Cytofluorimetric scanning: a tool for studying axonal transport in monoaminergic neurons.
A new technique is described which makes it possible to measure several substances and parameters related to axonal transport in peripheral nerves. The technique is based on histofluorescent techniques and measures accumulated amounts of fluorescent substances, e.g. proximal to a crush or local cooling of the nerve. Sections from nerves, treated according to the FIF method for visualization of catecholamines or for immunofluorescence, are placed in a cytofluorimeter (Leitz MPV 2). The nerve sections are passed under a measuring slit by a motor-driven cross-table and the fluorescence intensity is continuously registered via a recorder with integrator which gives a graphical "nerve-accumulation profile." Comparisons between accumulation curves obtained with the cytofluorimetric scanning technique and biochemically determined accumulation curves of noradrenaline, dopamine-beta-hydroxylase and tyrosine-hydroxylase in the sciatic nerve following crush operations, demonstrated a striking similarity. With this technique it is possible to semiquantify the accumulated amount of a fluorescent substance, study morphology, perform morphometry and photographical documentation in the same section. This scanning technique may prove useful, since the accumulation and distribution of several substances in consecutive sections, along the length of a nerve, can be demonstrated graphically using superimposed curves.


Chinese herbal medicines in the treatment of acute respiratory infections: a review of randomised and controlled clinical trials.
To review clinical trials of Chinese herbal medicines (CHMs) in the management of acute respiratory infections (ARIs). MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library and three Chinese medical journals available in Australia. Studies in which a control group was used in comparing CHMs with a placebo or "Western medicine" (usually antibiotics) for treating ARIs were included. 27 of 46 studies identified in the search of the databases and the Chinese journals fulfilled the inclusion criteria. Twenty-six of these were published in Chinese, and one in English. Twenty were randomised controlled trials and seven were "controlled clinical trials". Although most of the studies reported that CHMs are better than antibiotics for the treatment of ARIs, the quality of the studies was generally poor when evaluated for patient allocation, treatment description, outcome measurement and data analysis. Because the trial methodology of these studies was often inadequate or insufficiently documented, it is difficult to recommend the use of CHMs in ARIs. However, Shuang Huang Lian does appear to be useful for treating lower respiratory tract infections. More rigorous evaluation of CHMs is needed, as they are becoming popular treatments in many countries, including Australia.


A multicenter, randomized, and double-blind phase IV clinical trial to compare the efficacy and safety of fixed-dose combinations of amlodipine orotate/valsartan 5/160 mg versus valsartan/hydrochlorothiazide 160/12.5 mg in patients with essential hypertension uncontrolled by valsartan 160 mg monotherapy.
To determine whether the effectiveness and safety of fixed-dose combinations (FDCs) of amlodipine orotate/valsartan (AML/VAL) 5/160 mg are noninferior to those of valsartan/hydrochlorothiazide (VAL/HCTZ) 160/12.5 mg in hypertensive patients with inadequate response to valsartan 160 mg monotherapy. This 8-week, active-controlled, parallel-group, fixed-dose, multicenter, double-blind randomized controlled, and noninferiority trial was conducted at 17 cardiovascular centers in the Republic of Korea. Eligible patients had mean sitting diastolic blood pressure (msDBP) ≥90 mm Hg despite monotherapy with valsartan 160 mg for 4 weeks. Patients were randomly assigned to treatment with AML/VAL 5/160 mg FDC (AML/VAL) group or VAL/HCTZ 160/12.5 mg FDC (VAL/HCTZ) group once daily for 8 weeks. A total of 238 patients were enrolled (AML/VAL group, n = 121; VAL/HCTZ group, n = 117), of whom 228 completed the study. At 8 weeks after randomization, msDBP was significantly decreased in both groups (-9.44 ± 0.69 mm Hg in the AML/VAL group and -7.47 ± 0.71 mm Hg in the VAL/HCTZ group, both P < .001 vs baseline). Between group difference was -1.96 ± 1.00 mm Hg, indicating that AML/VAL 5/160 mg FDC was not inferior to VAL/HCTZ 160/12.5 mg FDC at primary efficacy endpoint. Control rate of BP defined as the percentage of patients achieving mean sitting SBP (msSBP) <140 mm Hg or msDBP <90 mm Hg (target BP) from baseline to week 8 was significantly higher in the AML/VAL group than that in the VAL/HCTZ group (84.3% [n = 102] in the AML/VAL group vs 71.3% [n = 82] in the VAL/HCTZ group, P = .016). At 8 weeks after randomization, mean uric acid level was significantly increased in the VAL/HCTZ group compared to that at baseline (0.64 ± 0.08 mg/dL; P < .001). However, it was slightly decreased from baseline in the AML/VAL group (-0.12 ± 0.08 mg/dL; P = .085). The intergroup difference was significant (P < .001). The effectiveness and safety AML/VAL 5/160 mg FDC are noninferior to those of VAL/HCTZ 160/12.5 mg FDC in patients with hypertension inadequately controlled by valsartan 160 mg monotherapy.


Association of the Gut Microbiota with Weight-Loss Response within a Retail Weight-Management Program.
Retail programs offer popular weight-loss options amid the ongoing obesity crisis. However, research on weight-loss outcomes within such programs is limited. This prospective-cohort observational study enrolled 58 men and women between ages 20 and 72 years from a retail program to assess the influence of client features on energy-restriction induced weight-loss response. DESeq2 in R-studio, a linear regression model adjusting for significantly correlating covariates, and Wilcoxon signed-rank and Kruskal-Wallis for within- and between-group differences, respectively, were used for data analyses. An average 10% (~10 kg) reduction in baseline-weight along with lower total-, android-, gynoid-, and android:gynoid-fat were observed at Week 12 (all, p < 0.05). Fifty percent of participants experienced a higher response, losing an average of 14.5 kg compared to 5.9 kg in the remaining low-response group (p < 0.0001). Hemoglobin-A1C (p = 0.005) and heart rate (p = 0.079) reduced in the high-response group only. Fat mass and A1C correlated when individuals had high android:gynoid fat (r = 0.55, p = 0.008). Gut-microbial β-diversity was associated with BMI, body fat%, and android-fat (all, p < 0.05). Microbiota of the high-response group had a higher baseline OTU-richness (p = 0.02) as well as differential abundance and/or associations with B. eggerthi, A. muciniphila, Turicibacter, Prevotella, and Christensenella (all, p/padj < 0.005). These results show that intestinal microbiota as well as sex and body composition differences may contribute to variable weight-loss response. This highlights the importance of various client features in the context of real-world weight control efforts.


Erratum: Synthesis of Novel Pinocembrin Amino Acid Derivatives and Their Antiaging Effect on Caenorhabditis elegans via the Modulating DAF-16/FOXO [Corrigendum].
[This corrects the article DOI: 10.2147/DDDT.S330223.].


Inhibition of chronic skin inflammation by topical anti-inflammatory flavonoid preparation, Ato Formula.
Flavonoids are known as natural anti-inflammatory agents. In this investigation, an anti-inflammatory potential of new topical preparation (SK Ato Formula) containing flavonoid mixtures from Scutellaria baicalensis Georgi roots and Ginkgo biloba L. leaves with an extract of Gentiana scabra Bunge roots was evaluated in an animal model of chronic skin inflammation. Multiple 12-O-tetradecanoylphorbol-13-acetate treatments for 7 consecutive days on ICR mouse ear provoked a chronic type of skin inflammation: dermal edema, epidermal hyperplasia and infiltration of inflammatory cells. When topically applied in this model, this new formulation (5-20 microL/ear/treatment) reduced these responses. Furthermore, it inhibited prostaglandin E2 generation (17.1-33.3%) and suppressed the expression of proinflammatory genes, cyclooxygenase-2 and interleulin-1beta in the skin lesion. Although the potency of inhibition was lower than that of prednisolone, all these results suggest that Ato Formula may be beneficial for treating chronic skin inflammatory disorders such as atopic dermatitis.


Assessing the quality of single particle reconstructions by atomic model building.
The 2015/2016 Map Challenge challenged cryo-EM practitioners to process a series of publicly available cryo-EM datasets. As part of the challenge, metrics needed to be developed to assess and compare the quality of the different map submissions. The most common metric for assessing maps is determining the resolution by Fourier shell correlation (FSC), but there are well known instances where the resolution can be misleading. In this manuscript, we present a new approach for assessing the quality of a map by determining the map "modelability" rather than on resolution. We used the automated map tracing and modeling algorithms in Rosetta to generate populations of models, and then compared the populations between different map entries by the Rosetta score, RMSD to a reference model provided by the map challenge, and by pair-wise RMSDs between different models in the population. These metrics were used to determine statistically significant rankings for the map challengers for each dataset. The rankings revealed inconsistencies between the resolution by FSC, emphasized the importance of the interplay between number of particles contributing to a map and map quality, and revealed the importance of software familiarity on single particle reconstruction results. However, because multiple variables changed between map entries, it was challenging to derive best practices from the map challenge results.


One Word to Describe My Experience as a COVID-19 Survivor Six Months after Its Onset: Findings of a Qualitative Study.
The COVID-19 pandemic emotionally affected the lives of patients cared for in different settings. However, a comprehensive view of the whole experience as lived by survived patients, from the onset of the disease and over time, is substantially unknown to date. A descriptive qualitative design was implemented according to the Standards for Reporting Qualitative Research. Adult patients (=1067) cared for during the first wave (March/April 2020) capable of answering an interview and willing to participate were interviewed (=397) by phone with an interview guide including open- and closed-ended questions. In this context, they were asked to summarise with a metaphor their entire COVID-19 experience at six months. Then, the emotional orientation (positive, neutral, or negative) of the metaphors expressed was identified. The participants were mainly female (206; 51.9%), with an average age of 52.6 years (CI 95% 50.4-53.6), reporting a mild severity of COVID-19 disease at the onset (261; 65.7%) and the perception of being completely healed (294; 70%) at six months. The patients summarised their experiences mainly using negative-oriented (248; 62.5%) metaphors; only 54 (13.6%) reported positive-oriented metaphors and a quarter (95; 23.95) neutral-oriented metaphors. Nearly all positive-oriented metaphors were reported by patients with symptoms at the onset (53; 98.1%), a significantly higher proportion compared to those reporting negative- (219; 88.3%) and neutral-oriented (78; 82.1%) metaphors (p = 0.014). While no other clinical features of the disease were associated, among females, significantly more negative-oriented metaphors emerged. Moreover, neutral-oriented metaphors were reported by younger patients (49.5 years, CI 95% 64.11-52.92) as compared to those negative and positive that were reported by more mature patients (53.9; CI 95% 52.04-55.93 and 54.8; CI 95% 50.53-59.24, respectively) (p = 0.044). Nurses and healthcare services require data to predict the long-term needs of patients. Our findings suggest that, for many patients, the COVID-19 lived experience was negative over time.


PDGF-AA effectively stimulates early events but has no mitogenic activity in AKR-2B mouse fibroblasts.
The response of AKR-2B mouse fibroblasts, which express approximately equal numbers of platelet-derived growth factor (PDGF)-alpha and -beta receptors on their surface (V. Hoppe et al. Eur. J. Biochem. 187, 207-214, 1990) to all three isoforms of PDGF, was studied. All isoforms stimulated early events, i.e., receptor autophosphorylation on tyrosine, total cellular phosphorylation, increase in 32P-labeled phospholipid content, but there was no correlation between the extents measured for the different effects. Although rPDGF-AA effectively stimulated these early events, it was unable to induce [3H]thymidine incorporation and cell growth whereas rPDGF-BB and -AB stimulated the division of more than 90% of the cells. This activity was restored by addition of insulin-like growth factor I (IGF-I), which itself exhibited only a low mitogenic activity. rPDGF-AB or -BB did not require the presence of IGF-I to fully stimulate cells for [3H]thymidine incorporation and cell division. Apparently, rPDGF-AA induced only a "competence" state of the cells whereas rPDGF-AB or -BB was also able to initiate "progression". It is speculated that some early events occurring during the competence phase might be part of a "maintenance" program elicited by growth factors.


Are circadian rhythms the code of hypothalamic-immune communication? Insights from natural killer cells.
Circadian rhythms in physiology and behavior are ultimately regulated at the hypothalamic level by the suprachiasmatic nuclei (SCN). This central oscillator transduces photic information to the cellular clocks in the periphery through the autonomic nervous system and the neuroendocrine system. The fact that these two systems have been shown to modulate leukocyte physiology supports the concept that the circadian component is an important aspect of hypothalamic-immune communication. Circadian disruption has been linked to immune dysregulation, and recent reports suggest that several circadian clock genes, in addition to their time-keeping role, are involved in the immune response. In this overview, we summarize the findings demonstrating that Natural Killer (NK) cell function is under circadian control.


Porous scaffold of gelatin-starch with nanohydroxyapatite composite processed via novel microwave vacuum drying.
Hydroxyapatite (HA) is a fundamental mineral-based biomaterial, used for preparing composites for bone repair and regeneration. Gelatin blended with starch results in scaffold composites with enhanced mechanical properties. A gelatin-starch blend reinforced with HA nanocrystals (nHA) gave biocompatible composites with enhanced mechanical properties. In this study, a porous scaffold of gelatin-starch-nHA composites was fabricated through microwave vacuum drying and crosslinking using trisodium citrate. Three different composite scaffolds were prepared at three different percentages of nHA: 20%, 30% and 40%. The microstructures and compositions of the composites were analyzed. Within the porous structure, the nHA crystals were observed to precipitate. The interaction between the gelatin-starch network film and nHA crystalline material was studied using Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction analysis (XRD). XRD reflections showed that there are two different minerals present in the scaffold composite. There were strong reflection peaks close to the 26 degrees and 32 degrees 2theta angles of HA, and close to the 8 degrees and 49 degrees 2theta angles for sodium citrate minerals. The FTIR result suggested that carboxyl groups, C=O and amino groups play crucial roles in HA formation on the surface of a gelatin network.


Comparative analysis of spinal extradural arteriovenous fistulas with or without intradural venous drainage: a systematic literature review.
Spinal arteriovenous malformations (AVMs) are classified into types according to anatomical characteristics: dural arteriovenous fistulas (AVFs), intramedullary AVMs, perimedullary AVFs, and extradural AVFs. Spinal extradural AVFs are much rarer than other types of spinal AVMs, and the available literature on this clinical entity has been based only on case reports or small case series. To investigate the clinical characteristics of patients with spinal extradural AVFs, the authors systematically reviewed the associated literature in the MRI era. The PubMed database was searched for all relevant English-language case reports and case series published from 1990 to 2011. The clinical differences between Type A with and Type B without intradural venous drainage were statistically compared, especially regarding clinical features and angiographic and MRI findings. Forty-five cases of spinal extradural AVFs were found. Type A spinal extradural AVFs were diagnosed in patients with a significantly older age (mean 63.5 years) as compared with Type B AVFs (mean 34.3 years, p < 0.0001). Most cases of Type A spinal extradural AVFs exhibited a diffuse high signal intensity of the spinal cord on T2-weighted MR images and no mass effect (p < 0.0001), and they commonly occurred in the thoracolumbar and lumbar regions (p < 0.0001). On the other hand, cases of Type B lesions exhibited a normal signal intensity of the cord with severe mass effect due to an enlarged extradural venous plexus, and they commonly occurred in the cervical and upper thoracic regions (p < 0.0001), frequently in patients with neurofibromatosis Type 1 (p = 0.049). Because Type B AVFs consisted of high-flow, multiple complex anastomoses between arteries and the epidural venous plexus, patients with these lesions tended to undergo multisession treatments, and the rate of partial AVF occlusion was significantly higher than for Type A AVFs (p = 0.018), although there was no difference in symptom outcomes between the 2 groups. To the best of the authors' knowledge, a comparative analysis of the clinical differences in patients with extradural AVFs with or without intradural venous drainage has yet to be described in the literature. They concluded that in the diagnosis of spinal extradural AVF, evaluation of intradural venous drainage is important because the cause of myelopathy determines the treatment goals.


Self-Reported Head Trauma Predicts Poor Dual Task Gait in Retired National Football League Players.
Symptomatic head trauma associated with American-style football (ASF) has been linked to brain pathology, along with physical and mental distress in later life. However, the longer-term effects of such trauma on objective metrics of cognitive-motor function remain poorly understood. We hypothesized that ASF-related symptomatic head trauma would predict worse gait performance, particularly during dual task conditions (ie, walking while performing an additional cognitive task), in later life. Sixty-six retired professional ASF players aged 29 to 75 years completed a health and wellness questionnaire. They also completed a validated smartphone-based assessment in their own homes, during which gait was monitored while they walked normally and while they performed a verbalized serial-subtraction cognitive task. Participants who reported more symptomatic head trauma, defined as the total number of impacts to the head or neck followed by concussion-related symptoms, exhibited greater dual task cost (ie, percentage increase) to stride time variability (ie, the coefficient of variation of mean stride time). Those who reported ≥1 hit followed by loss of consciousness, compared to those who did not, also exhibited greater dual task costs to this metric. Relationships between reported trauma and dual task costs were independent of age, body mass index, National Football League career duration, and history of musculoskeletal surgery. Symptomatic head trauma was not correlated with average stride times in either walking condition. Remote, smartphone-based assessments of dual task walking may be utilized to capture meaningful data sensitive to the long-term impact of symptomatic head trauma in former professional ASF players and other contact sport athletes. ANN NEUROL 2020;87:75-83.


State-Dependent Subnetworks of Parvalbumin-Expressing Interneurons in Neocortex.
Brain state determines patterns of spiking output that underlie behavior. In neocortex, brain state is reflected in the spontaneous activity of the network, which is regulated in part by neuromodulatory input from the brain stem and by local inhibition. We find that fast-spiking, parvalbumin-expressing inhibitory neurons, which exert state-dependent control of network gain and spike patterns, cluster into two stable and functionally distinct subnetworks that are differentially engaged by ascending neuromodulation. One group is excited as a function of increased arousal state; this excitation is driven in part by the increase in cortical norepinephrine that occurs when the locus coeruleus is active. A second group is suppressed during movement when acetylcholine is released into the cortex via projections from the nucleus basalis. These data establish the presence of functionally independent subnetworks of Parvalbumin (PV) cells in the upper layers of the neocortex that are differentially engaged by the ascending reticular activating system.


Epigenomically Bistable Regions across Neuron-Specific Genes Govern Neuron Eligibility to a Coding Ensemble in the Hippocampus.
Sensory inputs activate sparse neuronal ensembles in the dentate gyrus of the hippocampus, but how eligibility of individual neurons to recruitment is determined remains elusive. We identify thousands of largely bistable (CpG methylated or unmethylated) regions within neuronal gene bodies, established during mouse dentate gyrus development. Reducing DNA methylation and the proportion of the methylated epialleles at bistable regions compromises novel context-induced neuronal activation. Conversely, increasing methylation and the frequency of the methylated epialleles at bistable regions enhances intrinsic excitability. Single-nucleus profiling reveals enrichment of specific epialleles related to a subset of primarily exonic, bistable regions in activated neurons. Genes displaying both differential methylation and expression in activated neurons define a network of proteins regulating neuronal excitability and structural plasticity. We propose a model in which bistable regions create neuron heterogeneity and constellations of exonic methylation, which may contribute to cell-specific gene expression, excitability, and eligibility to a coding ensemble.


Triglyceride lipase activity in postheparin plasma and plasma lipoproteins in liver disease.
Hepatic lipase activity and lipoprotein lipase activity were studied in postheparin plasma from 14 patients with various liver disorders. Plasma lecithin: cholesterol acyltransferase (LCAT) activity and lipoprotein composition and structure were also estimated. Five patients had lower hepatic lipase activity than the lowest control value, and in three of these no hepatic lipase activity was detected. Lipoprotein lipase was low in 5 patients, but in only one of them was hepatic lipase activity also low. Hepatic lipase was not significantly correlated to the concentration of plasma triglycerides, either in controls or in patients, whereas lipoprotein lipase was negatively correlated with plasma triglycerides both in controls and patients. Lipoprotein lipase and LCAT activity, but not hepatic lipase, was negatively correlated to the triglyceride content of the low density lipoproteins (density 1.019-1.063 g/ml) from the patients. No specific lipid or lipoprotein pattern was found in plasma from the patients with a low or without any hepatic lipase activity. The results suggest an important role of lipoprotein lipase and LCAT, for the increased content of triglycerides in the low density lipoproteins in patients with liver disease. The role of hepatic lipase remains unclear.


[Inhibitory effect of silencing hTERT gene on growth of human squamous cell carcinoma xenograft in nude mice].
This study is to explore the inhibitory effect of silencing hTERT gene by short-hairpin RNA on growth of nasopharyngeal carcinoma xenograft in nude mice with RNAi technique. Construction and expression of hTERT cDNA sequence according to the specific hTERT mRNA, including fluorescein eukaryotic expression vector, packaged into a lentivirus. qPCR and Western blot analyzed hTER.T mRNA and protein levels in transfected cells. Proliferation rate of transfected cells was determined by MTT assay in vitro. Cell growth cycle was detected by flow cytometry. The invasiveness of each group was compared using in vitro cell invasion assay. RT-PCR and Western blot analysis showed that, hTERT siRNA significantly reduced hTERT mRNA and protein levels, especially hTERT siRNA1. siRNA treatment inhibited tumor cell proliferation, and cell migration and invasiveness were significantly lower. Tumor cell growth rate was significantly different between control group and siRNA group (P < 0.01) while tumor cell growth rate in empty virus group(NC group) and control group was not significantly different (P > 0.05). Lentivirus containing specific sequences of hTERT gene could significantly inhibit the growth of nasopharyngeal carcinoma cells line. hTERT siRNA expression vector can effectively inhibit NPC cell proliferation, migration and invasion, which may provide a novel molecular targets for gene therapy of nasopharyngeal carcinoma.


The Impact of Flash Glucose Monitoring on Glycaemic Control as Measured by HbA1c: A Meta-analysis of Clinical Trials and Real-World Observational Studies.
Glycated haemoglobin A1c (HbA1c) is the established standard measurement for assessment of glycaemic control in people with diabetes. Here we report on a meta-analysis of real-world observational studies on the impact of flash continuous glucose monitoring on glycaemic control as measured by HbA1c. A total of 271 studies were identified in our search, of which 29 contained data reporting changes in HbA1c over periods from 1 to 24 months that could be used in a statistical analysis. Our meta-analysis focuses on observed change in HbA1c at either 2, 3 or 4 months, in adult or paediatric subjects, as well as a longitudinal analysis up to 12 months in adult subjects. These data were drawn from 25 of the studies identified in our initial search. These reported HbA1c data up to 12 months in a total of 1723 participants with type 1 diabetes (T1D) or type 2 diabetes (T2D) using the FreeStyle Libre® flash glucose monitoring system. Overall mean change in laboratory HbA1c across study subjects at 2-4 months was - 0.55% (95% CI - 0.70, - 0.39). Amongst the 1023 adults, mean change in HbA1c was - 0.56% (95% CI - 0.76, - 0.36); for the 447 children and adolescents, mean change in HbA1c was - 0.54% (95% CI - 0.84, - 0.23). Based on regression analysis, the degree of change in HbA1c correlated with the initial HbA1c of the study population. A longitudinal analysis in adult subjects (n = 1276) shows that HbA1c fell within the first 2 months and changes were sustained up to 12 months. No significant differences were detected between T1D and T2D. The meta-analysis reported here confirms that starting the FreeStyle Libre system as part of diabetes care results in a significant and sustained reduction in HbA1c for adults and children with T1D and for adults with T2D. Abbott Diabetes Care.


Enhanced photodynamic activity of hypericin by penetration enhancer N-methyl pyrrolidone formulations in the chick chorioallantoic membrane model.
Hypericin (HY) was examined for photodynamic therapy (PDT)-induced vascular damage using the chick chorioallantoic membrane (CAM) model. Clinically, plasma protein was used to solubilize HY. Upon binding to albumin, free HY available to be transported through the membrane may be limited. Hence, formulations containing a biocompatible solvent, N-Methyl pyrrolidone (NMP), have the potential to enhance HY delivery into solid tumors. At suitable concentrations, NMP and/or light irradiation did not produce antivascular damage. Hypericin-PDT effects showed to be HY and NMP concentrations-dependent. These findings indicate that NMP is a promising solvent and penetration enhancer for HY-PDT clinical applications.


Capsaicin treatment induces selective sensory degeneration and increased sympathetic innervation in the rat ureter.
Quantitative immunohistochemistry was used to study the innervation of the ureter in adult rats pretreated with capsaicin as neonates (50 mg/kg) or as adults (100-150 mg/kg, 10-22 days prior to being killed) using antibodies against protein gene-product 9.5, neuron-specific enolase, substance P, calcitonin gene-related peptide, neuropeptide Y, dopamine-beta-hydroxylase and vasoactive intestinal polypeptide. The number of calcitonin gene-related peptide- and substance P-containing fibres was reduced in the subepithelial plexus (adult capsaicin treatment < 1%, neonatal treatment < 5% of control), the submucosa (adult treatment < 11%; neonatal treatment < 51%) and in the smooth muscle layer and adventitia (adult treatment < 11%; neonatal treatment < 58%). Fibres immunoreactive for protein gene-product 9.5, a general neuronal marker, were reduced to 11% (adult treatment) or 0.5% (neonatal treatment) in the subepithelial plexus, but unchanged in the other layers, indicating a selective regional degeneration. In the smooth muscle layer the number of neuropeptide Y- and vasoactive intestinal polypeptide-containing nerve fibres was not altered by capsaicin. The number of neuropeptide Y fibres in the subepithelial plexus, however, was significantly increased after adult treatment (174% of control). After neonatal capsaicin treatment the intensity of the neuropeptide Y immunoreactivity was increased, more neuropeptide Y-positive nerve bundles were found and immunoreactive cell bodies were observed regularly in the adventitia of the ureter. The data indicate that capsaicin produces a selective degeneration of most afferent fibres in the subepithelial plexus of the rat ureter. This loss of capsaicin-sensitive afferent nerves evokes neuroplastic changes resulting in a hyperinnervation by neuropeptide Y-immunoreactive, presumably sympathetic fibres. The results suggest a mutual regulation of the pattern and density of innervation of peripheral target tissues by sensory and sympathetic neurons.


Genome and protein evolution in eukaryotes.
The past year has seen the completion of the genome sequence of the flowering plant Arabidopsis thaliana and the initial sequence reports of the human genome. The availability of completely sequenced eukaryotic genomes from disparate phylogenetic lineages has opened the door to comparative analyses and a better understanding of the evolutionary processes shaping genomes. Complex many-to-many relationships between genes from different species appear to be the norm, suggesting that transfer of detailed functional annotation will not be straightforward. In addition to expansion and contraction of gene families, new genes evolve from recombination of pre-existing domains, although some domain families do appear to have evolved recently and to be specific to restricted phylogenetic lineages. The overall picture is of a huge diversity of gene content within eukaryotic genomes, reflecting different functional demands in different species.


Synthesis, characterization, and blood compatibility of polyamidoamines copolymers.
This work reports the development of new non-thrombogenic polymers based on the linear polymers of polyamidoamines (PAAs), having heparin binding ability, obtained by polyaddition of secondary amines to N,N'-methylene bis-acrylamide. PAAs could not be used directly in the making of blood-contacting materials due to their poor mechanical strength. In order to overcome this lacuna, copolymers of amidoamine with methylmethacrylate (MMA) were prepared. Characterization studies indicated that the PAAs have been suitably incorporated into the MMA matrix. The relative hydrophilic nature of the synthesized copolymers was established from the measurement of water contact angle. The heparinized copolymers showed significant improvement in non-thrombogenic characteristics.


Enhancing effect of lonidamine on the inhibition of mitochondrial respiration by adriamycin.
Pretreatment of rat liver mitochondria with lonidamine (LND), 1-(2,4 dichlorobenzyl)-1 H-indazol-3-carboxylic acid, increases their susceptibility to respiratory inhibition by adriamycin (ADM). Because LND does not inhibit the rate of oxygen consumption at the concentrations used, its potentiating effect may be exerted by favoring the interaction of ADM molecules with their sites in the inner mitochondrial membrane. LND does not modify the permeability on the inner membrane for large molecules. However, its enhancing effect can be ascribed to a modified permeability of the outer mitochondrial membrane which may represent a barrier for ADM entry.


Nontuberculous mycobacteria and water: a love affair with increasing clinical importance.
Water serves as a major reservoir for the environmental mycobacteria. Many cases of cutaneous mycobacterial disease result from water exposure. The current theory of the pathogenesis of M. avium complex lung disease involves inhalation of organisms aerosolized from surface water. Disseminated M. avium disease in AIDS invariably involves the gastrointestinal tract strongly suggesting that contaminated water could serve as the disease source for this increasingly important disease.


Preparation and evaluation of chitosan- and hyaluronic acid-grafted pullulan succinate films for skin wound healing.
A novel wound dressing that possesses antibacterial properties and accelerates skin wound repair was developed by physically blending hyaluronic acid-grafted pullulan succinate (HA-st-Pu) with chitosan (CS). The HA-st-Pu polymer was synthesized and characterized, and then CS/HA-st-Pu film dressings were prepared by a freeze-drying method. The novel film wound dressings exhibited a three-dimensional cavity structure under scanning electron microscopy (SEM) and a better swelling ratio than CS, HA and Pu alone, absorbing a large amount of liquid and effectively maintaining the moist environment of the wound. CS/HA-st-Pu materials had no cytotoxicity and increased cell proliferation when coincubated with L929 cells. Moreover, CS/HA-st-Pu wound dressings exhibited a certain antibacterial capability against E. coli and S. aureus. In rat skin wound healing, CS/HA-st-Pu film dressings outperformed both the control and market band-aid groups with respect to the reduction of inflammation and acceleration of wound closure.


Computerized tomography applied to gynecologic oncology.
Forty patients on the gynecologic oncology service at the University of North Carolina were evaluated with CT scans. Accuracy and clinical benefit of these scans were compared to those of manual clinical examinations. The CT scans were generally superior and had fewer (9) verified errors in the regions of the pelvic wall and para-aortic area than did the manual examinations (17). Both the CT and bimanual examinations had the same number of verified errors (3) in the central pelvic region. The authors found the CT scans to be beneficial in evaluation of pelvic wall and para-aortic regions for treatment planning of either primary or recurrent cancer.


Low potential of persistence and dissemination of antimicrobial-resistant Enterobacterales by wild nutria (Myocastor coypus) in a local river of Gifu Prefecture.
Environmental pollution caused by antimicrobial resistance is a global public health concern. To investigate the contribution of nutrias (Myocastor coypus) to the presence of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales in the Ijira River, prevalence of ESBL-producing Enterobacterales in their feces was examined using deoxycholate-hydrogen sulfide-lactose agar containing cefotaxime. Additionally, the composition of the fecal microbiota of nutria was examined using DNA metabarcoding analysis of the 16S ribosomal RNA gene and compared with that of Amami rabbit, deer, fox, and raccoon dog. The absence of ESBL-producing Enterobacterales and substantially lower abundance of Enterobacterales was observed in the feces of nutrias than in those of other wild mammals. Our results suggest the low potential of antimicrobial-resistant Enterobacterales persistence and dissemination by nutria.


Valorisation of the residual aqueous phase from hydrothermally liquefied black liquor by persulphate-based advanced oxidation.
Hydrothermal liquefaction of Kraft black liquor is a promising method for the production of valuable organic chemicals. However, the separation of the biochar and biocrude leaves a residual aqueous phase in large volumes, which needs to be properly managed to make the process profitable. In this work, the persulphate-based advanced oxidation was assessed, for the first time ever, as a pretreatment of this aqueous phase to reduce its content of phenolic compounds and alcohols, which hinder further valorisation strategies. Results revealed that the phenolic compounds and the alcohols were oxidised in presence of low persulphate anion concentrations (<50 mM), mainly to quinone-like compounds and organic acids. At higher oxidant concentrations, these intermediates were subsequently oxidised to valuable acetic acid. When Fe (II) was added as the catalyst, low concentrations (<9 mM) enhanced the degradation of both phenolic compounds and alcohols due to the increase of the sulphate radicals, consequently reducing persulphate requirements for their removal. Nevertheless, higher Fe (II) doses produced the sequestration of sulphate radicals, thus decreasing the oxidation performance and generating undesired parallel reactions.


A study on removing nitrogen from paddy field rainfall runoff by an ecological ditch-zeolite barrier system.
Ecological ditches and zeolite have been widely applied in the removal of farmland nonpoint source pollution separately; little research has been done on the effects of combining the two methods. Specifically, few studies have focused on the in situ regeneration of zeolite. A 2-year field experiment using an ecological ditch-zeolite barrier system was conducted in a paddy field of summer rice-winter wheat rotation in the Taihu Lake area. The system consisted of two zeolite barriers positioned at one third and two thirds of the length of the ditch. This study focused on the effect of the system on in situ nitrogen removal during the rice-growing season. Simultaneous laboratory kinetics experiments with natural zeolite and a series of adsorbed zeolites taken from the ditch at different time were also conducted. The concentration removal efficiencies of total nitrogen are averaged 24.66% in 2014 and 30.39% in 2015. Meanwhile, the cumulative adsorption quantity of ammonia nitrogen by the two barriers accounted for 49.27% of the ammonia nitrogen removed in 2014 and 54.35% of that in 2015. The amount of nitrogen adsorbed by plants was larger than that adsorbed by zeolite. The breakthrough curves of the zeolite and the characteristics of the zeolite surface structures from different periods all demonstrated that the zeolite can be regenerated in situ in the case of unsaturated zeolite within the ecological ditch. It can be concluded that an ecological ditch-zeolite barrier system is a realistic option for removing nitrogen from agricultural rainfall runoff in the Taihu Lake area.


Mother reports of maternal support following child sexual abuse: Preliminary psychometric data on the Maternal Self-report Support Questionnaire (MSSQ).
Maternal support is an important factor in predicting outcomes following disclosure of child sexual abuse; however, definition of the construct has been unclear and existing measures of maternal support are utilized inconsistently and have limited psychometric data. The purpose of this study was to develop a reliable and valid mother-report measure for assessing maternal support following the disclosure of child sexual abuse. Data from 2 very similar samples of mother-child pairs seeking forensic evaluation following the discovery of child sexual abuse were combined, resulting in a final sample of 246. Exploratory factor analysis resulted in two reliable 7-item factors labeled "Emotional Support" and "Blame/Doubt," each of which had acceptable internal consistency. Analyses with a child-report measure of general maternal support the construct validity of the MSSQ. Concurrent validity analyses revealed unique relations with maternal ratings of child behavior problems and case characteristic data. The study resulted in the development of a brief, easily scored self-report measure of maternal support with reasonable preliminary psychometric properties that could easily be utilized in other studies of sexually abused children. Adoption of this promising measure in future research will reduce the lack of cross-study measurement comparability that has characterized the maternal support literature to date, increase the feasibility of expanding upon current literature on maternal support, and may produce important information leading to clinical and theoretical innovation.


A rapid and efficient procedure for transformation of Saccharomyces cerevisiae intact cells with plasmid DNA.
A rapid and efficient yeast transformation procedure has been developed through investigation of factors affecting transformation efficiency. The manipulation of the entire procedure can be done within one and one half hours. High yield of transformants is obtained by: adding calf thymus DNA as carrier DNA; adding PEG4000, carrier DNA and plasmid DNA to cell suspension simultaneously; prolonging heat shock at 42 degrees C from 5 min to 25 min and spreading the transformation mixture directly onto agar plates after heat shock. The pretreatment of yeast intact cells with LiAc can be omitted in this procedure. The transformation rates of four types of plasmid DNA were as follows: pCN60: 3.5-7.2 x 10(4) (for linear pCN60/BamHI: 1.6 x 10(5)); YEp13: 1.7-2.6 x 10(4) (for linear YEp13/BamHI: 8.0 x 10(4)); RC4: 3.7 x 10(4); YIp5/StuI: 7.6 x 10(3). Seven recipient strains transformed by using this procedure all reached the yields of over 10(4) transformants per microgramme of DNA.


Neutrophil depletion reduces myocardial reperfusion morbidity.
We tested the hypothesis that depletion of neutrophil leukocytes from the cardioplegic and the initial myocardial reperfusion perfusates reduces clinical indices of reperfusion injury in patients undergoing elective coronary artery bypass. We studied 160 consecutive patients who underwent standard coronary revascularization with cardiopulmonary bypass. Patients with recent myocardial infarction or coronary angioplasty were excluded. Cold blood cardioplegia was used. Just before aortic unclamping, the hearts were perfused retrograde with 250 mL of normothermic cardioplegic solution and 750 mL of blood (pump perfusate). Patients were randomly assigned to two groups. In 80 patients (treated), neutrophils and platelets were removed from all cardiac perfusate during aortic crossclamping with leukocyte filtration. In the remaining 80 patients (control group), leukocyte filtration was not used. There was no significant difference between groups in age, sex, severity of disease, and number of bypass grafts implanted. Treated patients showed lower prevalence of low cardiac index and reperfusion ventricular fibrillation and lower levels of creatinine kinase MB isoenzyme and troponin I early postoperatively (p < 0.05). Neutrophil-filtered blood cardioplegia/reperfusion significantly reduced clinical and biochemical indices of myocardial reperfusion injury after elective coronary revascularization with cardiopulmonary bypass.


Successful management of postoperative necrotizing pancreatitis after infrarenal abdominal aortic aneurysm repair.
We present a case of severe necrotizing pancreatitis that developed after elective repair of an abdominal aortic aneurysm. Surgeons are confronted in cases of postoperative acute pancreatitis with the dilemma of potential intraabdominal infection and the high risk of a subsequent infection of the retroperitoneal synthetic material. The therapeutic options range from a restrictive regime to radical necrosectomy and multivisceral resection.


High antimetastatic efficacy of MEN4901/T-0128, a novel camptothecin carboxymethyldextran conjugate.
The antimetastatic activity of a novel camptothecan conjugate, MEN4901/T-0128, in which 7-ethyl-10-aminopropyloxy-camptothecin (T-2513) is bound to a biodegradable carboxymethyldextran via a Gly-Gly-Gly linker, was observed in this study. High antimetastatic activity of MEN4901/T-0128 was demonstrated in a clinically-relevant orthotopic mouse model of human colon cancer. MEN4901/T-0128 and irinotecan were compared for anti-metastatic activity as well as efficacy against the primary tumor. An imageable, metastatic model was made by surgical orthotopic implantation (SOI) of the green fluorescent protein (GFP)-expressing HT-29 tumor in nude mice. MEN4901/T-0128 and irinotecan were administered intravenously at various doses and schedules. MEN4901/T-0128, with treatment beginning on d 49 after SOI, was highly effective on lymph node metastasis as well as against the primary tumor. Both GFP imaging and histology demonstrated a markedly lower metastatic incidence of lymph nodes in all MEN4901/T-0128 treated mice compared with irinotecan-treated and untreated mice. At the most efficacious dose of MEN4901/T-0128, only 1 of 12 animals had lymph node metastasis compared with 19 of 20 in the control group. The present study demonstrates the principle that when a camptothecan is conjugated to an appropriate polymer, the drug can become extremely effective with important clinical potential for antimetastatic therapy, a most urgent need.


Rare case of obscure haemorrhage in the upper digestive tract (epiglottis).
An exceptional case of obscure bleeding in the upper digestive tract caused by an arteriovenous haemangioma of the epiglottis is presented. The clinical details and surgical findings are described.


The EPICAL trial, a phase Ib study combining first line afatinib with anti-EGF vaccination in EGFR-mutant metastatic NSCLC.
Combination of anti-EGFR monoclonal antibodies or immune checkpoint inhibitors with TKIs has shown minimal benefit in EGFR mutant (EGFR-mut) NSCLC patients. Consequently, new combination approaches are needed. The EPICAL was a single arm, phase 1b study to evaluate safety, tolerability and anti-tumor activity of first line afatinib combined with anti-EGF vaccination in advanced EGFR-mut patients. EGFR status and mutations in liquid biopsies were determined by reverse transcriptase-polymerase chain reaction; serum biomarkers by ELISA and Western blotting analysis. The assay enrolled 23 patients, 21 completed the anti-EGF immunization phase. Treatment was well tolerated and no serious adverse events (SAEs) related to the anti-EGF vaccine were reported. Objective response and disease control rates were 78.3% (95%CI = 53.6-92.5) and 95.7% (95%CI = 78.1-99.9), respectively. After a median follow-up of 24.2 months, median progression-free survival (PFS) was 14.8 months (95% CI = 9.5-20.1) and median overall survival (OS) 26.9 months (95% CI = 23.0-30.8). Among the 21 patients completing the immunization phase, PFS was 17.5 months (95% CI = 12.0-23.0) and OS 26.9 months (95% CI = 24.6-NR). At the end of the immunization phase, all 21 patients showed high serum titers of anti-EGF antibodies, while EGF levels had decreased significantly. Finally, treatment with fully immunized patient's sera inhibited the EGFR pathway in tumor cells growing in vitro. Combination treatment with an anti-EGF vaccine is well tolerated; induces a sustained immunogenic effect and might enhance the clinical efficacy of EGFR TKIs.


Quantitative Late Gadolinium Enhancement Cardiac Magnetic Resonance and Sudden Death in Hypertrophic Cardiomyopathy: A Meta-Analysis.
Quantitative late gadolinium enhancement (LGE) cardiac magnetic resonance provides important prognostic information for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). However, it has not been fully integrated into clinical practice. To assess the prognostic value of LGE extent in predicting SCD in adults with HCM across different methods of quantification, thresholds, and patients' clinical profile. The authors searched PubMed, Web of Science, and Cochrane Library for studies investigating the prognostic value of LGE% in predicting SCD in HCM. Pooled odds ratios were calculated with 95% CIs. The optimal threshold was determined using a multiple cutoffs model. Eleven studies were included in the meta-analysis with a total of 5,550 patients and a median follow-up time of 5.2 years. Two studies quantified LGE manually, 7 studies used the 6 SD technique, 1 study used the 4 SD technique, and 1 study the 2 SD technique. There was no statistically significant difference in predicting SCD between these 4 methods (P = 0.443). Optimal cutoff could be determined only for the 6 SD technique. LGE 10% was the optimal threshold of the 6 SD technique with sensitivity 0.73 and specificity 0.67. The different LGE quantification techniques have comparable accuracy in predicting SCD. When the more extensively studied 6 SD technique is used, LGE 10% is the optimal cutoff and can effectively restratify intermediate-risk patients. LGE extent can improve HCM risk stratification, but it is unlikely to become a standalone tool.


Placental mitochondria as a source of oxidative stress in pre-eclampsia.
Pre-eclampsia is a hypertensive disorder of human pregnancy that is a leading cause of premature delivery and fetal growth retardation. It is characterized by hypertension, reduced uteroplacental blood flow, proteinuria and oedema. Pre-eclampsia is associated with increased lipid peroxidation in the maternal circulation and in the placenta. Mitochondria are sources of oxygen radicals and are enriched with polyunsaturated fatty acids that are susceptible to peroxidation. Therefore, the mitochondria could be an important source of oxidative stress and lipid peroxidation. To study this, the level of lipid peroxidation in the mitochondrial fraction of placentae obtained from normally pregnant women (n=8) and women with pre-eclampsia (n=8) was examined. Placental tissues were homogenized and the mitochondrial fraction was isolated by ultracentrifugation. Mitochondrial lipid peroxides were estimated by malondialdehyde (MDA). NADPH and Fe++ were used to stimulate lipid peroxidation. Superoxide dismutase (SOD) was used to inhibit superoxide radicals and mannitol to inhibit hydroxyl radicals. The following results were found: (1) MDA levels were significantly greater in the mitochondrial fraction isolated from pre-eclamptic placentae than from normal placentae (27.4+/-3.0 versus 17.0+/-1.8 nmol/g tissue, mean+/-s.e., P<0.05); (2) the oxidative potential of the pre-eclamptic mitochondrial fraction was also higher than normal as evidenced by the significantly greater stimulation of lipid peroxidation by NADPH and Fe+ + (248+/-25 versus 164+/-35 nmol/g, P<0.05); (3) superoxide dismutase, but not mannitol, attenuated the lipid peroxidation induced by NADPH and Fe+ + demonstrating that superoxide is the radical responsible for mitochondrial lipid peroxidation in this system; and (4) the amount of mitochondrial protein was 47 per cent greater and the activity of the mitochondrial enzyme, citrate synthase, was 56 per cent greater in the pre-eclamptic placentae indicating an increase in the amount of mitochondria in the pre-eclamptic placentae. It is concluded that: (1) mitochondrial lipid peroxidation is increased in pre-eclampsia; (2) the amount of placental mitochondria is increased in pre-eclampsia; (3) placental mitochondria contribute to the abnormal increase in lipid peroxidation that occurs in pre-eclamptic placentae by both an increase in their amount and an increase in their susceptibility to oxidation; and (4) mitochondrial generation of superoxide could be an important source of oxidative stress in pre-eclampsia.


Heating of gases during neonatal resuscitation: a bench study.
Standard practice within the neonatal unit is to use heated humidified gas as it decreases respiratory complications in neonates requiring respiratory support. Using cold unhumidified gases during resuscitation could potentially cool the baby as well as exacerbate potential lung injury. We aimed to study the temperature and humidity aspects of using heated, humidified gas for neonatal resuscitation. A heated patient circuit was connected to a T-piece resuscitator via a humidifier. An oxygen flowmeter was set at 10 L/min. Temperature recordings at the humidifier chamber (T1), distal temperature probe (T2) and T-piece (T3) were taken over 20 min at 30s intervals. A humidity sensor was placed at T3. Target temperatures were not reached. Time to 36°C (mean (sd)): T1 11.1 min (1.71); T3 11.6 min (1.77). T2 took 13.6 min (1.07) to reach 39°C. T1 and T3 were within ±1°C at 5.1 min (0.6). A biphasic relationship demonstrated the time lag between the temperatures of the heated patient circuit and the humidifier chamber. T3 strongly correlated to T1 when T1 is ≥28°C (r(2)=0.85). Humidity was difficult to measure and results were inferred from temperature recordings. This in vitro test showed that heated, humidified gas is possible during neonatal resuscitation. Adequate time must be allowed for the humidifier chamber to warm to near optimal temperature. The patient circuit is initially heated faster than the humidifier chamber. The displayed T1 temperature correlates to the temperature at T3 at ≥28°C.


Metabolism of cyclic nucleotides in allergic rhinitis: studies on lymphocytes, granulocytes, and plasma level.
The effect of isoproterenol on the cyclic nucleotide level in peripheral lymphocytes and granulocytes with allergic rhinitis patients and normal subjects has been studied. Responsiveness to 10(-5) M isoproterenol of lymphocytes decreased in the case of allergic rhinitis patients. When asthma was complicated to perennial rhinitis, a more significant depression was noted. In granulocytes the same tendency as with lymphocytes was noted although the difference was not significant. Basal level and responsiveness to 5 X 10(-3) M theophylline of both lymphocytes and granulocytes were similar in allergic rhinitis patients to normal subjects. The ratio of plasma cAMP to cGMP concentration was lower in the allergic rhinitis patients although the difference was not significant.


Reshaping of the Broad and Bulbous Nasal Tip.
This article presents a contemporary overview of tip suturing and tip structural grafting techniques used to refine the wide nasal tip. Previous reductive techniques have proved to produce unnatural results over time. It is imperative to correctly evaluate the nose and assess all possible pitfalls during the preoperative period before outlining a surgical plan. Intraoperatively, an algorithmic approach helps obtain a reproducible and refined yet properly narrowed domal tip region with graceful contours that extend laterally to the alar lobule with proper shadowing.


A comparison of lysis mediated by Lyt 2+ TNP-specific cytotoxic-T-lymphocyte (CTL) lines with that mediated by rapidly internalized lymphotoxin-containing supernatant fluids: evidence for a role of soluble mediators in CTL-mediated killing.
A series of Lyt 2+, trinitrophenyl (TNP)-specific T-cell lines are shown to lyse 51Cr-labeled target cells in an antigen-specific, H-2-restricted fashion in a 4-hr assay. These cells also produce lymphotoxin, in addition to other factors, upon stimulation with TNP-haptenated syngeneic splenocytes. A technique for introducing macromolecules into the cytoplasm of fibroblasts by inducing the cells to pinocytose the molecule in hypertonic medium, and then lysing the newly formed pinocytic vesicles with a mild hypotonic shock was used to assess the role of soluble mediators in the cytotoxic T lymphocyte (CTL)-mediated lytic process. The technique itself has little effect on cell growth rate or viability. A minimum of 24 hr, and more frequently 48-72 hr is required for lymphotoxin to manifest it's lethal effect when it is merely included in the culture medium of growing fibroblasts. In contrast, supernatant fluids from the Lyt 2+ cells kill 51Cr-labeled fibroblasts in a dose-dependent fashion during a 4-hr assay when they are rapidly internalized via the osmotic procedure. The data serve as preliminary evidence of a role for soluble mediators such as lymphotoxin in T-cell-mediated lysis, and suggest that the cytotoxic-T-cell lethal hit may include a mechanism for rapidly internalizing a toxin into appropriate target cells.


Modulation by topiramate of AMPA and kainate mediated calcium influx in cultured cerebral cortical, hippocampal and cerebellar neurons.
The effect of the antiepileptic drug topiramate on Ca2+ uptake through (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate (AMPA) and kainate (KA) receptors was investigated in different cell culture systems consisting of neurons from the cerebral cortex, hippocampus, and cerebellum. Ca2+ influx was assayed using a fluorescent Ca2+ chelator to monitor changes in the intracellular Ca2+ concentration or cobalt staining to assess the effect of topiramate on Ca2+-permeable AMPA/KA receptors. In all types of neuronal cultures studied, AMPA and KA were found to elicit an influx of Ca2+ in a subset of the neuronal population. Topiramate, at concentrations of 30 and 100 microM, inhibited Ca2+ influx by up to 60%. Modulation of AMPA and KA-evoked Ca2+ influx may contribute to both the antiepileptic and neuroprotective properties of topiramate.


[Results of sigma resection in acute complicated diverticulitis : method and time of surgical intervention].
The aim of this study was to check the results of laparoscopic sigmoid resection for sigmoid diverticular disease with respect to stage of inflammation and time of surgical intervention. All patients were divided into four groups: uncomplicated (Group 1) vs complicated diverticular disease (Group 2), and depending on surgical intervention in early elective (4-8 days, Group A) vs late elective sigmoid resection (4-6 weeks, Group B). At total of 244 patients underwent laparoscopically-assisted resection during the examination period. Differences in favor of Group 1 were found in duration of surgery (153 min vs 167 min), postoperative wound infections (3.55% vs 15.5%), and postoperative hospitalization period (12.2 days vs 14.6 days). Group A had more conversions (7.8% vs 0.9%), more minor complications (25.9% vs 12.9%), and more wound infections (16.4% vs 4.6%) than Group B. Laparoscopic sigmoid resection can be performed in cases of complicated diverticulitis without significantly increasing their overall morbidity. Because of the lower complication rate, we recommend that patients with acute sigmoid diverticulitis receive initial antibiotic treatment and then undergo late elective laparoscopic sigmoid resection.


Osmotic diuresis-induced hypernatremia: better explained by solute-free water clearance or electrolyte-free water clearance?
Hypernatremia may result from inadequate water intake, excessive water loss or a combination of the two. Osmotic diuresis leads to losses of both solute and water. The relationship between solute and water losses determines the resulting changes in serum osmolality and sodium concentration. Total solute loss is routinely higher than loss of water in osmotic diuresis. Theoretically, then, decreases in serum osmolality (and serum sodium concentration) should follow. In clinical situations of osmotic diuresis, however, reduction in osmolality can take place, but not reduction in serum sodium concentration. It is of note that serum sodium concentration changes are related to urinary losses of sodium and potassium but not to the loss of total solute. In osmotic diuresis, the combined loss of sodium and potassium per liter of urine is lower than the concurrent serum sodium level. Consequently, hypernatremia can ensue. A patient who presented with osmotic diuresis and hypernatremia is described here. In this patient, we have shown that electrolyte-free water clearance is a better index of the effect of osmotic diuresis on serum sodium concentration than the classic solute-free water clearance.


Dimethyl fumarate therapy reduces memory T cells and the CNS migration potential in patients with multiple sclerosis.
Dimethyl fumarate (DMF) is a disease-modifying therapy for patients with relapsing-remitting multiple sclerosis (RRMS). T cells are major contributors to the pathogenesis of RRMS, where they regulate the pathogenic immune response and participate in CNS lesion development. In this study we evaluate the therapeutic effects of DMF on T cell subpopulations, their CNS migration potential and effector functions. Blood and CSF from untreated and DMF-treated patients with RRMS and healthy donors were analyzed by flow cytometry. DMF reduced the prevalence of circulating proinflammatory CD4+ and CD8+ memory T cells, whereas regulatory T cells were unaffected. Furthermore, DMF reduced the frequency of CD4+ T cells expressing CNS-homing markers. In coherence, we found a reduced recruitment of CD4+ but not CD8+ T cells to CSF. We also found that monomethyl fumarate dampened T cell proliferation and reduced the frequency of TNF-α, IL-17 and IFN-γ producing T cells. DMF influences the balance between proinflammatory and regulatory T cells, presumably favoring a less proinflammatory environment. DMF also reduces the CNS migratory potential of CD4+ T cells whereas CD8+ T cells are less affected. Altogether, our study suggests an anti-inflammatory effect of DMF mainly on the CD4+ T cell compartment.


α-Synuclein binds the K(ATP) channel at insulin-secretory granules and inhibits insulin secretion.
α-Synuclein has been studied in numerous cell types often associated with secretory processes. In pancreatic β-cells, α-synuclein might therefore play a similar role by interacting with organelles involved in insulin secretion. We tested for α-synuclein localizing to insulin-secretory granules and characterized its role in glucose-stimulated insulin secretion. Immunohistochemistry and fluorescent sulfonylureas were used to test for α-synuclein localization to insulin granules in β-cells, immunoprecipitation with Western blot analysis for interaction between α-synuclein and K(ATP) channels, and ELISA assays for the effect of altering α-synuclein expression up or down on insulin secretion in INS1 cells or mouse islets, respectively. Differences in cellular phenotype between α-synuclein knockout and wild-type β-cells were found by using confocal microscopy to image the fluorescent insulin biosensor Ins-C-emGFP and by using transmission electron microscopy. The results show that anti-α-synuclein antibodies labeled secretory organelles within β-cells. Anti-α-synuclein antibodies colocalized with K(ATP) channel, anti-insulin, and anti-C-peptide antibodies. α-Synuclein coimmunoprecipitated in complexes with K(ATP) channels. Expression of α-synuclein downregulated insulin secretion at 2.8 mM glucose with little effect following 16.7 mM glucose stimulation. α-Synuclein knockout islets upregulated insulin secretion at 2.8 and 8.4 mM but not 16.7 mM glucose, consistent with the depleted insulin granule density at the β-cell surface membranes observed in these islets. These findings demonstrate that α-synuclein interacts with K(ATP) channels and insulin-secretory granules and functionally acts as a brake on secretion that glucose stimulation can override. α-Synuclein might play similar roles in diabetes as it does in other degenerative diseases, including Alzheimer's and Parkinson's diseases.


Morbidity hotspot surveillance: A novel approach to detect lymphatic filariasis transmission in non-endemic areas of the Tillabéry region of Niger.
The Niger Lymphatic Filariasis (LF) Programme is making good progress towards the elimination goal and scaling up morbidity management and disability prevention (MMDP) activities. Clinical case mapping and the increased availability of services has prompted patients to come forward in both endemic and non-endemic districts. The latter included Filingué, Baleyara and Abala districts of the Tillabéry region, and in 2019, 315 patients were found during a follow-up active case finding activity, suggesting it may have low transmission. The aim of this study was to assess the endemicity status in areas reporting clinical cases, 'morbidity hotspots', in three non-endemic districts of the Tillabéry region. A cross-sectional survey was conducted in 12 villages in June 2021. Filarial antigen was detected using the rapid Filariasis Test Strip (FTS) diagnostic, and information obtained on gender, age, residency length, bed net ownership and usage, and presence of hydrocoele and/or lymphoedema. Data were summarised and mapped using QGIS software. A total of 4058 participants between 5 and 105 years old were surveyed, with 29 (0.7%) participants found to be FTS positive. Baleyara district had significantly higher FTS positive rates than the other districts. No significant differences were found by gender (male 0.8%; female 0.6%), age group (<26 years 0.7%; ≥26 years 0. 7%), and residency length (<5 years 0.7%; ≥5 years 0.7%). Three villages reported no infections; seven villages <1%, one village 1.1% and one village 4.1%, which was on the border of an endemic district. Bed net ownership (99.2%) and usage (92.6%) was very high and there was no significant difference between FTS infection rates. The results indicate that there are low levels of transmission in populations, including children, living in districts previously classified as non-endemic. This has implications for the Niger LF programme in terms of delivering targeted mass drug administration (MDA) in transmission hotspots, and MMDP services, including hydrocoele surgery to patients. The use of morbidity data may be a practical proxy to trigger mapping of ongoing transmission in low endemic areas. Continued efforts to study morbidity hotspots, post-validation transmission, cross-border and cross-district endemicity are needed to meet the WHO NTD 2030 roadmap targets.


Interferon-β therapy specifically reduces pathogenic memory B cells in multiple sclerosis patients by inducing a FAS-mediated apoptosis.
Growing evidences put B lymphocytes on a central stage in multiple sclerosis (MS) immunopathology. While investigating the effects of interferon-β (IFN-β) therapy, one of the most used first-line disease-modifying drugs for the treatment of relapsing-remitting MS, in circulating B-cell sub-populations, we found a specific and marked decrease of CD27+ memory B cells. Interestingly, memory B cells are considered a population with a great disease-driving relevance in MS and resulted to be also target of B-cell depleting therapies. In addition, Epstein-Barr virus (EBV), associated with MS etiopathogenesis, harbors in this cell type and an IFN-β-induced reduction of the memory B-cell compartment, in turn, resulted in a decreased expression of the EBV gene latent membrane protein 2A in treated patients. We found that in vivo IFN-β therapy specifically and highly induced apoptosis in memory B cells, in accordance with a strong increase of the apoptotic markers Annexin-V and active caspase-3, via a mechanism requiring the FAS-receptor/TACI (transmembrane activator and CAML interactor) signaling. Thus, efficacy of IFN-β therapy in MS may rely not only on its recognized anti-inflammatory activities but also on the specific depletion of memory B cells, considered to be a pathogenic cell subset, reducing their inflammatory impact in target organs.


Software-supported periodontal diagnostics with three-dimensional cone-beam computed tomography compared to conventional two-dimensional panoramic imaging and clinical diagnostics (a prospective study).
Aim of this study comprised the software-supported evaluation of measurement accuracy between cone-beam computed tomography (CBCT) and panoramic radiographs in the assessment of the periodontal bone level in patients with periodontitis and comparison with clinical periodontal parameters. Twenty patients with severe periodontitis (stage III-IV) were evaluated clinically and radiographically (panoramic and CBCT). Diagnostic interpretation comprised three blinded investigators with different levels of experience. Specific software-basing measurement procedure evaluated radiological distances for the mesial, central, and distal bone levels on the oral and vestibular sides of the teeth investigated and furcation upper and lower boundary. Jaw localization, anatomical region-of-interest, the number of roots and experience of the observers were evaluated. All measurements were carried out twice by the same observers within a 6-week interval. Slightly higher measurement deviations (SD) in the range of 0.47 (0.40) mm were found for CBCT evaluation compared to panoramic imaging. Pearson correlation analysis showed statistically strong positive correlation for the mesial and distal aspects, moderate positive correlation was found for the investigated furcations between both radiographic modalities. Compared to the clinical reference, the mean total error of measurement (SD) was larger for panoramic imaging (0.66 (0.48) mm) than CBCT (0.27 (0.08) mm) for all three observers. Software-supported CBCT analysis delivers better diagnostic information about the bony periodontal conditions of the patient compared to two-dimensional radiographs. However, it remains unclear if these additional information lead to better periodontal outcomes.


Estimating the contribution of transmission in primary healthcare clinics to community-wide TB disease incidence, and the impact of infection prevention and control interventions, in KwaZulu-Natal, South Africa.
There is a high risk of Mycobacterium tuberculosis (Mtb) transmission in healthcare facilities in high burden settings. WHO guidelines on tuberculosis (TB) infection prevention and control (IPC) recommend a range of measures to reduce transmission in healthcare settings. These were evaluated primarily based on evidence for their effects on transmission to healthcare workers in hospitals. To estimate the overall impact of IPC interventions, it is necessary to also consider their impact on community-wide TB incidence and mortality. We developed an individual-based model of Mtb transmission in households, primary healthcare (PHC) clinics, and all other congregate settings. The model was parameterised using data from a high HIV prevalence community in South Africa, including data on social contact by setting, by sex, age, and HIV/antiretroviral therapy status; and data on TB prevalence in clinic attendees and the general population. We estimated the proportion of disease in adults that resulted from transmission in PHC clinics, and the impact of a range of IPC interventions in clinics on community-wide TB. We estimate that 7.6% (plausible range 3.9%-13.9%) of non-multidrug resistant and multidrug resistant TB in adults resulted directly from transmission in PHC clinics in the community in 2019. The proportion is higher in HIV-positive people, at 9.3% (4.8%-16.8%), compared with 5.3% (2.7%-10.1%) in HIV-negative people. We estimate that IPC interventions could reduce incident TB cases in the community in 2021-2030 by 3.4%-8.0%, and deaths by 3.0%-7.2%. A non-trivial proportion of TB results from transmission in clinics in the study community, particularly in HIV-positive people. Implementing IPC interventions could lead to moderate reductions in disease burden. We recommend that IPC measures in clinics should be implemented for their benefits to staff and patients, but also for their likely effects on TB incidence and mortality in the surrounding community.


Adverse Drug Effects and Preoperative Medication Factors Related to Perioperative Low-Dose Ketamine Infusions.
High-dose opioid administration is associated with significant adverse events. Evidence suggests that low-dose ketamine infusions improve perioperative analgesia over conventional opioid management, but usage is highly variable. Ketamine's adverse drug effects (ADEs) are well known, but their prevalence during low-dose infusions in a clinical setting and how often they lead to infusion discontinuation are unknown. The purposes of this study were 3-fold: (1) to identify patient factors associated with initiation of ketamine infusions during spine surgery, (2) to identify specific spine procedures in which ketamine has been used most frequently, and (3) to identify ADEs associated with postoperative ketamine infusions and which ADEs most frequently led to discontinuation. Spine surgery was chosen because of its association with moderate to severe pain and a relatively high use of ketamine infusions in this population at our hospital.


Radiologic changes of the temporomandibular joint after condylar fractures in childhood.
The purpose of this investigation was to study the radiologic outcomes of pediatric condylar fractures. Radiographs of 37 patients with 45 condylar fractures that had been diagnosed at the Department of Oral and Maxillofacial Surgery, Helsinki University Central Hospital were retrospectively reviewed. The frequency and characteristics of incomplete remodeling at an average of 4.1 years after the injury were studied. The influence of age and fracture type on remodeling were considered. Incomplete remodeling was observed after 56% of the fractures. The most frequent signs of incomplete remodeling were alteration in the configuration of the surface of the condylar head and deformation of the condylar neck. Incomplete remodeling was frequently (83%) related to fracture dislocation. For this fracture type the radiologic prognosis seems poor in all age groups. A difference in ramus height between the 2 sides was observed in 52% of the fractures, particularly frequently (80%) after fracture dislocation. Radiologic aberrations are frequent after pediatric condylar fractures. Dislocated fractures, in particular, need special attention and long-lasting clinical follow-up.


Increased serum levels of aldehydes are associated with cardiovascular disease and cardiovascular risk factors in adults.
Previous studies have identified several genetic and environmental risk factors for cardiovascular disease (CVD), but little is known about the associations between serum aldehydes and CVD risk. Herein, we examined associations between serum levels of aldehydes and the risk of CVD and CVD subtypes among 1947 U.S. adults participating in the National Health and Nutrition Examination Survey (NHANES) 2013-2014. Bayesian kernel machine regression (BKMR) was used to analyze the combined effect of serum aldehydes on the overall risk of CVD. We found that isopentanaldehyde concentrations were positively associated with the odds of CVD (adjusted odds ratio (aOR): 2.17; 95 % confidence interval (95 % CI): 1.36, 3.46). The result of BKMR also indicated a positive association of mixed aldehydes with CVD risk. Isopentanaldehyde had the highest posterior inclusion probabilities (PIP = 0.90). Each one-unit (ng/mL) increase in the isopentanaldehyde concentration was associated with a 25.0 mg/dL increase in triglycerides and a 0.9 × 109/L increase in white blood cell (WBC) count in the fully adjusted model. Current evidence suggests that isopentanaldehyde may increase the risk of CVD by elevating triglycerides and WBC count.


The impact of the number of harvested central lymph nodes on the lymph node ratio.
The purpose of this study was to analyze the impact of lymph node harvest on the lymph node ratio (LNR). We retrospectively reviewed 106 patients diagnosed preoperatively with PTMC (papillary thyroid microcarcinoma), no evidence of central or lateral neck nodal metastasis, and who underwent a total thyroidectomy and bilateral central lymph node neck dissection (CND). The median number of retrieved lymph nodes in the central compartments was 7±6.59 (range: 1-42). The mean number of metastatic lymph nodes in the central compartments on pathology was 1.1±1.79 (range: 0-7). The high node volume group (>7) had a significantly higher rate of central lymph node (CLN) metastasis than the low node volume group (≤7) in the final pathologic report (p<0.001). With the linear regression method, the number of CLN metastasis increased as the number of retrieved lymph nodes increased (correlation coefficient=0.286, p=0.003). The multivariate analysis confirmed the number of retrieved lymph nodes in the central compartments was a risk factor for high LNR (p=0.008, odds ratio 3.737). The rates of vocal fold palsy and hypoparathyroidism did not differ according to the number of retrieved lymph nodes. The lymph node ratio in the final pathologic report is larger when a greater number of lymph nodes are retrieved during the central compartment neck dissection.


Organizations and further resources.
Local organizations can put you into contact with specialist centres and other resources in your area.


The Role of p53 Family in Cancer.
This Special Issue covers a broad topic on the role of the p53 protein family in cancer [...].


Diffeomorphic transforms for data augmentation of highly variable shape and texture objects.
Training a deep convolutional neural network (CNN) for automatic image classification requires a large database with images of labeled samples. However, in some applications such as biology and medicine only a few experts can correctly categorize each sample. Experts are able to identify small changes in shape and texture which go unnoticed by untrained people, as well as distinguish between objects in the same class that present drastically different shapes and textures. This means that currently available databases are too small and not suitable to train deep learning models from scratch. To deal with this problem, data augmentation techniques are commonly used to increase the dataset size. However, typical data augmentation methods introduce artifacts or apply distortions to the original image, which instead of creating new realistic samples, obtain basic spatial variations of the original ones. We propose a novel data augmentation procedure which generates new realistic samples, by combining two samples that belong to the same class. Although the idea behind the method described in this paper is to mimic the variations that diatoms experience in different stages of their life cycle, it has also been demonstrated in glomeruli and pollen identification problems. This new data augmentation procedure is based on morphing and image registration methods that perform diffeomorphic transformations. The proposed technique achieves an increase in accuracy over existing techniques of 0.47%, 1.47%, and 0.23% for diatom, glomeruli and pollen problems respectively. For the Diatom dataset, the method is able to simulate the shape changes in different diatom life cycle stages, and thus, images generated resemble newly acquired samples with intermediate shapes. In fact, the other methods compared obtained worse results than those which were not using data augmentation. For the Glomeruli dataset, the method is able to add new samples with different shapes and degrees of sclerosis (through different textures). This is the case where our proposed DA method is more beneficial, when objects highly differ in both shape and texture. Finally, for the Pollen dataset, since there are only small variations between samples in a few classes and this dataset has other features such as noise which are likely to benefit other existing DA techniques, the method still shows an improvement of the results.


Protective effect of adipose-derived stromal cell-secretome attenuate autophagy induced by liver ischemia-reperfusion and partial hepatectomy.
The therapeutic effects of adipose-derived mesenchymal stromal cells (ADSCs) may be mainly mediated by their paracrine effects. The ADSC-secretome can ameliorate hepatic ischemia-reperfusion injury (IRI). We explored the therapeutic effect of the ADSC-secretome from the perspective of excessive hepatocyte autophagy induced by hepatic IRI. We established a miniature pig model of hepatic ischemia-reperfusion (I/R) and hepatectomy using a laparoscopic technique and transplanted ADSCs and the ADSC-secretome into the liver parenchyma immediately after surgery. Liver injury and hepatocyte autophagy were evaluated by histopathological examination and assessment of relevant cytokines and other factors. The results showed that the ADSC-secretome alleviated the pathological changes of liver tissue and the microstructural damage of hepatocytes after IRI. Moreover, the expression levels of autophagy-related markers including Beclin-1, ATG5, ATG12, and LC3II/LC3I decreased, whereas those of p62 increased during phagophore expansion. Furthermore, the expression levels of markers related to the autophagy inhibition pathway phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR), including PI3K, Akt, and mTOR, increased. The ADSC-secretome attenuates hepatic I/R and hepatectomy-induced liver damage by inhibiting autophagy, which is possibly mediated by activation of the PI3K/Akt/mTOR signaling pathway. In addition, there was no significant difference between ADSCs and the ADSC-secretome in the regulation of hepatocyte autophagy. Therefore, ADSCs may improve the excessive autophagy-induced injury of hepatocytes in hepatic I/R and hepatectomy through paracrine effect. Our findings provide new insight into the therapeutic potential of cell-free products, which could replace cell therapy in liver diseases.


Purification, Kinetic, and Thermodynamic Characteristics of an Exo-polygalacturonase from Penicillium notatum with Industrial Perspective.
An extracellular exo-polygalacturonase (exo-PG) produced by Penicillium notatum was purified (3.07-folds) by ammonium sulfate fractionation, ion exchange, and gel filtration chromatography. Two distinct isoforms of the enzyme, namely exo-PGI and exo-PGII, were identified during column purification with molecular weights of 85 and 20 kDa, respectively, on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The enzyme displayed its optimum activity at pH 6.0 and 50 °C and was found to be stable in the slightly acidic pH (ranging from 4.5 to 6.0). Michaelis-Menten parameters, i.e., K m (app) and V max for pectin hydrolysis, were calculated to be 16.6 mg/mL and 20 μmol/mL/min, respectively. The enzyme followed biphasic deactivation kinetics. Phase I of the exo-PGI showed half-lives of 6.83 and 2.39 min at 55 and 80 °C, respectively, whereas phase II of the enzyme exhibited a half-life of 63.57 and 22.72 min at 55 and 80 °C, respectively. The activation energy for denaturation was 51.66 and 44.06 kJ/mol for phase I and phase II of the exo-PGI, respectively. The enzyme activity was considerably enhanced by Mn2+, whereas exposure to a hydrophobic environment (urea and sodium azide solution) drastically suppressed the enzyme activity. Results suggest that exo-PGI might be considered as a potential candidate for various applications, particularly in the food and textile industries.


Efficacy of OK-432 sclerotherapy for different types of lymphangiomas: a review and meta-analysis.
This study aims to perform a meta-analysis to figure out the efficacy of OK-432 sclerotherapy between Macrocystic (MAC) lymphangiomas and Microcystic (MIC) lymphangiomas. We conducted a systematic review and meta-analysis to clarify the relationship between OK-432 and lymphangiomas. PubMed and ISI Web of Science were searched from inception to May 2022. Joanna Briggs Institute (JBI) manual was used to evaluate the risk of bias. We calculated pooled Relative Risks (RR) and 95% Confidence Interval (95% CI) using random effects model to evaluate the relations between OK-432 and lymphangiomas. A total of 11 studies (including 352 cases) about OK-432 sclerotherapy for lymphangioma were included in the current meta-analyses. The results suggested that the efficacy of OK-432 was significantly in MAC lesions than in MIC (RR=1.51, 95% CI 1.298-1.764), with significant moderate degrees of heterogeneity among 11 studies (I2=51.2%, p=0.025). Subgroup analyses suggested that there was significant association in both retrospective studies (RR=1.26, 95% CI 1.03-1.53) and classification (by 1 cm) (RR=1.37, 95% CI 1.04-1.80) were associated with the efficacy of OK-432. To our knowledge, our study represents the first meta-analysis examining the efficacy of OK-432 in the treatment of different types of LMs. However, the regional differences and the age differences of the subjects are the main limitations of this study and should be avoided in further research. Our results suggested that OK-432 sclerotherapy for macrocystic lymphangiomas was more effective.


Cooccurrence of Alport syndrome and poststreptococcal acute glomerulonephritis with improvement after steroid administration.
It is clinically possible for patients with Alport syndrome (AS) to suffer from poststreptococcal acute glomerulonephritis (PSAGN). However, there is only one report of such a patient, and he had end-stage kidney disease. Here, we describe an 8-year-old male with X-linked AS and chronic kidney disease (CKD) stage G2. He presented with diffuse edema, gross hematuria, proteinuria, and body weight gain after streptococcal pharyngitis. Blood examination showed kidney dysfunction, hypocomplementemia, and increased anti-streptolysin-O levels. His kidney function did not improve with symptomatic treatment. Therefore, we started steroid administration on the 12th day of hospitalization. Then, his kidney function improved before he was discharged. We confirmed that his complement function had recovered at a later date. Pathological evaluation showed findings of AS and PSAGN, including cellular crescents in 3/30 glomeruli on light microscopy. In addition, electron dense deposits (EDDs) were seen in not only the visceral subepithelium but also the glomerular basement intramembrane and subendothelium, some of which were hump-like. Although AS and CKD are indicated to have a poor prognosis in PSAGN, our patient recovered after administration of steroids. Our case suggests that we can consider the administration of steroids, including pulse therapy for PSAGN, when patients have, for example, crescents on pathology, severe renal dysfunction, nephrotic proteinuria, or AS with CKD, as in our case. Kidney pathology suggested that a typical hump is not seen in patients with cooccurring AS and PSAGN. After the patient's kidney function recovered, we continued to follow him.


Patients' views on the impact of stroke on their roles and self: a thematic synthesis of qualitative studies.
To synthesize patients' views on the impact of stroke on their roles and self. PubMed, CINAHL, Embase, PsycINFO, and Cochrane searched from inception to September 2010, using a combination of relevant Medical Subject Headings and free-text terms. This search was supplemented by reference tracking. Qualitative studies reporting the views of people poststroke. The search yielded 494 records. Opinion articles, quantitative studies, or those reporting somatic functioning were excluded. Thirty-three studies were included. Data extraction involved identifying all text presented as "results" or "findings" in the included studies, and importing this into software for the analysis of qualitative data. The abstracted text was coded and then subject to a thematic analysis and synthesis, which was discussed and agreed by the research team. Three overarching themes were identified: (1) managing discontinuity is a struggle; (2) regaining roles: to continue or adapt? and (3) context influences management of roles and self. Regaining valued roles and self was an ongoing struggle, and discontinuity and uncertainty were central to the adjustment process after stroke. The thematic synthesis provides new insights into the poststroke experience. Regaining or developing a new self and roles was problematic. Interventions targeted at self-management should be focused on the recognition of this problem and included in rehabilitation, to facilitate adjustment and continuity as far as possible in life poststroke.


[Review of traditional Chinese medicine external applications to treat chemistry phlebitis].
This article reviewed the literatures in this area over the past 5 years according to three parts: simple traditional Chinese medicine external application, combination of traditional Chinese medicine and Western medicine, combination of traditional Chinese medicine and physical therapy, and came to several effective prescriptions.


Feedback regulation of platelet function by 12S-hydroxyeicosatetraenoic acid: inhibition of arachidonic acid liberation from phospholipids.
We have proposed a mechanism that platelet aggregation is regulated by its 12-lipoxygenase product, 12S-hydroxyeicosatetraenoic acid (12-HETE) (Sekiya, F., Takagi, J. and Saito, Y. (1989) Thrombos. Res. 56, 407-415). Inhibition of endogenous 12-HETE production by 15-HETE, a specific inhibitor of 12-lipoxygenase, accelerated aggregation of bovine platelets in response to collagen and arachidonic acid liberation from phospholipids was enhanced. Exogenously added 12-HETE suppressed collagen-induced liberation of arachidonic acid and the aggregation was also inhibited. On the other hand, 12-HETE did not interfere with thromboxane synthesis from free arachidonic acid in a cell-free system. These observations suggest that 12-HETE exerts a negative feedback to prevent excess aggregation through interference with arachidonic acid liberation from membrane phospholipids.


Antibodies reacting with Streptococcus mutans in secretions from minor salivary glands in humans.
1) Antibodies reacting with S. mutans in secretions from minor salivary glands in humans were determined by a modified Enzyme Linked Immunosorbent Assay. 2) IgA antibodies reacting with S. mutans serotype c were found in all samples examined. 3) The antibody level in the secretions of the minor salivary glands varied considerably between different subjects and was considerably higher than that of parotid saliva. 4) A variation in antibody concentration over time was observed in some individuals. 5) Topical application of a streptococcal vaccine consisting of formalin killed cells increased the level of antibodies in the secretions of one person. In two persons no effect was observed.


Global mammal conservation: what must we manage?
We present a global conservation analysis for an entire "flagship" taxon, land mammals. A combination of rarity, anthropogenic impacts, and political endemism has put about a quarter of terrestrial mammal species, and a larger fraction of their populations, at risk of extinction. A new global database and complementarity analysis for selecting priority areas for conservation shows that approximately 11% of Earth's land surface should be managed for conservation to preserve at least 10% of terrestrial mammal geographic ranges. Different approaches, from protection (or establishment) of reserves to countryside biogeographic enhancement of human-dominated landscapes, will be required to approach this minimal goal.


Pannexin-1 expression in developing mouse nervous system: new evidence for expression in sensory ganglia.
Pannexin1 (Panx1) is one of three members of the pannexin protein family. The expression of Panx1 mRNA has been extensively investigated from late embryonic to adult stages. In contrast, expression during early embryonic development is largely unknown. Our aim is to examine the temporal and spatial expression of Panx1 in mouse embryonic development by focusing on embryonic days (E) 9.5 to 12.5. Whole embryos are investigated in order to provide a comprehensive survey. Analyses were performed at the mRNA level by using reverse transcription plus the polymerase chain reaction and whole-mount in situ hybridization. Panx1 mRNA was detected in the heads and bodies of embryos at all developmental stages investigated (E9.5, E10.5, E11.5, E12.5). In particular, the nervous system expressed Panx1 at an early time point. Interestingly, Panx1 expression was found in afferent ganglia of the cranial nerves and spinal cord. This finding is of particular interest in the context of neuropathic pain and other Panx1-related neurological disorders. Our study shows, for the first time, that Panx1 is expressed in the central and peripheral nervous system during early developmental stages. The consequences of Panx1 deficiency or inhibition in a number of experimental paradigms might therefore be predicated on changes during early development.


Perceived cognitive function and emotional distress following coronary artery bypass surgery.
Many patients experience decrements in cognitive function and emotional adjustment following coronary artery bypass graft (CABG) surgery. Moreover, cognitive decline and emotional distress are often positively related. This study evaluated the cross-sectional and prospective associations of emotional and subjective cognitive complaints, to assess the hypothesis that they would be mutually reinforcing. Participants were 76 CABG patients recruited from Akron General Medical Center. Depression and anxiety symptoms and perceived cognitive difficulties were evaluated at a baseline postsurgical visit and re-assessed 5 months later. Emotional symptoms and perceived cognitive difficulties were significantly related both within and across time. After controlling for numerous potential confounds, baseline perceived cognitive difficulties predicted a more negative course of emotional symptoms during follow-up. Baseline emotional symptoms did not predict the course of perceived cognitive difficulties. Perceptions of cognitive decline may contribute to emotional distress in patients post-CABG.


Pleiotropic phenotype in Entamoeba histolytica overexpressing DNA methyltransferase (Ehmeth).
The protozoan parasite Entamoeba histolytica expresses a cytosine-5 DNA methyltransferase (Ehmeth) that belongs to the Dnmt2 proteins family. The biological function of members of the Dnmt2 family is unknown. Constitutive overexpression of Ehmeth resulted in a pleiotropic phenotype that includes accumulation of multinucleated cells, upregulation of Heat shock protein 70 (HSP70) expression and resistance to oxidative stress. This pleiotropic phenotype suggests that Ehmeth plays an important role in the control of key cellular processes in the parasite.


Detection of the TMPRSS2-ETS fusion gene in prostate carcinomas: retrospective analysis of 55 formalin-fixed and paraffin-embedded samples with clinical data.
The recent identification of fusion genes involving ETS family members in human prostate adenocarcinoma has confirmed the hypothesis that recurrent specific aberrations such as fusion genes may be as frequent in epithelial tumors as they are in leukemias and sarcomas. However, reciprocal translocations with fusion genes are often not detectable in carcinomas by conventional karyotyping because of additional complex chromosomal abnormalities. We retrospectively analyzed a large series of formalin-fixed, paraffin-embedded samples including 55 prostate carcinomas and 11 benign prostate tumors. We identified the fusion gene TMPRSS2-ERG by reverse-transcriptase polymerase chain reaction (RT-PCR) in 40/55 carcinomas (72%). Our study demonstrates that the detection of ETS fusion gene by RT-PCR is feasible on formalin-fixed and paraffin-embedded samples. No significant association between the presence of the fusion gene and any clinical feature, such as preoperative serum prostate-specific antigen (PSA) level (PSA>20 or PSA< or =20), pTNM stage including capsule invasion, seminal vesicle invasion, and lymph nodes metastases, or recurrence was observed in our series.


Exposure to an enriched environment up to middle age allows preservation of spatial memory capabilities in old age.
In rats, some cognitive capabilities, like spatial learning and memory, are preserved from age-related decline by whole adult life enriched environment (EE) exposure. However, to which extent late EE contributes to such maintenance remains to be investigated. Here we assessed the impact of late housing condition (e.g., from the age of 18 months) on spatial learning and memory of aged rats (24 months) previously exposed or unexposed to EE from young adulthood. The results showed that late EE was not required for spatial memory maintenance in aged rats previously housed in EE. In contrast, late EE mitigates spatial memory deficit in aged rats previously unexposed to EE. These outcomes suggest that EE exposure up to middle age provides a "reserve"-like advantage which supports an enduring preservation of spatial capabilities in old age.


Development of a potent high-affinity human therapeutic antibody via novel application of recombination signal sequence-based affinity maturation.
Therapeutic antibody development requires discovery of an antibody molecule with desired specificities and drug-like properties. For toxicological studies, a therapeutic antibody must bind the ortholog antigen with a similar affinity to the human target to enable relevant dosing regimens, and antibodies falling short of this affinity design goal may not progress as therapeutic leads. Herein, we report the novel use of mammalian recombination signal sequence (RSS)-directed recombination for complementarity-determining region-targeted protein engineering combined with mammalian display to close the species affinity gap of human interleukin (IL)-13 antibody 731. This fully human antibody has not progressed as a therapeutic in part because of a 400-fold species affinity gap. Using this nonhypothesis-driven affinity maturation method, we generated multiple antibody variants with improved IL-13 affinity, including the highest affinity antibody reported to date (34 fM). Resolution of a cocrystal structure of the optimized antibody with the cynomolgus monkey (or nonhuman primate) IL-13 protein revealed that the RSS-derived mutations introduced multiple successive amino-acid substitutions resulting in a de novo formation of a π-π stacking-based protein-protein interaction between the affinity-matured antibody heavy chain and helix C on IL-13, as well as an introduction of an interface-distant residue, which enhanced the light chain-binding affinity to target. These mutations synergized binding of heavy and light chains to the target protein, resulting in a remarkably tight interaction, and providing a proof of concept for a new method of protein engineering, based on synergizing a mammalian display platform with novel RSS-mediated library generation.