Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes.
Chronic inflammation, a risk factor for the development of bile duct cancer, induces inducible nitric oxide synthase (iNOS) with nitric oxide (NO) generation, which promotes oxidative damage of DNA, a process that probably is important in the initiation and progression of malignancies. Because inhibition of DNA repair is required for accumulation of oxidative DNA lesions, our aim was to determine if NO also inhibits repair of oxidative DNA damage. A cholangiocarcinoma cell line and a cholangiocyte cell line were transfected with iNOS. Extracts from transfected but not untransfected cells were unable to repair 8-oxodeoxyguanine (8-oxodG); this effect was irreversible because addition of dithiothreitol to cell extracts had no effect. NO inhibition of 8-oxodG repair was blocked by NO scavengers but not by peroxynitrite scavengers or inhibitors of the soluble guanylyl cyclase/protein kinase G pathway. NO also potentiated hydrogen peroxide-induced DNA damage. Finally, immunohistochemistry in human liver samples uniformly demonstrated de novo expression of iNOS and the presence of 3-nitrotyrosine and 8-oxodG formation in the biliary epithelia of 30 patients with primary sclerosing cholangitis (a premalignant disease of the biliary tract) compared with controls. Collectively, these data implicate NO-mediated inhibition of 8-oxodG base excision DNA repair processes as a mechanism potentiating DNA damage in human inflammatory diseases involving the biliary tract.


Using mechanical testing to assess the effect of lower-limb prosthetic socket texturing on longitudinal suspension.
To function effectively, a lower limb prosthetic socket must remain securely coupled to the residual limb during walking, running and other activities of daily living; this coupling is referred to as suspension. When this coupling is insufficient longitudinal pistoning of the socket relative to the residual limb occurs. Increasing friction of the socket/liner interface may improve socket suspension and textured sockets may be fabricated relatively easily with 3D printing. The aim of this study was to investigate longitudinal displacement of sockets with different types of textures under two suspension conditions: passive suction and active vacuum. In order to do this, we developed a mock residual limb and mechanical testing protocol. Prosthetic sockets, 14 textured sockets and an Original Squirt-Shape (OSS) Socket, were fabricated from polypropylene copolymer using the Squirt-Shape™ 3D Printer and compared to a smooth socket thermoformed from polypropylene copolymer. Sockets were mounted onto a dual durometer mock residual limb and subjected to four levels of distraction forces (100 N, 250 N, 500 N and 650 N) using a hydraulic material testing system. There was a statistically significant three-way interaction between suspension, force level and texture (p < 0.0005). Longitudinal displacements between textured and reference sockets, for all force levels and both suspension conditions, were significantly different (p < 0.0005). Using these newly developed mechanical testing protocols, it was demonstrated that texturing of polypropylene copolymer sockets fabricated using Squirt-Shape significantly decreased longitudinal displacements compared to a smooth socket. However, none of the novel textured sockets significantly reduced longitudinal displacement compared to the OSS socket under passive suction suspension.


Challenges in management of the Boston Keratoprosthesis Type 1.
The Boston Keratoprosthesis Type 1 was pioneered by Claes Dohlman several decades ago. Since its inception, the device has undergone multiple revisions to address challenges associated with retroprosthetic membrane formation, retention, extrusion, stromal melt and endophthalmitis. Although visual outcomes and retention rates have improved, challenges, especially glaucoma, remain. The Boston Keratoprosthesis Type I device has seen an increase in popularity because of the improvement in rates of retention and visual rehabilitation. Recent outcome studies have allowed clinicians to identify diagnoses and indications that can lead to more favorable results with the Boston Keratoprosthesis Type I device. The Boston Keratoprosthesis Type I device continues to play a vital role in visual rehabilitation for eyes with very low chance of realistic allograft survival -- such as in eyes where corneal grafting is considered high-risk: eyes with corneal limbal stem cell failure, extensive deep corneal stromal neovascularization, and multiple allograft failures. This review article summarizes the perioperative and postoperative challenges, as well as other considerations associated with the device.


MePIC, metagenomic pathogen identification for clinical specimens.
Next-generation DNA sequencing technologies have led to a new method of identifying the causative agents of infectious diseases. The analysis comprises three steps. First, DNA/RNA is extracted and extensively sequenced from a specimen that includes the pathogen, human tissue and commensal microorganisms. Second, the sequenced reads are matched with a database of known sequences, and the organisms from which the individual reads were derived are inferred. Last, the percentages of the organisms' genomic sequences in the specimen (i.e., the metagenome) are estimated, and the pathogen is identified. The first and last steps have become easy due to the development of benchtop sequencers and metagenomic software. To facilitate the middle step, which requires computational resources and skill, we developed a cloud-computing pipeline, MePIC: "Metagenomic Pathogen Identification for Clinical specimens." In the pipeline, unnecessary bases are trimmed off the reads, and human reads are removed. For the remaining reads, similar sequences are searched in the database of known nucleotide sequences. The search is drastically sped up by using a cloud-computing system. The webpage interface can be used easily by clinicians and epidemiologists. We believe that the use of the MePIC pipeline will promote metagenomic pathogen identification and improve the understanding of infectious diseases.


Ego-pathology, body experience, and body psychotherapy in chronic schizophrenia.
In a recent pilot RCT, looking at the efficacy of body oriented psychological therapy (BPT) in patients with chronic schizophrenia, a marked improvement in negative symptoms was found in the treatment group. To date, there have been no studies to evaluate the therapeutic processes, correlates and predictors of change in-patients receiving BPT. The aims of this study are to address three specific questions, namely how: (1) Ego-pathology and (2) Body experiences, may change during the treatment (BPT). We also looked at: (3) If these pathologies, and/or changes in them, or other characteristics are associated with specific clinical outcomes. Analysis of data obtained within a pilot randomized controlled trial. In a sample of patients with a diagnosis of chronic schizophrenia, allocated to receive a course of body oriented group psychotherapy, certain parameters were assessed pre- and post-treatment: (1) Ego-pathology, using the ego-pathology inventory (EPI); (2) Body experiences, (size perception/image marking procedure - IMP, body image/body distortion questionnaire - BDQ, and body cathexis/visual-analogue-scales - VAS); and (3) Common symptom factors, using the Positive And Negative Symptom Scale (PANSS). Subjective experiences were also recorded. Four out of six ego-pathology symptom scores improved over the course of therapy (t=2.9-3.5, p<.05-.01). Amongst the measures of body experiences, only the body perception indices of the lower extremities changed significantly from underestimation pre-therapy (BPI median 92.3), becoming accurate estimates post therapy (BPI median 101.1). Contrary to the hypothesis a reduction of negative symptoms in chronic schizophrenia patients was not associated with systematic improvements of ego-pathology or body experiences. The strongest predictor of change was a high score of ego-demarcation pre-treatment (beta=0.89, p<.001). In patients with chronic schizophrenia, body oriented psychological interventions may be effective for both positive therapeutic changes in ego-pathology and negative symptoms, even though these effects are not necessarily related. High scores of ego-pathology at baseline predicted a poor treatment outcome. This finding deserves more systematic studies, as it could potentially identify patients with poorer prognosis and underpin the development of new intervention strategies. Further studies are required to clarify more precisely the exact nature of the processes in BPT.


Tools for physiology labs: an inexpensive means of temperature control.
We describe a simple means of modulating preparation temperature, which may be useful in undergraduate physiology laboratories. The device was developed in an effort to make teaching exercises that involve temperature modulation accessible at low cost. Although we were interested in using the device specifically with the larval fruit fly preparation, it is applicable to many preparations and temperature sensitive phenomena. Feedback driven thermoregulators offer superior precision in experiments requiring temperature control, but can be prohibitively expensive, require power supplies and circuitry, and often generate large switching transients (artifacts) during physiological recording. Moreover, many interesting exercises involving temperature control can be carried out with a slightly reduced level of temperature precision.


Seizures triggered by blinking when beginning to speak.
A patient had seizures triggered by spontaneous blinking associated with the act of beginning to speak. Diffuse paroxysmal discharges in the EEG appeared when the patient was blinking in darkness or in bright light. Closing the eyes voluntarily, on command, or as a reflex reaction produced this response very infrequently. During intermittent photic stimulation the epileptic discharges were accompanied by myoclonic jerks. The act of beginning to speak was linked with spontaneous blinking and EEG changes and was accompanied consistently by seizures. These were characterized by a peculiar stuttering and an absencelike impairment of consciousness. Seizures have been controlled well using clonazepam and valproic acid.


A malignant gastrointestinal stromal tumour in a patient with multiple endocrine neoplasia type 1.
Loss of heterozygosity for polymorphic markers flanking the multiple endocrine neoplasia type 1 (MEN-1) gene in parathyroid and pancreatic islet tumours from subjects with MEN-1 has been well documented and has led to the hypothesis that the MEN-1 gene functions as a recessive tumour suppressor gene. We report a case of MEN-1 with duodeno-pancreatic gastrinoma, parathyroid hyperplasia, pituitary adenoma, adrenal adenoma, and lipomas, whose rare association with a malignant gastrointestinal stromal tumour (GIST) represents an undescribed combination. MEN-1 mutation in this family was shown as a frameshift (1607delA) in exon 10. To assess the role of the MEN-1 gene in the pathogenesis of tumours less commonly associated with MEN-1, we studied GIST DNA for loss of the unaffected MEN-1 gene allele. Stromal tumour and peripheral leucocyte DNAs from our patient were examined for loss of heterozygosity using the PYGM microsatellite polymorphism and an intragenic polymorphism (D418D in exon 9) in the MEN-1 gene. We showed no evidence for loss of the wild-type MEN-1 allele in GIST. The MEN-1 germline inactivating mutation 1607delA-ter558 in exon 10 was detected in the stromal tumour DNA, but no somatic mutation in the wild-type MEN-1 allele in GIST DNA was detected. Occurrence of GIST could be consistent with the possibility that this MEN-1-related uncommon neoplasm arose independently by a mechanism unrelated to the MEN-1 gene.


Glucagon-Like peptide-1: A new therapeutic target to treat abdominal aortic aneurysm?
Recent antidiabetic drugs including GLP-1 receptor agonists and DPP-IV inhibitors have demonstrated protective effects in several cardiovascular diseases but their effect in abdominal aortic aneurysm (AAA) is far less known. AAA can be associated with extremely high rates of mortality and pharmacological treatments are still lacking underlining the real need to identify new therapeutic targets. The aim of this review was to summarize current knowledge on the role of GLP-1 pathway in AAA. A systematic literature review was performed and 6 relevant studies (2 clinical and 4 experimental) were included. Experimental studies demonstrated a protective effect of both GLP-1 receptor agonists and DPP-IV inhibitors through targeting the main pathophysiological mechanisms underlying AAA formation. The effects of these drugs in human AAA are still poorly known. In the limelight of clinical and experimental studies, we discuss current limits and future directions.


4'-Ethynyl-2'-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress.
Anticancer nucleosides are effective against solid tumors and hematological malignancies, but typically are prone to nucleoside metabolism resistance mechanisms. Using a nucleoside-specific multiplexed high-throughput screening approach, we discovered 4'-ethynyl-2'-deoxycytidine (EdC) as a third-generation anticancer nucleoside prodrug with preferential activity against diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). EdC requires deoxycytidine kinase (DCK) phosphorylation for its activity and induced replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator. A 2.1Å co-crystal structure of DCK bound to EdC and UDP reveals how the rigid 4'-alkyne of EdC fits within the active site of DCK. Remarkably, EdC was resistant to cytidine deamination and SAMHD1 metabolism mechanisms and exhibited higher potency against ALL compared to FDA approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a pre-clinical nucleoside prodrug candidate for DLBCL and ALL.


The discrepancy between implicit and explicit attitudes in predicting disinhibited eating.
Disinhibited eating (i.e., the tendency to overeat, despite intentions not to do so, in the presence of palatable foods or other cues such as emotional stress) is strongly linked with obesity and appears to be associated with both implicit (automatic) and explicit (deliberative) food attitudes. Prior research suggests that a large discrepancy between implicit and explicit food attitudes may contribute to greater levels of disinhibited eating; however this theory has not been directly tested. The current study examined whether the discrepancy between implicit and explicit attitudes towards chocolate could predict both lab-based and self-reported disinhibited eating of chocolate. Results revealed that, whereas neither implicit nor explicit attitudes alone predicted disinhibited eating, absolute attitude discrepancy positively predicted chocolate consumption. Impulsivity moderated this effect, such that discrepancy was less predictive of disinhibited eating for those who exhibited lower levels of impulsivity. The results align with the meta-cognitive model to indicate that attitude discrepancy may be involved in overeating.


Environmental side effects of pharmaceutical cocktails: what we know and what we should know.
Cocktails of pharmaceuticals are released in the environment after human consumption and due to the incomplete removal at the wastewater treatment plants. Pharmaceuticals are considered as contaminants of emerging concern and, a plethora of journal articles addressing their possible adverse effects have been published during the past 20 years. The emphasis during the early years of research within this field, was on the assessment of acute effects of pharmaceuticals applied singly, leading to results regarding their environmental risk, potentially not realistic or relevant to the actual environmental conditions. Only recently has the focus been shifted to chronic exposure and to the assessment of cocktail effects. To this end, this review provides an up-to-date compilation of 57 environmental and human toxicology studies published during 2000-2014 dealing with the adverse effects of pharmaceutical mixtures. The main challenges regarding the design of experiments and the analysis of the results regarding the effects of pharmaceutical mixtures to different biological systems are presented and discussed herein. The gaps of knowledge are critically reviewed highlighting specific future research needs and perspectives.


Hydrolysis of glucosinolates using nylon-immobilized myrosinase to produce pure bioactive molecules.
Bioactive compounds were produced from natural glucosinolates, secondary plant metabolites, using myrosinase (thioglucoside glucohydrolase EC 22.214.171.124) isolated from ripe seeds of Sinapis alba. The enzyme was immobilized on granular nylon 6.6 with the crosslinking technique. Immobilized myrosinase displayed extraordinary operational and storage stability. Using a small thermostatted continuous packed-bed bioreactor, the enzyme activity was unchanged after 15 days of continuous use at 37 degrees C and after >1 year of storage at room temperature. The bioreactor was particularly efficient in producing pure isothiocyanates, but it was less efficient for pure nitrile production.


Mitochondrial arginase II constrains endothelial NOS-3 activity.
Emerging evidence supports the idea that arginase, expressed in the vascular endothelial cells of humans and other species, modulates endothelial nitric oxide (NO) synthase-3 (NOS-3) activity by regulating intracellular L-arginine bioavailability. Arginase II is thought to be expressed in the mitochondria of a variety of nonendothelial cells, whereas arginase I is known to be confined to the cytosol of hepatic and other cells. The isoforms that regulate NOS-3 and their subcellular distribution, however, remain incompletely characterized. We therefore tested the hypothesis that arginase II is confined to the mitochondria and that mitochondrial arginase II reciprocally regulates vascular endothelial NO production. Western blot analysis, immunocytochemistry with MitoTracker, and immunoelectron microscopy confirmed that arginase II is confined predominantly but not exclusively to the mitochondria. Arginase activity was significantly decreased, whereas NO production was significantly increased in the aorta and isolated endothelial cells from arginase II knockout (ArgII(-/-)) mice compared with wild-type (WT) mice. The vasorelaxation response to acetylcholine (ACh) was markedly enhanced and the vasoconstrictor response to phenylephrine (PE) attenuated in ArgII(-/-) in pressurized mouse carotid arteries. Furthermore, inhibition of NOS-3 by N(G)-nitro-L-arginine methyl ester (L-NAME) impaired ACh response and restored the PE response to that observed in WT vessels. Vascular stiffness, as assessed by pulse wave velocity (PWV), was significantly decreased in ArgII(-/-) compared with WT mice. On the other hand, 14 days of oral L-NAME treatment significantly increased PWV in both WT and ArgII(-/-) mice, such that they were not significantly different from one another. These data suggest that arginase II is predominantly confined to the mitochondria and that this mitochondrial arginase II regulates NO production, vascular endothelial function, and vascular stiffness by modulating NOS-3 activity.


Gene-Diet Interaction and Precision Nutrition in Obesity.
The rapid rise of obesity during the past decades has coincided with a profound shift of our living environment, including unhealthy dietary patterns, a sedentary lifestyle, and physical inactivity. Genetic predisposition to obesity may have interacted with such an obesogenic environment in determining the obesity epidemic. Growing studies have found that changes in adiposity and metabolic response to low-calorie weight loss diets might be modified by genetic variants related to obesity, metabolic status and preference to nutrients. This review summarized data from recent studies of gene-diet interactions, and discussed integration of research of metabolomics and gut microbiome, as well as potential application of the findings in precision nutrition.


[Clinical and economic issues in adjuvant chemotherapy for HER-2 positive breast cancer].
To examine efficacy figures and drug expenditure for adjuvant chemotherapy in human epidermal growth factor receptor 2 (HER-2) positive breast cancer, in the Brazilian supplemental health insurance market. We obtained efficacy data (disease free survival at 3-years) and drug cost estimate for current adjuvant strategies in HER-2 positive breast cancer: Finland Herceptin (FinHER), National Surgical Adjuvant Breast and Bowel Project (NSAPB-31), North Central Cancer Treatment Group (N9831), Herceptin Adjuvant (HERA) and Breast Cancer International Research Group (BCIRG-006). We estimated clinical impact measures--number needed to treat (NNT) and absolute risk reduction (ARR)--and total drug cost by protocol to avoid one single cancer recurrence. The largest ARR was 11.7% (95% CI: 2.2% to 21.2%) in the FinHER study, and the smallest in the nonanthracycline arm of the BCIRG trial, 4.9% (95% CI: 1.8% to 8.1%). The NNT was 8 (95% CI: 3 to 28) in the FinHER, 8 (95% CI: 7 to 11) in the NSABP-31/N9831, 12 (95% CI: 9 to 18) in the HERA, 14 (95% CI: 11 to 24) in the BCIRG/Anthracycline, and 17 (CI 95% CI: 12 to 34) in the BCIRG/Nonanthracycline. Drug cost to avoid one single cancer recurrence would be R$ 418,285.44 with the FinHER regimen, R$ 1,716,789.44 with the NSABP-31/N9831, R$ 2,481,891.58 with the HERA, R$ 2,963,634.62 with the BCIRG/Anthracycline, and R$ 3,930,520.43 with the BCIRG/Nonanthracycline (exchange rate: R$ 1.00=USD 0.56). From an economic viewpoint, four to seven times more patients could benefit by using a short-course of trastuzumab at the initial adjuvant chemotherapy cycles (FinHER regimen) than by the prolonged trastuzumab administration as used in other adjuvant schedules.


A mathematical model of oxygenation during venovenous extracorporeal membrane oxygenation support.
To develop a mathematical model of oxygenation during venovenous extracorporeal membrane oxygenation (vv-ECMO). Total oxygen consumption, cardiac output, blood flow, recirculation, intrapulmonary shunt, hemoglobin, natural lung, and membrane lung oxygen fractions were chosen as inputs. Content, partial pressure, and hemoglobin saturation of oxygen in arterial, venous, pulmonary, and extracorporeal blood were outputs. To assess accuracy and predictive power of the model, we retrospectively analyzed data of 25 vv-ECMO patients. We compiled 2 software (with numerical, 2D and 3D graphical outputs) to study the impact of each variable on oxygenation. The model showed high accuracy and predictive power. Raising blood flow and oxygen fraction to the membrane lung or reducing total oxygen consumption improves arterial and venous oxygenation, especially in severe cases; raising oxygen fraction to the natural lung improves oxygenation only in milder cases; raising hemoglobin always improves oxygenation, especially in the venous district; recirculation fraction severely impairs oxygenation. In severely ill patients, increasing cardiac output worsens arterial oxygenation but enhances venous oxygenation. Oxygen saturation of ECMO inlet is critical to evaluate the appropriateness of oxygen delivery. The model with the software can be a useful teaching tool and a valuable decision-making aid for the management of hypoxic patients supported by vv-ECMO.


A case of catamenial erythema multiforme major successfully treated with goserelin.
We report a case of catamenial erythema multiforme major in a 46-year-old female. She was treated successfully with goserelin, a GnRH agonist, until the expected age of menopause; however, its therapeutic effects persisted for longer than expected, possibly due to accumulation in adipose tissue. A group of menstrual cycle-related dermatoses and hypersensitivity syndromes exist but are rarely reported in the literature. A history of recurrent cutaneous eruptions in premenopausal females should be considered in the context of the menstrual cycle. The diagnosis of menstrual cycle-related dermatoses is largely clinical, although provocation testing can assist. Treatment options are broad and are aimed at reducing the immune response and/or suppressing ovulation. Goserelin may accumulate and have a gonadotrophin-suppressing effect for longer than expected.


Increment of serum C-peptide measured by glucagon test closely correlates with human relative beta-cell area.
Pancreatic beta-cell mass contributes to glucose tolerance. The aim of this study was to evaluate the relationships between human beta-cell mass and various clinical parameters, including insulin secretory capacity. The study included 32 Japanese patients who underwent pancreatectomy and were naive to oral hypoglycemic agents and insulin. They were classified into those with normal glucose tolerance (n=13), impaired glucose tolerance (n=9) and diabetes (n=10), and their insulin secretory capacity and insulin resistance were evaluated. Immunohistochemistry was used to determine relative beta-cell area (%) which represented the proportion of insulin-positive cell area to whole pancreatic section. Increment of C-peptide immunoreactivity level by glucagon test (ΔC-peptide, increment of serum C-peptide [nmol/L] at 6 min after intravenous injection of 1-mg glucagon; r=0.64, p=0.002), homeostasis model assessment of beta-cell function (HOMA-beta, fasting immunoreactive insulin [μIU/mL] x 20 / (fasting plasma glucose [mmol/L] - 3.5); r=0.50, p=0.003), C-peptide index (CPI, fasting C-peptide [nmol/L] / fasting plasma glucose [mmol/L]; r=0.36, p=0.042), and fasting immunoreactive insulin (F-IRI [pmol/L]; r=0.36, p=0.044) correlated significantly and positively with the relative beta-cell area. The area under the curve of plasma glucose level from 0 to 120 min by 75 g-OGTT (AUC0-120) also correlated significantly and inversely with the relative beta-cell area (r=-0.36, p=0.045). Stepwise multiple regression analysis identified ΔC-peptide as the only independent and significant determinant of the relative beta-cell area. We conclude that ΔC-peptide, HOMA-beta, CPI, F-IRI and AUC0-120 correlated closely with the relative beta-cell area, and ΔC-peptide was the most valuable index for the prediction of the area.


Detection of Antibodies Against Toxoplasma gondii in Indian Cattle by Recombinant SAG2 Enzyme-Linked Immunosorbent Assay.
A large number of recombinant proteins are tested over a period of time for diagnosis of toxoplasmosis throughout the world. However, such literature is very much limited from an Indian perspective. The aim of the study was to assess the sero prevalence of Toxoplasma gondii in adult cattle from Kerala, India, using recombinant surface antigen 2 (recSAG2) protein. An antibody detection recombinant ELISA specific for T gondii was laboratory-standardized using recSAG2 protein. The optimum antigen concentration, serum concentration, and conjugate dilutions were determined by the initial checkerboard titrations. Subsequently, the diagnostic potential of the recombinant protein was assessed with 258 field sera samples cattle and compared with indirect fluorescent antibody test (IFAT). Among the cattle sera tested, 61.5% showed sero positivity of T. gondii-speciic IgG. When compared to IFAT, the sensitivity of the recSAG2 ELISA was found to be 80.00% with 88.57% specificity at 95% confidence interval with substantial agreement between the tests. The results of present study have revealed the presence of high seroprevalence of the parasite and, hence, immense public health significance.


Cognitive-Behavioral Therapy for Immigrants Presenting With Social Anxiety Disorder: Two Case Studies.
Cognitive-behavioral therapy (CBT) for the treatment of Social Anxiety Disorder (SAD) has demonstrated efficacy in numerous randomized trials. However, few studies specifically examine the applicability of such treatment for ethnic minority clients. Thus, the purpose of this article is to present two case studies examining the utility of individualized CBT for SAD with two clients who immigrated to the United States, one from Central America and one from China, for whom English was not their primary language. Both clients demonstrated improvement on a semi-structured interview and self-report measures. Necessary adaptations were modest, suggesting that therapy could be conducted in a culturally sensitive manner without much deviation from the treatment protocol. Results are discussed in terms of adapting treatment to enhance acceptability for and better fitting the needs of ethnic minority clients and non-native speakers of English. Implications for treating ethnic minority clients, as well as the practice of culturally sensitive treatment, are discussed.


The application of entropy for detecting behavioral responses in Japanese medaka (Oryzias latipes) exposed to different toxicants.
Growing concern over environmental pollution by chemicals that may directly or indirectly impact human and ecosystem health make it increasingly necessary to establish a biological early warning system to minimize these impacts. To achieve this, simple and reliable approaches and criteria for environmental risk assessment must be developed. We propose a new approach for detecting behavioral responses to toxicants in flowing water. We conducted a series of tests to determine toxic responses of Japanese medaka (Oryzias latipes) to lethal concentrations of potassium cyanide (KCN; 10 mg L(-1)) and phenol (25 mg L(-1)). Fish movements were tracked by three-dimensional (3D) biomonitoring under flow-through conditions. The 3D data were used to evaluate behavioral responses in terms of swimming speed, vertical position in the water, and entropies of these parameters. Fish exposed to KCN surfaced more frequently than unexposed fish, whereas fish exposed to phenol stayed near the bottom. Maximum swimming speed significantly increased after exposure to both test chemicals, whereas median swimming speed significantly decreased after exposure. Despite large variations in swimming behavior between individual fish, toxic behavioral responses could be identified by the significant decrease in the entropy of vertical position after 10-30 min of exposure to the test chemicals. We conclude that the use of entropy can contribute to the development of a biological early warning system for detecting toxicants at early stages of pollution. To use the present approach to detect lower concentrations of toxicants, further studies should be conducted using long-term monitoring of fish exposed to sublethal concentrations.


Mapping intermolecular bonding in C₆₀.
The formation of intermolecular bonds in C₆₀ has been investigated in detail at pressures below 2.2 GPa and up to 750 K. Fullerene samples were heated in a temperature gradient to obtain data on the formation of dimers and low-dimensional polymers along isobars. Intermolecular bonding was analyzed ex situ by Raman scattering, using both intramolecular modes and intermolecular stretching modes. Semi-quantitative reaction maps are given for the formation of dimers and chains. The activation energy for dimer formation decreases by 0.2 meV pm(-1) when intermolecular distances decrease and dimer formation is noticeably affected by the rotational state of molecules. Above 400-450 K larger oligomers are formed; below 1.4 GPa most of these are disordered, with small domains of linear chains, but above this the appearance of stretching modes indicates the existence of ordered one-dimensional polymers. At the highest pressures and temperatures two-dimensional polymers are also observed.


Rhinosporidium seeberi and papovavirus infection of the conjunctiva: a clinical and ultrastructural study.
The present study describes, for the first time, the clinical and the ultrastructural findings of a rare case presented with concurrent conjunctival infection of Rhinosporidium seeberi and a papovavirus. In contradistinction to previous reports, the present case lacked the characteristic granulomatous inflammatory reaction of rhinosporidiosis. This finding, together with the frequent recurrence of the lesion, led us to postulate the presence of a Local Acquired Immune Deficiency State (LAIDS). This Local AIDS may be caused by an immunosuppression mechanism which is probably mediated by papovavirus.


[Reflex syndromes in cervical osteochondrosis].
Clinical, biochemical, x-ray findings are available for 430 patients who demonstrated reflex syndromes of acute cervical osteochondrosis as well as evidence on functioning of peripheral and cerebral hemodynamics, neuromuscular and sympatheticoadrenal systems obtained at rheovasography, rheoencephalography, Doppler ultrasonography, electromyography, electroneuromyography, electroencephalography.


Understanding the UVA environment at a sub-tropical site and its consequent impact on human UVA exposure.
Daily UVA and erythemal irradiance data on a horizontal plane at a sub-tropical site were measured during a period from March 2000 to February 2001. On a relative basis, UVA radiation was shown to be a greater concern to human exposure during the winter months than summer months. In summer (December to February), the peak daily UVA exposure was 205 J cm(-2) and in winter (June to August), the minimum daily value was 19 J cm(-2). The peak daily UVery exposure was 37 MED in summer and the winter minimum was 4 MED. The occupational work day UVA exposure to the vertex of the head was estimated using the collected UV data. The outdoor workers received 89% of the available UVA radiation whilst the home workers received 18% of the available ambient UVA radiation. This result parallels the exposure patterns of these two population groups, with the outdoor workers spending most of the working week outdoors, whilst the home workers spend small, intermittent time periods outdoors in the sun.


Trabecular bone structures in the edentulous diastema of osteoporotic sheep.
The edentulous ovine diastema represents a suitable region for implantological research. Due to distinctive embryonic origin and mechanical loading, the edentulous diastema may respond differently to osteoporosis than tooth-bearing areas. To test this assumption, we subjected geriatric sheep to ovariectomy, calcium-/vitamin-D-restricted diet, and methylprednisolone administration. Adult control sheep remained untreated. Structural parameters and bone mineral density were determined by microcomputed tomography and conventional computed tomography, respectively. We report that the trabecular microstructure in the diastema was preserved from catabolic changes. In contrast, the premolar maxillary region of osteoporotic sheep had diminished trabecular bone mineral density, with the corresponding structural deteriorations. These results suggest that maxillary trabecular bone of the edentulous diastema does not respond to catabolic changes which occur in the tooth-bearing area in osteoporosis. Our findings imply that regional anatomic domains must be considered in the planning of pre-clinical studies, taking osteoporotic changes into account.


Yeast Infections after Esophagectomy: A Retrospective Analysis.
Esophageal malignancy is a disease with poor prognosis. Curative therapy incorporates surgery and is burdensome with high rates of infection morbidity and mortality. The role of yeast as causative organisms of post-esophagectomy infections is poorly defined. Consequently, the benefits of specific antifungal prophylactic therapy in improving patient outcome are unclear. Therefore, this study aimed at investigating the incidence of yeast infections at the University Medical Center Groningen among 565 post-esophagectomy patients between 1991 and 2017. The results show that 7.3% of the patients developed a yeast infection after esophageal resection with significantly increased incidence among patients suffering from diabetes mellitus. For patients with yeast infections, higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores, more frequent intensive care unit readmissions, prolonged hospital stays and higher mortality rates were observed. One-year survival was significantly lower for patients with a yeast infection, as well as diabetes mellitus and yeast-positive pleural effusion. We conclude that the incidence of yeast infections following esophagectomy is considerable, and that patients with diabetes mellitus are at increased risk. Furthermore, yeast infections are associated with higher complication rates and mortality. These observations encourage further prospective investigations on the possible benefits of antifungal prophylactic therapy for esophagectomy patients.


Structural and functional analysis of the three MIF4G domains of nonsense-mediated decay factor UPF2.
Nonsense-mediated decay (NMD) is a eukaryotic quality control pathway, involving conserved proteins UPF1, UPF2 and UPF3b, which detects and degrades mRNAs with premature stop codons. Human UPF2 comprises three tandem MIF4G domains and a C-terminal UPF1 binding region. MIF4G-3 binds UPF3b, but the specific functions of MIF4G-1 and MIF4G-2 are unknown. Crystal structures show that both MIF4G-1 and MIF4G-2 contain N-terminal capping helices essential for stabilization of the 10-helix MIF4G core and that MIF4G-2 interacts with MIF4G-3, forming a rigid assembly. The UPF2/UPF3b/SMG1 complex is thought to activate the kinase SMG1 to phosphorylate UPF1 in vivo. We identify MIF4G-3 as the binding site and in vitro substrate of SMG1 kinase and show that a ternary UPF2 MIF4G-3/UPF3b/SMG1 complex can form in vitro. Whereas in vivo complementation assays show that MIF4G-1 and MIF4G-2 are essential for NMD, tethering assays reveal that UPF2 truncated to only MIF4G-3 and the UPF1-binding region can still partially accomplish NMD. Thus UPF2 MIF4G-1 and MIF4G-2 appear to have a crucial scaffolding role, while MIF4G-3 is the key module required for triggering NMD.


Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment.
Oligomers are intermediates of the β-amyloid (Aβ) peptide fibrillogenic pathway and are putative pathogenic culprits in Alzheimer's disease (AD). Here we report the biotechnological generation and biochemical characterization of an oligomer-specific antibody fragment, KW1. KW1 not only discriminates between oligomers and other Aβ conformations, such as fibrils or disaggregated peptide; it also differentiates between different types of Aβ oligomers, such as those formed by Aβ (1-40) and Aβ (1-42) peptide. This high selectivity of binding contrasts sharply with many other conformational antibodies that interact with a large number of structurally analogous but sequentially different antigens. X-ray crystallography, NMR spectroscopy, and peptide array measurements imply that KW1 recognizes oligomers through a hydrophobic and significantly aromatic surface motif that includes Aβ residues 18-20. KW1-positive oligomers occur in human AD brain samples and induce synaptic dysfunctions in living brain tissues. Bivalent KW1 potently neutralizes this effect and interferes with Aβ assembly. By altering a specific step of the fibrillogenic cascade, it prevents the formation of mature Aβ fibrils and induces the accumulation of nonfibrillar aggregates. Our data illuminate significant mechanistic differences in oligomeric and fibril recognition and suggest the considerable potential of KW1 in future studies to detect or inhibit specific types of Aβ conformers.


[Histology of reproductive cycle of tropical gar Atractosteus tropicus females (Lepisosteiformes: Lepisosteidae) in Tabasco, Mexico].
In Southeast Mexico, A. tropicus is a species with great ecological, economic, cultural and aquaculture value, however wild populations have diminished due to diverse anthropological causes. The objective of this study was to characterize the reproductive cycle of A. tropicus, with a description of complete gonad structure and the changes in germinal and somatic elements during oogenesis, for better management and use of this species. Six sexually mature females (N=72) were captured monthly with drag nets during one year cycle (October 2003-October 2004) in wild populations of Pomposu lagoon, municipality of Jalpa de Mendez, Tabasco, Mexico. Females were sacrificed by decapitation and the ovaries were processed by standard histological methods; the diameter of 10-20 oocytes taken at random was determined in different stages of development. Gonadosmatic index (GSI), gonadal volume (gV) and follicule diameter (fD) were determined monthly. Among results we could determine eight oogenesis developmental stages: I: chromatin nucleolus stage, II: early perinucleolus stage, III: mid perinucleolus stage, IV: advanced perinucleolus stage, V: early vitellogenesis stage, VI: mid vitellogenesis stage, VII) advanced vitellogenesis stage and VIII: final maturation stage. The reproductive cycle could be divided in four phases: 1: proliferative phase, II: initial maturation phase, III: late maturation phase, IV: regressing phase. Analysis of the data obtained from the IGS, gV and fD values, oogenesis stages and reproductive phases, indicate that in December previtellogenesis phase restarts, from March through July yolk deposition (vitellogenesis) occurs, and from August to November the maximum reproductive activity takes place. Contrasting this pattern with local environmental factors such as temperature and precipitation, we suggested that these may serve as an environmental activator in the development of oogenesis and spawning of this species.


Modified agar dilution susceptibility testing method for determining in vitro activities of antifungal agents, including azole compounds.
In vitro activities of antifungal agents, including azole compounds, against yeasts were easily determined by using RPMI-1640 agar medium and by incubating the plates in the presence of 20% CO2. The end point of inhibition was clear by this method, even in the case of azole compounds, because of the almost complete inhibition of yeast growth at high concentrations which permitted weak growth of some Candida strains by traditional methods. MICs obtained by the agar dilution method were similar to those obtained by the broth dilution method proposed by the National Committee for Clinical Laboratory Standards.


Treating pain in the emergency department.
The objective of this audit was to evaluate the impact of brief educational intervention on prompt recognition and treatment of pain in the emergency department. The audit was performed on all patients in the emergency department with pain presenting over a 24-h period on three occasions: preintervention, 1-week postintervention and at 4 months. In 151 patients, pain severity scores were mild (24%), moderate (42%), severe (16%) and unknown (18%). Pain score documentation at triage improved from 72 to 94% during the audit (P = 0.01). There was no significant difference in the number of patients treated within 20 min for severe pain (P = 0.076) and within 60 min for moderate pain (P = 0.796) between audits. The likelihood of receiving analgesia within 20 min increased with the patients' pain category (relative risk: 1.8 95% confidence interval: 1.4-2.3). Documentation of pain assessment and the use of pain scores at triage improved after a brief educational intervention but there was no measurable impact on treatment times.


Theiler's virus-induced central nervous system disease in mice.
Theiler's viruses, which are common enteric pathogenes of mice, produce an unusual buphasic disease in the natural host following IC inoculation. There is an early phase of virus growth in CNS gray matter resulting in motor neuron degeneration and microglial proliferation. Since the spinal cord is the principal site of involvement, infected animals develop flaccid limb paralysis (early disease). Immunosuppression of the host during the early phase of infection augments virus growth and pathological lesions in gray matter, suggesting that TV causes a cytocidal infection of neurons. More importantly, surviving mice have persistent infection and pathological change limited to the spinal cord. There is marked mononuclear cell infiltration in the leptomeninges and white matter and concomitant primary demyelination. These changes are associated with a distinctive late-developing neurological disorder characterized by general inactivity, slowed movement, poor righting ability, and stimulus-sensitive extensor spasms. It appears that there are differences in host susceptibility to the development of late disease with the SJL/J inbred strain of mouse regularly showing the most severe clinical manifestations. Both humoral and cell-mediated immunity to TV antigen are delayed, reaching a maximum after 2 months; hence, this temporal sequence of the immune response is atypical of acute virus infections. Certain features of the late disease process favor an immune-mediated mechanism for demyelination, and this possibility is currently under investigation. The cells chronically supporting virus replication and the mechanisms of persistent infection remain to be elucidated.


Advances in drug delivery systems: Work in progress still needed?
A new era of science and technology has emerged in pharmaceutical research with focus on developing novel drug delivery systems for oral administration. Conventional dosage forms like tablets and capsules are associated with a low bioavailability, frequent application, side effects and hence patient noncompliance. By developing novel strategies for drug delivery, researchers embraced an alternative to traditional drug delivery systems. Out of those, fast dissolving drug delivery systems are very eminent among pediatrics and geriatrics. Orally disintegrating films are superior over fast dissolving tablets as the latter are assigned with the risk of suffocation. Due to their ability of bypassing the dissolution and the first pass effect after oral administration, self-emulsifying formulations have also become increasingly popular in improving oral bioavailability of hydrophobic drugs. Osmotic devices enable a controlled drug delivery independent upon gastrointestinal conditions using osmosis as driving force. The advances in nanotechnology and the variety of possible materials and formulation factors enable a targeted delivery and triggered release. Vesicular systems can be easily modified as required and provide a controlled and sustained drug delivery to a specific site. This work provides an insight of the novel approaches in drug delivery covering the critical comparison between traditional and novel "advanced-designed" systems.


FPLC and liquid-chromatography mass spectrometry identify candidate necrosis-inducing proteins from culture filtrates of the fungal wheat pathogen Zymoseptoria tritici.
Culture filtrates (CFs) of the fungal wheat pathogen Zymoseptoria tritici were assayed for necrosis-inducing activity after infiltration in leaves of various wheat cultivars. Active fractions were partially purified and characterized. The necrosis-inducing factors in CFs are proteinaceous, heat stable and their necrosis-inducing activity is temperature and light dependent. The in planta activity of CFs was tested by a time series of proteinase K (PK) co-infiltrations, which was unable to affect activity 30min after CF infiltrations. This suggests that the necrosis inducing proteins (NIPs) are either absent from the apoplast and likely actively transported into mesophyll cells or protected from the protease by association with a receptor. Alternatively, plant cell death signaling pathways might be fully engaged during the first 30min and cannot be reversed even after PK treatment. Further fractionation of the CFs with the highest necrosis-inducing activity involved fast performance liquid chromatography, SDS-PAGE and mass spectrometry. This revealed that most of the proteins present in the fractions have not been described before. The two most prominent ZtNIP encoding candidates were heterologously expressed in Pichia pastoris and subsequent infiltration assays showed their differential activity in a range of wheat cultivars.


Estimating survival of patients receiving radiosurgery alone for cerebral metastasis from melanoma.
This study aimed to identify clinical factors associated with survival and to develop a prognostic tool in patients receiving radiosurgery alone for very few cerebral metastases from melanoma. Ten characteristics of 69 patients treated with radiosurgery alone for 1-3 cerebral metastases from melanoma were retrospectively analyzed for survival. Serum lactate dehydrogenase levels before radiosurgery, Karnofsky performance score, maximum diameter of all irradiated cerebral lesions, and extracranial lesions were significantly associated with survival and included in the tool. Twelve-month survival rate (in %) divided by 10 was calculated for each of these four factors. The four scores were summed resulting in total scores ranging 9-22 points. Based on the 12-month survival rates, three groups were formed: less than 15 points (group I, n = 25); 15-20 points (group II, n = 34); and more than 20 points (group III, n = 10). Corresponding 12-month survival rates were 10 ± 6%, 51 ± 9% and 90 ± 9%, respectively (P < 0.001). In group I, death within 12 months following radiosurgery occurred mostly due to extracranial progression, whereas cerebral progression was the major cause of death in group II. In group III, only one of 10 patients died within 1 year. This new prognostic tool helps predict the survival time following radiosurgery of very few cerebral metastases from melanoma. An individual treatment approach should consider a patient's survival time and the most likely cause of death (cerebral or extracranial progression).


Calling for help is independently modulated by brain systems underlying goal-directed behavior and threat perception.
In primates, during times of need, calling for help is a universal experience. Calling for help recruits social support and promotes survival. However, calling for help also can attract predators, and it is adaptive to inhibit calls for help when a potential threat is perceived. Based on this, we hypothesized that individual differences in calling for help would be related to the activity of brain systems that mediate goal-directed behavior and the detection of threat. By using high-resolution positron emission tomography in rhesus monkeys undergoing social separation, we demonstrate that increased [18F]-fluoro-2-deoxy-D-glucose uptake in the right dorsolateral prefrontal cortex and decreased uptake in the amygdala independently predict individual differences in calling for help. When taken together, these two regions account for 76% of the variance in calling for help. This result suggests that the drive for affiliation and the perception of threat determine the intensity of an individual's behavior during separation. These findings in monkeys are relevant to humans and provide a conceptual neural framework to understand individual differences in how primates behave when in need of social support.


Interactive Structure-aware Blending of Diverse Edge Bundling Visualizations.
Many edge bundling techniques (i.e., data simplification as a support for data visualization and decision making) exist but they are not directly applicable to any kind of dataset and their parameters are often too abstract and difficult to set up. As a result, this hinders the user ability to create efficient aggregated visualizations. To address these issues, we investigated a novel way of handling visual aggregation with a task-driven and user-centered approach. Given a graph, our approach produces a decluttered view as follows: first, the user investigates different edge bundling results and specifies areas, where certain edge bundling techniques would provide user-desired results. Second, our system then computes a smooth and structural preserving transition between these specified areas. Lastly, the user can further fine-tune the global visualization with a direct manipulation technique to remove the local ambiguity and to apply different visual deformations. In this paper, we provide details for our design rationale and implementation. Also, we show how our algorithm gives more suitable results compared to current edge bundling techniques, and in the end, we provide concrete instances of usages, where the algorithm combines various edge bundling results to support diverse data exploration and visualizations.


Safety of real-time convection-enhanced delivery of liposomes to primate brain: a long-term retrospective.
Convection-enhanced delivery (CED) is gaining popularity in direct brain infusions. Our group has pioneered the use of liposomes loaded with the MRI contrast reagent as a means to track and quantitate CED in the primate brain through real-time MRI. When co-infused with therapeutic nanoparticles, these tracking liposomes provide us with unprecedented precision in the management of infusions into discrete brain regions. In order to translate real-time CED into clinical application, several important parameters must be defined. In this study, we have analyzed all our cumulative animal data to answer a number of questions as to whether real-time CED in primates depends on concentration of infusate, is reproducible, allows prediction of distribution in a given anatomic structure, and whether it has long term pathological consequences. Our retrospective analysis indicates that real-time CED is highly predictable; repeated procedures yielded identical results, and no long-term brain pathologies were found. We conclude that introduction of our technique to clinical application would enhance accuracy and patient safety when compared to current non-monitored delivery trials.


Dementia with Lewy bodies. Review of diagnosis and pharmacologic management.
To review clinical features of dementia with Lewy bodies (DLB) and to guide family physicians in pharmacologic management, including medications to avoid. QUALITY OF EVIDENCE A MEDLINE: search of literature from 1995 to 2002 used the MeSH terms dementia with Lewy bodies/diagnosis, dementia with Lewy bodies/therapy, and antipsychotics/dementia with Lewy bodies. Level II and III evidence was available for diagnosis and treatment of DLB. One randomized controlled trial of rivastigmine was reviewed and appraised. Dementia with Lewy bodies is common. Diagnosis can be made by family physicians using clinical criteria including presence of dementia with marked fluctuation in performance, hallucinations, and the onset of parkinsonism. Cholinesterase inhibitors should be considered for neuropsychiatric symptoms. Levodopa-carbidopa combinations should be considered for treatment of parkinsonism. Neuroleptics should be used with caution because of the risk of serious sensitivity reactions. If they are needed, atypical agents could be safer. Recognition and diagnosis of DLB is important to optimize pharmacologic management and to minimize risk of adverse reactions to neuroleptics.


Relationship between Parenting and Cognitive Schemas in a Group of Male Adult Offenders.
This work analyzes the correlation of retrospective ratings on parental binding with cognitive patterns in the inmates for property crimes. The participant group comprehended 248 adults men, including 130 marked out as offenders (the target group), aged between 19 and 70, currently serving sentences in the Cavadonna prison in Siracusa, and 118 marked out as non-offenders (the control group), aged between 20 and 70, living in Siracusa (Sicily). The instruments used were the Parental Bonding Instrument (PBI), and the Young Schema Questionnaire-3 (YSQ). The preliminary analysis showed a high percentage of offenders who experienced an affectionate constraint parenting. Offenders scored significantly higher than the non-offenders on the level of paternal control and the YSQ subscales. The study underlines the influence of maternal care on most of the cognitive schemas, and the role of father's control on the tendency to social isolation and defectiveness in the offenders.


Early loading of single crowns supported by 6-mm-long implants with a moderately rough surface: a prospective 2-year follow-up cohort study.
To evaluate prospectively the clinical and radiographic outcomes after 2 years of loading of 6 mm long moderately rough implants supporting single crowns in the posterior regions. Forty SLActive Straumann short (6 mm) implants were placed in 35 consecutively treated patients. Nineteen implants, 4.1 mm in diameter, and 21 implants, 4.8 mm in diameter, were installed. Implants were loaded after 6 weeks of healing. Implant survival rate, marginal bone loss and resonance frequency analysis (RFA) were evaluated at different intervals. The clinical crown/implant ratio was also calculated. Two out of 40 implants were lost before loading. Hence, the survival rate before loading was 95%. No further technical or biological complications were encountered during the 2-year follow-up. The mean marginal bone loss before loading was 0.34+/-0.38 mm. After loading, the mean marginal bone loss was 0.23+/-0.33 and 0.21+/-0.39 mm at the 1- and 2-year follow-ups. The RFA values increased between insertion (70.2+/-9) and the 6-week evaluation (74.8+/-6.1). The clinical crown/implant ratio increased with time from 1.5 at the delivery of the prosthesis to 1.8 after 2 years of loading. Short implants (6 mm) with a moderately rough surface loaded early (after 6 weeks) during healing yielded high implant survival rates and moderate loss of bone after 2 years of loading. Longer observation periods are needed to draw more definite conclusions on the reliability of short implants supporting single crowns.


Long-term remission of adenoid cystic tongue carcinoma with low dose naltrexone and vitamin D3--a case report.
Naltrexone (ReVia®) is a long-acting oral pure opiate antagonist which is approved for the treatment of alcohol addiction as a 50mg per day tablet. The mechanism of action is complete opiate blockade, which removes the pleasure sensation derived from drinking alcohol (created by endorphins). Low Dose Naltrexone ("LDN") in the range of 3-4.5 mg per day has been shown to have the opposite effect - brief opiate receptor blockade with resulting upregulation of endogenous opiate production. Through the work of Bihari and Zagon, it has been determined that the level of the endogenous opiate methionine-enkephalin is increased by LDN. Met-enkephalin is involved in regulating cell proliferation and can inhibit cancer cell growth in multiple cell lines. Increased met-enkepahlin levels created by LDN thus have the potential to inhibit cancer growth in humans. Phase II human trials of met-enkephalin, case reports published by Berkson and Rubin, and the clinical experience of Bihari confirmed the potential role of LDN in treating pancreatic and other cancers. However, large scale trials are lacking and are unlikely to be funded given the current non-proprietary status of naltrexone. A case report is presented of successful treatment of adenoid cystic carcinoma as further evidence of LDN's potential as a unique non-toxic cancer therapy.


Quantifying uncertainties of sandy shoreline change projections as sea level rises.
Sandy shorelines are constantly evolving, threatening frequently human assets such as buildings or transport infrastructure. In these environments, sea-level rise will exacerbate coastal erosion to an amount which remains uncertain. Sandy shoreline change projections inherit the uncertainties of future mean sea-level changes, of vertical ground motions, and of other natural and anthropogenic processes affecting shoreline change variability and trends. Furthermore, the erosive impact of sea-level rise itself can be quantified using two fundamentally different models. Here, we show that this latter source of uncertainty, which has been little quantified so far, can account for 20 to 40% of the variance of shoreline projections by 2100 and beyond. This is demonstrated for four contrasting sandy beaches that are relatively unaffected by human interventions in southwestern France, where a variance-based global sensitivity analysis of shoreline projection uncertainties can be performed owing to previous observations of beach profile and shoreline changes. This means that sustained coastal observations and efforts to develop sea-level rise impact models are needed to understand and eventually reduce uncertainties of shoreline change projections, in order to ultimately support coastal land-use planning and adaptation.


Distribution of periodontal pathogens in Korean aggressive periodontitis.
Microbial associations in aggressive periodontitis versus different ethnic origins are substantially unknown. We undertook this study to determine the prevalence of seven putative periodontopathogens in Korean patients and to evaluate microbial differences in localized and generalized aggressive periodontitis patients. Thirty-nine aggressive periodontitis patients between 20 and 35 years old (24 males and 15 females; mean age 29.6 years) were selected according to clinical criteria. The patients were subclassified into 17 localized and 22 generalized aggressive periodontitis patients. In each of the 39 individuals, subgingival plaque samples were collected from four diseased teeth (> or = 6 mm probing depth, 156 sites) and one healthy site (< or = 3 mm probing depth, 39 sites). Polymerase chain reaction (PCR) of the 16S ribosomal RNA gene fragments (about 530 bp) of plaque bacteria and their subsequent detection by dot-blot hybridization using specific oligonucleotide probes were performed to determine the presence of seven periodontopathogens. The prevalences were 75% for Actinobacillus actinomycetemcomitans, 94.2% for Tannerella forsythensis (formerly Bacteroides forsythus), 99.4% for Fusobacterium sp., 85.9% for Micromonas micros (formerly Peptostreptococcus micros), 96.8% for Porphyromonas gingivalis, 78.8% for Prevotella intermedia, and 96.8% for Treponema sp. The prevalences of these bacteria were significantly higher in diseased sites than in healthy sites. Logistic regression analysis showed that P. intermedia was more significantly associated with generalized aggressive periodontitis than the localized form, with an odds ratio of 3.28 (95% confidence interval 1.26-8.56, P = 0.015). Our results demonstrate that the seven periodontal pathogens analyzed are strongly associated with Korean aggressive periodontitis. In particular, P. intermedia are more significantly associated with generalized aggressive periodontitis, a more severe and progressive form, than with localized aggressive periodontitis.


Taenia saginata cysticercosis in an Ohio cattle feeding operation.
In January to March 1981, 37 slaughter cattle from a single Ohio feeding operation were determined, at postmortem inspection, to be infected with Taenia saginata cysticerci. A subsequent outbreak on this same farm in March 1983 involved 7 slaughter cattle. An epidemiologic investigation was conducted of possible sources of the T saginata ova; these included leakage of raw sewage onto the pasture after a flood in 1980, municipal sewage sludge application on the farm, defecation in feed or water by farm workers, and other off-farm sources. Temporal and spatial observations implicated raw sewage contamination of pastures as the most likely source of infection in the 1981 outbreak. The outbreak in 1983 was more likely associated with sludge application. The possibility of an infected worker exposing the cattle to infected feces was not excluded definitely as a possible source.


Increased testing for Neisseria gonorrhoeae with duplex nucleic acid amplification tests in Australia: implications for surveillance.
Background Gonorrhoea notifications have been increasing in Australia's cities, in both men and women. We investigated if this could be, at least in part, a result of a testing artefact. We surveyed 28 laboratories that were known to test for both Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) to determine their testing and reporting practices, and when these practices were instituted. By 2012, 23 (82%) of the laboratories were routinely performing duplex nucleic acid amplification tests for both CT and NG even if a test for only one organism was requested, up from 9 (32%) laboratories before 2007. Although written reports of negative NG tests were not provided if the test was not requested, positive NG tests were always communicated to the attending clinician. The move towards routine duplex testing for CT and NG has probably resulted in more Australians being tested for NG than ever before. While this change has advantages for case-finding and improved public health outcomes, it also brings an increasing potential for false-positive NG tests. Recent trends in NG notifications should be interpreted with caution.


Monoclonal antibodies for prophylaxis and therapy of infectious diseases.
Monoclonal antibodies (mAb) are attractive biologic drugs due to their exquisite specificity and well understood mechanisms of action, which results in a higher predictability and lower attrition rate compared with other drugs. Therefore, it may seem surprising that only a single mAb is presently marketed for an infectious disease indication. However, the antibiotic resistance crisis, emerging viral diseases and bioterroristic threats have recently spurred the development of anti-infective mAbs, of which more than a dozen are being tested in clinical trials. Conceptually, and validated in many preclinical models, mAbs will be most effective when used prophylactically against acute viral infections and bacterial toxins. The acute bacterial and chronic viral infections, which are medically and economically far more important, are much more difficult to control by antibodies, as the recent clinical failure of some polyclonal antibody products has shown. In these situations, the synergistic action of two or more mAbs together with a small molecule drug will most likely be required for therapeutic efficacy. This review aims to highlight the scientific and economic opportunities and obstacles that are encountered in the quest to add mAbs to the armament of anti-infective drugs.


CT of the brain in taste and smell dysfunction.
Three hundred fifty-four patients with taste and/or smell disorders were evaluated with computed tomography (CT). The largest group was characterized by head trauma (27%), followed by idiopathic causes (26%), postinfluenza-like hyposmia and hypogeusia (15%), and congenital etiologies (14%). Hyposmia and hypogeusia occurred concomitantly in 21%-45%, the percentage varying according to etiologic subgroup. CT abnormalities were found in 108 (31%) of the 354 patients. The most frequent pathologies were frontal encephalomalacia, subfrontal atrophy in the region of the olfactory bulbs, and anterior temporal lobe atrophy. These changes were found alone or in tandem. Some CT findings suggest common cerebral taste and smell centers and common neural pathways and association centers.


A photon-counting time-of-flight ranging technique developed for the avoidance of range ambiguity at gigahertz clock rates.
This paper describes a rapid data acquisition photon-counting time-of-flight ranging technique that is designed for the avoidance of range ambiguity, an issue commonly found in high repetition frequency time-off-light systems. The technique transmits a non-periodic pulse train based on the random bin filling of a high frequency time clock. A received pattern is formed from the arrival times of the returning single photons and the correlation between the transmitted and received patterns was used to identify the unique target time-of-flight. The paper describes experiments in laboratory and in free space at over several hundred meters range at clock frequencies of 1GHz. Unambiguous photon-counting range-finding is demonstrated with centimeter accuracy.


Neuro-muscular differentiation of adult porcine skin derived stem cell-like cells.
Due to the genetic relationship to humans, porcine stem cells are a very important model system to investigate cell differentiation, associated cell signaling pathways, and cell fate. Porcine skin derived stem cells have been isolated from mid-gestation porcine fetus recently. To our knowledge, stem cells from the skin of the adult porcine organism have not been isolated until now. Hence, to our knowledge, we here describe the isolation, expansion, characterization and differentiation of multipotent porcine skin derived stem cell-like cells (pSSCs) from the adult porcine organism for the first time. pSSCs had a spindle shaped morphology similar to mesenchymal stem cells (MSCs). They could be maintained proliferatively active in vitro for more than 120 days and were able to form colonies from single cells. pSSCs expressed Sox2 and Oct3/4, both transcription factors essential to the pluripotent and self-renewing phenotypes of embryonic stem cells, which recently gained attention due to their function in inducing pluripotent stem cells. Furthermore, the expression of the progenitor marker nestin, the somatic stem cell markers Bcrp1/ABCG2, Bmi1, and Stat3 was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in undifferentiated pSSCs. Flow cytometry revealed the expression of the MSC related proteins CD9, CD29, CD44 and CD105, but not CD90. After neuronal differentiation cells with a characteristic morphology of neuronal and smooth muscle-like cells were present in the cultures. Subsequent immunochemistry and flow cytometry revealed the down-regulation of nestin and the up-regulation of the neuron specific protein beta-III-tubulin and the astrocyte marker GFAP. Also, alpha-SMA expressing cells increased during differentiation suggesting the neuro-muscular differentiation of these skin derived cells. pSSCs could also be induced to differentiate into adipocyte-like cells when cultured under specific conditions. Adult porcine skin harbors a population of stem cell-like cells (pSSCs) that can be isolated via enzymatic digestion. These pSSCs show characteristic features of MSCs originated in other tissues and express the embryonic stem cell marker Oct3/4, Sox2, and Stat3. Furthermore, pSSCs have the potential to differentiate into cells from two different germ lines, the ectoderm (neurons, astrocytes) and the mesoderm (smooth muscle cells, adipocytes).


Intralesional cryosurgery combined with topical silicone gel sheeting for the treatment of refractory keloids.
A variety of therapeutic procedures for treating keloids have been previously reported, with varying success and recurrence rates. As a monotherapy, intralesional cryosurgery has yielded convincing clinical results. We combined intralesional cryosurgery with the application of topical silicone gel sheeting. In this retrospective study, which was conducted between 2008 and 2012, 21 patients with 32 keloids were enrolled. Twenty-five lesions were treated with intralesional cryotherapy combined with postoperative silicone gel sheeting (the cryotherapy + silicone group), and 7 keloids were treated with intralesional cryotherapy alone (the cryotherapy group). The scar volume reduction was assessed, and the patients' subjective and objective parameters were evaluated. Additionally, patient satisfaction was estimated using a modified Gorney Gram scale (0-3). In all cases (n = 32 for both groups), a significant keloid volume reduction was observed. The patients' subjective complaints were significantly improved, whereas the combined therapy showed slightly better results in hardness (p < .0012), pain (p < .0233), and discomfort (p < .0029), whereas monotherapy achieved higher satisfaction scores in redness (p < .0220) and pruritus (p < .0206), although these differences were not significant between the treatment modalities. The results of this study support the use of combined intralesional cryosurgery followed by the application of silicone gel sheeting to treat refractory keloids.


Sequential Multiple Borylation Toward an Ultrapure Green Thermally Activated Delayed Fluorescence Material.
Multiple-resonance thermally activated delayed fluorescence (MR-TADF) emitters have emerged as an important component of organic light-emitting diodes (OLEDs) because of their narrowband emission and high exciton utilization efficiency. However, the chemical space of MR-TADF emitters remains mostly unexplored because of the lack of suitable synthetic protocols. Herein, we demonstrate a sequential multiple borylation reaction that provides new synthetically accessible chemical space. ω-DABNA, the proof-of-concept material, exhibited narrowband green TADF with a full width at half-maximum of 22 nm and a small singlet-triplet energy gap of 13 meV. The OLED employing it as an emitter exhibited electroluminescence at 512 nm, with Commission International de l'Éclairage coordinates of (0.13, 0.73) and a high external quantum efficiency (EQE) of 31.1%. Moreover, the device showed minimum efficiency roll-off, with an EQE of 29.4% at 1000 cd m-2.


Chylous abdominal effusion in a cat with feline infectious peritonitis.
A 10-year-old cat was diagnosed with chyloperitoneum based on the effusion characteristics. Feline coronavirus serology was positive. The owner declined further evaluation and elected euthanasia. Necropsy revealed vasculitis with multifocal areas of necrosis and lymphocytic-plasmacytic inflammation in multiple solid organs, most likely due to feline infectious peritonitis (FIP). Immunohistochemistry was negative for FIP antigen. Notwithstanding, the final diagnosis of FIP was based on the characteristic histopathological lesions. Underlying causes of chyloperitoneum in cats and humans are discussed, and possible pathogenesis of the chyloperitoneum in association with a vasculitis such as FIP is discussed.


Applications of novel processing technologies to enhance the safety and bioactivity of milk.
Bioactive compounds in food can have high impacts on human health, such as antioxidant, antithrombotic, antitumor, and anti-inflammatory activities. However, many of them are sensitive to thermal treatments incurred during processing, which can reduce their availability and activity. Milk, including ovine, caprine, bovine, and human is a rich source of bioactive compounds, including immunoglobulins, vitamins, and amino acids. However, processing by various novel thermal and non-thermal technologies has different levels of impacts on these compounds, according to the studies reported in the literature, predominantly in the last 10 years. The reported effect of these technologies either covers microbial inactivation or the bioactive composition; however, there is a lack of comprehensive compilation of studies that compare the effect of these technologies on bioactive compounds in milk (especially, caprine and ovine) to microbial inactivation at similar settings. This research gap makes it challenging to conclude on the specific processing parameters that could be optimized to achieve targets of microbial safety and nutritional quality at the same time. This review covers the effect of a wide range of thermal and non-thermal processing technologies including high-pressure processing, pressure-assisted thermal sterilization, pulsed-electric field treatment, cold plasma, microwave-assisted thermal sterilization, ultra-high-pressure homogenization, ultrasonication, irradiation on the bioactive compounds as well as on microbial inactivation in milk. Although a combination of more than one technology could improve the reduction of bacterial contaminants to meet the required food safety standards and retain bioactive compounds, there is still scope for research on these hurdle approaches to simultaneously achieve food safety and bioactivity targets.


Mass cytometry reveals species-specific differences and a new level of complexity for immune cells in the prostate.
Chronic inflammation in the benign prostate has been associated with a higher risk of developing prostate cancer. While a range of immune lineages is found in the prostate including T cells, B cells and myeloid cells, the specific subsets of immune cells with each major lineage have not been well described. In this study, we use mass cytometry (CyTOF) to comprehensively and reproducibly profile immune cells in mouse and human prostate. Using 4 myeloid markers (CD11b, CD11c, F4/80, Ly6C) in the mouse, we identified 8 phenotypically-distinct myeloid populations, demonstrating considerable heterogeneity within the immune compartment of the mouse prostate. We then profiled the prostate immune microenvironment from 9 human patients. Unlike the mouse prostate which is myeloid-dominant, the immune compartment in the benign human prostate is consistently T-lymphocyte-dominant. Using the X-shift algorithm to identify individual immune subsets based on marker expression, we found 57 phenotypically-distinct immune cell types in the human prostate. Despite similar proportions of T, B and myeloid lineage cells in the benign human prostate of all patients evaluated, we observed considerable interpatient heterogeneity in the abundance of more specific immune subsets. These findings highlight the importance of studying the immune compartment in the prostate at a granular level and will lead to future studies addressing the functional role of specific immune subsets in prostate epithelial transformation.


A Scoping Review on Clinical Trials of Pain Reduction With Cannabis Administration in Adults.
Indications of cannabis use are numerous although the indication to relief pain remains a major research interest and clinical application. Studies investigating the effect of herbal cannabis and cannabis-based medicine on neuropathic, non-neuropathic pain, acute pain and experimentally induced pain were reviewed. A search was performed in PubMed and Cochrane library for articles published in English between January 1, 2000 and May 8, 2020. The search terms used were related to cannabis and pain in adults. We identified 34 studies, of which 30 were randomized controlled clinical trials (RCTs). Varying effects were identified from the RCTs, and as expected more promising effects from non-RCTs. Cannabis-based medications were found most effective as an adjuvant therapy in refractory multiple sclerosis, and weak evidence was found to support the treatment of cancer pain especially in advanced stages. Chronic rheumatic pain showed promising results. Adverse events of cannabis-based treatment were found to be more frequent with tetrahydrocannabinol herbal strains compared to other cannabis-derived products.


Feedback-induced voltage change of a Vertical-Cavity Surface-Emitting Laser as an active detection system for miniature optical scanning probe microscopes.
We propose a novel detection technique for scanning probe microscopy based on the measuring of the feedback-induced voltage change of 780-nm VCSEL operating at constant current in far-field regime when we modulate mechanically the length of a coupled-cavity generating the feedback conditions. The voltage change of the VCSEL is produced by light back reflected from the sample to the laser cavity. Two-dimensional image probing is successfully demonstrated with high temporal resolution, offering a viable solution for miniature parallel scanning probe optical microscopes, such as confocal microscope, where the use of a photodetector is avoided. This approach opens the possibility to perform imaging tasks in a low cost and hand-held miniature device with much improved effective-space.


Community-based surveillance: a pilot study from rural Cambodia.
This study seeks to assess the performance of a community-based surveillance system (CBSS), developed and implemented in seven rural communes in Cambodia from 2000 to 2002 to provide timely and representative information on major health problems and life events, and so permit rapid and effective control of outbreaks and communicable diseases in general. Lay people were trained as Village Health Volunteers (VHVs) to report suspected outbreaks, important infectious diseases, and vital events occurring in their communities to local health staff who analysed the data and gave feedback to the volunteers during their monthly meetings. Over 2 years of its implementation, the system was able to detect outbreaks early, regularly monitor communicable disease trends, and to provide continuously updated information on pregnancies, births and deaths in the rural areas. In addition, the system triggered effective responses from both health staff and VHVs for disease control and prevention and in outbreaks. A CBSS can successfully fill the gaps of the current health facility-based disease surveillance system in the rapid detection of outbreaks, in the effective monitoring of communicable diseases, and in the notification of vital events in rural Cambodia. Its replication or adaptation for use in other rural areas in Cambodia and in other developing countries is likely to be beneficial and cost-effective.


The effects of prior high intensity double poling on subsequent diagonal stride skiing characteristics.
To investigate the influence of prior high intensity double poling (DP) on physiological and biomechanical responses during subsequent diagonal stride (DIA). Eight well-trained male cross-country skiers (age 22 ± 3 yr; VO2max 69 ± 3 ml · kg(-1) · min(-1)) roller-skied on a treadmill sequentially for 3 min at 90% DIA VO2max (DIA1), 3 min at 90% DP VO2peak and 3 min at 90% DIA VO2max (DIA2). Cardio-respiratory responses were monitored continuously and gases and metabolites in blood from the a. femoralis, v. femoralis and v. subclavia determined. Pole and plantar forces and EMG from 6 lower- and upper-body muscles were measured. VO2 decreased from DIA1 to DP and increased again to DIA2 (both P < 0.05), with no difference between the DIA sessions. Blood lactate rose from DIA1 to DP to DIA2. O2 extraction was attenuated during DP (P < 0.05), but was the same during DIA1 and DIA2. EMGRMS for arm muscles during poling phase, as well as peak pole force and cycle rate were higher, while leg muscle activity was lower during DP than both sessions of DIA (all P < 0.05). The ratio of upper-/whole-body EMGRMS correlated negatively with O2 extraction in the arms during both sessions of DIA (P < 0.05). In well-trained skiers skiing at high-intensity DP prior to DIA did not influence VO2, muscle activation or forces in the latter. At race intensity DP does not influence the distribution of work between upper- and lower-body during a subsequent bout of DIA. O2 extraction is coupled to technical skills during skiing.


Focal granulomatous meningoencephalomyelitis in a pup.
Granulomatous meningoencephalomyelitis (GME) was diagnosed in an 8-month-old Maltese with signs of CNS disease. Serum immunoglobulin (Ig) G concentration was decreased, and CSF analysis revealed high concentrations of mononuclear WBC and IgG. Initial improvement of the pup's signs in association with prednisolone treatment and postmortem examination of CNS tissues confirmed GME. Granulomatous meningoencephalomyelitis occurs rarely in young dogs and the abnormal Ig concentrations in this pup's serum and CSF suggest that immune responses may have a role in the cause and/or pathogenesis of GME.


Diet-Microbe-Host Interactions That Affect Gut Mucosal Integrity and Infection Resistance.
The gastrointestinal tract microbiome plays a critical role in regulating host innate and adaptive immune responses against pathogenic bacteria. Disease associated dysbiosis and environmental induced insults, such as antibiotic treatments can lead to increased susceptibility to infection, particularly in a hospital setting. Dietary intervention is the greatest tool available to modify the microbiome and support pathogen resistance. Some dietary components can maintain a healthy disease resistant microbiome, whereas others can contribute to an imbalanced microbial population, impairing intestinal barrier function and immunity. Characterizing the effects of dietary components through the host-microbe axis as it relates to gastrointestinal health is vital to provide evidence-based dietary interventions to mitigate infections. This review will cover the effect of dietary components (carbohydrates, fiber, proteins, fats, polyphenolic compounds, vitamins, and minerals) on intestinal integrity and highlight their ability to modulate host-microbe interactions as to improve pathogen resistance.


Predictors of back pain in adolescent idiopathic scoliosis surgical candidates.
There are contradictory reports on the overall prevalence of back pain in the adolescent population compared with adolescent idiopathic scoliosis (AIS) patients. Most reports do not investigate pain in patients with AIS but try to identify in which subgroup of patients with AIS an underlying pathology should be excluded. The objective of this study was to find whether AIS in operative candidate patients is a painful condition and to try and find clinical and radiologic predisposing factors, which will help us to predict patients who are going to have pain. Candidates who had to undergo an operative treatment for AIS between October 2004 and October 2009 in our institution, were enrolled to the study. Pain was graded with the use of visual analogue scale (VAS) on a scale from 0 to 10. We recorded the age at presentation, sex, menarchal status, family history of scoliosis, brace treatment history, and neurological findings. Radiologic parameters recorded were: the type of curve according to the Lenke classification, Cobb angle, thoracic kyphosis angle, apex vertebra rotation, Risser grade, coronal balance, and curves flexibility. Seventy patients with AIS were included in this study. Fifty patients (71%) reported of some kind of back pain with 34 patients (48%) grading their pain as ≥5 on the VAS.Patients in whom scoliosis was diagnosed in older age and patients with a more rigid lumbar curve had statistically significant higher VAS scores (P=0.014, P=0.036). Patients who were treated with a brace had a statistically significant lower VAS scores (P=0.019). Back pain is common in patients with AIS who are candidates for operative treatment. The following parameters correlate with worse back pain: older age at diagnosis, no use of brace, and rigid lumbar curve. Type III.


Predictive risk modelling in health: options for New Zealand and Australia.
Predictive risk models (PRMs) are case-finding tools that enable health care systems to identify patients at risk of expensive and potentially avoidable events such as emergency hospitalisation. Examples include the PARR (Patients-at-Risk-of-Rehospitalisation) tool and Combined Predictive Model used by the National Health Service in England. When such models are coupled with an appropriate preventive intervention designed to avert the adverse event, they represent a useful strategy for improving the cost-effectiveness of preventive health care. This article reviews the current knowledge about PRMs and explores some of the issues surrounding the potential introduction of a PRM to a public health system. We make a particular case for New Zealand, but also consider issues that are relevant to Australia.


Defending information-free genocentrism.
Genocentrism, the thesis that the genes play a special role in the causation of development is often rejected in favor of a 'causal democracy thesis' to the effect that all causally necessary conditions for development are equal. Genocentrists argue that genes play a distinct causal role owing to their informational content and that this content enables them to program the embryo. I show that the special causal role of the genome hinges not on its informational status--it has none, or at least no more than computer programs have independent of our interpretations of them--but on its power literally to program the embryo, a power nicely illustrated in the use of polynucleotide sequences to compute solutions to NP hard problems in mathematics.


Neutral upright sagittal spinal alignment from the occiput to the pelvis in asymptomatic adults: a review and resynthesis of the literature.
An increasing emphasis is being placed on the preservation or restoration of neutral upright sagittal spinal alignment in both deformity surgery and routine spinal operations. Sagittal spinal alignment is becoming recognized as an important predictor of a patient's outcome after spinal surgery. In this literature review, the authors analyze data obtained from previously published studies conducted to evaluate neutral upright sagittal spinal alignment from the occiput to the pelvis in asymptomatic adults. A review of the English-language literature was conducted to identify studies conducted to evaluate neutral upright sagittal spinal (occiput-pelvis) alignment in asymptomatic adult volunteers with no spinal disease. The authors identified 12 articles that met the strict primary inclusion criteria of the current study. From these articles, 23 angles and displacements were selected to depict neutral upright sagittal occiput-pelvis alignment. Pooled estimates of the mean and variance were calculated for angles and displacements that met secondary inclusion criteria. The greatest variation in the regional spinal curves occurred in the cervical spine from C-2 to C-7, whereas the greatest focal angulation in the spine occurred from L-4 to S-1. Sagittal spinal balance was maintained in a narrow range for alignment of the spine over the pelvis and femoral heads. Neutral upright sagittal occiput-pelvis alignment in asymptomatic adults has been well studied regionally. Despite a wide variation in the undulating lordotic and kyphotic regional curves from the occiput to the pelvis, sagittal spinal balance is maintained in a narrower range for alignment of the spine over the pelvis and femoral heads.


Design and validation of an interpretative strategy for cardiopulmonary exercise tests.
Cardiopulmonary exercise testing (CPET) is a common investigation for the evaluation of exertional dyspnoea. At present, there is no consensus on the best interpretative strategy and none of the available algorithms have been validated. The aim of this study was to develop and validate a standardized strategy for the interpretation of CPET. This study analysed 199 CPETs from patients with exertional dyspnoea. Using a set of 100 CPETs a standardized interpretation using a four-step approach was developed that scored: examination quality, performance, exercise limitation and cofactors. A second set of 99 CPETs was interpreted by two experts in the field, initially independently and then in a consensus conference. The standardized interpretation was compared with each expert, the expert's consensus and the original clinical reports. Matching between the standardized interpretation strategy and the expert consensus was 82%, 82% with one expert and 86% with a second expert and 64% with the original clinical reports. From one to four exercise-relevant cofactors were found in 77% of the patients. The standardized interpretation showed a precision comparable to the opinion of a single expert and significantly improved the consistency in CPET reports in a pulmonary centre with different physicians and varying degrees of expertise.


Effect of Hydrogel-based Model Fibrosis on Electrical Properties of Bioelectrodes.
Fibrous tissue encapsulation can impact the performance of bioelectrodes following implantation. For example, significant increases in electrode impedance can occur within four weeks post-implantation. A key limitation hindering the understanding of host response-mediated impedance change is the reliance on animal models or complex in vitro cell cultures for electrode testing. This study aimed to develop an in vitro acellular model that can reproduce the changes in electrical properties of bioelectrodes that occur due to host responses following implantation. Specifically, the effect of synthetic, biological, and bio-synthetic co-polymer hydrogel coatings on electrode impedance was measured. Poly(vinyl alcohol) (PVA), gelatin, and PVA-gelatin co-polymers (10 and 20 wt%) were coated onto platinum (Pt) electrodes. Polarisation and access voltage, key components of the voltage response that relate to cell adhesion and protein adsorption respectively, were measured pre and post hydrogel coating and the impedance change was calculated. Results showed that increasing the polymer concentration affects the access resistance regardless of the hydrogel chemistry but only high content gelatin hydrogels increased the polarisation resistance. The increase in total impedance was ~ 2-fold of bare Pt, similar to clinical observations. This study demonstrated that an acellular fibrosis model using hydrogels could reproduce the impedance changes observed in vivo. Such a model system will support research to better understand in vivo changes in electrical properties and the longer term function of neuroprosthetic electrodes.Clinical Relevance-This study proposes an acellular fibrosis model for preclinical research. This will support the design of improved clinical stimulation strategies and better understanding of the mechanisms of impedance change at the device-tissue interface.


The NERP-4-SNAT2 axis regulates pancreatic β-cell maintenance and function.
Insulin secretion from pancreatic β cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. The granin protein VGF has dual roles in β cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca2+ influx in the pancreata of transgenic mice expressing apoaequorin, a Ca2+-induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and β-cell-derived MIN6-K8 cells. NERP-4 administration reverses the impairment of β-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into β cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on β-cell maintenance. These findings demonstrate a novel autocrine mechanism of β-cell maintenance and function that is mediated by the peptide-amino acid transporter axis.


The dementia severity rating scale: A potential community screening tool for dementia in low- and middle-income countries.
The Dementia Severity Rating Scale (DSRS) is an informant report, dementia staging tool that is quick to administer and has previous been shown to differentiate between people with dementia and healthy controls. However, it is not clear how accurate the tool is screening against diagnostic criteria in middle-income settings. Embedded within the STRiDE programme, older adults (aged ≥65 years) and their informants were randomly recruited from four sites across Indonesia and South Africa. All informants were asked to complete DSRS. We report the tool's psychometric properties and accuracy against the 10/66 short diagnostic algorithm. Between September and December 2021, data was collected from 2110 older adults in Indonesia and 408 in South Africa. Overall, the DSRS scores significantly differed between those with and without dementia, as identified on the 10/66 short algorithm (p < .05). The difference between groups remained significant after controlling for key factors related to older adult and informant demographics. A score >2 on the DSRS had the greatest agreement with the 10/66 short algorithm and had excellent discriminative properties in both Indonesia (Area Under Curve (AUC) = .75, 95% CIs = .72-.77) and South Africa (AUC = .82, 95% CIs = .76-.88). The DSRS has potential as a screening tool for dementia in middle-income countries, with high sensitivity and specificity against a standardized diagnostic algorithm.


[Effect of calcium ions on sorption of phthalocyanin dye by membranes of individual nerve fibers].
The binding of vital anionic phthalocyanine dye Heliogen blue K (HBK) by crab axons has been studied cytophotometrically. HBK koes not penetrate the cell but stains membranes selectively. The removal of Ca-ions from the surrounding artificial sea water (a.s.w.) leads to an obvious desorption of an ion-bound fraction of HBK from the fibre, provided the removal of Ca-ions from a.s.w. is combinded with slight hypotonia or with addition of EDTA. The hypotonia, which has no effect on sorption, causes swelling of fibres facilitating the removal of Ca-ions from membrane, i.e. the effect similar to that of EDTA. In the Ca-ions devoid hypotonic solution, the decrease of sorbed dye makes up 1.4% per minute of the initial concentration, and in the hypotonic solution with EDTA - this decrease reaches 0.95%. It is suggested that the withdrawal of Ca-ions from the membrane results in conformational changes of the membrane protein component. These changes are expressed as redistribution of changes, detected with the aid of the HBK anion.


Dedifferentiated Liposarcoma of the Gastroesophageal Junction.
Liposarcoma is one of the most common sarcomas in adults, but very rarely presents as a primary in the upper gastrointestinal system. Herein, we present a 71-year-old male patient who underwent wedge excision biopsy twice and then fine needle aspiration and total gastrectomy for a recurrent gastroeosophageal junction mass. In microscopic sections, both well-differentiated and dedifferentiated components were seen. Tumor cells were positive for MDM2, CDK4 and negative for CD117, DOG1, CD34, SMA, Desmin, S-100, HMB45, SOX10, AE1/AE3, CAM5.2, CK18. Fluorescence in situ hybridization (FISH) was performed and MDM2 gene (12q15) amplification was detected. According to these findings, a diagnosis of dedifferentiated liposarcoma was supported. We believe this is the first reported case of dedifferentiated liposarcoma of the gastroesophageal junction.