An investigation into the reliability and methodology of the Linburg-Comstock anomaly clinical test.
This is a cross-sectional study. An intertendinous connection between the flexor pollicis longus (FPL) and index flexor digitorum profundus (IFDP) tendons causes involuntary index flexion during active thumb flexion and has been named the Linburg-Comstock anomaly (LCA). It may become symptomatic or cause functional limitations. Literature has documented the prevalence to range from 13% to 70%. Cadaver studies have reported an anatomical connection in 5% to 25%. This study aimed to examine the methodology and reliability of the LCA clinical diagnostic test and to explore the wide range of reported incidence and the discrepancy between cadaver and subject prevalence. Two examiners observed for the presence of involuntary index flexion during 3 separate variations of thumb flexion in 67 subjects (134 limbs); results were considered positive if involuntary flexion occurred at either index interphalangeal joint. Intertester reliability was assessed using Cohen's kappa coefficient. The volar forearm and wrist of 53 cadavers (106 limbs) were dissected and assessed for an observable and mechanical tendinous connection between the FPL and IFDP tendons. Prevalence for subjects (5%-32%) was at the lower end of the range of previously reported values; results differed with altering thumb flexion motion. Observation for the presence of an intertendinous connection between the FPL and IFDP tendons in cadaver specimens (23%) fell within previously reported ranges. Intertester reliability coefficients ranged from no to weak agreement and varied according to specific thumb flexion motion performed during the test. The identification of index finger flexion during thumb flexion varied both with thumb flexion motions and with whether flexion was assessed at the index proximal interphalangeal or distal interphalangeal joint. Intertester reliability was low for all variations of the LCA clinical test performed. The wide range in previously reported LCA incidence may be due to variability in testing procedure, and there is a need to establish a reliable and valid clinical test for this potentially symptomatic anatomic anomaly.


Catalpol improves cholinergic function and reduces inflammatory cytokines in the senescent mice induced by D-galactose.
The neuroprotective effects of catalpol, an iridoid glycoside isolated from the fresh rehmannia roots, on the cholinergic system and inflammatory cytokines in the senescent mice brain induced by D-galactose were assessed. The results showed that acetylcholinesterase (AChE) activity increased in senescent mice brain and choline acetyltransferase (ChAT) positive neurons, detected by immunohistochemical staining, decreased remarkably in the basal forebrain of senescent mice. Simultaneously, muscarinic acetylcholine receptor M1 (mAChR1) expression declined in senescent mice brain by western blotting method. We also found that the contents of tumor necrosis factor (TNF-α), interleukin-1β (IL-1β) and advanced glycation endproducts (AGEs) increased in senescent mice brain by ELISA method. However, administration of catalpol for 2-weeks significantly reversed the biochemical markers mentioned above. These results suggest that catalpol can exert protective effects on senescent mice brain induced by D-galactose and this effect may be due to its protective effects on cholinergic and immune impairment in mice brain. Thus catalpol is worth testing for further preclinical study aimed for senescence or neurodegenerative diseases such as Alzheimer's disease.


Engineering non-natural inhibitor sensitivity in protein tyrosine phosphatase H1.
Protein tyrosine phosphatase H1, a member of the ubiquitous protein tyrosine phosphatase (PTP) superfamily of enzymes, is an important signaling molecule, mutant forms of which have been found in human colorectal cancers. Selective PTPH1 inhibitors would be valuable tools for investigating PTPH1's roles in cellular regulation. However, no PTPH1-specific inhibitors are known. To identify target-selective inhibitors of human PTPH1, we have redesigned a PTPH1/inhibitor interface. Structure-based protein design was used to identify two amino-acid residues, isoleucine 846 and methionine 883, that control PTPH1's sensitivity to oxalylaminoindole PTP inhibitors. Mutation of residues 846 and 883 to alanine and glycine, respectively, conferred novel inhibitor sensitivity onto PTPH1. From a small panel of putative inhibitors, compounds that potently and selectively target the inhibitor-sensitized PTPH1 mutants were identified.


Understanding non-stationarity of hydroclimatic extremes and resilience in Peninsular catchments, India.
Climate change significantly impacts the global hydrological cycle, leading to pronounced shifts in hydroclimatic extremes such as increased duration, occurrence, and intensity. Despite these significant changes, our understanding of hydroclimatic risks and hydrological resilience remains limited, particularly at the catchment scale in peninsular India. This study aims to address this gap by examining hydroclimatic extremes and resilience in 54 peninsular catchments from 1988 to 2011. We initially assess extreme precipitation and discharge indices and estimate design return levels using non-stationary Generalized Extreme Value (GEV) models that use global climate modes (ENSO, IOD, and AMO) as covariates. Further, hydrological resilience is evaluated using a convex model that inputs simulated discharge from the best hydrological model among SVM, RVM, random forest, and a conceptual model (abcd). Our analysis shows that the spatial patterns of mean extreme precipitation indices (R1 and R5) mostly resemble with extreme discharge indices (Q1 and Q5). Additionally, all extreme indices, including R1, Q1, R5, and Q5, demonstrate non-stationary behavior, indicating the substantial influence of global climate modes on extreme precipitation and flooding across the catchments. Our results indicate that the random forest model outperforms the others. Furthermore, we find that 68.52% of the catchments exhibit low to moderate hydrological resilience. Our findings emphasize the importance of understanding hydroclimatic risks and catchment resilience for accurate climate change impact predictions and effective adaptation strategies.


Molecular detection of Setaria tundra (Nematoda: Filarioidea) and an unidentified filarial species in mosquitoes in Germany.
Knowledge of the potential vector role of Culicidae mosquitoes in Germany is very scanty, and until recently it was generally assumed that they are not involved in the transmission of anthroponotic or zoonotic pathogens in this country. However, anticipated changes in the course of global warming and globalization may alter their status. We conducted a molecular mass screening of mosquitoes for filarial parasites using mitochondrial 12S rRNA-based real-time PCR. No parasites causing disease in humans such as Dirofilaria spp. were detected in about 83,000 mosquitoes tested, which had been collected in 2009 and 2010 in 16 locations throughout Germany. However, minimum infection rates of up to 24 per 1000 mosquitoes were revealed, which could be attributed to mosquito infection with Setaria tundra and a yet unidentified second parasite. Setaria tundra was found to be widespread in southern Germany in various mosquito species, except Culex spp. In contrast, the unidentified filarial species was exclusively found in Culex spp. in northern Baden-Württemberg, and is likely to be a bird parasite. Although dirofilariasis appears to be emerging and spreading in Europe, the absence of Dirofilaria spp. or other zoonotic filariae in our sample allows the conclusion that the risk of autochthonous infection in Germany is still very low. Potential vectors of S. tundra in Germany are Ochlerotatus sticticus, Oc. cantans, Aedes vexans and Anopheles claviger. Technically, the synergism between entomologists, virologists and parasitologists, combined with state-of-the-art methods allows a very efficient near-real-time monitoring of a wide spectrum of both human and veterinary pathogens, including new distribution records of parasite species and the incrimination of their potential vectors.


Automatic analysis of the trunk thermal images from healthy subjects and patients with faulty posture.
This paper presents an automatic method for assessing temperature distribution on the patient׳s back using thermal imaging. It discusses the advantages and disadvantages of thermal imaging and presents an algorithm for image analysis and processing that runs automatically and reproducibly. The proposed new method of image analysis relates to automatic and reproducible analysis of temperature distribution on the patient׳s back. It includes the following steps: (1) detection of the external contours of the human body, (2) identification and recognition of the position of the arms, hips and shoulders, (3) application of a mesh having a fixed number of fields (which automatically adapts to the size of the patient׳s back), (4) analysis of the paraspinal muscles. These steps are preceded by image pre-processing. Based on a thermal image, this new fully automated algorithm enables to: (1) evaluate temperature distribution in the paraspinal area; (2) pre-assess the degree of lateral spinal curvature in screening, and (3) evaluate anomalies (deviations from the norm) in temperature distribution. The algorithm was practically implemented in Matlab Image Processing Toolbox.


Lineage infidelity following exposure of T lymphoblasts (MOLT-3 cells) to 5-azacytidine.
The appearance on single leukemic blast cells of markers of at least two different lineages has been termed lineage infidelity. MOLT-3 cells, a continuous line of human T lymphoblasts, express T cell markers as defined immunologically with monoclonal antibodies. Following a single exposure to 5-azacytidine, other markers, usually associated with non-T cell lineages, appeared transiently. A stable clone with lineage infidelity was obtained by selection from colonies expressing novel markers. Marker expression followed reproducible kinetics during growth. 5-Azacytidine-treated MOLT-3 subclones may be useful models in the study of lineage infidelity and gene expression.


Randomized placebo-controlled trial comparing fluticasone aqueous nasal spray in mono-therapy, fluticasone plus cetirizine, fluticasone plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis.
Corticosteroids are considered to be particularly effective in reducing nasal congestion and are therefore recommended as first-line treatment in allergic rhinitis patients with moderate to severe and/or persistent symptoms. We compared the clinical efficacy of fluticasone propionate aqueous nasal spray (FPANS) 200 microg given once daily, administered in mono-therapy or combined therapy with a H1 receptor antagonist (cetirizine, CTZ) or with a leukotriene antagonist (montelukast, MSK), and the combined therapy of CTZ plus MSK in the treatment of patients affected by allergic rhinitis to Parietaria during natural pollen exposure. In addition, we examined the effect of the treatment on eosinophil counts and eosinophil cationic protein (ECP) in nasal lavage performed at beginning of season, during season and at the end of the season. One hundred patients aged 12-50 years (mean+/-SD 31.8+/-9.6) with a history of moderate to severe Parietaria pollen-induced seasonal allergic rhinitis were selected. A randomized, double-blind, double dummy, placebo (PLA)-controlled, parallel-group study design was used. Patients were treated FPANS 200 microg once daily (n=20) or with FPANS 200 microg once daily, plus CTZ (10 mg) in the morning (n=20), or with FPANS 200 microg once daily, plus MSK (10 mg) in the evening (n=20) or with CTZ (10 mg) in the morning plus MSK in the evening (n=20) or matched PLA (n=20). Assessment of efficacy was based on scores of daily nasal symptoms and on eosinophil counts and ECP in nasal lavage. All treatments showed significant differences (P<0.001) compared with PLA in terms of total symptom, rhinorrhea, sneezing and nasal itching scores. Concerning nasal congestion on waking and daily only the groups treated with FPANS in mono-therapy or in combined therapy showed significant differences compared with PLA. Comparing the group treated with FPANS alone and the groups treated with FPANS plus CTZ, we found significant differences for total symptom score (P=0.04) and for nasal itching (P=0.003). The comparison between FPANS plus CTZ and FPANS plus MSK showed significant difference for nasal itching (P=0.003). Finally, there were significant differences between the group treated with FPANS and the group treated with CTZ plus MSK for total symptom score (P=0.009), for nasal congestion on waking (P<0.001) and nasal congestion daily (P<0.001). Also the comparisons between the group treated with FPANS plus CTZ and the group treated with CTZ plus MSK demonstrated significant differences (P<0.001) for total symptom, for nasal congestion on waking and for nasal congestion on daily, for rhinorrhea (P=0.04) and for nasal itching (P=0.003) scores. Concerning the comparison between the group treated with FPANS plus MSK and the group treated with CTZ plus MSK we found significant differences for total symptom score (P=0.005), for nasal congestion on waking (P<0.001) and for nasal congestion on daily (P<0.001). No other differences were observed between the groups. Concerning blood eosinophil counts, significant differences were found between the treatments with FPANS in mono-therapy or in combined therapy with PLA group during and at the end of the season (P=0.0003 and P<0.0001, respectively). Concerning eosinophils and ECP in nasal lavage, all treatments showed significant differences (P<0.001) compared with PLA. Besides, there were significant differences (P<0.001) between the groups treated with FPANS alone or in combined therapy and the group treated with CTZ plus MSK. The results of this comparative study demonstrate that FPANS is highly effective for treating patients affected by allergic rhinitis, with efficacy exceeding that of CTZ plus MSK in combined therapy. In addition, the regular combined therapy of FPANS plus CTZ or plus MSK would not seem to offer substantial advantage with respect to FPANS in mono-therapy in patients affected by seasonal allergic rhinitis.


Hypomyelination in the neonatal rat central and peripheral nervous systems following tellurium intoxication.
Neonatal rats were exposed to Tellurium (Te), via the mother's milk, from the day of birth until sacrifice at 7, 14, 21, and 28 days of age. Light and electron microscopy revealed Schwann cell and myelin degeneration in the sciatic nerves at each age studied. These changes were similar to those described in weanling rats as a result of Te intoxication. In the CNS, hypomyelination of the optic nerves was convincingly demonstrated at 14, 21, and 28 days of age, accompanied by some evidence of myelin degeneration. These changes were also seen in the ventral columns of the cervical spinal cords, although less markedly, and were confirmed by quantitative methods. There was little evidence of oligodendrocyte pathology in the CNS, and it appears that degeneration of these cells is not the primary cause of the CNS hypomyelination, in contrast to the PNS where Schwann cell degeneration has been shown to precede the myelin pathology.


Identification of SNP-containing regulatory motifs in the myelodysplastic syndromes model using SNP arrays and gene expression arrays.
Myelodysplastic syndromes have increased in frequency and incidence in the American population, but patient prognosis has not significantly improved over the last decade. Such improvements could be realized if biomarkers for accurate diagnosis and prognostic stratification were successfully identified. In this study, we propose a method that associates two state-of-the-art array technologies--single nucleotide polymor-phism(SNP) array and gene expression array--with gene motifs considered transcription factor-binding sites (TFBS). We are particularly interested in SNP-containing motifs introduced by genetic variation and mutation as TFBS. The potential regulation of SNP-containing motifs affects only when certain mutations occur. These motifs can be identified from a group of co-expressed genes with copy number variation. Then, we used a sliding window to identify motif candidates near SNPs on gene sequences. The candidates were filtered by coarse thresholding and fine statistical testing. Using the regression-based LARS-EN algorithm and a level-wise sequence combination procedure, we identified 28 SNP-containing motifs as candidate TFBS. We confirmed 21 of the 28 motifs with ChIP-chip fragments in the TRANSFAC database. Another six motifs were validated by TRANSFAC via searching binding fragments on co-regulated genes. The identified motifs and their location genes can be considered potential biomarkers for myelodysplastic syndromes. Thus, our proposed method, a novel strategy for associating two data categories, is capable of integrating information from different sources to identify reliable candidate regulatory SNP-containing motifs introduced by genetic variation and mutation.


Fluorescence microscopical study of 5-hydroxytryptamine storage organelles in mepacrine-incubated blood platelets of beige mice (Chediak-Higashi syndrome).
The number and fluorescence intensity of fluorescent granules (5-HT storage organelles) of mepacrine-incubated blood platelets of beige mice (Chediak-Higashi syndrome) are decreased compared to those of control mice platelets. This indicates both quantitative and qualitative changes of the 5-HT organelles, namely a reduced number and a reduced storage capacity, respectively.


Teaching teamwork to adolescents with autism: the cooperative use of activity schedules.
We used a multiple baseline design to assess the effects of prompting and reinforcement to teach three pairs of adolescents with autism to use photographic activity schedules to cooperatively complete a multistep vocational task (e.g., cleaning a kitchen). Baseline data indicated that despite being competent schedule followers, participants did not coordinate their actions to complete the schedule cooperatively. Following intervention, we observed an increase in cooperative schedule following. All prompts were removed and the schedule of reinforcement was thinned to the end of the task for two of the three pairs. We discuss the results in terms of increasing the collaborative work skills of individuals with autism.


Single posterior debridement, interbody fusion, and fixation on patients with continuous multivertebral lumbar spine tuberculosis (CMLSTB).
Patients with continuous multi-vertebral lumbar spine tuberculosis (CMLSTB) were subjected to single posterior debridement, interbody fusion, and fixation to explore their clinical outcomes. Sixty-seven CMLSTB patients who underwent single posterior debridement interbody fusion and fixation between January 2008 to December 2017 were studied. The operation time, blood loss, perioperative complication rate, cure rate, Visual Analog Scale (VAS), Oswetry disability index (ODI), Japanese Orthopedic Association (JOA), Erythrocyte Sedimentation Rate (ESR), C-reactive protein (CRP), kyphotic Cobb's angle and time of interbody fusion were analyzed to understand their therapeutic effects on CMLSTB patients. The patients were followed up for 20-48 months, with a mean of 24.3 months. The mean operation time was 215.5 min (range, 120-280 min), whereas 818.0 ml of blood was lost (range, 400-1500 ml) with a perioperative complication rate of 6.0% and a cure rate of 95.5%. During the last phase of follow-up, the mean preoperative VAS score (5.7) and ODI (72.0%) decreased significantly to 1.4 (t = 31.4, P<0.01) and 8.4% (t = 48.4, P<0.01), respectively. Alternatively, the mean preoperative ESR and CRP (74.7 mm /h and 69.3 mg/L, respectively) decreased to average values (tESR = 39.7, PESR<0.001; tCRP = 50.2, PCRP<0.001), while the JOA score (13.9) significantly increased to 23.0 (t = - 11.6, P<0.01). The preoperative kyphotic Cobb's angle (20.5°) decreased to 4.8° after the operation (t = 14.0, P<0.01); however, the kyphotic correction remained intact at the time of follow-up (t = - 0.476, P = 0.635). Furthermore, the mean of interbody fusion time was identified to be 8.8 months (range, 6-16 months). Single posterior debridement, interbody fusion, and fixation may be one of the surgical choices for the treatment of CMLSTB patients.


Memantine for the patients with mild cognitive impairment in Parkinson's disease: a pharmacological fMRI study.
Mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with an increased risk of cognitive decline. PD-MCI is characterized by impairments in executive function and visuospatial recognition. The visuospatial n-back test is useful for assessing both domains. The 0-back test reflects visuospatial recognition, while the 1-back and 2-back tests reflect working memory. Cholinesterase inhibitors are effective in the treatment of PD-MCI and dementia in PD (PDD). Although some studies have reported the efficacy of memantine for PDD, the therapeutic efficacy of memantine in patients with PD-MCI remains uncertain. This study aimed to investigate the effects of memantine on brain function in patients with PD-MCI, using a randomized double-blinded crossover protocol and functional MRI (fMRI). Ten patients who completed 16 weeks of follow-up were included. They were randomly assigned to either the memantine or placebo. Patients in the memantine group received 5 mg/day of memantine in the first week. The memantine dose was increased by 5 mg/day per week, until a final dose of 20 mg/day. Patients in the placebo group received the placebo following the same regimen as memantine. After the intervention, they underwent a 4 weeks washout period. Following the crossover protocol, a second intervention was conducted after the washout period. In each intervention, fMRI and neuropsychological tests were performed at the maximum dose period. Comparing the memantine and placebo groups, we investigated difference in the brain regions using the visuospatial n-back test. There were no significant regions enhanced by memantine comparing with placebo at any load of n-back tests. In contrast, exploring regions reduced by memantine, we found significant reduction of activations within right lingual gyrus and left superior frontal gyrus in comparison between 2-back and 0-back test. A number of correct answers of the 2-back test and time to complete Trail Making Test-A were worse during memantine intervention. Memantine did not improve visuospatial working memory of the patients with PD-MCI. Treatment for PD should be planned carefully considering the impact on cognitive function. Further study is needed to establish new therapeutic strategy. UMIN000046104. Retrospectively registered. First registration date: 28 Sept 2017.


Remote temporal wavepacket narrowing.
Quantum communication protocols can be significantly enhanced by careful preparation of the wavepackets of the utilized photons. Following the theoretical proposal published recently by our group, we experimentally demonstrate the effect of remote temporal wavepacket narrowing of a heralded single photon produced via spontaneous parametric down-conversion. This is done by utilizing a time-resolved measurement on the heralding photon which is frequency-entangled with the heralded photon. We then investigate optimal photon pair source characteristics to minimize heralded wavepacket width.


Relation of early menarche to high bone mineral density.
The study of background factors in individuals with high bone mineral density (BMD) may provide useful information in the prevention of osteoporosis. We investigated the relationship of reproductive factors to BMD. In 519 female volunteers (327 postmenopausal and 192 premenopausal women) ranging in age from 21 to 74 (mean 52.3 +/- 11.8) years, spinal BMD values were obtained using both quantitative computed tomography and dual x-ray absorptiometry. The z score was calculated from the mean BMD in each 5-year age group, and high BMD and low BMD was defined as BMD with z score > + 1.5 and < -1.5, respectively. Normal BMD was defined as BMD within the range - 1.0 < z score < +1.0. Long reproductive period, early menarche, and late menopause were associated with high BMD. Among these, the reproductive period showed the strongest association with BMD. In postmenopausal women, early menopause had a significant relationship with low BMD, and early menarche also had some relation to high BMD. In premenopausal women, there was a significant relationship between early menarche and high BMD. The age at menarche may have a strong association with peak bone mass, as suggested by the positive correlation of early menarche with high BMD observed in this study. It is considered important to prevent risk factors that disturb the beginning of menstruation in adolescent girls.


Modification of malachite green by Fomes sclerodermeus and reduction of toxicity to Phanerochaete chrysosporium.
Malachite green (MG) is a triphenylmethane dye used as a fungicide but also possesses a high toxicity to mammalian cells. The toxicity of MG to Fomes sclerodermeus and Phanerochaete chrysosporium was assessed. P. chrysosporium was highly sensitive to the dye and it was unable to grow on solid media containing 64 microM of MG, lower concentrations caused a delay in growth. The radial growth of F. sclerodermeus was not affected at this concentration and up to 128 microM. In liquid media both fungi were more sensitive. F. sclerodermeus not only was able to grow in the presence of high concentrations of MG, but also it was able to decolorize and detoxify the dye. MG treated with supernatants containing high laccase activity in the presence or absence of 1-hydroxybenzotriazole (1-HBT) gave a colorless product (DMG) that was not toxic to P. chrysosporium and other white rot fungi tested. On the basis of the data of maximal absorbance, it is probable that the mechanism involved in the modification of the dye was different if 1-HBT was added to the reaction.


The transport and processing of carbamyl phosphate synthetase-I in mouse hepatic mitochondria.
Carbamyl phosphate synthetase-I (CPS-I)2, purified from mouse hepatic mitochondria consists of electrophoretically homogeneous polypeptide species of 160 kilodaltons molecular weight (Kd). Monospecific antibody to CPS-I immunoprecipitated a putative precursor of 165Kd protein from in vitro translation products programmed with mouse liver free polysomes or poly(A) RNA. Isolated mitochondrial particles can take up and process pCPS-I into mature CPS-I of 160Kd in an in vitro transport system. The in vitro transport of CPS-I is energy dependent and requires intact mitochondria. The processing of pCPS-I appears to involve a single endoproteolytic cleavage.


[Supplementary arthrolysis of the proximal interphalangeal joint of fingers in surgical treatment of Dupuytren's contracture].
Correction of residual flexion deformity of the proximal interphalangeal (PIP) joint after excision of diseased connective tissue in Dupuytren's contracture by stepwise arthrolysis. Flexion deformity of the PIP joint of 20° or more after excision of the diseased connective tissue in Dupuytren's contracture. Joint deformities, osteoarthrosis, intrinsic muscle contracture, instability of the PIP joint. Arthrolysis of the PIP joint is performed by six consecutive steps: dissection of the remaining skin ligaments, opening the flexor tendon sheath by transverse incision at the distal end of the A2 pulley, dissection of the checkrein ligaments, dissection of the accessory collateral ligaments, releasing the palmar plate proximally, releasing the palmar plate up to its insertion at the middle phalanx base. Dorsal plaster of Paris with extended fingers and compressive dressing in the palm for 2 days, occupational/physical therapy, static and possible dynamic extension splint several weeks/months. A total of 31 fingers in 28 patients with Dupuytren's contracture were evaluated an average of 22 months after arthrolysis of the PIP joint. In all, 26 joints with an average recurrent flexion contracture of 29° were improved compared to the preoperative flexion contracture of 81°; 4 PIP joints with a recurrent flexion contracture averaging 60° were worse. In one patient, PIP flexion contracture of 90° was unchanged at follow-up although the joint could be extended intraoperatively to 10° of flexion.


River habitat quality from river velocities measured using acoustic Doppler current profiler.
Prior research has demonstrated the utility of metrics based on spatial velocity gradients to characterize and describe stream habitat, with higher gradients generally indicative of higher levels of physical heterogeneity and thus habitat quality. However, detailed velocity data needed to compute these metrics are difficult to obtain. Acoustic Doppler current profilers (ADCP) may be used to rapidly collect detailed representations of river velocity fields. Herein we demonstrate use of ADCP to obtain ecologically relevant data and compute associated metrics. Data were collected from four reaches of the Little Tallahatchie River in northern Mississippi. Sampled reaches were selected to observe velocity regimes associated with three distinctly different conditions: downstream from a major flow obstruction (a low weir), downstream from the apices of each of two bends, and within an extremely long, straight reach created by channelization. Three-dimensional velocity data sets from each site were used to compute metrics of habitat quality proposed by others. A habitat metric based on the presence of rotational flow in the vertical plane proved to be the best discriminator among conditions within the sampled reaches. Two of four habitat quality metrics computed from these measured velocities were greatest for the sharpest meander bend. ADCP hold great potential for study of riverine physical aquatic habitats, particularly at the reach scale. Additional work is needed to develop generally applicable field protocols and data reduction tools. Specifically, guidelines for ADCP settings and configuration appropriate for a range of riverine site conditions must be developed. Advances in instrumentation are needed to allow collection of information in closer proximity to the free surface and solid boundaries.


Gadolinium-Based Contrast Agents: Associated Adverse Reactions.
Gadolinium-based contrast agents have been considered extremely safe drugs with a low incidence of acute adverse reactions. Most of the reactions are mild and physiologic. However, despite being extremely rare, acute severe adverse reactions, including anaphylaxis, may occur. In this article adverse reactions are discussed with regard to their classification, pathophysiology, symptoms, and risk factors.


Yaws, Haemophilus ducreyi, and Other Bacterial Causes of Cutaneous Ulcer Disease in the South Pacific Islands.
Cutaneous ulcers in the tropics are a painful and debilitating condition that anchors people into poverty. In rural regions of the South Pacific, infectious cutaneous ulcers are caused mainly by bacteria, including Treponema pallidum pertenue (yaws), Haemophilus ducreyi, and polymicrobial ulcers. For this group of infections the term cutaneous ulcer disease (CUD) is proposed. Some infections can cause malformations on the bone that have a permanent impact on lives in endemic communities. Better characterization of CUD may help design diagnostic tools and more effective antimicrobial therapies. This review updates the knowledge of CUD and discusses optimized terminology and syndromic management.


Potential errors when using a computerized pantograph.
This study determined the effect on articulator settings of using an arbitrary hinge axis as compared with the terminal hinge axis in orienting a computerized pantograph on a patient. The effect of an error in measuring the reference plane angle or clutch angle was also determined. Two subjects were pantographed 30 times by using the terminal hinge axis and 30 times by using the arbitrary hinge axis. Statistically the articulator settings obtained by using the arbitrary hinge axis and the terminal hinge axis were different, but the difference was small. One subject was pantographed on 18 occasions by using different reference plane angle and clutch angle settings. Analysis showed that 1-degree change in the reference plane angle setting produced approximately 0.9-degree change in the protrusive and orbiting path articulator settings. A 1-degree change in the clutch angle setting produced approximately 0.9-degree change in the progressive side shift settings. It was concluded that the terminal hinge axis should be used as the posterior reference point and the reference plane angle and clutch angle should be carefully recorded.


Measurement of a glycoprotein with blood group A activity by light scattering.
A light scattering method for quantifying glycoproteins is presented. Conditions of ethanol concentration, wavelength, time of reading, and sample and reagent volumes have been examined. The definitive assay involves addition of 9 vol absolute ethanol to 1 vol sample, mixing, and readings at 105 degrees angle at the interval between 10 and 13 min after placing the cell into the photometer. The obtained values are temperature-dependent. Thus, temperature control is essential. In this assay, a concentration range of 10-60 micrograms glycoprotein has been used. As described, the method is independent of the chemical composition of the different glycoproteins and is barely influenced by size and shape of glycoproteins.


Burkitt lymphoma presenting as a mass in the thyroid gland: a clinicopathologic study of 7 cases and review of the literature.
Burkitt lymphoma presenting in the thyroid gland is rare, and only a few cases have been reported. We retrospectively reviewed 7 patients diagnosed with Burkitt lymphoma of the thyroid gland between 2000 and 2015. There were 4 men and 3 women with a median age of 41 years (range, 19-49 years). All patients presented with a rapidly growing neck mass associated with upper airway compression in 5 (71%) patients. Two patients presented with localized (stage I/II) and 5 patients with disseminated (stage III/IV) disease. All cases showed morphologic and immunophenotypic features of Burkitt lymphoma with MYC rearrangement in all 5 cases tested. One case showed evidence of concurrent Hashimoto thyroiditis. Six of 7 patients were treated primarily with rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone. One patient was treated primarily with dose-adjusted rituximab, etoposide, prednisolone, vincristine, and cyclophosphamide. At the end of the study period, 5 patients were alive: 4 in complete remission and 1 with persistent disease. Two patients died with persistent disease (median follow-up, 25 months; range, 12-361 months). We conclude that Burkitt lymphoma of the thyroid gland shows clinicopathologic features similar to sporadic Burkitt lymphoma at other anatomic sites, but patients present at an older median age. The clinical course is aggressive with a high frequency of disseminated disease at diagnosis; however, a subset of patients responds well to aggressive chemotherapy.


Detection of phosphorus oxyanions in synthetic geothermal water using ion chromatography-mass spectrometry techniques.
Recent developments in microbiology suggest that reduced inorganic phosphorus oxyanions, including hypophosphite and phosphite, may be present in nature. These studies have inspired the development of specific and sensitive methods that detect phosphorus oxyanions in natural water. This paper will discuss a new technique that couples suppressed conductivity ion chromatography (Dionex AS17 analytical column and potassium hydroxide eluent) with electrospray mass spectrometry (IC/MS) with limits of detection nearly 200 times lower than those reported using suppressed conductivity detection. The technique was optimized for the detection of hypophosphite, phosphite, and phosphate in a synthetic geothermal water matrix. Samples were pre-treated with silver and sulfonic acid cartridges, and injection loop sizes as large as 800microl were employed to enhance instrument sensitivity. All peaks were clearly resolved, and calibrations were linear with estimated 3sigma limits of detection of 0.011, 0.0020, and 0.029microM for hypophosphite, phosphite, and phosphate, respectively.


Clonal evolution in leukemia.
Human leukemias are liquid malignancies characterized by diffuse infiltration of the bone marrow by transformed hematopoietic progenitors. The accessibility of tumor cells obtained from peripheral blood or through bone marrow aspirates, together with recent advances in cancer genomics and single-cell molecular analysis, have facilitated the study of clonal populations and their genetic and epigenetic evolution over time with unprecedented detail. The results of these analyses challenge the classic view of leukemia as a clonal homogeneous diffuse tumor and introduce a more complex and dynamic scenario. In this review, we present current concepts on the role of clonal evolution in lymphoid and myeloid leukemia as a driver of tumor initiation, disease progression and relapse. We also discuss the implications of these concepts in our understanding of the evolutionary mechanisms involved in leukemia transformation and therapy resistance.


Biomarkers Enhance Discrimination and Prognosis of Type 2 Myocardial Infarction.
The observed incidence of type 2 myocardial infarction (T2MI) is expected to increase with the implementation of increasingly sensitive cTn assays. However, it remains to be determined how to diagnose, risk-stratify, and treat patients with T2MI. We aimed to discriminate and risk-stratify T2MI using biomarkers. Patients presenting to the emergency department with chest pain, enrolled in the CHOPIN study (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction), were retrospectively analyzed. Two cardiologists adjudicated type 1 MI (T1MI) and T2MI. The prognostic ability of several biomarkers alone or in combination to discriminate T2MI from T1MI was investigated using receiver operating characteristic curve analysis. The biomarkers analyzed were cTnI, copeptin, MR-proANP (midregional proatrial natriuretic peptide), CT-proET1 (C-terminal proendothelin-1), MR-proADM (midregional proadrenomedullin), and procalcitonin. The prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular event (a composite of acute myocardial infarction, unstable angina pectoris, reinfarction, heart failure, and stroke) at 180-day follow-up was also investigated. Among the 2071 patients, T1MI and T2MI were adjudicated in 94 and 176 patients, respectively. Patients with T1MI had higher levels of baseline cTnI, whereas those with T2MI had higher baseline levels of MR-proANP, CT-proET1, MR-proADM, and procalcitonin. The area under the receiver operating characteristic curve for the diagnosis of T2MI was higher for CT-proET1, MR-proADM, and MR-proANP (0.765, 0.750, and 0.733, respectively) than for cTnI (0.631). Combining all biomarkers resulted in a similar accuracy to a model using clinical variables and cTnI (0.854 versus 0.884, P=0.294). Addition of biomarkers to the clinical model yielded the highest area under the receiver operating characteristic curve (0.917). Other biomarkers, but not cTnI, were associated with mortality and major adverse cardiovascular event at 180 days among all patients, with no interaction between the diagnosis of T1MI or T2MI. Assessment of biomarkers reflecting pathophysiologic processes occurring with T2MI might help differentiate it from T1MI. All biomarkers measured, except cTnI, were significant predictors of prognosis, regardless of the type of myocardial infarction.


Combined modality therapy for pancreatic cancer.
In spite of the high mortality in pancreatic cancer, significant progress is being made. This review discusses multimodality therapy for patients with pancreatic cancer. According to several phase II trials and Gastrointestinal Tumor Study Group results, improvements in locoregional control and survival may be achieved when chemotherapy is added to radiation for locally advanced pancreatic cancer. Radiosensitizing chemotherapy agents such as 5-fluorouracil, gemcitabine, paclitaxel, and cisplatin have shown promise. Selected patients with locally advanced disease have been downstaged with chemoradiation, facilitating surgical resection. For patients with resectable disease, the completion of Radiation Therapy Oncology Group study 97-04 represents a major achievement and brings gemcitabine into the forefront of adjuvant therapy. Neoadjuvant chemoradiation may eliminate the delay of initiating adjuvant treatment and spare unnecessary surgery for patients with rapid systemic progression. Molecular agents are being combined with chemoradiation in an attempt to delay or prevent systemic progression.


The influence of halogen substituents on the biological properties of sulfur-containing flavonoids.
A series of halogen-substituted tricyclic flavonoids containing a 1,3-dithiol-2-ylium moiety has been synthesized from the corresponding 3-dithiocarbamic flavanones. The influence of halogen substituents on the antibacterial properties of the tricyclic flavonoids has been investigated against Staphylococcus aureus and Escherichia coli. On going from fluorine to iodine, these compounds exhibit good to excellent inhibitory properties against both Gram-positive and Gram-negative pathogens. These results suggest that size is the main factor for the change in potency rather than polarity/electronics.


BUBR1 Pseudokinase Domain Promotes Kinetochore PP2A-B56 Recruitment, Spindle Checkpoint Silencing, and Chromosome Alignment.
The balance of phospho-signaling at the outer kinetochore is critical for forming accurate attachments between kinetochores and the mitotic spindle and timely exit from mitosis. A major player in determining this balance is the PP2A-B56 phosphatase, which is recruited to the kinase attachment regulatory domain (KARD) of budding uninhibited by benzimidazole 1-related 1 (BUBR1) in a phospho-dependent manner. This unleashes a rapid, switch-like phosphatase relay that reverses mitotic phosphorylation at the kinetochore, extinguishing the checkpoint and promoting anaphase. Here, we demonstrate that the C-terminal pseudokinase domain of human BUBR1 is required to promote KARD phosphorylation. Mutation or removal of the pseudokinase domain results in decreased PP2A-B56 recruitment to the outer kinetochore attenuated checkpoint silencing and errors in chromosome alignment as a result of imbalance in Aurora B activity. Our data, therefore, elucidate a function for the BUBR1 pseudokinase domain in ensuring accurate and timely exit from mitosis.


Short Report. An innovative training programme for families of children and adolescents with Autism Spectrum Disorder in Qatar: Parents as interventionists.
Previous research has established the association of maladaptive behaviours exhibited by individuals with Autism Spectrum Disorder (ASD) with an increase in the extent of care burden among their caregivers. The mental health needs of caregivers and their effective management, therefore, need to be given due consideration. The main aim of this paper is to reiterate the significance of the role of training programmes for caregivers in enhancing their knowledge and enabling them to manage behavioural challenges with more independence and confidence. The aims, structure, and content of the ASD training programme for caregivers implemented by the specialist child and adolescent mental health service, Hamad Medical Corporation, are described. Sixty families have benefited from this initiative so far. A summary of the feedback provided by forty caregivers, all biological parents, is also summarised. The mean score related to knowledge among participants before and after attending the training increased from 3.28 to 4.41. Out of the 40 parents who provided feedback, 27 (67.5%) reported an increase in their understanding of the topic after attendance. This initiative consolidates the significance of programmes focusing on enhancing awareness and improving coping among caregivers of children and young people with ASD.


Hedgehog signals inhibit postnatal beta cell neogenesis from adult rat exocrine pancreas in vitro.
Transdifferentiation of pancreatic exocrine cells into insulin-producing beta cells may represent an important alternative to islets required for diabetes cell therapy. Rat pancreatic acinar cells are known to transdifferentiate into functional beta cells, with recapitulation of several pancreas developmental features. Considering the inhibitory functions of hedgehog signalling in early and mid-stage pancreatic development, we questioned whether it also operates in transdifferentiating acinar cells and whether its modulation would influence postnatal beta cell neogenesis in vitro. Rat exocrine cells were precultured in suspension for 4 days and then incubated with EGF and leukaemia inhibitory factor (LIF) for 72 h. The hedgehog signalling pathway was modulated during this, and its effects analysed by RT-PCR, immunocytochemistry and western blot. Our data indicate induction of Dhh and Ihh, but not Shh, expression during acinar cell culture, resulting in activation of hedgehog targets (Ptc1, Gli1). Exposure of the metaplastic cells to EGF and LIF induced beta cell differentiation without affecting endogenous hedgehog activity. Whereas blocking endogenous hedgehog only slightly increased beta cell neogenesis, exposure to embryoid body-conditioned medium activated hedgehog signalling as well as other pathways such as Notch, resulting in severe blockade of beta cell neogenesis. Interestingly, this effect was partially rescued by treatment with the hedgehog inhibitor, 3-keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl)-cyclopamine (KAAD-cyclopamine), alone. We report here Dhh/Ihh-dependent activation of hedgehog targets during pancreatic exocrine cell metaplasia in vitro and a persistent inhibitory function of hedgehog signalling in a model of postnatal beta cell differentiation.


Ambras syndrome: delineation of a unique hypertrichosis universalis congenita and association with a balanced pericentric inversion (8) (p11.2; q22)
Congenital hypertrichosis universalis is a rare autosomal dominant disease. We report the further development of a Greek girl, now aged 3 years, the first case associated with a balanced structural chromosomal aberration. She was described as a neonate by Sigalas et al. (1990). Her persistent generalized hypertrichosis is most excessive on the face, ears and shoulders. Her fine silky hair is of the vellus, not the lanugo type. The syndrome features are characterized, referring to nine further published case reports. It is distinguished from other types of congenital hypertrichoses, which have been described in the literature under different synonyms. To avoid confusion in the terminology, we propose to name this type of hypertrichosis Ambras syndrome in reference to the first documented family with congenital hypertrichosis universalis in the 16th century.


Distance art groups for women with breast cancer: guidelines and recommendations.
To overcome barriers that prevent women with breast cancer from attending support groups, innovative formats and modes of delivery both need to be considered. The present study was part of an interdisciplinary program of research in which researchers from counseling psychology, psycho-oncology, nursing, computer science, and fine arts have explored art making as an innovative format and telehealth as a mode of delivery. For this study, we conducted focus groups and interviews with 25 people with expertise about breast cancer, art, art therapy, and distance delivery of mental health services to generate guidelines for distance art-based psychosocial support services to women with breast cancer. A qualitative analysis of the focus group and interview data yielded guidelines for developers and facilitators of distance art groups for women with breast cancer pertaining to (a) emotional expression, (b) emotional support, (c) emotional safety, and (d) accommodating individual differences, plus special considerations for art therapy groups. Further research is needed pertaining to the use of computers, involvement of art therapists, and screening out vulnerable clients.


[Proposals for the community orientation of primary health care: to identify key agents for training].
To identify the strengths available for the community orientation of primary health care (PHC) in the context of the evaluation of the piloting of a training program in Community Health for Resident Internal Specialists in Andalusia (Spain). We will conduct a qualitative, phenomenologically-oriented, explanatory research in which the opinion of the participants is analyzed. Sixty-seven professionals from six PHC Districts of Andalusia which were part of the training program called Project to Support the Revitalization of Primary Care Assets for Community Health (PARAC) were interviewed. There is consensus in giving training a key weight in the community orientation of PHC. For this reason, those agents linked to training are identified as assets: general practice (GP) trainers, young professionals in training who bring updated perspectives and approaches to accredited PHC training centers, whose professionals must respond to the needs of their GP trainees, the multi-professional teaching units responsible for the GP trainees training and a medium and long-term health system thinking along with structures that coordinate and support the community work at the PHC centers. The community orientation of PHC is an objective that requires the participation of all levels of the health system. Knowing its assets and working with them can contribute to provide proposals to advance towards a community-oriented PHC system.


Investigation into mechanism of lack of reflex tachycardia in response to hypotensive action of indoramin in dogs.
In animals and man, the selective alpha 1-adrenoceptor antagonist indoramin reduces arterial pressure without increasing heart rate. We studied this mechanism of absence of reflex tachycardia in anaesthetised dogs. Indoramin reduced (p less than 0.05) arterial pressure with no reflex increase in heart rate, whereas phenoxybenzamine reduced (p less than 0.05) pressure but increased (p less than 0.05) heart rate. Atropine and propranolol pretreatment, vagotomy and division of the cardio-accelerator nerve did not prevent the reduction (p less than 0.05) in arterial pressure and heart rate seen with indoramin. Mexiletine, a drug which has membrane-stabilising activity, had no effect on heart rate or arterial pressure. Mexiletine and indoramin did not affect the increases in heart rate produced by stimulation of the cardio-accelerator nerve. Indoramin reduced (p less than 0.05) the increases in heart rate and arterial pressure produced by bilateral carotid occlusion, and potentiated the arterial pressure reduction but attenuated the heart rate response to intravenous isoprenaline. It also reduced (nonsignificantly) the responses to intravenous noradrenaline and phenylethylamine but had no effect on the arterial pressure and heart rate responses to bilateral central vagal stimulation. We conclude that the absence of the reflex tachycardia with hypotensive doses of indoramin does not result from the myocardial membrane-stabilising action of indoramin or from alteration in sympathetic and parasympathetic activity, but may occur partly from a reduction in baroreceptor sensitivity.


Proliferating cell nuclear antigen in breast carcinomas. An immunohistochemical study with correlation to histopathological features and prognostic factors.
Proliferating cell nuclear antigen (PCNA), was examined by immunohistochemistry in 509 breast carcinomas. The immunoreactivity was found to be independent of the length of fixation when the tissue sections were microwaved before incubation with the primary antibody. The PCNA immunoreactivity was assessed by two semi-quantitative methods, which were correlated but not exchangeable. The comedo type of intraductal carcinomas and invasive ductal carcinomas had a higher PCNA score than other types. Lymph node metastases had a significantly higher PCNA score than primary carcinomas. High PCNA immunoreactivity was correlated with the presence of lymph node metastases, absence of tubule formation, numerous mitoses, severe nuclear pleomorphism, high histological grade and absence of progesterone receptors (PgR). PCNA in lymph node positive tumours was correlated with tumour type, especially with ductal carcinomas, absence of tubule formation, high histological grade and absence of PgR, whereas PCNA in lymph node negative tumours was correlated with large tumour size, numerous mitoses, severe nuclear pleomorphism and high histological grade. Number of mitoses and nuclear pleomorphism were the two most important factors in predicting the PCNA score; the absence of PgR and nuclear pleomorphism were important in lymph node negative and positive tumours, respectively. In a univariate analysis high PCNA score was found to be correlated with shorter relapse-free period and poorer over-all survival.


The effect of competition on heart rate during kart driving: A field study.
Both the act of competing, which can create a kind of mental stress, and participation in motor sports, which induces physical stress from intense g-forces, are known to increase heart rate dramatically. However, little is known about the specific effect of competition on heart rate during motor sports, particularly during four-wheel car driving. The goal of this preliminary study, therefore, was to investigate whether competition increases heart rate under such situations. The participants drove an entry-level formula kart during two competitive races and during solo driving against the clock while heart rate and g-forces were measured. Analyses showed that heart rate values during the races (168.8 beats/min) were significantly higher than those during solo driving (140.9 beats/min) and rest (75.1 beats/min). The results of this preliminary study indicate that competition heightens heart rate during four-wheel car driving. Kart drivers should be concerned about maintaining good health and developing physical strength.


HOXA-AS2 may predict the prognosis of solid tumors among Chinese patients: A meta-analysis and bioinformatic analysis.
HOXA cluster antisense RNA 2 (lncRNA HOXA-AS2) is a long noncoding RNA (lncRNA) that aberrantly expressed in various cancers and is closely associated with cancer progression. To overcome the limitation of small sample sizes that are inherent to single studies, a meta-analysis was conducted to explore the relationship between the expression level of HOXA-AS2 and cancer prognosis. Correlational studies were retrieved by searching the databases of PubMed, Embase and Web of Science (up to August 10, 2022). The survival and prognosis data included overall survival (OS), and clinical parameters were gathered and analyzed. Eighteen publications with 1181 patients who were diagnosed with solid tumors were ultimately included. The results showed that, compared with patients with low HOXA-AS2 expression, patients with high HOXA-AS2 expression tended to have poorer overall survival (OS) (HR= 2.52, 95% CI 1.87-3.38, P < 0.01) and shorter disease-free survival (DFS) (HR=7.19, 95% CI 3.20-16.17, P < 0.01). In addition, elevated HOXA-AS2 expression indicated a larger tumor size (OR =2.43, 95% CI 1.53-3.88,P < 0.01), more advanced TNM stage (OR=3.85, 95% CI 2.79-5.31, P < 0.01), earlier lymph node metastasis (LNM) (OR = 4.41, 95% CI 3.05-6.39, P < 0.01) and distant metastasis (DM) (OR= 2.96, 95% CI 1.87-4.7, P < 0.01). Furthermore, HOXA-AS2 expression was notassociated with age (OR=1.15, 95% CI 0.90-1.47), gender (OR=1.16, 95% CI 0.89-1.53), or tumor differentiation (OR=1.21, 95% CI 0.56-2.63). Moreover, aberrant HOXA-AS2 expression was related to drug sensitivity in various types of cancers. The overexpression of HOXA-AS2 predicted poor cancer prognosis in the Chinese population, including poor OS, DFS, TNM, LNM, and DM. HOXA-AS2 could serve as a promising prognostic biomarker and therapeutic target. https://www.crd.york.ac.uk/prospero/, identifier CRD42022352604.


Mechanism of enhanced cyclic AMP stimulation by isoproterenol in aged human fibroblasts.
Human diploid lung fibroblasts (IMR-90) were used to investigate the reported increase in beta-adrenergic-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) levels in fibroblasts aged in culture. Under basal conditions cellular cAMP was 34.2 +/- 5.6 and 38.4 +/- 9.1 pmol/mg protein in early (PDL 22-24) and late (PDL 47-52) passage fibroblasts, respectively. Net release of cAMP from fibroblasts was 67.8 +/- 8.6 and 18.5 +/- 7.0 pmol/30 min/mg protein in early and late passage cultures, respectively. In confluent, early passage fibroblasts, cellular cAMP and net release of cAMP increased by 2.7-fold and 3.8-fold, respectively, after a 30 min incubation in 2 microM isoproterenol. In confluent late passage fibroblasts, isoproterenol incubation increased cellular cAMP and net release of cAMP by 7.8-fold and 26.1-fold, respectively. Adenosine failed to inhibit isoproterenol-induced stimulation of cAMP in early or late passage fibroblasts. There was no passage-related difference in basal, isoproterenol, or forskolin-stimulated adenylyl cyclase activity in crude fibroblast membrane preparations. The activity of cAMP-phosphodiesterase in sonicates of early and late passage IMR-90 was 9.61 +/- 1.15 and 5.81 +/- 1.11 pmol/min/mg protein respectively. Measurements of cAMP in subconfluent early passage fibroblasts indicated that mechanisms related to the reduced cell density in confluent late passage IMR-90 may, in part, account for the enhanced isoproterenol-induced cAMP levels observed in these cultures. The results suggest that the remainder of the enhanced cAMP response to isoproterenol of in vitro aged fibroblasts may be due to a lower cAMP phosphodiesterase activity in these cells.


Decentration associated with asymmetric capsular shrinkage and intraocular lens design in a rabbit model.
We evaluated intraocular lens (IOL) decentration resulting from asymmetric capsular shrinkage. In 19 eyes of 10 white rabbits, a D-shaped incision was made in the anterior capsule and one of three IOL types implanted in the capsular bag: three-piece with polypropylene haptics, one-piece all-poly-(methyl methacrylate) (PMMA), or compressible disk. Eight weeks later, eyes were enucleated for assessment of IOL decentration. Mean decentration was 0.75 mm for three-piece IOLs, 0.46 mm for one-piece IOLs, and 0.30 mm for compressible-disk lenses. Decentration was significantly less in eyes with compressible-disk lenses than in those with three-piece IOLs. Although decentration was less with the compressible-disk lens, the lens is not commonly used because of the large incision and special insertion technique required. If an open-loop IOL is to be used in eyes at risk for asymmetric capsular shrinkage, our results indicate that an all-PMMA one-piece IOL would be preferable to a three-piece lens with a polypropylene haptic.


Management of People With a Fontan Circulation: a Cardiac Society of Australia and New Zealand Position statement.
The Fontan circulation describes the circulatory state resulting from an operation in congenital heart disease where systemic venous return is directed to the lungs without an intervening active pumping chamber. As survival increases, so too does recognition of the potential health challenges. This document aims to allow clinicians, people with a Fontan circulation, and their families to benefit from consensus agreement about management of the person with a Fontan circulation. The document was crafted with input from a multidisciplinary group of health care providers as well as individuals with a Fontan circulation and families. It is hoped that the shared common vision of long-term wellbeing will continue to drive improvements in care and quality of life in this patient population and eventually translate into improved survival. KEYPOINTS.


Effect of Metformin on Hormonal and Biochemical Profile in PCOS Before and After Therapy.
Insulin resistance and the resultant hyperinsulinemia exacerbate the reproductive abnormalities of Polycystic Ovarian Syndrome by increasing ovarian androgen productions and decreasing serum sex hormone binding globulin. The present study was conducted to estimate serum insulin and testosterone level in 44 PCOS cases and 32 control patients. Simultaneously the role of metformin (an insulin sensitizing agent) in modulating insulin resistance and serum androgen level was also analyzed. A significant rise in serum insulin and testosterone (P < 0.001) was observed in cases in comparison to control. Fasting Plasma Glucose to insulin ratio, a marker of insulin resistance revealed a significant fall in PCOS group. Follow up of cases with metformin for 3 months revealed a significant fall in serum insulin (P < 0.05) with improvement in insulin resistance along with a nonsignificant fall in testosterone level. Serum insulin registered a significant positive correlation (P < 0.05) with serum testosterone revealing its etiological association. Thus administration of drugs ameliorating insulin levels is expected to provide new therapeutic modality for PCOS.


LC-MS/MS determination and comparative pharmacokinetics of strychnine, brucine and their metabolites in rat plasma after intragastric administration of each monomer and the total alkaloids from Semen Strychni.
A rapid, specific and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the simultaneous determination of strychnine, brucine, strychnine N-oxide and brucine N-oxide in rat plasma. Plasma samples were pretreated via simple protein precipitation with methanol and ephedrine hydrochloride was used as internal standard. Chromatographic separation was carried out on an ZORBAX Eclipse XDB-C18 column (2.1×150mm, 3.5μm) by gradient elution with methanol and 10mM ammonium acetate (adjusted to pH 4.0 with formic acid). The quantification of the analytes was performed by mass spectrometry with TurboIonSpray ionization (ESI) inlet in the positive ion multiple reaction monitoring (MRM) mode. The results showed that the calibration curve was linear in the concentration range of 0.510∼306.3ngmL(-1) for strychnine, brucine and 0.102∼306.0ngmL(-1) for strychnine N-oxide and brucine N-oxide, respectively. The intra- and inter-day precisions were less than 14.9%, and the accuracy ranged from 89.4 to 113% at three QC levels for the 4 analytes. The validated method was successfully applied to the pharmacokinetic study of strychnine, brucine, strychnine N-oxide and brucine N-oxide in rat plasma after oral administration of each monomer and the total alkaloids from Semen Strychni. After single oral administration of the total alkaloids from Semen Strychni at 4 dose levels, Cmax, AUC0-t of strychnine and brucine increased and were proportional to the oral doses. In comparative pharmacokinetics studies, no significant difference was found between each monomer and the total strychnos alkaloids on the pharmacokinetic parameters such as Cmax and AUC. Mean Cmax and AUC of strychnine and brucine were slight increased in the monomer groups in comparison to the total strychnos alkaloids groups, which suggested that some other alkaloids in the Semen Strychni may decrease the absorption of strychnine and brucine in body.


Polypeptide clearing in model membranes: an analysis of the partition of gramicidin a' between cadmium ion induced gel and liquid-crystalline phases in vesicles of phosphatidic acid and phosphatidylcholine.
Using a simple model for a biological membrane we examine cation-induced gel phase formation and the depletion of polypeptide from the gel phase. The model system consists of vesicles of phosphatidic acid and phosphatidylcholine which contain gramicidin A'. By use of electron spin resonance to monitor lipid phase behavior, Cd2+ is found to induce gel and liquid-crystal phase coexistence over a wide range of lipid composition. Quenching of gramicidin A' tryptophanyl fluorescence by spin-labeled phosphatidic acid or spin-labeled phosphatidylcholine is analyzed to obtain the partition coefficient, Kp, for gramicidin A' between gel and liquid-crystal phases. The value of Kp = 3 favoring the liquid-crystal phase indicates a partial clearing of the membrane-bound polypeptide from Cd2+-induced gel phase regions of the membrane.


Type 2 diabetes mellitus and chronic hepatitis C: which is worse? Results of a long-term retrospective cohort study.
The long-term outcome in patients with chronic hepatitis C and type 2 diabetes mellitus treated with interferon and ribavirin is unclear. We compared incidence of liver-related events and mortality rates between hepatitis C virus-positive patients with or without diabetes mellitus, and the incidence of diabetes-related events between diabetic patients with and without hepatitis C. Retrospective study of 309 patients with chronic hepatitis C. Incidence of liver-related events, diabetes-related events and mortality rates were assessed over a mean follow-up of 11.02±4.9 years. 50 (16%) chronic hepatitis C patients had diabetes mellitus. Diabetics showed a higher number of diabetes- and liver-related events than non-diabetics (10% vs 1.5%, p=0.006; 18% vs 5.7%, p=0.007, respectively) with a mortality of 14% vs 1.5% (p=0.0003). Baseline cirrhosis (p=0.002) and non-sustained virological response (p=0.01) were independent risk factors for liver events; diabetes mellitus (p=0.01) and hypertension (p=0.0017) were independent factors for diabetes-related events. In patients with chronic hepatitis C, comorbidity with diabetes mellitus was associated with a higher mortality rate and incidence of liver/diabetes-related events. Independent risk factors for liver-related events were the non-response to antiviral therapy and cirrhosis at baseline.


Buprenorphine Induction in Persons With Opioid Use Disorder Hospitalized with Acute Hepatitis A.
It is not known whether buprenorphine/naloxone (bup/nx) can be safely initiated in hospitalized patients with acute hepatitis A infection. We assessed liver function and tolerability of bup/nx induction in patients with acute Hepatitis A Virus (HAV). Retrospective review of patients (N = 31) admitted to a tertiary care facility for acute HAV who were evaluated by an addiction medicine consultant. No significant difference was seen in aspartate aminotransferase, alanine aminotransferase, total bilirubin, or INR trends in patients receiving bup/nx during hospitalization versus those not receiving bup/nx. Nausea was the most common reported symptom in patients receiving bup/nx. With careful monitoring and induction dose adjustment, bup/nx can be administered to patients with acute HAV without hepatic encephalopathy. Similarly, patients on bup/nx before hospitalization should not have this medication held in the setting of acute HAV. This strategy may engage patients with acute HAV in treatment of OUD earlier and minimize disruptions in treatment.


Diagnosis of thoracic outlet syndrome by magnetic stimulation of the brachial plexus.
The abductor pollicis brevis (APB) and abductor digiti minimi (ADM) compound muscle action potential (CMAP) latencies, and median and ulnar motor conduction velocities (MCVs), obtained by magnetic stimulation of the brachial plexus, were evaluated for the diagnosis of thoracic outlet syndrome (TOS). These measurements were compared in three groups of limbs: (1) the symptomatic limbs of patients with TOS (symptomatic group), (2) the asymptomatic con-tralateral limbs of these patients (asymptomatic group), and (3) the limbs of healthy control subjects (control group). Although no significant differences were observed in MCVs among the three groups, the APB CMAP latency in the sym-ptomatic group (12.0 +/- 1.2 ms) was significantly prolonged compared with that in the control group (10.4 +/- 0.64 ms; P < 0.01), and the ADM CMAP latency in the symptomatic group (11.0 +/- 0.82 ms) was also significantly prolonged compared with that in the control group (10.1 +/- 0.59 ms; P < 0.01). The possibility is suggested that the evaluation of APB and ADM CMAP latencies by magnetic stimulation of the brachial plexus may be helpful for the diagnosis of TOS.


Maxillary Sinus Angiofibroma: A Rare Entity.
Juvenile Nasopharyngeal Angiofibroma (JNA) is an unusual benign, although destructive fibrovascular tumor of the nasopharynx which rarely present itself at other sites. Maxilla is the most frequent extranasopharyngeal site of origin. We report a case of Extranasopharyngeal Angiofibroma (ENA) arising from maxillary sinus in an adult patient which was excised into successfully.


Optimized Synthesis of Salicylate-based Poly(anhydride-esters).
The synthesis of a salicylate-based poly(anhydride-ester) was optimized to improve the overall efficiency and quality of the polymer. First, a new approach for the preparation of the polymer precursor minimizes the overall number of synthetic steps and increases the overall yield. Second, the melt-polymerization apparatus was modified to include dynamic mixing, which yields polymer with increased molecular weights on both the milligram and gram scale.


Optimising Outcomes and Surveillance Strategies of Rectal Neuroendocrine Neoplasms.
Rectal neuroendocrine neoplasms are increasing in incidence, in part due to increased endoscopic procedures being performed for bowel cancer screening. Whilst most of these lesions are low-grade well-differentiated neuroendocrine tumours, they can have a varied clinical behaviour. Frequently, these lesions are incorrectly characterised at endoscopy and, therefore, incompletely excised using standard polypectomy techniques. Furthermore, some cases are not fully staged prior to or post resection. In this article we discuss the endoscopic and surgical options available to improve the likelihood of achieving an R0 resection and the staging procedures that should be used in these NETs. We also review factors that may suggest a higher risk of nodal involvement or recurrence. This information may help determine whether endoscopic or surgical resection techniques should be considered. In cases of R1 resection we discuss the management options available and the long-term surveillance options and when these should be offered to patients.


Taurine depletion in very low birth weight infants receiving prolonged total parenteral nutrition: role of renal immaturity.
In a prospective, controlled study, plasma and urinary taurine concentrations were determined weekly, between postnatal weeks 3 and 18, in (1) seven sick infants (gestational age less than 28 weeks, birth weight less than or equal to 1000 gm) who received a taurine-free total parenteral nutrition solution for 32 to 49 days (group P) and who subsequently were formula fed and (2) eight sick infants matched by gestational age and birth weight, who received formula or human milk from day 3 to 4 of life (group E). Ten healthy full-term infants ranging in age from 1 to 18 weeks and fed with formula provided normal values (group C). Significantly lower mean plasma taurine values (range 1.59 to 3.43 mumol/dl) were found between postnatal weeks 3 and 7 in group P compared with group E (range 5.54 to 6.97 mumol/dl) and with group C (5.6 +/- 0.34 mumol/dl). After initiation of feeding, plasma taurine concentrations in group P increased to normal. Markedly elevated values of mean fractional excretion of taurine, 38% to 56%, were found between weeks 3 and 5 in group P and E compared with group C (15.5 +/- 3.2%). In contrast, during the same period, low urinary taurine values (4.9% to 6.7%) were found in two larger, older infants receiving total parenteral nutrition whose plasma taurine values were in the normal range. After week 5, urinary taurine values were in the control range in all groups. We conclude that the absence of taurine in total parenteral nutrition solutions administered to very low birth weight infants and the limited ability of the immature kidney to adapt to low taurine intake by "up-regulation" of tubular taurine reabsorption may result in depleted taurine body pools during the first weeks of life. This inability to conserve taurine by the immature nephron could potentially have a deleterious effect on the developing brain and retina in these infants, and indicates a possible need for taurine supplementation.


Local cerebral blood flow mapping before and after removal of acute subdural hematoma in the rat.
The cause of hemispheric swelling and high intracranial pressure after acute subdural hematoma is unknown, yet this is a major cause of death related to this condition. To investigate whether vascular engorgement is the cause of this form of hemisphere swelling, we have autoradiographically mapped regional cerebral blood flow before and after removal of acute subdural hematoma in a rat model. Hyperemia was patchy and infrequent. The major cause of the significant hemisphere swelling seen after hematoma removal was enlargement of the zone of focal tissue ischemia and edema under the hematoma.


Three force fields' views of the 3(10) helix.
Slowly but steadily bibliographic evidence is accumulating that the apparent convergence of the various biomolecular force fields as evidenced from simulations of proteins in the folded state does not hold true for folding simulations. Here we add one more example to the growing list of peptides and proteins for which different force fields show irreconcilable differences in their folding predictions, even at such a fundamental level as that of a peptide's secondary structure. We show that for an undecamer peptide that is known from two independent NMR structure determinations to have a mainly 3(10)-helical structure in solution, three mainstream biomolecular force fields give completely disparate predictions: The CHARMM force field (with the CMAP correction) predicts an outstandingly stable α-helical structure, in disagreement not only with the experimental structures, but also with experimental evidence obtained from circular dichroism. OPLS-AA shows an almost totally disordered peptide with the most frequently observed folded conformation corresponding to a β-hairpin-like structure, again in disagreement with all available experimental evidence. Only the AMBER99SB force field appears to qualitatively agree with not only the general structural characteristics of the peptide (on the account of both NMR- and CD-based experiments), but to also correctly predict some of the experimentally observed interactions at the level of side chains. Possible interpretations of these findings are discussed.


Paradoxical sleep and coping with environmental change.
Long-term sleep recordings of mice from 3 inbred strains showed that the amount of time spent in sleep over successive 24-h periods varied as the subjects adapted to experimental conditions. A sinusoidal type variation, with a period of about 15 days, modulating the basic trends in sleep times is described; but the principal finding of this study relates to a monotonic decrease in Paradoxical Sleep (PS) as recording continued. Age, stimulus deprivation and fatigue effects do not appear to be causative factors for this decrement, indicating that the changes in PS might reflect a habituation process. On this basis it is hypothesized that an increase in PS time in the mouse is a specific response to a significant environmental stimulus and could, therefore, form part of the coping strategy. This hypothesis is generalized and discussed in terms of its implications, both for experimentation concerned with measuring PS times and with the possible functional significance of PS.


Urine DNA methylation assay enables early detection and recurrence monitoring for bladder cancer.
BACKGROUNDCurrent methods for the detection and surveillance of bladder cancer (BCa) are often invasive and/or possess suboptimal sensitivity and specificity, especially in early-stage, minimal, and residual tumors.METHODSWe developed an efficient method, termed utMeMA, for the detection of urine tumor DNA methylation at multiple genomic regions by MassARRAY. We identified the BCa-specific methylation markers by combined analyses of cohorts from Sun Yat-sen Memorial Hospital (SYSMH), The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) database. The BCa diagnostic model was built in a retrospective cohort (n = 313) and validated in a multicenter, prospective cohort (n = 175). The performance of this diagnostic assay was analyzed and compared with urine cytology and FISH.RESULTSWe first discovered 26 significant methylation markers of BCa in combined analyses. We built and validated a 2-marker-based diagnostic model that discriminated among patients with BCa with high accuracy (86.7%), sensitivity (90.0%), and specificity (83.1%). Furthermore, the utMeMA-based assay achieved a great improvement in sensitivity over urine cytology and FISH, especially in the detection of early-stage (stage Ta and low-grade tumor, 64.5% vs. 11.8%, 15.8%), minimal (81.0% vs. 14.8%, 37.9%), residual (93.3% vs. 27.3%, 64.3%), and recurrent (89.5% vs. 31.4%, 52.8%) tumors. The urine diagnostic score from this assay was better associated with tumor malignancy and burden.CONCLUSIONUrine tumor DNA methylation assessment for early diagnosis, minimal, residual tumor detection and surveillance in BCa is a rapid, high-throughput, noninvasive, and promising approach, which may reduce the burden of cystoscopy and blind second surgery.FUNDINGThis study was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.


Host transcriptomic signatures of tuberculosis can predict immune reconstitution inflammatory syndrome in HIV patients.
Immune reconstitution inflammatory syndrome (IRIS) can be a complication of antiretroviral therapy (ART) in patients with advanced HIV, but its pathogenesis is uncertain. In tuberculosis (TB) endemic countries, IRIS is often associated with mycobacterial infections or Bacille-Calmette-Guerin (BCG) vaccination in children. With no predictive or confirmatory tests at present, IRIS remains a diagnosis of exclusion. We tested whether RISK6 and Sweeney3, validated immune-based blood transcriptomic signatures for TB, could predict or diagnose IRIS in HIV+ children and adults. Transcripts were measured by RT-qPCR in BCG-vaccinated children and by microarray in HIV+ adults with TB including TB meningitis (TBM). Signature scores before ART initiation and up to IRIS diagnosis were compared between participants who did or did not develop IRIS. In children, RISK6 and Sweeney3 discriminated IRIS cases from non-IRIS controls before ART, and at diagnosis. In adults with TB, RISK6 discriminated IRIS cases from controls after half-week on ART and at TB-IRIS onset. In adults with TBM, only Sweeney3 discriminated IRIS cases from controls before ART, while both signatures distinguished cases from controls at TB-IRIS onset. Parsimonious whole blood transcriptomic signatures for TB showed potential to predict and diagnose IRIS in HIV+ children and adults.


In vivo anticlastogenic and antimutagenic effects of tannic acid in mice.
The anticlastogenic effect of tannic acid was studied in vivo in the mouse micronucleus test. The frequencies of micronuclei induced by mitomycin C, ethyl nitrosourea (ENU) or 4-nitroquinoline 1-oxide in mouse bone marrow cells were decreased by the oral administration of tannic acid 6 h before the mutagen injection. The observed suppressing effect was not a reflection of a delay in the formation of micronuclei by the cytotoxic effect of tannic acid. The antimutagenic effect of tannic acid was also investigated in vivo in the mouse spot test using male PW and female C57BL/10 mice. Tannic acid was given orally to pregnant females 6 h before the intraperitoneal injection of ENU on the 10th day of pregnancy. The frequency of pups with recessive color spots induced by ENU was decreased by the administration of tannic acid. The observed decrease was not due to toxic effects on the embryo. These results indicate that tannic acid acts as an anticlastogen and antimutagen in vivo.


An evaluation of techniques used for the detection of anthelmintic resistance in nematode parasites of domestic livestock.
In vitro and in vivo techniques used for the detection of anthelmintic resistance are reviewed in terms of their versatility, reliability, accuracy, cost and simplicity. The faecal egg count reduction test is considered the most suitable for field screening of resistance but the larval development assay is likely to prove a valuable adjunct in such investigations. Other in vitro techniques, such as egg hatch tests, larval motility and tubulin binding assays are recommended as suitable only for research investigations. Similarly, in vivo procedures such as the critical and controlled anthelmintic efficacy tests are considered to be appropriate only for specific research purposes because of the costs involved in such studies.


A transdiagnostic examination of anxiety and stress on executive function outcomes in disorders with social impairment.
Executive function (EF) difficulties characterise a number of psychiatric conditions and EF impairment may be a predisposing factor and/or consequence of anxiety and stress. The aim of the study was to examine EF factors in a mixed clinical cohort (Autism Spectrum Disorder and Social Anxiety Disorder) characterised by social impairment and investigate the influence of trait anxiety and state-based depression, anxiety and stress. In Study 1, a factor analysis identified EF and non-EF latent factor structures (N=205). In Study 2, (N=137) multiple regression analyses investigated the association between trait anxiety and state based depression, anxiety and stress, on EF and non-EF cognitive domains and on the two composite indices of the Behavioural Rating Inventory of Executive Function (BRIEF). Trait anxiety was associated with better performance on neuropsychological measures of EF while state-based stress was associated with lower EF performance. A dissociation was observed between trait anxiety and state stress on the two behavioural indices of the BRIEF. Depression, anxiety and stress did not predict performance on non-EF cognitive domains. The cross-sectional design precludes cause-effect conclusions, further only self-report measures of affect were utilised and our performance measures of EF did not include a working memory test. The results demonstrate that trait anxiety and state-based stress influence EF processes across disorders with social impairment. The transdiagnostic efficacy of this finding can facilitate remediation strategies, it may also contribute to individuals with Autism Spectrum Disorder gaining better access to mental health services.


A prospective randomized study comparing the efficacy between povidone-iodine gargling and benzydamine hydrochloride for mucositis prevention in head and neck cancer patients receiving concurrent chemoradiotherapy.
Concurrent chemoradiation (CCRT) has been the standard treatment for organ preservation or locally advanced head and neck cancer (LAHNC). Radiation-induced oral mucositis (RIOM) is an important treatment-limiting toxicity. Benzydamine hydrochloride was recommended to prevent oral mucositis. Povidone-iodine had also been adopted to use as an oral rinse to prevent mucositis. This study compared the efficacy between benzydamine hydrochloride and 0.1% povidone-iodine to prevent RIOM in HNC patients who received concurrent chemoradiotherapy. We conducted a randomized control study in HNC patients receiving CCRT with curative intent. The stratification factors were primary site of disease, treatment modality, chemotherapy regimen, and schedule. The primary outcome was RIOM assessed by Oral Mucositis Assessment Scale (OMAS). Secondary outcomes included RIOM assessed by NCI-CTCAE, use of analgesic, antibiotics and anti-fungal drugs, hospitalization, and participant satisfaction. There were 83 participants recruited for this study with 71 completing the trial. Demographic characteristics were well-balanced between both arms. The univariate regression analysis revealed that povidone-iodine correlated with less RIOM compared to benzydamine hydrochloride (coefficient -2.25, 95% CI -4.37 to -0.012, p-value 0.03). The incidence of grade III-IV CTCAE RIOM during the study period was 51.4% with benzydamine hydrochloride compared to 26.5% with 0.1% povidone iodine (p-value 0.032). The peak incidence of grade III-IV CTCAE RIOM occurred in the 7th week of treatment (40.5% vs. 11.8%, p-value 0.01). This indicated the efficacy of povidone-iodine to prevent severe RIOM which usually most severity in the last week of CCRT treatment. The multivariate analysis revealed that the CCRT setting (definitive vs. adjuvant) and gargling agents (povidone-iodine vs. benzydamine hydrochloride were the factors associated with RIOM. This study demonstrated higher efficacy of 0.1% povidone-iodine gargle than benzydamine hydrochloride in mucositis prevention.


Monoclonal antipeptide antibodies: affinity and kinetic rate constants measured for the peptide and the cognate protein using a biosensor technology.
The interaction of antipeptide antibodies with the corresponding peptide and the cognate protein has been compared using a novel biosensor technology (BIAcore, Pharmacia). The peptide corresponds to residues 110-135 of the coat protein of tobacco mosaic virus, known to encompass an alpha-helical region reactive with antiprotein antibodies. A panel of 33 monoclonal antibodies raised against the peptide was studied and the epitope recognized by these antibodies was determined by the pepscan method. Further discrimination between the antibodies was performed by measurements of association and dissociation kinetic constants. Several antibodies showed an heterogeneous binding profile when reacting with the 25 residue long peptide but not with a shorter 10 residue peptide suggesting that they recognized different conformational states in the longer peptide. Equilibrium affinity constants were calculated for five of the antibodies and were found to be 10-50 times higher for the peptide than for the protein, the difference being caused mainly by a lower association rate constant.


Functional mu opioid receptors are expressed in cholinergic interneurons of the rat dorsal striatum: territorial specificity and diurnal variation.
Striatal cholinergic interneurons play a crucial role in the control of movement as well as in motivational and learning aspects of behaviour. Neuropeptides regulate striatal cholinergic transmission and particularly activation of mu opioid receptor (MOR) inhibits acetylcholine (ACh) release in the dorsal striatum. In the present study we investigated whether this cholinergic transmission could be modulated by an enkephalin/MOR direct process. We show that mRNA and protein of MORs are expressed by cholinergic interneurons in the limbic/prefrontal territory but not by those in the sensorimotor territory of the dorsal striatum. These MORs are functional because potassium-evoked release of ACh from striatal synaptosomes was dose-dependently reduced by a selective MOR agonist, this effect being suppressed by a MOR antagonist. The MOR regulation of cholinergic interneurons presented a diurnal variation. (i) The percentage of cholinergic interneurons containing MORs that was 32% at the beginning of the light period (morning) increased to 80% in the afternoon. (ii) The MOR-mediated inhibition of synaptosomal ACh release was higher in the afternoon than in the morning. (iii) While preproenkephalin mRNA levels remained stable, enkephalin tissue content was the lowest (-32%) in the afternoon when the spontaneous (+35%) and the N-methyl-d-aspartate-evoked (+140%) releases of enkephalin (from microsuperfused slices) were the highest. Therefore, by acting on MORs present on cholinergic interneurons, endogenously released enkephalin reduces ACh release. This direct enkephalin/MOR regulation of cholinergic transmission that operates only in the limbic/prefrontal territory of the dorsal striatum might contribute to information processing in fronto-cortico-basal ganglia circuits.


Molecular analysis of muscular dystrophy.
It is now possible to map almost any disease locus to a chromosomal region in the human genome by family studies with restriction fragment length polymorphisms. Duchenne and Becker muscular dystrophies have been shown to be localized within the same small region of Xp21 on the human X chromosome. Myotonic dystrophy has been localized to a region close to the centromere of chromosome 19. Technologies are now available to identify candidate genes for the diseases. Autosomal recessive muscular dystrophies are more difficult to study, but even these will be amenable to analysis in the very near future. The next decade should witness some exciting advances in the molecular analysis and clinical management of human muscular dystrophies.


[Visualization of the guinea pig fetus in utero by x-ray densitometry].
The total body X-ray scanner (computer assisted axial tomography) was used to observe the guinea-pig fetus in utero. This new method of investigating obstetrical physiology provides a suitable animal model with quantitative facts about the density of the fetal organs and, using a non-invasive technique, allows precise intrauterine pictures of the anatomy of the fetus to be obtained.


A new enzymatic method for determination of serum choline-containing phospholipids.
A new enzymatic method is presented for the determination of serum choline-containing phospholipids with a combined enzymatic method using phospholipase D (from Streptomyces species), choline oxidase (from Arthrobacter species) and peroxidase. The method is reproducible, and the results correlate well with those obtained by the conventional digestion method (Hoeflmayr, J. and Fried, R. (1966) Med. Ernaehr. 7, 9-10). The method affords better specificity, requires a smaller quantity of the sample and shorter time than those previously reported, and has excellent precision.


Anabolic-androgenic steroid use is associated with psychopathy, risk-taking, anger, and physical problems.
Previous research has uncovered medical and psychological effects of anabolic-androgenic steroid (AAS) use, but the specific relationship between AAS use and risk-taking behaviors as well as between AAS use and psychopathic tendencies remains understudied. To explore these potential relationships, we anonymously recruited 492 biologically male, self-identified bodybuilders (median age 22; range 18-47 years) from online bodybuilding fora to complete an online survey on Appearance and Performance Enhancing Drug (APED) use, psychological traits, lifestyle choices, and health behaviors. We computed odds ratios and 95% confidence intervals using logistic regression, adjusting for age, race, education, exercise frequency, caloric intake, and lean BMI. Bodybuilders with a prior history of AAS use exhibited heightened odds of psychopathic traits, sexual and substance use risk-taking behaviors, anger problems, and physical problems compared to those with no prior history of AAS use. This study is among the first to directly assess psychopathy within AAS users. Our results on risk-taking, anger problems, and physical problems are consistent with prior AAS research as well as with existing frameworks of AAS use as a risk behavior. Future research should focus on ascertaining causality, specifically whether psychopathy is a risk associated with or a result of AAS use.


Circadian pattern of total and free corticosterone concentrations, corticosteroid-binding globulin, and physical activity in mice selectively bred for high voluntary wheel-running behavior.
In vertebrates, baseline glucocorticoid concentrations vary predictably on a diel basis, usually peaking shortly before the onset of activity. Presumably, circadian patterns in glucocorticoid secretion have evolved to match predictable rises in energetic need. In mice from lines selectively bred for high voluntary wheel-running, previous studies have reported that baseline plasma corticosterone concentrations at two different times during the photophase are elevated twofold above those of non-selected control lines. Here, we tested the hypothesis that the elevated daytime corticosterone levels could be explained by a shift in the circadian pattern of corticosterone levels. We measured baseline total plasma corticosterone levels, corticosteroid-binding globulin (CBG) capacity, and calculated free corticosterone levels (corticosterone not bound to corticosteroid-binding globulin and potentially biologically active) at six points during the 24-hour cycle in males on a 12:12 photoperiod. We also examined the daily pattern of both wheel-running and home-cage activity. Based on combined analysis of all six points, the circadian pattern of total corticosterone, corticosteroid-binding globulin, and free corticosterone levels did not significantly differ between high-runner and control mice (linetype * time interaction P=0.56, 0.45, and 0.55, respectively); however, all varied with time (all P<0.0001) and mice from the selected lines had significantly elevated total (P=0.0125) and free (P=0.0140) corticosterone, with no difference in CBG binding capacity (P=0.77). All mice were active primarily during the dark phase, and the factorial increase in activity of selected relative to controls lines was 2.33 for total daily wheel revolutions and 2.76 for total daily home-cage activity. The onset of the active period for both measures of locomotor activity coincided with peak total and free corticosterone levels in both selected and control lines. These findings lend support to our hypothesis that elevated circulating corticosterone levels have evolved as an adaptation to support increased locomotor activity in the selected lines.


CAR T cells expressing a bacterial virulence factor trigger potent bystander antitumour responses in solid cancers.
Chimeric antigen receptor T cells (CAR T cells) are effective against haematologic malignancies. However, in solid tumours, their potency is hampered by local immunosuppression and by the heterogeneous expression of the antigen that the CAR targets. Here we show that CAR T cells expressing a pluripotent pro-inflammatory neutrophil-activating protein (NAP) from Helicobacter pylori trigger endogenous bystander T-cell responses against solid cancers. In mice with subcutaneous murine pancreatic ductal adenocarcinomas, neuroblastomas or colon carcinomas, CAR(NAP) T cells led to slower tumour growth and higher survival rates than conventional mouse CAR T cells, regardless of target antigen, tumour type and host haplotype. In tumours with heterogeneous antigen expression, NAP secretion induced the formation of an immunologically 'hot' microenvironment that supported dendritic cell maturation and bystander responses, as indicated by epitope spreading and infiltration of cytotoxic CD8+ T cells targeting tumour-associated antigens other than the CAR-targeted antigen. CAR T cells armed with NAP neither increased off-tumour toxicity nor hampered the efficacy of CAR T cells, and hence may have advantageous translational potential.


The perioperative surgical home: An innovative, patient-centred and cost-effective perioperative care model.
Contrary to the intraoperative period, the current perioperative environment is known to be fragmented and expensive. One of the potential solutions to this problem is the newly proposed perioperative surgical home (PSH) model of care. The PSH is a patient-centred micro healthcare system, which begins at the time the decision for surgery is made, is continuous through the perioperative period and concludes 30 days after discharge from the hospital. The model is based on multidisciplinary involvement: coordination of care, consistent application of best evidence/best practice protocols, full transparency with continuous monitoring and reporting of safety, quality, and cost data to optimize and decrease variation in care practices. To reduce said variation in care, the entire continuum of the perioperative process must evolve into a unique care environment handled by one perioperative team and coordinated by a leader. Anaesthesiologists are ideally positioned to lead this new model and thus significantly contribute to the highest standards in transitional medicine. The unique characteristics that place Anaesthesiologists in this framework include their systematic role in hospitals (as coordinators between patients/medical staff and institutions), the culture of safety and health care metrics innate to the specialty, and a significant role in the preoperative evaluation and counselling process, making them ideal leaders in perioperative medicine.