Altered expression of genes involved in brain energy metabolism as adaptive responses in rats exposed to chronic variable stress; changes in cortical level of glucogenic and neuroactive amino acids.
Brain metabolism is closely associated with neuronal activity and enables the accurate synthesis and function of neurotransmitters. Although previous studies have demonstrated that chronic stress is associated with the overproduction of reactive oxygen species (ROS), which leads to oxidative stress and the disruption of glucose metabolism, the molecular mechanisms and cerebral gluconeogenesis in depression have not yet been completely elucidated. In order to examine this subject, the present study evaluated changes in the expression of selected genes involved in the glycolytic pathway and the levels of glucogenic and neuroactive amino acids in the brain of rats exposed to chronic variable stress. Male Wistar rats (50‑55 days old, weighing 200‑250 g) were divided into two groups: control and stressed, and the rats in the stressed group were exposed to stress conditions for 40 days. Depressive‑like states were observed and recorded by measuring the body weight and forced swim test (FST). The mRNA levels of Slc2a3 (coding GLUT3) and Tfam (activator of mitochondrial transcription and a participant in mitochondrial genome replication) were markedly increased, while a decrease in the expression of Ldhb and GAPDH was also observed. These modifications were associated with the redirection of glucose metabolism to appropriate defensive pathways under chronic stress conditions, and an increased ability to maintain mitochondrial function as potential adaptive responses. A marked reduction of glucogenic and neuroactive amino acids levels indicate the support of energy metabolism by stimulation of the gluconeogenesis pathway. The findings of the present study provide a novel insight into the molecular and biochemical events that impact the development of depression under chronic stress conditions, and they may identify novel targets for therapeutic intervention.


[The role of oxidative stress in the etiopathogenesis of rheumatoid arthritis].
Numerous scientific investigations confirmed the occurrence of oxidative stress in rheumatoid arthritis patients. There is evidence demonstrating elevated levels of oxidative stress markers and oxidative damage caused by reactive oxygen species (ROS) to lipids, proteins, sugars, and DNA, as well as a significant decrease in total antioxidant capacity, which protects the organism against ROS activity. Extensive ROS production can significantly accelerate the process of articular cartilage damage. It is believed that many disease-modifying anti-rheumatic drugs (DMARDs) affect oxidative stress, although there has been insufficient research to confirm such a relationship.


Concurrent Methane Production and Oxidation in Surface Sediment from Aarhus Bay, Denmark.
Marine surface sediments, which are replete with sulfate, are typically considered to be devoid of endogenous methanogenesis. Yet, methanogenic archaea are present in those sediments, suggesting a potential for methanogenesis. We used an isotope dilution method based on sediment bag incubation and spiking with 13C-CH4 to quantify CH4 turnover rates in sediment from Aarhus Bay, Denmark. In two independent experiments, highest CH4 production and oxidation rates (>200 pmol cm-3 d-1) were found in the top 0-2 cm, below which rates dropped below 100 pmol cm-3 d-1 in all other segments down to 16 cm. This drop in overall methane turnover with depth was accompanied by decreasing rates of organic matter mineralization with depth. Molecular analyses based on quantitative PCR and MiSeq sequencing of archaeal 16S rRNA genes showed that the abundance of methanogenic archaea also peaked in the top 0-2 cm segment. Based on the community profiling, hydrogenotrophic and methylotrophic methanogens dominated among the methanogenic archaea in general, suggesting that methanogenesis in surface sediment could be driven by both CO2 reduction and fermentation of methylated compounds. Our results show the existence of elevated methanogenic activity and a dynamic recycling of CH4 at low concentration in sulfate-rich marine surface sediment. Considering the common environmental conditions found in other coastal systems, we speculate that such a cryptic methane cycling can be ubiquitous.


Neuropsychological correlates of Pisa syndrome in patients with Parkinson's disease.
A complex relationship exists between postural control and cognition in the elderly. Namely, neural mechanisms that are required for the regulation of posture have been variably associated with cognitive dysfunctions. Parkinson's disease (PD) is the second most common neurodegenerative disease among the elderly, and it has been associated with both cognitive and postural abnormalities such as Pisa syndrome (PS). Although its onset has been considered to be multifactorial, the pathophysiological mechanisms underpinning PS are still not fully explained. Until now, no study investigated the possible contribution of cognitive dysfunction to occurrence of PS in PD. Twenty PD patients with PS and 20 PD patients without PS were enrolled. All patients with PD underwent neuropsychological battery to assess behavioural disturbances, memory, attention, frontal/executive and visuospatial functions. The two groups did not differ on demographic features, age at PD onset and disease duration, whereas they significantly differed on UPDRS-Part III, and levodopa-equivalent daily dose (LEDD). MANCOVA with above-mentioned clinical variable as covariates revealed significant differences on tasks tapping verbal long-term memory, and attentional and visuoperceptual abilities between groups. The binary logistic regression revealed that higher LEDD and lower performance on visuospatial task (Benton Judgment of Lines Orientation test) significantly predicted occurrence of PS. Our results revealed a significant association of PS with altered attention and visuoperceptual functions in PD, suggesting that the occurrence of PS may be associated with alteration of both frontal-striatal systems and posterior cortical areas.


FaceTime validation study: Low-cost streaming video for cytology adequacy assessment.
Adequacy assessment for fine-needle aspiration procedures is a standard of care in large medical centers. Although the benefits of this approach include higher adequacy rates with fewer passes, it costs cytopathologist time and affects other clinical responsibilities. The objective of the current study was to evaluate the use of mobile video streaming (FaceTime) technology with the help of smartphone adapters attached to microscopes for remote adequacy assessment of cytologic samples. The study consisted of 2 phases: Phase 1 was a retrospective assessment of 25 samples by a primary pathologist with simultaneous streaming to a second pathologist using a smartphone (iPhone/iPad) FaceTime connection. Data on the adequacy of each sample and preliminary diagnoses were recorded. In phase 2, live cases were assessed prospectively by an onsite primary pathologist and by a remote pathologist using an iPhone/iPad-FaceTime connection. The testing phase involved prospective assessment of additional samples with a resident or cytotechnologist as the slide driver. In phase 1, retrospective evaluation of 25 samples yielded considerable agreement (22 of 25 samples; 88%) between onsite and remote adequacy assessments. Three samples (12%) yielded results that did not agree, including 2 samples that were read as adequate in the onsite evaluation that were assessed as indeterminate using FaceTime. In phase 2 and in the testing phase, 14 samples exhibited considerable agreement on both adequacy and preliminary diagnosis (6 samples in phase 2 and 8 samples in the testing phase) and are currently available for reporting. Problems encountered include software version standardization, camera alignment, and (rarely) comprehension of the audio stream. The current data indicate that iPhone/iPad FaceTime technology can be used to perform remote adequacy assessments of fine-needle aspirations and can help save valuable time for pathologists.


The effect of the hypocholesteremic drug, AY 9944 on the synthesis of bile salts in rat liver.
1. The compound trans-1,4 bis-(2-dichlorobenzylaminomethyl)cyclohexane dihydrochloride (AY9944) blocks cholesterol synthesis at a late stage. This leads to a decrease in cholesterol and accumulation of cholesta-5,7-diene-3-beta-ol (7-dehydrocholesterol) in tissues and plasma. 2. The effect of AY9944 on bile salt synthesis in rat liver was studied. The synthesis of conjugated cholic and chenodeoxycholic acids was measured in hepatocytes isolated from rats 2 h, 24 h and 48 h after administration of a single oral dose of AY9944. Production of the two bile salts was inhibited by 70-80% in hepatocytes from AY9944-treated as compared to untreated animals. 3. When AY9944 was added to the incubation medium in vitro of hepatocytes prepared from untreated rats the synthesis of conjugated cholic and chenodeoxycholic acids was not inhibited during the first hour of incubation, probably because of the presence of endogenous cholesterol. However when hepatocytes from untreated rats were incubated with AY9944 for periods of 2 h or longer, bile salt production was decreased markedly. 4. Bile salt synthesis is stimulated when rats are subjected to total biliary drainage for 24 h. The effect of AY9944 on this stimulation was studied. The content of conjugated cholic and chenodeoxycholic acid in the bile was measured as an indicator of bile salt synthesis. 5. In control animals the rate of secretion of biliary bile salts began to increase after about 24 h of total biliary drainage and reached a maximum after approximately 36 h. A single oral dose of AY9944 given 2 h after the start of total biliary drainage delayed and reduced this response. 6. The results show that inhibition of cholesterol synthesis by AY9944 resulting in the replacement of cholesterol by 7-dehydrocholesterol decreases but does not completely prevent bile salt synthesis.


Alzheimer's Prevention Education: If We Build It, Will They Come? www.AlzU.org.
Internet-based educational interventions may be useful for impacting knowledge and behavioral change. However, in AD prevention, little data exists about which educational tools work best in terms of learning and interest in participating in clinical trials. Primary: Assess effectiveness of interactive webinars vs. written blog-posts on AD prevention learning. Secondary: Evaluate the effect of AD prevention education on interest in participating in clinical trials; Assess usability of, and user perceptions about, an online AD education research platform; Classify target populations (demographics, learning needs, interests). Observational. Online. Men/Women, aged 25+, recruited via facebook.com. Alzheimer's Universe (www.AlzU.org) education research platform. Pre/post-test performance, self-reported Likert-scale ratings, completion rates. Over two-weeks, 4268 visits were generated. 503 signed-up for a user account (11.8% join rate), 196 participated in the lessons (39.0%) and 100 completed all beta-testing steps (19.9%). Users randomized to webinar instruction about AD prevention and the stages of AD demonstrated significant increases (p=0.01) in pre vs. post-testing scores compared to blog-post intervention. Upon joining, 42% were interested in participating in a clinical trial in AD prevention. After completing all beta-test activities, interest increased to 86%. Users were primarily women and the largest category was children of AD patients. 66.3% joined to learn more about AD prevention, 65.3% to learn more about AD treatment. Webinar-based education led to significant improvements in learning about AD prevention and the stages of AD. AlzU.org participation more than doubled interest in AD prevention clinical trial participation. Subjects were quickly and cost-effectively recruited, and highly satisfied with the AD education research platform. Based on these data, we will further refine AlzU.org prior to public launch and aim to study the effectiveness of 25 interactive webinar-based vs. blog-post style lessons on learning and patient outcomes, in a randomized, within-subjects design trial.


Structural and redox plasticity in the heterodimeric periplasmic nitrate reductase.
The structure of the respiratory nitrate reductase (NapAB) from Rhodobacter sphaeroides, the periplasmic heterodimeric enzyme responsible for the first step in the denitrification process, has been determined at a resolution of 3.2 A. The di-heme electron transfer small subunit NapB binds to the large subunit with heme II in close proximity to the [4Fe-4S] cluster of NapA. A total of 57 residues at the N- and C-terminal extremities of NapB adopt an extended conformation, embracing the NapA subunit and largely contributing to the total area of 5,900 A(2) buried in the complex. Complex formation was studied further by measuring the variation of the redox potentials of all the cofactors upon binding. The marked effects observed are interpreted in light of the three-dimensional structure and depict a plasticity that contributes to an efficient electron transfer in the complex from the heme I of NapB to the molybdenum catalytic site of NapA.


PVD growth of spiral pyramid-shaped WS2 on SiO2/Si driven by screw dislocations.
Atomically thin layered transition metal dichalcogenides (TMDs), such as MoS2 and WS2, have been getting much attention recently due to their interesting electronic and optoelectronic properties. Especially, spiral TMDs provide a variety of candidates for examining the light-matter interaction resulting from the broken inversion symmetry, as well as the potential new utilization in functional optoelectronic, electromagnetic and nanoelectronics devices. To realize their potential device applications, it is desirable to achieve controlled growth of these layered nanomaterials with a tunable stacking. Here, we demonstrate the Physical Vapor Deposition (PVD) growth of spiral pyramid-shaped WS2 with ∼200 μ m in size and the interesting optical properties via AFM and Raman spectroscopy. By controlling the precursors concentration and changing the initial nucleation rates in PVD growth, WS2 in different nanoarchitectures can be obtained. We discuss the growth mechanism for these spiral-patterned WS2 nanostructures based on the screw dislocations. This study provides a simple, scalable approach of screw dislocation-driven (SDD) growth of distinct TMD nanostructures with varying morphologies, and stacking.


Efficacy and safety profile of paliperidone palmitate injections in the management of patients with schizophrenia: an evidence-based review.
The course of schizophrenia is characterized by multiple relapses, incomplete remission of symptoms, enduring cognitive deficits, and social and occupational functional impairments. Nonadherence to antipsychotic medication is a major determinant of this poor outcome. Long-acting injectable antipsychotics were developed specifically to address the nonadherence problem and are increasingly considered as an early treatment option, in an attempt to prevent accruing morbidity. This review focuses on paliperidone palmitate, the long-acting injectable (LAI) formulation of paliperidone. After considering the pharmacology of paliperidone palmitate, we review the randomized controlled trials, as well as pertinent observational, pragmatic studies for paliperidone once-monthly injections in schizophrenia. Finally, we review the recently introduced 3-monthly formulation of paliperidone palmitate. Taken together, the studies indicate that paliperidone palmitate (PP) has good efficacy compared with placebo and comparable with other antipsychotics including risperidone. The tolerability profile of PP is similar to that of risperidone, with the most important side effects being prolactin elevation, weight gain, and extrapyramidal symptoms. Advantages of PP include the extensive research database and clinical experience with paliperidone and its parent compound risperidone, the availability of different LAI formulations (once-monthly, 3-monthly, and perhaps even longer acting formulations in future), and the novel dose initiation procedure that provides rapid onset of action without the need for oral antipsychotic supplementation.


Quantitative immunoelectrophoretic analysis of Salmonella typhi antigens and of corresponding antibodies in human sera.
By quantitative immunoelectrophoretic methods, 86 different antigens were found in sonicated preparations of a Salmonella typhi, using corresponding rabbit antiserum. Lipopolysaccharide was identified, and 5 other antigens characterized. Antibodies against a total of 19 S. typhi antigens were found in human sera. The antibody response in patients with typhoid fever was significantly more pronounced compared to that in normal persons. When the antibody response was expressed as a precipitin score, the predictive value of both a positive (precipitin score greater than or equal to 8) test and a negative test was 100%, when sera from patients suffering from typhoid fever were compared with sera from normal persons.


[Circadian rhythm and lacunar syndromes].
There is scarce knowledge on the mode of onset of disease related to circadian rhythm in lacunar syndromes. A prospective clinical analysis was conducted in 181 patients with lacunar infarcts (LI) and 47 patients with lacunar syndromes not due to lacunar infarcts. In every patient the onset of the disease was recorded for each of the four 6-hour equal periods of the day. The injure volume of the LI was measured by means of a computer and image analyzer. A descriptive analysis of the hour of onset of the disease and a comparative analysis of clinical differences and injure size for each day period, relating to circadian rhythm were made. For LI, the onset occurred during nocturnal sleep in 32.5% and during wakening hours in 67.5%. The morning onset of the disease was significantly more frequent in lacunar syndromes by cerebral hemorrhage (55.5%) than in LI (24.5%) (p < 0.001). For LI, the mean injure volume was significantly larger when associated with a morning onset (2,574 mm3), during the afternoon (1,678 mm3) or during the night (1,328 mm3) (p < 0.04). At discharge, no significant differences were documented between hospital stay length and also between functional disability, when compared with disease onset and circadian rhythm. A third of patients with LI had their onset of symptoms during nocturnal sleep. The morning onset of the disease regarding circadian rhythm in LI is associated with a larger injure volume.


Use of the 1,2 intercompartmental supraretinacular artery as a vascularized pedicle bone graft for difficult scaphoid nonunion.
Fourteen patients with established scaphoid nonunion were treated with vascularized pedicle bone grafting. All nonunions healed at a mean of 11.1 weeks (range, 8-16 weeks). Wrist motion was minimally affected by surgery. Intercarpal and scaphoid angles were improved after surgery, particularly in patients with preoperative humpback deformity who had previous interposition grafting. Outcome, based on a self-assessment questionnaire administered at a mean 30 months of follow-up (range, 19-53 months), showed 2 excellent, 7 good, 4 fair, and 1 poor result. Three patients showed progressive radioscaphoid arthrosis. Vascularized bone grafts are indicated in proximal pole fracture nonunions, in the presence of avascular necrosis, and after conventional grafts. Radiocarpal arthritis, if present before surgery, is a poor prognostic sign.


Mental health law: a comparison of compulsory hospital admission in Italy and the UK.
In Europe, the mental health law legal framework has had several changes throughout the years to achieve and develop new reforms, better mental health care, and protect the human rights of patients. The UK national data shows rising detention rates and the disproportionate use of the legal framework among people from black and minority ethnic groups. At the national level, compulsory admissions are lower in Italy; it also shows that it has increased in the last few years in both countries. The lack of ethnic national data, especially in Italy, limited the ability to understand compulsory admission, discrimination, and stigma in mental health. The present study aims to compare the legal framework of mental health law and compulsory hospital admission in Italy and the UK. A review of each country's latest amendments to mental health law and the number of compulsory hospital admissions was conducted to understand the impact of changes in mental health care.


Comparative evaluation of p53 mutation in pancreatic adenocarcinoma and chronic pancreatitis.
Pancreatic adenocarcinoma (PA) has a very poor prognosis. In patients suffering from chronic pancreatitis (CP) the risk for the PA development is higher than in the general population. The purpose of the study was to compare the prevalence of p53 mutations in PA and CP in order to evaluate their usefulness in differential diagnosis of those diseases. We examined 49 patients who underwent Whipple resection or distal pancreatectomy for pancreatic adenocarcinoma (26 subjects) or chronic pancreatitis (23 subjects). DNA from pancreatic tissue was analyzed for p53 mutations with PCR/SSCP methods. The p53 gene mutation has been shown in 16 (61.5%) of the PA patients (9 in exon 5 and 7 in exon 7) and in 2 (8.6%) of CP patients (1 in exon 5 and 1 in exon 8; p < 0.001). There was a significant correlation between p53 mutation and G3 tumor differentiation (p < 0.01). Overall median survival in patients with PA was 8.5 months. No relationship between presence of p53 mutation and survival time in PA patients has been observed. The specificity of p53 mutation for pancreatic cancer is very high. Our results indicate that p53 gene mutation may provide an additional tool in differential diagnosis of CP and PC.


Clinical Short-Term Outcome and Hemodynamic Comparison of Six Contemporary Bovine Aortic Valve Prostheses.
Conventional stented valves (CV) remain gold standard for aortic valve disease. Bovine prostheses have been improved and rapid deployment valves (RDV) have arrived in the recent decade. We compare clinical and hemodynamic short-term outcome of six bovine valves. We retrospectively evaluated 829 consecutive patients (all-comers) receiving bovine aortic valve replacement (AVR). Four CV from different manufacturers (Mitroflow, Crown, Perimount, Trifecta) and two RDV (Perceval, Intuity) were compared in terms of pre-, intra-, and postprocedural data. A risk model for mortality was created. All valves reduced gradients. From 23 mm, all CV showed acceptable gradients. Twenty-one millimeter Mitroflow/Perceval and 19 mm Crown showed above-average gradients. As baseline data differed, we performed propensity matching between aggregated isolated CV and RDV groups. Cardiopulmonary bypass (CPB), clamp, and surgery times were shorter with RDV (87.4 ± 34.0 min vs 111.0 ± 34.2, 54.3 ± 21.1 vs 74.9 ± 20.4, 155.2 ± 42.9 vs 178.0 ± 46.8, p < 0.001). New pacemaker rate (10.1 vs 1.3%, p = 0.016) and the tendency toward neurologic events (8.9 vs 2.5%, p = 0.086) were higher using RDV, induced mainly by the Perceval. Early mortality was equal (2.5 vs 1.3%, p = 0.560). Revision for bleeding, dialysis, blood products, length-of-stay, gradients, and regurgitation was also equal. Risk analysis showed that low valve size, low ejection fraction, endocarditis, administration of red cells, and prolonged CPB time were predictors of elevated mortality. Isolated bovine AVR has low mortality. Valves ≥ 23 mm show comparable gradients while the valve model matters < 23 mm. RDV should be used with care. Procedure-related times are shorter than those of CV but pacemaker implantation and neurologic events are more frequent (Perceval). Early mortality is low and valve performance comparable to CV.


Antibiotic Dixiamycins from a Cold-Seep-Derived Streptomyces olivaceus.
Two new (1 and 2) along with six known (3-8) dixiamycins were isolated from the culture broth of a cold-seep-derived actinomycete, Streptomyces olivaceus OUCLQ19-3. Structures of the isolated compounds were elucidated based on extensive MS and NMR spectroscopic analyses together with ECD calculations. In the antibacterial test, compounds 1-8 exhibited notable growth inhibitions against a panel of multi-drug-resistant (MDR) strains with MIC values of 0.78-6.25 μg/mL, among which 1, 2, and 5-7 were more potent than the positive control tetracycline.


Biochemical and molecular impacts of glyphosate-based herbicide on the gills of common carp.
Glyphosate (GLY)-based herbicide, one of the most widely used herbicides, might cause a series of environmental problems and pose a toxicological risk to aquatic organisms. However, data on the potential hazard and toxicity mechanism of GLY to fish gills are relatively scarce. In this study, a subacute toxicity test of common carp (Cyprinus carpio L.) treated with commercial GLY at 52.08 and 104.15 mg L-1 for 7 d was conducted. The results revealed that GLY exposure significantly inhibited Na+/K+-ATPase and increased AST and ALT activities in the fish gills. The biochemical assays results revealed that GLY treatment remarkably altered the transcriptional levels of HSP70 and HSP90; inhibited the activities of SOD, CAT, GPx, GR, and T-AOC; reduced the contents of GSH, but remarkably promoted MDA and PC contents, suggesting that GLY exposure induced oxidative stress and lipids and proteins damage in the carp gills. Further research revealed that GLY exposure also promoted expression of NF-κB, iNOS, IL-1β, IL-6, IL-8, and TNF-α; altered the levels of IL-10 and TGF-β, indicating that GLY exposure induced inflammatory response in the fish gills. Additionally, we found that GLY exposure activated apaf-1 and bax and inhibited bcl-2, induced caspase-9 and caspase-3 expression and caused remarkable histological damage in the fish gills. These results may further enriches the toxicity mechanistic theory of GLY to fish gills, which may be useful for the risk assessment of GLY and aquatic organism protection.


Cerebellar metastatic papillary thyroid carcinoma in a pediatric patient with complex congenital heart disease.
This case describes the first pediatric case of metastatic papillary thyroid carcinoma (PTC) to the cerebellum as the presenting sign of cancer in a child with CHARGE syndrome and complex congenital heart disease. Diagnostic radiation exposure as a strong risk factor for PTC is discussed.


Effects of Probiotic Lactobacilli plantarum in Treatment of Experimentally Induced Periodontal Disease in Rabbits.
The aim of this study was to evaluate the therapeutic effects of probiotic Lactobacillus plantarum in experimentally induced periodontal disease in rabbits. The incisor teeth of 24 rabbits were scaled under general anesthesia. Two weeks later, silk ligatures were placed at the gingival margin of the incisor teeth to induce periodontal disease. After confirming the presence of periodontal disease by periodontal probing four weeks later, incisor mucogingival flaps were created and gingival pocket lavage and debridement was performed. The rabbits were randomly divided into four groups. Group 1: Control; Group 2: Microencapsulated form of the probiotic; Group 3: Planktonic form of the probiotic; and Group 4: Biofilm form of the probiotic. The rabbits were euthanized eight weeks later, and gingival connective tissue and epithelium were resected for histopathological and histomorphometric evaluation. The results showed that the rate of epithelial regeneration was lower and bone regeneration was significantly higher in the treatment groups compared to the Control group. The highest level of bone regeneration was in Group 2 (Microencapsulated probiotic). There was no significant difference in bone regeneration observed between the biofilm and planktonic probiotic groups. This study showed that applying the probiotic Lactobacillus plantarum in microencapsulated form improved bone regeneration in experimentally induced periodontal disease in rabbits.


Prodrugs in genetic chemoradiotherapy.
Improvements in the radiotherapeutic management of solid tumors through the concurrent use of gene therapy is a realistic possibility. Of the broad array of candidate genes that have been evaluated, those encoding prodrug-activating enzymes are particularly appealing since they directly complement ongoing clinical chemoradiation regimes. Gene-Directed Enzyme-Prodrug Therapy (GDEPT) only requires a fraction of the target cells to be genetically modified, providing that the resultant cytotoxic prodrug metabolites redistribute efficiently (the bystander effect). This transfer of cytotoxicity to neighboring non-targeted cancer cells is central to the success of any gene therapy strategy, irrespective of the therapeutic gene employed. In the context of genetic chemoradiotherapy, efficient prodrug metabolite diffusion will be a prerequisite for efficient radiosensitization. Some, but not all GDEPT approaches have been analysed in combination with radiotherapy. Examples of prodrugs of clinically established chemotherapeutic agents currently used in conjunction with radiotherapy include: 5-fluorocytosine (5FC), cyclophosphamide (CPA), irinotecan (CPT-11), gemcitabine (dFdC), capecitabine, mitomycin C (MMC) and AQ4N. Other GDEPT paradigms, such as ganciclovir (GCV) and Herpes Simplex thymidine kinase (HSV-tk), dinitrobenzamide (DNB) mustard or aziridinyl analogs and the E. coli nitroreductase (NTR), CMDA or ZP2767P with Pseudomonas aeruginosa carboxypeptidase G2 (CPG2), and indole-3-acetic acid (IAA) activated by horseradish peroxidase (HRP) have no clinically established chemotherapeutic counterpart. Each prodrug is discussed in this review in the context of GDEPT, with a particular attention to translational research and clinical utility in combination with radiotherapy.


Bioelectrical impedance analysis in small- and appropriate-for-gestational-age newborn infants.
To determine the reliability of bioelectrical impedance analysis, and to compare and contrast the anthropometric and BIA status of newborns. BIA and anthropometric parameters were compared in the few days after birth and at about 3 weeks of age. At the maternity hospital or in a paediatric care unit. Small- or appropriate-for-gestational-age newborns, with birth weight below or above the 10th percentile of the reference value, respectively. Measurements were performed on 36 and 47 newborns at birth, and for a subgroup (21 and 11) again about 3 weeks later, respectively. At birth, length2/resistance was 4.3 +/- 0.6 and 6.1 +/- 1.2 cm2/omega (P = 10(-7)), and at 3 weeks of age length2/resistance was 5.0 +/- 0.6 and 5.7 +/- 0.8 cm2/omega (P = 0.11), for small- and appropriate-for-gestational-age newborns, respectively. Percentage reliability was 2.2% and 2.6% for intra- and inter-observer measurements of resistance. Importance of a correct placement of the sensor electrode was demonstrated. Ease of measurement and reliability of BIA in neonates were shown. Evolution of BIA values is in agreement with the known increase in total body water linked to regrowth of cell mass in small-for-gestational-age infants. Additional study is required before BIA should be used in usual clinical setting in newborns due to the lack of prediction equation.


Turning curses into blessings: an Eastern approach to psychosocial oncology.
Cancer patients experience enormous psychological stress in addition to their physical suffering. Neither disease- nor symptomspecific approaches in the conventional Western medical model or single- modal psychological intervention focusing on stress and anxiety are sufficient to relieve patients of their pain and trauma resulting from cancer. Through years of working with Chinese cancer patients and witnessing their growth and resilience, we were motivated to develop an Eastern Body-Mind-Spirit (BMS) Group Intervention model which has a strong emphasis on turning crisis into opportunities, and growth through pain. This model blends different intervention approaches, techniques, and outcome measures both from the East and the West. This paper describes our intervention approaches and discusses the theoretical background in relation to the concept of transformation and some qualitative findings which provide evidence for the study's applicability and effectiveness.


[Establishment and application of human CHO/NTR1 system].
Neurotensin receptor-1 (NTR1), which can stimulate the intracellular cascade signal pathway, belongs to the large superfamily of G-protein coupled receptors. NTR1 is related to the occurrence and development of several kinds of diseases. In order to screen the inhibitors for the cancers associated with NTR1 protein, we established a CHO (Chinese hamster ovary) cell line in which human neurotensin receptor-1 was highly expressed. The method is to construct the recombinant plasmid which was lysed with the hNTR1 gene and transfect it into CHO cells. After selected with G418, the cell line was evaluated by Western blotting analysis and calcium flux assays. Through the calcium flux assays on FlexStation 3, we got the EC50 value of neurotensin peptide which is the natural NTR1 agonist, and the IC 50 value of SR48692 which is the known NTR1 antagonist. The established human CHO/NTR1 cell line can be used to study the profile of NTR1 biological activity and further screen of NTR1 antagonists and agonists.


Looking back at 40 years of cancer education.
The American Association for Cancer Education and its antecedent organization, The Coordinators of Cancer Teaching, have been deeply interested in problems attendant to cancer pedagogy since 1948 at which time the first of 38 successive annual national conferences was held. This was in Chicago and attended by coordinators from medical schools which had been recipients from the National Cancer Institute of non-competitive categorical grants to improve the quality of undergraduate teaching of cancer. (They included dental schools in 1949 and osteopathic schools of medicine in 1953.) For the ensuing 18 years these conferences were held nationwide under the chairmanship of a coordinator elected from a representative group of interested institutions. This ushered in a period of competitive grants without fixed ceilings. Initially, they were awarded for three years. Programming was targeted for widening its scope and for participation of all qualified health service personnel interested in Cancer Education. Thus the Cancer Education Program of the AACE and its antecedent CCT can be summarized in four phases: [table: see text].


Psychosocial Adjustment to Illness Scale (PAIS-SR) in a Norwegian material of patients with functional dyspepsia, duodenal ulcer, and urinary bladder dysfunction. Clinical validation of the instrument.
There is an increasing interest in the psychosocial impact of a disease, but few instruments available to measure it. The internal consistency and construct validity of the Norwegian translation of the Psychosocial Adjustment to Illness Scale (PAIS-SR) was examined in a total of 557 patients. The seven dimensions of the psychosocial adjustment to medical illness from the original test were represented in the Norwegian translation. Psychologic distress, social environment, and vocational environment explained most of the variance. The instrument had high internal consistency with Cronbach's alpha coefficients of > 0.75 on six of seven subscales. The PAIS-SR differentiated between groups of patients with urologic and upper gastrointestinal disease and seemed to give meaningful and useful clinical data. Patients with functional dyspepsia (n = 97) had higher score on psychologic distress than the other groups, whereas patients with duodenal ulcer (n = 97) were significantly less affected in their social life than the other patients. The Norwegian translation of the PAIS-SR had high internal consistency, acceptable construct validity, and good discriminating validity.


Escherichia coli K-12 mutants altered in the transport systems for oligo- and dipeptides.
Two mutants of Escherichia coli K-12, defective in the oligopeptide and dipeptide transport system, are described. A mutant defective in the oligopeptide transport system (opp-1) was isolated as resistant to the inhibitory action of triornithine; this mutant is also resistant to glycylglycylvaline and does not concentrate (14)C-glycylglycylglycine, although it is still as sensitive as the parental strain to glycylvaline and valine. Starting from the opp-1 strain, a mutant defective also in the dipeptide transport system (dpp-1) was isolated; this mutant is resistant to the inhibitory action of glycylvaline, valylleucine, and leucylvaline and does not concentrate (14)C-glycylglycine, although it is still as sensitive as the parental strain to valine. The apparent kinetic constants for oligopeptide and dipeptide transport were measured. The opp marker is co-transducible with trp at 27 min on the E. coli genetic map. The dpp locus is separated from opp and is located between proC (10 min) and opp.


Design and optimization of an advanced time-of-flight neutron spectrometer for deuterium plasmas of the large helical device.
A time-of-flight neutron spectrometer based on the Time-Of-Flight Enhanced Diagnostic (TOFED) concept has been designed and is under development for the Large Helical Device (LHD). It will be the first advanced neutron spectrometer to measure the 2.45 MeV D-D neutrons (DDNs) from helical/stellarator plasmas. The main mission of the new TOFED is to study the supra-thermal deuterons generated from the auxiliary heating systems in helical plasmas by measuring the time-of-flight spectra of DDN. It will also measure the triton burnup neutrons (TBNs) from the d+t reactions, unlike the original TOFED in the EAST tokamak. Its capability of diagnosing the TBN ratios is evaluated in this work. This new TOFED is expected to be installed in the basement under the LHD hall and shares the collimator with one channel of the vertical neutron camera to define its line of sight. The distance from its primary scintillators to the equatorial plane of LHD plasmas is about 15.5 m. Based on Monte Carlo simulation by a GEANT4 model, the resolution of the DDN energy spectra is 6.6%. When projected onto the neutron rates that are typically obtained in LHD deuterium plasmas (an order of 1015 n/s with neutral beam injection), we expect to obtain the DDN and TBN counting rates of about 2.5 · 105 counts/s and 250 counts/s, respectively. This will allow us to analyze the DDN time-of-flight spectra on time scales of 0.1 s and diagnose the TBN emission rates in several seconds with one instrument, for the first time in helical/stellarator plasmas.


[Vascular tumours and malformations, classification, pathology and imaging].
The understanding of vascular anomalies (vascular tumours and vascular malformations) was obscured, for a long time, by confusion and uncertainties in nosology and terminology. The International Society for the Study of Vascular Anomalies (ISSVA) recently adopted a classification scheme, clearly separating vascular tumours (hemangiomas of different types) which result from active cell proliferation, from vascular malformations, which are inborn defects in vascular morphogenesis. These two types of lesions have different clinical behaviour and require different diagnostic and therapeutic strategies. The most frequent vascular tumour is infantile hemangioma. Its clinical aspects and evolution are well-known. New data have been recently obtained concerning the phenotype of tumour cells and its histogenesis. Of the numerous new vascular tumours, which have been recently described, only the congenital hemangiomas, the vascular tumours associated with the Maffucci syndrome and the tumours that may be complicated by a profound thrombocytopenia (Kasabach and Merritt phenomenon) will be considered. Vascular malformations can be classified according to the vessel(s) types they are composed of. A classification table is presented, separating the malformations of vascular trunks from tissular malformations which are more intimately embedded in the surrounding tissues. The different syndromes associated with vascular anomalies take also place in this table. The clinical, imaging and histological aspects of the most frequent malformations (capillary, venous, lymphatic and arteriovenous) are presented. This classification intend to clarify the nosology and terminology of the complex field of vascular tumours and malformation and to offer a common language to the different physicians and specialists contributing, preferably with a interdisciplinary approach, to the diagnosis and treatment of these difficult lesions.


Pulmonary function after thoracoplasty in adolescent idiopathic scoliosis.
The current study evaluated sequential pulmonary function tests prospectively at a minimum of 2 years after thoracoplasty in adolescent patients with idiopathic scoliosis. Twenty patients were divided into two groups: Group I (n=12) was comprised of patients who had posterior instrumented fusion with external thoracoplasty, and Group II (n=8) was comprised of patients who in addition to a posterior instrumented fusion, had an anterior release and fusion via video-assisted thoracoscopic surgery (n=4) or open thoracotomy (n=4) because of rigid severity. Forced vital capacity and forced expiratory volume in 1 second of percent predicted values in Group I declined 9% at 3 months postoperatively and returned to the preoperative baseline at 1 year. However, forced vital capacity and forced expiratory volume in 1 second of percent predicted values in Group II declined 11% to 18% postoperatively and did not return to the preoperative baseline at 2 years. Posterior instrumented fusion with thoracoplasty in adolescent patients with idiopathic scoliosis significantly decreased pulmonary function at 3 months, but returned to the preoperative baseline at 1 year. The addition of an anterior releasing procedure resulted in poorer pulmonary function, which did not return to the preoperative baseline by the 2-year followup.


Synthesis and apparent secretion of prothymosin alpha by different subpopulations of calf and rat thymocytes.
Prothymosin alpha (ProT alpha), a polypeptide containing the sequence of thymosin alpha 1 (T alpha 1) at its NH2-terminus, has been isolated from calf thymocytes in a concentration in the order of that found in the whole thymic gland. As deduced from the analysis of their tryptic peptides, calf ProT alpha differs from the rat polypeptide at least in an alanine residue replacing valine at position 92. Thymocytes cultured in a radioactive medium exhibit an important secretory activity, ProT alpha being one of the products synthesized and exported to the culture medium. Large and small thymocyte subpopulations from calf and rat differ in their capacity to synthesize ProT alpha. The polypeptide is produced in a major concentration by large thymocytes. However, all the calf and rat thymocyte subpopulations show a similar capacity to secrete ProT alpha, the amount of the newly synthesized polypeptide recovered from cell culture supernatants being 80-90% of that found in thymocyte extracts.


Glandular trichomes of Ceratotheca triloba (Pedaliaceae): morphology, histochemistry and ultrastructure.
This study was initiated to characterize the distribution, morphology, secretion mode, histochemistry and ultrastructure of the glandular trichomes of Ceratotheca triloba using light and electron microscopy. Its leaves bear two morphologically distinct glandular trichomes. The first type has long trichome with 8-12 basal cells of pedestal, 3-14 stalk cells, a neck cell and a head of four cells in one layer. The second type has short trichome comprising one or two basal epidermal cells, a unicellular or bicellular stalk and a multicellular head of two to eight cells. There is a marked circular area in the upper part of each head cell of the long trichome. This area is provided with micropores to exudate directly the secretory product onto the leaf surface by an eccrine pathway. The secretory product has copious amount of dark microbodies arising from plastids which are positive to Sudan tests and osmium tetroxide for unsaturated lipids. The secretion mode of short trichomes is granulocrine and involves two morphologically and histochemically distinct vesicle types: small Golgi-derived vesicles which are positive to Ruthenium Red test for mucilaginous polysaccharides; the second type is dark large microbodies similar to that of long trichomes with low quantity. These two types are stored in numerous peripheral vacuoles and discharge their contents accompanied by the formation of irregular invaginations of the plasmalemma inside the vacuoles via reverse pinocytosis. These two secretion modes of long and short trichomes are reported for the first time in the family Pedaliaceae. The long trichomes have more unsaturated lipids, while the short trichomes contain more mucilaginous polysaccharides.


[A case of jejunum cancer diagnosed by anemia].
The patient was an 85-year-old woman who was referred to a nearby clinic complaining of shortness of breath. Blood test showed anemia, and she was referred to our hospital for identification of the source of bleeding. Upper and lower endoscopy were performed and revealed no abnormalities. Computed tomography (CT) was performed and showed a >7- cm thickening in the wall of her small intestine. The presence of small bowel cancer was suspected. Oral double-balloon endoscopy was performed and showed a near-circumferential ulcerative lesion in the jejunum that was causing small bowel stenosis. A biopsy yielded a diagnosis of signet-ring cell carcinoma. We performed a partial resection of the patient's jejunum. The histopathological diagnosis of the resected specimen (according to the Union for International Cancer Control [UICC]TNM Classification of Malignant Tumours, seventh edition) was poorly differentiated adenocarcinoma, signet-ring cell carcinoma, mucinous carcinoma, T2 (MP), N0, H0, P0, stage I. 7 months after surgery, the patient is alive without recurrence. The incidence of small intestinal cancer is generally reported to be 1% to 2% of all gastrointestinal malignancies. We report a rare case in which cancer of the small intestine was identified during investigation of anemia.


How Attention Changes in Response to Carbohydrate Mouth Rinsing.
Research investigating the effects of carbohydrate (CHO) mouth rinsing on neurocognitive functions is currently limited and has yielded inconsistent results. In this study, we employed the event-related potential (ERP) electroencephalography technique to investigate the effect of CHO mouth rinsing on electrophysiological correlates of visuospatial attention. Using a double-blind, non-nutritive sweetener (NNS)-controlled, within-subjects design, 53 young adults performed a standard cognitive task (modified Simon task) on two separate days in a fasted state (16 h). Intermittently, mouth rinsing was performed either with a CHO (glucose, 18%, 30 mL) or an NNS solution (aspartame, 0.05%, 30 mL). Results revealed that relative to NNS, electrophysiological correlates of both more bottom-up controlled visuospatial attention (N1pc-ERP component) were decreased in response to CHO rinsing. In contrast, compared to NNS, more top-down controlled visuospatial attention (N2pc-ERP component) was increased after CHO rinsing. Behavioral performance, however, was not affected by mouth rinsing. Our findings suggest that orosensory signals can impact neurocognitive processes of visuospatial attention in a fasted state. This may suggest a central mechanism underlying the ergogenic effects of carbohydrate mouth rinsing on endurance performance could involve modulations of attentional factors. Methodologically, our study underlines that understanding the effects of carbohydrate mouth rinsing at the central level may require combining neuroscientific methods and manipulations of nutritional states.


Tumor necrosis factor-alpha and neuropsychiatric lupus erythematosus: relation to single photon emission computed tomography findings.
Abstract This study was designed to highlight the relation of tumor necrosis factor-α (TNF-α) to neuropsychiatric lupus (NPLE) manifestations. The relation of TNF-α to the type of single photon emission computed tomography (SPECT) findings in this context was also studied. Twenty-one systemic lupus erythematosus (SLE) females, mean age 27.57 ± 9.89 years, and twenty age-matched normal females (controls), were subjected to TNF-α assessment. Different clinical and neuropsychiatric manifestations were evaluated. SPECT was carried out for all patients. The results showed that the mean TNF-α level (pg/ml) was significantly raised in patients compared with controls (167.8 ± 102.5 versus 64 ± 50.2, respectively, P < 0.005). Thirteen patients (69.1%) had NPLE manifestations. NPLE patients had a significantly higher mean TNF-α than patients without NPLE (203 ± 102.8 versus 109 ± 47.3, respectively, P < 0.03). Positive SPECT findings were found in 18 lupus patients (85.7%), including all 13 patients with NPLE (100% sensitivity), with a multiple focal pattern of hypoperfusion being the most frequent type (9/13), followed by diffuse (3/13), and then single focal pattern (1/13). The mean TNF-α was significantly higher in patients with multiple focal pattern (P < 0.001). In conclusion, results of this work support the hypothesis that TNF-α could be involved in the pathogenesis of NPLE, and hence, it could be speculated that the evolving anti-TNF therapy can play a potential role in the management of this disease.


Current pharmacological approaches and potential future therapies for Celiac disease.
Celiac Disease (CeD) is estimated to currently affect 2 million Americans in the United States. This autoimmune disorder occurs when the consumption of gluten-based products leads to an inflammatory response in the small intestine. Over time, this inflammatory response permanently damages the villi in the small intestine. Celiac disease patients generally present with fatigue, diarrhea, and weight loss due to the disease. The current gold standard for diagnosing CeD is the endoscopy with duodenal biopsy indicating villous atrophy and crypt hyperplasia. No FDA-approved medication exists for the treatment of CeD and the only recommended course to alleviate CeD induced symptoms is to abstain from consuming any gluten-based products. There are several clinical trials actively developing and testing pharmacological approaches to treat CeD. Two of the further advanced clinical trials include AT-1001 (Larazotide acetate) and IMGX-003 (Latiglutenase; formerly known as ALV003) therapies. These drugs aim to alleviate celiac disease-induced symptoms using two different approaches. AT-1001 aims to close the villi's tight junctions, while IMGX-003 acts as a gluten endopeptidase that degrades gluten before being absorbed in the small intestine. This review article summarizes the various preclinical research and clinical trials being conducted and specifies the mechanism by which these drugs function.


Nasal absorption of growth hormone in normal subjects: studies with four different formulations.
Current growth hormone (GH) therapy with daily subcutaneous injections results in elevated serum concentrations of GH lasting for several hours, whereas physiologic GH secretion is characterized by a short-duration peak and low basal concentrations. A closer imitation of this pattern might be achieved by administering GH nasally. We studied the effect on the absorption of nasally administered human GH of increasing concentrations of the enhancer didecanoyl-L-alpha-phosphatidylcholine (DDPC). Four formulations of nasal GH containing the enhancer DDPC in the relative concentrations 0, 4, 8, and 16% w/w were administered in random order. Participants were admitted to the hospital during the four study periods. On four occasions the subjects received GH 6 IU (2 mg) in each nostril. Blood was sampled frequently for four hours. Anterior rhinoscopy was performed at 0 and 4 h. During the study the subjects completed a questionnaire to record nasal symptoms. Sixteen healthy subjects were examined at 0800 h after an overnight fast. Bioavailability of a nasal preparation of human GH: area under the curve (AUC), the maximum concentration (Cmax), and the time to reach maximum concentration (tmax). Scores for each nasal symptom were recorded as were the total scores. AUC, Cmax, and tmax were not significantly affected by increasing the DDPC concentration from 0 to 4 percent or from 8 to 16 percent. AUC and Cmax, however, increased significantly when the concentration of DDPC was changed from 4 to 8 percent. Mean (+/- SD) AUC (microgram.h/L) increased from 20.51 +/- 10.53 (4 percent) to 46.14 +/- 34.59 (8 percent), (p < 0.005). Mean (+/- SD) of Cmax (microgram/L) increased from 11.11 +/- 5.02 (4 percent) to 28.22 +/- 20.85 (8 percent), (p = 0.002). Mean (+/- SD) of tmax (min) was not significantly different on the four occasions (range 40.6 +/- 36.4 to 61.0 +/- 45.2 min, p = 0.13). The symptom scores (range 17.56-21.5, maximum 360) were not significantly different (p = 0.59). Increasing the relative concentration of the enhancer DDPC increases the absorption of nasally administered GH.


GRBase, a new gene regulation data base available by anonymous ftp.
The Gene Regulation Database (GRBase) is a compendium of information on the structure and function of proteins involved in the control of gene expression in eukaryotes. These proteins include transcription factors, proteins involved in signal transduction, and receptors. The database can be obtained by FTP in Filemaker Pro, text, and postscript formats. The database will be expanded in the coming year to include reviews on families of proteins involved in gene regulation and to allow online searching.


Carveol Attenuates Seizure Severity and Neuroinflammation in Pentylenetetrazole-Kindled Epileptic Rats by Regulating the Nrf2 Signaling Pathway.
Epilepsy is a neurodegenerative brain disorder characterized by recurrent seizure attacks. Numerous studies have suggested a strong correlation between oxidative stress and neuroinflammation in several neurodegenerative disorders including epilepsy. This study is aimed at investigating the neuroprotective effects of the natural compound carveol against pentylenetetrazole- (PTZ-) induced kindling and seizure model. Two different doses of carveol (10 mg/kg and 20 mg/kg) were administered to male rats to determine the effects and the effective dose of carveol and to further demonstrate the mechanism of action of nuclear factor E2-related factor (Nrf2) in PTZ-induced kindling model. Our results demonstrated reduced levels of innate antioxidants such as superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), and glutathione (GSH), associated with elevated lipid peroxidation (LPO) and inflammatory cytokines level such as tumor necrosis factor-alpha (TNF-α), and mediators like cyclooxygenase (COX-2) and nuclear factor kappa B (NFκB). These detrimental effects exacerbated oxidative stress and provoked a marked neuronal alteration in the cortex and hippocampus of PTZ-intoxicated animals that were associated with upregulated Nrf2 gene expression. Furthermore, carveol treatment positively modulated the antioxidant gene Nrf2 and its downstream target HO-1. To further investigate the role of Nrf2, an inhibitor of Nrf2 called all-trans retinoic acid (ATRA) was used, which further exacerbated PTZ toxicity. Moreover, carveol treatment induced cholinergic system activation by mitigating acetylcholinesterase level which is further linked to attenuated neuroinflammatory cascade. The extent of blood-brain barrier disruption was evaluated based on vascular endothelial growth factor (VEGF) expression. Taken together, our findings suggest that carveol acts as an Nrf2 activator and therefore induces downstream antioxidants and mitigates inflammatory insults through multiple pathways. This eventually alleviates PTZ-induced neuroinflammation and neurodegeneration.


Role of W181 in modulating kinetic properties of Plasmodium falciparum hypoxanthine guanine xanthine phosphoribosyltransferase.
Hypoxanthine-guanine-xanthine phosphoribosyltransference (HGXPRT), a key enzyme in the purine salvage pathway of the malarial parasite, Plasmodium falciparum (Pf), catalyses the conversion of hypoxanthine, guanine, and xanthine to their corresponding mononucleotides; IMP, GMP, and XMP, respectively. Out of the five active site loops (I, II, III, III', and IV) in PfHGXPRT, loop III' facilitates the closure of the hood over the core domain which is the penultimate step during enzymatic catalysis. PfHGXPRT mutants were constructed wherein Trp 181 in loop III' was substituted with Ser, Thr, Tyr, and Phe. The mutants (W181S, W181Y and W181F), when examined for xanthine phosphoribosylation activity, showed an increase in Km for PRPP by 2.1-3.4 fold under unactivated condition and a decrease in catalytic efficiency by more than 5-fold under activated condition as compared to that of the wild-type enzyme. The W181T mutant showed 10-fold reduced xanthine phosphoribosylation activity. Furthermore, molecular dynamics simulations of WT and in silico W181S/Y/F/T PfHGXPRT mutants bound to IMP.PPi.Mg2+ have been carried out to address the effect of the mutation of W181 on the overall dynamics of the systems and identify local changes in loop III'. Dynamic cross-correlation analyses show a communication between loop III' and the substrate binding site. Differential cross-correlation maps indicate altered communication among different regions in the mutants. Changes in the local contacts and hydrogen bonding between residue 181 with the nearby residues cause altered substrate affinity and catalytic efficiency of the mutant enzymes. Proteins 2016; 84:1658-1669. © 2016 Wiley Periodicals, Inc.


Complication Rate of Laparoscopic Hysterectomies in Denmark, 2011-2016.
After the U. S. Food and Drug Administration's recommendation against the use of power morcellation for tissue extraction in minimally invasive hysterectomy, the number of procedures completed laparoscopically declined in favor of open surgery laparotomy. We conducted a retrospective cohort study comparing perioperative and long-term outcomes, including complications associated with laparoscopic hysterectomy before and after the FDA recommendation. We included procedures performed in Danish government hospitals (GHs) and a hospital specializing in minimally invasive gynecological surgery (MIGS). Different types of hysterectomy over the period from January 2011 through May 2016 were examined. Hysterectomies were analyzed from GHs (n = 21,495) and from a hospital specializing in MIGS (n = 749). In the GHs, we found a decrease in open hysterectomy from 40% in 2011 to 20% in 2016. In the MIGS hospital, 4 of 749 (0.05%) open hysterectomies were performed during the 6 years; however, there was a change in operative technique. After the FDA recommendation, there was a shift from laparoscopic subtotal hysterectomy (LSH) to total laparoscopic hysterectomy (TLH) from 32% in 2011 to 82% by May 2016. Containment bags were used in LSH and large-uterus TLH after the 2014 advisory. Significantly more complications occurred in the GHs than in the MIGS hospital: 3224/21,495 (15%) vs 53/749 (7.0%), respectively. The rate of minimally invasive hysterectomies continues to increase. However, after 2014, many of the morcellation techniques have been replaced by a minilaparotomy to extract the uterus at the end of surgery, compared to the use of the contained morcellation in 100% of cases in the MIGS hospital. There was a major difference in complication rates between the hospitals that is partly explainable by the challenge in training residents and the low operative volume of surgeons in GHs.


Difficulties identifying and targeting COPD and population-attributable risk of smoking for COPD: a population study.
Respiratory public health interventions depend on accurate identification of the target group, yet this may vary depending on the diagnostic criteria used. We therefore compared the relative performance of various international criteria in identifying COPD cases. The burden of COPD due to smoking can only be determined from population-attributable risk (PAR) studies. These studies, lacking in the COPD literature, are necessary research in support of public health initiatives for COPD. In this representative population study, we also assessed the PAR for current and ex-smokers. A representative biomedical population sample of 2,501 South Australians aged > or = 18 years (The Northwest Adelaide Health [Cohort] Study). COPD diagnosis and severity were determined according to various FEV1/FVC and FEV1 percentage of predicted criteria recommended by international respiratory authorities. Demographic, health behavior, and quality-of-life data were obtained by telephone interview and self-completed questionnaire. Northwest Adelaide. The PAR of smoking (smokers and ex-smokers) for COPD ranged from 51 to 70% depending on the diagnostic respiratory criteria used. COPD prevalence varied depending on the criteria used: American Thoracic Society, 5.4%; British Thoracic Society, 3.5%; European Respiratory Society (ERS), 5.0%; Global Initiative for Chronic Obstructive Lung Disease, 5.4%. There was also substantial disagreement in the cases identified. An alternative approach using ERS reference values one residual SD from the mean produced a COPD prevalence estimate of 6.9%, with improved level of agreement with the established respiratory criteria suggesting their potential as screening criteria. The COPD risks associated with smoking and ex-smoking history were quantifiable using PAR, but PAR also suggests other, yet unquantified, risks. Targeting COPD cases for public health interventions is difficult given the range of spirometry criteria and the associated high level of underdiagnosis.


Molecular self-assembly using peptide nucleic acids.
Peptide nucleic acids (PNAs) are extensively studied for the control of genetic expression since their design in the 1990s. However, the application of PNAs in nanotechnology is much more recent. PNAs share the specific base-pair recognition characteristic of DNA together with material-like properties of polyamides, both proteins and synthetic polymers, such as Kevlar and Nylon. The first application of PNA was in the form of PNA-amphiphiles, resulting in the formation of either lipid integrated structures, hydrogels or fibrillary assemblies. Heteroduplex DNA-PNA assemblies allow the formation of hybrid structures with higher stability as compared with pure DNA. A systematic screen for minimal PNA building blocks resulted in the identification of guanine-containing di-PNA assemblies and protected guanine-PNA monomer spheres showing unique optical properties. Finally, the co-assembly of PNA with thymine-like three-faced cyanuric acid allowed the assembly of poly-adenine PNA into fibers. In summary, we believe that PNAs represent a new and important family of building blocks which converges the advantages of both DNA- and peptide-nanotechnologies.


Revolutionising hepatocellular carcinoma surveillance: Harnessing contrast-enhanced ultrasound and serological indicators for postoperative early recurrence prediction.
This study aimed to develop a noninvasive predictive model for identifying early postoperative recurrence of hepatocellular carcinoma (within 2 years after surgery) based on contrast-enhanced ultrasound and serum biomarkers. Additionally, the model's validity was assessedthrough internal and external validation. Clinical data were collected from patients who underwent liver resection at the First Hospital of Quanzhou and Mengchao Hepatobiliary Hospital. The data included general information, contrast-enhanced ultrasound parameters, Liver Imaging Reporting and Data System (LI-RADS) classification, and serum biomarkers. The data from Mengchao Hospital were divided into 2 groups, with a ratio of 6:4, to form the modeling and internal validation sets, respectively. On the other hand, the data from the First Hospital of Quanzhou served as the external validation group. The developed model was named the Hepatocellular Carcinoma Early Recurrence (HCC-ER) prediction model. The predictive efficiency of the HCC-ER model was compared with other established models. The baseline characteristics were found to be well-balanced across the modeling, internal validation, and external validation groups. Among the independent risk factors identified for early recurrence, LI-RADS classification, alpha-fetoprotein, and tumor maximum diameter exhibited hazard ratios of 1.352, 1.337, and 1.135 respectively. Regarding predictive accuracy, the HCC-ER, Tumour-Node-Metastasis, Barcelona Clinic Liver Cancer, and China Liver Cancer models demonstrated prediction errors of 0.196, 0.204, 0.201, and 0.200 in the modeling group; 0.215, 0.215, 0.218, and 0.212 in the internal validation group; 0.210, 0.215, 0.216, and 0.221 in the external validation group. Using the HCC-ER model, risk scores were calculated for all patients, and a cutoff value of 50 was selected. This cutoff effectively distinguished the high-risk recurrence group from the low-risk recurrence group in the modeling, internal validation, and external validation groups. However, the calibration curve of the predictive model slightly overestimated the risk of recurrence. The HCC-ER model developed in this study demonstrated high accuracy in predicting early recurrence within 2 years after hepatectomy. It provides valuable information for developing precise treatment strategies in clinical practice and holds considerable promise for further clinical implementation.


Leukotriene B4 Enhances NOD2-Dependent Innate Response against Influenza Virus Infection.
Leukotriene B4 (LTB4), a central mediator of inflammation, is well known for its chemoattractant properties on effectors cells of the immune system. LTB4 also has the ability to control microbial infection by improving host innate defenses through the release of antimicrobial peptides and modulation of intracellular Toll-like receptors (TLRs) expression in response to agonist challenge. In this report, we provide evidences that LTB4 acts on nucleotide-binging oligomerization domain 2 (NOD2) pathway to enhance immune response against influenza A infection. Infected mice receiving LTB4 show improved survival, lung architecture and reduced lung viral loads as compared to placebo-treated animals. NOD2 and its downstream adaptor protein IPS-1 have been found to be essential for LTB4-mediated effects against IAV infection, as absence of NOD2 or IPS-1 diminished its capacity to control viral infection. Treatment of IAV-infected mice with LTB4 induces an increased activation of IPS-1-IRF3 axis leading to an enhanced production of IFNβ in lungs of infected mice. LTB4 also has the ability to act on the RICK-NF-κB axis since administration of LTB4 to mice challenged with MDP markedly increases the secretion of IL-6 and TNFα in lungs of mice. TAK1 appears to be essential to the action of LTB4 on NOD2 pathway since pretreatment of MEFs with TAK1 inhibitor prior stimulation with IAV or MDP strongly abrogated the potentiating effects of LTB4 on both IFNβ and cytokine secretion. Together, our results demonstrate that LTB4, through its ability to activate TAK1, potentiates both IPS-1 and RICK axis of the NOD2 pathway to improve host innate responses.


The TaqI gene polymorphisms of VDR and the circulating 1,25-dihydroxyvitamin D levels confer the risk for the keloid scarring in Chinese cohorts.
to investigate the association between vitamin D receptor polymorphisms and circulating 1,25-Dihydroxyvitamin D (1,25(OH)2D) levels with keloid scar (KS) risk. A total of 261 patients with KS and 261 normal healthy individuals were enrolled. VDR gene polymorphisms were determined. Circulating 1,25(OH)2D levels were detected. In this study, we investigated the role of four loci of VDR gene polymorphisms in determining the risk of KS in a Chinese cohort. We found that the TaqI C>T polymorphism was closely associated with the KS incidence. Carriers with CC genotype of TaqI had a higher chance of developing KS. Stratification analyses by sex showed that this trend exists only in female subjects but not in male subjects. Furthermore, the TaqI C>T polymorphism affects the circulating 25-Hydroxyvitamin D levels. The CC carriers had a significantly lower mean circulating 1,25(OH)2D level than TT carriers and CT carriers. KS subjects had significantly lower mean serum circulating 1,25(OH)2D level than controls. The receiver operating characteristic curve analysis revealed that the serum circulating 1,25(OH)2D level at the cut-off point of 16.1 ng/ml could discriminate KS subjects from controls. Collectively, these data provide evidence that the vitamin D/VDR pathway plays an important role in the development of KS. The TaqI gene polymorphisms of VDR and circulating 1,25(OH)2D levels may thus be used as potential markers for prediction of KS development.


Unplugging the Drain: Treatment of a Rare Late Complication of Cardiac Resynchronization Therapy.
Central vein thrombosis (CVT) is a rare cause of chylothorax. We report a patient with chylothorax secondary to CVT, despite being on anticoagulation, who was successfully treated with balloon angioplasty of the occluded vein. A 65-year-old male presented with shortness of breath of one-month duration. He had end-stage heart failure and was on milrinone infusion. Physical exam was consistent with elevated central venous pressure. Chest x-ray showed a large left-sided pleural effusion. Right heart catheterization (RHC) showed normal right atrial pressure and normal pulmonary capillary wedge pressure. Diagnostic thoracentesis was consistent with chylothorax. A venogram revealed bilateral brachiocephalic vein occlusion. The right brachiocephalic vein was recanalized by angioplasty, which led to resolution of pleural effusion. Our case not only highlights the identification of a rare complication of a common device (i.e., cardiac resynchronization therapy defibrillator) used in heart failure patients but also highlights the treatment for this rare but reversible complication.


Development of poly(p-coumaric acid) as a self-anticancer nanocarrier for efficient and biosafe cancer therapy.
Using biocompatible polymers with potential therapeutic activity is an appealing strategy for the development of new functional drug carriers. In this study, we report the synthesis of therapeutic poly(p-coumaric acid) (PCA) from p-coumaric acid, a common plant phenolic acid with multiple bioactivities. The prepared PCA was formulated into nanoparticles (NPs) using the nanoprecipitation method and docetaxel (DTX) was encapsulated to form DTX-loaded PCA NPs (DTX@PCA NPs). Their potential as a nanocarrier for anticancer drug delivery was systematically evaluated. The DTX@PCA NPs not only had a small particle size and good stability, but also exhibited superior in vitro anticancer activity, anti-metastasis ability compared with free drugs, and preferable cellular uptake by tumor cells. In addition, the three-dimensional tumor spheroid assay revealed the effective tumor penetration and anticancer activity of the DTX@PCA NPs. Importantly, the DTX@PCA NPs preferentially accumulated in tumors and prolonged systemic circulation, significantly inhibiting tumor growth in vivo and simultaneously attenuating the side effects of DTX. Interestingly, the blank PCA NPs themselves also exhibited additional tumor suppression activity to some extent with high biosafety, further indicating the significant potential of PCA as a novel self-therapeutic nanocarrier for anticancer drug delivery and enhanced cancer therapy.


Workshop report: Caenorhabditis nematodes as model organisms to study trait variation and its evolution.
A fundamental problem in biology is to understand how genome expression translates into variation in molecular, cellular, developmental, physiological, behavioral, or life-history traits. During the summer of 2014, worm biologists with a keen interest in evolutionary biology and natural ecology met in Les Treilles (France) to define the problems of trait variation better and to discuss empirical approaches using Caenorhabditis species to address these problems. Compared with other model organisms, Caenorhabditis has several advantages, such as well-defined traits that can be subjected to highly controlled environmental and genetic manipulation and the possibility for long-term experimental evolution that can be coupled with genome-wide mapping of trait variation. The Les Treilles workshop brought together researchers studying the evolution of phenotypic plasticity, gene-networks, genome structure and population genetics, sex-determination and development in the laboratory, behavior and the life-history of natural Caenorhabditis populations. Here, we outline the key aims of this workshop and summarize the contributions of each participant.


Implant and clinical characteristics for pediatric and congenital heart patients in the national cardiovascular data registry implantable cardioverter defibrillator registry.
In 2010, the National Cardiovascular Data Registry enhanced pediatric, nonatherosclerotic structural heart disease and congenital heart disease (CHD) data collection. This report characterizes CHD and pediatric patients undergoing implantable cardioverter defibrillator implantation. In this article, we report implantable cardioverter defibrillator procedures (April 2010 to December 2012) in the registry for 2 cohorts: (1) all patients with CHD (atrial septal defect, ventricular septal defect, tetralogy of Fallot, Ebstein anomaly, transposition of the great vessels, and common ventricle) and (2) patients <21 years. We evaluated indications and characteristics to include transvenous and nontransvenous lead implants, CHD type, and New York Heart Association class. There were 3139 CHD procedures, 1601 for patients <21 years and 126 for CHD <21 years. Implantable cardioverter defibrillator indications for patients with CHD were primary prevention in 1943 (61.9%) and secondary prevention in 1107 (35.2%). Pediatric patients had 935 (58.4%) primary prevention and 588 (36.7%) secondary prevention devices. Primary prevention had higher New York Heart Association class. Nontransvenous age (35.9 ± 23.2 versus 40.1 ± 24.6 years; P=0.05) and nontransvenous height (167.1 ± 18.9 cm; range, 53-193 cm versus 170.4 ± 13.1 cm; range, 61-203 cm; P<0.01) were lower than for transvenous patients. CHD and pediatrics had similar rates of transvenous (97%) and nontransvenous (3%) leads and did not differ from the overall registry. Transposition of the great vessels and common ventricle had higher rates of nontransvenous leads. Primary prevention exceeds secondary prevention for CHD and pediatrics. Nontransvenous lead patients were younger, with higher rates of transposition of the great vessels and common ventricle patients compared with transvenous lead patients.


An antiparallel alpha-helical coiled-coil model system for rapid assessment of side-chain recognition at the hydrophobic interface.
Both parallel and antiparallel alpha-helical coiled-coil dimers are common among proteins; however, biophysical scrutiny has focused almost entirely on parallel dimers. We describe the development of a model system that enables efficient and systematic analysis of hydrophobic packing between antiparallel alpha-helices. Our findings reveal significant differences in packing preferences between parallel and antiparallel coiled-coils.


Pharmaceutical applications of hot-melt extrusion: part I.
Interest in hot-melt extrusion techniques for pharmaceutical applications is growing rapidly with well over 100 papers published in the pharmaceutical scientific literature in the last 12 years. Hot-melt extrusion (HME) has been a widely applied technique in the plastics industry and has been demonstrated recently to be a viable method to prepare several types of dosage forms and drug delivery systems. Hot-melt extruded dosage forms are complex mixtures of active medicaments, functional excipients, and processing aids. HME also offers several advantages over traditional pharmaceutical processing techniques including the absence of solvents, few processing steps, continuous operation, and the possibility of the formation of solid dispersions and improved bioavailability. This article, Part I, reviews the pharmaceutical applications of hot-melt extrusion, including equipment, principles of operation, and process technology. The raw materials processed using this technique are also detailed and the physicochemical properties of the resultant dosage forms are described. Part II of this review will focus on various applications of HME in drug delivery such as granules, pellets, immediate and modified release tablets, transmucosal and transdermal systems, and implants.


Organocatalytic enantioselective conjugate additions to enones.
Conjugate addition reactions of a wide range of nucleophilic enol species with enones, catalyzed by a cinchona alkaloid derived thiourea organocatalyst, have been developed with attending good yields and high enantioselectivities under a mild reaction condition. The general method provides an efficient approach to the preparation of versatile building blocks possessing various functional groups.


Murepavadin induces envelope stress response and enhances the killing efficacies of β-lactam antibiotics by impairing the outer membrane integrity of Pseudomonas aeruginosa.
Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen that can cause a variety of acute and chronic infections. The bacterium is highly resistant to numerous antibiotics. Murepavadin is a peptidomimetic antibiotic that blocks the function of P. aeruginosa lipopolysaccharide (LPS) transport protein D (LptD), thus inhibiting the insertion of LPS into the outer membrane. In this study, we demonstrated that sublethal concentrations of murepavadin enhance the bacterial outer membrane permeability. Proteomic analyses revealed the alteration of protein composition in bacterial inner and outer membranes following murepavadin treatment. The antisigma factor MucA was upregulated by murepavadin. In addition, the expression of the sigma E factor gene algU and the alginate synthesis gene algD was induced by murepavadin. Deletion of the algU gene reduces bacterial survival following murepavadin treatment, indicating a role of the envelope stress response in bacterial tolerance. We further demonstrated that murepavadin enhances the bactericidal activities of β-lactam antibiotics by promoting drug influx across the outer membrane. In a mouse model of acute pneumonia, the murepavadin-ceftazidime/avibactam combination showed synergistic therapeutic effect against P. aeruginosa infection. In addition, the combination of murepavadin with ceftazidime/avibactam slowed down the resistance development. In conclusion, our results reveal the response mechanism of P. aeruginosa to murepavadin and provide a promising antibiotic combination for the treatment of P. aeruginosa infections.IMPORTANCEThe ever increasing resistance of bacteria to antibiotics poses a serious threat to global public health. Novel antibiotics and treatment strategies are urgently needed. Murepavadin is a novel antibiotic that blocks the assembly of lipopolysaccharide (LPS) into the Pseudomonas aeruginosa outer membrane by inhibiting LPS transport protein D (LptD). Here, we demonstrated that murepavadin impairs bacterial outer membrane integrity, which induces the envelope stress response. We further found that the impaired outer membrane integrity increases the influx of β-lactam antibiotics, resulting in enhanced bactericidal effects. In addition, the combination of murepavadin and a β-lactam/β-lactamase inhibitor mixture (ceftazidime/avibactam) slowed down the resistance development of P. aeruginosa. Overall, this study demonstrates the bacterial response to murepavadin and provides a new combination strategy for effective treatment.


Fiber Bragg gratings for low-temperature measurement.
We demonstrate the use of fiber Bragg gratings (FBGs) as a monolithic temperature sensor from ambient to liquid nitrogen temperatures, without the use of any auxiliary embedding structure. The Bragg gratings, fabricated in three different types of fibers and characterized with a high density of points, confirm a nonlinear thermal sensitivity of the fibers. With a conventional interrogation scheme it is possible to have a resolution of 0.5 K for weak pure-silica-core FBGs and 0.25 K using both boron-doped and germanium-doped standard fibers at 77 K. We quantitatively show for the first time that the nonlinear thermal sensitivity of the FBG arises from the nonlinearity of both thermo-optic and thermal expansion coefficients, allowing consistent modeling of FBGs at low temperatures.


Analysis of Lactobacillus rhamnosus GG in Mulberry Galacto-Oligosaccharide Medium by Comparative Transcriptomics and Metabolomics.
Lactobacillus rhamnosus GG (LGG) has strong acid resistance and can survive passing through the stomach to colonize the intestines, where it promotes the growth of beneficial bacteria. Prebiotics such as mulberry galacto-oligosaccharide (MGO), mulberry polysaccharide solution (MPS), and galactooligosaccharides (GOS) promote LGG proliferation, and MGO has the greatest effect. After culturing LGG with prebiotics, changes in gene expression were studied at the transcriptomic and metabolomic levels. The results showed that, in the stable 24-h growth period of cultivation, ~63 and 132% more differential genes were found after MPS and MGO were added to the MRS medium, respectively, than after GOS was added, and the numbers of up-regulated genes were about 18 and 66% higher with MPS and MGO, respectively, than GOS. Analysis using the KEGG database revealed that, when LGG was cultured with MGO, 120 genes that were up-regulated as the growth rate increased were mainly enriched in pathways such as membrane transport, amino acid metabolism, and carbohydrate metabolism. The genes gatB and gatC were up-regulated for galactose metabolism, and bglA was up-regulated in the glycolysis/gluconeogenesis pathway. The qRT-RCR results, which were in agreement with the RNA-seq, indicated the genes involved in the proliferation effect of LGG were up-regulated. UDP-glucose may be a key metabolite for MGO to promote LGG proliferation.


Scanning electron microscopy of proliferating bile ductules.
Rats were subjected to ligation of the common bile duct to provoke bile ductular proliferation and were studied at intervals from 1 day to 6 weeks. After perfusion fixation with glutaraldehyde, and ethanol dehydration, blocks of liver were frozen in liquid nitrogen, fractured, and returned to ethanol prior to critical point drying. Examination with the scanning electron microscope showed a remarkable proliferation of bile ductules and preductules in addition to canalicular dilation. The ductules were surrounded by a longitudinal array of collagen fibers. The luminal surfaces contained many microvilli and cable-like structures, some identifiable as cilia by transmission electron microscopy. The present techniques offer the possibility for a reevaluation of obstructive jaundice and cholestasis.


Advantage of Early Focus on Visual Information in Bi-Modal Training of Bimanual Coordination.
Previous studies have shown that learning bimanual coordination is modality-specific, and both visual and kinesthetic information about relative phase can be used to facilitate learning. However, an extended training with focus on visual information leads to the neglect of kinesthesis and a complete reliance on vision to perform the coordination. The current study explored the bi-modal training of bimanual coordination, where the participants were guided to attend to both visual and kinesthetic information to learn 90° coordination. Thirty participants in their 20s were trained for 10 sessions (two sessions a day for five days), during which they were randomly divided into three groups of 10 participants each to practice the coordination. The V-K group was focused first on visual information, and then on kinesthetic information, to learn the 90° coordination. The K-V group was focused first on kinesthetic information, and then on visual information to learn the coordination. The Random group randomly shifted their focus between visual and kinesthetic information to learn the coordination. All participants were tested as they performed the 90° coordination with and without visual information before, halfway, and after the training. The results showed that the bi-modal training yielded more improved and transferred coordination than the uni-modal training. However, among the three types of bi-modal training, the V-K schedule exhibited the most modality-specific learning and transfer. Therefore, when using both visual demonstration and physical guidance to teach bimanual coordination skills, providing visual demonstration in the early stage should be recommended.


Anxiety and the measurement of handedness.
University students completed Annett's (1970) Handedness Inventory (n = 254) and the Trait Scale of the Spielberger Anxiety Questionnaire (n = 247). No relationship was found between anxiety and the hand preference classes distinguished by Annett (1970). Discrepancies between these findings and others reported in the literature are attributed to methodological factors concerning the measurement of handedness.


Racial differences in self-reports of sleep duration in a population-based study.
Racial and ethnic differences in sleep duration are not well understood. Research shows that short (< or =6 hours) and long (> or =9 hours) sleepers have higher mortality risks than mid-range sleepers. We investigated whether sleep duration varies by racial and ethnic characteristics and if some of these associations may be explained by residential context. Cross-sectional National Health Interview Survey. Non-institutionalized adults living in the United States in 1990. 32,749 people aged 18 years or older. We estimate a multinomial logistic regression that predicts short, mid-range, and long sleep duration; including covariates for race/ethnicity, among other demographic, health, and neighborhood characteristics. Black respondents had an increased risk of being short and long sleepers (OR=1.41, 95% CI=1.27-1.57 and OR=1.62, 95% CI=1.40-1.88, respectively) relative to white respondents. Hispanics (excluding Mexican Americans) and non-Hispanic "Others" were also associated with increased risk of short sleeping (OR=1.26, 95% CI= 1.07-1.49 and OR=1.35, 95% CI= 1.11-1.64, respectively). Living in an inner city was associated with increased risk of short sleeping and reduced risk of long sleeping, compared to non-urban areas. Some of the higher risk of short sleeping among blacks can be explained by higher prevalence of blacks living in the inner city. Blacks and other racial minorities are more likely to have sleep durations that are associated with increased mortality. The results are consistent with the hypothesis that unhealthy sleep patterns among minorities may contribute to health differentials.


A comparative study on three different transducers for the measurement of nonlinear solitary waves.
In the last decade there has been an increasing interest in the use of highly- and weakly- nonlinear solitary waves in engineering and physics. Nonlinear solitary waves can form and travel in nonlinear systems such as one-dimensional chains of particles, where they are conventionally generated by the mechanical impact of a striker and are measured either by using thin transducers embedded in between two half-particles or by a force sensor placed at the chain's base. These waves have a constant spatial wavelength and their speed, amplitude, and duration can be tuned by modifying the particles' material or size, or the velocity of the striker. In this paper we propose two alternative sensing configurations for the measurements of solitary waves propagating in a chain of spherical particles. One configuration uses piezo rods placed in the chain while the other exploits the magnetostrictive property of ferromagnetic materials. The accuracy of these two sensing systems on the measurement of the solitary wave's characteristics is assessed by comparing experimental data to the numerical prediction of a discrete particle model and to the experimental measurements obtained by means of a conventional transducer. The results show very good agreement and the advantages and limitations of the new sensors are discussed.


Recent Progress in Self-Powered Skin Sensors.
Self-powered skin sensors have attracted significant attention in recent years due to their great potential in medical care, robotics, prosthetics, and sports. More importantly, self-powered skin sensors do not need any energy-supply components like batteries, which allows them to work sustainably and saves them the trouble of replacement of batteries. The self-powered skin sensors are mainly based on energy harvesters, with the device itself generating electrical signals when triggered by the detected stimulus or analyte, such as body motion, touch/pressure, acoustic sound, and chemicals in sweat. Herein, the recent research achievements of self-powered skin sensors are comprehensively and systematically reviewed. According to the different monitoring signals, the self-powered skin sensors are summarized and discussed with a focus on the working mechanism, device structure, and the sensing principle. Based on the recent progress, the key challenges that exist and the opportunities that lie ahead are also discussed.


Primary sensory symptoms in parkinsonism.
Forty-three of 101 outpatients with parkinsonism reported that they regularly experienced primary sensory symptoms, i.e., spontaneous abnormal sensations not caused by somatic disease. This is in contrast to similar symptoms reported by only 8 percent of a control population. The most striking and severe symptom was burning of the trunk and proximal extremities, occurring in 11 patients. Twenty-nine patients reported spontaneous pain; a variety of other paresthesialike sensations, e.g., tingling, numbness, and formication, occurred in 32 patients. These subjective sensory phenomena were not associated with sensory loss or autonomic or motor signs. In 20 percent of affected individuals (9 percent of the total), sensory symptoms preceded the onset of the movement disorder, causing difficulty in diagnosis. It is concluded that at least some sensory symptoms originate within the nervous system as a manifestation of the disease process and are not secondary effects of the motor disorder.


Red Blood Cells from Individuals with Abdominal Obesity or Metabolic Abnormalities Exhibit Less Deformability upon Entering a Constriction.
Abdominal obesity and metabolic syndrome (MS) are multifactorial conditions associated with increased risk of cardiovascular disease and type II diabetes mellitus. Previous work has demonstrated that the hemorheological profile is altered in patients with abdominal obesity and MS, as evidenced for example by increased whole blood viscosity. To date, however, no studies have examined red blood cell (RBC) deformability of blood from individuals with obesity or metabolic abnormalities under typical physiological flow conditions. In this study, we pumped RBCs through a constriction in a microfluidic device and used high speed video to visualize and track the mechanical behavior of ~8,000 RBCs obtained from either healthy individuals (n = 5) or obese participants with metabolic abnormalities (OMA) (n = 4). We demonstrate that the OMA+ cells stretched on average about 25% less than the healthy controls. Furthermore, we examined the effects of ingesting a high-fat meal on RBC mechanical dynamics, and found that the postprandial period has only a weak effect on the stretching dynamics exhibited by OMA+ cells. The results suggest that chronic rigidification of RBCs plays a key role in the increased blood pressure and increased whole blood viscosity observed in OMA individuals and was independent of an acute response triggered by consumption of a high-fat meal.


Importance of control in type II diabetes mellitus.
To determine the effect of maintenance of control of type II diabetes mellitus on the occurrence of complications. Various published studies of populations of patients with diabetes are reviewed, and their results in terms of diabetic control and development of retinopathy, nephropathy, neuropathy, and macrovascular disease are summarized. Maintenance of near-euglycemia reduced the risk of worsening diabetic retinopathy; proliferative retinopathy developed in few patients with well-controlled diabetes. Similarly, worsening proteinuria was more common in patients with fair and poor control of diabetes in comparison with those who were able to maintain good control of diabetes. Furthermore, patients with poor diabetic control experienced a faster deterioration of peripheral neurologic function than did the patients with well-controlled diabetes. In five prospective studies of a total of 2,471 patients with type II diabetes, stricter control of diabetes was associated with fewer cardiovascular events and deaths. Overwhelming evidence from published prospective studies indicates that the complications often associated with type II diabetes can be minimized or delayed by maintaining good control of the disease.


Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia.
Diazoxide is the first-line treatment for pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to elucidate the pharmacokinetics of diazoxide in children with HI. We obtained 81 blood samples from 22 children with HI. Measured serum diazoxide concentrations were used for population pharmacokinetic analysis. Patient factors influencing pharmacokinetics were estimated using nonlinear mixed-effects model analysis. Relationships between drug exposure and adverse drug reactions were also investigated. Diazoxide disposition in the body was described by a 1-compartment model. Oral clearance (CL/F) and the volume of distribution were proportional to body weight (WT), as expressed by CL/F in males (liters/h) = 0.0358 + 0.00374 × WT (kg). CL/F in females was 39% greater than that in males. Steady-state concentrations of diazoxide were similar following twice- and 3 times-daily dosing when the total daily doses were comparable. A patient whose serum diazoxide concentration exceeded 100 μg/mL over a 4-month period developed hyperglycemia. No significant correlation was observed between severity of hirsutism and diazoxide concentration. We have proposed for the first time a population pharmacokinetic model for diazoxide in children with HI. The potential risk of diabetes mellitus and/or hyperglycemia increases when serum concentrations of diazoxide exceed 100 μg/mL.


Impairment of Trk-neurotrophin receptor by the serum of a patient with subacute sensory neuropathy.
Paraneoplastic peripheral neuropathy is sometimes associated with unidentified neuronal autoantibodies. To examine the effects of serum from a patient with subacute sensory axonopathy on the function of the Trk high-affinity nerve growth factor receptor. An 86-year-old man with sensory neuropathy exhibiting an autoantibody to Trk. Immunoblot analyses of the brain homogenates and immunoprecipitation were performed with human sera. We further examined the effect of sera on nerve growth factor-induced neurite outgrowth and Trk autophosphorylation. The patient showed sensory nerve axonopathy without well-known paraneoplastic autoantibodies. His serum inhibited nerve growth factor-induced neurite outgrowth and Trk autophosphorylation in PCtrk cells. Moreover, the patient's serum, but not control serum, immunoprecipitated Trk and recognized Trk in brain homogenates as well as in Trk immunoprecipitates. These data strongly suggest that an anti-Trk autoantibody might cause subacute sensory neuropathy.


Skin changes with aging and disease.
Skin undergoes numerous macroscopic changes during the aging process. These alterations in the skin result from both intrinsic changes to the cells and connective tissue of the skin that are inherent with the chronologic aging of the individual and changes as a result of environmental insults to the organ, particularly ultraviolet irradiation. The combination of these factors produces a tissue which possesses quite different attributes compared with the skin of a young individual and which may result in characteristic lesions, both malignant and benign. Understanding these changes and the underlying mechanisms for them will help to treat older individuals in whom specific lesions develop as well as help to prevent the occurrence of these pathologic conditions.


[Secondary dermatologic effects of serotonin reuptake inhibitor antidepressants: hypothesis of cross-reacting allergy. Apropos of 2 cases].
Toxidermia is a well-known complication of antidepressant therapy. The authors report two cases of adverse cutaneous reactions after treatment by several serotonin uptake blockers. The first case concerns a 38-year-old woman, who suffered from depressive disorder. She has been treated with fluoxetine. After eight days, a cutaneous reaction appeared. This reaction subsided when fluoxetine was stopped. Two months later, she had a prescription of paroxetine, and the same skin adverse effect appeared. The cutaneous lesion decreased with the suppression of paroxetine. The chronology of the eruption suggests that it was caused by an adverse reaction to the both serotonin uptake blockers. The second case concerns a 40-year-old man who had several prescriptions of antidepressant treatment in a period of one year: fluoxetine, fluvoxamine, paroxetine and sertraline. Each time a cutaneous reaction appeared. It is advisable to substitute after an adverse effect a medication from one of the other classes of antidepressants. But what we saw in these cases is that the serotonin uptake blockers could be involved in the same allergic reaction while these drugs have different chemistry structures. Only three of them have the same excipient. These cases ask the question of cross-reactivity between the serotonin uptake blockers.