Regulatory peptides of the gastrointestinal and respiratory tracts.
The gastrointestinal and respiratory tracts contain numerous regulatory peptides produced by and released from specialised epithelial cells and the organ innervation. This complex system of endocrine cells and nerves is generally called "the diffuse neuroendocrine system". Markers are now available which permit the visualisation of the diffuse neuroendocrine system or its individual components. These include antibodies to neuron-specific enolase, chromogranin, neurofilament triplet proteins, the brain protein S100 and antibodies to a variety of regulatory peptides. Peptides present in the gut and lung innervation include: vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine (PHI), galanin, substance P, calcitonin gene-related peptide (CGRP), neuropeptide tyrosine (NPY), somatostatin and cholecystokinin (the latter two are also localised to endocrine cells of the gut). Bombesin-immunoreactivity is found in nerves in the gut and in endocrine cells of the foetal/neonatal lung. Neuropeptides of the gut and lung originate either from local neurons (e.g. VIP, PHI, galanin) or extrinsic neurons localised in sensory ganglia (e.g. substance P and CGRP) or the sympathetic chain (e.g. NPY). Recent studies point to the involvement of regulatory peptides in diseases of the gut and lung. These, together with detailed distribution studies, provide supportive data on the putative role of the peptides in the control of normal bowel and respiratory functions. The gastrointestinal and respiratory tracts were within the systems investigated by Feyrter during his original observations on the existence of specialised epithelial cells with a putative regulatory function (Feyrter, 1938). These "endocrine/paracrine" cells were found to be scattered in epithelial organs throughout the body. In fact, endocrine cells of the respiratory tract are frequently referred to as "Feyrter's cells". The term "regulatory peptides" was introduced as a generic term (Polak and Bloom, 1983) after the finding that active peptides are produced both by cells of the diffuse endocrine or APUD (amine precursor uptake and decarboxylation) system (Pearse, 1983) and autonomic/sensory nerves. These peptides are released into the circulation from endocrine cells or locally from nerve terminals or paracrine cells. The concept of "gut/brain" peptides was dispelled after the findings that the respiratory tract was provided abundantly with numerous active peptides produced by and released from mucosal endocrine cells and/or the innervation.


Comparing police use of drug detection dogs amongst injecting and non-injecting groups of people who regularly use drugs in Australia.
Drug detection dogs are utilised across multiple settings, however existing literature focuses predominantly on festival-based encounters. We compare drug dog encounters in non-festival settings among two samples of people who regularly use drugs, and investigate factors associated with witness only versus stop and/or search encounters. Australians who regularly (i.e., ≥monthly) use ecstasy and/or other illegal stimulants (n = 777; Ecstasy and Related Drugs Reporting System (EDRS)) or inject illegal drugs (n = 862; Illicit Drugs Reporting System (IDRS)) were surveyed between April-June, 2019. Univariable regression analyses were used to test for differences in drug dog encounters between samples, and to identify factors associated with a more intensive drug dog encounter (namely those that involved a stop and/or search). People who inject drugs were less likely to witness drug dogs than those who regularly use ecstasy and/or other illegal stimulants (odds ratio (OR) 0.46; 95 % CI 0.30-0.69). They were significantly more likely than EDRS participants to report being stopped and searched (3.29; 1.68-6.44) however. Among those carrying drugs at their last stop and/or search encounter, the majority of both samples reported that their drugs were not detected by police. IDRS participants aged 35-49 were more likely to report a stop and/or search encounter than those aged 17-34; no significant associations were found among the EDRS sample. Despite participants who use ecstasy and/other stimulants being more likely than those who regularly inject drugs to report encountering drug dogs in non-festival settings, participants who inject drugs were more likely to report an intensive or invasive drug dog encounter and/or receiving a formal criminal justice consequence. This study reinforces questions about the efficacy and appropriateness of drug dog operations.


The Epigenomic Landscape in Osteoarthritis.
Epigenomics has emerged as a key player in our rapidly evolving understanding of osteoarthritis. Historical studies implicated epigenetic alterations, particularly DNA methylation, in OA pathogenesis; however, recent technological advances have resulted in numerous epigenome-wide studies examining in detail epigenetic modifications in OA. The purpose of this article is to introduce basic concepts in epigenetics and their recent applications to the study of osteoarthritis development and progression. Epigenetics describes three major phenomena: DNA modification via methylation, histone sidechain modifications, and short noncoding RNA sequences which work in concert to regulate gene transcription in a heritable fashion. Cartilage has been the most widely studied tissue in OA, and differential methylation of genes involved in inflammation, cell cycle, TGFβ, and HOX genes have been confirmed several times. Bone studies suggest similar findings, and the intriguing possibility of epigenetic changes in subchondral bone during many OA processes. Multiple studies have demonstrated the involvement of certain noncoding RNAs, particularly miR-140, in OA development via modulation of key catabolic factors. Although much work has been done, much is still unknown. Future epigenomic studies will no doubt continue to widen our understanding of extraarticular tissues and OA pathogenesis, and studies in animal models may offer glimpses into epigenome alterations in the earliest stages of OA.


Variations of the Mycobacterium abscessus F-ATP synthase subunit a-c interface alter binding and potency of the anti-TB drug bedaquiline.
The anti-tuberculosis therapeutic bedaquiline (BDQ) is used against Mycobacterium abscessus. In M. abscessus BDQ is only bacteriostatic and less potent compared to M. tuberculosis or M. smegmatis. Here we demonstrate its reduced ATP synthesis inhibition against M. abscessus inside-out vesicles, including the F1FO-ATP synthase. Molecular dynamics simulations and binding free energy calculations highlight the differences in drug-binding of the M. abscessus and M. smegmatis FO-domain at the lagging site, where the drug deploys its mechanistic action, inhibiting ATP synthesis. These data pave the way for improved anti-M. abscessus BDQ analogs.


MR of extraocular muscles in chronic progressive external ophthalmoplegia.
Our goal was to determine whether the extraocular muscles in patients with chronic progressive external ophthalmoplegia (CPEO) could be distinguished from those of age-matched control subjects by MR imaging. Nine patients with CPEO and eight age-matched healthy control subjects were studied. The extraocular muscles of eight of the patients (16 eyes) and all the control subjects (16 eyes) were measured digitally. Images consisted of 1.5-mm contiguous sections acquired using a volume (three-dimensional) gradient-echo acquisition. In all, measurements were performed on 11 interpolated 1.0-mm coronal sections, five on each side of the muscle center. Only the medial, inferior, and lateral rectus muscles were evaluated. The superior rectus was omitted to avoid averaging problems with the superior ophthalmic vein and levator palpebrae muscle. The 11 sections were summed to obtain a volume measurement of the central portion of each muscle. The digitally measured extraocular muscles in the patients with CPEO had statistically significantly smaller volumes than those of the control subjects. The average muscle volumes for the patients with CPEO were 215 mm3 for the medial rectus, 202 mm3 for the inferior rectus, and 269 mm3 for the lateral rectus. The average extraocular muscle volumes for the control subjects were 366 mm3 for the medial rectus, 365 mm3 for the inferior rectus, and 425 mm3 for the lateral rectus. MR imaging can show small extraocular muscles in patients with CPEO, which may help to distinguish this disorder from other entities. Since denervated extraocular muscles do not readily atrophy, this MR sign would support a myogenic pathologic substrate for CPEO. Variation in the degree of extraocular muscle atrophy may simply reflect the length of time the mitochondrial defect and ophthalmoplegia have been present.


Low-Frequency rTMS of the Primary Motor Area Does Not Modify the Response of the Cerebral Cortex to Phasic Nociceptive Stimuli.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique of cortical stimulation. Although the exact mechanism of action is not clearly understood, it has been postulated that rTMS action on pain depends most on stimulation sites and stimulation parameters. Most studies concern high-frequency rTMS of the primary motor cortex (M1). High-frequency rTMS over motor cortex seems to induce an analgesic effect while contrasting results were reported after low-frequency rTMS. The aim of the current study was to investigate the effects of 1 Hz rTMS stimulation over the left primary motor cortex on subjective laser pain rating and laser evoked potential (LEP) amplitudes in healthy subjects. Subjects underwent two different sessions (real and sham rTMS) according to a cross-sectional design. In each session, LEPs and laser-pain rating to stimulation of both right and left hand dorsum were collected before 1 Hz rTMS over the left M1 area (baseline), which lasted 20 min. Then, LEPs and laser-pain rating were measured immediately after rTMS (T0), after 20 min from T0 (T0+20), and after 40 min from T0 (T0+40). We could not find any modification of both laser-pain rating and LEP parameters (latencies and amplitudes) following 1 Hz rTMS. Therefore, our results show that the low-frequency rTMS of the M1 area does not change the response of the cerebral cortex to pain.


Help-seeking in a national sample of victimized Latino women: the influence of victimization types.
The current study aimed to examine formal and informal help-seeking responses to interpersonal victimization among a national sample of Latino women. In addition, an examination of help-seeking by victimization type was undertaken. Data came from the Sexual Assault Among Latinas (SALAS) study that obtained help-seeking rates among a victimized subsample of Latino women (n = 714; 35.7% of a national sample). Results show a majority (76.6%) of the victimized participants engaged in some form of help-seeking with informal resources (68.9%) more often used than formal (32.5%). Medical attention was the type of formal help-seeking sought most often among victimized women who were injured (34.7%), and parents were the most common source of informal help-seeking (26.6%). However, logistic regression analyses show that help-seeking responses were significantly affected by type of victimization. Latino women who experienced childhood victimization were significantly less likely to engage in formal and informal help-seeking. Latino women who experienced stalking were significantly less likely to engage in formal help-seeking. Victimization with a weapon was significantly related to increased odds of formal help-seeking. Thus, women respond to violence in a way that is shaped by the dynamics of the victimization experience. Practice implications include the need to increase knowledge and availability of formal help-seeking venues.


Quantitative time-resolved chemoproteomics reveals that stable O-GlcNAc regulates box C/D snoRNP biogenesis.
O-linked GlcNAcylation (O-GlcNAcylation), a ubiquitous posttranslational modification on intracellular proteins, is dynamically regulated in cells. To analyze the turnover dynamics of O-GlcNAcylated proteins, we developed a quantitative time-resolved O-linked GlcNAc proteomics (qTOP) strategy based on metabolic pulse-chase labeling with an O-GlcNAc chemical reporter and stable isotope labeling with amino acids in cell culture (SILAC). Applying qTOP, we quantified the turnover rates of 533 O-GlcNAcylated proteins in NIH 3T3 cells and discovered that about 14% exhibited minimal removal of O-GlcNAc or degradation of protein backbones. The stability of those hyperstable O-GlcNAcylated proteins was more sensitive to O-GlcNAcylation inhibition compared with the more dynamic populations. Among the hyperstable population were three core proteins of box C/D small nucleolar ribonucleoprotein complexes (snoRNPs): fibrillarin (FBL), nucleolar protein 5A (NOP56), and nucleolar protein 5 (NOP58). We showed that O-GlcNAcylation stabilized these proteins and was essential for snoRNP assembly. Blocking O-GlcNAcylation on FBL altered the 2'-O-methylation of rRNAs and impaired cancer cell proliferation and tumor formation in vivo.


In defence of moral imperialism: four equal and universal prima facie principles.
Raanan Gillon is a noted defender of the four principles approach to healthcare ethics. His general position has always been that these principles are to be considered to be both universal and prima facie in nature. In recent work, however, he has made two claims that seem to present difficulties for this view. His first claim is that one of these four principles, respect for autonomy, has a special position in relation to the others: he holds that it is first among equals. We argue that this claim makes little sense if the principles are to retain their prima facie nature. His second claim is that cultural variation can play an independent normative role in the construction of our moral judgments. This, he argues, enables us to occupy a middle ground between what he sees as the twin pitfalls of moral relativism and (what he calls) moral imperialism. We argue that there is no such middle ground, and while Gillon ultimately seems committed to relativism, it is some form of moral imperialism (in the form of moral objectivism) that will provide the only satisfactory construal of the four principles as prima facie universal moral principles.


[Transfer of T-DNA from agrobacteria into plant cells through cell walls and membranes].
Discusses probable routes of agrobacterial penetration through the plant integumental tissues, cell wall, and plant cell plasmodesma. Analyzes the contribution of extracellular structures of agrobacteria in penetration through barriers of a plant cell, primary contact (adhesion), and during DNA transfer from bacterial (E. coli, A. tumefaciens) to recipient (bacterial or plant) cells. Discusses the relationship between donor cell adhesion to recipient cell surface and the infectious and conjugation processes. Considers the probable role of piles in conjugative transfer of agrobacterial DNA through membranes of donor and recipient (bacterial and plant) cells. Analyzes the contribution of the plant cell cytoskeleton to T-DNA transfer. Suggests a model of transport of T-DNA-VirD2 complex and VirE2 proteins through independent channels consisting of vir-coded proteins.


When does testing enhance retention? A distribution-based interpretation of retrieval as a memory modifier.
Tests, as learning events, can enhance subsequent recall more than do additional study opportunities, even without feedback. Such advantages of testing tend to appear, however, only at long retention intervals and/or when criterion tests stress recall, rather than recognition, processes. We propose that the interaction of the benefits of testing versus restudying with final-test delay and format reflects not only that successful retrievals are more powerful learning events than are re-presentations but also that the distribution of memory strengths across items is shifted differentially by testing and restudying. The benefits of initial testing over restudying, in this view, should increase as the delay or format of the final test makes that test more difficult. Final-test difficulty, not the similarity of initial-test and final-test conditions, should determine the benefits of testing. In Experiments 1 and 2 we indeed found that initial cued-recall testing enhanced subsequent recall more than did restudying when the final test was a difficult (free-recall) test but not when it was an easier (cued-recall) test that matched the initial test. The results of Experiment 3 supported a new prediction of the distribution framework: namely, that the final cued-recall test that did not show a benefit of testing in Experiment 1 should show such a benefit when that test was made more difficult by introducing retroactive interference. Overall, our results suggest that the differential consequences of initial testing versus restudying reflect, in part, differences in how items distributions are shifted by testing and studying.


Interdigestive biliary output in man: relationship to fluctuations in plasma motilin and effect of atropine.
The fasting output of bile into the bowel was investigated in nine healthy volunteers by hepatobiliary scanning. Subjects were studied twice, on each occasion for 2.5 hours. A significant flow of radioactivity from the gall bladder to the duodenum was observed on one or two occasions during each experiment. A 32 +/- 4% mean decrease in counts over the gall bladder was recorded, indicating partial emptying of this organ in the interdigestive state. The output of bile into the bowel was found to be related to fluctuations in fasting plasma motilin levels in that a significant motilin increment (18 +/- 4 pmol/l, p less than 0.005) paralleled the appearance of radioactivity in the duodenum. The onset of gall-bladder emptying regularly preceded the peak in plasma motilin (mean: 25 +/- 2 minutes). Atropine, intravenously, 0.6 mg followed by 0.3 mg, nearly abolished both fasting biliary output and plasma motilin fluctuations. Thus, bile output appears to occur frequently in fasting humans, but our data do not allow any conclusions as to the possible causal relationship between fasting gall-bladder emptying and release of motilin. Cholinergic influences appear to be of importance in the regulation of interdigestive biliary output in man.


Literature-based discovery of IFN-gamma and vaccine-mediated gene interaction networks.
Interferon-gamma (IFN-gamma) regulates various immune responses that are often critical for vaccine-induced protection. In order to annotate the IFN-gamma-related gene interaction network from a large amount of IFN-gamma research reported in the literature, a literature-based discovery approach was applied with a combination of natural language processing (NLP) and network centrality analysis. The interaction network of human IFN-gamma (Gene symbol: IFNG) and its vaccine-specific subnetwork were automatically extracted using abstracts from all articles in PubMed. Four network centrality metrics were further calculated to rank the genes in the constructed networks. The resulting generic IFNG network contains 1060 genes and 26313 interactions among these genes. The vaccine-specific subnetwork contains 102 genes and 154 interactions. Fifty six genes such as TNF, NFKB1, IL2, IL6, and MAPK8 were ranked among the top 25 by at least one of the centrality methods in one or both networks. Gene enrichment analysis indicated that these genes were classified in various immune mechanisms such as response to extracellular stimulus, lymphocyte activation, and regulation of apoptosis. Literature evidence was manually curated for the IFN-gamma relatedness of 56 genes and vaccine development relatedness for 52 genes. This study also generated many new hypotheses worth further experimental studies.


The impact of family history on pathological and clinical outcomes in non-syndromic clear cell renal cell carcinoma.
To investigate the impact of family history on pathological and clinical outcomes after surgery for clear-cell renal cell carcinoma (ccRCC) in patients with non-syndromic disease. We reviewed 2677 patients treated with radical nephrectomy or nephron-sparing surgery for non-cystic ccRCC between 1970 and 2004 to identify patients with a family history of ccRCC. Patients with von Hippel-Lindau, tuberous sclerosis, or Birt-Hogg-Dube syndrome were excluded from analysis. Demographics and clinico-pathological outcomes were compared to patients with ccRCC without a family history of kidney cancer using chi-squared and Fisher's exact tests. Postoperative cancer-specific survival was estimated using the Kaplan-Meier method. We identified 42 patients (1.6%) with a family history of ccRCC who were treated for non-cystic ccRCC, with a median follow-up of 4.7 years (range 1-34). Demographics and tumour characteristics, including tumour stage and grade, were similar between the two groups. Patients with a family history of ccRCC were more likely to have bilateral tumours (11.9 vs 2.2%, P= 0.003). Nevertheless, cancer-specific survival rates for patients with and without a family history of ccRCC were similar at 5 years (75.7 vs 71.1%) and 10 years (53.9 vs 62.2%). Patients with a family history of ccRCC have pathological and clinical outcomes similar to patients with sporadic ccRCC. The increased incidence of bilateral tumours associated with a family history of ccRCC provides further evidence to support a nephron-sparing surgical approach when feasible.


MiR-182 promotes apoptosis of neural cells in cerebral infarction rats by PI3K/AKT signaling pathway.
To explore the effects of micro ribonucleic acid (miR)-182 on the proliferation and apoptosis of neural cells in cerebral infarction rats and its underlying mechanism. The rat model of cerebral infarction was established, and neural cells were extracted accordingly. The cell proliferation ability was detected via cell counting kit-8 (CCK8) assay. In addition, the apoptosis rate was determined through flow cytometry and the activity of active caspase-3. Furthermore, the interaction between miR-182 and PI3K was explored via dual luciferase reporter assay, and the protein expression levels were observed via Western blotting. The neural cells in mouse brain tissues significantly decreased in the model group compared with that in the control group via HE stain. Additionally, the expression level of miR-182 was significantly increased in the model group compared with that in the control group. Furthermore, overexpression of miR-182 could inhibit the proliferation of neural cells through inducing cell apoptosis. Besides, the results of the luciferase reporter assay showed that the relative luciferase activity in neural cells could be inhibited by the transfection with miR-182 (P<0.05). Overexpression of miR-182 significantly reduced the protein expression levels of phosphatidylinositol 3-hydroxy kinase (PI3K) and p-AKT. MiR-182 induces apoptosis of neural cells through inhibiting the PI3K/AKT signaling pathway, which plays an important regulatory role in the apoptosis of neural cells in cerebral infarction rats.


Actin filament organization in aligned prefusion myoblasts.
The organization of the actin cytoskeleton in prefusion aligning myoblasts is likely to be important for their shape and interaction. We investigated actin filament organization and polarity by transmission electron microscopy (TEM) in these cells. About 84% of the filaments counted were either found in a subplasmalemma sheet up to 0.5 microm thick that was aligned with the long axis of the cell, or in protrusions. The remaining filaments were found in the cytoplasm, where they were randomly orientated and not organized into bundles. The polarity of the subplasmalemma filaments changed progressively from one end of the cell to the other. At the ends of the cells and in protrusions, the majority of filaments were organized such that their barbed ends faced the tip of the protrusion. We did not find any actin filament bundles or stress fibres in these cells. Time-lapse phase microscopy demonstrated that aligned cells were still actively migrating at the time of our TEM observations, and their direction of movement was restricted to the long axis of the cell group. The ability of these cells to locomote actively in the absence of actin filament bundles suggests that in these cells the subplasmalemma actin sheet contributes not only to cell shape but also to cell locomotion.


Testicular germ cell tumour cells release microRNA-containing extracellular vesicles that induce phenotypic and genotypic changes in cells of the tumour microenvironment.
Malignant germ-cell-tumours (GCTs) are characterised by microRNA (miRNA/miR-) dysregulation, with universal over-expression of miR-371~373 and miR-302/367 clusters regardless of patient age, tumour site, or subtype (seminoma/yolk-sac-tumour/embryonal carcinoma). These miRNAs are released into the bloodstream, presumed within extracellular-vesicles (EVs) and represent promising biomarkers. Here, we comprehensively examined the role of EVs, and their miRNA cargo, on (fibroblast/endothelial/macrophage) cells representative of the testicular GCT (TGCT) tumour microenvironment (TME). Small RNA next-generation-sequencing was performed on 34 samples, comprising representative malignant GCT cell lines/EVs and controls (testis fibroblast [Hs1.Tes] cell-line/EVs and testis/ovary samples). TME cells received TGCT co-culture, TGCT-derived EVs, and a miRNA overexpression system (miR-371a-OE) to assess functional relevance. TGCT cells secreted EVs into culture media. MiR-371~373 and miR-302/367 cluster miRNAs were overexpressed in all TGCT cells/subtypes compared with control cells and were highly abundant in TGCT-derived EVs, with miR-371a-3p/miR-371a-5p the most abundant. TGCT co-culture resulted in increased levels of miRNAs from the miR-371~373 and miR-302/367 clusters in TME (fibroblast) cells. Next, fluorescent labelling demonstrated TGCT-derived EVs were internalised by all TME (fibroblast/endothelial/macrophage) cells. TME (fibroblast/endothelial) cell treatment with EVs derived from different TGCT subtypes resulted in increased miR-371~373 and miR-302/367 miRNA levels, and other generic (eg, miR-205-5p/miR-148-3p) and subtype-specific (seminoma, eg, miR-203a-3p; yolk-sac-tumour, eg, miR-375-3p) miRNAs. MiR-371a-OE in TME cells resulted in increased collagen contraction (fibroblasts) and angiogenesis (endothelial cells), via direct mRNA downregulation and alteration of relevant pathways. TGCT cells communicate with nontumour stromal TME cells through release of EVs enriched in oncogenic miRNAs, potentially contributing to tumour progression.


Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos).
The mitochondrial protein apoptosis-inducing factor (AIF) plays a pivotal role in poly(ADP-ribose) polymerase-1 (PARP-1)-mediated cell death (parthanatos), during which it is released from the mitochondria and translocates to the nucleus. We show that AIF is a high-affinity poly(ADP-ribose) (PAR)-binding protein and that PAR binding to AIF is required for parthanatos both in vitro and in vivo. AIF bound PAR at a site distinct from AIF's DNA binding site, and this interaction triggered AIF release from the cytosolic side of the mitochondrial outer membrane. Mutation of the PAR binding site in AIF did not affect its NADH (reduced form of nicotinamide adenine dinucleotide) oxidase activity, its ability to bind FAD (flavin adenine dinucleotide) or DNA, or its ability to induce nuclear condensation. However, this AIF mutant was not released from mitochondria and did not translocate to the nucleus or mediate cell death after PARP-1 activation. These results suggest a mechanism for PARP-1 to initiate AIF-mediated cell death and indicate that AIF's bioenergetic cell survival-promoting functions are separate from its effects as a mitochondrially derived death effector. Interference with the PAR-AIF interaction or PAR signaling may provide notable opportunities for preventing cell death after activation of PARP-1.


Mobile elements create strain-level variation in the services conferred by an aphid symbiont.
Heritable, facultative symbionts are common in arthropods, often functioning in host defence. Despite moderately reduced genomes, facultative symbionts retain evolutionary potential through mobile genetic elements (MGEs). MGEs form the primary basis of strain-level variation in genome content and architecture, and often correlate with variability in symbiont-mediated phenotypes. In pea aphids (Acyrthosiphon pisum), strain-level variation in the type of toxin-encoding bacteriophages (APSEs) carried by the bacterium Hamiltonella defensa correlates with strength of defence against parasitoids. However, co-inheritance creates difficulties for partitioning their relative contributions to aphid defence. Here we identified isolates of H. defensa that were nearly identical except for APSE type. When holding H. defensa genotype constant, protection levels corresponded to APSE virulence module type. Results further indicated that APSEs move repeatedly within some H. defensa clades providing a mechanism for rapid evolution in anti-parasitoid defences. Strain variation in H. defensa also correlates with the presence of a second symbiont Fukatsuia symbiotica. Predictions that nutritional interactions structured this coinfection were not supported by comparative genomics, but bacteriocin-containing plasmids unique to co-infecting strains may contribute to their common pairing. In conclusion, strain diversity, and joint capacities for horizontal transfer of MGEs and symbionts, are emergent players in the rapid evolution of arthropods.


Metabolic profile of fetal dopamine neurons transplanted to the adult rat striatum.
In the present study, we have examined the expression and distribution of the metabolic marker neuron-specific enolase (NSE) in solid-tissue transplants of fetal substantia nigra (SN) to the striatum of intact and 6-hydroxydopamine lesioned mature rats. Immunocytochemistry was applied to label NSE and tyrosine hydroxylase (TH) respectively. Cellular content of NSE is indicative of metabolic activity as well as synaptogenesis/maturation. Three months after implantation, the fetal grafts exhibited intensely TH-immunoreactive neurons, typically organized in elongated clusters, especially along the graft-host border and along blood vessels penetrating into the graft interior. Moderate to high metabolic activity as indicated by NSE immunoreactivity was observed in neuronal perikarya, principally in non-TH immunoreactive areas. In contrast to these immunohistochemical findings, in situ hybridization for TH mRNA, carried out exclusively on grafts into the intact striatum, demonstrated DA cell bodies both at the graft-host interface and, significantly, throughout the graft interior. The number of transcripts per cell, moreover, did not differ significantly in these two locations. We propose that conditions at the graft-host border promote tissue-specific regulation of nigral DA neurons, and that this regulation occurs post-transcriptionally. Thus, DA neurons relatively distant from the host parenchyma are underregulated, resulting in a higher level of metabolic activity and an increased turnover of TH in the grafted neurons.


Cost-effectiveness analysis of the Not On Tobacco program for adolescent smoking cessation.
Public health researchers and practitioners emphasize the need for effective, adoptable, and available youth smoking cessation interventions. Scarce resources demand that such interventions also be cost effective. This study describes a cost-effectiveness analysis (CEA) of the American Lung Association's Not On Tobacco (N-O-T) national and international teen smoking cessation program. N-O-T has been rigorously evaluated as an effective and adoptable program, and was recently found to be the most frequently-used teen smoking cessation program in the nation. N-O-T studies show intent-to-treat quit rates between 15% and 19%, among the highest reported in the literature. The current CEA resulted from a 2-year state-wide demonstration study in Florida, comparing the effectiveness of N-O-T with a 20-min brief intervention (BI). The CEA utilized a Markov transition model of decision analysis to explain stage progression of smoking cessation among participants from the age of 17 to 25 years. The Markov simulation predicted that out of a cohort of 100 N-O-T students, 10 will quit smoking and remain smoke-free at the age of 25 years and 14 will reduce smoking, resulting in 102.22 life years saved and a total of 20.11 years discounted life years (DLY) saved. Among BI youth, six will quit smoking and nine will reduce, indicating 64.31 life years saved and a total 12.65 DLY saved. The incremental DLY saved is 7.46 years. Results indicate that N-O-T is a very cost-effective option school-based smoking cessation, as cost effective as school-based primary tobacco prevention, and potentially more cost effective than adult tobacco use cessation.


Does Treatment Response With Antidementia Drugs After 6 Months in Alzheimer's Disease Predict Long-term Treatment Outcome?
Alzheimer's disease (AD) is a chronic, progressive disorder that causes declines in cognitive and physical functions. This condition places severe burdens on families and caregivers. Delaying progressive declines in cognitive function and reducing their burden are thus important. Relationships between early treatment response and subsequent outcomes of schizophrenia and major depressive disorder have been reported. We thus aimed to investigate the relationships between treatment response to antidementia drugs in AD after 6 months (M) and subsequent outcomes. Eligible individuals comprised 194 patients diagnosed with presumed AD. Of these, 110 patients who received antidementia drugs for the first time and were assessed using the Mini-Mental State Examination (MMSE) at 6 M, 12 M, and 24 M were categorized as responders (n = 84) or nonresponders (n = 26). Responders were defined as showing a change in MMSE after 6 M the same as or lower than that in the natural course according to previously reported data. No significant differences in baseline characteristics (age, sex, education, or comorbidities) were seen between groups. Mean MMSE score at baseline was significantly lower in responders (18.0) than in nonresponders (20.7; P = 0.008). Mean change from baseline MMSE was significantly smaller in responders than in nonresponders at both 12 M (-0.46 vs -2.5; P = 0.04) and 24 M (-0.78 vs -4.4; P = 0.001). Treatment response with antidementia drugs after 6 M predicted better outcomes at 12 M and 24 M. Treatment response should be assessed every 6 M, and treatment should be reconsidered accordingly.


Large expansion of oil industry in the Ecuadorian Amazon: biodiversity vulnerability and conservation alternatives.
Ecuador will experience a significant expansion of the oil industry in its Amazonian region, one of the most biodiverse areas of the world. In view of the changes that are about to come, we explore the conflicts between oil extraction interests and biodiversity protection and apply systematic conservation planning to identify priority areas that should be protected in different oil exploitation scenarios. First, we quantified the current extent of oil blocks and protected zones and their overlap with two biodiversity indicators: 25 ecosystems and 745 species (whose distributions were estimated via species distribution models). With the new scheme of oil exploitation, oil blocks cover 68% (68,196 km(2)) of the Ecuadorian Amazon; half of it occupied by new blocks open for bids in the southern Amazon. This region is especially vulnerable to biodiversity losses, because peaks of species diversity, 19 ecosystems, and a third of its protected zones coincide spatially with oil blocks. Under these circumstances, we used Marxan software to identify priority areas for conservation outside oil blocks, but their coverage was insufficient to completely represent biodiversity. Instead, priority areas that include southern oil blocks provide a higher representation of biodiversity indicators. Therefore, preserving the southern Amazon becomes essential to improve the protection of Amazonian biodiversity in Ecuador, and avoiding oil exploitation in these areas (33% of the extent of southern oil blocks) should be considered a conservation alternative. Also, it is highly recommended to improve current oil exploitation technology to reduce environmental impacts in the region, especially within five oil blocks that we identified as most valuable for the conservation of biodiversity. The application of these and other recommendations depends heavily on the Ecuadorian government, which needs to find a better balance between the use of the Amazon resources and biodiversity conservation.


Peptide Receptor Radionuclide Therapy of Late-Stage Neuroendocrine Tumor Patients with Multiple Cycles of 177Lu-DOTA-EB-TATE.
This study aimed to evaluate the safety and efficacy of multiple cycles of 177Lu-DOTA-Evans blue (EB)-TATE peptide receptor radionuclide therapy (PRRT) at escalating doses in neuroendocrine tumors (NETs). Methods: Thirty-two NET patients were randomly divided into 3 groups and treated with escalating doses. Group A received 1.17 ± 0.09 GBq/cycle; group B, 1.89 ± 0.53 GBq/cycle; and group C, 3.97 ± 0.84 GBq/cycle. The treatment was planned for up to 3 cycles. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Treatment response was evaluated according to the European Organisation for Research and Treatment of Cancer criteria and modified PERCIST. Results: Administration of PRRT was well tolerated, without life-threatening adverse events (CTCAE grade 4). CTCAE grade 3 hematotoxicity was recorded in 1 patient (16.6%) in group B (thrombocytopenia) and 3 patients (21.4%) in group C (thrombocytopenia in 3, anemia in 1). CTCAE grade 3 hepatotoxicity (elevated aspartate aminotransferase) was recorded in 1 patient in group A (8.3%) and 1 patient in group C (7.1%). No nephrotoxicity was observed. According to the criteria of the European Organisation for Research and Treatment of Cancer, the overall disease response rates were similar in groups A, B, and C (50.0%, 50.0%, and 42.9%, respectively), and the overall disease control rates were higher in groups B (83.3%) and C (71.5%) than in group A (66.7%). According to modified PERCIST, a lower disease response rate but a similar disease control rate were found. When a comparable baseline SUVmax ranging from 15 to 40 was selected, the percentage change in SUVmax increased slightly in group A (2.1% ± 40.8%) but decreased significantly in groups B and C (-38.7% ± 10.0% and -14.7% ± 20.0%, respectively) after the first PRRT (P = 0.001) and decreased in all 3 groups after the third PRRT (groups A, B, and C: -6.9% ± 42.3%, -49.2% ± 30.9%, -11.9% ± 37.9%, respectively; P = 0.044). Conclusion: Dose escalations of up to 3.97 GBq/cycle seem to be well tolerated for 177Lu-DOTA-EB-TATE. 177Lu-DOTA-EB-TATE doses of 1.89 and 3.97 GBq/cycle were effective in tumor control and more effective than 1.17 GBq/cycle.


Hypertriglyceridemia is a risk factor for acute kidney injury in the early phase of acute pancreatitis.
The aim of this study was to investigate the risk factors for acute kidney injury (AKI) in patients with acute pancreatitis (AP). Patients with AP were retrospectively divided into AKI group and non-AKI group. To investigate the risk factors for AKI, logistic regression analysis was performed with demography, etiologies, and comorbidities. Mortalities of patients with different body mass indexes were compared. There were 43 patients with AKI and 202 patients without AKI. The risk factor for AKI in AP was hypertriglyceridemia (odds ratio, 2.964; 95% confidence interval, 1.485-5.915; P = 0.007). Forty-two patients developed AKI within the first 48 hours. The mortalities of normal weight, overweight, and obese groups in patients with AKI were 16.7%, 17.4%, and 62.5%, respectively. All the 4 patients who died in the non-AKI group were of normal weight. Hypertriglyceridemia is an independent risk factor for AKI in the early phase of AP. Obesity does not increase mortality of patients without AKI. We hypothesize that the role of pancreatic enzymes on triglyceride accumulated in renal may be an explanation for AKI in the early phase of AP.


The effects of Clostridium difficile crude toxins and purified toxin A on stripped rabbit ileal mucosa in Ussing chambers.
Clostridium difficile crude toxins and purified toxin A had similar effects on stripped rabbit ileal mucosa in Ussing chambers. Both toxin preparations caused secretion of sodium and chloride ions by increasing serosa to mucosa (s----m) fluxes. Transmural potential difference and resistance decreased after toxin treatment. Onset of changes in electrical measurements and ion fluxes coincided with onset of histological changes. The response to theophylline was greatly reduced in toxin-treated tissue compared with control tissue.


[Specificity of action of anticancer agents].
Since the first cancer chemotherapy use, efforts have been made in identifying drugs with an antitumor specific action, but cancer is a very complex situation to be cured with a single agent, and to increase drugs selective cytotoxicity new agent combinations, or innovative cellular cycle related schedule, or the use of pro-drugs have been developed. Notwithstanding some relevant improvements in results, chemotherapy remains often a palliative approach. The improved knowledge of the biology of cancer, and of molecular mechanisms and specific targets, has recently modified the approach to various tumors. In particular, the identification of a single and specific genetic alteration in some tumors such as myeloid chronic leukaemia or gastrointestinal stromal tumors (GIST) led to the development of imatinib, a "target" drug with a multikinase inhibitor activity towards the specific genetic alteration; this unique opportunity is not applicable to other tumors, because usually tumors have multiple genetic alterations with very complex molecular pathways. The development of drugs with a multitarget action is probably the best approach to the majority of human cancers, but other possibility are the combination of multiple agents, each with known selective activity towards a specific molecular target, or the choice of a chemotherapic drug in combination with one or more molecularly targeted drugs. The knowledge of the multiple and extremely complex molecular pathways of the neoplastic cells will hopefully drive oncologic science towards a more "exact" science, with the use of "personalized" treatment in each cancer patient.


Clinical presentation and surgical management of intramedullary spinal cord cavernous malformations.
Intramedullary cavernous malformation (CM) is a rare entity, accounting for 5% of all intraspinal lesions. The objective in this study was to define the clinical characteristics of this disease, detail the surgical approach and technique, and present the clinical outcome. Retrospective chart review was performed in 22 patients with histologically confirmed CMs. The authors used a laminectomy approach for midline dorsal lesions, with unilateral radical facetectomy and dentate ligament resection for laterally or ventrally located lesions. Patient profiles, operative indications, surgical approaches, operative findings, complications, and long-term follow-up were reviewed. The average age of patients in the cohort was 43 +/- 14 years, the average duration of symptoms was 7 +/- 7 months, and the average follow-up was 6 +/- 4 years. The average size of the lesion was 1 +/- 0.4 cm, the average surgical time was 4 +/- 0.96 hours, and the average estimated blood loss was 350 +/- 131 ml. The rate of complication was 5% (1 patient; due to a wound infection). According to the McCormick classification, the score for the cohort was 1.8 +/- 1.2 preoperatively, 2.1 +/- 1.2 postoperatively, and 1.3 +/- 0.65 at late follow-up. (All preceding values are given as the mean +/- SD.) There was a significant neurological improvement at follow-up compared with the preoperative state (p < 0.05). The majority of patients (50%) had a stable outcome compared with their preoperative state, with a large proportion (41%) having an improved outcome. A minority of patients (9%) had a worsened outcome due to dysesthetic pain. Patients with dysesthesia had a longer duration of clinical symptoms prior to surgery compared with patients without dysesthesia (p < 0.05). The authors demonstrated the safety, efficacy, and durability of their surgical approach for resection of spinal intramedullary CM. Proper examination, preoperative imaging, and prompt surgical intervention were necessary for a satisfactory outcome.


Inhaled Glucocorticoids and Pneumonia in Preterm Infants: Post Hoc Results from the NEuroSIS Trial.
Inhaled glucocorticoids may increase the risk of pneumonia in adults. Thus, respiratory infections may be a potential explanation for the non-significantly increased mortality seen in the glucocorticoid group in the largest randomized trial on inhaled glucocorticoids for preventing bronchopulmonary dysplasia in preterm infants published to date (NEuroSIS). To evaluate the effect of inhaled budesonide on the risk of death due to respiratory infections in the NEuroSIS trial. We performed post hoc analyses of prospectively collected data from 856 preterm infants on presumed but not culture-proven sepsis and antimicrobial drug use. Additionally, pulmonary complications reported on adverse event forms, death certificates and autopsy reports were compared between study groups. Treatment groups did not differ in the number of episodes with suspected sepsis (184/437 [42.1%] in the budesonide vs. 171/419 [40.8%] in the placebo group). Neither the number of patients receiving antimicrobial drugs nor the length of antimicrobial treatment differed between groups. Our analyses for pulmonary adverse events as well as for pulmonary complications reported on death certificates and autopsy reports did not suggest a negative impact of inhaled budesonide on these outcomes. The current analysis does not support the assumption that respiratory tract infections explain the increased mortality seen in the glucocorticoid group in the NEuroSIS trial.


Advancement through epidermis using tape stripping technique and Reflectance Confocal Microscopy.
The tape stripping technique is increasingly used in research regarding skin barrier function. However, number of tape strips varies between studies, and literature considering advancement into stratum corneum/epidermis in relation to number of tape strips is scarce. The aim of this pilot study was to assess the advancement through epidermis using tape stripping technique in healthy volunteers. A total of ten healthy volunteers were included. From all volunteers 0, 5, 15 and 35 consecutive tape strips (D-squame) were taken from four adjacent skin areas on the middle volar forearm, followed by Reflectance Confocal Microscopy (RCM) of the four areas to assess epidermal thickness. Squame Scan was used to determine amount of protein removed. Stratum corneum was completely removed in all volunteers after 35 tape strips. Advancement into epidermis was predominantly achieved by the first 15 tape strips, removing 25% of the total epidermis, whereas 35 tape strips removed 33% of epidermis. Protein removal per tape decreased with increasing depth. Information on advancement into the epidermis according to number of tape strips taken, is a significant step forward. The possibility to obtain samples from different layers of epidermis may lead to an improved understanding of skin barrier properties.


Low neutralization of SARS-CoV-2 Omicron BA.5.2.48, BF.7.14, XBB.1 subvariants by homologous or heterologous booster.
The recently mutated severe acute respiratory syndrome coronavirus 2 variant Omicron has very high infectivity and a strong ability to evolve and evade immunity. We collected six sets of sera from uninfected individuals and individuals recovering from breakthrough infections who completed homologous or heterologous booster immunization and assessed their susceptibility against the BA.5.2.48, BF.7.14, XBB.1.5, XBB.1.5.4, and XBB.1.16 subvariants. The results demonstrated that the Omicron variants possess an exceptional potential to evade the immune barriers strengthened by vaccine administration and natural infections in the population, particularly XBB.1.16, and showed that heterologous boosters exhibit higher vaccine efficacy compared with homologous boosters.


Teleaudiology hearing aid fitting follow-up consultations for adults: single blinded crossover randomised control trial and cohort studies.
To evaluate and compare the effectiveness and quality of standard face-to-face and teleaudiology hearing aid fitting follow-up consultations and blended services for adult hearing aid users. Fifty-six participants were randomly allocated to two equal groups, with equal numbers of new and experienced users. One standard and one teleaudiology follow-up consultation were delivered by an audiologist, the latter assisted by a facilitator. The order was reversed for the second group. Outcome measurement tools were applied to assess aspects of participants' communication, fitting (physical, sensorial), quality of life, and service. Cross-sectional and longitudinal outcomes were analysed. Most participants presented with moderate, sloping, and symmetrical sensorineural hearing loss. The duration of teleaudiology (42.96 ± 2.73 min) was equivalent to face-to-face consultations (41.25 ± 2.61 min). All modes of service delivery significantly improved outcomes for communication, fitting, and quality of life (p > 0.05). Satisfaction for both consultation modes was high, although significantly greater with standard consultations. The mode and order of delivery of the consultations did not influence the outcomes. Teleaudiology hearing aid follow-up consultations can deliver significant improvements, and do not differ from standard consultations. Blended services also deliver significant improvements. Satisfaction can be negatively impacted by technical or human-related issues.


Preemptive alcohol septal ablation prior to transcatheter mitral valve replacement.
Alcohol septal ablation (ASA) has been shown to increase the neo-left ventricular outflow tract (LVOT) area before transcatheter mitral valve replacement (TMVR) but there is little literature on its success and use with dedicated devices. To describe our experience with preemptive ASA to increase the predicted neo-LVOT area and its utility with both dedicated TMVR devices and balloon-expandable valves. All patients who underwent ASA for TMVR candidacy in our center between May 2018 and October 2022 and had computed tomography (CT) scans done before and after ASA were included. Each CT was assessed for the minimum predicted neo-LVOT area at end-systole, using a virtual valve of the desired TMVR device for each patient. The primary outcome was an increase in the predicted neo-LVOT area after ASA that was deemed sufficient for safe implantation of the desired TMVR device. The secondary outcome was the absence of acute LVOT obstruction after TMVR. A total of 12 patients underwent ASA and all but 1 (n = 11, 91.6%) achieved the primary outcome of having sufficient predicted neo-LVOT area to proceed with TMVR. The mean increase in neo-LVOT area after ASA was 126 ± 64 mm2 (median 119.5, interquartile range: 65.0-163.5 mm2 ). Two patients (16.7%) required a permanent pacemaker after ASA. Nine patients went on and underwent TMVR with their respective devices and none had LVOT obstruction after the procedure. Among the remaining three patients, one had insufficient neo-LVOT clearance after ASA, one had unrelated mortality before TMVR, and one had advanced heart failure before TMVR. In appropriately selected patients and at centers experienced with ASA, preemptive ASA can achieve sufficient neo-LVOT clearance for TMVR with a variety of devices in approximately 90% of patients.


A Comprehensive Review of the Current Status of the Cellular Neurobiology of Psychedelics.
Psychedelic substances have gained significant attention in recent years for their potential therapeutic effects on various psychiatric disorders. This review delves into the intricate cellular neurobiology of psychedelics, emphasizing their potential therapeutic applications in addressing the global burden of mental illness. It focuses on contemporary research into the pharmacological and molecular mechanisms underlying these substances, particularly the role of 5-HT2A receptor signaling and the promotion of plasticity through the TrkB-BDNF pathway. The review also discusses how psychedelics affect various receptors and pathways and explores their potential as anti-inflammatory agents. Overall, this research represents a significant development in biomedical sciences with the potential to transform mental health treatments.


Prevalence and predictors of hepatitis B virus (HBV) infection in east Africa: evidence from a systematic review and meta-analysis of epidemiological studies published from 2005 to 2020.
The epidemiology of hepatitis B virus (HBV) in the general population in east Africa is not well documented. In this meta-analysis, we examined 37 full published research articles to synthesise up-to-date data on the prevalence and predictors of the HBV burden for the effective prevention and management of the virus in our region. We examined 37 full published research articles found using PubMed, Scopus, African Journal Online (AJOL), and Google Scholar between May and October 2020. Dichotomous data on HBV prevalence and predictors of infection were extracted from the individual studies. The HBV prevalence, test of proportion, relative risk, and I2 statistics for heterogeneity were calculated using MedCalc software version 19.1.3. Begg's tests was used to test for publication bias. Sources of heterogeneity were analysed through sensitivity analysis, meta-regression, and sub-group analysis at 95% CI. P < 0.05 was considered significant for all analyses. The prevalence of HBV was generally high (6.025%), with publications from Kenya (8.54%), Uganda (8.454%) and those from between 2011 and 2015 (8.759%) reporting the highest prevalence (P < 0.05). Blood transfusion, scarification, promiscuity, HIV seropositivity, and being male were independent predictors significantly associated with HBV infection (P < 0.05), with the male sex being the most strongly associated predictor of HBV infection. Meta-regressions for the pooled HBV prevalence and sample size, as well as the year of publication, lacked statistical significance (P > 0.05). Omitting the study with the largest sample size slightly increased pooled HBV prevalence to 6.149%, suggesting that the studies are robust. Begg's test showed no evidence of publication bias for overall meta-analysis (p > 0.05). The burden of HBV is still high, with the male sex, blood transfusion, body scarification, and HIV seropositivity being potential predictors of infection. Thus, it is important to scale up control and prevention measures targeting persons at high risk.


Horizontal and Vertical Transmission of a Mycovirus Closely Related to the Partitivirus RhsV717 That Confers Hypovirulence in Rhizoctonia solani.
Rhizoctonia solani virus717 (RhsV717) was isolated from the Rhizoctonia solani (R. solani) AG-2 strain Rhs717. This study isolated a virus designated as Rhizoctonia solani partitivirus BS-5 (RsPV-BS5) from the R. solani AG-3 strain BS-5, the causal agent of tobacco target spot disease. The virus was identified as a strain of RhsV717. Transmission electron microscopy (TEM) images showed that RsPV-BS5 had virus particles with a diameter of approximately 40 nm. Importantly, it can be horizontally transmitted through hyphal anastomosis and vertically transmitted via sexual basidiospores. Furthermore, this study demonstrated that RsPV-BS5 infection significantly impedes mycelial growth and induces hypovirulence in tobacco leaves. Thus, RsPV-BS5 presents a promising avenue for biocontrolling tobacco target spot disease. Transcriptome analysis unveiled differential expression of four genes related to cell wall-degrading enzymes between two isogenic strains, 06-2-15V and 06-2-15. These findings shed light on the molecular mechanism through which RsPV-BS5 reduces host pathogenicity.


Genetic architecture of microRNA expression and its link to complex diseases in the Japanese population.
Understanding the genetic effects on non-coding RNA (ncRNA) expression facilitates functional characterization of disease-associated genetic loci. Among several classes of ncRNAs, microRNAs (miRNAs) are key post-transcriptional gene regulators. Despite its biological importance, previous studies on the genetic architecture of miRNA expression focused mostly on the European individuals, underrepresented in other populations. Here, we mapped miRNA expression quantitative trait loci (miRNA-eQTL) for 343 miRNAs in 141 Japanese using small RNA sequencing and whole-genome sequencing, identifying 1275 cis-miRNA-eQTL variants for 40 miRNAs (false discovery rate < 0.2). Of these, 25 miRNAs having eQTL were unreported in the European studies, including 5 miRNAs with their lead variant monomorphic in the European populations, which demonstrates the value of miRNA-eQTL analysis in diverse ancestral populations. MiRNAs with eQTL effect showed allele-specific expression (ASE; e.g. miR-146a-3p), and ASE analysis further detected cis-regulatory variants not captured by the conventional miRNA-eQTL mapping (e.g. miR-933). We identified a copy number variation associated with miRNA expression (e.g. miR-570-3p, P = 7.2 × 10-6), which contributes to a more comprehensive landscape of miRNA-eQTLs. To elucidate a post-transcriptional modification in miRNAs, we created a catalog of miRNA-editing sites, including 10 canonical and 6 non-canonical sites. Finally, by integrating the miRNA-eQTLs and Japanese genome-wide association studies of 25 complex traits (mean n = 192 833), we conducted a transcriptome-wide association study, identifying miR-1908-5p as a potential mediator for adult height, colorectal cancer and type 2 diabetes (P < 9.1 × 10-5). Our study broadens the population diversity in ncRNA-eQTL studies and contributes to functional annotation of disease-associated loci found in non-European populations.


Linear skin atrophy, scarring alopecia, anonychia, and tongue lesion: a "new" syndrome?
One of a pair of female monozygotic twins showed skin atrophy with linear alternation of depressed scarlike areas and intervening ridges of normal or nearly normal skin. She was born with friable skin and a vesicular-bullous eruption which was followed by gradual scabbing. Hypohidrosis in the affected areas, heat intolerance, and febrile convulsions were noted in infancy and childhood. No new skin lesions developed, and the existing ones, the sweating disturbance, and the heat intolerance gradually improved with time. Scarring alopecia, congenital absence of three toenails, and a scarlike lesion of the tongue were also present. Their absence in the other twin supports the view that 1) these manifestations all are part of the same syndrome, and 2) this syndrome is nongenetic. Histologically, there were no diagnostic or consistent findings, but the number of skin appendages was diminished, and the elastic fibers were reduced in number and size in one biopsy. The calculated probability for the twins being monozygotic was 0.9998. This family was also remarkable for the presence of alopecia areata in three successive generations with only one instance of apparent nonpenetrance. We conclude that this may represent a previously undescribed syndrome of congenital fragility of connective tissue which predisposed to damage of the elastica, possibly caused by an early inflammatory phase.


Evidence for direct estrogen regulation of the human gonadotropin-releasing hormone gene.
This study is an attempt to determine whether estrogen could directly regulate human gonadotropin-releasing hormone (GnRH) gene expression. Human GnRH expression vectors were constructed by fusing various 5' flanking regions of the human GnRH gene upstream of the luciferase reporter gene (LUC) or the thymidine kinase promoter linked to the chloramphenicol acetyltransferase reporter gene (CAT). These constructs were transiently transfected into a human choriocarcinoma cell line (JEG-3) and LUC or CAT activity was measured after either no treatment or treatment with various concentrations of estradiol. A stimulatory estrogen response element (ERE) was localized to a 32-bp region between -547 and -516 bp. To determine whether estrogen receptor bound to this region of the gene, we performed DNase I footprinting using purified calf uterine estrogen receptor. DNase I footprinting demonstrates a strong footprint between -567 and -514 bp of the human GnRH gene. In addition, an avidin-biotin complex DNA-binding assay demonstrated that a biotinylated DNA fragment containing -541 to -517 bp of the human GnRH gene bound 35S-labeled estrogen receptor as well as a biotinylated DNA fragment containing the xenopus vitellogenin ERE. On the other hand, the negative control biotinylated DNA fragment derived from adenovirus 5 bound insignificant amounts of 35S-labeled estrogen receptor. Both the GnRH ERE and vitellogenin ERE bound 35S-labeled estrogen receptor with high affinity (approximately 1 nM). These data indicate that the human GnRH gene contains an ERE sufficient to mediate a stimulatory response to estrogen in heterologous cells. Based upon these data we hypothesize that the human GnRH gene might also be directly regulated by estrogen in the hypothalamus, and that this regulation may explain the GnRH hypersecretion observed at the time of the preovulatory luteinizing hormone (LH) surge.


Phosphite-oxazole/imidazole ligands in asymmetric intermolecular Heck reaction.
We describe the application of a new class of ligands--the phosphite-oxazole/imidazole (L1-L5a-g)--in asymmetric intermolecular Pd-catalyzed Heck reactions under thermal and microwave conditions. These ligands combine the advantages of the oxazole/imidazole moiety with those of the phosphite moiety: they are more stable than their oxazoline counterparts, less sensitive to air and other oxidizing agents than phosphines and phosphinites, and easy to synthesize from readily available alcohols. The results indicate that activities, regio- and enantioselectivities, are highly influenced by the type of nitrogen donor group (oxazole or imidazole), the oxazole and biaryl-phosphite substituents and the axial chirality of the biaryl moiety of the ligand. By carefully selecting the ligand components, we achieved high activities, regio- (up to 99%) and enantioselectivities (up to 99%) using several triflate sources. Under microwave-irradiation conditions, reaction times were considerably shorter (from 24 h to 30 min) and regio- and enantioselectivities were still excellent.


Updates on treatment of irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder characterized by abdominal pain and discomfort in association with altered bowel habits. It is estimated to affect 10%-15% of the Western population, and has a large impact on quality of life and (in)direct healthcare costs. IBS is a multifactorial disorder involving dysregulation within the brain-gut axis, and it is frequently associated with gastrointestinal motor and sensory dysfunction, enteric and central nervous system irregularities, neuroimmune dysregulation, and post-infectious inflammation. As with other functional medical disorders, the treatment for IBS can be challenging. Conventional therapy for those with moderate to severe symptoms is largely unsatisfactory, and the development of new and effective drugs is made difficult by the complex pathogenesis, variety of symptoms, and lack of objective clinical findings that are the hallmark of this disorder. Fortunately, research advances over the past several decades have provided insight into potential mechanisms responsible for the pathogenesis of IBS, and have led to the development of several promising pharmaceutical agents. In recent years there has been much publicity over several of these new IBS medications (alosetron and tegaserod) because of their reported association with ischemic colitis and cardiovascular disease. While these agents remain available for use under restricted prescribing programs, this highlights the need for continued development of safe and effective medication for IBS. This article provides a physiologically-based overview of recently developed and frequently employed pharmaceutical agents used to treat IBS, and discusses some non-pharmaceutical options that may be beneficial in this disorder.


Clinical exome sequencing reveals a novel pathogenic variant in KIF12 underlying cholestasis with highly variable phenotypes.
Four affected individuals from a large consanguineous family were diagnosed with variable phenotypes of cholestasis based on their clinical laboratory and biopsy findings. Cholestasis is a condition when there is not enough bile flow between liver and small intestine. Two of the affected individuals (IV-1, IV-4) died of cholestatic liver at an early age, while the other two patients are alive with chronic liver disease. Clinical exome and Sanger sequencing identified a novel homozygous pathogenic variant (c.482-7_500del) in the patients.


Modular dynamic biomolecular modelling with bond graphs: the unification of stoichiometry, thermodynamics, kinetics and data.
Renewed interest in dynamic simulation models of biomolecular systems has arisen from advances in genome-wide measurement and applications of such models in biotechnology and synthetic biology. In particular, genome-scale models of cellular metabolism beyond the steady state are required in order to represent transient and dynamic regulatory properties of the system. Development of such whole-cell models requires new modelling approaches. Here, we propose the energy-based bond graph methodology, which integrates stoichiometric models with thermodynamic principles and kinetic modelling. We demonstrate how the bond graph approach intrinsically enforces thermodynamic constraints, provides a modular approach to modelling, and gives a basis for estimation of model parameters leading to dynamic models of biomolecular systems. The approach is illustrated using a well-established stoichiometric model of Escherichia coli and published experimental data.


Importance of silicon and mechanisms of biosilica formation in plants.
Silicon (Si) is one of the most prevalent macroelements, performing an essential function in healing plants in response to environmental stresses. The purpose of using Si is to induce resistance to distinct stresses, diseases, and pathogens. Additionally, Si can improve the condition of soils, which contain toxic levels of heavy metals along with other chemical elements. Silicon minimizes toxicity of Fe, Al, and Mn, increases the availability of P, and enhances drought along with salt tolerance in plants through the formation of silicified tissues in plants. However, the concentration of Si depends on the plants genotype and organisms. Hence, the physiological mechanisms and metabolic activities of plants may be affected by Si application. Peptides as well as amino acids can effectively create polysilicic species through interactions with different species of silicate inside solution. The carboxylic acid and the alcohol groups of serine and asparagine tend not to engage in any significant role in polysilicates formation, but the hydroxyl group side chain can be involved in the formation of hydrogen bond with Si(OH)4. The mechanisms and trend of Si absorption are different between plant species. Furthermore, the transportation of Si requires an energy mechanism; thus, low temperatures and metabolic repressors inhibit Si transportation.


Is inferential reasoning a distinctly human cognitive feature? Testing reasoning in cotton-top tamarins (Saguinus oedipus).
Logical inference is often assumed a human-unique ability, although many species of apes and monkeys have shown some facility within a two-cup task in which one cup is baited, the primate is shown the cup which is empty (an exclusion cue), and subsequently chooses the other baited cup. In published reports, New World monkey species show a limited ability to choose successfully, often with half or more of the subjects tested not showing the ability with auditory cues or with exclusion cues. In this study, five cotton-top tamarins (Saguinus oedipus) were tested in a two-cup task with visual or auditory cues which revealed the presence or absence of bait, and in a second study, were tested with a four-cup array using a variety of walls to define the baiting space and a variety of visual cues including inclusion and exclusion. Tamarins demonstrated the ability to use either visual or auditory exclusion cues to find rewards in the two-cup study, although the visual cue required some exposure before accuracy was expressed. Experiment 2 revealed that two of three tamarins' first guesses to find rewards matched best a logic model. When they made errors, they typically chose cups adjacent to the cued location or made choices that seemed generated from avoiding empty cups. These results suggest that tamarins can deduce the location of food using reasoning, although the ability is only applied robustly to first guesses, while second guesses are motivated by approach/avoidance and proximity to cued locations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Idiopathic hypercalciuria and hyperparathyroidism.
With provocative tests of parathyroid activity based on phosphate deprivation and the administration of chlorothiazide 8 out of 19 patients with idiopathic hypercalciuria developed hypercalcaemia. Five of the eight underwent exploration of the neck and four of them had parathyroid adenomas; the fifth patient had "normal" glands but responded satisfactorily to subtotal parathyroidectomy. One patient who failed to develop hypercalcaemia had primary chief cell hyperplasia of the parathyroids.


Recent Advances in Antibody Drug Conjugates for Lymphoma
Antibody-drug conjugates (ADCs) comprise a unique class of chemoimmunotherapy agents, incorporating cytotoxic payloads covalently linked to a monoclonal antibody via specialized linkers. This strategy attempts to exploit antibody-antigen specificity to selectively deliver a potent 'warhead' payload to tumor cells (Figure), while sparing nontumor antigen-negative cells. Decades of development have culminated in the recent approvals of a handful of ADCs across multiple tumor types. ADCs for the treatment of lymphoma are particularly attractive due in part to the favorable spectrum of cell surface markers uniquely expressed on lymphocytes compared with other tissues. Here we discuss general principles of ADC design, including antigen/antibody, payload, and linker selection. We highlight the clinical successes of the 2 approved ADCs for treatment of lymphomas: brentuximab vedotin (Adcetris) and polatuzumab vedotin (Polivy). Finally, we describe several ADC agents currently under development for lymphoma, including emerging efficacy and toxicity data from early-stage clinical trials.


Market effects on electronic health record adoption by physicians.
Despite the advantages of electronic health record (EHR) systems, the adoption of these systems has been slow among community-based physicians. Current studies have examined organizational and personal barriers to adoption; however, the influence of market characteristics has not been studied. The purpose of this study was to measure the effects of market characteristics on EHR adoption by physicians. Generalized hierarchal linear modeling was used to analyze EHR survey data from Florida which were combined with data from the Area Resource File and the Florida Office of Insurance Regulation. The main outcome variable was self-reported use of EHR by physicians. A total of 2,926 physicians from practice sizes of 20 or less were included in the sample. Twenty-one percent (n = 613) indicated that they personally and routinely use an EHR system in their practice. Physicians located in counties with higher physician concentration were found to be more likely to adopt EHRs. For every one-unit increase in nonfederal physicians per 10,000 in the county, there was a 2.0% increase in likelihood of EHR adoption by physicians (odds ratio = 1.02, confidence interval = 1.00-1.03). Health maintenance organization penetration rate and poverty level were not found to be significantly related to EHR adoption. However, practice size, years in practice, Medicare payer mix, and measures of technology readiness were found to independently influence physician adoption. Market factors play an important role in the diffusion of EHRs in small medical practices. Policy makers interested in furthering the adoption of EHRs must consider strategies that would enhance the confidence of users as well as provide financial support in areas with the highest concentration of small medical practices and Medicare beneficiaries. Health care leaders should be cognizant of the market forces that enable or constrain the adoption of EHR among their practices and those of their competitors.


Morphologic alterations in early acid-induced epithelial injury of the rabbit esophagus.
To arrive at a basic understanding of the pathogenesis of reflux esophagitis, we developed an acute experimental model in the rabbit for studying the early lesion. Acid was perfused in vivo into the lower esophagus while potential difference was monitored intermittently. At varying degrees of potential difference decline, indicating epithelial injury, the esophageal stratified squamous epithelial tissue was removed for morphologic studies and in vitro electrophysiologic and transport studies. At 50 per cent reduction in potential difference, there was dilation of intercellular spaces, which when correlated with physiologic results of increased permeability indicates increased intercellular water. At 100 per cent reduction in potential difference, cells in the midepithelium were observed to be swollen and ruptured, forming vesicular spaces, midepithelial cleavages, and later early ulceration. Results of functional studies at this stage showed inhibition of sodium transport. The midepithelial site of disruption corresponds to the site of active sodium pumping out of cells in other stratified squamous epithelia. Since sodium is transported by esophageal epithelium and this function was inhibited by acid, we propose that this early morphologic lesion may be the result of damage to the sodium-transporting mechanisms of the epithelium.


Bacterial Envelope Damage Inflicted by Bioinspired Nanostructures Grown in a Hydrogel.
Surface-associated bacterial communities, known as biofilms, are responsible for a broad spectrum of infections in humans. Recent studies have indicated that surfaces containing nanoscale protrusions, like those in dragonfly wings, create a hostile niche for bacterial colonization and biofilm growth. This functionality has been mimicked on metals and semiconductors by creating nanopillars and other high aspect ratio nanostructures at the interface of these materials. However, bactericidal topographies have not been reported on clinically relevant hydrogels and highly compliant polymers, mostly because of the complexity of fabricating nanopatterns in hydrogels with precise control of the size that can also resist aqueous immersion. Here, we report the fabrication of bioinspired bactericidal nanostructures in bacterial cellulose (BC) hydrogels using low-energy ion beam irradiation. By challenging the currently accepted view, we show that the nanostructures grown in BC affect preferentially stiff membranes like those of the Gram-positive bacteria Bacillus subtilis in a time-dependent manner and, to a lesser extent, the more deformable and softer membrane of Escherichia coli. Moreover, the nanostructures in BC did not affect the viability of murine preosteoblasts. Using single-cell analysis, we demonstrate that indeed B. subtilis requires less force than E. coli to be penetrated by nanoprobes with dimensions comparable to those of the nanostructured BC, providing the first direct experimental evidence validating a mechanical model of membrane rupture via a tension-induced mechanism within the activation energy theory. Our findings bridge the gap between mechano-bactericidal surfaces and low-dimensional materials, including single-walled carbon nanotubes and graphene nanosheets, in which a higher bactericidal activity toward Gram-positive bacteria has been extensively reported. Our results also demonstrate the ability to confer bactericidal properties to a hydrogel by only altering its topography at the nanoscale and contribute to a better understanding of the bacterial mechanobiology, which is fundamental for the rational design bactericidal topographies.


Impact of single and multiple residual sprayings of pyrethroid insecticides against Triatoma dimidiata (Reduviiade; Triatominae), the principal vector of Chagas disease in Jutiapa, Guatemala.
This study investigated the impact of single, double, and triple insecticide sprayings on indoor infestation of Triatoma dimidiata in Jutiapa, Guatemala. Up to three successive insecticide sprayings were applied in villages, where the indoor infestation index was > 5% before each spraying round or located adjacent to the persistently infested villages. Among 64 villages with single spraying, the mean indoor infestation index reduced from 20.8% to 1.4% after 12 months, but rose to 8.1% after 33 months. In 40 double-sprayed villages, it decreased from 41.9% to 11.9% by the first spraying and to 4.8% by the second spraying. For 12 villages with triple spraying, it reduced from 40.6% to 13.2%, 10.9%, and 4.1% through each spraying round. Geographic analysis showed that originally highly infested villages were spatially clustered and were likely to remain infested after the sprayings. Indoor infestation of T. dimidiata can be controlled with less than three rounds of spraying.


Clinical factors associated with dementia in ischaemic stroke.
71 patients with an ischaemic stroke were studied. The patients were separated into two groups on the basis of the results of clinical investigation, computed tomography and psychological testing (WAIS). 40 patients showed an early dementia and 31 were without mental impairment. The mean age was 57 years in the demented group and 54 years in the non-demented group. The mean duration of the history of cerebrovascular disease was also not statistically different in both groups. The frequency of strokes was identical since 50% of the patients in both groups had more than one stroke. The history of neurological symptoms together with the neurological deficits seen on admission were distributed evenly. The dominant hemisphere was more often diseased in the demented group. Bilateral symptoms were also more common in the demented stroke patients. The WAIS showed a similar IQ in both groups but the deterioration index was significantly altered in the demented group. Hypertension was the only risk factor which differed between both groups. Cardiac disease, diabetes, viscosity and fibrinogen did not differ in both groups. The CT showed more normal scans in the non-demented group, the distribution of atrophy on its own and infarction in the left or right hemisphere were both inconclusive, whilst patients with bilateral infarcts were more common in the dementia group. Also, generalised atrophy in combination with an infarct was found more often in the demented patients.


Physical inactivity, excess adiposity and premature mortality.
The purpose of this report is to review the evidence that physical inactivity and excess adiposity are related to an increased risk of all-cause mortality, and to better identify the independent contributions of each to all-cause mortality rates. A variance-based method of meta-analysis was used to summarize the relationships from available studies. The summary relative risk of all-cause mortality for physical activity from the 55 analyses (31 studies) that included an index of adiposity as a covariate was 0.80 [95% confidence interval (CI) 0.78-0.821, whereas it was 0.82 [95% CI 0.80-0.84] for the 44 analyses (26 studies) that did not include an index of adiposity. Thus, physically active individuals have a lower risk of mortality by comparison to physically inactive peers, independent of level of adiposity. The summary relative risk of all-cause mortality for an elevated body mass index (BMI) from the 25 analyses (13 studies) that included physical activity as a covariate was 1.23 [95% CI 1.18-1.29], and it was 1.24 [95% CI 1.21-1.28] for the 81 analyses (36 studies) that did not include physical activity as a covariate. Studies that used a measure of adiposity other than the BMI show similar relationships with mortality, and stratified analyses indicate that both physical inactivity and adiposity are important determinants of mortality risk.


Divergent Anticancer Activity of Free and Formulated Camel Milk α-Lactalbumin.
Alpha-lactalbumin (α-LA), a small milk calcium-binding globular protein, is known to possess noticeable anticancer activity, which is determined by the ability of this protein to form complexes with oleic acid (OA). To date, in addition to human and bovine α-LA, the ability to form such anti-tumor complexes with OA was described for goat and camel α-LA. Although the mechanisms of the anticancer activity of human and bovine α-LA are already well-studied, little is currently known about the anticancer action of this camel protein. The goal of this study was to fill this gap and to analyze the anticancer and pro-apoptotic activities of camel α-LA in its free form (α-cLA) and as an OA-containing complex (OA-α-cLA) using four human cancer cell lines, including Caco-2 colon cancer cells, PC-3 prostate cancer cells, HepG-2 hepatoma cells, and MCF-7 breast cancer cells as targets. The anti-tumor activities of OA-α-cLA and α-cLA were analyzed using MTT test, annexin/PI staining, cell cycle analysis, nuclear staining, and tyrosine kinase (TK) inhibition methods. We show here that the OA-α-cLA complex does not affect normal cells but has noticeable anti-cancer activity, especially against MCF-7 cells, thus boosting the anticancer activity of α-cLA and improving the selectivity of OA. The OA-α-cLA complex mediated cancer cell death via selective induction of apoptosis and cell-cycle arrest at lower IC50 than that of free α-cLA by more than two folds. However, OA induced apoptosis at higher extent than OA-α-cLA and α-cLA. OA also caused unselective apoptosis-dependent cell death in both normal and cancer cells to a similar degree. The apoptosis and cell-cycle arresting effect of OA-α-cLA may be attributed to the TK inhibition activity of OA. Therefore, OA-α-cLA serves as efficient anticancer complex with two functional components, α-cLA and OA, possessing different activities. This study declared the effectiveness of OA-α-cLA complex as a promising entity with anticancer activity, and these formulated OA-camel protein complexes constitute an auspicious approach for cancer remedy, particularly for breast cancer.


Expression of therapeutic targets in Ewing sarcoma family tumors.
Ewing sarcoma family tumor is an aggressive malignant tumor of bone and soft tissue in children and adolescents. Despite advances in modern therapy, metastasis occurs in 20% to 25% of cases and results in mortality in 80% of patients. Intracellular molecules mammalian target of rapamycin, Akt, vascular endothelial growth factor, nuclear factor κB, and BRAF are important kinases and transcription factors that regulate the proliferation of tumor cells. We studied the expression of these proteins in 72 Ewing sarcoma family tumors. Patients' survival data were available in 55 cases. Formalin-fixed, paraffin-embedded tumor sections were stained with antibodies against phosphorylated mammalian target of rapamycin, Akt, BRAF, vascular endothelial growth factor, and nuclear factor κB proteins. Stained sections were analyzed for percentage and strength of staining, and a composite score (0-200) was subsequently generated. Although most tumors expressed mammalian target of rapamycin, Akt, nuclear factor κB, and vascular endothelial growth factor, only 37%, 86%, 55%, and 12%, respectively, showed high expression (staining score ≥ 100). There was no significant correlation between mammalian target of rapamycin and Akt expression and clinical outcome. High nuclear factor κB expression was significantly associated with tumors in pelvic locations. Decreased vascular endothelial growth factor expression (score <100) was significantly associated with better prognosis (P < .05). BRAF was not expressed in most cases and showed negative or weak staining (score <100) in 97% of cases. Thus, except for BRAF, Ewing sarcoma family tumors may be amenable to treatment that targets the expressed proteins. High Akt expression suggests potential universal response to Akt-targeted therapy. BRAF kinase inhibitors are unlikely to be effective in the treatment of Ewing sarcoma family tumors.


Correlates of preschool children's physical activity.
Physical activity is important for children's health, and identifying factors associated with their physical activity is important for future interventions and public health programs. This study sought to identify multidimensional correlates of preschool children's physical activity. The social-ecological model (SEM) was used to identify constructs potentially associated with preschool children's physical activity. Data were collected from 1004 preschool children, aged 3-5 years, and parents in 2008-2009, and analyzed in 2010-2011. Physical activity was measured over 8 days using ActiGraph accelerometers. Parents completed a comprehensive survey. Generalized linear modeling was used to assess associations between potential correlates and percentage of time spent in physical activity. Correlates of physical activity were found across all the domains of the SEM and varied between boys and girls and week and weekend days. Age was the only consistent correlate, with children spending approximately 10% less time in physical activity for each advancing year of age. Some modifiable correlates that were related to more than one physical activity outcome were rules restricting rough games inside and usual daily sleep time for boys. For girls, a preference to play inside/draw/do crafts rather than be active, and child constraints, was associated with more than one of the physical activity outcomes. A novel finding in this study is the counterintuitive association between parental rules restricting rough games inside and boys' higher physical activity participation levels. Potential strategies for promoting children's physical activity should seek to influence children's preference for physical activity and parent rules. Gender-specific strategies also may be warranted.


The efficacy of interventions to reduce adolescent childbearing in low- and middle-income countries: a systematic review.
This study reviews the scope and quality of existing literature regarding the interventions to reduce adolescent childbearing in low- and middle-income countries and compiles findings concerning their effectiveness. A total of 737 studies published between 2000 and 2011 were reviewed; 19 were identified as meeting eligibility criteria. Studies were included that: evaluated program effects on adolescents and young people, either as the primary target population or as a subset of a broader target group; evaluated an intervention intended to reduce adolescent fertility or generate improvements on a related outcome; and reported childbearing-related outcomes. Evidence indicates that a variety of interventions may be successful at reducing fertility, including school-based programs, health counseling, and cash transfers. An overview of evaluation efforts to date is provided, and potential best practices are highlighted. Conclusions are that funding for adolescent fertility initiatives should be directed toward programs for which a sound evidence base exists, such as cash transfers or other interventions that encourage school enrollment, and that programs of unknown effectiveness should be conducted in tandem with rigorous evaluation.


A three-dimensional non-invasive study of head flexion and extension in young non-patient subjects.
Head flexion and extension movements near the natural head position (NHP) were analysed for the location of the mean instantaneous centre of rotation (ICR). Forty-six healthy young adults (30 women and 16 men) with sound dentitions, free from cranio-cervical disorders, performed habitual movements that were automatically detected and measured by an infrared three-dimensional motion analyser. ICR and curvature radius were calculated for each movement and subject. In both extension and flexion, ICR position changed during the motion. The movement was symmetrical in all subjects. No gender or flexion/extension differences were found for both ICR position and relevant curvature radius. On average, ICR relative to NHP soft-tissue nasion was located at about 150% of the soft-tissue nasion-right tragus distance, with an angle of about 220 degrees relative to the true horizontal. Results suggest that head flexion or extension is always performed with a combination of rotation (atlanto-occipital joint) and translation (cervical spine) even in the first degrees of motion. Moreover, NHP at rest seems to be some degree more flexed and anterior than head position during movements. These relative positions and their muscular determinants could also influence mandibular posture at rest and during functional movements.


[Variability of cardiac rhythm in patients with a symptomatic renal hypertension and effect of ramipril on its changes].
Variability of cardiac rhythm and influence of Ramipril on it have been studied in 31 patients with a secondary renal hypertension of 1 and 2 stages. Obtained data have shown, that treatment with Ramipril normalizes neurohumoral regulation at the expense of decrease of excessive sympathetic stimulation and decrease of peripheral parasympathetic insufficiency rate. All above mentioned changes were accompanied by reduction in frequency and grade of blood pressure increase and improvement in tolerance to physical activity.


Fluorophilic ionophores for potentiometric pH determinations with fluorous membranes of exceptional selectivity.
Ionophore-doped sensor membranes exhibit greater selectivities and wider measuring ranges when they are prepared with noncoordinating matrixes. Since fluorous phases are the least polar and least polarizable liquid phases known, a fluorous phase was used for this work as the membrane matrix for a series of ionophore-based sensors to explore the ultimate limit of selectivity. Fluorous pH electrode membranes, each comprised of perfluoroperhydrophenanthrene, sodium tetrakis[3,5-bis(perfluorohexyl)phenyl]borate, and one of four fluorophilic H(+)-selective ionophores were prepared. All the ionophores are highly fluorinated trialkylamines containing three electron withdrawing perfluoroalkyl groups shielded from the central nitrogen by alkyl spacers of varying lengths: [CF(3)(CF(2))(7)(CH(2))(3)](2)[CF(3)(CF(2))(6)CH(2)]N, [CF(3)(CF(2))(7)(CH(2))(3)](2)(CF(3)CH(2))N, [CF(3)(CF(2))(7)(CH(2))(3)](3)N, and [CF(3)(CF(2))(7)(CH(2))(5)](3)N. Their pKa values in the fluorous matrix are as high as 15.4 +/- 0.3, and the corresponding electrodes exhibit logarithmic selectivity coefficients for H(+) over K(+) as low as <-12.8. The pKa and selectivity follow the trends expected from the degree of shielding and the length of the perfluoroalkyl chains of the ionophores. These electrodes are the first fluorous ionophore-based sensors described in the literature. The selectivities of the sensor containing [CF(3)(CF(2))(7)(CH(2))(5)](3)N are not only greater than those of analogous sensors with nonfluorous membranes but were of the same magnitude as the best ionophore-based pH sensors ever reported.


A Review of Healthy Dietary Choices for Cardiovascular Disease: From Individual Nutrients and Foods to Dietary Patterns.
Cardiovascular disease (CVD) remains the first cause of mortality globally. Diet plays a fundamental role in cardiovascular health and is closely linked to the development of CVD. Numerous human studies have provided evidence on the relationship between diet and CVD. By discussing the available findings on the dietary components that potentially influence CVD progression and prevention, this review attempted to provide the current state of evidence on healthy dietary choices for CVD. We focus on the effects of individual macronutrients, whole food products, and dietary patterns on the risks of CVD, and the data from population-based trials, observational studies, and meta-analyses are summarized. Unhealthy dietary habits, such as high intake of saturated fatty acids, sugar-sweetened beverages, red meat, and processed meat as well as high salt intake are associated with the increased risk of CVD. Conversely, increased consumption of plant-based components such as dietary fiber, nuts, fruits, and vegetables is shown to be effective in reducing CVD risk factors. The Mediterranean diet appears to be one of the most evidence-based dietary patterns beneficial for CVD prevention. However, there is still great debate regarding whether the supplementation of vitamins and minerals confers cardioprotective benefits. This review provides new insights into the role of dietary factors that are harmful or protective in CVD, which can be adopted for improved cardiovascular health.


An analysis of dimensionality using factor analysis (true-score theory) and Rasch measurement: what is the difference? Which method is better?
One often hears the question asked, "For questionnaire data measuring a variable, what difference does it make to use factor analysis/principal components analysis (true-score theory) or Rasch measurement in testing for dimensionality?" This paper reports both factor analysis and Rasch measurement analysis for two sets of data. One set of data measures social anxiety for primary school students (N=436, I=10) and the second measures attitude to mathematics for primary-aged students (N=774, I=10). For both sets of data, the factor analysis suggests that the scores are reliable, and that inferences can be made that are valid for measuring school anxiety and attitude to mathematics. For both sets of data analyzed with Rasch measurement techniques, the reliability of the measures, the dimensionality of the measures, and the initial conceptualisation of the items, are called into question. It suggests that one cannot make valid inferences from the measures that were initially set up for true-score theory. The Rasch analysis suggests that items intended to measure a variable should be initially developed on a conceptualized scale from easy to hard, and that students should answer the items from this perspective, so that the Rasch analysis of the data tests this conceptualisation, and a linear scale can be created based on a mathematical measurement model with consistent units (logits).


[The concept of reinforcement in research on simple nervous systems].
Analysis of applicability of the reinforcement concept to the learning studies in invertebrate systems is performed basing on literature and own data. It is suggested that reinforcement can be regarded not as an independent phenomenon, but as a state of the nervous system which precedes a long-term changes of behavior. Such consideration of reinforcement allows to use this concept in studies of plasticity and learning in simple nervous systems, investigate neurochemical mechanisms of reinforcement.


Random amplified polymorphic DNA analysis of salt-tolerant tobacco mutants generated by gamma radiation.
Salinity is one of the major problems limiting the yield of agricultural products. Radiation mutagenesis is used to improve salt-tolerant mutant plants. In this study, we aimed to improve salt-tolerant mutants of two oriental tobacco varieties. One thousand seeds of each variety (M₀) were irradiated with 100, 200, 300, and 400 Gy gamma rays by Cs-137 gamma. In the M₁ generation, 2999 single plants were harvested. The next season, these seeds were bulked and planted to obtain M₂ progeny. The seeds of 1900 M₂ plants were picked separately. Salinity tolerance was tested in the M₃ generation. Among M₃ plantlets, 10 salt-tolerant tobacco mutants were selected. According to the results of the selection studies, 100- and 200-Gy gamma radiation doses were the effective doses to obtain the desired mutants. Glutathione reductase enzyme activities of salt-tolerant tobacco mutants were determined biochemically as a stress-tolerance marker. The differences between control and salt-tolerant mutants belonging to the Akhisar 97 and İzmir Özbaş tobacco varieties were evaluated by random amplified polymorphic DNA analysis. The total polymorphism rate was 73.91%.