Safety and Efficacy of Indocyanine Green Tracer-Guided Lymph Node Dissection During Laparoscopic Radical Gastrectomy in Patients With Gastric Cancer: A Randomized Clinical Trial.
The application of indocyanine green (ICG) imaging in laparoscopic radical gastrectomy is in the preliminary stages of clinical practice, and its safety and efficacy remain controversial. To investigate the safety and efficacy of ICG near-infrared tracer-guided imaging during laparoscopic D2 lymphadenectomy in patients with gastric cancer. Patients with potentially resectable gastric adenocarcinoma (clinical tumor stage cT1-cT4a, N0/+, M0) were enrolled in a prospective randomized clinical trial at a tertiary referral teaching hospital between November 2018 and July 2019. Patients were randomly assigned to the ICG group or the non-ICG group. The number of retrieved lymph nodes, rate of lymph node noncompliance, and postoperative recovery data were compared between the groups in a modified intention-to-treat analysis. Statistical analysis was performed from August to September 2019. The ICG group underwent laparoscopic gastrectomy using near-infrared imaging after receiving an endoscopic peritumoral injection of ICG to the submucosa 1 day before surgery. Total number of retrieved lymph nodes. Of 266 participants randomized, 133 underwent ICG tracer-guided laparoscopic gastrectomy, and 133 underwent conventional laparoscopic gastrectomy. After postsurgical exclusions, 258 patients were included in the modified intention-to-treat analysis, which comprised 129 patients (86 men and 43 women; mean [SD] age, 57.8 [10.7] years) in the ICG group and 129 patients (87 men and 42 women; mean [SD] age, 60.1 [9.1] years) in the non-ICG group. The mean number of lymph nodes retrieved in the ICG group was significantly more than the mean number retrieved in the non-ICG group (mean [SD], 50.5 [15.9] lymph nodes vs 42.0 [10.3] lymph nodes, respectively; P < .001). Significantly more perigastric and extraperigastric lymph nodes were retrieved in the ICG group than in the non-ICG group. In addition, the mean total number of lymph nodes retrieved in the ICG group within the scope of D2 lymphadenectomy was also significantly greater than the mean number retrieved in the non-ICG group (mean [SD], 49.6 [15.0] lymph nodes vs 41.7 [10.2] lymph nodes, respectively; P < .001). The lymph node noncompliance rate of the ICG group (41 of 129 patients [31.8%]) was lower than that of the non-ICG group (74 of 129 patients [57.4%]; P < .001). The postoperative recovery process was comparable, and no significant difference was found between the ICG and non-ICG groups in the incidence (20 of 129 patients [15.5%] vs 21 of 129 [16.3%], respectively; P = .86) or severity of complications within 30 days after surgery. Indocyanine green can noticeably improve the number of lymph node dissections and reduce lymph node noncompliance without increased complications in patients undergoing D2 lymphadenectomy. Indocyanine green fluorescence imaging can be performed for routine lymphatic mapping during laparoscopic gastrectomy, especially total gastrectomy. ClinicalTrials.gov Identifier: NCT03050879.


Computational design principles for bioactive dendrimer based constructs as antagonists of the TLR4-MD-2-LPS complex.
The cell surface interaction between bacterial lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) and MD-2 is central to bacterial sepsis syndromes and wound healing. We have shown that a generation (G) 3.5 polyamidoamine (PAMAM) dendrimer that was partially glycosylated with glucosamine inhibits TLR4-MD-2-LPS induced inflammation in a rabbit model of tissue scaring. However, it was a mixture of closely related chemical species because of the polydispersity of the starting PAMAM dendrimer. Generation 2 triazine dendrimers with single chemical entity material status are available at low cost and at the kilogram scale. PAMAM dendrimer can be synthetically grafted onto this triazine core dendrimer to make new triazine-PAMAM hybrid dendrimers. This led us to examine whether molecular modelling methods could be used to identify the key structural design principles for a bioactive lead molecule that could be synthesized and biologically evaluated. We describe our computer aided molecular studies of several dendrimer based constructs and the key design principles identified. Our approach should be more broadly applicable to the biologically focused, rational and accelerated design of molecules for other TLR receptors. They could be useful for treating infectious, inflammatory and malignant diseases.


Psychometric properties of HeartQoL, a core heart disease-specific health-related quality of life questionnaire, in Danish implantable cardioverter defibrillator recipients.
Background Patient-reported health-related quality of life is increasingly used as an outcome measure in clinical trials and as a performance measure to evaluate quality of care. The objective of this study was to assess the psychometric properties of the Danish HeartQoL questionnaire, a core heart disease-specific health-related quality of life questionnaire, in implantable cardioverter defibrillator recipients. Design This study involved cross-sectional and test-retest study designs. Method Implantable cardioverter defibrillator recipients in the cross-sectional study completed the HeartQoL, the Short-Form 36 Health Survey, and the Hospital Anxiety and Depression Scale. The HeartQoL structure, construct-related validity (convergent and discriminative) and reliability (internal consistency) were assessed. HeartQoL reproducibility (test-retest) was assessed in an independent sample of implantable cardioverter defibrillator recipients. Results Mokken scale analysis supported the bi-dimensional structure of HeartQoL among 358 implantable cardioverter defibrillator recipients. Convergent ( r > 0.72) and discriminative validity were confirmed. The HeartQoL scales demonstrated satisfactory internal consistency (Cronbach's alpha > 0.90). Test-retest reliability (two weeks interval) was assessed in 89 implantable cardioverter defibrillator recipients and found to be acceptable for each scale (intra-class correlation > 0.90). Conclusion The Danish HeartQoL questionnaire demonstrated satisfactory key psychometric attributes of validity and reliability in this implantable cardioverter defibrillator population. This study adds support for the HeartQoL as a core heart-specific health-related quality of life questionnaire in a broad group of patients with heart disease including implantable cardioverter defibrillator recipients.


Differentiation of platelet-leukocyte conjugate formation by short term exercise.
Platelet-leukocyte conjugates are increased in cardiovascular disease, but exercise is also able to trigger platelet-leukocyte formation in healthy subjects. The aim was to investigate the heterogeneity of platelet-leukocyte conjugate formations triggered by short term exercise. 18 healthy non-smokers underwent a 90 second maximal test on a SRM cycle ergometry system and a control experiment. Blood samples were taken after 30 min rest, immediately before and after, 15 min and 1 h after exercise. The different platelet-leukocyte conjugates were detected by flow cytometry via CD45, CD14, CD16, CD41, together with CD62P antibodies for the investigation of platelet activation in the conjugates. In addition, a stimulation of conjugate formation in vitro with 8 microM TRAP-6 was initiated. Immediately after exercise platelet-granulocyte (+24%), and -lymphocyte (+17%) conjugates were increased (p<0.01), while the platelet-monocyte conjugates (+40%) were enhanced (p<0.05) 15 min after exercise. The differentiation after stimulation showed that the regular (CD14(+)16(-); +32%) and mature (CD14(+)16(+); +35%) monocytes were both increased after exercise (p<0.01) but the regular monocytes were preferred (p<0.001) in platelet-monocyte conjugate formation. In addition, these conjugates revealed the highest CD62P expression. Maximal short term exercise is useful for the investigation of platelet-leukocyte formation; e.g., it could be shown, that regular monocytes may be preferred in conjugate formation and that these conjugates revealed the highest CD62P expression.


Superpixels of RGB-D Images for Indoor Scenes Based on Weighted Geodesic Driven Metric.
Serving as a key step for applications of image processing, superpixel generation has been attracting increasing attention. RGB-D images are used pervasively in scenes reconstruction and representation, benefiting from their contained depth data. In this paper, we present a novel framework for generating superpixels focus on RGB-D images of indoor scenes, based on a weighted geodesic driven metric that combines both color and geometric information. In particular, taking into account the unique structures of indoor scenarios, we first denoise the given RGB-D image, and construct the corresponding triangular mesh. A new weighted geodesic driven metric is defined by introducing a weight function constrained with normal vectors and colors. Under this metric, an energy function is defined to measure our over-segmentation of the triangular mesh, by optimizing which, we can acquire an optimal over-segmentation of the triangular mesh with object boundaries respected, such that vertices in each sub-region have similar geometric structures and color intensities. Re-mapping the over-segmentation of the triangular mesh to the RGB-D image results in desired superpixels. We perform extensive experiments on a large-scale database of RGB-D images to verify the efficacy of our algorithm. The results show that our algorithm has considerable advantages over the existing state-of-the-art methods.


Abdominal ultrasonography in HIV/AIDS patients in southwestern Nigeria.
Though the major target of the HIV-virus is the immune system, the frequency of abdominal disorders in HIV/AIDS patients has been reported to be second only to pulmonary disease. These abdominal manifestations may be on the increase as the use of antiretroviral therapy has increased life expectancy and improved quality of life. Ultrasonography is an easy to perform, non invasive, inexpensive and safe imaging technique that is invaluable in Africa where AIDS is most prevalent and where sophisticated diagnostic tools are not readily available. To describe the findings and evaluate the clinical utility of abdominal ultrasonography in HIV/AIDS patients in Ibadan, Nigeria A Prospective evaluation of the abdominal ultrasonography of 391 HIV-positive patients as well as 391 age and sex-matched HIV-negative patients were carried out at the University College Hospital, Ibadan. Of the 391 cases studied, 260 (66.5%) were females; the mean age was 38.02 years, (range 15-66 years). The disease was most prevalent in the 4th decade with an incidence of 40.4%. Compared with the HIV-negative individuals, the HIV+ group of patients had a significantly higher proportion of splenomegaly (13.5% vs. 7.7%; p < 0.01), lymphadenopathy (2.0% vs. 1.3%; p < 0.70), and renal abnormalities (8.4% vs. 3.8%; p < 0.02). There were no differences in hepatic and pancreatic abnormalities between the HIV+ and HIV- groups. There were significantly fewer gallstones in the HIV+ group (1.4% vs. 5.1%; p < 0.01). AIDS is a multi-systemic disease and its demographic and clinical pattern remains the same globally. Ultrasonography is optimally suited for its clinical management especially in Africa. Its accuracy and sensitivity may be much improved with clinico-pathologic correlation which may not be readily available in developing countries; further studies may provide this much needed diagnostic algorithms.


Inhibitory effects of acyclic nucleoside phosphonate analogs, including (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, on Epstein-Barr virus replication.
(S)-9-(3-Hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-2,6-diaminopurine [(S)-HPMPDAP], cyclic (S)-HPMPA [(S)-cHPMPA], 9-(2-phosphonylmethoxyethoxyethyl)-2,6-diaminopurine (PMEDAP), and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC] were examined for their inhibitory effects on Epstein-Barr virus (EBV) replication. The 50% effective concentrations for inhibition of viral DNA replication were 0.16, 0.03, 2.0, 1.5, and 0.08 microM for PMEDAP, (S)-HPMPC, (S)-HPMPDAP, (S)-cHPMPA, and (S)-HPMPA, respectively. The relative efficacies based on the in vitro therapeutic index was (S)-HPMPC (5,000) greater than PMEDAP (1,000) = (S)-HPMPA (1,000) greater than (S)-cHPMPA (136) greater than (S)-HPMPDAP (78). Certain ratios of combinations of (S)-HPMPC with 3'-azido-3'-deoxythymidine produced a synergistic inhibitory effect on EBV genome replication, but others exhibited an antagonistic effect. These results indicate that this series of acyclic nucleoside phosphonate analogs, and in particular (S)-HPMPC, are potent and selective anti-EBV agents in vitro.


QuorUM: An Error Corrector for Illumina Reads.
Illumina Sequencing data can provide high coverage of a genome by relatively short (most often 100 bp to 150 bp) reads at a low cost. Even with low (advertised 1%) error rate, 100 × coverage Illumina data on average has an error in some read at every base in the genome. These errors make handling the data more complicated because they result in a large number of low-count erroneous k-mers in the reads. However, there is enough information in the reads to correct most of the sequencing errors, thus making subsequent use of the data (e.g. for mapping or assembly) easier. Here we use the term "error correction" to denote the reduction in errors due to both changes in individual bases and trimming of unusable sequence. We developed an error correction software called QuorUM. QuorUM is mainly aimed at error correcting Illumina reads for subsequent assembly. It is designed around the novel idea of minimizing the number of distinct erroneous k-mers in the output reads and preserving the most true k-mers, and we introduce a composite statistic π that measures how successful we are at achieving this dual goal. We evaluate the performance of QuorUM by correcting actual Illumina reads from genomes for which a reference assembly is available. We produce trimmed and error-corrected reads that result in assemblies with longer contigs and fewer errors. We compared QuorUM against several published error correctors and found that it is the best performer in most metrics we use. QuorUM is efficiently implemented making use of current multi-core computing architectures and it is suitable for large data sets (1 billion bases checked and corrected per day per core). We also demonstrate that a third-party assembler (SOAPdenovo) benefits significantly from using QuorUM error-corrected reads. QuorUM error corrected reads result in a factor of 1.1 to 4 improvement in N50 contig size compared to using the original reads with SOAPdenovo for the data sets investigated. QuorUM is distributed as an independent software package and as a module of the MaSuRCA assembly software. Both are available under the GPL open source license at http://www.genome.umd.edu. email@example.com.


[The susceptibility of different animal species to synanthropic and natural populations of Trichinella].
Pigs have been found to be highly susceptible to the synanthropic (domestic) population of Trichinella [correction of Trachina] and weakly susceptible to the natural (native) one. Fur-bearing animals (polar foxes and foxes) are more susceptible to the natural population of Trichinella [correction of Trachina], but minks are equally sensible to the two variants of T. spiralis. In the host's body, synanthropic Trichinella [correction of Trachinas] form capsules of lemon-like, less frequently, oval shape, but the native population do round capsules. There is larval adaptation when Trichinella [correction of Trachina] larvae enter the nonspecific host's body after their prepassage through the organism of domestic carnivorous animals (cats, dogs). The pig is successfully infected with T. spiralis nativa via the cat or dog; the infection rate is approximately close to that observed during control infection of pigs with synanthropic Trichinella [correction of Trachina].


Hospital variables associated with quality of care for breast cancer patients.
To determine the degree of compliance with clinical standards among hospitals for care of breast cancer patients and account for variations in compliance. Analysis of cancer registry data submitted to the American Cancer Society, Illinois Division, Chicago, for a concurrent prospective descriptive study of breast cancer, supplemented by other hospital data from public sources. Ninety-nine Illinois hospitals evenly distributed among rural counties, counties with small cities outside the Chicago metropolitan area, exurban counties in the Chicago metropolitan area, suburban Cook County, and urban Chicago. A total of 5766 newly diagnosed patients with histologically confirmed breast cancer in 1988, representing 84% of the estimated 6900 new cases in the state for that year. Descriptive statistics and multiple linear regression analyses of five dependent quality variables from clinical indicators related to early diagnosis, hormone receptor determination, adjuvant therapy, radiation therapy, and axillary lymph node dissection. At the hospitals studied, (1) late stage (IIb through IV) at diagnosis was associated with urban location, higher proportion of poorly insured patients, fewer breast cancer cases treated, and lower oncology charges (proportion of variance explained, R2 = .50, P less than .00001); (2) omission of hormone receptor test for stages II through IV was associated with urban location and higher proportion of poorly insured patients (R2 = .18, P less than .00003); and (3) omission of indicated radiation therapy was associated with urban location and fewer breast cancer cases (R2 = .21, P less than .00001). Omission of adjuvant therapy and omission of axillary lymph node dissection were not significantly associated with any of the hospital variables examined. The findings suggest that there is a group of urban hospitals, generally small and marginally reimbursed, where comprehensive diagnosis and treatment of breast cancer are not obtained.


[Metabolic disorders of chronically critically ill patients caused by consequences of traumatic brain injury].
The problem of chronic critical illness therapy is relevant all over the world. Revealing the metabolic function in patients in chronic critical condition is an important link in the development of adequate treatment and rehabilitation tactics. The aim - identification of metabolic features in chronic critical patients after brain injury in the first 3 days from the moment of admission to the rehabilitation center. Material and methods. Single-center observational study included a group of 25 patients with chronic critical illness, aged 38.7±14.0 years with body mass index 20.8± 4.3 kg/m2 (min 14.5; max 29.7), who were on independent breathing through a tracheostomy tube, and who have pronounced neurological disorders in the form of depression of minimally conscious state, FOUR scale from 12 to 16 points, as well as bedsores 1-2 stage and polysegmental pneumonia. The patients underwent indirect calorimetry and analysis of biochemical parameters of protein, carbohydrate, fat and mineral metabolism, as well as the level of nitrogen excretion with urine. Results and discussion. The data obtained indicate that chronic critical ill patients with the consequences of traumatic brain injury had pronounced metabolic disorders, mainly of a protein component. Total protein level decreased up to 61.0±9.4 g/l (min 39.1; max 83.1), albumin up to 30.2±6.0 g/l (min 17.4; max 37.8), prealbumin up to 0.13± 0.06 g/l (min 0.04; max 0.23) and transferrin up to 147.7±37.7 mg/dl (min 84.0; max 209.0). The patients' requirement in protein was 106.4±38.5 g/day (min 57.1; max 160.5) or 1.55±0.46 g/kg/day (min 0.75; max 2.22). The level of resting energy expenditure measured by indirect calorimetry was 1549.1±421.8 kcal/day (min 673.0; max 2430.0) or in terms of body weight 24.8±7.6 kcal/kg/day (min 12.4; max 45.8). Conclusion. The data obtained indicate a continuing catabolic phase in patients more than 30 days after the primary injury, which led to their chronic critical condition.


Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs.
Considerable progress has been made in testing stem cell-derived retinal pigment epithelium (RPE) as a potential therapy for age-related macular degeneration (AMD). However, the recent reports of oncogenic mutations in induced pluripotent stem cells (iPSCs) underlie the need for robust manufacturing and functional validation of clinical-grade iPSC-derived RPE before transplantation. Here, we developed oncogenic mutation-free clinical-grade iPSCs from three AMD patients and differentiated them into clinical-grade iPSC-RPE patches on biodegradable scaffolds. Functional validation of clinical-grade iPSC-RPE patches revealed specific features that distinguished transplantable from nontransplantable patches. Compared to RPE cells in suspension, our biodegradable scaffold approach improved integration and functionality of RPE patches in rats and in a porcine laser-induced RPE injury model that mimics AMD-like eye conditions. Our results suggest that the in vitro and in vivo preclinical functional validation of iPSC-RPE patches developed here might ultimately be useful for evaluation and optimization of autologous iPSC-based therapies.


Swine influenza virus in swine and man in Illinois.
Serum samples from 2,091 persons from Illinois populations of swine abattoir employees, 4-H Club youths and their advisors, veterinary medical students, pork producers, and veterinarians were tested for hemagglutination-inhibition (HI) antibodies to A/Swine/Ill./63. A total of 231 positive reactions of 1:20 or above were found (11%). The highest prevalence of antibody was found in veterinarians, followed by pork producers and future swine abattoir employees. Age-adjusted reactor rates were highest in pork producers. Of 305 abattoir employees from whom two serum samples were examined 26(8.5%) had positive seroconversions. The abattoir population studied consisted largely of males under 40 years of age. A low prevalence of antibody was found in veterinary medical students and none was found in 4-H Club youths having swine contact. It is postulated that in Illinois there is occupational exposure of veterinarians, pork producers, and swine abattoir employees.


Profile of hepatic involvement by dengue virus in dengue infected children.
The spectrum of liver dysfunction in children with dengue infection is wide and has been associated with disease severity. This study was undertaken to estimate the range of hepatic involvement in dengue infection in children. This study assessed the biochemical and clinical profile of hepatic involvement by dengue virus in 120 children with serologically positive dengue fever (DF), aged 2 months to 14 years. All cases were grouped into DF without warning signs (Group 1), DF with warning signs (Group 2) and severe dengue (Group 3) according to revised World Health Organization 2009 criteria. The spectrum of hepatic manifestations included hepatomegaly (80.8%), hepatic tenderness (46.3%), jaundice (60%), raised aspartate transaminase (AST), alanine transaminase (ALT) and prolonged prothrombin time (41.7%) and reduced serum albumin (56%). Hepatic dysfunction was observed more in Groups 2 and 3. There was 84.4% and 93.75% ALT and AST elevation respectively in Group 2 and 94.5% and 95.9% ALT and AST elevation respectively in Group 3 and fulminant hepatic failure was observed in Group 3. Therefore in a child with fever, jaundice, hepatomegaly and altered liver function tests, the diagnosis of dengue infection should be strongly considered in areas where dengue infection is endemic.


Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects about 0.1% of the worldwide population. This deleterious disease is marked by infiltration of myelin-specific T cells that attack the protective myelin sheath that surrounds CNS nerve axons. Upon demyelination, saltatory nerve conduction is disrupted, and patients experience neurologic deficiencies. The exact cause for MS remains unknown, although most evidence supports the hypothesis that both genetic and environmental factors contribute to disease development. Epidemiologic evidence supports a role for environmental pathogens, such as viruses, as potentially key contributors to MS induction. Pathogens can induce autoimmunity via several well-studied mechanisms with the most postulated being molecular mimicry. Molecular mimicry occurs when T cells specific for peptide epitopes derived from pathogens cross-react with self-epitopes, leading to autoimmune tissue destruction. In this review, we discuss an in vivo virus-induced mouse model of MS developed in our laboratory, which has contributed greatly to our understanding of the mechanisms underlying molecular mimicry-induced CNS autoimmunity.


The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene.
Severe protein C (PC) deficiency is a rare heritable thrombophilia leading to thromboembolic events during the neonatal period. It remains unclear how individuals with complete PC gene (PROC) defects develop or escape neonatal stroke or purpura fulminans (PF). We studied the onset of disease and the genotype of 22 PC-deficient patients with double mutations in PROC based on our cohort (n = 12) and the previous reports (n = 10) in Japan. Twenty-two patients in 20 unrelated families had 4 homozygous and 18 compound heterozygous mutations. Sixteen newborns presented with PF (n = 11, 69%), intracranial thromboembolism and hemorrhage (n = 13, 81%), or both (n = 8, 50%), with most showing a plasma PC activity of <10%. Six others first developed overt thromboembolism when they were over 15 years of age, showing a median PC activity of 31% (range: 19-52%). Fifteen of the 22 patients (68%) had the five major mutations (G423VfsX82, V339M, R211W, M406I, and F181V) or two others (E68K and K193del) that have been reported in Japan. Three of the six late-onset cases, but none of the 16 neonatal cases, had the K193del mutation, which has been reported to be the most common variant of Chinese thrombophilia. A novel mutation of A309V was determined in a family of two patients with late onset. The genotype of double-PROC mutants might show less diversity than heterozygous mutants in terms of the timing of the onset of thrombophilia (newborn onset or late onset).


Glucose metabolism in perfused skeletal muscle. Pyruvate dehydrogenase activity in starvation, diabetes and exercise.
1. The interconversion of pyruvate dehydrogenase between its inactive phosphorylated and active dephosphorylated forms was studied in skeletal muscle. 2. Exercise, induced by electrical stimulation of the sciatic nerve (5/s), increased the measured activity of (active) pyruvate dehydrogenase threefold in intact anaesthetized rated within 2 min. No further increase was seen after 15 min of stimulation. 3. In the perfused rat hindquarter, (active) pyruvate dehydrogenase activity was decreased by 50% in muscle of starved and diabetic rats. Exercise produced a twofold increase in its activity in all groups; however, the relative differences between fed, starved and diabetic groups persisted. 4. Perfusion of muslce with acetoacetate (2 mM) decreased (active) pyruvate dehydrogenase activity by 50% at rest but not during exercise. 5. Whole-tissue concentrations of pyruvate and citrate, inhibitors of (active) pyruvate dehydrogenase kinase and (inactive) pyruvate dehydrogenase phosphate phosphatase respectively, were not altered by excerise. A decrease in the ATP/ADP ratio was observed, but did not appear to be sufficient to account for the increase in (active) pyruvate dehydrogenase activity. 6. The results suggest that interconversion of the phosphorylated and dephosphorylated forms of pyruvate dehydrogenase plays a major role in the regulation of pyruvate oxidation by eomparison of enzyme activity with measurements of lactate oxidation in the perfused hindquarter [see the preceding paper, Berger et al. (1976)] suggest that pyruvate oxidation is also modulated by the concentrations of substrates, cofactors and inhibitors of (active) pyruvate dehydrogenase activity.


Cortical microvascular raspberries and ageing: an independent but not exclusive relationship.
Raspberries are cerebral microvascular formations of unknown origin, defined as three or more transversally sectioned vascular lumina surrounded by a common perivascular space. We have previously demonstrated an increased raspberry density in the cortex of patients with vascular dementia and cerebral atherosclerosis, while studies by other authors on overlapping and synonymously defined vascular entities mainly associate them with advancing age. The aim of the present study was to examine the relationship between raspberries and age in a large study sample while including multiple potential confounding factors in the analysis. Our study sample consisted of 263 individuals aged 20-97 years who had undergone a clinical autopsy including a neuropathological examination. The cortical raspberry density had either been quantified as part of a previous study or was examined de novo in a uniform manner on haematoxylin- and eosin-stained tissue sections from the frontal lobe. The medical records and autopsy reports were assessed regarding neurodegeneration, cerebral infarcts, cerebral atherosclerosis and small vessel disease, cardiac hypertrophy, nephrosclerosis, hypertension, and diabetes mellitus. With the patients grouped according to 10-year age interval, non-parametric tests (the Kruskal-Wallis test, followed by pairwise testing with Bonferroni-corrected P values) and multiple linear regression models (not corrected for multiple tests) were performed. The average raspberry density increased with advancing age. The non-parametric tests demonstrated statistically significant differences in raspberry density when comparing the groups aged 60-99 years and 70-99 years to those aged 20-29 years (P < 0.012) and 30-59 years (P < 0.011), respectively. The multiple linear regression models demonstrated positive associations with age interval (P < 0.001), cerebral atherosclerosis (P = 0.024), cardiac hypertrophy (P = 0.021), hypertension subgrouped for organ damage (P = 0.006), and female sex (P = 0.004), and a tendency towards a negative association with Alzheimer's disease neuropathologic change (P = 0.048). The raspberry density of the frontal cortex increases with advancing age, but our results also indicate associations with acquired pathologies. Awareness of the biological and pathological context where raspberries occur can guide further research on their origin.


Low-noise phase of a two-dimensional active nematic system.
We consider a collection of self-driven apolar particles on a substrate that organize into an active nematic phase at sufficiently high density or low noise. Using the dynamical renormalization group, we systematically study the two-dimensional fluctuating ordered phase in a coarse-grained hydrodynamic description involving both the nematic director and the conserved density field. In the presence of noise, we show that the system always displays only quasi-long-ranged orientational order beyond a crossover scale. A careful analysis of the nonlinearities permitted by symmetry reveals that activity is dangerously irrelevant over the linearized description, allowing giant number fluctuations to persist although now with strong finite-size effects and a nonuniversal scaling exponent. Nonlinear effects from the active currents lead to power-law correlations in the density field, thereby preventing macroscopic phase separation in the thermodynamic limit.


Cardiac ECMO for biventricular hearts after paediatric open heart surgery.
To delineate predictors of hospital survival in a large series of children with biventricular physiology supported with extracorporeal membrane oxygenation (ECMO) after open heart surgery. 81 children were placed on ECMO after open heart surgery. 58% (47 of 81) were transferred directly from cardiopulmonary bypass to ECMO. Hospital survival was 49% (40 of 81) but there were seven late deaths among these survivors (18%). Factors that improved the odds of survival were initiation of ECMO in theatre (64% survival (30 of 47)) rather than the cardiac intensive care unit (29% survival (10 of 34)) and initiation of ECMO for reactive pulmonary hypertension. Important adverse factors for hospital survival were serious mechanical ECMO circuit problems, renal support, residual lesions, and duration of ECMO. Hospital survival of children with biventricular physiology who require cardiac ECMO is similar to that found in series that include univentricular hearts, suggesting that successful cardiac ECMO is critically dependent on the identification of hearts with reversible ventricular dysfunction. In our experience of postoperative cardiac ECMO, the higher survival of patients cannulated in the operating room than in the cardiac intensive care unit is due to early effective support preventing prolonged hypoperfusion and the avoidance of a catastrophic cardiac arrest.


Primary adenocarcinoma of the middle ear.
Two patients with primary adenocarcinoma of the middle ear displayed symptoms in the affected ear many years before their condition was diagnosed as adenocarcinoma. Treatment included simple extirpation of the tumor, radical mastoidectomy with or without radiation. A review of the literature shows 11 cases reported previously. Follow-up of the patients for more than four years revealed four deaths in the reported cases-one from causes unrelated to the tumor and the others showing only local invasion without distant metastases. These tumors grow slowly and have a low-grade of malignancy.


CT measurement of the normal ventricular system in premature infants.
In order to develop quantitative criteria for normal lateral ventricular dimensions, 70 cerebral computed tomographic scans of premature infants were reviewed and 31 normal scans were selected as suitable for establishing cerebroventricular indices. In 15 normal premature infants of less than 32 weeks gestational age the mean bifrontal index was 0.28 +/- 0.05, the mean bicaudate index 0.10 +/- 0.02, and the mean bioccipital index 0.19 +/- 0.05. In 16 normal premature infants of more than 32 weeks gestational age the mean bifrontal, bicaudate, and bioccipital indices were 0.26 +/- 0.06, 0.11 +/- 0.03, and 0.17 +/- 0.04, respectively. No statistically significant differences were found in the values of the indices between the two groups, which demonstrates the uniformity of the ventricular size in normal premature infants.


Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients.
This prospective phase II study was designed to test the activity and toxicity of a regimen of fluorouracil (5-FU) and cisplatin (CDDP) in combination with radiation therapy in the treatment of epidermoid cancer of the anal canal. Thirty-five consecutive patients with untreated epidermoid cancer of the anal canal were candidates for chemoradiation therapy (CRT). Staging of cancer was as follows: T1, 26%; T2, 60%; T3, 14%; and N1, 2,3, 26%. No patient had distant metastases. The treatment protocol consisted of two to three cycles of chemotherapy starting on days 1 and 21 and concurrent radiotherapy at a daily dose of 1.8 Gy up to a total dose of 36 to 38 Gy in 4 weeks, delivered to the anal region, perineum, middle and lower pelvis, and inguinal and external iliac nodes. Radiotherapy was then delivered to the anoperineal region and metastatic inguinal nodes to a total dose of 18 to 24 Gy in 10 fractions. Chemotherapy consisted of 24-hour intravenous (IV) infusion of 5-FU 750 mg/m2 on days 1 to 4 and CDDP 100 mg/m2 by 60-minute IV infusion on day 1. All patients received two cycles of chemotherapy; the second was delayed in three patients because of leukopenia that was evident in 11 (31%). In eight patients, a third cycle was added. They all experienced nausea or vomiting; one patient showed signs of cardiotoxicity and one developed proctitis, dermatitis, and diarrhea (grade 3). Complete regression (CR) was assessed in 33 patients (94%); nine patients with metastatic lymph nodes also had CR. Two patients had a partial response (PR); both underwent abdominoperineal resection, which was not curative in one. Two patients (6%) had a local recurrence; in one, this was associated with hepatic metastases. One of these patients underwent surgery and is alive after about 4 years, while the other is undergoing chemotherapy. After a median follow-up duration of 37 months, 94% of patients are alive without evidence of disease and 86% are colostomy-free. This regimen is well tolerated; its toxicity does not exceed that observed with the combination of 5-FU and mitomycin (MMC). Compared with our previous experience based on the classic CRT (5-FU, MMC, and radiation), the objective response rate observed with this new combination was similar. However, the local recurrence rate, observed in patients treated with the new regimen, was lower (6% v 24%). According to more recent data from the literature, primary CRT is the elective indication in epidermoid cancer of the anus and replacement of MMC with CDDP seems an effective and logical evolution.


Comparison of UV-absorbing nets in pepper crops: spectral properties, effects on plants and pest control.
In horticultural crops, the use of screens to protect plants is the usual strategy in the Mediterranean area. Screen manufacturers offer a range of netting that vary in their UV-absorbing properties. We compared the photoeffects of seven different screens. Sweet pepper trials were conducted at the Gilat Research Center, Israel, where the spectral properties of the nets and their influence on pest infestation and crop development were evaluated. UV transmittance varied among the materials studied ranging from 40% to 70% of the incident radiation. BioNet white and P-Optinet, which absorbed and reflected the highest amount of UV radiation, performed the best protection against the main pepper pest (thrips, whiteflies and broad mites). Spectral measurements also showed that the photosynthetically active radiation differentially penetrated the nets, which together with the amount of UV absorbed by the screenings, resulted in a range of plant height and chlorophyll content. A global understanding of the UV-absorbing nets' effect on pepper crops and their pests was evaluated in this work because of the importance of these screens to integrated pest management and sustainable agriculture production.


Orbital Schwannoma-Management and Clinical Outcomes.
To evaluate the clinical features, management, and outcomes of orbital schwannomas. Retrospective study analyzing 20 orbital schwannomas in 18 patients managed in an orbital service over 26 years. Clinical, radiological, histological, and surgical procedural data were analyzed. Mean age of the study population was 40.89 ± 20.84 years. The most common nerve of origin was frontal nerve (50%), and majority of patients (70%) had a superior and/or posteriorly located tumor. Five patients (27.8%) had optic neuropathy at presentation, and 3 of them showed improved vision after intervention. Surgical resection was performed for all except for 1 patient who underwent fractionated stereotactic radiotherapy. Six subjects had extension of tumor into the cavernous sinus, and 3 of them underwent combined neurosurgical intervention with stereotactic neuronavigation. Outcomes were largely favorable with majority achieving complete excision. Two out of 6 incomplete resections experienced regrowth requiring second surgical intervention. Surgical complications include decreased vision, diplopia, ptosis, and mydriasis. Orbital schwannomas are uncommon slow-growing tumors which can result in visual loss. Prognosis can be favorable even in presence of pre-operative optic neuropathy if there is early intervention. Schwannomas confined to the orbit can usually be completely excised with good outcomes. Schwannomas extending intra-cranially may undergo incomplete excision to preserve vital structures, leaving residual disease, but generally have satisfactory results. Stereotactic neuronavigation and frozen section are useful intra-operative tool to aid management and minimize complications. Fractionated radiotherapy can be considered as an alternative or adjunctive treatment for patients not amenable for surgical resections.


Meiosis in asynaptic yeast.
The Saccharomyces cerevisiae red1 mutant fails to assemble synaptonemal complex during meiotic prophase. This mutant displays locus-specific reductions in interchromosomal gene conversion and a moderate reduction in crossing over. The occurrence of a significant amount of meiotically induced recombination in the red1 mutant indicates that the synaptonemal complex is not absolutely required for meiotic exchange. The RED1 gene product is required for intrachromosomal recombination in some assays but not others. Chromosomes that have undergone reciprocal exchange nevertheless nondisjoin in red1 mutants, indicating that crossovers are not sufficient for disjunction. Epistasis studies reveal that HOP1 is epistatic to RED1, and that RED1 acts in an independent pathway from MER1. A model for the function of the RED1 gene product in chromosome synapsis is discussed.


Physiological and molecular bases of the boron deficiency response in tomatoes.
Boron is an essential microelement for plant growth. Tomato is one of the most cultivated fruits and vegetables in the world, and boron deficiency severely inhibits its yield and quality. However, the mechanism of tomato in response to boron deficiency remains largely unclear. Here, we investigated the physiological and molecular bases of the boron deficiency response in hydroponically grown tomato seedlings. Boron deficiency repressed the expression of genes associated with nitrogen metabolism, while it induced the expression of genes related to the pentose phosphate pathway, thereby altering carbon flow to provide energy for plants to cope with stress. Boron deficiency increased the accumulation of copper, manganese and iron, thereby maintaining chlorophyll content and photosynthetic efficiency at the early stage of stress. In addition, boron deficiency downregulated the expression of genes involved in cell wall organization and reduced the contents of pectin and cellulose in roots, ultimately retarding root growth. Furthermore, boron deficiency markedly altered phytohormone levels and signaling pathways in roots. The contents of jasmonic acid, jasmonoy1-L-isoleucine, trans-zeatin riboside, abscisic acid, salicylic acid, and SA glucoside were decreased; in contrast, the contents of isopentenyladenine riboside and ethylene precursor 1-aminocyclopropane-1-carboxylic acid were increased in the roots of boron-deficient tomato plants. These results collectively indicate that tomato roots reprogram carbon/nitrogen metabolism, alter cell wall components and modulate phytohormone pathways to survive boron deficiency. This study provides a theoretical basis for further elucidating the adaptive mechanism of tomato in response to boron deficiency.


Relationships between opioid disposition and their pharmacological effects--an overview.
The understanding of the metabolic disposition and pharmacokinetics of opioid analgesics and their relationship to therapeutic and adverse effects has been an area of considerable research activity in the past two decades and has provided the beginning of an applied science in this area. Given the experimental nature and complexity of pharmacokinetic/pharmacodynamic relationships and the state of the art in this area, the most meaningful therapeutic conclusions and extrapolations remain those based on the results of the most adequate and well-controlled therapeutic evaluations. In contrast, advances in analytical methodology and an understanding of the pharmacokinetics of opioid analgesics in specific patient populations (e.g. severe hepatic cirrhosis, renal failure) have provided clinically useful guidance towards the appropriate precautions for the use of opioid analgesics.


Conserved target for group II intron insertion in relaxase genes of conjugative elements of gram-positive bacteria.
The lactococcal group II intron Ll.ltrB interrupts the ltrB relaxase gene within a region that encodes a conserved functional domain. Nucleotides essential for the homing of Ll.ltrB into an intronless version of ltrB are found exclusively at positions required to encode amino acids broadly conserved in a family of relaxase proteins of gram-positive bacteria. Two of these relaxase genes, pcfG from the enterococcal plasmid pCF10 and the ORF4 gene in the streptococcal conjugative transposon Tn5252, were shown to support Ll.ltrB insertion into the conserved motif at precisely the site predicted by sequence homology with ltrB. Insertion occurred through a mechanism indistinguishable from retrohoming. Splicing and retention of conjugative function was demonstrated for pCF10 derivatives containing intron insertions. Ll.ltrB targeting of a conserved motif of a conjugative element suggests a mechanism for group II intron dispersal among bacteria. Additional support for this mechanism comes from sequence analysis of the insertion sites of the E.c.I4 family of bacterial group II introns.


Modulation of immune response by nanoparticle-based immunotherapy against food allergens.
The increasing prevalence of food allergies worldwide and the subsequent life-threatening anaphylactic reactions often have sparse treatment options, providing only symptomatic relief. Great strides have been made in research and in clinics in recent years to offer novel therapies for the treatment of allergic disorders. However, current allergen immunotherapy has its own shortcomings in terms of long-term efficacy and safety, due to the local side effects and the possibility of anaphylaxis. Allergen-specific immunotherapy is an established therapy in treating allergic asthma, allergic rhinitis, and allergic conjunctivitis. It acts through the downregulation of T cell, and IgE-mediated reactions, as well as desensitization, a process of food tolerance without any allergic events. This would result in a protective reaction that lasts for approximately 3 years, even after the withdrawal of therapy. Furthermore, allergen-specific immunotherapy also exploits several routes such as oral, sublingual, and epicutaneous immunotherapy. As the safety and efficacy of allergen immunotherapy are still under research, the exploration of newer routes such as intra-lymphatic immunotherapy would address unfulfilled needs. In addition, the existence of nanoparticles can be exploited immensely in allergen immunotherapy, which would lead to safer and efficacious therapy. This manuscript highlights a novel drug delivery method for allergen-specific immunotherapy that involves the administration of specific allergens to the patients in gradual increasing doses, to induce desensitization and tolerance, as well as emphasizing different routes of administration, mechanism, and the application of nanoparticles in allergen-specific immunotherapy.


Autonomic nervous system dysfunction in advanced systolic heart failure.
An alteration of the autonomic nervous system has been described in heart failure (HF). The aim of this study was to assess, compare and relate the impairment of both arms of the autonomic nervous systems, the sympathetic and parasympathetic (SNS and PNS) in a same group of patients. We analyzed 23 patients with advanced HF (NYHA III-IV/IV and IV/IV) and EF<35% who were on the waiting list for heart transplantation. We assessed the SNS by determining cardiac uptake of (123)I metaiodobenzylguanidine, and analyzed the heart mediastinum rate (HMR) and the myocardial washout rate (WR). The PNS was assessed by 24-hour Holter ECG recording and subsequent analyses of heart rate turbulence (HRT) in which turbulence onset (TO) and turbulence slope (TS) were determined. In the study of the SNS, HMR values were 1.32 ± 0.12, and WR 0.36 ± 0.1. Higher creatinine levels were associated with a lower WR (r=-0.604; p=0.02). In the study of the SNP, TO was higher the lower the LVEF (r=-0.410; p=0.052), and age was associated with a lower TS (r=-0.4; p=0.059). In the study of the relationships between the SNS and PNS, HMR was correlated in a nearly significant manner with TO (r=-0.399; p=0.059) and WR with TS (r=-0.447; p=0.033). In stable patients with advanced HF (NYHA III-IV and IV/IV), a significant and parallel impairment occurs in both arms of the autonomic nervous system. This could have prognostic implications and would help to prioritize patients on the waiting list for heart transplantation.


Comparison of TachoComb and TissuDura in Terms of Adverse Effects and Complications in Duraplasty in Rats.
To compare two synthetic graft materials, TachoComb®, a fibrin sealant composed of collagen, fibrinogen, thrombin and aprotinin and TissuDura®, a collagen-based biomatrix. Thirty Sprague?Dawley rats were randomly divided into three groups with 10 animals in each group. A dural defect was created on the left parietal bone of each animal, and the dural defect was repaired using either TachoComb® (TachoComb group) or TissuDura® (TissuDura group). Sham animals did not receive any dural graft. After 21 days of follow-up, the brain was dissected, and inflammation, oedema, gliosis and foreign body reaction in the bone and parenchymal tissue were investigated histopathologically. The TachoComb group showed significantly greater inflammation, gliosis and parenchymal foreign body reaction compared with the sham group. By contrast, the TissuDura group had significantly lower gliosis and insignificantly less inflammation in the bone and parenchymal foreign body reaction compared with the TachoComb group. In conclusion, our results suggest that TissuDura® may be considered more biocompatible than TachoComb® in duraplasty.


Street outreach and shelter care elective for senior health professional students: an interprofessional educational model for addressing the needs of vulnerable populations.
University of New Mexico Health Sciences Center (UNMHSC), located in Albuquerque, New Mexico, USA, has an international reputation for developing and implementing curricular initiatives addressing health inequities. The Street Outreach and Shelter Care elective is designed to provide interprofessional service learning opportunities for senior pharmacy and medical students addressing the needs of our nation's most marginalized population-those experiencing homelessness. Our institution collaborated with multiple community partners serving the homeless to develop, implement and teach a 4-week senior elective for health professions students. During this elective, senior pharmacy and medical student teams provide individualized health care to men in local homeless shelter facilities. Students also participate in street outreach programs across a continuum of homeless populations. Weekly interprofessional education (IPE) faculty-facilitated sessions allow students to reflect on their experiences and learn from other discipline perspectives. Student evaluations uniformly reflect the transformative nature of the rotation since its inception, April 2009. Our outcomes corroborated the findings of similar service learning models developed to sensitize health professions students to the complex challenges of homeless populations. Academic centers can play a central role in health education reform by instituting curricula focusing on the primacy of population welfare and just distribution of resources. Senior year is an opportune time to reinforce social accountability among health professions before graduation. This elective is based on adult principles of learning and can serve as an international educational model for developing interprofessional curricular innovations addressing the healthcare needs of vulnerable populations.


Advanced alveolar rhabdomyosarcoma of the uterus: a case report.
Alveolar rhabdomyosarcoma is an uncommon malignant soft tissue tumour rarely found in the female genital tract and carries a very poor prognosis especially in adults. A 44 year old premenopausal woman was evaluated for a lower abdominal mass, intermittent unprovoked vaginal bleeding and weight loss. Examination showed a huge abdomino-pelvic mass, and an irregular cauliflower mass protruding from the cervix, from which a biopsy was taken. Exploratory laparotomy revealed a widespread disseminated uterine tumour with an "omental cake" and involving virtually all the abdominal viscera. Debulking surgery was found to be non-beneficial and uterine and omental biopsies were taken. The cervical, uterine and omental biopsies were all diagnosed alveolar rhabdomyosarcoma. Neither chemotherapy nor radiotherapy could be started before the client died of fulminant neoplastic dissemination 17 days postoperatively. While the optimal management of this rare tumour is unknown, early recognition and diagnosis, and a prompt multimodality treatment approach of surgery, chemotherapy and radiotherapy offers the best chance of cure.


Formation and Growth of Co-Culture Tumour Spheroids: New Compartment-Based Mathematical Models and Experiments.
Co-culture tumour spheroid experiments are routinely performed to investigate cancer progression and test anti-cancer therapies. Therefore, methods to quantitatively characterise and interpret co-culture spheroid growth are of great interest. However, co-culture spheroid growth is complex. Multiple biological processes occur on overlapping timescales and different cell types within the spheroid may have different characteristics, such as differing proliferation rates or responses to nutrient availability. At present there is no standard, widely-accepted mathematical model of such complex spatio-temporal growth processes. Typical approaches to analyse these experiments focus on the late-time temporal evolution of spheroid size and overlook early-time spheroid formation, spheroid structure and geometry. Here, using a range of ordinary differential equation-based mathematical models and parameter estimation, we interpret new co-culture experimental data. We provide new biological insights about spheroid formation, growth, and structure. As part of this analysis we connect Greenspan's seminal mathematical model to co-culture data for the first time. Furthermore, we generalise a class of compartment-based spheroid mathematical models that have previously been restricted to one population so they can be applied to multiple populations. As special cases of the general model, we explore multiple natural two population extensions to Greenspan's seminal model and reveal biological mechanisms that can describe the internal dynamics of growing co-culture spheroids and those that cannot. This mathematical and statistical modelling-based framework is well-suited to analyse spheroids grown with multiple different cell types and the new class of mathematical models provide opportunities for further mathematical and biological insights.


Substrate and inhibitor specificity of the cloned human 11 beta-hydroxysteroid dehydrogenase type 2 isoform.
The 11 beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) enzyme is thought to confer specificity on the mineralocorticoid receptor by inactivating glucocorticoids in mineralocorticoid target organs. The cloned 11 beta HSD2 displayed Michaelis constant values for corticosterone and cortisol of 5.1 and 61 nM, respectively. Linearity in the dose-response curve ranged between 1 and 200 nM for corticosterone and 25 and 2,000 nM for cortisol, with no evidence for complex kinetics. Inhibition of cortisol oxidation by other steroids was purely competitive in nature. Inhibition of 11 beta HSD2 activity by the end product or aldosterone occurred only at supraphysiological levels, whereas corticosterone and deoxycorticosterone displayed significant inhibition at physiological concentrations and progesterone at concentrations that occur during pregnancy. In intact transfected CHOP cells, dexamethasone was converted to 11-dehydrodexamethasone by 11 beta HSD2 but not type 1 11 beta-hydroxysteroid dehydrogenase, an aspect that may be useful in evaluating 11 beta HSD activity in intact cells.


Quantitative analysis of staphylococcus enterotoxin A by differential expression of IFN-γ in splenocyte and CD4⁺ T-cells.
Staphylococcus aureus is an important bacterial pathogen that produces a range of Staphylococcal Enterotoxins (SEs) which cause gastroenteritis and superantigen activation of T cells, the mechanism of which is not well understood. The ability to rapidly detect and quantify SEs is very important in order to learn the causes of staphylococcal outbreaks and to stop similar outbreaks in the future. Enzyme-linked immunosorbent assays (ELISAs) have been developed for detection of several SEs. However, these immunological methods cannot distinguish between active and inactive toxin. It is known that interferon-gamma (IFN-γ) expressed in response to stimulation by SEs contributes significantly to the pathogenesis of S. aureus infection. Nonetheless, the cellular source of IFN-γ is still unclear and the contributions of the specific splenocyte types. In our effort to understand the immunologic response to Staphylococcal Enterotoxin A (SEA) exposure, we studied IFN-γ production in mouse splenocytes. We demonstrated that short term ex vivo exposure of splenocytes or primary naïve CD4+ T-cells to biologically active SEA induces differential expression of IFN-γ mRNA in a time and dose dependent manner and the expression levels reflect the levels of IFN-γ secreted protein. Positive isolated CD4+ T-cells accounted for only 10% of IFN-γ production. We also demonstrate that expression of IFN-γ can be used for rapid quantitative analysis of active SEA with a detection limit of 1 ng/mL.


Neuropsychological assessments and psychotherapeutic services in Veterans with multiple sclerosis: Rates of utilization and their associations with socio-demographics and clinical characteristics using Veterans Health Administration-based data.
As cognitive, emotional, and health-related behavioral issues are prevalent among persons with multiple sclerosis (MS), mental health services are a valuable component of comprehensive care. However, it is unknown how many participate in neuropsychological and psychotherapeutic services, and whether the presence of certain co-occurring conditions increase service use. This study aimed to examine the frequency and associated factors (e.g., age, gender, education, race/ethnicity, and co-occurring conditions) of neuropsychological and psychotherapeutic service utilization in the Veterans Health Administration (VHA) among Veterans with MS. Data were extracted from VHA Corporate Data Warehouse as part of the Women Veterans Cohort Study (WVCS), a longitudinal project with Veterans who served during the Iraq and Afghanistan conflicts. Participants (n = 1,686) were Veterans from the overall WVCS dataset who had three or more VHA MS-related encounters (inpatient, outpatient, and/or disease modifying therapy) within one calendar year between fiscal years 2010 and 2015. Neuropsychological assessment participation was identified by procedural codes 96118 and 96119, while psychotherapeutic services were defined using 90804, 90806, 90808, 96150, 96151, and 96152. Bivariate analyses were conducted to identify socio-demographics and clinical characteristics that differed between Veterans who did and did not use these services. Service dates were compared to the diagnosis dates of the co-occurring conditions to determine whether the majority of the diagnoses preceded the service (e.g., a recognized problem) or were coded the day of or after the initial appointment (e.g., a suspected problem), which informed what co-occurring conditions and participants were included in the subsequent logistic regressions. Two hundred eighty-one Veterans (16.67%) participated in a neuropsychological assessment. Veterans who had an evaluation had higher rates of several co-occurring conditions (ps <0.01), though no significant relationships emerged with any of the socio-demographic variables and participation. After controlling for age, gender, education, and race/ethnicity, two previously diagnosed co-occurring conditions predicted service utilization: traumatic brain injuries (TBIs; OR: 2.33, 95% CI: 1.60, 3.35) and mood disorders (i.e., depressive and bipolar disorders; OR: 1.71, 95% CI: 1.26, 2.31). Psychotherapeutic service usage was more common, occurring in over 45% (n = 771) of the sample. Service utilization was associated with several co-occurring conditions (ps <0.001), as well as level of education (p = .003). Focusing on participants who were diagnosed the day of or after the initial encounter, five co-occurring conditions were predictors of psychotherapeutic service use: mood disorders (OR: 1.81, 95% CI: 1.34, 2.46), anxiety disorders (OR: 1.38, 95% CI: 1.03, 1.85), sleep disorders (OR: 1.55, 95% CI: 1.19, 2.01), alcohol-related disorders (OR: 3.29, 95% CI: 1.79, 6.21), and cognitive disorders (OR: 3.72, 95% CI: 2.29, 6.16). These findings suggest that these services are being utilized by clinicians and Veterans to address the clinical complexity related to having MS and one or more of these other conditions.


Epidemiology and outcomes of gastroparesis, as documented in general practice records, in the United Kingdom.
To generate real-world evidence for the epidemiology of gastroparesis in the UK, we evaluated the prevalence, incidence, patient characteristics and outcomes of gastroparesis in the Clinical Practice Research Datalink (CPRD) database. This was a retrospective, cross-sectional study. Prevalence and incidence of gastroparesis were evaluated in the CPRD database, with linkage to Hospital Episodes Statistics Admitted Patient Care and Office for National Statistics mortality data. Prevalence and incidence were age and sex standardised to mid-2017 UK population estimates. Descriptive analyses of demographics, aetiologies, pharmacological therapies and mortality were conducted. Standardised prevalence of gastroparesis, as documented in general practice records, was 13.8 (95% CI 12.6 to 15.1) per 100 000 persons in 2016, and standardised incidence of gastroparesis rose from 1.5 (95% CI 1.1 to 1.8) per 100 000 person-years in 2004 to 1.9 (95% CI 1.4 to 2.3) per 100 000 person-years in 2016. The most common disease aetiologies were idiopathic (39.4%) and diabetic gastroparesis (37.5%), with a similar distribution of type 1 and type 2 diabetes among the 90% who had type of diabetes documented. Patients with diabetic gastroparesis had a significantly higher risk of mortality than those with idiopathic gastroparesis after diagnosis (adjusted HR 1.9, 95% CI 1.2 to 3.0). Of those with gastroparesis, 31.6% were not offered any recognised pharmacological therapy after diagnosis. This is, to our knowledge, the first population-based study providing data on epidemiology and outcomes of gastroparesis in Europe. Further research is required to fully understand the factors influencing outcomes and survival of patients with gastroparesis.


A Method for Preparing Difficult Plant Tissues for Light and Electron Microscopy.
Although the advent of microwave technologies has both improved and accelerated tissue processing for microscopy, there still remain many limitations in conventional chemical fixation, dehydration, embedding, and sectioning, particularly with regard to plant materials. The Proteaceae, a family of plants widely distributed in the Southern Hemisphere and well adapted to harsh climates and nutrient-poor soils, is a perfect example; the complexity of Proteaceae leaves means that almost no ultrastructural data are available as these are notoriously difficult to both infiltrate and section. Here, a step-by-step protocol is described that allows for the successful preparation of Banksia prionotes (Australian Proteaceae) leaves for both light and transmission electron microscopy. The method, which applies a novel combination of vibratome sectioning, microwave processing and vacuum steps, and the utilization of an ultra low viscosity resin, results in highly reproducible, well-preserved, sectionable material from which very high-quality light and electron micrographs can be obtained. With this, cellular ultrastructure from the level of a leaf through to organelle substructure can be studied. This approach will be widely applicable, both within and outside of the plant sciences, and can be readily adapted to meet specific sample requirements and imaging needs.


The effect of the oxidizing agents chloramine-T and cigarette smoke on dog serum proteinase inhibitor(s).
Dog serum treated with the oxidant chloramine-T is rapidly and selectively depleted of its ability to inhibit porcine pancreatic elastase or dog neutrophil elastase. Trypsin inhibitory capacity of serum is not affected. Purified dog alpha-1-proteinase inhibitor (alpha-1-PI) is similarly oxidized with an apparent rate constant of 1.1 x 10(3) M-1 sec-1. Reversal of the oxidative inactivation using dithiothreitol was demonstrated. Cigarette smoke also directly affects the inhibitory capacity of both serum and pure alpha-1-PI. These studies form a basis for developing a model of functionally deficient alpha-1-PI by taking advantage of oxidative inactivation of normal proteinase inhibitor levels.


Collagen: relatively invariant (helical) and variable (nonhelical) regions.
The structural identity of certain helical regions of collagen from human and rat skin equals or exceeds that of other homologous proteins. In contrast, the short nonhelical sequences in the two proteins, although homologous, differ appreciably in structure. The requirements of the collagen helix and the numerous intermolecular interactions characteristic of collagen may restrict the number of functionally acceptable amino acid replacements occurring during evolution.


[Egg distribution of Plutella xylostella (L.) (Lepidoptera: Plutellidae) and the parasitism by Trichogramma pretiosum Riley (Hymenoptera: Trichogrammatidae)].
Oviposition site preference of Plutella xylostella (L.) and the parasitism by Trichogramma pretiosum Riley on cabbage plants at pre- and post-head formation were investigated in commercial cabbage field. Groups of six plants were randomly caged. In each cage three pairs of 24h-old P. xylostella moths were released, followed by 1,200 T. pretiosum females released 12h later. After 48 h from parasitoid release, plants were harvested and fully inspected with the oviposition mapped according to the leaf position and their parts (basal, median and border) and upper and bellow leaf surfaces. Moth oviposition and egg parasitism were equally distributed across the plant leaves at the pre-head formation stage. At this stage, the basal part and the upper leaf surface were the preferred places for oviposition and egg parasitism, respectively. Cabbage plants at the post-head formation stage exhibited greater oviposition and egg parasitism in the inner leaf attached to the head. At this stage, the leaf border and the upper leaf surface were the preferred places for oviposition and egg parasitism, respectively. The infestation of P. xylostella on cabbage can be determined by egg counting at the pre- and post-head formation stages at the basal part of the leaves or at the border of the leaf attached to the head, respectively. And, in both plant stages parasitized eggs by T. pretiosum are more likely to be found at the upper leaf surface.


Inducing experimental arthritis and breaking self-tolerance to joint-specific antigens with trackable, ovalbumin-specific T cells.
The importance of T cell Ag specificity and Th1 vs Th2 phenotype in synovial inflammation remains controversial. Using OVA-specific TCR transgenic T cells from DO11.10 mice, we demonstrate that mice receiving Th1, but not Th2, cells display a transient arthritis following immunization that is characterized by synovial hyperplasia, cellular infiltration, and cartilage erosion. OVA-specific T cells also accumulated in inflamed joints, suggesting that they could exert their inflammatory effect locally in the joint or in the draining lymph node. Importantly, this pathology was accompanied by a breakdown in self-tolerance, as evidenced by the induction of collagen-specific T and B cell responses. This model directly demonstrates a pivotal role for Th1 cells of an irrelevant specificity in the development of inflammatory arthritis. Furthermore, the ability to track these cells in vivo will make feasible studies revealing the dynamic role of T cells in arthritis.


The Effects of Psychedelics on Neuronal Physiology.
Psychedelics are quite unique among drugs that impact the central nervous system, as a single administration of a psychedelic can both rapidly alter subjective experience in profound ways and produce sustained effects on circuits relevant to mood, fear, reward, and cognitive flexibility. These remarkable properties are a direct result of psychedelics interacting with several key neuroreceptors distributed across the brain. Stimulation of these receptors activates a variety of signaling cascades that ultimately culminate in changes in neuronal structure and function. Here, we describe the effects of psychedelics on neuronal physiology, highlighting their acute effects on serotonergic and glutamatergic neurotransmission as well as their long-lasting effects on structural and functional neuroplasticity in the cortex. We propose that the neurobiological changes leading to the acute and sustained effects of psychedelics might be distinct, which could provide opportunities for engineering compounds with optimized safety and efficacy profiles. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.


Quantitative structure-activity relationship study of amide mosquito repellents.
A quantitative structure-activity relationship (QSAR) study on 43 amide repellents was carried out by the heuristic method in order to reveal the correlations between molecular parameters of these amides and their repellency against Aedes aegypti. Sketches and optimizations of molecular structures were achieved by the Gaussian software package. Generation and screening of molecular parameters were accomplished using CODESSA 2.7.10 software. The leave-one-out method was applied for the model validation. The results showed that a four-descriptor QSAR model with r2 of 0.897 was obtained. The average r2 values of the training set and test set of the QSAR model were 0.901 and 0.863, respectively, which suggested that the stability and predictability of the model were confirmed. Analysis of the implications of the descriptors that constitute the QSAR model indicated that all the descriptors were related to the charge distribution over the molecule and affect the dipole moment of the repellents.


Increased plasma levels of soluble CD23 in haemorrhagic fever with renal syndrome; relation to virus-specific IgE.
In 15 consecutive patients hospitalized with nephropathia epidemica, a European form of haemorrhagic fever with renal syndrome (HFRS) caused by Puumala virus, plasma concentrations of soluble CD23 (sCD23) and Puumala virus-specific IgE were determined. In the acute phase of illness, 11/15 patients had increased sCD23 levels (> 91 U/ml), whereas in convalescence, values of 8/10 patients were normalized. Maximal sCD23 values were correlated to maximal concentrations of Puumala virus-specific serum IgE (r = 0.597; P = 0.025). The results are compatible with a known ability of sCD23 to augment IgE production.


Sialylated human apolipoprotein E (apoEs) is preferentially associated with neuron-enriched cultures from APOE transgenic mice.
Mice transgenic for human APOE2, E3, and E4 alleles express native 34-kDa human apoE and two sialylated apoE isoproteins with approximate molecular weights of 37 kDa (apoEs) and 39 kDa (apoEs2) in brain. These multiple apoE/apoEs/apoEs2 band patterns on Western blot are also observed in human brain, but are not seen in wild-type mouse brain. Both the 37-kDa apoEs and 39-kDa apoEs2 are coprecipitated with native 34-kDa apoE by antibody to human apoE. Neuraminidase digestion eliminates the 37- and 39-kDa forms and results in a downward shift in the bands to the position of the 34-kDa native form. These sialylated apoE isoproteins are found preferentially associated with neurons and contribute significantly (50-60%) to the total neuronal apoE in neuronal cultures from transgenic mice, while only 5-10% of total apoE is sialylated in cultures enriched in glial cells. In situ hybridization and immunocytochemistry demonstrate apoE mRNA and apoE immunoreactivity are predominantly located in cell soma of neurons, not in neuronal processes.


Socio-economic factors of high trash generation in the city of Los Angeles.
Trash is one of major pollutants in urban runoff. Some studies have been conducted to verify the different impacts of land use on trash generation in a qualitative way and focused on the performance of trash control measures. Few studies have explored the human impacts on trash generation or developed a quantitative model to describe the phenomenon. This paper examined the impact of human activity on trash generation. Spatial regimes on high trash generation areas were identified using the selected variables from best subset model regression and validated with Moran's I scatter plot and spatial analysis of variance. Bidirectional spatial lag regression with regimes was performed to develop the final model to explain the spatial distribution of trash generation and identify its major causes. The result showed that economic status and occupation of the population were correlated with trash accumulation and the dominant land use type, and the distance to rivers most affected trash generation. The effects of these indicators were different within and outside the high trash generation areas.


Quantifying gender disparity in physician authorship among commentary articles in three high-impact medical journals: an observational study.
Scholarship plays a direct role in career advancement, promotion and authoritative recognition, and women physicians remain under-represented as authors of original research articles. We sought to determine if women physician authors are similarly under-represented in commentary articles within high-impact journals. In this observational study, we abstracted and analysed author information (gender and degree) and authorship position from commentary articles published in three high-impact journals between 1 January 2014 and 16 October 2018. Authorship rate of commentary articles over a 5-year period by gender, degree, authorship position and journal. To compare the proportion of men and women physician authorship of commentaries relative to the proportion of men and women physician faculty within academic medicine; and to examine the gender concordance among the last and first authors in articles with more than one author. Of the 2087 articles during the study period, 48% were men physician first authors compared with 17% women physician first authors (p<0.0001). Of the 1477 articles with more than one author, similar distributions were found with regard to last authors: 55% were men physicians compared with only 12% women physicians (p<0.0001). The proportion of women physician first authors increased over time; however, the proportion of women physician last authors remained stagnant. Women coauthored with women in the first and last authorship positions in 9% of articles. In contrast, women coauthored with men in the first and last author positions, respectively, in 55% of articles. Women physician authors remain under-represented in commentary articles compared with men physician authors in the first and last author positions. Women also coauthored commentaries with other women in far fewer numbers.


Oral presentation to publication: publication rates of abstract presentations across two pediatric neurosurgical meetings.
OBJECTIVE Both the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Section on Pediatric Neurological Surgery (AANS/CNS Pediatric Section) and the International Society for Pediatric Neurosurgery (ISPN) annual meetings provide a platform for pediatric neurosurgeons to present, discuss, and disseminate current academic research. An ultimate goal of these meetings is to publish presented results in peer-reviewed journals. The purpose of the present study was to investigate the publication rates of oral presentations from the 2009, 2010, and 2011 AANS/CNS Pediatric Section and ISPN annual meetings in peer-reviewed journals. METHODS All oral presentations from the 2009, 2010, and 2011 AANS/CNS Pediatric Section and ISPN annual meetings were reviewed. Abstracts were obtained from the AANS/CNS Pediatric Section and ISPN conference proceedings, which are available online. Author and title information were used to search PubMed to identify those abstracts that had progressed to publication in peer-reviewed journals. The title of the journal, year of the publication, and authors' country of origin were also recorded. RESULTS Overall, 60.6% of the presented oral abstracts from the AANS/CNS Pediatric Section meetings progressed to publication in peer-reviewed journals, as compared with 40.6% of the ISPN presented abstracts (p = 0.0001). The journals in which the AANS/CNS Pediatric Section abstract-based publications most commonly appeared were Journal of Neurosurgery: Pediatrics (52%), Child's Nervous System (11%), and Journal of Neurosurgery (8%). The ISPN abstracts most often appeared in the journals Child's Nervous System (29%), Journal of Neurosurgery: Pediatrics (14%), and Neurosurgery (9%). Overall, more than 90% of the abstract-based articles were published within 4 years after presentation of the abstracts on which they were based. CONCLUSIONS Oral abstract presentations at two annual pediatric neurosurgery meetings have publication rates in peer-reviewed journal comparable to those for oral abstracts at other national and international neurosurgery meetings. The vast majority of abstract-based papers are published within 4 years of the meeting at which the abstract was presented; however, the AANS/CNS Pediatric Section abstracts are published at a significantly higher rate than ISPN abstracts, which could indicate the different meeting sizes, research goals, and resources of US authors compared with those of authors from other countries.


In vivo modification of the C-terminal lysine of human lens alphaB-crystallin.
Both the structural and chaperone-like properties of lens alpha-crystallins have been implicated in maintaining lens transparency. Modifications of lens alpha-crystallins may lead to formation of cataract by affecting the close-packing of the crystallins or by reducing the chaperone-like activity of the alpha-crystallins. A previously unreported modified alphaB-crystallin, whose molecular weight is 72 u greater than unmodified alphaB-crystallin, has been isolated from human lenses by size exclusion chromatography, reversed phase HPLC and ion exchange HPLC. Approximately one nanomole of this modified alphaB-crystallin was obtained from each of five human eye lenses. Molecular weight determinations of peptides produced by digestion with trypsin or endoproteinase Asp-N showed that the modification is in the C-terminal region of alphaB-crystallin. The fragmentation pattern of peptides from the C-terminal region, analysed by tandem mass spectrometry, located the modification of the epsilon-amino group of the C-terminal lysine. The elemental composition of this modification, determined from its exact mass, is C3H4O2. Because this modification decreases the net charge of alphaB-crystallin by one unit, and because the C-terminus has been implicated in the chaperone activity attributed to alphaB-crystallin, this modification at Lys 175 may have a significant role in cataractogenesis.


Prediction of Atherosclerotic Plaque Development in an In Vivo Coronary Arterial Segment Based on a Multilevel Modeling Approach.
The aim of this study is to explore major mechanisms of atherosclerotic plaque growth, presenting a proof-of-concept numerical model. To this aim, a human reconstructed left circumflex coronary artery is utilized for a multilevel modeling approach. More specifically, the first level consists of the modeling of blood flow and endothelial shear stress (ESS) computation. The second level includes the modeling of low-density lipoprotein (LDL) and high-density lipoprotein and monocytes transport through the endothelial membrane to vessel wall. The third level comprises of the modeling of LDL oxidation, macrophages differentiation, and foam cells formation. All modeling levels integrate experimental findings to describe the major mechanisms that occur in the arterial physiology. In order to validate the proposed approach, we utilize a patient specific scenario by comparing the baseline computational results with the changes in arterial wall thickness, lumen diameter, and plaque components using follow-up data. The results of this model show that ESS and LDL concentration have a good correlation with the changes in plaque area [R2 = 0.365 (P = 0.029, adjusted R2 = 0.307) and R2 = 0.368 (P = 0.015, adjusted R2 = 0.342), respectively], whereas the introduction of the variables of oxidized LDL, macrophages, and foam cells as independent predictors improves the accuracy in predicting regions potential for atherosclerotic plaque development [R2 = 0.847 (P = 0.009, adjusted R2 = 0.738)]. Advanced computational models can be used to increase the accuracy to predict regions which are prone to plaque development. Atherosclerosis is one of leading causes of death worldwide. For this purpose computational models have to be implemented to predict disease progression.


Osteopontin expressions correlate with WHO grades and predict recurrence in meningiomas.
Recurrence of meningiomas is a major prognostic issue. Although World Health Organization (WHO) histopathological grading correlates strongly with recurrence, it has some limitations, and predicting the biological behavior of grade I meningiomas is particularly difficult. Osteopontin (OPN) is a protein known to be involved in tumor progression. The purpose of this study is to determine expression of OPN in meningiomas and to investigate its correlation with WHO grades and tumor recurrence. Immunohistochemical (IHC) evaluation of expression of OPN was performed by two different methods to ensure reliability. OPN IHC and Allred scores were calculated on the basis of intensity and extent of staining. Both scores were in agreement and correlated significantly with meningioma grade and Ki-67 index. OPN scores were also significantly correlated with recurrence of WHO grade I meningiomas. Cut-off values for OPN IHC and OPN Allred scores between non-recurrent and recurrent grade I meningiomas were calculated as 70 and 5.5 respectively. We concluded that OPN is a valuable marker for grading meningiomas and for predicting the recurrence in WHO grade I tumors.


[Single-layer uninterrupted suture at the surgery of chronic pancreatitis].
Single-layer uninterrupted suture is uncommon at the pancreatic surgery. This method has been used at 44 patients during pancreatic resection, cysto-enterostomy, pancreato-enterostomy and pancreato-cysto-enterostomy. Techniques of suture is described and illustrated. There were no cases of anastomosis insufficiency or other anastomosis complications. Method is simple, reliable and may be interesting for surgeons operating on pancreas.


The relationship between daily positive future thinking and past-week suicidal ideation in youth: An experience sampling study.
Reduced positive future thinking has been associated with suicidal ideation and behavior in adults, and appears to be exacerbated by negative affect. Yet, this has received little attention in youth. Prior research has also focused on longer-term future thinking, e.g., months and years, and relied on lab-based assessments. Using the experience sampling method (ESM), we investigated whether short-term future thinking in daily life was associated with suicidal ideation in youth and explored the role of affect in the future thinking-suicidal ideation relationship. A community sample of N = 722 adolescent twins and their non-twin siblings completed ESM as part of the TwinssCan study (n = 55 with, and n = 667 without, past-week suicidal ideation). Participants completed self-report questionnaires, including on past-week suicidal ideation as part of the SCL-90. Subsequently, daily future thinking was assessed each morning for six days with ESM. To investigate the relationship between daily positive future thinking and past-week suicidal ideation, we estimated a mixed-effects linear regression model with a random intercept for participant, including age and sex as covariates. The relationship between daily positive future thinking, past-week suicidal ideation, and average positive and negative affect from the previous day was investigated by estimating two separate mixed-effects linear regression models (one for negative affect, one for positive affect), with a random intercept for participant, and random slopes for average positive and negative affect. Our results showed that participants reporting higher past-week suicidal ideation also reported significantly less daily positive future thinking during the ESM period, and this association remained significant when controlling for previous-day average positive and negative affect. Higher average positive affect from the previous day was significantly associated with higher positive future thinking. Although average negative affect from the previous day was associated with lower positive future thinking, this association was not statistically significant. Our findings indicate that short-term future thinking relates to suicidal ideation among a non-clinical sample of adolescents. Future research should investigate the directionality of the future thinking-suicidal ideation relationship, in order to investigate whether impaired future thinking may be an early warning signal for escalating suicidal ideation in youth.


Voluntary-assisted Upper Limb Training for Severe Cerebral Palsy Using Robotics Devices and Neuromuscular Electrical Stimulation: Three Case Reports.
Constraint-induced movement therapy (CIMT) improves the motor function of paralyzed upper limbs of adults after stroke. However, in patients with severe spastic cerebral palsy (CP), the use of CIMT is not warranted. Our aim was to investigate the feasibility and effectiveness of repetitive voluntary-assisted upper limb training (VAUT) for three patients with severe CP using a combination of robotics [Hybrid Assistive Limb (HAL)] and functional electrical stimulation [Integrated Volitional Control Electrical Stimulation (IVES)]. Three patients with CP were enrolled. Patients 1, 2, and 3 were 8-, 19-, and 18-year-old males, respectively. Patient 1 had spastic hemiplegia, while patients 2 and 3 had spastic quadriplegia. VAUT using single-joint HAL was performed for 1 or 2 sessions/month for 50 min/session over an 8-month period for 9-13 sessions in total. One patient's voluntary hand movement was insufficient, affecting his upper limb exercise performance; therefore, IVES was required in addition to HAL. Outcome measures included motor function of the upper limbs and use of paralyzed hands, which were measured before and after intervention. No adverse events were observed during VAUT. After intervention, the Action Research Arm Test scores showed improvements in all three patients. The Children's Hand-use Experience Questionnaire showed improvements in two patients. The use of VAUT, together with new systems such as HAL and IVES, for severe CP is safe and may be effective. Our study suggested that upper limb function can be improved for patients with severe CP.


Xenopus: leaping forward in kidney organogenesis.
While kidney donations stagnate, the number of people in need of kidney transplants continues to grow. Although transplanting culture-grown organs is years away, pursuing the engineering of the kidney de novo is a valid means of closing the gap between the supply and demand of kidneys for transplantation. The structural organization of a mouse kidney is similar to that of humans. Therefore, mice have traditionally served as the primary model system for the study of kidney development. The mouse is an ideal model organism for understanding the complexity of the human kidney. Nonetheless, the elaborate structure of the mammalian kidney makes the discovery of new therapies based on de novo engineered kidneys more challenging. In contrast to mammals, amphibians have a kidney that is anatomically less complex and develops faster. Given that analogous genetic networks regulate the development of mammalian and amphibian nephric organs, using embryonic kidneys of Xenopus laevis (African clawed frog) to analyze inductive cell signaling events and morphogenesis has many advantages. Pioneering work that led to the ability to generate kidney organoids from embryonic cells was carried out in Xenopus. In this review, we discuss how Xenopus can be utilized to compliment the work performed in mammalian systems to understand kidney development.


A single-fibre study of the relationship between MHC and TnC isoform composition in rat skeletal muscle.
In the present study, we investigated the possibility that MHC (myosin heavy chain) and TnC (troponin C) isoforms exist in specific combinations in rat-skeletal-muscle fibres. Single fibres (numbering 245) from soleus (predominantly slow-twitch) and sternomastoid (predominantly fast-twitch) muscles of adult rats were analysed for MHC and TnC isoform composition, using alanine-SDS/PAGE for separating MHC isoforms, and a novel method (based on the previously reported influence of Ca2+ on the mobility of Ca2+-binding proteins in SDS gels) for unequivocal identification of TnC isoforms in single-fibre segments. In this study, all fibres that contained only one MHC isoform (slow or fast) contained only the matching TnC isoform and all fibres that contained multiple fast MHC isoforms contained only the fast TnC isoform. Fibres expressing both slow and fast MHC isoforms displayed either both TnC isoforms or only one TnC isoform of a type depending on the relative proportion of fast/slow MHC present. Our results suggest a close relationship between MHC and TnC isoform composition in non-transforming skeletal muscles of adult rat.


Evidence that iron accelerates Alzheimer's pathology: a CSF biomarker study.
To investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF β-amyloid (Aβ) and tau. Mixed-effects models of CSF Aβ1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aβ1-42 for up to 5 years. In subjects with biomarker-confirmed Alzheimer's pathology, high CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aβ1-42 (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aβ1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aβ deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aβ from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aβ over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aβ levels to the average level of Alzheimer's subjects from 18.8 to 10.8 years. Iron might facilitate Aβ deposition in Alzheimer's and accelerate the disease process.


Decreased sensitivity to aspirin is associated with altered polyamine metabolism in human prostate cancer cells.
Aspirin is a well-known analgesic, anti-inflammatory and antipyretic drug and is recognised as a chemopreventative agent in cardiovascular disease and, more recently, in colorectal cancer. Although several studies indicate that aspirin is capable of reducing the risk of developing cancers, there is a lack of convincing evidence that aspirin can prevent prostate cancer in man. In this study, aspirin was shown to be an effective inhibitor of the growth of human prostate cancer cells. In order to investigate the link between polyamine catabolism and the effects of aspirin we used a "Tet off" system that induced the activity of spermidine/spermine N (1)-acetyltransferase (SSAT) in human prostate cancer cells (LNCap). Treatment with aspirin was found to decrease induced SSAT activity in these cells. A negative correlation was observed between increased polyamine catabolism via increased SSAT activity and the sensitivity to aspirin. In the presence of increased SSAT activity high amounts of N (1)-acetylspermidine and putrescine were observed. These cells were also found to grow more slowly than the non-induced cells. The results indicate that SSAT and its related polyamine metabolism may play a key role in sensitivity of cancer cells to aspirin and possibly other NSAIDs and this may have implications for the development of novel chemopreventative agents.


Saturation of long-term potentiation in the dorsal cochlear nucleus and its pharmacological reversal in an experimental model of tinnitus.
Animal models have demonstrated that tinnitus is a pathology of dysfunctional excitability in the central auditory system, in particular in the dorsal cochlear nucleus (DCN) of the brainstem. We used a murine model and studied whether acoustic over-exposure leading to hearing loss and tinnitus, affects long-term potentiation (LTP) at DCN multisensory synapses. Whole cell and field potential recordings were used to study the effects on release probability and synaptic plasticity, respectively in brainstem slices. Shifts in hearing threshold were quantified by auditory brainstem recordings, and gap-induced prepulse inhibition of the acoustic startle reflex was used as an index for tinnitus. An increased release probability that saturated LTP and thereby induced metaplasticity at DCN multisensory synapses, was observed 4-5days following acoustic over-exposure. Perfusion of an NMDA receptor antagonist or decreasing extracellular calcium concentration, decreased the release probability and restored LTP following acoustic over-exposure. In vivo administration of magnesium-threonate following acoustic over-exposure restored LTP at DCN multisensory synapses, and reduced gap detection deficits observed four months following acoustic over-exposure. These observations suggest that consequences of noise-induced metaplasticity could underlie the gap detection deficits that follow acoustic over-exposure, and that early therapeutic intervention could target metaplasticity and alleviate tinnitus.


Dark inhibition of ribulose-1,5-bisphosphate carboxylase/oxygenase in legumes: A biosystematic study.
2-carboxyarabinitol 1-phosphate (CA 1-P) is a naturally occurring inhibitor of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). Members of the Fabaceae exhibit a particularly wide range in the extent of CA 1-P accumulation during darkness and include Phaseolus vulgaris, whose dark/light regulation of Rubisco activity is principally achieved by synthesis/degradation of CA 1-P. An extensive survey of the degree of dark inhibition of Rubisco was undertaken for the subfamily Papilionoideae to elucidate evolutionary patterns in the occurrence of this regulatory mechanism. Seventy-five species from 21 tribes were examined. Dark inhibition of Rubisco was found in ancestral tribes such as the Sophoreae, but was substantially reduced or absent in representative species of three more recently evolved tribes, Cicereae, Hedysareae and Vicieae. We conclude that regulation of Rubisco by CA 1-P is neither of recent origin nor of restricted distribution among the Papilionoideae. On the contrary, it becomes lost or less pronounced only in a minority of the more evolutionarily advanced species in this important subfamily.


Topical p38 MAPK inhibition reduces bacterial growth in an in vivo burn wound model.
Although the inflammatory response is a prerequisite for wound healing, excessive activation of the innate immune system can induce epithelial cell damage and apoptosis, which may further compromise dermal integrity. In a noninfectious burn wound model, we previously demonstrated that topical inhibition of p38 MAPK, an important inflammatory signaling pathway, attenuated epithelial cell damage and apoptosis. We now question whether attenuating local inflammation would weaken bacterial wound resistance and compromise host defense. Rats received 30% total body surface area burn, and the wound was treated with topical application of a p38 MAPK inhibitor or vehicle. At 24 hours after injury, burn wounds were inoculated with Pseudomonas aeruginosa. At 48 hours postinjury, animals were sacrificed, and the burn wound was analyzed. Inoculating burn wounds induced significant bacterial growth. Dermal inflammatory changes were markedly accentuated in the inoculated animals. Topical p38 MAPK inhibition reduced the proinflammatory cytokine expression in the burn wounds and neutrophil sequestration with or without bacterial inoculation. Interestingly, the bacterial wound growth was significantly attenuated in animals treated with topical p38 MAPK inhibitor. Topical p38 MAPK inhibition attenuated wound inflammation without interfering with bacterial host defense. Attenuation of excessive burn wound inflammatory signaling may prevent secondary damage of the dermal barrier and reduce the growth of opportunistic pathogens.