Immunohistochemical expression of CA19-9 and CA125 in mucoepidermoid and adenoid cystic carcinomas of the salivary gland.
This study examined the immunohistochemical expression of carbohydrate antigens CA19-9 and CA125 and their relationship to various biological parameters in 27 mucoepidermoid carcinomas (MEC) and 18 adenoid cystic carcinomas (ACC) arising from salivary glands. The series showed higher immunopositivity for CA125 (67% for MEC; 33% for ACC) than for CA19-9 (59% for MEC; 11% for ACC). CA19-9 epitope was mainly expressed in cystic (MEC) and cribriform/tubular (ACC) components of carcinoma tissues. Solid components in MEC occasionally showed positive staining for CA19-9. CA125 was evenly expressed in both ACC and MEC tissues regardless of their different histological components. The positive expression of CA19-9 and CA125 in the carcinoma tissues did not influence the clinical course of patients with MEC and ACC. A significant relationship was only demonstrated between the immunohistochemical expression of CA125 and the low proliferative activity (LI) evaluated by Ki-67 immunohistochemistry. However, no significant relationship was found between LI and the patients' clinical course. These results suggest that the immunostaining for CA19-9 and CA125 provide no reliable data to predict the clinical course of patients with MEC and ACC of the salivary glands.


Deficiency in the transcription factor interferon regulatory factor (IRF)-2 leads to severely compromised development of natural killer and T helper type 1 cells.
Interferon (IFN) regulatory factor (IRF)-2 was originally described as an antagonist of IRF-1-mediated transcriptional regulation of IFN-inducible genes. IRF-1(-/)- mice exhibit defective T helper type 1 (Th1) cell differentiation. We have used experimental leishmaniasis to show that, like IRF-1(-/)- mice, IRF-2(-/)- mice are susceptible to Leishmania major infection due to a defect in Th1 differentiation. Natural killer (NK) cell development is compromised in both IRF-1(-/)- and IRF-2(-/)- mice, but the underlying mechanism differs. NK (but not NK(+) T) cell numbers are decreased in IRF-2(-/)- mice, and the NK cells that are present are immature in phenotype. Therefore, like IRF-1, IRF-2 is required for normal generation of Th1 responses and for NK cell development in vivo. In this particular circumstance the absence of IRF-2 cannot be compensated for by the presence of IRF-1 alone. Mechanistically, IRF-2 may act as a functional agonist rather than antagonist of IRF-1 for some, but not all, IFN-stimulated regulatory element (ISRE)-responsive genes.


Secretion of leptin throughout pregnancy and early postpartum period in Japanese monkeys: placenta as another potential source of leptin.
Leptin is one of the most important factors linking nutrition and reproduction. In the present study, plasma concentrations of leptin during pregnancy and early lactation in the Japanese monkey were determined. Plasma concentrations of gonadotropins, immunoreactive (ir-)inhibin, and steroid hormones were also measured. Plasma concentrations of leptin significantly increased during the second quarter of pregnancy and progressively elevated throughout pregnancy. During the fourth quarter of pregnancy, leptin levels reached up to 89 and 64 times of those during prepregancy and first quarter of pregnancy periods, respectively. After parturition, the circulating leptin level abruptly decreased. During the first 10 d of lactation, its average level decreased to the levels of the second quarter of pregnancy. Plasma irinhibin and estradiol-17beta were elevated throughout the pregnancy and decreased after parturition, and both of them were positively correlated with leptin levels during the whole pregnancy and early lactation. Plasma concentrations of progesterone significantly increased during the first quarter of pregnancy and kept at a higher level compared with prepregnancy and sharply decreased after parturition. Placental homogenates contain a large amount of leptin protein. These results suggest that placenta secretes a large amount of leptin and may be another source of leptin during pregnancy in Japanese monkeys. In addition, high correlations among leptin, irinhibin, and estradiol-17beta during these stages suggest that these hormones may have important regulating roles on leptin secretion during pregnancy in the Japanese monkey.


Juxtapapillary hemangioma: a case report and review of clinical features and management of von Hippel-Lindau disease.
The phakomatose von Hipple-Lindau (VHL) disease is a multisystem disorder characterized by hemangioblastomas of the central nervous system (CNS), retinal angiomas, and multiple cysts and tumors of the viscera. Retinal capillary hemangiomas are the most common manifestation of VHL disease, which can occur in the optic nerve, where it may simulate disc edema, or in the retinal periphery, which is characterized by massive retinal exudation. Both locations can result in progressive accumulation of exudates leading to a decrease in visual acuity and potentially to a serous retinal detachment. A juxtapapillary hemangioma was observed in a 72-year-old man who presented for a routine examination. The patient was asymptomatic, despite the presence of a trace afferent papillary defect. This finding had to be carefully differentiated from sectoral disc edema. Blood tests, computed tomography (CT), and magnetic resonance imaging (MRI) all had normal results. Fluorescein angiography was a valuable secondary test showing early filling of the vascular network overlying the nerve head and characteristic late hyperfluorescence. There are 2 distinct forms of capillary hemangiomas--the juxtapapillary tumor or the peripheral capillary hemangioma. Although both types are similar histologically, they do vary in their appearance, differential diagnosis, and treatment. In both types, fluorescein angiography is an extremely helpful ancillary test in making the initial diagnosis. This case report reviews the ocular manifestations and systemic findings associated with VHL disease.


The CR2 receptor (CD21) shows increased expression in the more differentiated cells of an antigen-specific B cell line.
The complement receptor 2 (CR2; CD21), a 145,000 MW glycoprotein, has been useful as a marker of B lymphocyte maturation. It is expressed on the 1:13 monoclonal, EBV-transformed, B cell line which produces TNP-specific IgM-kappa and displays an in vitro capacity for differentiation. The line expresses the CD20+CD21+ phenotype. We studied whether CR2 receptor surface expression varied in relation to the cell cycle or state of differentiation in the 1:13 line. High CD21 and IgM expression occurred in the G1 phase of the cell cycle. In contrast to CD21, there were no distinctly brighter subpopulations of CD20 positive cells in the G1, S, or G2M compartments of the cell cycle. When sorted according to size, smaller cells were predominantly in G1, whereas a greater proportion of the larger cells were in the G2M phase of the cell cycle. The smaller 1:13 cells expressed more CD21 surface antigen and IgM than the larger cells. Cells which formed stable rosettes with TNP-SRBC expressed more surface IgM and CD21 antigen than nonrosetting cells. We have previously shown that the TNP-SRBC rosetting cells were more differentiated, resided in G1, and secreted more immunoglobulin than the nonrosetting cells. Thus increased CR2 expression occurred in the more differentiated cells of this human monoclonal B cell line.


Reduced level of serine(16) phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity.
Heart failure is associated with alterations in contractile parameters and accompanied by abnormalities in intracellular calcium homeostasis. Sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) and phospholamban (PLB) are important in intracellular calcium cycling. The aim of the present study was to examine mechanisms causing reductions in SERCA2 activity in the failing heart. Myocardial infarction (MI) was induced in male Wistar rats, and animals with congestive heart failure were examined 6 weeks after the primary operation. Serine(16) monomeric and pentameric phosphorylated PLB were significantly downregulated (50 and 55%, respectively), whereas threonine(17) phosphorylated PLB was unchanged in failing compared to sham hearts. Protein phosphatases 1 and 2A were significantly upregulated (26 and 42%, respectively) and phosphatase 2C significantly downregulated (29%), whereas the level of protein kinase A regulatory subunit II remained unchanged during heart failure. Increasing PLB phosphorylation by forskolin in isolated cardiomyocytes after inhibition of the Na(+)-Ca(2+) exchanger activity had significantly greater effect on SERCA2 activity in failing than in sham cells (49 and 20% faster transient decline, respectively). Decreasing PLB phosphorylation by the protein kinase A inhibitor H89 had significantly less effect on SERCA2 activity in failing compared to sham cardiomyocytes (20 and 75% slower transient decline, respectively). The observed changes in SERCA2 activity after increasing and decreasing serine(16) PLB phosphorylation in cardiomyocytes from sham and failing hearts, suggest that the observed reduction in serine(16) PLB phosphorylation is one major factor determining the reduced SERCA2 activity in heart failure after MI.


Interaction of the hepatitis B virus X protein with the lysine methyltransferase SET and MYND domain-containing 3 induces activator protein 1 activation.
Hepatitis B virus (HBV) is a widespread human pathogen that often causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The detailed mechanisms underlying HBV pathogenesis remain poorly understood. The HBV X protein (HBx) is a multifunctional regulator that modulates viral replication and host cell functions, such as cell cycle progression, apoptosis and protein degradation through interaction with a variety of host factors. Recently, the nonstructural protein 5A (NS5A) of hepatitis C virus has been reported to interact with methyltransferase SET and MYND domain-containing 3 (SMYD3), which is implicated in chromatin modification and development of cancer. Because HBx shares fundamental regulatory functions concerning viral replication and pathogenesis with NS5A, it was decided to examine whether HBx interacts with SMYD3. In the present study, it was demonstrated by co-immunoprecipitation analysis that HBx interacts with both ectopically and endogenously expressed SMYD3 in Huh-7.5 cells. Deletion mutation analysis revealed that the C-terminal region of HBx (amino acids [aa] 131-154) and an internal region of SMYD3 (aa 269-288) are responsible for their interaction. Immunofluorescence and proximity ligation assays showed that HBx and SMYD3 co-localize predominantly in the cytoplasm. Luciferase reporter assay demonstrated that the interaction between HBx and SMYD3 activates activator protein 1 (AP-1) signaling, but not that of nuclear factor-kappa B (NF-κB). On the other hand, neither overexpression nor knockdown of SMYD3 altered production of HBV transcripts and HBV surface antigen (HBsAg). In conclusion, a novel HBx-interacting protein, SMYD3, was identified, leading to proposal of a novel mechanism of AP-1 activation in HBV-infected cells.


Chromosome banding: specification of structural features of dyes giving rise to G-banding.
Metaphase chromosomes were stained in a routine G-banding procedure with 39 basic dyes of varied structures substituted for the Giemsa stain. Staining outcomes were categorized as: overstained, differentially stained, trivially or unstained. Certain structural features of the dyes were described numerically, namely, largest conjugated fragment (LCF), conjugated bond number (CBN) and cationic weight. The staining outcomes were compared to these numerical structural parameters, and structure--staining correlations sought. Dyes with large conjugated systems (and high LCF values) were seen to be overstained; dyes with low LCF values were often non-staining. At intermediate LCF values, the more hydrophobic dyes (with high Hansch pi values) stained differentially; the more hydrophilic dyes failed to stain. Expressed numerically, 89% of the dyes with the following characteristics stained differentially: 30 greater than or equal to LCF greater than or equal to 10; Hansch pi greater than -5.0. It was concluded that contributions to dye-chromosome affinity included coulombic forces and van der Waals attractions and that the selectivity of G-banding was largely due to hydrophobic bonding. Induction of bands could be due to the loss of hydrophilic histones, amplifying underlying variations in the hydrophobic-hydrophilic character of the chromosome structure. Relatively hydrophobic sites include AT-rich DNA and disulphide-rich proteins. The effects on Romanowsky G-banding of chemically modifying chromosomes were in keeping with this model. Overstaining resulted from formation of either hydrophobic or conjugated derivatives or both, whereas trivial or non-staining arose from the formation of hydrophilic derivatives. Intriguingly, the efficacy of the dyes used for Q-banding also correlated positively with their hydrophobic character.


Duhuo Jisheng decoction alleviates neuroinflammation and neuropathic pain by suppressing microglial M1 polarization: a network pharmacology research.
Neuropathic pain (NP) is the most prevalent form of chronic pain resulting from nerve damage or injury. Despite the widespread use of Duhuo Jisheng decoction (DHJSD) in traditional Chinese medicine (TCM) to treat chronic pain, the mechanism underlying its analgesic action remains unclear. Using network pharmacology, we obtained DHJSD and NP-related target information from public databases to construct protein-protein interactions (PPI) and compound-target networks based on common target genes. These networks were further analyzed using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG). The interaction between molecules was verified through molecular docking using AutoDock Tools software. Additionally, we treated a chronic constriction injury (CCI) rat model with DHJSD and determined the mechanical withdrawal threshold (MWT). We used an enzyme-linked immunosorbent assay kit to determine the levels of inflammatory cytokines. Furthermore, qRT-PCR was employed to analyze ACHE, NOS2, MAPK3, PTGS2, AKT1, and PPARG mRNA expression, and immunofluorescence was used to evaluate changes in microglia. Our screening of compounds and targets identified 252 potential targets of DHJSD associated with NP. PPI analysis, along with GO and KEGG analyses, revealed that the potential mechanism of DHJSD in NP treatment may be related to inflammatory reactions, the IL-17 signaling pathway, MAP kinase activity, and endocrine activity. Based on molecular docking, the core target showed significant affinity for DHJSD's active components. Moreover, DHJSD treatment repaired the CCI-induced inflammatory reaction in the spinal cord while regulating the expression of ACHE, NOS2, MAPK3, PTGS2, AKT1, and PPARG mRNA. Immunofluorescence results indicated that the active components of DHJSD may regulate microglial M1 polarization to improve neuroinflammation, PPARG may have been involved in the process. The multi-component, multi-target, and multi-pathway actions of DHJSD provide new insights into its therapeutic mechanism in NP.


Opiates and their antagonists modulate luteinizing hormone acting outside the blood brain barrier.
The effects of morphine methyl-iodide and naloxone methyl-bromide, two quaternary derivatives of morphine and naloxone, were evaluated on the modulation of luteinizing hormone secretion in intact and gonadectomized rats. Quaternary compounds are effective in modulating LH release, indicating a site outside the blood brain barrier for their action. More precisely, the median eminence and not the pituitary seems to be the site of action of opiates in modulating LH secretion, since the effect of the quaternary derivatives is abolished by surgical ablation of the median eminence.


Impact of SARS CoV-2 /COVID-19 infection on the course of advanced chronic liver disease and hepatocellular carcinoma.
About 20% of patients infected with SARS-CoV-2 develop COVID-19-the disease that has dominated health care in the last two years. The course of COVID-19 in patients with advanced liver disease tends to be severe, patients also suffer from a higher risk of complications and death. The primary object of this study was to assess the risk and causes of death in patients with cirrhosis and hepatocellular carcinoma (HCC). From a group of 4,314 patients hospitalized at Jerzy Gromkowski Regional Specialist Hospital in Wroclaw (Poland) due to SARS-CoV-2/COVID-19 infection between March 15, 2020, and January 31, 2022, we selected a cohort of 31 patients with liver cirrhosis (12 women and 19 men) and 7 patients with HCC developed on the cirrhotic liver (1 woman, 6 men). The control group included 123 patients without liver disease. In the entire cohort, we analyzed the course of COVID-19 infection, baseline oxygen demand, liver function (assessed using the CTP-Child-Turoctte-Pugh score and MELD-Model of End-Stage Liver Disease scales), length of hospitalization, development of acute-on-chronic liver failure, and deaths. The mean age of the patients was 56.6 years in the liver cirrhosis group, 63.3 years for patients with (HCC) hepatocellular carcinoma, and 64 years in the control group. Time of hospitalization averaged 15.52 days and 11.14 days for patients with liver cirrhosis and liver cancer, respectively. For the control group, the average duration of the hospital stay was 11.61 days. With respect to baseline liver function assessed using the CTP score, in the cirrhosis group 10 patients were CTP class A, 19 patients were class B and 9 patients were class C. The cancer group included 3 patients with class A, 2 patients with class B, and 2 patients with class C. In the studied cohort, 22 patients had a baseline MELD score < 12 points, and in 15 patients was > 12. In the HCC group, it was, respectively, CTP A:3, B: 2, C: 2, and MELD < 12: 3, ≥12: 4 people. Most of these patients presented with a progression of liver disease. Fifteen patients died, including 12 with cirrhosis and 3 with HCC, accounting for 39.47% in the entire cohort, 39% in the cirrhotic group and 43% in the HCC group, and 13 in the control group (10.6%), There was a clear statistical difference between the mortality rate in the group with liver disease and in the control group. Infection with SARS-CoV-2/COVID-19 in patients with cirrhosis and HCC tends to have a more severe course and leads to exacerbation of the liver disease. The most common cause of death in the analyzed cohort infected with SARS-CoV-2/COVID-19 was the progression of liver disease, complicated by liver failure.


The effect of social determinants of health on utilization of surgical treatment for hepatocellular carcinoma patients.
A paucity of data exists on how social determinants of health (SDOH) influence treatment for Hepatocellular carcinoma (HCC). We investigated associations between SDOH (healthcare access, education, social/community context, economic stability, and built/neighborhood environment) and receipt of surgery. The Pennsylvania Liver Cancer Registry was linked with neighborhood SDOH from the American Community Survey. Multilevel logistic regression models with patient and neighborhood SDOH variables were developed. Of 9423 HCC patients, 2393 were stage I. Only 36.3% of stage I patients received surgery. Black patients had significantly lower odds of surgery vs Whites (OR = 0.73; p < 0.01), but not after adjustments for SDOH. All 5 SDOH domains were associated with odds of surgery overall; 2 domains were associated in Stage I patients, social context (e.g., racial concentration, p = 0.03) and insurance access (p < 0.01). SDOH impact utilization of surgery for HCC. Findings can guide healthcare professionals to create programs for populations at risk for poor liver cancer outcomes.


Post-schiff base chemistry of the Maillard reaction: mechanism of imine isomerization.
Schiff bases play a critical role, not only in initiating the Maillard reaction, but also in its propagation. Little attention has been paid so far to the ability of these imines to undergo isomerization and thus contribute to the diversity of Maillard reaction products. In this study, imine isomerization through 5-oxazolidinone formation was explored in a phenylalanine/glyceraldehyde model system, and spectroscopic evidence was provided for its formation by taking advantage of the strong carbonyl absorption band centered at 1784 cm(-1). The importance of 5-oxazolidinone formation lies in its ability to decarboxylate to azomethine ylide and subsequently form two isomeric imines, each capable of producing distinct Maillard products. Evidence for the formation of such ylides was also provided through their ability to undergo 1,3-dipolar cycloaddition with dipolarophiles.


Evolvability-enhancing mutations in the fitness landscapes of an RNA and a protein.
Can evolvability-the ability to produce adaptive heritable variation-itself evolve through adaptive Darwinian evolution? If so, then Darwinian evolution may help create the conditions that enable Darwinian evolution. Here I propose a framework that is suitable to address this question with available experimental data on adaptive landscapes. I introduce the notion of an evolvability-enhancing mutation, which increases the likelihood that subsequent mutations in an evolving organism, protein, or RNA molecule are adaptive. I search for such mutations in the experimentally characterized and combinatorially complete fitness landscapes of a protein and an RNA molecule. I find that such evolvability-enhancing mutations indeed exist. They constitute a small fraction of all mutations, which shift the distribution of fitness effects of subsequent mutations towards less deleterious mutations, and increase the incidence of beneficial mutations. Evolving populations which experience such mutations can evolve significantly higher fitness. The study of evolvability-enhancing mutations opens many avenues of investigation into the evolution of evolvability.


Energy Expenditure of Female International Standard Soccer Players: A Doubly Labeled Water Investigation.
The purpose of this study is to quantify total daily energy expenditure (TEE) of international adult female soccer players. Twenty-four professional players were studied during a 12-d period where they participated in an international training camp (also inclusive of two competitive games) representing the English national team. The TEE was assessed via the doubly labeled water method during the full 12 d as well as the initial 4-d period before game one. Energy intake was also assessed (via weighed food analysis) during the initial 4-d period to permit estimation of energy availability (EA). Mean TEE did not differ (P = 0.31) between the 12-d (2693 ± 432 kcal·d-1; range, 2105-3507 kcal·d-1; 54 ± 6 kcal·kg-1 fat-free mass [FFM]) versus the 4-d assessment period (2753 ± 359 kcal·d-1; range, 1942-3280 kcal·d-1; 56 ± 8 kcal·kg-1 FFM). Mean 4-d energy intake was 1923 ± 357 kcal·d-1 (range, 1639-2172 kcal·d-1) and mean activity energy expenditure was 1069 ± 278 kcal·d-1 (range, 155-1549 kcal·d-1). When assessed for estimated EA, 88% of players were categorized with low EA status according to the threshold of <30 kcal·kg-1 FFM. Mean daily carbohydrate intake equated to 3.3 ± 0.7 g·kg-1 body mass. When compared with previously published data from adult male players, we demonstrate that the relative daily energetic requirements of engaging in professional soccer training and match play are comparable between sexes. From a practical perspective, data suggest that practitioners should likely focus education and behavior change strategies on "fuelling" for match play and training to optimize both player health and performance.


[Experimental study of the visual system using unidimensional Walsh gratings].
Threshold characteristics of the visual system for an orderly set of the Walsh aperiodic gratings were estimated prior to and after adaptation. Narrow--band channels of Walsh with the band width about 1 octave by the Walsh scale of function orders, were revealed. The model of summation by the power of spectral sinusoidal components of the Walsh aperiodic lattices well accounts for the data on gratings the Walsh aperiodic gratings.


Thorotrast: analysis of the time evolution of its α activity concentration, in the 70 years following the chemical purification of Thorium.
We simulate the α-activity of the Thorium series elements present in the contrast medium named Thorotrast, used until 1960 and cause of certified deaths until today. Assuming, as active components at t=0, (232)Th and (228)Th in the same relative concentration they have in nature, α-activity oscillates for some decades before reaching a stationary value that in absence of biological depletion would be AST =24000Bq/g. Our Montecarlo code generates the nuclear decays of the Thorium series with and without in-vivo biological depletion, arriving to three kinds of results for the activity: 1) Theoretical activity concentration (no biological depletion). Our result is fitted by: A(t)=A(ST).{[1-exp(-t/10)]+[exp(-t/tB)(1-0.8exp(-t/tA))]}, with t in years, tA=1.07.10(-2) years, and tB=2.38 years. 2) Weak biological depletion (228Ra/232 Th equilibrium activity ratio 0.6, 224Ra/228Ra e.a.r 0.9, 10% excretion for 220Rn). The ratio of the activity concentration to the theoretical activity concentration is fitted by: A weak (t)/A(t)=0.61+0.29 exp[-(t/15)2] (t in years). 3) Strong biological depletion (228Ra/232Th e.a.r 0.4, 224Ra/228Ra e.a.r. 0.8, 10% excretion for 220Rn). The ratio of the activity concentration to the theoretical activity concentration is fitted by A(strong)(t)/A(t)=0.44+0.4 exp[-(t/13)2](t in years). We also report fluctuation calculation for two cases where standard statistical behavior is not expected.


Relationship between lectin binding properties and the expression of blood group ABH antigens in vascular endothelia and red blood cells from 18 primate species.
The reactivity was examined of horseradish peroxidase labelled Ulex europaeus agglutinin-I (UEA-I) and Griffonia simplicifolia agglutinin I-B4 (GSAI-B4) with red blood cells and vascular endothelium in formalin-fixed, paraffin embedded tissues from 18 primate species. The expression of blood group ABH antigens in these cells as well as secretions from other tissues was also examined by the indirect immunoperoxidase method using monoclonal anti-ABH antibodies as primary antibodies. In Prosimians and New World monkeys which lack ABH antigens on both red blood cells and endothelial cells, but produce these antigens in other tissue secretions, GSAI-B4 always reacted with both red blood cells and endothelial cells. In Old World monkeys, which express blood group antigens on endothelial cells but not on red blood cells, neither GSAI-B4 nor UEA-I reactivity were observed, except the endothelial cells from blood group B or O individuals occasionally reacted with GSAI-B4 or UEA-I, respectively. Although UEA-I reactivity was not observed in the endothelial cells of gibbon, it reacted with these cells from chimpanzees. In these two anthropoid apes, both endothelial cells and red blood cells expressed ABH antigens as in humans. These results suggest the close evolutionary relationship between the expression of blood group ABH antigens and lectin binding properties of red blood cells and endothelial cells in primate species.


Parathyroid gland detection using an intraoperative autofluorescence handheld imager - early feasibility study.
Parathyroid glands may be compromised during thyroid surgery which can lead to hypoparathyroidism and hypocalcemia. Identifying the parathyroid glands relies on the surgeon's experience and the only way to confirm their presence was through tissue biopsy. Near infrared autofluorescence technology offers an opportunity for real-time, non-invasive identification of the parathyroid glands. We used a new research prototype (hANDY-I) developed by Optosurgical, LLC. It offers coaxial excitation light and a dual-Red Green Blue/Near Infrared sensor that guides anatomical landmarks and can aid in identification of parathyroid glands by showing a combined autofluorescence and colored image simultaneously. We tested the imager during 23 thyroid surgery cases, where initial clinical feasibility data showed that out of 75 parathyroid glands inspected, 71 showed strong autofluorescence signal and were correctly identified (95% accuracy) by the imager. The hANDY-I prototype demonstrated promising results in this feasibility study by aiding in real-time visualization of the parathyroid glands. However, further testing by conducting randomized clinical trials with a bigger sample size is required to study the effect on levels of hypoparathyroidism and hypocalcemia.


F-wave and H-reflex alterations in recently diagnosed diabetic patients.
To explore the frequency of F-wave and H-reflex alterations in recently diagnosed type 2 diabetes mellitus patients and to determine if the alterations are dependent on the levels of glycemia. A cross-sectional study was carried out on 50 asymptomatic patients, with a mean age of 45.4 +/- 9.8 years and a disease evolution of less than 10 years. Patients were classified as either normoglycemic (7 mmol/L; n = 20) or hyperglycemic (7 mmol/L; n = 30). H-reflex (HR), F-wave (FW), and nerve-conduction measurements (NCM) between the diabetic and non-diabetic (control) groups were compared. The H-reflex was absent in 22% of the patients, while the M-component of this reflex was altered in 58% of patients. The F-wave was altered in 12% of the patients. The motor nerve compound action potential showed a diminution in amplitude (26% of patients, n = 13), area (32%, n = 16), and conduction velocity (20%, n = 10). No positive correlation between glycemia levels and the above alterations was found. This study demonstrated that asymptomatic diabetic patients showed a high incidence of subclinical neurophysiological abnormalities.


Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II.
Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.


Random Insertional Mutagenesis Identifies Genes Associated with Virulence in the Wheat Scab Fungus Fusarium graminearum.
ABSTRACT Fusarium graminearum is an important pathogen of small grains and maize in many areas of the world. To better understand the molecular mechanisms of F. graminearum pathogenesis, we used the restriction enzyme-mediated integration (REMI) approach to generate random insertional mutants. Eleven pathogenicity mutants were identified by screening 6,500 hygromycin-resistant transformants. Genetic analyses indicated that the defects in plant infection were tagged by the transforming vector in six of these mutants. In mutant M8, the transforming plasmid was integrated 110-bp upstream from the start codon of the cystathionine betalyase gene (CBL1). Gene replacement mutants deleted for CBL1 and the methionine synthase gene MSY1 were also obtained. Both the cbl1 and msy1 deletion mutants were methionine auxotrophic and significantly reduced in virulence on corn silks and wheat heads. We also identified genes disrupted by the transforming DNA in three other REMI mutants exhibiting reduced virulence. In mutants M68, the transforming vectors were inserted in the NADH: ubiquinone oxidoreductase. The putative b-ZIP transcription factor gene and the transducin beta-subunit-like gene disrupted in mutants M7 and M75, respectively, had no known homologs in filamentous fungi and were likely to be novel fungal virulence factors.


Disease-modifying therapies in relapsing-remitting multiple sclerosis.
What is the best current disease-modifying therapy for relapsing-remitting multiple sclerosis? The evidence shows that the most effective disease-modifying therapy for delaying short- to medium-term disability progression, prevention of relapses, reducing the area and activity of lesions on magnetic resonance imaging, with the least side effects, is high-dose, high-frequency subcutaneous interferon-β1a 44 μg three times per week. The pitfalls in treatment of MS can be avoided by remembering the following points: The most effective therapy to prevent or delay the appearance of permanent neurological disability with the fewest side effects should be chosen, and treatment should not be delayed.Adherence to treatment should be monitored closely, and needs comprehensive patient information and education to establish long-term adherence, which is a critical determinant of long-term outcome.The correct approach to the disease includes disease management, symptom management, and patient management. A combination of tools is necessary to ease the various symptoms, which fall into three broad categories, i.e. rehabilitation, pharmacological, and procedural.It is important to understand that no treatment modality should be used alone, unless it is in itself sufficient to remedy the particular symptom/problem.


Towards national systems for continuous surveillance of antimicrobial resistance: Lessons from tuberculosis.
In a Perspective on the research article from Jacobson and colleagues, Amitabh Suthar and colleagues from the Centers for Disease Control and Prevention discuss the importance of and considerations for developing real-time and large-scale reporting systems for tracking and controlling antimicrobial resistance.


Biochemical stability and molecular dynamic characterization of Aspergillus fumigatus cystathionine γ-lyase in response to various reaction effectors.
Cystathionine γ-lyase (CGL) is a key enzyme in the methionine-cysteine cycle in all living organisms forming cysteine, α-ketobutyrate and ammonia via homocysteine and cystathionine intermediates. Although, human and plant CGLs have been extensively studied at the molecular and mechanistic levels, there has been little work on the molecular and catalytic properties of fungal CGL. Herein, we studied in detail for the first time the molecular and catalytic stability of Aspergillus fumigatus CGL, since conformational instability, inactivation and structural antigenicity are the main limitations of the PLP-dependent enzymes on various therapeutic uses. We examined these properties in response to buffer compositions, stabilizing and destabilizing agents using Differential Scanning Fluorometery (DSF), steady state and gel-based fluorescence of the intrinsic hydrophobic core, stability of internal aldimine linkage and catalytic properties. The activity of the recombinant A. fumigatus CGL was 13.8U/mg. The melting temperature (Tm) of CGL in potassium phosphate buffer (pH 7.0-8.0) was 73.3°C, with ∼3°C upshifting in MES and sodium phosphate buffers (pH 7.0). The conformational thermal stability was increased in potassium phosphate, sodium phosphate and MES buffers, in contrast to Tris-HCl, HEPES (pH 7.0) and CAPS (pH 9.0-10.0). The thermal stability and activity of CGL was slightly increased in the presence of trehalose and glycerol that might be due to hydration of the enzyme backbone, unlike the denaturing effect of GdmCl and urea. Modification of surface CGL glutamic and aspartic acids had no significant effect on the enzyme conformational and catalytic stability. Molecular modeling and dynamics simulations unveil the high conformational stability of the overall scaffold of CGL with high flexibility at the non-structural regions. CGL structure has eight buried Trp residues, which are reoriented to the enzyme surface and get exposed to the solvent under perturbation of destabilizers. Furthermore, electrostatic calculations of selected snapshots of CGL 3D structure under different experimental conditions showed a remarkable differences on the polarity of the enzyme surface.


Evolutionary dynamics and adaptive analysis of Seneca Valley virus.
Over the past 20 years, the Seneca Valley virus (SVV) has emerged in various countries and regions around the world. Infected pigs display symptoms similar to foot-and-mouth disease and other vesicular diseases, causing severe economic losses to affected countries. In recent years, the number of SVV infections has been increasing in Brazil, China, and the United States. In this study, we comprehensively analyzed SVV genomic sequence data from the perspectives of evolutionary dynamics, phylogeography, and codon usage bias. We aimed to gain further insights into SVV's genetic diversity, spatiotemporal distribution patterns, and evolutionary adaptations. Phylogenetic analysis revealed that SVV has evolved into eight distinct lineages. Based on the results of phylogeographic analysis, it is speculated that the United States might have been the source of SVV, from where it subsequently spread to different countries and regions. Moreover, our analysis of positive selection sites in SVV capsid proteins suggests their potential importance in the process of receptor recognition. Finally, codon preference analysis indicates that natural selection has been a primary evolutionary driver influencing SVV codon usage bias. In conclusion, our in-depth investigation into SVV's origin, dissemination, evolution, and adaptation emphasizes the significance of SVV surveillance and control measures.


A different transcriptional landscape sheds light on Russian sturgeon (Acipenser gueldenstaedtii) mechanisms to cope with bacterial infection and chronic heat stress.
Sturgeons are chondrostean fish of high economic value and critically endangered due to anthropogenic activities, which has led to sturgeon aquaculture development. Russian sturgeon (Acipenser gueldenstaedtii), the second most important species reared for caviar, is successfully farmed in subtropical countries, including Uruguay. However, during the Uruguayan summer, sturgeons face intolerable warmer temperatures that weaken their defences and favour infections by opportunistic pathogens, increasing fish mortality and farm economic losses. Since innate immunity is paramount in fish, for which the liver plays a key role, we used deep RNA sequencing to analyse differentially expressed genes in the liver of Russian sturgeons exposed to chronic heat stress and challenged with Aeromonas hydrophila. We assembled 149.615 unigenes in the Russian sturgeon liver transcriptome and found that metabolism and immune defence pathways are among the top five biological processes taking place in the liver. Chronic heat stress provoked profound effects on liver biological functions, up-regulating genes related to protein folding, heat shock response and lipid and protein metabolism to meet energy demands for coping with heat stress. Besides, long-term exposure to heat stress led to cell damage triggering liver inflammation and diminishing liver ability to mount an innate response to A. hydrophila challenge. Accordingly, the reprogramming of liver metabolism over an extended period had detrimental effects on fish health, resulting in weight loss and mortality, with the latter increasing after A. hydrophila challenge. To our knowledge, this is the first transcriptomic study describing how chronic heat-stressed sturgeons respond to a bacterial challenge, suggesting that liver metabolism alterations have a negative impact on the innate anti-bacterial response.


The long-term results of a pilot study of three times a day radiotherapy and escalating doses of daily cisplatin for locally advanced non-small-cell lung cancer.
This analysis was performed to determine the long-term results of a Phase I trial that included 3-times-a-day radiotherapy (TIDRT) and concurrent daily cisplatin (CDDP) for Stage III non-small-cell lung cancer. Twenty patients with Stage III non-small-cell lung cancer were treated with TIDRT delivered over 12 weekdays that included 57.6 Gy administered in 1.5 Gy fractions at 8 a.m. and 4 p.m., and 1.8 Gy fractions at noon. AP-PA fields were used at 8 a.m. and 4 p.m. Opposed oblique off cord fields were used at noon. The first 5 patients were given no CDDP, the second 5 patients received 5 mg/m2 of CDDP, and the remaining 10 patients received 7.5 mg/m2 of CDDP. All survivors were followed for greater than 5 years. The maximum tolerated dose of daily CDDP during this program of radiation therapy was 7.5 mg/m2. None of the patients died as a result of toxicity. The median survival was 19.2 months, and the 5-year survival rate was 25%. Tumor response and patterns of failure were also evaluated. This study was performed to determine the maximum tolerated dose of CDDP when administered daily during an aggressive program of TIDRT. The survival results were promising, suggesting that the combination of TIDRT and systemic therapy deserves further study.


The effects of steroidal and nonsteroidal anti-inflammatory agents on uptake of Evans blue in experimental metastasis.
The effects of anti-inflammatory drugs on uptake of Evans blue were studied in solitary Walker carcinosarcomas implanted in the livers of Sprague-Dawley rats. Animals were sacrificed at 5 min, 30 min, and 6 hr after administration of the anti-inflammatory drugs and Evans blue, and spectrophotometric measurements of the Evans blue in tumor and normal liver tissue were carried out. Uptake of Evans blue in the tumors was significantly decreased at all time periods after the injection of the following, as compared to controls: steroids (cortisol, methylprednisolone, and triamcinolone), the antihistamine diphenhydramine, and nonsteroidal anti-inflammatory agents (naproxen, ibuprofen, indomethacin, and phenylbutazone). The effects of these drugs on uptake of Evans blue in the normal liver were more variable.


[Functional results of retinoblastoma treatment with local treatment used in isolation or associated with chemotherapy].
Because of long-term complications of external beam radiation in retinoblastoma, a new therapeutic modality using chemotherapy and local treatments is used whenever possible. We conducted a retrospective study to evaluate visual results. We studied visual acuity and ocular side effects in children presenting uni- or bilateral retinoblastoma in whom we were able to achieve conservative management without external beam treatment. The treatments that were used included chemotherapy, chemothermotherapy, diode laser, iodine 125 plaque brachytherapy, and cryotherapy. The initial characteristics (diameter, subretinal or vitreous seeding, and location) of each tumor, the treatments used, their results, and the visual function after age 4 years were recorded. We treated 429 children for retinoblastoma at the Curie Institute between October 1994 and December 2002. Two hundred twenty-seven eyes had conservative treatment without external beam. We were able to study the visual function in 102 eyes at a median age of 67 months. The median follow-up after the end of the treatment was 5 years. The mean visual acuity was 20/37 and 60% of the children had visual acuity of more than 20/40. Macular alteration was observed in 34 eyes. Statistical analysis showed that a larger tumor diameter of the retinal surface (p<0.0003) and location close to the macula (p<0.0001) were the most significant risk factors for vision loss. The visual results of the treatment of retinoblastoma by chemotherapy and local treatments is good when the tumors are not located close to the macula. Larger tumors also have a worse prognosis for vision.


Retraction: a case of meningitis due to Achromobacter xylosoxidans in a child with a polymalformative syndrome: a case report.
[This retracts the article DOI: 10.11604/pamj.2021.39.124.29794.].


The socialization of modality capital in sign language ecologies: A classroom example.
Gaze behavior is an important component of children's language, cognitive, and sociocultural development. This is especially true for young deaf children acquiring a signed language-if they are not looking at the language model, they are not getting linguistic input. Deaf caregivers engage their deaf infants and toddlers using visual and tactile strategies to draw in, support, and promote their child's visual attention; we argue that these caregiver actions create a developmental niche that establishes the visual modality capital their child needs for successful sign language learning. But most deaf children do not have deaf signing parents (reportedly over 90%) and they will need to rely on adult signing teachers if they are to acquire a signed language at an early age. This study examines classroom interactions between a Deaf teacher, her teacher's aide, and six deaf preschoolers to document the teachers' "everyday practices" as they socialize the gaze behavior of these children. Utilizing a detailed behavioral and linguistic analysis of two video-recorded book-sharing contexts, we present data summarizing the teacher's attention-getting actions directed toward the children and the discourse-embedded cues that signal the teacher's expectations for student participation in the signed conversation. We observed that the teacher's behaviors differed according to the parent status of the deaf preschooler (Deaf parents vs. hearing parents) suggesting that Deaf children of Deaf parents arrive to the preschool classroom with well-developed self-regulation of their attention or gaze. The teachers also used more physical and explicit cueing with the deaf children of hearing parents-possibly to promote their ability to leverage the visual modality for sign language acquisition. We situate these socialization patterns within a framework that integrates notions of intuitive or indigenous practices, developmental niche, and modality capital. Implications for early childhood deaf education are also discussed.


Slow Cortical Potential Neurofeedback in Chronic Tinnitus Therapy: A Case Report.
This study is the first to demonstrate outcomes of slow cortical potential (SCP) Neurofeedback training in chronic tinnitus. A 50-year old male patient with tinnitus participated in three SCP training blocks, separated with 1-month breaks. After the training the patient reported decreased tinnitus loudness and pitch, as well as improved quality of daily life. A quantitative electroencephalography analysis revealed close to normal changes of resting state bioelectrical activity in cortical areas considered to be involved in tinnitus generation. The present case study indicates that SCP Neurofeedback training can be considered a promising method for tinnitus treatment.


Neuronal uptake inhibitors, nisoxetine and fluoxetine on rat vascular contractions.
The importance of neuronal uptake processes in rat arteries and veins was compared using nisoxetine and fluoxetine, selective inhibitors for neuronal uptake of norepinephrine and serotonin, respectively. Nisoxetine (10(-7) - 10(-5) M) increased the sensitivity to exogenous norepinephrine in the portal and mesenteric veins (10-fold) and in the mesenteric artery (2.5-fold). Responses to field stimulation were also increased afternisoxetine in all three vessels. After nisoxetine, aortic responses to norepinephrine were unaltered and in all tissues, serotonin-induced contractions were reduced. Fluoxetine did not potentiate responses to norepinephrine or to field stimulation except in the mesenteric vein where sensitivity to norepinephrine was increased and the relaxation rate after field stimulation was prolonged. Although serotonin has been detected in blood vessels, fluoxetine did not increase vascular responses to serotonin. These studies suggest that rat mesenteric veins have a highly sensitive neuronal uptake mechanism of norepinephrine. Furthermore, these data provide indirect evidence against a functionally important serotonergic uptake process in rat blood vessels and suggest that neuronal uptake of serotonin does not exert a major role in terminating the vascular action of this biogenic amine.


Distribution of natural ingredients suggests a complex network of metabolic transport between source and sink tissues in the brown alga Fucus vesiculosus.
Tight regulation of intra-thallus metabolite distribution in Fucus vesiculosus in late summer reveals the complex biochemical processes complying with reproduction and the preparation to the dark season. We used inductively coupled plasma atomic emission spectroscopy to study the tissue-specific elemental composition, and gas chromatography coupled to mass spectrometry to study the distribution of small-molecular weight primary and secondary metabolites of the brown alga Fucus vesiculosus thalli in the reproductive phase. Beyond general physiological requirements, the observed distribution of the analysed nutrients was also found to depend on characteristics related to the season of harvesting, i.e., the reproductive period. However, a particular curious result was the high metabolic activity found in the stipe of the plant. In conclusion, our data not only provide valuable information for industrial use of fucoids targeting specific algal ingredients, but also give highly interesting insights in the multifaceted system of intra-thallus biochemical interactions during reproduction of the brown algae.


Mouse brain IgG-like immunoreactivity: strain-specific occurrence in microglia and biochemical identification of IgG.
Unlike the brains of most mammals, the mouse brain appears unique in the massive appearance of cells showing IgG-like immunoreactivity, which has repeatedly been shown via immunohistochemistry. In the present study, we first examined possible species differences in IgG-like immunohistochemical staining in the brains of various rodents, including mice. In four of six mouse strains examined (ICR, Balb/c, C57BL/6, and AKR/J), antibodies against mouse IgG revealed positive staining in many brain microglia. However, no such positive staining was detected in brains of the rat, hamster, guinea pig, or two other mouse strains (CBA/N and CBA/J). We purified IgG-like-immunoreactive molecule(s) biochemically from brain of the ICR mouse as a representative mouse strain. Our amino-acid-sequence analysis proved that the purified protein was identical to serum IgG. The possibility of IgG synthesis by brain microglia in the ICR mouse was denied by our RT-PCR experiments and in situ hybridization histochemistry. In addition, Fcgamma-receptor-deficient double-knockout mice of the C57BL/6 genetic background contained no IgG-immunoreactive microglia in the brain. These results clearly indicate that microglial IgG staining is due to the uptake of serum IgG through Fcgamma receptors. However, the strain-specific mechanisms resulting in microglial IgG uptake remain to be elucidated, in that Fcgamma receptors are omnipresent in microglia of all rodents examined here.


Novel active fixation lead guided by electrical delay can improve response to cardiac resynchronization therapy in heart failure.
Cardiac resynchronization therapy (CRT) for heart failure (HF) recently has shown optimal results by targeting electrically delayed sites in coronary sinus (CS) branches. However this purpose often cannot be reached because of unstable left ventricular (LV) lead position. In current study were assessed the long-term effects of the novel active fixation LV lead in CS, guided by electrical delay (QLV), in patients with HF due to coronary artery disease. One hundred eighty-five consecutive patients underwent CRT with intraoperative evaluation of QLV in the target position of the LV lead. When the novel active fixation LV lead was available, 98 consecutive patients received it, composing the Fix group. They were compared with 87 patients with a conventional passive fixation lead (No Fix group). The final LV lead position was assessed by fluoroscopy. Clinical response to CRT was assessed within a period of about 3 years: patients experiencing HF rehospitalization and death due to HF were defined as non-responders. There were no significant differences between groups in the final position of LV lead in left anterior oblique view (Pearson χ2 = 0.12; P = 0.73). In right anterior oblique view, a basal position was reached more in the Fix group (38%) than in the No Fix group (6.5%) (Pearson χ2 = 23.095; P < 0.001). QLV was significantly greater in the Fix group (122.6 ± 33.2 ms; SE = 3.6) than in the No Fix group (97.5 ± 37.8 ms; SE = 4.9) (t = 4.17; P < 0.001). Rehospitalizations for HF were 37 in the No Fix group and 14 in the Fix group. Deaths due to HF were 49 in the No Fix group and 18 in the Fix group. Survival analysis, assessed by Cox regression, showed that the Fix group had a better outcome both for HF rehospitalizations [hazard ratio (HR) = 0.48; 95% confidence interval (CI) = 0.25-0.9; P = 0.023] and death due to HF (HR = 0.55; 95% CI = 0.31-0.97; P = 0.04) in comparison with the No Fix group. Adjustment for baseline characteristics by multivariate analysis showed that an active fixation lead in CS, as a covariate, was still significant both for HF rehospitalizations (HR 0.46; 95% CI = 0.24-0.88; P = 0.019) and for death due to HF (HR 0.5; 95% CI = 0.28-0.9; P = 0.021). The novel active fixation LV lead allowed to target sites with greater QLV. Often maximum QLV was documented in basal segments, were stability of conventional passive fixation leads is not enough. Patients receiving it experienced less HF rehospitalizations and less death due to HF. Active fixation lead in CS guided by QLV can improve long-term prognosis in patients with HF due to coronary artery disease undergoing to CRT.


Omeprazole (40 mg) is superior to ranitidine in short-term treatment of ulcerative reflux esophagitis.
The efficacy and safety of omeprazole, 40 mg once daily for four to eight weeks of treatment, were studied in 61 patients with ulcerative reflux esophagitis. A double-blind controlled study design was used, and the patients were randomly allocated to treatment with either omeprazole 40 mg once daily or ranitidine 150 mg twice daily. Endoscopy was performed prior to inclusion into the study, after four weeks and, if unhealed, again after eight weeks. Healing of esophagitis was defined as complete disappearance of all esophageal ulcerations. Symptoms were recorded before entry, after four weeks, and again after eight weeks in unhealed patients. Fifty-one patients were included in the per-protocol analysis at day 29, and 50 patients at day 57. The healing rate after four weeks of treatment was 22 of 26 patients (85%) treated with omeprazole and 10 of 25 patients (40%) treated with ranitidine (P less than 0.001). The corresponding figures after eight weeks were 24 of 25 (96%), and 13 of 25 (52%) (P less than 0.001). These results were confirmed in the intent-to-treat analysis. Patients treated with omeprazole showed a significantly faster and more profound relief in heartburn than patients treated with ranitidine: 85% had no heartburn after four weeks of treatment with omeprazole compared to 24% in patients treated with ranitidine (P = 0.00007). The percentage of patients who were free of all reflux symptoms was significantly greater in the omeprazole-treated group as compared to the ranitidine-treated group (62% and 12% respectively; P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)


Migraine aura: a knockin mouse with a knockout message.
Migraine aura is a sometimes disabling disorder of the brain that involves significant neurological symptoms in about 30% of patients. In this issue of Neuron, van den Maagdenberg et al. characterize a mouse with a knockin mutation known to cause familial hemiplegic migraine and provide evidence that a lowered threshold to the triggering of CSD may account for the devastating phenotype of familial hemiplegic migraine.


Nutrigenomics: A controversy.
Nutrigenomics is an emerging science which investigates a certain area of nutrition that uses molecular tools to search access and understand the several responses obtained through a certain diet applied between individual and population groups. The increased need for the use of personalised nutrition in patients is increasing and research is being made on its possible effects. However, research on nutrigenomics and in particular, obesity is still ongoing. Following a current metanalysis on thirty-eight nutrigenomics genes, it seems that a definite association between the genes usually examined in nutrigenomics testing and several diet-related diseases is lacking, even though there is a limited number of studies associating them. In 2014, literature search results in a great number of studies on several polymorphisms. This heterogeneity could only show the way towards new research aims. Nutrigenomics was born due to the need to move from Epidemiology and Physiology to Molecular Biology and Genetics. Currently, there are steps that need to be considered in order for nutrigenomics to be applied: the genes, the gene/protein network, and the strategy towards the determination of the nutrients' influence on gene/protein expression. It is certainly an interesting evolving science with many areas to be investigated further and from different perspectives, as it involves ethics, medicine, genetics and nutrition.


Radiographic quantitative assessment of caudal proximal tibial angulation in 100 dogs with cranial cruciate ligament rupture.
To evaluate inter- and intraobserver variability in the measurement of distal tibial axis/proximal tibial axis angle (DPA) from lateral radiographs of canine tibia in dogs with cranial cruciate ligament rupture (CCLR). Retrospective clinical study. Dogs (n=100) with cranial cruciate ligament rupture. Medical records of dogs diagnosed with CCLR were reviewed. In addition to signalment and TPA measurements, measured DPA (mDPA) was calculated for each lateral view of the tibia in each animal, twice, by 3 blinded observers. Subjective scoring of DPA (sDPA) was also recorded, twice, by 3 additional blinded observers from lateral views of the proximal half of the tibia in each dog. Inter- and intraobserver variability was measured by intraclass correlation coefficient (ICC) for each measurement. Correlation between mDPA and sDPA was also determined. Median tibial plateau angle (TPA) of the subject population was 27.9° (range 18.8-41.3°; IQR: 25.5-30.75°). Mean ± SD mDPA was 6.50 ± 2.81° (confidence intervals [CI]: 5.94-7.06°; range 0-13.33°). There was no correlation between age and weight of dogs and the mDPA (P=.58 and .12). There was a moderate correlation between mDPA and TPA (r(2)=0.49, P<.0001). There was a moderate correlation between sDPA and mDPA (r(2)=0.27, P<.0001). Good inter- and intraobserver agreement was found in the measurement of mDPA. mDPA is a reproducible measurement of caudal angulation of proximal tibia. Furthermore, mDPA of dogs with cranial cruciate ligament disease in this report are in concordance with previous reports.


Differentiation between glioblastomas and solitary brain metastases using diffusion tensor imaging.
The purpose of this study is to determine whether diffusion tensor imaging (DTI) metrics including tensor shape measures such as linear and planar anisotropy coefficients (CL and CP) can help differentiate glioblastomas from solitary brain metastases. Sixty-three patients with histopathologic diagnosis of glioblastomas (22 men, 16 women, mean age 58.4 years) and brain metastases (13 men, 12 women, mean age 56.3 years) were included in this study. Contrast-enhanced T1-weighted, fluid-attenuated inversion recovery (FLAIR) images, fractional anisotropy (FA), apparent diffusion coefficient (ADC), CL and CP maps were co-registered and each lesion was semi-automatically subdivided into four regions: central, enhancing, immediate peritumoral and distant peritumoral. DTI metrics as well as the normalized signal intensity from the contrast-enhanced T1-weighted images were measured from each region. Univariate and multivariate logistic regression analyses were employed to determine the best model for classification. The results demonstrated that FA, CL and CP from glioblastomas were significantly higher than those of brain metastases from all segmented regions (p<0.05), and the differences from the enhancing regions were most significant (p<0.001). FA and CL from the enhancing region had the highest prediction accuracy when used alone with an area under the curve of 0.90. The best logistic regression model included three parameters (ADC, FA and CP) from the enhancing part, resulting in 92% sensitivity, 100% specificity and area under the curve of 0.98. We conclude that DTI metrics, used individually or combined, have a potential as a non-invasive measure to differentiate glioblastomas from metastases.


Use of novel picolinoyl derivatization for simultaneous quantification of six corticosteroids by liquid chromatography-electrospray ionization tandem mass spectrometry.
Simultaneous quantification method of six corticosteroids, cortisone, cortisol, cortexolone, corticosterone, dehydrocorticosterone and deoxycorticosterone, by LC-electrospray ionization (ESI)-MS in a positive mode using novel picolinoyl derivatization was investigated. Conversion of each corticosteroid into the corresponding picolinoyl derivative was performed by mixed anhydride method using picolinic acids and 2-methyl-6-nitrobenzoic anhydride. Derivatization proceeded smoothly to afford the corresponding 21-monopicolinoyl derivatives. Positive ion-ESI mass spectra of the picolinoyl derivatives were dominated by the appearance of [M+H](+) as base peaks. The picolinoyl derivatives provided 5-10 times higher ESI response in the LC-ESI-MS-selected reaction monitoring (SRM) when compared to those of underivatized molecules in a positive LC-ESI-MS mode. The use of the picolinoyl ester, solid-phase extraction, and deuterium labeled internal standards enabled to determine the concentrations of these corticosteroids in human saliva simultaneously by LC-ESI-MS-SRM.


A systematic review of communication interventions to help healthcare professionals discuss genetic testing for breast cancer.
This systematic review examined educational training interventions for healthcare professionals (HCPs) discussing genetic testing and risk for hereditary breast cancer. There was a particular focus on the presence, and content, of communication elements within these packages. Searches were run via CINAHL, EMBASE, PUBMED, and PsychInfo in February 2019 to identify training interventions available to HCPs with reference to communication skills. Studies were assessed for quality, with relevant intervention and outcome data extracted and synthesized. This review followed the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement and was registered on the PROSPERO database (CRD42019124010). Of 3,988 items, seven papers, two of which were linked, were eligible for inclusion. There was a mix of randomized and single arm studies with web-based and face-to-face interventions. Content included an overview of genetics, hereditary and familial background, and recommended practice techniques. Outcomes focused on communication, self-efficacy, knowledge, and satisfaction. Interventions were designed for genetic counselors, physicians, primary care physicians (PCPs), medical students, and nurses. None of the papers featured oncologists or surgeons. This review revealed an overall lack of publications which evaluated interventions to assist HCPs discussing hereditary breast cancer risk and testing. Studies failed to operationalize which 'communication skills' they included, nor did they consistently report randomization, outcome measures, or analysis. Discussing the need for, and management of, genetic testing for inherited cancer risk with individuals and their families can be challenging. As genetic testing in breast cancer becomes more common, the provision of specific communication-based training programs, with reference to genetic testing, risk assessments, and counseling skills is warranted.


Clinical presentation, diagnosis, and hospital outcome of patients with documented aortic dissection: the Albany Medical Center experience, 1986 to 1996.
In recent years, the diagnostic approach to patients with suspected aortic dissection has changed dramatically. Noninvasive studies such as transesophageal echocardiography (TEE), computed tomography, and magnetic resonance imaging have supplanted angiography as the initial tests of choice. The effect of this change in diagnostic approach has not previously been evaluated. The records of all patients discharged from Albany Medical Center Hospital between January 1, 1986, and December 31, 1996, were screened for an "aortic dissection" entry in the medical record database. For those records in which aortic dissection was confirmed, data concerning the diagnostic evaluation, treatment, and hospital course were recorded and analyzed. During the study period, there were 160 cases of documented aortic dissection discharged from the hospital. There were 100 type A and 60 type B dissections. The most commonly used diagnostic tests were TEE (83 of 160) and angiography (60 of 160). In patients who had TEE, diagnosis was made more quickly but overall mortality rate was not different from patients who had angiography. Renal dysfunction and neurologic events were less frequent in the TEE group. Hospital stay was significantly shorter in the TEE group (24.8 +/- 3.9 vs 14.0 +/- 1.8 days, P =.01). The use of TEE reduces morbidity rate and hospital stay in patients with aortic dissection but does not affect mortality rate.


[Research progress on the role of HIFs-PHDs oxygen-sensing pathway in cellular ferroptosis].
Hypoxia-inducible factors (HIFs) are one of the primary transcription factors regulating oxygen balance, and their stability is determined by the hydroxylation state of the prolyl hydroxylase domain (PHD) that is sensitive to oxygen. In recent years, studies have shown that HIFs-prolyl hydroxylases (PHDs) oxygen-sensing pathway is involved in the process of cellular ferroptosis. Ferroptosis, a new type of cell death, different from necrosis, apoptosis, necrotizing apoptosis, and pyroptosis, is essentially a programmed death caused by the accumulation of iron-dependent lipid peroxides in cells. This paper focuses on the role and mechanism of the HIFs-PHDs oxygen-sensing pathway in cellular ferroptosis involved in nerve diseases, tumors, lung injury, and chemical nerve damage from three aspects of iron metabolism, lipid metabolism, and glutathione (GSH) synthesis/metabolism. This review will provide a theoretical basis and new ideas for the development of novel drugs targeting the HIFs-PHDs oxygen-sensing pathway and capable of regulating ferroptosis for the treatment of diseases related to ferroptosis such as nervous system diseases and tumors.


Indolyl and dihydroindolyl N-glycinamides as potent and in vivo active NPY5 antagonists.
A novel series of indolyl and dihydroindolyl glycinamides were identified as potent NPY5 antagonists with in vivo activity from screen hit 1. The dihydroindolyl glycinamide 10a significantly inhibits NPY5 agonist induced feeding at a dose of 0.1 mg/kg. The indolyl glycinamide 12c also inhibits NPY5 agonist induced feeding at a dose of 1 mg/kg. Both compounds 10a and 12c represent potential tools for further investigation into the biology of the NPY5 receptor.


A "Bumper-Car" Curriculum for Teaching Deep Learning to Radiology Residents☆.
Our goal was to create an artificial intelligence (AI) training curriculum for residents that taught them to create, train, evaluate and refine deep learning (DL) models. Hands-on training of models was emphasized and didactic presentations of the mathematical and programmatic underpinnings of DL were minimized. We created a three-session, 6-hour curriculum based on a "no-code" machine learning system called Lobe.ai. This class met weekly in June 2021. Pre-class homework included reading assignments, software installation, dataset downloads, and image-collection and labeling. The class sessions included several short, didactic presentations, but were largely devoted to hands-on training of DL models. After the course, our residents completed a short, anonymous, online survey about the course. Our residents learned to acquire and label a wide variety of image datasets. They quickly learned to train DL models to classify these datasets, as well as how to evaluate and refine these models. Our survey showed that most residents felt AI to be important and worth learning, but most were not very interested in learning to program. Most felt that the course taught them useful things about DL, and they were now more interested in the topic. Most would recommend the course to other residents, as well as to medical students and to radiology faculty. The course met our objectives of teaching our residents to create, train, evaluate, and refine DL models. We hope that the hands-on experience they gained in this course will enable them to recognize problems in diagnostic AI systems, and to help solve such problems in their own radiology practices.


Membrane open-system cell for oxygen consumption measurement.
A membrane-diffusion cell for oxygen uptake measurements in an open system is described. Polarographic oxygen measurements with a Clark electrode are combined with simultaneous pH and absorbance or fluorescence determinations. Examples of its use are given and discussed, including experiments on mitochondrial respiration. Advantages of this cell are analyzed and comparisons are made with other open-system respirographs.


Effect of treatment with azathioprine on the responses of rat lymphocytes to phytohaemagglutinin.
The proliferative responses of rat peripheral blood lymphocytes (PBL) and spleen cells to phytohaemagglutinin (PHA) were studied after single or multiple (daily for 4 days) injections of azathioprine (AZ). Lymphopenia developed within 4 h of a single dose (78 mg/kg) of AZ and persisted for at least 72 h. There was no lymphopenia 24 h after the last of 4 daily injections. In vitro, PBL were more sensitive than spleen cells to the inhibitory effect of AZ. Likewise, the responses of PBL were relatively more depressed than those of spleen cells after single or multiple injections of AZ. The degree of depression was less than was expected from the effect of AZ in vitro. Multiple small doses were more depressive than multiple large doses. Serum from treated rats, used at 20% concentration, was more depressive than normal. Thus, rat lymphocytes are quite sensitive to AZ in vitro, but appear to be relatively resistant in vivo, this resistance resembling the resistance of the primary antibody response to AZ treatment.


Inhibition of human leucocytes locomotion by anti-inflammatory drugs.
In this study we have demonstrated that acidic non-steroidal anti-inflammatory drugs in low concentrations inhibited human PMN locomotion in vitro. A speculative mechanism of action is proposed.


Characterization of soft tissue masses: can quantitative diffusion weighted imaging reliably distinguish cysts from solid masses?
To investigate the accuracy of quantitative diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping for characterizing soft tissue masses (STMs) as cysts or solid masses. This IRB-approved retrospective study included 36 subjects with 37 STMs imaged by conventional MRI (T1-weighted, T2-weighted, contrast-enhanced T1-weighted sequences) and DWI (b-values 50, 400, 800 s/mm(2)) with ADC mapping. STMs were defined as non-solid cysts by histology or clinical follow-up, and as solid by histology. For each STM, ADC values (range, mean) were recorded by two observers. Differences between ADC values in cysts and solid STMs were compared using Wilcoxon rank-sum and receiver-operating characteristic (ROC) analysis. There were higher minimum (1.65 vs 0.68, p = 0.003) and mean (2.31 vs 1.45, p = 0.005) ADC values in cysts than solid STMs respectively. Areas under the ROC for minimum and mean ADC values were 0.82 and 0.81 respectively. Using threshold ADC values of 1.8 (minimum) or 2.5 (mean) yielded a sensitivity of 60 % and 80 % respectively, and a specificity of 100 % for classifying a STM as a cyst; for tumors with high fluid-signal intensity, the performance of these threshold values was maintained. Diffusion-weighted imaging with ADC mapping provides a non-contrast MRI alternative for the characterization of STMs as cysts or solid masses. Threshold ADC values exist that provide 100 % specificity for differentiating cysts and solid STMs, even for tumors of high fluid-signal intensity on T2-weighted images.


Down-regulation of long non-coding RNA ANRIL inhibits the proliferation, migration and invasion of cervical cancer cells.
Cervical cancer (CC) is a common malignant tumor in the female reproductive system that is characterized by a high metastatic potential. LncRNA ANRIL has been found to be a cancer oncogene in multiple tumors. In our study, we altered the expression of ANRIL in CC cells and evaluated its ability on influencing proliferation, migration and invasion of CC cells and associated mechanism. Differentially expressed lncRNAs in CC were identified by microarray and TCGA analyses. CC tissues and adjacent tissues were collected in order to extract CC cells. The expression of ANRIL was determined by RT-qPCR. The CC cells were transfected with siRNA or si-NC against ANRIL to find out whether ANRIL can influence the expression of Cyclin D1, CDK4, CDK6, E-cadherin, vimentin and N-cadherin, as well as affect cell proliferation, cell apoptosis, cell migration and cell invasion of CC cells. Based on TCGA and microarray analyses, ANRIL was predicted to be highly expressed in CC and CC with migration. Then further verification was obtained by means of RT-qPCR that ANRIL was highly expressed in CC tissues. In addition, high expression of ANRIL was related to increased E-cadherin expression, high migration of CC as well as decreased cell apoptosis rate. On the other hand, inhibition of ANRIL expression led to decreased expressions of Cyclin D1, CDK4, CDK6, N-cadherin and Vimentin, along with attenuated cell proliferation, migration and invasion of CC cells. The key findings of our study demonstrated that the inhibition of lncRNA ANRIL reduces the proliferation, migration and invasion capabilities of CC cells. Down-regulation of ANRIL may serve as a potential therapeutic target in the treatment of CC.


Activation changes induced by cognitive training are consistent with improved cognitive reserve in older adults with subjective cognitive decline.
Functional magnetic resonance imaging (fMRI) was used to assess the effect of cognitive training on brain activation as a function of the learning phase and level of education. Forty older adults with subjective cognitive decline (SCD) received 6 1-hour memory training sessions with the method of loci. Brain imaging (N = 29) was measured during word list encoding and retrieval before training (PRE), after 3 training sessions (POST3), and after 6 training sessions (POST6). Participants showed increased activation of the left inferior pre-frontal gyrus from PRE to POST6 during encoding and reduced bilateral frontostriatal activation from PRE to POST3 during retrieval, regardless of education. Activation changes from PRE to POST3 varied as a function of education in 2 regions of the right temporal lobe: participants with lower education showed increased activation, while those with higher education showed decreased activation. These regions were initially less active in people with lower education. Results suggest a strategic shift in people with lower education and expertise building in those with higher education, along with a restoration of initial education-related differences.


The structure of chlorophyll a-water complexes: insights from quantum chemistry calculations.
Computations show that chlorophyll a is able to coordinate a maximum of two water molecules in hydrophobic media that form a bridge between the Mg atom and the methyl ester carbonyl group.


Statistically sound comparison of standardized and simulation methods for oil spill source identification in real spill scenarios.
The comparison of oil patterns of a spill (Sp) and suspected spill source (SS) samples is based on ratios between correlated GC-MS signals of oil-discriminating compounds, i.e., diagnostic ratios (DR). The Student's t statistics (S-t) and a maximum relative difference (SC), proposed in standard methods, have been used for DR comparison due to their simplicity. An alternative methodology based on Monte Carlo Method (MCM) simulations of correlated signals, capable of accurately defining DR comparison criteria, proved that S-t and SC assumptions regarding DR normality and precision are frequently not valid, affecting comparison reliability. The performance of the approaches was accurately compared from independent signals of the same oil sample from a perfect match between Sp and SS. The present study describes the comparison of the approaches in real oil spill scenarios reproduced in International Round Robin Tests. Since as the number of compared DR increases, also rises the probability of not all equivalent DR being actually considered equivalent, the decision of oil pattern equivalence was based on two comparisons of independent sets of Sp and SS signals. The risk of true oil standard equivalency claims is compared for the three oil spill scenarios studied, which are different considering oil types, DR sets and spill weathering. The ability of the approaches to distinguish the Sp sample from an oil sample known not to be the source of the spill was also assessed. The MCM based on two independent DR comparison trials was the only one consistently producing fingerprint comparison risks of correct equivalence claims larger than 98 %. MCM also performed better in distinguishing different oil patterns. It was concluded that comparing >22 DR does not change the risk of correct oil pattern equivalence assessment significantly. The complexity of the MCM approach is overcome by using user-friendly and validated software.


Effect of cogon grass fibre on the thermal, mechanical and biodegradation properties of thermoplastic cassava starch biocomposite.
Thermoplastic cassava starch (TPCS) is a promising alternative material to replace the non-biodegradable petroleum based polymer due to its good environmental-friendly aspect i.e. abundant, sustainable, recyclable and biodegradable in nature. However, TPCS have some limitation such as poor mechanical properties. Therefore, in the present study, cogon grass fibre (CGF) were incorporated into TPCS using compression molding. Then the fundamental properties of CFG/TPCS biopolymer composites were carried out in order to evaluate their potential as a biodegradable reinforcement. From the study it was found that, the incorporation of CFG has improved the tensile and flexural properties of the TPCS composites, while the impact strength and elongation were reduced. The thermal properties of the biocomposite were reduced as the cogon grass fibres increase from 0 to 5%. In term of morphological, SEM shows good fibre adhesion between CGF and TPCS. Soil burial test shows that incorporation of CGF into TPCS has slow down the biodegradation process of the composites. Thus, CGF/TPCS biopolymer composites can be classified as composites with great potential as environmental-friendly material that biodegradable and renewable.


Tracing carbon flow in an arctic marine food web using fatty acid-stable isotope analysis.
Global warming and the loss of sea ice threaten to alter patterns of productivity in arctic marine ecosystems because of a likely decline in primary productivity by sea ice algae. Estimates of the contribution of ice algae to total primary production range widely, from just 3 to >50%, and the importance of ice algae to higher trophic levels remains unknown. To help answer this question, we investigated a novel approach to food web studies by combining the two established methods of stable isotope analysis and fatty acid (FA) analysis--we determined the C isotopic composition of individual diatom FA and traced these biomarkers in consumers. Samples were collected near Barrow, Alaska and included ice algae, pelagic phytoplankton, zooplankton, fish, seabirds, pinnipeds and cetaceans. Ice algae and pelagic phytoplankton had distinctive overall FA signatures and clear differences in delta(13)C for two specific diatom FA biomarkers: 16:4n-1 (-24.0+/-2.4 and -30.7+/-0.8 per thousand, respectively) and 20:5n-3 (-18.3+/-2.0 and -26.9+/-0.7 per thousand, respectively). Nearly all delta(13)C values of these two FA in consumers fell between the two stable isotopic end members. A mass balance equation indicated that FA material derived from ice algae, compared to pelagic diatoms, averaged 71% (44-107%) in consumers based on delta(13)C values of 16:4n-1, but only 24% (0-61%) based on 20:5n-3. Our estimates derived from 16:4n-1, which is produced only by diatoms, probably best represented the contribution of ice algae relative to pelagic diatoms. However, many types of algae produce 20:5n-3, so the lower value derived from it likely represented a more realistic estimate of the proportion of ice algae material relative to all other types of phytoplankton. These preliminary results demonstrate the potential value of compound-specific isotope analysis of marine lipids to trace C flow through marine food webs and provide a foundation for future work.


Paraventricular nucleus: a primary site mediating adrenergic stimulation of feeding and drinking.
Central injection of norepinephrine (NE) has been found to elicit preprandial drinking and feeding responses in the satiated rat. In the present study, 35 different brain areas, in over 500 rats, were examined to localize the precise region of NE sensitivity. Essentially all sites outside the hypothalamus, as well as in the lateral portion of the hypothalamus, were relatively or totally unresponsive to NE. In the medial hypothalamic area, the paraventricular nucleus (PVN) was clearly distinguished as the most effective site for initiating both feeding and drinking with noradrenergic activation in the satiated animal. Sites greater than 0.5 mm rostral, caudal, dorsal, ventral or lateral to this nucleus yielded significantly smaller effects. In mildly hungry rats, NE was found to potentiate the ongoing feeding response, and anatomical analyses of this phenomenon showed the PVN to be most responsive, with a smaller but reliable potentiation occurring along the periventricular hypothalamus adjacent to the third ventricle. Norepinephrine injected into the lateral perifornical hypothalamic area actually produced a suppression of feeding in these hungry animals. These findings, together with results from other studies, converge on the medial PVN region as being a key link in the process of increased food and water consumption associated with increased noradrenergic activity.


Association between postprandial lipoprotein subclasses and Framingham cardiovascular disease risk stratification.
To determine the ability of postprandial lipoprotein subclass concentrations to stratify patients with respect to their risk for cardiovascular disease (CVD). Using the Framingham cardiovascular disease risk score (FRS) algorithm, a total of 112 consecutive patients referred for community health screening were stratified into two groups: (a) low-risk (FRS < 10%) and (b) intermediate/high-risk (FRS ≥ 10%). Serum lipoprotein subclass concentrations were determined by Vertical Auto Profile (VAP-II). Fasting and postprandial levels of LDL4, HDL2, VLDL1 + 2, VLDL3, and RLP, as well as fasting levels of ApoB and postprandial levels of LDL3 and IDL1, were significantly different in the intermediate/high risk FRS group vs. the low-risk group (P < 0.05). Correlations between Framingham CVD risk and LDL3, LDL4, IDL1, VLDL1 + 2, VLDL3, RLP, and ApoB were positive while negative for HDL2 in both the fasting and postprandial states. Intermediate/high risk for CVD was shown to be significantly associated with both fasting and postprandial levels of VLDL1 + 2 and RLP, as well as with postprandial LDL4 and VLDL3, as determined using forward conditional logistic regression analysis. Postprandial levels of VLDL1 + 2 were better at identifying patients in the intermediate/high-risk FRS group than fasting levels, although the differences were not significant due to overlapping reference intervals. In addition, the association between RLP and VLDL subclasses relative to Framingham CVD risk increased significantly in the postprandial state (ΔR2 = 0.023; ΔF = 7.178; ΔP = 0.025) but not in the fasting state. The use of postprandial lipoprotein subclass concentrations is not inferior to the use of fasting levels in identifying intermediate/high-risk FRS individuals. In addition, changes in RLP and VLDL subclass concentrations in fasting vs. postprandial states may reveal lipid metabolic mechanisms associated with CVD.


Improved semen collection method for wild felids: urethral catheterization yields high sperm quality in African lions (Panthera leo).
For wild and domestic felids, electroejaculation (EE) is the most common semen collection method. However, the equipment is expensive, there is a risk of urine contamination and animals usually show strong muscular contraction despite general anesthesia. Accordingly, we tested the feasibility of a different approach using urethral catheterization (UC) in seven African lions, previously described for domestic cats only. After general anesthesia with the α2-agonist medetomidine (which also stimulates semen release into the urethra) and ketamine, a transrectal ultrasound was performed to locate the prostate. A commercial dog urinary catheter (2.6 or 3.3 mm in diameter) was advanced approximately 30 cm into the urethra to allow semen collection into the lumen of the catheter by capillary forces. After retraction, sperm volumes between of 422.86 ± 296.07 μl yielded motility of 88.83 ± 13.27% (mean ± SD) with a mean sperm concentration of 1.94 × 10(9)/ml. Here we describe a simple, field friendly and effective method to attain highly concentrated semen samples with excellent motility in lions and potentially other wild felid species as an alternative to electroejaculation.


Plasma membrane redox and control of sirtuin.
We consider possible contributions of plasma membrane redox systems to Aging control by sirtuin (SIR). Reported changes in plasma membrane redox introduced by calorie restriction (CR) may lead to activation of SIR. The most obvious effect would lie in the increase of NAD+ as a result of NADH oxidation. So the question arises, do the observed changes herald an increase in NADH oxidase under CR? The other possibility is an increase in expression of SIR by activation of plasma membrane oxidase. Previous experiments have shown that activation of the plasma membrane redox system can increase cellular NAD+ concentration. The plasma membrane redox systems are also involved in control of protein kinase activity through oxygen radical generation. This activity may be related to control of SIR expression.


Hepatitis C virus associated ALT, AST, GGT, Bili T, HB, HBA1C, CREAT, PT, aPPT, AFP, CEA, CA 125, CA 19-9, iPTH biomarkers, computed tomography and HCV burden of disease during pre COVID-19 era (2018-2019) and post COVID-19 era (2020-2022) in Pakistan.
The national burden of HCV has significantly mounted over the period of last few decades placing Pakistan at the worst placement of second largest burden of HCV globally. Herein for the first time from Pakistan, we examined clinical correlation of potential biomarkers with HCV. Nation-wide study was conducted on 13,348 suspected HCV patients during 2018-2022. During pre-COVID-19 era of 2018-2019, prevalence of HCV remained 30%. During 2018, among HCV positive patients, 91% of ALT, 63% of AST, 67% of GGT, 28% of Bili T, 62% of HB, 15% of HBA1C, 25% of CREAT, 15% of PT, 15% of aPTT and 64% of AFP were abnormal. During 2019, among HCV infected 74.47% of ALT, 63.54% of AST, 70.24% of GGT, 24.71% of Bili T, 8.77% of HB and 75% of AFP were raised. CT/CAT scan revealed 4.65% liver complications (mild 13.04%, moderate 30.43% and severe 56.52%). During 2020, HCV prevalence remained 25%. 65.17% of ALT, 64.20% of AST, 68.75% of GGT, 31.25% of Bili T, 20.97% of HB, 4.65% of CREAT and 73.68% of AFP levels were raised. CAT analysis revealed liver complications among 4.41% (14.81% mild, 40.74% moderate, and 44.44% sever). 85.71% of participants diabetes was out of control. During 2021, HCV prevalence remained 27.1%. ALT (73.86%), AST (50.6%), GGT (67.95%), Bili T (28.21%), HB (20%), CREAT (5.8%) and AFP (82.14%) levels were abnormal. During 2022, the levels of ALT (56.06%), AST (56.36%), GGT (56.6%), Bili T (19.23%), HB (43.48%), HBA1C (14.81), CREAT (18.92%), AFP (93.75%) were abnormal. CAT analysis revealed 7.46% liver complications (25% mild, 30.36% moderate, and 42.86% sever). During 2021-2022, 83.33% of subject's diabetes was not controlled.


Hyposmia correlates with SNCA variant and non-motor symptoms in Chinese patients with Parkinson's disease.
Hyposmia plays an important role in the early and differential diagnosis of Parkinson's disease (PD); however its underlying mechanism is poorly understood. The aim of the present study is to explore the clinical phenotypic and genotypic correlation of hyposmia in Chinese PD patients. Olfactory function evaluated by 16-item odor identification test from Sniffin' Sticks (SS-16) of 218 Chinese Han PD patients and 110 healthy controls was compared. 186 patients also had the genetic information of two positive GWAS-linked SNCA loci (rs11931074, rs894278) previously validated in our center. The associations of hyposmia with SNCA variants and disease phenotypic characteristics including motor symptoms (UPDRS motor score) and other common NMSs (clinical possible RBD-cpRBD, depression and chronic constipation) were analyzed. Nearly 39.9% (n = 87) of PD reported subjective complaints of hyposmia, while 60.1% (n = 131) patients had objective hyposmia (SS-16 < 8.3). Patients with hyposmia had older age (p = 0.001), later onset age (p = 0.020), higher SCOPA-AUT scores (p = 0.011), higher percentage of chronic constipation (p = 0.001) and cpRBD (p = 0.003). Binary logistic regression analysis revealed that ageing (OR = 1.058; 95%CI: 1.012-1.106; p = 0.013), chronic constipation (OR = 2.072; 95% CI: 1.157-3.710; p = 0.014) and cpRBD (OR = 2.234; 95% CI: 1.040-4.797; p = 0.039) were independent influential factors of hyposmia in Chinese PD patients. Subgroup analysis of patients with both clinical and genetic results demonstrated that after adjusting for age, sex, chronic constipation and cpRBD, rs11931074 TT genotype may increase the risk of hyposmia in PD (OR = 3.24 95% CI = 1.23-8.51, p = 0.017) compared to GG genotype via an additive model. Age, cpRBD, chronic constipation and SNCA rs11931074 may correlate with hyposmia in Chinese PD patients.


The Effect of Laser Panretinal Photocoagulation on Diabetic Macular Edema Using the Pascal® Photocoagulator versus the Conventional Argon Laser Photocoagulator.
The aim of this study was to compare the effect of panretinal photocoagulation for proliferative diabetic retinopathy (PDR) on diabetic macular edema (DME) using a Pascal® Photocoagulator (PP) or a conventional argon laser photocoagulator (CALP). Eighty eyes with PDR and center-involving DME were randomized to PP or CALP. Both groups had baseline assessment of best-corrected visual acuity (BCVA) and were examined with optical coherence tomography and fluorescein angiography. The mean number of laser shots for the PP and CALP groups was 1,726.10 and 752.00 at session 1 and 1,589.00 and 830.00 (p < 0.001) at session 2, respectively. The mean central foveal thickness (CFT) at baseline was 306 ± 100 and 314 ± 98 for the PP and CALP groups, respectively. At 8 weeks, the mean CFT was 332 ± 116 and 347 ± 111 for the PP and CALP groups, respectively (p > 0.05). The mean BCVA was similar during the study period with no significant difference between the groups (p > 0.05). PP and CALP had similar effects on DME in PDR eyes and were equally safe with no significant increase in CFT.


A CADD-alog of strategies in pharma.
A special issue on computer-aided drug design (CADD) strategies in pharma discusses how CADD groups in different environments work. Perspectives were collected from authors in 11 organizations: four big pharmaceutical companies, one major biotechnology company, one smaller biotech, one private pharmaceutical company, two contract research organizations (CROs), one university, and one that spans the breadth of big pharmaceutical companies and one smaller biotech.


Inflammatory muscle involvement in systemic vasculitis: A systematic review.
Vasculitis are severe systemic autoimmune diseases which may involve different organs and systems. Conversely, muscles do not represent an organ commonly involved by systemic vasculitis and myositis is not include among any classification or diagnostic criterion of vasculitis. In this regard, we aimed to review the literature in order to report all the available evidence concerning the inflammatory involvement of muscle in patients affected by systemic vasculitis. We collected a total of 108 papers, for a sum of 395 patients affected by muscle vasculitis. Most of them suffered from medium and small vessels vasculitis (mainly polyarteritis nodosa and ANCA-associated vasculitis) or from vasculitis secondary to rheumatoid arthritis. Conversely, muscle involvement in case of large vessel vasculitis occurred seldom, while only few papers reported such occurrence in Kawasaki or Behçet's disease. Histological findings may differ, but the most common ones displayed a necrotizing vasculitis of perimysium vessels, while granulomatous vasculitis was assessed only in case of ANCA-associated vasculitis patients. Creatine kinase were usually within normal range, seldom elevated, while imaging findings were generally undistinguishable from the ones found in idiopathic inflammatory myopathies: magnetic resonance imaging displays signal hyperintensity in T2 and STIR scans, while few data exist for positron emission tomography. The presentation of the disease may be fearsome and severe, sometimes life-threatening, but an overall good response to conventional immunosuppressants and/or glucocorticoids has been reported.


Hypofractionated stereotactic radiotherapy for challenging brain metastases using 36 Gy in six fractions.
Stereotactic radiosurgery and hypofractionated stereotactic radiotherapy are standard treatments for brain metastases when they are small in size (at the most 3cm in diameter) and limited in number, in patients with controlled extracerebral disease and a good performance status. Large inoperable brain metastases usually undergo hypofractionated stereotactic radiotherapy while haemorrhagic brain metastases have often been contraindicated for both stereotactic radiosurgery or hypofractionated stereotactic radiotherapy. The objective of this retrospective study was to assess a six 6Gy-fractions hypofractionated stereotactic radiotherapy scheme in use at our institution for haemorrhagic brain metastases, large brain metastases (size greater than 15cm3) or brain metastases located next to critical structures. Patients with brain metastases treated with the 6×6Gy scheme since 2012 to 2016 were included. Haemorrhagic brain metastases were defined by usual criteria on CT scan and MRI. Efficacy, acute and late toxicity were evaluated. Sixty-two patients presenting 92 brain metastases were included (32 haemorrhagic brain metastases). Median follow up was 10.1 months. One-year local control rate for haemorrhagic brain metastases, large brain metastases, or brain metastases next to critical structures were 90.7%, 73% and 86.7% respectively. Corresponding overall survival rates were 61.2%, 32% and 37.8%, respectively. Haemorrhagic complications occurred in 5.3% of patients (N=5), including two cases of brain metastases with pretreatment haemorrhagic signal. Tolerance was good with only one grade 3 acute toxicity. The 6×6Gy hypofractionated stereotactic radiotherapy scheme seems to yield quite good results in patients with haemorrhagic brain metastases, which must be confirmed in a prospective way.