. We summarize the existing literature on the known toxicities of thoracic radiation therapy, summarize the technological advances that have made toxicity reduction possible, and provide an overview of emerging technologies and biomarkers that are being evaluated to assess future toxicity reductions.


Aromatization of 19-norandrogens by equine testicular microsomes.
In the stallion testis, aromatase activity was localized in the microsomal fraction. Androgen aromatization occurred through the loss of 1 beta,2 beta hydrogen atoms and appeared to involve free sulfhydryl groups. A single enzyme system seemed to aromatize androgen and norandrogen at the same rate while having a much lower affinity for norandrogens.


Association between hypertension requiring medication and 30-day outcomes in head and neck microvascular surgery.
Hypertension has been shown to be both a protective factor and a risk factor for complications in head and neck reconstructive surgery. Retrospective analysis of microvascular free tissue transfer patients using the National Surgical Quality Improvement Program database. Hypertensive patients (n = 1598; 46.9%) had a significantly higher rate of complications, including pneumonia (p < 0.001), myocardial infarction (p = 0.003), and intra/post-operative transfusion (p < 0.001). In a multivariable model, hypertension was associated with returning to the operating room (OR = 1.45 [95% CI 1.20, 1.76], p < 0.001), post-operative medical complications (OR = 1.53 [95% CI 1.24, 1.90], p < 0.001), and surgical complications (OR = 1.17 [95% CI 1.00, 1.37], p = 0.047). However, no difference in 30-day readmission was found (p > 0.05). Hypertension is a modifiable risk factor for post-operative complications in head and neck free tissue transfer, in which prospective studies are required to establish causation. This study may serve as an impetus for proactive recommendations to manage hypertension before undergoing head and neck microvascular surgery.


Type I to type II ovarian carcinoma progression: mutant Trp53 or Pik3ca confers a more aggressive tumor phenotype in a mouse model of ovarian cancer.
A dualistic pathway model of ovarian carcinoma (OvCA) pathogenesis has been proposed: type I OvCAs are low grade, genetically stable, and relatively more indolent than type II OvCAs, most of which are high-grade serous carcinomas. Endometrioid OvCA (EOC) is a prototypical type I tumor, often harboring mutations that affect the Wnt and phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathways. Molecular and histopathologic analyses indicate type I and II OvCAs share overlapping features, and a subset of EOCs may undergo type I→type II progression accompanied by acquisition of somatic TP53 or PIK3CA mutations. We used a murine model of EOC initiated by conditional inactivation of the Apc and Pten tumor suppressor genes to investigate mutant Trp53 or Pik3ca alleles as key drivers of type I→type II OvCA progression. In the mouse EOC model, the presence of somatic Trp53 or Pik3ca mutations resulted in shortened survival and more widespread metastasis. Activation of mutant Pik3ca alone had no demonstrable effect on the ovarian surface epithelium but resulted in papillary hyperplasia when coupled with Pten inactivation. Our findings indicate that the adverse prognosis associated with TP53 and PIK3CA mutations in human cancers can be functionally replicated in mouse models of type I→type II OvCA progression. Moreover, the models should represent a robust platform for assessment of the contributions of Trp53 or Pik3ca defects in the response of EOCs to conventional and targeted drugs.


Obesity in Women: The Clinical Impact on Gastrointestinal and Reproductive Health and Disease Management.
Approximately 36% of adult women in the United States are obese. Although obesity affects women similarly to men in terms of prevalence, there seem to be gender-specific differences in the pathophysiology, clinical manifestations, and treatment of obesity. Obesity is linked to comorbid diseases involving multiple organ systems, including the gastrointestinal tract, like gastroesophageal reflux disease, fatty liver disease, and gallstones. This article focuses on obesity in women, specifically the impact of obesity on gastrointestinal diseases and reproductive health, as well as the treatment of obesity in women.


Novel estrogen and tamoxifen induced genes identified by SAGE (Serial Analysis of Gene Expression).
The breast cancer promoting effects of estrogen and the chemopreventive effects of tamoxifen are thought to be mediated by the estrogen receptor, a ligand-dependent transcription factor. Therefore, comprehensive analysis of gene expression profiles following estrogen or tamoxifen treatment may help us better understand the role estrogen plays in tumorigenesis. We utilized SAGE (Serial Analysis of Gene Expression) technology to identify genes regulated by estrogen and tamoxifen in the ZR75-1 estrogen dependent breast cancer cell line. In this manner we have identified several genes that were regulated by estrogen or tamoxifen. Here we report the identification and initial characterization of EIT-6 (Estrogen Induced Tag-6), a novel nuclear protein and a new member of the evolutionarily conserved SM-20 family of growth regulatory immediate-early genes. EIT-6 appears to be a direct transcriptional target of the estrogen receptor and constitutive expression of EIT-6 promotes colony growth in human breast cancer cells. These data indicate that EIT-6 may play a role in estrogen induced cell growth.


Pandemic modelling and model citizens: Governing COVID-19 through predictive models, sovereignty and discipline.
Pandemic modelling functions as a means of producing evidence of potential events and as an instrument of intervention that Tim Rhodes and colleagues describe as entangling science into social practices, calculations into materializations, abstracts into effects and models into society. This article seeks to show how a model society evinced through mathematical models produces a model not only for society but also for citizens, showing them how to act in a certain model manner that prevents an anticipated pandemic future. To this end, we analyse political speeches by various Norwegian ministers to elucidate how various model-based COVID-19 responses enact a 'model citizen'. Theoretically, we combine Rhodes et al.'s arguments with Foucault's concepts of law, discipline and security, thus showing what a model society might imply for the model citizen. Finally, we conclude that although the model society is largely informed by epidemiological models and liberal biopolitics that typically place responsibility on individual subjects, sovereign state power remains manifestly present in the speeches' rhetoric.


Serum retinol-binding protein 4 concentration and its ratio to serum retinol are associated with obesity and metabolic syndrome components in children.
Although retinol-binding protein (RBP)-4 concentrations are elevated in animal models of obesity and insulin resistance (IR), the link between RBP4 and IR in humans is less clear. There are few published data on RBP4 levels in overweight children, and most previous studies did not control for vitamin A (VA) status and/or subclinical inflammation. The objective of the study was to measure serum RBP4, serum retinol (SR), the RBP4-to-SR molar ratio, and dietary VA intakes in normal-weight and overweight children and investigate the relationship of these variables to IR, subclinical inflammation, and the metabolic syndrome in this age group. This was a cross-sectional study. The study was conducted in Northern Switzerland. Patients included 6- to 14-yr-old normal-weight, overweight, and obese children (n = 79). Body mass index, body fat percentage, waist-to-hip ratio, dietary VA intakes, serum RBP4, and SR were determined. IR was assessed using fasting insulin and the quantitative insulin sensitivity check index, and components of the metabolic syndrome and indices of subclinical inflammation were measured. Only 3% of children had low VA status. Independent of age, VA intakes, and C-reactive protein, body mass index, body fat percentage, and waist-to-hip ratio were significant predictors of RBP4, SR, and RBP4/SR. Independent of adiposity, RBP4 and RBP4/SR were significantly correlated with serum triglycerides, and RBP4/SR was correlated with fasting insulin. The RBP4-to-SR ratio more strongly correlated with components of the metabolic syndrome than serum RBP4. Independent of subclinical inflammation and vitamin A intakes, serum RBP4 and the RBP4-to-SR ratio are correlated with obesity, central obesity, and components of the metabolic syndrome in prepubertal and early pubertal children.


Speed and heading control-based collision avoidance for a ship towing system.
Collision avoidance is a priority task for ensuring the safety of a maritime transportation system. However, for a ship towing system, which is characterized by multiple vessels and physical connections, the research works about collision avoidance is limited. Thus, this paper proposes a speed and heading control-based conflict resolution of a ship towing system for collision avoidance. Two systems compose the core of the proposed conflict resolution: the risk assessment system and the coordination control system. The risk assessment is to identify the conflict and determine the time of avoiding action by calculating the index of conflict and the available maneuvering margin. The coordination control is based on the model predictive control (MPC) strategy to cooperatively control two tugboats for regulating the position, heading, and speed of the manipulated ship. Simulation experiments show that according to the index of conflict, the time cost, and the fuel consumption, a selected operation of combined heading and speed can be recommended for a ship towing system to provide a safer and more efficient towage manipulation.


Assessment of Biochemical and Densitometric Markers of Calcium-Phosphate Metabolism in the Groups of Patients with Multiple Sclerosis Selected due to the Serum Level of Vitamin D3.
In addition to the widely known effect of vitamin D3 (vitD3) on the skeleton, its role in the regulation of the immune response was also confirmed. The assessment of biochemical and densitometric markers of calcium-phosphate metabolism in the groups of patients with relapsing-remitting multiple sclerosis (RRMS) selected due to the serum level of vitamin D3. The concentrations of biochemical markers and indices of lumbar spine bone densitometry (DXA) were determined in 82 patients divided into vitamin D3 deficiency (VitDd), insufficiency (VitDi), and normal vitamin D3 level (VitDn) subgroups. The highest level of the parathyroid hormone (PTH) and the highest prevalence of hypophosphatemia and osteopenia were demonstrated in VitDd group compared to VitDi and VitDn. However, in VitDd, VitDi, and VitDn subgroups no significant differences were observed in the levels of alkaline phosphatase (ALP) and ionized calcium (Ca2+) and in DXA indices. A negative correlation was observed between the level of vitamin D3 and the Expanded Disability Status Scale (EDSS) in the whole MS group. The subgroups were significantly different with respect to the EDSS scores and the frequency of complaints related to walking according to the EQ-5D. It is necessary to assess calcium-phosphate metabolism and supplementation of vitamin D3 in RRMS patients. The higher the clinical stage of the disease assessed with the EDSS, the lower the level of vitamin D3 in blood serum. Subjectively reported complaints related to difficulties with walking were reflected in the EDSS in VitDd patients.


Exon-level expression profiling of ocular tissues.
The normal gene expression profiles of the tissues in the eye are a valuable resource for considering genes likely to be involved with disease processes. We profiled gene expression in ten ocular tissues from human donor eyes using Affymetrix Human Exon 1.0 ST arrays. Ten different tissues were obtained from six different individuals and RNA was pooled. The tissues included: retina, optic nerve head (ONH), optic nerve (ON), ciliary body (CB), trabecular meshwork (TM), sclera, lens, cornea, choroid/retinal pigment epithelium (RPE) and iris. Expression values were compared with publically available Expressed Sequence Tag (EST) and RNA-sequencing resources. Known tissue-specific genes were examined and they demonstrated correspondence of expression with the representative ocular tissues. The estimated gene and exon level abundances are available online at the Ocular Tissue Database.


Interaction between basal ganglia and limbic circuits in learning and memory processes.
Hippocampus and striatum play distinctive roles in memory processes since declarative and non-declarative memory systems may act independently. However, hippocampus and striatum can also be engaged to function in parallel as part of a dynamic system to integrate previous experience and adjust behavioral responses. In these structures the formation, storage, and retrieval of memory require a synaptic mechanism that is able to integrate multiple signals and to translate them into persistent molecular traces at both the corticostriatal and hippocampal/limbic synapses. The best cellular candidate for this complex synthesis is represented by long-term potentiation (LTP). A common feature of LTP expressed in these two memory systems is the critical requirement of convergence and coincidence of glutamatergic and dopaminergic inputs to the dendritic spines of the neurons expressing this form of synaptic plasticity. In experimental models of Parkinson's disease abnormal accumulation of α-synuclein affects these two memory systems by altering two major synaptic mechanisms underlying cognitive functions in cholinergic striatal neurons, likely implicated in basal ganglia dependent operative memory, and in the CA1 hippocampal region, playing a central function in episodic/declarative memory processes.


Selective measurement of triacylglycerol lipase activities in pig post-heparin plasma.
Immunochemical methods for the selective measurement of pig post-heparin plasma lipoprotein lipase and hepatic lipase are described and validated. A simple two step purification method for porcine hepatic lipase from hepatic perfusate based on affinity chromatography and gel filtration is reported. The activity of the post-heparin plasma lipoprotein lipase and hepatic lipase in swine is reported. It is demonstrated that fasting decreases the activity of post-heparin plasma lipoprotein lipase activity more than two-fold while it does not affect the hepatic lipase activity significantly.


Acute hemolysis and methemoglobinemia secondary to fava beans ingestion in a patient with G6PD deficiency: A case report of a rare co-occurrence.
Favism is a well-known cause of acute hemolytic anemia. Rarely, methemoglobinemia can also happen because of fava bean ingestion in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Few cases with this co-occurrence have been reported in the literature. We report a case of a 47-year-old patient who presented with jaundice that started 2 days after eating fava beans. Laboratory investigations revealed anemia with evidence of hemolysis (high reticulocytes count, high indirect bilirubin, bite cells in peripheral smear). Blood gases showed high methemoglobin level. Reduced level of G6PD enzyme confirmed the diagnosis of G6PD deficiency. The patient was kept on supplemental oxygen. He was counselled to avoid food and drugs that can cause acute hemolysis. Oxygen saturation improved gradually. The patient was discharged without any complications after 2 days. Patients with G6PD deficiency can develop both acute hemolytic anemia and methemoglobinemia secondary to fava beans ingestion. These patients should not receive methylene blue to avoid worsening hemolysis.


Out-of-hospital cardiac arrest in patients with cardiac amyloidosis: presenting rhythms, management and outcomes in four patients.
Primary systemic amyloidosis (AL) is a well-recognized systemic disease, and cardiac amyloidosis accounts for 10% of all nonischemic cardiomyopathies [J S C Med Assoc 97 (2001) 201-206]. The median survival of patients with symptomatic congestive heart failure secondary to cardiac amyloidosis is 4 months [New Engl J Med 336 (1997) 1202-1207; Am J Med 100 (1996) 290-298]. The cause of death in most patients is refractory congestive heart failure or sudden arrhythmic [Mayo Clin Proc 59 (1984) 589-597]. While there are reports of in-hospital arrhythmic deaths in these patients, there are no detailed reports that describe the presentation and management of patients with cardiac amyloidosis who have experienced an out-of-hospital cardiac arrest (OHCA). We describe here our experience with four patients with AL who had an OHCA, including presenting rhythms, interventions, and outcomes.


Diagnostic imaging of spinal trauma.
The radiologist has a pivotal role in evaluation of spinal trauma patients because proper treatment cannot begin before the abnormality is diagnosed. Plain films remain the screening modality of choice, and by understanding the radiographic signs of injury, patterns produced by various traumatic mechanisms can be recognized. As radiologists we can then provide insight to our clinical colleagues into the optimal methods of further investigation. The objective is to eliminate the possibility of further damage and to identify lesions amenable to correction.


Evaluation of a typhoid/paratyphoid diagnostic assay (TPTest) detecting anti-Salmonella IgA in secretions of peripheral blood lymphocytes in patients in Dhaka, Bangladesh.
Rapid and reliable diagnostic assays for enteric (typhoid and paratyphoid) fever are urgently needed. We report the characterization of novel approach utilizing lymphocyte secretions, for diagnosing patients with enteric fever by the TPTest procedure. TPTest detects Salmonella-specific IgA responses in lymphocyte culture supernatant. We utilized TPTest in patients with suspected enteric fever, patients with other illnesses, and healthy controls. We also evaluated simplified modifications of TPTest for adaptation in laboratories with limited facilities and equipment. TPTest was positive in 39 (27 typhoid and 12 paratyphoid A) patients confirmed by blood culture and was negative in 74 healthy individuals. Among 32 individuals with other illnesses, 29 were negative by TPTest. Of 204 individuals with suspected enteric fever who were negative by blood culture, 44 were positive by TPTest and the patients were clinically indistinguishable from patients with confirmed bacteremia, except they were more likely to be under 5 years of age. We evaluated simplifications in TPTest, including showing that lymphocytes could be recovered using lysis buffer or buffy coat method as opposed to centrifugation, that incubation of cells at 37°C did not require supplemental CO2, and that results were available for majority of samples within 24 hours. Positive results by TPTest are transient and revert to negative during convalescence, supporting use of the test in endemic areas. The results can also be read using immunodot blot approach as opposed to ELISA. Since no true gold standard currently exists, we used a number of definitions of true positives and negatives. TPTest had sensitivity of 100% compared to blood culture, and specificity that ranged from 78-97% (73-100, 95% CI), depending on definition of true negative. The TPTest is useful for identification of patients with enteric fever in an endemic area, and additional development of simplified TPTest is warranted.


Efficacy and tolerability of vildagliptin as first line treatment in patients with diabetes type 2 in an outpatient setting.
Inhibitors of dipeptidyl-peptidase IV are recommended as second-line therapy in type 2 diabetes (DT2), but data, as a first-line treatment in everyday clinical practice are scarce. To address this issue we conducted a 12-month, clinical study in an outpatient setting, using vildagliptin as the first-line treatment. Ninety-one drug naïve patients with DT2 started with vildagliptin monotherapy (100 mg daily) for 4 months and were scheduled to regular 4-monthly visits for 1 year. Patients received add-on treatment with metformin or metformin and glimepiride according to their glycosylated hemoglobin (HbA1c) at each study-visit. HbA1c was significantly decreased with vildagliptin monotherapy from 8.16 % ± 1.60 to 7.52 % ± 1.60, p < 0.001. Only 39 % of the patients achieved the target of HbA1c ≤ 7.0 % at the end of the 4th month. Mean change in HbA1c was significantly correlated with baseline HbA1c values (r = -0.51, p < 0.001). At the end of the study only 35 % of the patients remained on vildagliptin monotherapy while the rest required add-on treatment with metformin or metformin and sulfonylurea. Vildagliptin is well tolerated either as monotherapy or in combination but the majority of patients require add-on therapy shortly after the beginning of treatment.