Characterization of a Musculoskeletal Syndrome of Enthesitis and Arthritis in Patients With Atopic Dermatitis Treated With Dupilumab, an Interleukin-4/13 Inhibitor.
To characterize the presentation and outcomes of patients with atopic dermatitis (AD) who developed musculoskeletal symptoms after treatment with dupilumab, a human IgG4 monoclonal antibody that blocks the functions of interleukin-4 (IL-4) and IL-13, key pathologic pathways in AD. This article reports an observational cohort of patients receiving dupilumab who developed new-onset musculoskeletal symptoms after dupilumab therapy at our center. All patients had a comprehensive rheumatologic history and examination, with imaging by ultrasonography (US) or magnetic resonance imaging (MRI) in most patients. Between October 2018 and February 2021, we recorded 470 patients with AD commencing dupilumab treatment from routine clinical care records. Of 36 patients referred for rheumatologic assessment, we identified 26 patients (14 male, 12 female) with a musculoskeletal syndrome of inflammatory enthesitis, arthritis, and/or tenosynovitis. Clinical findings were confirmed by US and MRI. All patients had very good response to dupilumab treatment, and no specific predictors of musculoskeletal syndrome were noted. Symptoms were mild in 16 patients, moderate in 6 patients, and severe in 4 patients. Receipt of nonsteroidal antiinflammatory drugs or cyclooxygenase 2 inhibitors, reduction of dupilumab dose/frequency, and cessation of dupilumab therapy led to improvement, but moderate or severe symptoms persisted for many months. We report a new musculoskeletal syndrome of inflammatory enthesitis/arthritis/tenosynovitis in some patients receiving the IL-4 receptor antagonist dupilumab. This response to a cytokine-targeting therapy provides key insights into the pathogenesis of enthesitis.


Brain connectivity abnormalities in patients with functional (psychogenic nonepileptic) seizures: A systematic review.
The aim of the current endeavor was to systematically review the existing evidence on brain connectivity abnormalities in patients with functional seizures (FS). This systematic review was prepared according to the instructions of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. MEDLINE (accessed from PubMed) and Scopus from inception to April 4, 2020 were systematically searched. The following search strategy was implemented and these key words (in the title/abstract) were used: "connectivity" OR "network" AND "psychogenic" OR "dissociative" OR "nonepileptic". Through the search strategy, we could identify eighteen articles. These studies have applied various methodologies and they could identify a variety of brain connectivity abnormalities in people with FS. However, none of these studies provided a high level of evidence. They were all small studies (none had a sample size of more than 21 patients). In addition, most of the studies did not match their cases and their controls with respect to the psychiatric comorbidities and other significant confounders. Abnormal functional connectivity between emotion processing areas of the brain with regions involved in executive control and cognitive performance, and the functional connections of the anterior cingulate cortex are of major interest and may be involved in the pathophysiology of FS. Pursuing the concept of brain connectivity abnormalities in patients with FS and comparing the findings with well-matched controls in well-designed studies may result in a breakthrough in identifying the exact neurobiological origin of FS.


Penetration of rifampin through Staphylococcus epidermidis biofilms.
Rifampin penetrated biofilms formed by Staphylococcus epidermidis but failed to effectively kill the bacteria. Penetration was demonstrated by a simple diffusion cell bioassay and by transmission electron microscopic observation of antibiotic-affected cells at the distal edge of the biofilm.


3-Substituted 2-formylquinoxaline 1,4-dioxides.
The methylnitrone of 3-methyl-1,4-dioxidoquinoxaline-2-carboxaldehyde (1) has been exceptional antibacterial activity in vivo. Derivatives of 3-hydroxymethyl-1,4-dioxidoquinoxaline-2-carboxaldehyde and 3-acetoxymethyl-1,4-dioxidoquinoxaline-2-carboxaldehyde were prepared. Several of these compounds were found to be antibacterial agents of the same order of activity as I.


Simultaneous determination of hydrophobicity and dissociation constant for a large set of compounds by gradient reverse phase high performance liquid chromatography-mass spectrometry technique.
Fast and reliable methods for the determination of hydrophobicity and acidity are desired in pre-clinical drug development phases to eliminate compounds with poor pharmacokinetic properties. Reversed-phase high-performance liquid chromatography (RP HPLC) coupled with time-of-flight mass spectrometry (RP HPLC-ESI-TOF-MS) is a convenient technique for that purpose. In this work we determined the chromatographic measure of hydrophobicity (logkw) and dissociation constant (pKa) simultaneously for a large and diverse group of 161 drugs. Retention times were determined by means of RP HPLC-ESI-TOF-MS for a series of pH and organic modifier gradients. We were able to measure retention times for 140 out of 161 (87%) compounds. For those analytes logkw and pKa parameters were calculated and compared with literature and ACD Labs-calculated data. The determined chromatographic measure of hydrophobicity and dissociation constant was closely related to literature and theoretically calculated values. Applied methodology achieved the medium-throughput screening rate of 100 compounds per day and proved to be a simple, fast and reliable approach of assessing important physicochemical properties of drugs. This technique has certain limitations as it is not applicable for very hydrophilic analytes (logP<0.5) and compounds with identical molar masses.


Recombinant BCG coexpressing Ag85B, ESAT-6 and Rv3620c elicits specific Th1 immune responses in C57BL/6 mice.
Tuberculosis (TB) remains to be an enormous global health problem. The inconsistent protection efficacy of Bacille Calmette-Guérin (BCG) calls for new vaccines for TB. One choice to improve the efficacy of BCG vaccine is recombinant BCG (rBCG). Experimental evidences have revealed that Ag85B, ESAT-6 and Rv3620c are important immunodominant antigens of Mycobacterium tuberculosis. In this study, we have constructed a novel rBCG expressing fusion protein Ag85B-ESAT6-Rv3620c and evaluated the immunogenicity of this rBCG in C57BL/6 mice. Results show that there is a strong TB-specific CD4(+) and CD8(+) T lymphocytes proliferation in mice immunized with this rBCG vaccine. A single dose immunization of rBCG could induce a significantly strong Th1 immune response characterized by an increasing ratio of antigen-specific IgG2b/IgG1 as well as a high expression level of Th1 cytokines such as IFN-γ, TNF-α and IL-2. This conclusion was confirmed by a decreased secretion of Th2 cytokine IL-10. Moreover, this rBCG induced a strong humoral response in mice with an increasing antigen-specific IgG titer. Therefore, we concluded that this rBCG could significantly increase both Th1 type cellular immune response and antigen-specific humoral response compared with BCG. The above observations demonstrated that rBCG::Ag85B-ESAT6-Rv3620c is a potential candidate vaccine against M. tuberculosis for further study.


Burn center management of necrotizing soft-tissue surgical infections in unburned patients.
Patients with necrotizing soft-tissue infections present great challenges in management from initial presentation through definitive care. Because burn centers concentrate expertise in critical care, wound management, and rehabilitation, we examined the effectiveness of burn center care for patients with necrotizing infections. We reviewed our burn center's experience with all patients admitted from 1990 through 1999 with a primary diagnosis of necrotizing fasciitis (NF) or Fournier's gangrene (FG). Fifty-seven patients were identified, 18 with FG and 39 with NF. Patients had a high incidence of preexisting medical problems, including diabetes (37%), obesity defined as greater than 20% above ideal body weight (33%), and hypertension (33%). Seven of 57 (12%) patients died. Patients required a mean of 4.1 operative procedures (range 1 to 15) for definitive wound closure. The mean length of stay (survivors only) was 28.5 days, (range 3 to 70). Although costs increased throughout this period, a formal program of cost-containment resulted in no increase in actual charges per day, from a mean of $4,735 in 1991 to $5,202 in 1999. Burn centers can provide successful and cost-effective acute care, definitive wound closure, and rehabilitation for patients with NF and FG.


Venom characterization of the three species of Ophryacus and proteomic profiling of O. sphenophrys unveils Sphenotoxin, a novel Crotoxin-like heterodimeric β-neurotoxin.
Venoms of the three species of Ophryacus (O. sphenophrys, O. smaragdinus, and O. undulatus), a viperid genus endemic to Mexico, were analyzed for the first time in the present work. The three venoms lacked procoagulant activity on human plasma, but induced hemorrhage and were highly lethal to mice. These venoms also displayed proteolytic and phospholipase A2 activities in vitro. The venom of O. sphenophrys was the most lethal and caused hind-limb paralysis in mice. Proteomic profiling of O. sphenophrys venom showed a predominance of metalloproteinase (34.9%), phospholipase A2 (24.8%) and serine protease (17.1%) in its composition. Strikingly, within its PLA2 components, 12.9% corresponded to a Crotoxin-like heterodimer, here named Sphenotoxin, which was not found in the other two species of Ophryacus. Sphenotoxin, like Crotoxin, is composed of non-covalently bound A and B subunits. Partial amino acid sequence was obtained for Sphenotoxin B and was similar (78-89%) to other subunits described. The mouse i.v. LD50 of Sphenotoxin at 1:1 M radio was 0.16 μg/g. Also, like Crotoxin, Sphenotoxin induced a potent neuromuscular blockade in the phrenic nerve-diaphragm preparation. Ophryacus is the fifth genus and O. sphenophrys the third non-rattlesnake species shown to contain a novel Crotoxin-like heterodimeric β-neurotoxin. BIOLOGICAL SIGNIFICANCE: Ophryacus is an endemic genus of semi-arboreal pitvipers from Mexico that includes three species with restricted distributions. Little is known about the natural history of these species and nothing is known about the properties of their venoms. Research on these species' venoms could generate relevant information regarding venom composition of Mexican pitvipers. Additionally, research into the presence of neurotoxic Crotoxin-like molecules outside of rattlesnakes (genera Crotalus and Sistrurus) has identified this molecule in several new genera. Knowing which genera and species possess neurotoxic components is important to fully understand the repercussions of snakebites, the interaction with prey and predators, and the origin, evolution, and phylogenetic distribution of Crotoxin-like molecules during the evolutionary history of pitvipers. Our study expands current knowledge regarding venom's compositions and function from Mexican pitvipers, providing a comparative venom characterization of major activities in the three Ophryacus species. Additionally, the discovery and characterization of a novel Crotoxin-like molecule, here named Sphenotoxin, in O. sphenophrys, and the detailed protein composition of O. sphenophrys venom supports the hypotheses that Crotoxin-like -β-neurotoxins are more widespread than initially thought.


A qualitative investigation of the health behaviours of young children from refugee families using photo elicitation interviews.
To explore the experiences and perspectives of refugee parents regarding health behaviour changes among their children (i.e. changes in diet, levels of physical activity) and the impact of these changes on the health of their children aged 2-12 years. A qualitative approach using semi-structured interviews supported by photo-elicitation. Parents of 2-12 years old children who had relocated to the UK within the past three or more years were recruited from two refugee organisations in the UK. Semi-structured face-to-face interviews and photo-elicitation were used to stimulate face-to-face in-depth discussions with participants. Data were analysed using an inductive and latent thematic analysis approach. Twenty-seven parent refugees were recruited. Participants were primarily mothers (85%) and from Syria (70%). Other countries of origin were Sudan, Eritrea, Iraq, Kuwait, Libya and Tunisia. Twenty-six interviews were conducted in Arabic and one in English. The analysis identified three themes: (1) Reflection on acculturation, (2) Changed parental role, and (3) Environmental barriers to being healthy. Participants described facing substantial changes to their lifestyle and personal context, including a restricted living space, restricted neighbourhood/community and inclement weather. These differences in the environment required parents to adjust their roles, and practices around their own and their child's eating habits. These changes influenced refugee children's health behaviours. Of particular concern to parents were increased sedentary behaviour and consumption of unhealthy snacks. Multiple factors were identified relating to changes in family circumstances and environments that influenced refugee children's health behaviours. Targeting these behaviours in tailored interventions may help improve refugee children's health.


Pre-binding prior to full engagement improves loading conditions for front-row players in contested Rugby Union scrums.
We investigated the effect of a "PreBind" engagement protocol on the biomechanics of contested Rugby Union scrummaging at different playing levels. "PreBind" requires front-row props to take a bind on opposing players prior to the engagement, and to maintain the bind throughout the scrum duration. Twenty-seven teams from five different playing levels performed live scrums under realistic conditions. Video analysis, pressures sensors, and inertial measurement units measured biomechanical outcomes as teams scrummaged following different engagement protocols: the CTPE (referee calls "crouch-touch-pause-engage"), the CTS ("crouch-touch-set"), and the PreBind ("crouch-bind-set") variants. PreBind reduced the set-up distance between the packs (-27%) and the speed at which they came into contact by more than 20%. The peak biomechanical stresses acting on front rows during the engagement phase were decreased in PreBind by 14-25% with respect to CTPE and CTS, without reducing the capability to generate force in the subsequent sustained push. No relevant main effects were recorded for playing level due to within-group variability and there were no interaction effects between playing level and engagement protocol. Pre-binding reduced many mechanical quantities that have been indicated as possible factors for chronic and acute injury, and may lead to safer engagement conditions without affecting subsequent performance.


Placenta mediates the effect of maternal hypertension polygenic score on offspring birth weight: a study of birth cohort with fetal growth velocity data.
Low birth weight (LBW) and fetal growth restriction are associated with the development of cardio-metabolic diseases later in life. A recent Mendelian randomization study concluded that the susceptibility of LBW infants to develop hypertension during adulthood is due to the inheritance of hypertension genes from the mother and not to an unfavorable intrauterine environment. Therein, a negative linear association has been assumed between genetically estimated maternal blood pressure (BP) and birth weight, while the observed relationship between maternal BP and birth weight is substantially different from that assumption. As many hypertension genes are likely involved in vasculature development and function, we hypothesized that BP-increasing genetic variants could affect birth weight by reducing the growth of the placenta, a highly vascular organ, without overtly elevating the maternal BP. Using a birth cohort in the Japanese population possessing time-series fetal growth velocity data as a target and a GWAS summary statistics of BioBank Japan as a base data, we performed polygenic score (PGS) analyses for systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure. A causal mediation analysis was performed to assess the meditation effect of placental weight on birth weight reduced by maternal BP-increasing PGS. Maternal genetic risk score constituted of only "vasculature-related" BP single nucleotide polymorphisms (SNPs) was constructed to examine the involvement of vascular genes in the mediation effect of placental weight. We identified gestational week in which maternal SBP-increasing PGS significantly decreased fetal growth velocity. We observed that maternal SBP-increasing PGS was negatively associated with offspring birth weight. A causal mediation analysis revealed that a large proportion of the total maternal PGS effect on birth weight was mediated by placental weight. The placental mediation effect was remarkable when genetic risk score was constituted of "vasculature-related" BP SNPs. The inverse association between maternal SBP PGS and fetal growth velocity only became apparent in late gestation. Our study suggests that maternal hypertension genes are strongly associated with placental growth and that fetal growth inhibition is induced through the intrauterine environment established by the placenta.


[Writing the clinical trial report].
The clinical study report is a key document, representing as it does one of the elements of the drug registration file. The authors propose here a general design for a controlled trial which offers the advantage of a methodical approach covering most clinical study situations.


Panax notoginseng saponins inhibits NLRP3 inflammasome-mediated pyroptosis by downregulating lncRNA-ANRIL in cardiorenal syndrome type 4.
Cardiorenal syndrome type 4 (CRS4) is a complication of chronic kidney disease. Panax notoginseng saponins (PNS) have been confirmed to be efficient in cardiovascular diseases. Our study aimed to explore the therapeutic role and mechanism of PNS in CRS4. CRS4 model rats and hypoxia-induced cardiomyocytes were treated with PNS, with and without pyroptosis inhibitor VX765 and ANRIL overexpression plasmids. Cardiac function and cardiorenal function biomarkers levels were measured by echocardiography and ELISA, respectively. Cardiac fibrosis was detected by Masson staining. Cell viability was determined by cell counting kit-8 and flow cytometry. Expression of fibrosis-related genes (COL-I, COL-III, TGF-β, α-SMA) and ANRIL was examined using RT-qPCR. Pyroptosis-related protein levels of NLRP3, ASC, IL-1β, TGF-β1, GSDMD-N, and caspase-1 were measured by western blotting or immunofluorescence staining. PNS improved cardiac function, and inhibited cardiac fibrosis and pyroptosis in a dose-dependent manner in model rats and injured H9c2 cells (p < 0.01). The expression of fibrosis-related genes (COL-I, COL-III, TGF-β, α-SMA) and pyroptosis-related proteins (NLRP3, ASC, IL-1β, TGF-β1, GSDMD-N, and caspase-1) was inhibited by PNS in injured cardiac tissues and cells (p < 0.01). Additionally, ANRIL was upregulated in model rats and injured cells, but PNS reduced its expression in a dose-dependent manner (p < 0.05). Additionally, the inhibitory effect of PNS on pyroptosis in injured H9c2 cells was enhanced by VX765 and reversed by ANRIL overexpression, respectively (p < 0.05). PNS inhibits pyroptosis by downregulating lncRNA-ANRIL in CRS4.


Trisomy 13 in a case of myelodysplastic syndrome.
The clinical and cytogenetic findings of a patient with refractory anemia with excess of blasts are presented. Trisomy 13 was present as the sole numerical aberration in all analyzed bone marrow metaphases; this finding has not been reported previously in myelodysblastic syndrome.


Captopril and its probable contaminants: NMR and MS features of analytical value.
The 400 MHz 1H NMR spectrum of captopril in a variety of solvents is analysed and compared with those of epicaptopril and its disulphide analogue. A method for detecting isomeric and oxidative impurities by examination of a 1H NMR spectrum of captopril in DMSO-d6 is proposed. 13C NMR and MS data enable differentiation of captopril from its disulphide analogue but not from its diastereoisomer epicaptopril.


Antisense oligonucleotide technology can be used to investigate a circular but not linear RNA-mediated function for its encoded gene locus.
As a class of powerful molecular tool, antisense oligonucleotides (ASOs) are not only broadly used in protein and RNA biology, but also a highly selective therapeutic strategy for many diseases. Although the concept that ASO reagents only reduce expression of the targeted gene in a post-transcriptional manner has long been established, the effect and mechanism of ASO reagents on RNA polymerase II (Pol II) transcription are largely unknown. This raised question is particularly important for the appropriate use of ASOs and the valid interpretation of ASO-mediated experiments. In this study, our results show that linear RNA ASO attenuates transcription of nascent transcripts by inducing premature transcription termination which is combinatorially controlled by Integrator, exosome, and Rat1 in Drosophila. However, circular RNA (circRNA) ASO transfection does not affect transcription activity of the encoded gene. These data suggest that the ASO technique can be applied to study a circRNA-mediated but not linear RNA-mediated function for its encoded gene locus.


Brain stem projections from cortical area 18 in the albino rat.
Efferent brain stem projections from area 18 of the albino rat cortex were traced by autoradiography. Since results could have been compromised by spread of injected label to neighboring areas 17 and 29, studies of projections from these areas were used as controls. A hitherto unreported projection from area 18 to the thalamus in the region of its anterior nuclei was found, terminating in a roughly circular area including parts of the anteromedial, ventral, ventromedial and rhomboid nuclei. At this same level, a very light projection was seen in the contralateral anteromedial nucleus. More caudally the projection pattern was similar to that of area 17, with the lateral, lateral posterior, posterior and pretectal nuclei as targets. However, area 18 showed no projections to either division of lateral geniculate nucleus, projections which are commonly seen following injections in area 17. More caudally, the area 18 projection to the superior colliculus was confined to its four deepest laminae, a projection identical to that from areas 29c and 29b. Area 18 also resembled the cingulate cortex in that it sent a small projection to the dorsolateral central gray, although the routes taken to this region were slightly different. It was decided that the projections from this visual association area were, for the most part, unique to that area, although some of them resembled those from either the cingulate cortex or the primary visual area.


Deacetylase sirtuin 2 negatively regulates myeloid-derived suppressor cell functions in allograft rejection.
Although myeloid-derived suppressor cells (MDSCs) are critical for allograft survival, their regulatory mechanism remains unclear. Herein, our results showed that metabolism sensor sirtuin 2 (SIRT2) negatively regulates the functions of MDSCs in inducing allogeneic skin graft rejection. Genetic deletion of SIRT2 in myeloid cells (Sirt2Δmye) increased the number of CD11b+Gr1+ MDSCs in bone marrow, spleens, draining lymph nodes, and allografts, inhibited the production of proinflammatory cytokine tumor necrosis factor ɑ, enhanced the production of anti-inflammatory cytokine interleukin 10, and potentiated the suppressive activation of MDSCs in prolonging allograft skin survival. C-X-C motif chemokine receptor 2 is critical for mediating the recruitment and cytokine production of MDSCs induced by SIRT2. Mechanistically, Sirt2Δmye enhanced NAD+ levels, succinate dehydrogenase subunit A (SDHA) activities, and oxidative phosphorylation (OXPHOS) levels in MDSCs after transplantation. Pharmacologically blocking nicotinamide phosphoribosyltransferase effectively reverses the production of cytokines and suppressive activities of MDSC induced by Sirt2Δmye. Blocking OXPHOS with knockdown of SDHA or pharmacological blocking of SDHA significantly restores Sirt2Δmye-mediated stronger MDSC suppressive activity and inflammatory factor productions. Thus, our findings identify a previously unrecognized interplay between NAD+ and SDH-mediated OXPHOS metabolic pathways in regulating MDSC functions induced by the metabolic sensor SIRT2 in allogeneic transplantation.


Artifactually elevated serum bicarbonate results caused by elevated serum lactate dehydrogenase concentrations.
An accurate estimation of serum bicarbonate concentration (HCO3(-)) is essential to the diagnosis and treatment of acid-base disorders and electrolyte disturbances. We noted significant discrepancies between HCO3(-) concentration measured by the Olympus AU2700 analyser and total serum carbon dioxide (TCO2) concentration derived from a Radiometer blood gas analyser on several patient samples. This was reported to the manufacturer which led to a recall of certain reagent lot numbers. We hypothesised the mechanism for this interference to be elevated levels of lactate dehyrogenase (LD). We investigated the effect of increasing LD concentration on HCO3(-) with the reagent lot that was recalled and compared this with a subsequent reagent lot that was known to be unaffected on an Olympus AU2700. The experimental data confirmed a positive interference in the Olympus AU2700 HCO3(-) assay using older reagent lot numbers. The false positive HCO3(-) interference was significant (>10% change) when the LD concentration exceeded 845 U/L. Very high levels of LD concentrations were the cause of interference in the Olympus AU2700 HCO3(-) enzymatic assay. Laboratorians should be aware that very high levels of LD may be a potential interference in some enzymatic HCO3(-) assays.


[An improved method to stimulate water and biological tissues in relation to linear interactions with photons and fast electrons (author's transl)].
Radiation physical problems in clinical dosimetry often need for their experimental solution the linear coefficients of interaction between radiation and irradited matter. Using modified material parameters (the products of mass density and the earlier defined effective material parameters) it was possible to derive an improved method to calculate the composition of an equivalent for a material to be substituted. The method is described and its usefulness demonstrated by some examples. A geometric analogue facilitates the solution if a computer is not available. Some comparisons are made between this method and the basic data method of White.


Identification of senescence-associated genes in human bone marrow mesenchymal stem cells.
Human bone marrow mesenchymal stem cells (hBMMSCs) are multipotent stem cells that can differentiate into several specialized cell types, including bone, cartilage, and fat cells. The proliferative capacity of hBMMSCs paves the way for the development of regenerative medicine and tissue engineering. However, long-term in vitro culture of hBMMSCs leads to a reduced life span of the cells due to senescence, which leads eventually to growth arrest. To investigate the molecular mechanism behind the cellular senescence of hBMMSCs, microarray analysis was used to compare the expression profiles of early passage hBMMSCs, late passage hBMMSCs and hBMMSCs ectopically expressing human telomerase reverse transcriptase (hTERT). Using an intersection analysis of 3892 differentially expressed genes (DEGs) out of 27,171 total genes analyzed, we identified 338 senescence-related DEGs. GO term categorization and pathway network analysis revealed that the identified genes are strongly related to known senescence pathways and mechanisms. The genes identified using this approach will facilitate future studies of the mechanisms underlying the cellular senescence of hBMMSCs.


[Evaluation of the effectiveness and safety of compression hosiery «Mediven Plus» in the treatment of elderly patients with chronic venous diseases of the lower extremities].
This publication presents the results of a study aimed at assessing the justification of the use of compression hosiery «Mediven Plus» among patients in the older age group on the basis of demographic, anthropometric data (gender, age, weight of the patient; the volume of the lower leg, upper thigh), clinical examination, data of instrumental examination (duplex ultrasound, volumetry, legometry), data of laboratory tests (fibrinogen, soluble fibrin-monomer complexes). The effectiveness of therapeutic effects of compression underwear is proved for all parameters.


Inhibitors of nuclear factor kappa B cause apoptosis in cultured macrophages.
The precise role of the transcription factor nuclear factor kappa B (NF- kappaB) in the regulation of cell survival and cell death is still unresolved and may depend on cell type and position in the cell cycle. The aim of this study was to determine if three pharmacologic inhibitors of NF-kappaB, pyrrolidine dithiocarbamate, N-tosyl-L-lysl chloromethyl ketone and calpain I inhibitor, induce apoptosis in a murine macrophage cell line (RAW 264.7) at doses similar to those required for NF-kappaB inhibition. We found that each of the three inhibitors resulted in a dose- and time-dependent increase in morphologic indices of apoptosis in unstimulated, LPS-stimulated and TNF-stimulated cells. Lethal doses were consistent with those required for NF- kappaB inhibition. We conclude that nuclear NF-kappaB activation may represent an important survival mechanism in macrophages.


Autolysin as a fibronectin receptor on the cell surface of Clostridium perfringens.
Clostridium perfringens causes food poisoning and gas gangrene, a serious wound-associated infection. C. perfringens cells adhere to collagen via fibronectin (Fn). We investigated whether the peptidoglycan hydrolase of C. perfringens, i.e., autolysin (Acp), is implicated in Fn binding to C. perfringens cells. This study used recombinant Acp fragments, human Fn and knockout mutants (C. perfringens 13 acp::erm and HN13 ΔfbpC ΔfbpD). Ligand blotting, Western blotting analysis, and complementation tests were performed. The Fn-binding activity of each mutant was evaluated by ELISA. From an Fn-binding assay using recombinant Acp fragments, Fn was found to bind to the catalytic domain of Acp. In mutant cells lacking Acp, Fn binding was significantly decreased, but was restored by the complementation of the acp gene. There are three known kinds of Fn-binding proteins in C. perfringens: FbpC, FbpD, and glyceraldehyde-3-phosphate dehydrogenase. We found no difference in Fn-binding activity between the mutant cells lacking both FbpC and FbpD (SAK3 cells) and the wild-type cells, indicating that these Fn-binding proteins are not involved in Fn binding to C. perfringens cells. We found that the Acp is an Fn-binding protein that acts as an Fn receptor on the surface of C. perfringens cells.


Differential gene expression between inbred Roman high- (RHA-I) and low- (RLA-I) avoidance rats.
Microarray technology was used to explore differences in brain gene expression under basal conditions in two strains of psychogenetically selected rats which differ in anxiety/stress responses, the inbred Roman High-(RHA-I) and Roman Low-(RLA-I) Avoidance rats. Microarray analysis detected 14 up-regulated and 24 down-regulated genes in RLA-I vs. RHA-I rats functionally related to neurobiological processes. The differentially expressed genes CAMKK2, CRHBP, EPHX2, HOMER3, NDN, PRL and RPL6 were selected for microarray validation using qRT-PCR. EPHX2, CAMKK2 (both up-regulated in RLA-I vs. RHA-I rats) and HOMER3 (down-regulated in RLA-I vs. RHA-I rats) showed a similar tendency and fold-change both in microarray and RT-PCR analyses; PRL (up-regulated in RLA-I vs. RHA-I rats), CRHBP and RPL6 (both down-regulated in RLA-I vs. RHA-I animals) showed a similar tendency but a different order of magnitude of change among experiments; finally, NDN was validated neither in tendency nor in magnitude of change.


Increased frequency of the angiotensin-converting enzyme gene D-allele is associated with noninfectious pulmonary dysfunction following allogeneic stem cell transplant.
Noninfectious pulmonary dysfunction (NIPD) is a common and often fatal complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). An insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene has been extensively studied in relation to cardiovascular and renal disease, and lung fibrosis. In pulmonary fibrosis, D-allele frequency is significantly higher than in the control population. We hypothesized that a similar mechanism exists between post-HSCT NIPD and pulmonary fibrosis in the absence of HSCT. We retrospectively analyzed the incidence of NIPD and the ACE genotype polymorphism in 118 Japanese patients who underwent HSCT from HLA-identical sibling donors. NIPD occurred in 17 cases. Deletion/deletion genotype carriers were more common in the NIPD group than in the other 101 patients (41.2 vs 11.9%; hazard ratio, 5.19; 95% confidence interval, 1.67-16.21). There were no significant relationships between the clinical characteristics of patients and the development of NIPD. These findings suggest that the ACE genotype is associated with the development of NIPD following HSCT. This study is the first to report the relationship between genetic background and NIPD.


Spectral analysis of neocortical and hippocampal EEG in the protein malnourished rat.
In these studies, power spectral analysis techniques were utilized to quantify changes in the cortical and hippocampal EEG obtained from rats reared on either an 8% or 25% casein diet as they mature from 14 to 22 days of age. Analyses of the power spectral data obtained from the frontal cortex of rats reared on the 25% casein diet during this preweaning period (14-22 days) indicated increases in the power in the 0.5-3.5 c/sec frequency band primarily during slow-wave sleep. Prenatal protein malnutrition (8% casein diet) significantly reduced the low frequency power content in the cortical EEG obtained during slow-wave sleep at 18 and 22 days of age. Analyses of power spectral data obtained from the hippocampal EEG during REM sleep also revealed developmental and diet-related differences. The frequency at which the peak power occurs in the theta band (4-11 c/sec) was found to increase normally in a linear fashion from 14 to 22 days of age (from 4.4 to 5.5 c/sec) in rats reared on the 25% casein diet. In addition, power in the 4-7 c/sec band significantly increased during this preweaning period. Prenatal protein malnutrition significantly slowed the development of theta frequency and produced higher values of power in the component of theta rhythm. Finally, vigilance profiles showed that rats normally progress from 14 days of age when REM sleep dominates their vigilance profile, to 22 days of age when they spend significantly more time in slow-wave sleep. Prenatal protein malnutrition retards this normal developmental sequence by significantly reducing the REM sleep time at 14 and 18 days of age and increasing the time spend in aroused waking at both these ages. However, at the time of weaning, i.e., at 22 days of age, these differences in sleep-waking behavior were no longer observed to be significant.


International perspectives on screening.
The estimated population of the world in 2008 was 6.75 billion people, increasing by around 79 million people each year. The world population is aging. In 1970, the world median age was 22 years; it is projected to reach 38 years by 2050. The number of people in the world aged 60 years and older is expected to almost triple to 2 billion by 2050. Because cancer, especially prostate cancer, is predominantly a disease of the elderly, increases in the number of older people will lead to more cases of cancer, even if current incidence rates remain the same.


Effects of vitamin A supplementation on ovarian development of Astyanax lacustris (Teleostei: Characidae) during the non-breeding season.
Vitamin A (VA) is essential for fish reproduction, however, knowledge of VA requirement of broodstock fish is scarce. We investigated the physiological role of VA supplementation in the ovarian maturation of Astyanax lacustris throughout the non-breeding season. Adult females were distributed in five nutritional treatments, which differed by the amount of VA supplemented in a plant-based diet: T1 = 0, T2 = 1800, T3 = 3600, T4 = 7200, and T5 = 14,400 IU kg-1 of VA for 60 days after a period of 16 days feeding on a diet poor in VA to reduce body VA content. Plasma total lipids (TL), lipoproteins, and 17β-estradiol (E2) levels were measured after 30 and 60 days. Somatic indexes and morphophysiological ovarian parameters were calculated and VA concentration was analyzed in the ovaries and liver after 60 days. VA supplementation did not increase the concentration of this nutrient in the liver and ovaries. E2 plasma level increased in animals fed on 3600 IU kg-1 of VA (T3) after 60 days and females from T5 group presented a higher RF after 60 days. Ovarian development increased after 60 days compared to that after 30 days, confirmed by the higher gonadosomatic index (all groups). The supplementation with the highest VA level increased RF and decreased plasma TL (after 30 days) and low-density lipoprotein (LDL) (after 60 days) concentrations, showing a potential to improve reproduction even during the non-breeding season; however, its nutritional requirements of VA could be higher.


Falls in residential carpentry and drywall installation: findings from active injury surveillance with union carpenters.
Active injury surveillance was conducted with a large, unionized workforce of residential and drywall carpenters over a 3-year period. Injured carpenters were interviewed by trained carpenter investigators and sites were visited where falls occurred. Qualitative information was collected on exposures, risk perception, training, and mentoring. Falls accounted for 20% of injuries. Same-level falls were often related to weather, carrying objects-sometimes with an obstructed view-housekeeping, terrain of the lot, and speed of work. Falls from height occurred from a variety of work surfaces and involved ladders, scaffolding, roofs, work on other unsecured surfaces, unprotected openings, speed, and weather conditions. Recognized fall protection strategies, such as guardrails, toe boards, tying off to appropriate anchors, and guarding openings, would have prevented many of these falls; these practices were not the norm on many sites.


Structure-based mechanisms of 2'3'-cGAMP intercellular transport in the cGAS-STING immune pathway.
Upon activation by double-stranded DNA (dsDNA), the cytosolic dsDNA sensor cyclic GMP-AMP synthase (cGAS) synthesizes the diffusible cyclic dinucleotide 2'3'-cGAMP (cyclic GMP-AMP), which subsequently binds to the adaptor STING, triggering a cascade of events leading to an inflammatory response. Recent studies have highlighted the role of 2'3'-cGAMP as an 'immunotransmitter' between cells, a process facilitated by gap junctions as well as by specialized membrane-spanning importer and exporter channels. This review highlights recent advances from a structural perspective of intercellular trafficking of 2'3'-cGAMP, with particular emphasis on the binding of importer SLC19A1 to 2'3'-cGAMP, as well as the significance of associated folate nutrients and antifolate therapeutics. This provides a path forward for structure-guided understanding of the transport cycle in immunology, as well as for candidate targeting approaches towards therapeutic intervention in inflammation.


Calmodulin-antagonist drugs and porcine malignant hyperpyrexia.
1. Landrace swine were identified as malignant hyperpyrexia susceptible (MHS) or control by the contracture responses of gracilis muscle fibre bundles to 3% halothane, 2 mmol/l caffeine and 80 mmol/l KCl. The effects of calmodulin-antagonist drugs on the contractile behaviour of control and MHS preparations were investigated in vitro. 2. Calmodulin-antagonists at micromolar concentrations induced contracture in both control and MHS muscle. Pretreatment of MHS muscle with calmodulin-antagonist drugs potentiated its response to halothane and caffeine. 3. These results suggest that calmodulin-antagonist drugs cause an increase in myoplasmic Ca2+ concentration in both control and MHS muscle.


Recent advances in cutaneous lymphomas.
Cutaneous lymphomas are a heterogeneous group of extranodal lymphomas that are characterized by an initial accumulation of mononuclear, mostly lymphocytic cells in the skin. Recent discoveries of changes in molecular biology and immunology of these tumors have paved the way to a better understanding of the processes that govern lymphomagenesis in the skin and more importantly, they have contributed to the development of the new WHO-EORTC classification system. Only now has the field of cutaneous lymphomas gained a novel, long-awaited basis that may act as a new starting point in the collection of clinical as well molecular and immunological data on comparative basis. This review will try to highlight the newest findings in the pathogenesis of primary cutaneous T- and B-cell lymphomas, hematodermic neoplasm and HTLV-1 positive disorders as well as their translation into efficient therapeutic strategies.


Ischemic extent as a biomarker for characterizing severity of coronary artery stenosis with blood oxygen-sensitive MRI.
To investigate whether a statistical analysis of myocardial blood-oxygen-level-dependent (mBOLD) signal intensities can lead to the identification and quantification of the ischemic area supplied by the culprit artery. Cardiac BOLD images were acquired in a canine model (n = 9) with controllable LCX stenosis at rest and during adenosine infusion on a 1.5T clinical scanner. Statistical distributions of myocardial pixel-intensities derived from BOLD images were used to compute an area metric (ischemic extent, IE). True myocardial perfusion was estimated from microsphere analysis. IE was compared against a standard metric (segment-intensity-response, SIR). Additional animals (n = 3) were used to investigate the feasibility of the approach for identifying ischemic territories due to LAD stenosis from mBOLD images. Regression analyses showed that IE and myocardial flow ratio between rest and adenosine infusion (MFR) were exponentially related (R(2) > 0.70, P < 0.001, for end-systole and end-diastole), while SIR and MFR were linearly related to end-systole (R(2) = 0.51, P < 0.04) and unrelated to end-diastole (R(2) ≈ 0, P = 0.91). Receiver-operating-characteristic analysis that IE was superior to SIR for detecting critical stenosis (MFR ≤ 2) in end-systole and end-diastole. Feasibility studies on LAD narrowing demonstrated that the proposed approach could also identify oxygenation changes in the LAD territories. The proposed evaluation of cardiac BOLD magnetic resonance imaging (MRI) offers marked improvement in sensitivity and specificity for detecting critical coronary stenosis at 1.5T compared to the mean segmental intensity approach. Patient studies are now warranted to determine its clinical utility.


Evaluation of fatty acid profiles of Chlorella Vulgaris microalgae grown in dairy wastewater for producing biofuel.
Biodiesel is a biofuel made from plant oils and animal lipids. Utilization of lipid accumulation in algae biomass as biodiesel is a good alternative to fossil fuels. In this research Chlorella vulgaris microalga was applied after planting in BG11 culture medium in effluent and wastewater of dairy industry after preparation of 25, 50, and 75% dilutions. Algae in two concentrations with low (13 million cells/mL) and high density (26 million cells/mL) were injected. According to the results obtained in the wastewater environment the highest amount of C16:0 fatty acid was observed in F2 25% treatment, and C18:0 fatty acid is related to F1 75% treatment. In the effluent environment, the highest amount of fatty acids C16:0 and C16:1n7 occur in P1 50% treatment, and C18:0 and C18:3n3 fatty acids are related to P1 50% treatment, respectively. The highest amount of saturated fatty acids (SFA) was reported at P2 75% treatment (56.25%) and monounsaturated fatty acids (MUFA) has accumulated in F175% (40.13%) treatment. Chlorella vulgaris microalgae can be considered as a rich source of lipid and fatty acid profiles in both wastewater and effluents, and it can be regarded as potential significance source for biodiesel production.


Muscarinic receptor-mediated excitation of rat intracardiac ganglion neurons.
Modulation of the membrane excitability of rat parasympathetic intracardiac ganglion neurons by muscarinic receptors was studied using an amphotericin B-perforated patch-clamp recording configuration. Activation of muscarinic receptors by oxotremorine-M (OxoM) depolarized the membrane, accompanied by repetitive action potentials. OxoM evoked inward currents under voltage-clamp conditions at a holding potential of -60 mV. Removal of extracellular Ca(2+) markedly increased the OxoM-induced current (IOxoM). The inward IOxoM in the absence of extracellular Ca(2+) was fully inhibited by removal of extracellular Na(+), indicating the involvement of non-selective cation channels. The IOxoM was inhibited by organic cation channel antagonists including SKF-96365 and ML-204. The IOxoM was antagonized by muscarinic receptor antagonists with the following potency: 4-DAMP > pirenzepine = darifenacin > methoctramine. Muscarinic toxin 7 (MT-7), a highly selective inhibitor for M1 receptor, produced partial inhibition of the IOxoM. In the presence of MT-7, concentration-inhibition curve of the M3-preferring antagonist darifenacin was shifted to the left. These results suggest the contribution of M1 and M3 receptors to the OxoM response. The IOxoM was inhibited by U-73122, a phospholipase C inhibitor. The membrane-permeable IP3 receptor blocker xestospongin C also inhibited the IOxoM. Furthermore, pretreatment with thapsigargin and BAPTA-AM inhibited the IOxoM, while KN-62, a blocker of Ca(2+)/calmodulin-dependent protein kinase II, had no effect. These results suggest that the activation mechanism involves a PLC pathway, release of Ca(2+) from intracellular Ca(2+) stores and calmodulin. The cation channels activated by muscarinic receptors may play an important role in neuronal membrane depolarization in rat intracardiac ganglion neurons.


Infection patterns and new definitive host records for New Zealand gordiid hairworms (phylum Nematomorpha).
Some parasites modify the phenotype of their host in order to increase transmission to another host or to an environment suitable for reproduction. This phenomenon, known as host manipulation, is found across many parasite taxa. Freshwater hairworms are known for the behavioural changes they cause in their terrestrial arthropod hosts, increasing their likelihood of entering water to exit the host and reproduce. Understanding how infected arthropods move around in the natural environment could help uncover alterations in spatial distribution or movement induced by hairworms in their terrestrial definitive hosts. Moreover, few hairworm-host records exist for New Zealand, so any additional record could help elucidate their true host specificity. Here, we investigated whether infected terrestrial arthropods were more likely to approach streams in two subalpine communities of invertebrates, using a spatial grid of specialised pitfall traps. Although hairworm infection could not explain the movements of arthropod hosts near streams, we found several new host records for hairworms, including the first records for the recently described Gordionus maori. We also found some new host-parasite associations for mermithid nematodes. These records show that the host specificity of hairworms is quite low, suggesting that their diversity and distribution may be greater than what is currently known for New Zealand.


Inhibitory effect of trilinolein on endothelin-1-induced c-fos gene expression in cultured neonatal rat cardiomyocytes.
Trilinolein, isolated from the traditional Chinese herb Sanchi (Panax notoginseng), has been shown to have myocardial protective effects via its antioxidant ability. However, the cellular and molecular mechanisms of the protective effect of trilinolein in the heart remain to be elucidated. Oxidative mechanisms have been implicated in neonatal cardiomyocyte hypertrophy. We previously reported that ET-1 induces ROS generation via the ET(A) receptor and ROS modulates c-fos gene expression. We have therefore examined whether trilinolein attenuates ROS production and ET-1-induced c-fos gene expression in cardiomyocytes. Cultured neonatal rat cardiomyocytes were stimulated with ET-1 (10 nM), and c-fos gene expression was examined. Trilinolein (1 and 10 microM) inhibited ET-1-induced c-fos gene expression in cardiomyocytes. We also examined the effects of trilinolein on ET-1-increased NADPH oxidase activity and superoxide formation. Trilinolein inhibited ET-1-increased NADPH oxidase activity and superoxide formation in a concentration-dependent manner. This increase in superoxide production by ET-1 was significantly inhibited by trilinolein, diphenyleneiodonium, or N-acetylcysteine. Trilinolein also decreased ET-1- or H2O2-induced extracellular signal-regulated kinase (ERK) phosphorylation, c-Jun NH2-terminal kinase (JNK) phosphorylation, and activator protein-1 activation. These data indicate that trilinolein inhibits ET-1-induced ERK phosphorylation, JNK phosphorylation, and c-fos gene expression via attenuating superoxide production in cardiomyocytes.


A Liquid Biopsy to Assess Brain Tumor Recurrence: Presence of Circulating Mo-MDSC and CD14+ VNN2+ Myeloid Cells as Biomarkers That Distinguish Brain Metastasis From Radiation Necrosis Following Stereotactic Radiosurgery.
Brain metastases (BM) are the most common type of brain tumor malignancy in the US. They are also the most common indication for stereotactic radiosurgery (SRS). However, the incidence of both local recurrence and radiation necrosis (RN) is increasing as treatments improve. MRI imagery often fails to differentiate BM from RN; thus, patients must often undergo surgical biopsy or resection to obtain a definitive diagnosis. To hypothesize that a marker of immunosuppression might serve as a surrogate marker to differentiate patients with active vs inactive cancer-including RN. We thus purified and quantified Monocytic Myeloid-Derived Suppressor Cells (Mo-MDSC) by flow cytometry in patients proven by biopsy to represent BM or RN. We report the utility of the previously reported HLA-Dr-Vnn2 Index or DVI to discriminate recurrent BM from RN using peripheral blood. The presence of CD14+ HLA-DRneg/low Mo-MDSC is significantly increased in the peripheral blood of patients with brain metastasis recurrence compared to RN (Average 61.5% vs 7%, n = 10 and n = 12, respectively, P < .0001). In contrast, expression of VNN2 on circulating CD14+ monocytes is decreased in BM patients compared to patients with RN (5.5% vs 26.5%, n = 10 and n = 12, respectively, P = .0008). In patients with biopsy confirmed recurrence of brain metastasis, the average DVI was 11.65, whereas the average DVI for RN patients was consistently <1 (Avg. of 0.17). These results suggest that DVI could be a useful diagnostic tool to differentiate recurrent BM from RN using a minimally invasive blood sample.


Noncontingent reinforcement is an empirically supported treatment for problem behavior exhibited by individuals with developmental disabilities.
Noncontingent reinforcement (NCR) is a function-based treatment for problem behavior that has produced robust effects across a variety of response topographies and reinforcement functions among individuals with developmental disabilities. Several narrative reviews have adequately described this literature. The purpose of the present article was to quantitatively analyze and classify the empirical support for NCR using the criteria developed by The Task Force on the Promotion and Dissemination of Psychological Procedures [Task Force Promoting Dissemination of Psychological Procedures. (1995). Training in and dissemination of empirically-validated psychological treatments: Report and recommendations. Clinical Psychology, 48, 3-23]. Of the 59 studies identified for analysis, 24 met the criteria to be included in treatment classification. Fixed-time reinforcer delivery (plus extinction and schedule thinning) was classified as well established, while fixed-time reinforcer delivery (plus extinction) and variable-time reinforcer delivery (plus extinction) were deemed probably efficacious.


Factors for changes in self-care and mobility capabilities in young children with cerebral palsy involved in regular outpatient rehabilitation care.
Assessing prognosis of self-care and mobility capabilities in children with cerebral palsy (CP) is important for goal setting, treatment guidance and meaningful professional-caregiver conversations. Identifying factors associated with changes in self-care and mobility capabilities in regular outpatient multidisciplinary paediatric CP rehabilitation care. Routinely monitored longitudinal data, assessed with the Paediatric Evaluation of Disability Inventory (PEDI-Functional-Skills-Scale, FSS 0-100) was retrospectively analysed. We determined contributions of age, gross-motor function, bimanual-arm function, intellectual function, education type, epilepsy, visual function, and psychiatric comorbidity to self-care and mobility capability changes (linear-mixed-models). For 90 children (53 boys), in all Gross-Motor-Function-Classification-System (GMFCS) levels, 272 PEDI's were completed. Mean PEDI-FSS-scores at first measurement (median age: 3,2 years) for self-care and mobility were 46.3 and 42.4, and mean final FSS-scores respectively were 55.1 and 53.1 (median age: 6,5 years). Self-care capability change was significantly associated with age (2.81, p < 0.001), GMFCS levels III-V (-9.12 to -46.66, p < 0.01), and intellectual impairment (-6.39, p < 0.01). Mobility capability change was significantly associated with age (3.25, p < 0.001) and GMFCS levels II-V (-6.58 to -47.12, p < 0.01). Most important prognostic factor for self-care and mobility capabilities is GMFCS level, plus intellectual impairment for self-care. Maximum capability levels are reached at different ages, which is important for individual goal setting and managing expectations.


Intra-arterial long term infusion chemotherapy via transverse cervical artery for intra-abdominal malignancies.
An original method of intra-arterial catheter placement for long term infusion chemotherapy, using a transverse cervical artery, is described. Twelve patients with far advanced intra-abdominal malignancies, which precluded abdominal explorations, were catheterized and treated for prolonged periods. All patients were ambulated during the infusion chemotherapy and there were few catheter associated vascular complications. This method is a simple and safe procedure and seems superior to the conventional method using axillary or femoral arteries.


Ginsenoside Rg1 supplementation clears senescence-associated β-galactosidase in exercising human skeletal muscle.
Ginsenoside Rg1 has been shown to clear senescence-associated beta-galactosidase (SA-β-gal) in cultured cells. It remains unknown whether Rg1 can influence SA-β-gal in exercising human skeletal muscle. To examine SA-β-gal change, 12 young men (age 21 ± 0.2 years) were enrolled in a randomized double-blind placebo controlled crossover study, under two occasions: placebo (PLA) and Rg1 (5 mg) supplementations 1 h prior to a high-intensity cycling (70% VO2max). Muscle samples were collected by multiple biopsies before and after cycling exercise (0 h and 3 h). To avoid potential effect of muscle biopsy on performance assessment, cycling time to exhaustion test (80% VO2max) was conducted on another 12 participants (age 23 ± 0.5 years) with the same experimental design. No changes of SA-β-gal were observed after cycling in the PLA trial. On the contrary, nine of the 12 participants showed complete elimination of SA-β-gal in exercised muscle after cycling in the Rg1 trial (p < 0.05). Increases in apoptotic DNA fragmentation (PLA: +87% vs. Rg1: +133%, p < 0.05) and CD68+ (PLA: +78% vs. Rg1: +121%, p = 0.17) occurred immediately after cycling in both trials. During the 3-h recovery, reverses in apoptotic nuclei content (PLA: +5% vs. Rg1: -32%, p < 0.01) and increases in inducible nitrate oxide synthase and interleukin 6 mRNA levels of exercised muscle were observed only in the Rg1 trial (p < 0.01). Rg1 supplementation effectively eliminates senescent cells in exercising human skeletal muscle and improves high-intensity endurance performance.


Stimulation of wound healing by means of laser rays. Part III--Investigation of the effect on immune competent cells.
The immune-suppressive action of laser rays was studied in directly irradiated human lymphocytes. It was found that the argon ion gas laser is more effective in the range between 488 and 501 nm than at other wavelengths and than the He--Ne laser (632 nm) of the same performance. It is assumed that the suppression of some undesirable immune reaction (auto-aggressive process) contributes to the stimulating effect of laser rays on wound healing.


Endometrial thickness in the evaluation of clinical response to medical treatment for deep infiltrating endometriosis: a retrospective study.
Deep infiltrating endometriosis (DIE) is associated with severe pelvic pain and functional impairment of bowel, urinary, and sexual functions. Though hormone therapy with progestins, either as single agents or combined with estrogens, is effective in managing symptoms, some patients may experience a suboptimal response. Endometrial thickness assessed by transvaginal ultrasound examination, reflecting the overall estrogen stimulation, may correlate with the clinical response to hormonal treatments. A retrospective study was carried out on 61 women with DIE affecting the bowel or the recto-vaginal septum, undergoing hormone treatment. The symptoms of patients were evaluated at the baseline and after 12 months of therapy, calculating a global Visual Analogue Scale score (gVAS) encompassing dysmenorrhea, dyspareunia, chronic pelvic pain, dyschezia, abdominal pain and dysuria. Patients were divided into two subgroups using, as a calculated cut-off value, the mean endometrial thickness in our population at 12 months. The change in gVAS score during the 12 months of treatment was then compared between the two groups. Women with a thinner endometrium (< 3.3 mm) showed a better response to treatment in terms of symptoms control as compared to patients with a thicker endometrium (mean gVAS score reduction 9.2 ± 1.3 vs. 5.2 ± 1.3, p = 0.036). The correlation between endometrial thickness and symptomatic response was also confirmed (p = 0.041) on multivariate linear regression analysis including as covariates age, size of lesions of DIE, presence of uterine adenomyosis, ovarian endometriosis and type of medical treatment. Endometrial thickness on ultrasound transvaginal examination is correlated with better response rates to hormone therapy in terms of symptoms control. A thinner endometrium, probably resulting from a more efficient suppression of estrogen stimulation, is associated with improved symptoms. These results may aid clinicians in monitoring and tailoring hormonal treatments during follow-up of women with symptomatic DIE.


Radiotherapy of the rhabdomyosarcoma R1H of the rat: the influence of the number of fractions on tumor and skin response.
The influence of the number of fractions on tumor and skin response to fractionated irradiation was studied. R1H rhabdomyosarcomas of the rat (volume doubling time 3 days) were irradiated with 6, 18, 30, or 42 fractions in 6 weeks. Total doses of 45, 60, or 75 Gy were applied in each fractionation scheme, that is, the dose per fraction ranged from 1.07 to 12.5 Gy. Tumor response was assessed by tumor control probability and tumor net growth delay. A clearcut reduction of skin damage was observed with increasing number of fractions, whereas the tumor response was found to be the same whether the dose was given in 6, 18, 30, or 42 fractions. Thus, the fractionation regimens were more effective than expected from calculations based on single-dose in situ survival curves. This result can be explained by assuming that the clonogenic tumor cells become less hypoxic with increasing number of fractions. Since normal tissue damage decreases with increasing number of fractions, the therapeutic gain may be improved by applying a greater number of fractions.


Enhancing vaccine effectiveness with delivery technology.
Vaccines stand as a very powerful means of disease prevention and treatment. Fundamental to the success of vaccination is the efficient delivery of antigenic cargo needed to trigger an effective immune response. In this article, we will review recent advances in delivery technology with a focus on devices designed to optimally maximize responses to antigen cargo. Included with the review is an overview of traditional vaccine applications and how these approaches can benefit by well-designed delivery methods.


Genetics of drug resistance in methicillin-resistant Staphylococcus aureus from Australian hospitals.
The drug-resistance determinants in methicillin-resistant Staphylococcus aureus (MRSA) from three different hospitals in Eastern Australia have been examined. With one exception, all the isolates had chromosomal determinants for penicillinase and resistance to cadmium (Cd), mercury (Hg), phenyl mercuric acetate, methicillin, tetracycline, erythromycin, lincomycin and low level streptomycin. The strain which was the exception differed in that it did not have chromosomal resistance to Cd and lincomycin. In addition, the strains often contained plasmids which belonged to one of three categories: a small cryptic plasmid of either c. 1.4 Mdal, c. 1.7 Mdal or c. 1.9 Mdal; a chloramphenicol resistance plasmid of c. 2.8 Mdal; and a gentamicin resistance plasmid within the range of c. 15.3 to c. 28.5 Mdal. The predominant gentamicin-resistant plasmid in isolates from two hospitals had a molecular weight of c. 18 Mdal, whereas the isolates from the third hospital had a plasmid of molecular weight c. 15.3 Mdal. The only other gentamicin resistance plasmids detected were associated with penicillinase determinants. In one isolate, this corresponded to a plasmid of c. 19.6 Mdal and in the other to a plasmid of c. 28.5 Mdal. These results indicate that MRSAs which are prevalent in Eastern Australian hospitals are substantially different in the location of their drug resistance determinants to earlier strains reported in the literature.


Microbiological analysis of multi-level borehole samples from a contaminated groundwater system.
A range of bacteriological, geochemical process-related and molecular techniques have been used to assess the microbial biodegradative potential in groundwater contaminated with phenol and other tar acids. The contaminant plume has travelled 500 m from the pollutant source over several decades. Samples were obtained from the plume using a multi-level sampler (MLS) positioned in two boreholes (boreholes 59 and 60) which vertically transected two areas of the plume. Activity of the microbial community, as represented by phenol degradation potential and ability to utilise a range of substrates, was found to be influenced by the plume. Phenol degradation potential appeared to be influenced more by the concentration of the contaminants than the total bacterial cell numbers. However, in the areas of highest phenol concentration, the depression of cell numbers clearly had an effect. The types of bacteria present were assessed by culture and DNA amplification by polymerase chain reaction (PCR). Bacterial groups or processes associated with major geochemical processes, such as methanogenesis, sulphate reduction and denitrification, that have the potential to drive contaminant degradation, were detected at various borehole levels. A comparative molecular analysis of the microbial community between samples obtained from the MLS revealed the microbial community was diverse. The examination of microbial activity complemented those results obtained through chemical analysis, and when combined with hydrological data, showed that MLS samples provided a realistic profile of plume effects and could be related to the potential for natural attenuation of the site.


NKG2C Natural Killer Cells in Bronchoalveolar Lavage Are Associated With Cytomegalovirus Viremia and Poor Outcomes in Lung Allograft Recipients.
Cytomegalovirus (CMV) infection is a risk factor for chronic lung allograft dysfunction (CLAD), which limits survival in lung allograft recipients. Natural killer (NK) cells that express the NKG2C receptor mediate CMV-specific immune responses. We hypothesized that NKG2C NK cells responding to CMV in the lung allograft would reduce CMV-related inflammation and would improve CLAD-free survival. We prospectively followed 130 subjects who underwent lung transplantation from 2012 to 2016. Bronchoalveolar lavage (BAL) NK cells were immunophenotyped for NKG2C, maturation, and proliferation markers. CMV viral load, serologies, serial spirometry, and mortality were recorded from medical records. Natural killer cell subset association with CMV endpoints were made using generalized estimating equation-adjusted linear models. BAL NKG2C NK cell association with CLAD-free survival was assessed by Cox proportional hazards modeling. NKG2C NK cells were more mature and proliferative than NKG2C NK cells and represented a median of 7.8% of BAL NK cells. The NKG2C NK cell proportion increased prior to the first detection of viremia and was nearly tripled in subjects with high level viremia (>1000 copies/mL) compared with no detected viremia. Subjects with increased BAL NKG2C NK cells, relative to the median, had a significantly increased risk for CLAD or death (hazard ratio, 4.2; 95% confidence interval, 1.2-13.3). The BAL NKG2C NK cell proportion may be a relevant biomarker for assessing risk of CMV viremia and quantifying potential CMV-related graft injury that can lead to CLAD or death.


Efficacy and safety of Nd:YAG laser alone compared with combined Nd:YAG laser with intralesional steroid or botulinum toxin A in the treatment of hypertrophic scars.
The aim of this study is to evaluate the efficacy and safety of Nd:YAG laser alone or in combination with intralesional injection of botulinum toxin type A or intralesional injection of steroid in treatment of hypertrophic scars. This study included 45 patients with hypertrophic scars who were randomly divided into three equal groups. All participants received 4 sessions of Nd:YAG laser at 4-week intervals. Immediately after the laser treatment, patients in group II were assigned to intralesional triamcinolone acetonide, and those in group III were assigned to intralesional botulinum toxin type A. All patients were followed up monthly for 3 months after the last session for any recurrence, or side effects. Clinical evaluation of the cases was done by Vancouver Scar Scale. Hypertrophic scars in the three groups showed a significant improvement (p < 0.001) compared with before treatment in all variables (except for pigmentation) and also a significant improvement in pruritus, pain, and patient relief. The highest percentage of improvements was seen in patients treated with Nd:YAG laser combined with intralesional steroid in all variables according to Vancouver Scar Scale. The degree of improvement was negatively correlated with the patients' age. The three treatment modalities were effective, safe with minimal side effects. Nd:YAG laser followed by intralesional injection of Triamcinolone acetonide had the highest percentage of Vancouver Scar Scale reduction. Combination therapy of Nd:YAG laser with intralesional injection of either Triamcinolone acetonide or Botox revealed better results than using Nd:YAG as a single therapeutic modality for HTS.


Improved Root Growth by Liming Aluminum-Sensitive Rice Cultivar or Cultivating an Aluminum-Tolerant One Does Not Enhance Fertilizer Nitrogen Recovery Efficiency in an Acid Paddy Soil.
The root is the main site of nitrogen (N) acquisition and aluminum (Al) toxicity. The objective of this study is to investigate whether liming and cultivation of an Al-tolerant rice (Oryza sativa L.) cultivar can improve root growth, thereby increasing N acquisition by rice plants in acid paddy soil. Two rice cultivars ('B690', Al-sensitive, and 'Yugeng5', Al-tolerant) were cultivated with 15N-labeled urea, and with or without lime in an acid paddy soil (pH 4.9) in pots. We examined root and shoot growth, soil pH, soil exchangeable Al, N uptake, 15N distribution in plant-soil system, and fertilizer N recovery efficiency. Results showed that liming improved the root growth of 'B690' by decreasing soil exchangeable Al concentrations, in both N-limited and N-fertilized soils. Liming enhanced the N uptake of 'B690' only in the absence of N fertilizer. The root weight of 'Yugeng5' was greater than that of 'B690' without lime, but the two cultivars showed similar N uptake. The fertilizer N recovery efficiency and N loss did not differ significantly between limed and non-limed conditions, or between the two rice cultivars. Thus, liming an Al-sensitive rice cultivar and cultivating an Al-tolerant one improves root growth, but does not enhance fertilizer N recovery efficiency in the present acid paddy soil.


A dual pH/Redox responsive copper-ligand nanoliposome bioactive complex for the treatment of chronic inflammation.
A novel dual pH/redox-responsive polymeric nanoliposome system (NLs) loaded with a copper-liganded bioactive complex was prepared and designed as a controlled delivery system for the management of inflammation. The NLs were synthesised after preparation of the copper-glyglycine-prednisolone succinate] ([(Cu(glygly)(PS)]) complex, and the dual pH/redox responsive biopolymer respectively. The methodology undertaken for the development of the drug delivery system involved coordination of the bioactive to Copper (II), preparation of dual pH/redox responsive biopolymer, and the synthesis of dual pH/redox nanoliposomes. Characterisations of the prepared copper-liganded bioactive [Copper-glyglycine-prednisolone succinate] ([(Cu(glygly)(PS)]) complex, dual pH/redox responsive biopolymer (Eudragit E100-cystamine) and [(Cu(glygly)(PS)]-loaded NLs were carried out using spectroscopic and physicochemical techniques. Results indicated a high inflammatory/oxidant inhibitory activity of [Cu(glygly)(PS)] in comparison to the free PS drug. The [Cu(glygly)(PS)] complex exhibited a significant free radical-scavenging activity (60.1±1.2%) and lipoxygenase (LOX-5) inhibitory activity (36.6±1.3%) in comparison to PS which resulted in activity of 4.4±1.4% and inhibition of 6.1±2.6% respectively. The [Cu(glygly)(PS)] loaded NLs demonstrated low release profiles of 22.9±5.4% in 6h at pH 7.4, in comparison to a significant accelerated release at pH 5 in a reducing environment of 75.9±3.7% over 6h duration. Results suggest that the novel copper-liganded bioactive delivery system with controlled drug release mechanism could serve as a potential drug delivery system candidate in the management of inflammation.


Prognostic Significance of Nonobstructive Left Main Coronary Artery Disease in Patients With and Without Diabetes: Long-Term Outcomes From the CONFIRM Registry.
Prognostic significance of non-obstructive left main (LM) disease was recently reported. However, the influence of diabetes mellitus (DM) on event rates in patients with and without non-obstructive LM disease is not well-known. We evaluated 27,252 patients undergoing coronary computed tomographic angiography from the COroNary CT Angiography Evaluation For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) Registry. Cumulative long-term incidence of all-cause mortality (ACM) was assessed between DM and non-DM patients by normal or non-obstructive LM disease (1-49% stenosis). The mean age of the study population was 57.6±12.6 years. Of the 27,252 patients, 4,434 (16%) patients had DM. A total of 899 (3%) deaths occurred during the follow-up of 3.6±1.9. years. Compared to patients with normal LM, those with non-obstructive LM had more pronounced overall coronary atherosclerosis and more cardiovascular risk factors. After clinical risk factors, segment involvement score, and stenosis severity adjustment, compared to patients without DM and normal LM, patients with DM were associated with increased ACM regardless of normal (HR 1.48, 95% CI 1.22-1.78, p<0.001) or non-obstructive LM (HR 1.46, 95% CI 1.04-2.04, p=0.029), while nonobstructive LM disease was not associated with increased ACM in patients without DM (HR 0.85, 95% CI 0.67-1.07, p=0.165) and there was no significant interaction between DM and LM status (HR 1.03, 95% CI 0.69-1.54, p=0.879). From the CONFIRM registry, we demonstrated that DM was associated with increased ACM. However, the presence of non-obstructive LM was not an independent risk marker of ACM, and there was no significant interaction between DM and non-obstructive LM disease for ACM.


Oxidative stress inhibition by resveratrol in alcohol-dependent mice.
Uncontrolled ingestion of alcohol has dramatic consequences on the entire organism that are also associated with the oxidation process induced by alcohol and elevate radical oxygen species. Resveratrol, a nonflavonoid phenol, shows well-documented antioxidant properties. We investigated the potential antioxidant ability of this natural compound in a mouse model of alcohol addiction. We administered (per os) for 60 d 10 mg · kg-1 · d-1 of resveratrol in alcoholic adult male mice. Oxidative stress was evaluated by measuring serum-free oxygen radicals defense and free oxygen radical levels. Resveratrol metabolites were measured in the serum of mice that were administered with resveratrol. Finally, the effect of resveratrol on the alcohol-induced alteration of brain-derived neurotrophic factors (BDNF) in the liver was investigated. Prolonged consumption of resveratrol strongly counteracts serum radical oxygen species formation caused by chronic alcohol intake without effects on natural, free oxygen radical defense. The presence of resveratrol metabolites in the serum only of animals supplemented with resveratrol potentiates the evidence that the antioxidant effect observed is due to the ingestion of the natural compound. Moreover, resveratrol supplementation can counteract alcohol-induced BDNF elevation in the liver, which is the main target of organ alcohol-induced damage. The consumption of resveratrol through metabolite formation may play a protective role by decreasing free radical formation and modulating the BDNF involved in hepatic disruption induced by chronic alcohol consumption. Further investigation into the mechanism underlying the protective effect could reinforce the potential use of resveratrol as a dietary supplement to prevent damage associated with chronic alcohol abuse.


Post-surgical pyoderma gangrenosum of the vaginal vault associated with ulcerative colitis and Behçet's disease; a case report.
A case is described in which a patient with ulcerative colitis developed chronic vaginal ulceration around the incision lines after cone biopsy. The ulcers persisted at the vaginal vault after abdominal hysterectomy and removal of a cuff of vagina. Non-specific histological features compatible with pyoderma gangrenosum were found on biopsy. The auto-immune nature of this chronic ulcer is further supported by its rapid response to steroid therapy and the subsequent development of Behçet's syndrome.


Ultrasonic studies on polystyrene/styrene butadiene rubber polymer blends filled with glass fiber and talc.
The compatibility of solid blends: PS/SBR, PS/SBR filled with glass fiber and PS/SBR filled with talc were studied using ultrasonic pulse echo technique. Measurements were carried out at room temperature (298 K) and a frequency of 3 MHz. The ultrasonic velocity for the compressional wave and that for shear wave have been measured to obtain the elastic moduli data by knowing of density. The variation of ultrasonic wave velocities and elastic moduli with weight percent of the blend was found to be linear in PS/SBR blend, indicating some degree of compatibility but the drawback of elastic moduli indicate incompatibility of the system blend, while it deviates from linearity in blends of PS/SBR filled with glass fiber and talc but the increase in elastic moduli indicates that there is an increase in degree of compatibility between PS and SBR due to adding of glass fiber or talc. The ultrasonic absorptions for longitudinal wave in the temperature range from 298 to 423 K in the studied system were measured using ultrasonic pulse echo technique. Typical results showing the temperature dependence of the ultrasonic absorption at frequencies of 1, 2, 3 and 5 MHz are illustrated for all samples of the different compositions. The study of compositional and temperature dependence of the ultrasonic absorption in the present studied blends reveals the same behavior of the compatibility degree of the blends. Density data of the blends confirmed the ultrasonic results. Also the correlation between hardness and elastic moduli for the present blend systems has been studied.


RNA splicing regulators play critical roles in neurogenesis.
Alternative RNA splicing increases transcript diversity in different cell types and under varying conditions. It is executed with the help of RNA splicing regulators (RSRs), which are operationally defined as RNA-binding proteins (RBPs) that regulate alternative splicing, but not directly catalyzing the chemical reactions of splicing. By systematically searching for RBPs and manually identifying those that regulate splicing, we curated 305 RSRs in the human genome. Surprisingly, most of the RSRs are involved in neurogenesis. Among these RSRs, we focus on nine families (PTBP, NOVA, RBFOX, ELAVL, CELF, DBHS, MSI, PCBP, and MBNL) that play essential roles in the neurogenic pathway. A better understanding of their functions will provide novel insights into the role of splicing in brain development, health, and disease. This comprehensive review serves as a stepping-stone to explore the diverse and complex set of RSRs as fundamental regulators of neural development. This article is categorized under: RNA-Based Catalysis > RNA Catalysis in Splicing and Translation RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Processing > Splicing Regulation/Alternative Splicing.


Intimate Partner Relationships, Work-Life Factors, and Their Associations With Burnout Among Partnered Pediatric Residents.
Burnout is prevalent among pediatric residents, and reducing burnout is a priority for pediatric residency programs. Understanding residents' personal circumstances, including relationship satisfaction and perceived work-life conflict, may identify novel determinants of burnout. To describe intimate partner relationships among pediatric residents and examine associations among relationship satisfaction, work-life factors, and burnout. We identified 203 partnered residents (married or in a self-identified committed, ongoing relationship) from a cross-sectional survey of 258 residents in 11 New England pediatric programs (response rate 54% of 486 surveys distributed), conducted from April through June of 2013. We analyzed associations among relationship satisfaction, work-life factors, and burnout using multivariable regression. Burnout was measured with the brief Maslach Burnout Inventory, and relationship satisfaction with the validated Relationship Assessment Scale. Burnout was reported by 40.9% of partnered respondents. The vast majority of partnered residents (n = 167; 85.2%) reported high relationship satisfaction. Lower relationship satisfaction was not associated with burnout. Approximately half of the respondents (n = 102; 51.5%) reported being satisfied with life as a resident. When controlling for common stressors, such as sleep deprivation, work-life measures associated with burnout included frequent perceived conflicts between personal and professional life (adjusted odds ratio, 4.35; 95% confidence interval, 1.91-9.88) and dissatisfaction with life as a resident (adjusted odds ratio, 11.74; 95% confidence interval, 4.23-32.57). Low relationship satisfaction and common work-life stressors were not associated with burnout among partnered pediatric residents. However, perceived work-life conflict and dissatisfaction with resident life were strongly associated with burnout and are targets for residency programs seeking to ameliorate burnout.


Formation and Characterization of α-Synuclein Oligomers.
The aggregation of α-synuclein (αSN) into oligomeric structures has received increasing interest during the last 10-15 years. The oligomers' potential involvement in Parkinson's disease makes them a promising therapeutic target. Therefore reproducible protocols to prepare and analyze oligomers are very important to allow direct comparison of results obtained by different research groups. In this chapter we present one established method to obtain αSN oligomers from a monomeric ensemble in a relatively easy manner. Also, we briefly discuss a selection of biophysical methods which allow for a quick characterization of oligomer purity and structure.


Suppression of feeding by sodium depletion in food-deprived rats.
Food-deprived rats were depleted of sodium peritoneal dialysis (pd) against 5.0% glucose solution and offered food 24 h later. Food intake was suppressed compared with fasting sham-dialyzed controls, or controls dialyzed against Ringer-Tyrode. Sodium depletion by subcutaneous formalin also suppressed feeding. Measurements of osmolality and sodium chloride (NaCl) concentrations of the ascitic fluid showed that osmolality increased 19% mainly due to NaCl diffused 96.2 +/- 7.23 mEq/l. Consequently serum sodium concentration fell significantly (5.5% below control value). Serum potassium concentration did not change. Measurements of blood glucose levels showed that 1.87 g/l of glucose had been absorbed while it was in the peritoneum. Twenty four hours after sodium depletion, blood glucose levels of fasting sodium-depleted animals did not differ from nondepleted controls. Stomach load of glucose, in the same amount given for pd, did not suppress feeding in fasting rats 24 h later. Fasting sodium-depleted rats, offered 0.3 M NaCl to drink instead of food, drank as much as non-fasting sodium-depleted controls, ruling out the possibility of impaired behavior. Suppression of feeding was reversed in fasting sodium-depleted animals which were allowed to replace their sodium deficit by free-drinking or by stomach loading of sodium solutions. These results provide the first demonstration that depletion of sodium suppresses feeding in food-deprived rats.


On the nature and meaning of human finitude.
This article considers the interaction between psychoanalysis and philosophy by examining the meaning of human finitude in the work of Freud and Heidegger. Although Freud and Heidegger develop radically different systems of thought, they are surprisingly close in their examination of the human attitude toward death. Freud's philosophical reflections on the nature of death are ultimately subsumed in his speculative theory of the death instinct, which is far removed from the lived experience of finitude. Heidegger's ontological account of death draws from lived experience but neglects the relational nature of finitude. Drawing on the connection between the work of Binswanger and Stolorow, I maintain that finitude is a fundamentally relational phenomenon. While philosophy can help us to understand and formulate an account of human finitude, the relational nature of psychoanalysis can help us bear the trauma associated with death.


Osteoprotegerin in gingival crevicular fluid under long-term continuous orthodontic force application.
To investigate the level of osteoprotegerin (OPG) in gingival crevicular fluid (GCF) during tooth movement. Twelve patients (13-17 years of age) requiring canine distalization participated in the study. GCF sampling was done at baseline, 1 hour, 24 hours, 168 hours, 1 month, and 3 months from the distal sites of the test and with control teeth after the application of mechanical stress. OPG concentration was detected by enzyme-linked immunosorbent assay. OPG concentrations in distal sites of the test teeth were decreased in a time-dependent manner. Decreasing is significant when compared with the baseline measurements (P = .038). Variability was detected in the levels of OPG concentration in the distal sites of the control tooth throughout the experimental period. OPG is one of the key mediators responsible for alveolar bone remodeling during tooth movement.


Semen abnormalities in artificial insemination donor candidates.
We screened 43 healthy adult male medical students as potential anonymous donors for the artificial insemination program at our university. Of the candidates 10 had varicoceles (5 bilaterally). Over-all, 34 men (79 per cent) had inadequate semen analyses by 1 or more criteria. Of the men with varicoceles 80 per cent also had abnormal findings. Three abnormalities were discovered most frequently in the semen of men with a normal physical examination and 5 deficiencies were found in those with a varicocele. Problems with semen quality were more common than those of sperm numbers.


Ca2(+)-channel agonist BAY K8644 mimics 1,25(OH)2-vitamin D3 rapid enhancement of Ca2+ transport in chick perfused duodenum.
To further understand the molecular mechanism by which 1,25(OH)2-vitamin D3 [1,25(OH2D3] rapidly stimulates intestinal calcium transport (termed "transcaltachia"), the effect of the calcium channel agonist BAY K8644 was studied in vascularly perfused duodenal loops from normal, vitamin D-replete chicks. BAY K8644, 2 mu M, was found to stimulate 45Ca2+ transport from the lumen to the vascular effluent to the same extent as physiological levels of 1,25(OH)2D3. The sterol and the Ca2+ channel agonist both increased 45Ca2+ transport 70% above control values within 2 min and 200% after 30 min of vascular perfusion. The effect of the Ca2+ channel agonist was dose dependent. Also, 1,25(OH)2D3-enhanced transcaltachia was abolished by the calcium channel blocker nifedipine. Collectively, these results suggest the involvement of 1,25(OH)2D3 in the activation of basal lateral membrane Ca2+ channels as an early effect in the transcaltachic response.


Influenza A hemagglutinin-specific T cell clones strictly restricted by HLA-DR1 or HLA-DR7 molecules.
The antigenic specificities, major histocompatibility complex restrictions and functional properties of influenza virus-specific proliferative cloned cell lines have been studied. These lines were specific for the H3 hemagglutinin subtype of influenza A viruses. By using a large panel of HLA-phenotyped antigen-presenting cells, it was found that the polymorphic structures, defined as DR1 and DR7 molecules, or closely associated structures, function as the restricting elements. We excluded for these lines a possible restricting role of supertypic specificities, known cross-reacting elements on DR molecules, or products of other loci in known linkage disequilibrium with the HLA-DR molecules. Such exquisitely restricted clones might be of great help in the class II typing of antigen-presenting cells. Their specific activity was stable for several months. This has allowed the study of some functional properties of these long-term-cultured cloned cell lines: interleukin 2 sensitivity and production, helper function in specific antibody synthesis and ability to stimulate in mixed leukocyte reactions.


Fine mapping of the 2p11 dyslexia locus and exclusion of TACR1 as a candidate gene.
Developmental dyslexia, or reading disability, is a multigenic complex disease for which at least five loci, i.e. DYX1-3 and DYX5-6, have been clearly identified from the human genome. To date, DYX1C1 is the only dyslexia candidate gene cloned. We have previously reported linkage to 2p11 and 7q32 in 11 Finnish pedigrees. Here, we report the fine mapping of the approximately 40-cM linked region from chromosome 2 as we increased marker density to one per 1.8 cM. Linkage was supported with the highest NPL score of 3.0 (P=0.001) for marker D2S2216. Association analysis using the six pedigrees showing linkage pointed to marker D2S286/rs3220265 (P value <0.001) in the near vicinity of D2S2216. We went on to further characterise this approximately 15-cM candidate region (D2S2110-D2S2181) by adding six SNPs covering approximately 670 kb centred at D2S286/rs3220265. A haplotype pattern could no longer be observed in this region, which was therefore excluded from the candidate area. This also excluded the TACR1 (tachykinin receptor 1) gene, located at marker D2S286. The dyslexia candidate region on 2p11 is, therefore, now limited to the chromosomal area D2S2116-D2S2181, which is approximately 12 Mbp of human sequence and is at a distinct location from the previously reported DYX3 locus, raising the possibility of two distinct loci on chromosome 2p.


Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation.
We previously reported that daily dose pomalidomide (CC-4047), a thalidomide analogue, has excellent anti-myeloma activity but is associated with myelosuppression and deep vein thrombosis. We report here a phase 1 study to determine the maximum tolerated dose (MTD) of pomalidomide at 1 mg, 2 mg, 5 mg and 10 mg on alternate days (ad). Twenty patients with relapsed myeloma were treated. Grade 4 neutropenia occurred in all patients receiving 10 mg and the MTD was defined as 5 mg ad. No thrombotic events were observed. Pomalidomide was continued following the 4-week MTD study in 17/20 patients for a median of 14 months. 10% of patients had a complete response and >50% reduction in paraprotein was achieved in 50% of subjects. Progression-free survival was 10.5 months and median overall survival was 33 months. A significant rise was observed in the proportion of CD8(+) cells. Alternate day pomalidomide was associated with a marked reduction in the incidence of thrombosis whilst maintaining excellent anti-myeloma activity. This trial provides further in vivo evidence that pomalidomide modulates the immune system in myeloma patients. Phase 2 studies to further assess the optimal schedule of administration and anti-myeloma activity of this agent are planned.


Association Strategies of Speech Behavior of Communicators in Coding Discourse: An Interdisciplinary Approach Towards Understanding the Role of Cognitive and Linguistic Processes in Communication.
In modern media, the names of fairy-tale and mythological images are used to convey certain emotions and connotations. The aim of the study is to analyze the characteristic associative strategies presented with the mythological images of a dragon, a paper tiger and a chimera in news texts of European and Chinese mass media. In this article, the method of text analysis was used to identify patterns and the most possible interpretations of lexical units. 100 articles from Chinese and European publications were selected for the analysis (About People's Daily Online, China News Service, Guardian and France 24). The required lexemes were most widely used in articles on political topics. The most used was the image of a paper tiger (4001 and 3587 units). This is due to its well-known metaphorical meaning in both cultures, while dragon differs in Chinese and European ones. Further research may focus on the search and analysis of other fairy tale and mythological images in mass media. The present study results may also be applied for further research in the field of linguistics and journalism.


What radiolabeled FAPI pet can add in breast cancer? A systematic review from literature.
To provide an overview of the current available data about FAPI PET in breast cancer patients, with a perspective point of view. A literature search for studies about FAPI PET in the last 5 years (from 2017 to January 2023) was carried out on MEDLINE databases, such as PubMed, EMBASE, Web of Science and Google Scholar using the following keywords: "PET" AND "FAPI" AND "Breast Cancer" AND "Fibroblast imaging". The Critical Appraisal Skills Program (CASP) checklist for diagnostic test studies was used for testing the quality of selected papers. 13 articles were selected, including 172 patients affected by breast cancer who underwent FAPI-based PET images. CASP checklist was used in 5/13 papers, demonstrating a general low quality. Different types of FAPI-based tracers were used. No difference in terms of FAPI uptake was reported based on the histopathological characteristics, such as immunohistochemistry and grading of breast cancer. FAPI demonstrated more lesions and yielded much higher tumor-to-background ratios than 2-[18F]FDG. Preliminary experiences with FAPI PET in breast cancer showed some advantages than the current available 2-[18F]FDG, although prospective trials are needed to further evaluate its diagnostic utility in clinical practice.


Ecological aspects, explosive range extension and impact of a mass invader, Corophium curvispinum Sars, 1895 (Crustacea: Amphipoda), in the Lower Rhine (The Netherlands).
A few years after it invaded, the amphipod Corophium curvispinum Sars appeared to be the most numerous macroinvertebrate species in the River Rhine. From 1987 to 1991 the densities of this species on the stones of groins in the Lower Rhine at a depth of 0.5 m increased from 2 to 200000 specimens per m2. In the Lower Rhine and its branches the densities of C. curvispinum increased with increasing current velocities and with increasing water depths. So far, a maximum population density of 750000 specimens per m2 has been found in the Lower Rhine, which is many times the densities recorded elsewhere. Population parameters, densities and distribution of C. curvispinum were studied in the Lower Rhine and its branches, using artificial substrates and sampling stones from groins. The success of this immigrant is related to its competitive strategy, which shows several aspects of a r-strategy. In addition, the heavily eutrophicated Lower Rhine provides abundant food (phytoplankton, suspended organic matter) for this opportunistic filter-feeder. The increased salinity and water temperatures in the Lower Rhine resulting from industrial discharges have contributed to the current success of this southern species originating in brackish waters. The very high densities of C. curvispinum might have an enormous impact on the river ecosystem by changing food webs.


Clinical, hemodynamic, and angiographic predictors of operative mortality in patients undergoing single valve replacement. Veterans Administration Cooperative Study on Valvular Heart Disease.
Preoperative characteristics of 964 patients in the Veterans Administration Cooperative Study on Valvular Heart Disease undergoing single valve replacement were examined to determine predictors of operative mortality. The operative mortality rate was 8.3% in 661 patients having isolated aortic valve disease and 7.5% in 239 patients having isolated mitral valve disease, but 12.5% in 64 patients with multivalve disease undergoing single valve replacement. For the aortic valve replacement subgroup, three-vessel coronary artery disease, left ventricular systolic pressure, prior cardiac operation, body surface area, and cardiac index were related to operative mortality. In the mitral valve replacement group, there was a strong association of operative mortality with advanced age, exertional dizziness, reduced cardiac index, left ventricular contraction grade, ST segment depression on the resting electrocardiogram, and pleural effusion. The risk of operative death for an individual patient undergoing aortic or mitral valve replacement may be estimated with the use of independent risk factors.


Neck lymphadenitis due to silicone granuloma after mammary implants.
A foreign body reaction due to silicone where it is infiltrated or at the places to which it can migrate is known as siliconoma. The use of silicone in breast augmentation procedures can provoke this reaction at the neck level in cases of leakage from mammary implants. We reviewed the cases of patients with increased size neck lymph nodes who had previously undergone plastic surgery of the breast with highly cohesive silicone gel implants. In a 10-year period, we identified 12 cases with silicone-infiltrated neck lymphadenopathies, histologically confirmed by fine needle aspiration. They represented 3.5% of patients attended for neck lymph node study. We removed those detected by physical examination and CT in 5 cases, due to pathological characteristics of the node or a previous malignant history. In 2 of these nodes recurred, and node size also increased in 2 of the other 7 non-operated cases. After implant removal, silicone leakage was observed in only 7 cases. Cohesive gel silicone used for mammary implants can generate increased neck lymphadenopathies as a secondary effect due to systemic reactions against the silicone when it migrates in cases of implant failure. Surgical options for involved nodes usually do not offer good long-term results.