Surface-emitting circular DFB, disk- and ring- Bragg resonator lasers with chirped gratings: a unified theory and comparative study.
We have developed a theory that unifies the analysis of the modal properties of surface-emitting chirped circular grating lasers. This theory is based on solving the resonance conditions which involve two types of reflectivities of chirped circular gratings. This approach is shown to be in agreement with previous derivations which use the characteristic equations. Utilizing this unified analysis, we obtain the modal properties of circular DFB, disk-, and ring- Bragg resonator lasers. We also compare the threshold gain, single mode range, quality factor, emission efficiency, and modal area of these types of circular grating lasers. It is demonstrated that, under similar conditions, disk Bragg resonator lasers have the highest quality factor, the highest emission efficiency, and the smallest modal area, indicating their suitability in low-threshold, high-efficiency, ultracompact laser design, while ring Bragg resonator lasers have a large single mode range, high emission efficiency, and large modal area, indicating their suitability for high-efficiency, large-area, high-power applications.


ZC3H12A (MCPIP1): molecular characteristics and clinical implications.
ZC3H12A is a gene whose absence is related to autoimmune disorders and to other phenotypical alterations. A comprehensive review of the structure, molecular functions and regulation of ZC3H12A gene and its protein MCPIP1 is done in order to understand their clinical implications. ZC3H12A, at 1p34.3, has 9860bp, six exons and 61 described SNPs. Eleven are non-synonymous thus leading to changes in MCPIP1, the protein encoded by ZC3H12A. MCPIP1 is induced by MCP-1 and IL-1 whose signals are transduced through the NF-kβ and MAPkinase pathways. This protein acts as an RNAse by degrading chemokine transcripts such as IL-1 as well as its own mRNA and as a transcription factor by reducing the expression of other chemokines induced by NF-kβ such as MCP-1. It also up-regulates genes involved in several differentiation processes and apoptosis. Therefore, ZC3H12A is an equilibrium gatekeeper that not only regulates its own inducers but also controls the regulation by degrading its own mRNA. Understanding ZC3H12A gives a comprehensive panorama that promises to improve our understanding of processes in which this gene is involved including autoimmune, infectious and cardiovascular diseases.


All-optical control of long-lived nuclear spins in rare-earth doped nanoparticles.
Nanoscale systems that coherently couple to light and possess spins offer key capabilities for quantum technologies. However, an outstanding challenge is to preserve properties, and especially optical and spin coherence lifetimes, at the nanoscale. Here, we report optically controlled nuclear spins with long coherence lifetimes (T2) in rare-earth-doped nanoparticles. We detect spins echoes and measure a spin coherence lifetime of 2.9 ± 0.3 ms at 5 K under an external magnetic field of 9 mT, a T2 value comparable to those obtained in bulk rare-earth crystals. Moreover, we achieve spin T2 extension using all-optical spin dynamical decoupling and observe high fidelity between excitation and echo phases. Rare-earth-doped nanoparticles are thus the only nano-material in which optically controlled spins with millisecond coherence lifetimes have been reported. These results open the way to providing quantum light-atom-spin interfaces with long storage time within hybrid architectures.


Amphibian skin defences show variation in ability to inhibit growth of Batrachochytrium dendrobatidis isolates from the Global Panzootic Lineage.
The fungal pathogen Batrachochytrium dendrobatidis has caused declines and extinctions in hundreds of amphibian species across the world. Virulence varies among and within lineages; the Global Panzootic Lineage (GPL) is the most pathogenic, although there is also variation in lethality among GPL isolates. Amphibians have a number of defences against pathogens, and skin products including the microbiota and host peptides have considerable influence over disease progression. Here we demonstrate that the collective skin products (the mucosome) of two amphibian species show significant variation in their ability to inhibit different globally distributed isolates of GPL. This may in part explain the variation in disease susceptibility of hosts to different strains of B. dendrobatidis. More work is required to identify particular traits associated with mucosomes that confer broad-spectrum inhibition across GPL in order to facilitate the development of prophylaxis and/or treatments for chytridiomycosis in situ.


The opossum genome: insights and opportunities from an alternative mammal.
The strategic importance of the genome sequence of the gray, short-tailed opossum, Monodelphis domestica, accrues from both the unique phylogenetic position of metatherian (marsupial) mammals and the fundamental biologic characteristics of metatherians that distinguish them from other mammalian species. Metatherian and eutherian (placental) mammals are more closely related to one another than to other vertebrate groups, and owing to this close relationship they share fundamentally similar genetic structures and molecular processes. However, during their long evolutionary separation these alternative mammals have developed distinctive anatomical, physiologic, and genetic features that hold tremendous potential for examining relationships between the molecular structures of mammalian genomes and the functional attributes of their components. Comparative analyses using the opossum genome have already provided a wealth of new evidence regarding the importance of noncoding elements in the evolution of mammalian genomes, the role of transposable elements in driving genomic innovation, and the relationships between recombination rate, nucleotide composition, and the genomic distributions of repetitive elements. The genome sequence is also beginning to enlarge our understanding of the evolution and function of the vertebrate immune system, and it provides an alternative model for investigating mechanisms of genomic imprinting. Equally important, availability of the genome sequence is fostering the development of new research tools for physical and functional genomic analyses of M. domestica that are expanding its versatility as an experimental system for a broad range of research applications in basic biology and biomedically oriented research.


An iterative identification procedure for dynamic modeling of biochemical networks.
Mathematical models provide abstract representations of the information gained from experimental observations on the structure and function of a particular biological system. Conferring a predictive character on a given mathematical formulation often relies on determining a number of non-measurable parameters that largely condition the model's response. These parameters can be identified by fitting the model to experimental data. However, this fit can only be accomplished when identifiability can be guaranteed. We propose a novel iterative identification procedure for detecting and dealing with the lack of identifiability. The procedure involves the following steps: 1) performing a structural identifiability analysis to detect identifiable parameters; 2) globally ranking the parameters to assist in the selection of the most relevant parameters; 3) calibrating the model using global optimization methods; 4) conducting a practical identifiability analysis consisting of two (a priori and a posteriori) phases aimed at evaluating the quality of given experimental designs and of the parameter estimates, respectively and 5) optimal experimental design so as to compute the scheme of experiments that maximizes the quality and quantity of information for fitting the model. The presented procedure was used to iteratively identify a mathematical model that describes the NF-kappaB regulatory module involving several unknown parameters. We demonstrated the lack of identifiability of the model under typical experimental conditions and computed optimal dynamic experiments that largely improved identifiability properties.


Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma.
To investigate sequence variations in the optineurin (OPTN) gene and their association with TNF-alpha polymorphisms in Japanese patients with glaucoma. The OPTN gene was analyzed in blood samples from 629 Japanese subjects. There were 194 patients with primary open-angle glaucoma (POAG), 217 with normal-tension glaucoma (NTG), and 218 with no eye disease (control subjects). The gene was screened for mutations by denaturing high-performance liquid chromatography. Genotyping of three polymorphisms of -308G-->A, -857C-->T, and -863C-->A in the TNF-alpha promoter region was performed. The associations between the genotypes and age, intraocular pressure (IOP), and visual field defects at the time of diagnosis were examined. A possible glaucoma-causing mutation, His26Asp, was identified in 1 of the 411 Japanese patients with glaucoma. A c.412G-->A (Thr34Thr) polymorphism in the OPTN gene was significantly associated with POAG (genotype frequency, P = 0.011; allele frequency, P = 0.003). The frequency of TNF-alpha/-857T and optineurin/412A carriers was significantly higher (P = 0.006) in patients with POAG than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-857T, the optineurin/412A carriers had significantly worse (P = 0.020) visual field scores than the non-optineurin/412A ones. The frequency of TNF-alpha/-863A and optineurin/603A (or Lys98) carriers was significantly higher in patients with POAG (P = 0.008) or NTG (P = 0.027) than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-863A, the ones with optineurin/603A (or Lys98) had significantly worse (P = 0.026) visual field scores than did those with non-optineurin/603A (or Lys98). These findings demonstrated that the OPTN gene is associated with POAG rather than NTG in the Japanese. Statistical analysis showed a possible interaction between polymorphisms in the OPTN and the TNF-alpha genes that would increase the risk for glaucoma.


Phenotype of intramyocardial leukocytic infiltrates in acquired immunodeficiency syndrome (AIDS): a postmortem immunohistochemical study in 34 consecutive cases.
In 34 hearts, obtained at autopsy in consecutive AIDS cases, leukocytic phenotype and presence of viral antigens were investigated in paraffin-embedded (34 cases) and frozen myocardial sections (10 cases) by different monoclonal antibodies. The total frequency of focal lymphocytic infiltrates with and without myocell necrosis was 26.4 and 32.3%, respectively. In six control cases (HIV-negative i.v. drug abusers dying from acute fulminating hepatitis), these infiltrates were absent. In AIDS patients, the number of infiltrative foci per section, their wall distribution (subendocardial, middle layer, subepicardial), number of leukocytes per focus, and cell phenotype (prevalence of CD8+ suppressor/cytotoxic T-lymphocytes with CD4/CD8 ratio of 0.6 +/- 0.09 SE, absence of B-cells and granulocytes) were similar in cases with and without myocell necrosis. Significant differences were not observed between homosexual and i.v. drug abuser patients. In inflammatory foci associated with myocell necrosis CD45+/CD68+ monocytes prevailed, as a possible manifestation of nonspecific reparative process. In addition, in both AIDS patients and HIV-negative drug abusers, a population of CD68+ dendritic monocytes (histiocytes) characterized by a restricted CD45 expression (PanLeu-/9.4+) was found dispersed in the interstitium, with a significant higher frequency in the subendocardial layer. Histologic evidences of myocardial virus infections were not observed. Cytomegalovirus (CMV) antigens, however, were found in frozen sections of five of the six cases with lymphocytic infiltrates, supporting the view that this virus can be one of the possible causes of myocarditis in AIDS. Moreover, in two of these CMV-positive cases, a concomitant expression of HIV1 antigens in isolated intramyocardial leukocytes was also observed.(ABSTRACT TRUNCATED AT 250 WORDS)


Resistance to thyroid hormones. A disorder frequently confused with Graves' disease.
Five patients from two unrelated families were found to have goiter and elevated serum concentrations of thyroxine (T4) and triiodothyronine (T3) without symptoms or signs of hyperthyroidism. All had measurable concentrations of thyroid stimulating hormone (TSH), and in four who were tested, there was an increase in TSH concentration following thyrotropin releasing hormone (TRH) administration. We believe these five patients have general resistance to the effects of thyroid hormones and need elevated concentrations of T4 and T3 to maintain a eumetabolic state. Study of nuclear T3 receptors from cultured fibroblasts of one patient disclosed a normal equilibrium association constant and a maximal binding capacity that was greater than normal control values. These findings suggest that thyroid hormone resistance in this patient is not due to a decrease in either the affinity or the number of specific nuclear T3 receptors. This disorder can easily be confused with Graves' disease and result in inappropriate treatment for hyperthyroidism, as was the case in three of our patients.


A review of wireless SAW sensors.
Wireless measurement systems with passive surface acoustic wave (SAW) sensors offer new and exciting perspectives for remote monitoring and control of moving parts, even in harsh environments. This review paper gives a comprehensive survey of the present state of the measurement systems and should help a designer to find the parameters required to achieve a specified accuracy or uncertainty of measurement. Delay lines and resonators have been used, and two principles have been employed: SAW one-port devices that are directly affected by the measurand and SAW two-port devices that are electrically loaded by a conventional sensor and, therefore, indirectly affected by the measurand. For radio frequency (RF) interrogation, time domain sampling (TDS) and frequency domain sampling (FDS) have been investigated theoretically and experimentally; the methods of measurement are described. For an evaluation of the effects caused by the radio interrogation, we discuss the errors caused by noise, interference, bandwidth, manufacturing, and hardware tuning. The system parameters, distance range, and measurement uncertainty are given numerically for actual applications. Combinations of SAW sensors and special signal processing techniques to enhance accuracy, dynamic range, read out distance, and measurement repetition rate (measurement bandwidth) are presented. In conclusion, an overview of SAW sensor applications is given.


Colorectal adenomatous and serrated polyps in rural South Australia: who, why, what and where?
The adenoma-carcinoma and serrated pathways offer a window of opportunity for the removal of pre-malignant polyps and prevention of colorectal cancer (CRC) through the use of colonoscopy. The aim of this study was to investigate variation in polyp incidence in different age groups, gender and indications for undertaking colonoscopy. We also address histological types of polyps found and where in the bowel they are located. This study is based on the colonoscopy data collected prospectively over a one-year period in multiple South Australian rural centres, 24 general surgeons contributed to this study. All histopathology results were subsequently entered into the dataset. A total of 3497 colonoscopies were performed, with a total of 2221 adenomatous and serrated polyps removed. Both serrated and adenomatous polyps were more common in the distal colon. Patients of male gender, aged 70 years and over and with an indication of polyp surveillance had higher adenoma and serrated polyp detection rates (ADR and SPDR). Patients aged 40-49 years old who underwent colonoscopy for positive faecal occult blood had an ADR and SPDR of 25.0% and 6.3%, respectively. This study has shown variation in ADR and SPDR depending on age, gender and indication for colonoscopy. This variation will help further develop key performance indicators in colonoscopy. The high ADR and SPDR in patients aged 40-49 years old whom underwent colonoscopy for positive faecal occult blood may support lowering the age of commencement of CRC screening in Australia.


Holographic solitons in photorefractive dissipative systems.
A new kind of holographic soliton is proposed for a photorefractive dissipative system consisting of a biased photorefractive crystal and a strong pump beam with a uniform spatial distribution in both transverse dimensions. The self-trapping beam in the system can evolve into a spatial soliton when it couples coherently with the pump beam by two-wave mixing. Unlike the holographic solitons recently proposed by Cohen et al. [Opt. Lett. 27, 2031 (2002)], the most unique features of the present solitons are that they have a fixed amplitude and width that are determined completely by the system parameters and that their existence conditions are independent of the polarity of the bias field. Numerical simulations show that these solitons are stable relative to small perturbations.


The effect of age and carbohydrate and protein sources on digestibility, fecal microbiota, fermentation products, fecal IgA, and immunological blood parameters in dogs.
The present study compared the effects of diets formulated with fibers of different fermentability and protein sources of animal or vegetable origins on old and adult dogs. The experiment was organized in a 3 (diets) × 2 (ages) factorial arrangement, totaling 6 treatments. Thirty-six Beagle dogs were used (18 old dogs [10.2 ± 1.0 yr] and 18 young adult dogs [2.6 ± 0.9 yr]), with 6 dogs per treatment. Three diets with similar compositions were used: a nonfermentable insoluble fiber source (sugarcane fiber) and chicken byproduct meal (nonfermentable fiber [NFF] diet), a fermentable fiber source (beet pulp) and chicken byproduct meal (fermentable fiber [FF] diet), and soybean meal as a protein and fiber source (soybean meal [SM] diet). Data were evaluated using the MIXED procedure and considering the effects and interactions of block, animal, diets, and age. Means were compared using Tukey's test ( < 0.05). Age × diet interactions were evaluated when < 0.1. Old dogs had a reduced coefficient of total tract apparent digestibility of DM, which was explained by the age and diet interaction of CP and fat digestibility that was lower for old than for adult dogs fed the FF diet ( < 0.05). The SM diet obtained higher DM, OM, CP, and fiber digestibility compared with the NFF diet ( < 0.05). The feces of dogs fed the NFF diet had increased DM content ( < 0.05). The short-chain fatty acids (SCFA) did not change by age group and were higher for dogs fed the FF and SM diets compared with dogs fed the NFF diet ( < 0.05). An age and diet interaction was observed for lactate and was increased in the feces of old dogs compared with adult dogs fed the FF diet ( < 0.05). Fecal putrescine, cadaverine, and spermine were increased for old dogs compared with adult dogs ( < 0.05), and the spermidine fecal concentration was increased for dogs fed the SM diet regardless of age ( < 0.05). Old dogs had reduced peripheral T and B lymphocytes ( < 0.05). An age and diet interaction was observed for fecal IgA ( < 0.001). Adult dogs fed the SM diet had increased IgA in feces compared with animals fed the NFF and FF diets ( < 0.05). However, for old dogs, both the FF and SM diets induced increased IgA compared with the NFF diet ( < 0.05). In conclusion, beet pulp may reduce digestibility and induce increased lactate in the feces of old dogs. The protein and oligosaccharides of soybean meal are digestible by dogs, induce the production of SCFA and spermidine, and increase fecal IgA. Old dogs had increased putrecine, cadaverine, and spermine fecal concentrations.


Value of cytology in small cell lung carcinoma diagnostic--single-center study.
Small cell carcinoma of the lung (SCLC) together with the large cell neuroendocrine carcinoma (LCNEC), typical carcinoid (TC), and atypical carcinoid (AC) make a group of morphologically identifiable neuroendocrine tumors. The differential diagnosis of SCLC includes, first of all, other neuroendocrine tumors, and primary or metastatic non-small cell carcinomas. Although the criteria for the morphologic separation from other tumors of the lung are defined, in everyday practice it can be a problem, both in cytology and with histological samples. Accurate and early differentiation of the SCLC is important because it exhibits aggressive behavior, rapid growth, early spread to distant sites, but also exquisite sensitivity to chemotherapy and radiation. The study included 127 patients who underwent bronchoscopic examination or percutaneous transthoracic fine-needle aspiration (PTTFNA) during the period from early 2003 to 2007 in University Hospital Center Osijek whose cytological diagnosis was SCLC. The value of cytological diagnosis was determined by comparing it with histological findings obtained from a biopsy sample during bronchoscopy or on a resection specimen in 50 patients. In the remaining 77 patients, histological verification of cytological diagnosis was not made and the patients were treated based on cytological diagnosis of small cell carcinoma. In 76% of cases (38/50) cytological diagnosis of small cell lung carcinoma was also confirmed histologically. In 8% of cases (4/50) adenocarcinoma was histologically confirmed, in 10% (5/50) of the cases the squamous carcinoma was confirmed, and there was one case of urothelial carcinoma, one case of sarcoma and one undifferentiated carcinoma. Cytological diagnosis of SCLC was made in all cases in a brush smear while the catheter aspirate was positive in only 32 cases (25.8%). Median survival in the group of patients with histologically confirmed small cell cancer was 238 days, for women 250 days, and for men 237 days. Cumulative survival was 63.2% for 6 months, 26.3% for 12 months, 13.2% for 18 months and 7.9% for two years. In conclusion, cytology is a reliable and relatively non-invasive method for patients. Our results confirm that there is a good correlation between cytology and histology diagnoses, especially when it comes to malignant lesions. In determining the type of tumor cytology must be supported with additional methods, especially in cases when it is not possible to take samples for histological verification.


Retroperitoneal metastatic germ cell tumor presenting as a psoas abscess: a diagnostic pitfall.
Most testicular neoplasms are germ cell tumors, the vast majority of which represent seminomas. Most seminomas present localized to the testis, whereas nonseminomatous germ cell tumors more often present with lymph node metastases. Psoas abscesses generally arise from a contiguous intra-abdominal or pelvic infectious process, an adjacent focus of osteomyelitis or septic emboli from distant infectious foci. In this study, the case of a 24-year-old man who presented with a right psoas mass presumptively diagnosed as an abscess secondary to fever and leukocytosis is presented. The patient had a history of right testicular seminoma, and normal serum levels of alpha-fetoprotein and human chorionic gonadotropin. Surgical exploration and biopsy demonstrated seminoma metastasis. This case represents an extremely unusual clinical presentation of metastatic germ cell tumor presenting as a psoas abscess. This unique case represents an unusual presentation of a recurrent germ cell tumor mimicking a psoas abscess. Awareness of possible metastatic testicular germ cell neoplasm as a psoas abscess could prevent diagnosis delay before retroperitoneal tumor debulking.


Murine natural killer cells limit coxsackievirus B3 replication.
Previous indirect evidence suggested that natural killer (NK) cells play a role in coxsackie virus B3 serotype 3, myocarditic variant (CVB3m)-induced myocarditis by limiting virus replication. In this study, we present direct evidence that NK cells can limit CVB3m replication both in vitro and in vivo. Virus titers are lowered in primary murine neonatal skin fibroblast (MNSF) cultures incubated with activated splenic large granular lymphocytes (LGL) taken from mice 3 days postinoculation of CVB3m, a time of maximal NK cell activity. The antiviral effect of this cell population is diminished by complement-mediated lysis with the use of anti-asialo GM1 antiserum but not with anti-Lyt-2 monoclonal antibody. Neither interferon nor anti-CVB3m-neutralizing antibody was detected in these cultures. Although activated LGL initiate lysis within CVB3m-infected MNSF in vitro within 3 hr of addition, they do not lyse uninfected MNSF cultures. CVB3m replication is required for expression of surface changes on MNSF that result in lysis by NK cells because cell cultures treated with compounds that prevent CVB3m replication are not killed by LGL. LGL also do not lyse MNSF cultures inoculated with UV-inactivated virus. Mice inoculated with activated LGL and subsequently challenged with CVB3m had reduced titers of virus in heart tissues in comparison to titers of CVB3m in heart tissues of mice not given LGL. The antiviral activity of the LGL preparation was abolished by prior treatment with anti-asialo GM1 antiserum plus complement but not by prior treatment with anti-Lyt-2 monoclonal antibody and complement. These data suggest that NK cells can specifically limit a nonenveloped virus infection by killing virus-infected cells.


Tanshinone IIA protects against cardiac fibrosis through inhibition of β-tubulin expression.
Cardiac fibrosis is a significant global health problem that occurs after pathological stimuli to the cardiovascular system. Previous researchers have shown the protective role of Salvia miltiorrhiza Bunge (Danshen) as well as its extracted compound Tanshinone IIA (Tan IIA) against cardiac fibrosis. However no previous work has shown the effects of Tanshinone IIA on cardiac cytoskeleton or the possible relations with its role on cardiac fibrosis. The present study confirms that Tan IIA inhibits the pro iferation of mouse cardiac fibroblasts in cultures by MTT assay. It was also observed that Tan IIA decreases β-tubulin expression, especially in the perinuclear area of fibroblasts. Furthermore, we presented by Western blot that TanII A attenuates VEGF expression through HIF-1α and Keap1-Nrf2 pathways, which could be the underlying mechanisms of the Tan IIA's role on cardiac fibrosis. This work demonstrated, for the first time, that the protective role of TanII A against cardiac fibrosis through inhibition of cardiac β-tubulin involves regulation on the antioxidant pathways.


Elders' schema for taking medication: implications for instruction design.
We examined whether elders share a schema for taking medication and if instructions are better understood and recalled when organized to match this pre-existing schema. Experiment 1 investigated if elders agree on how to group medication information into categories, and if they agree on an order for arranging this information. Elders tended to organize information into three categories, arranged in the following order: General information about the medication (purpose), How to take (dose and schedule), and Outcomes (emergency information). In Experiment 2, we compared instructions that were: (a) compatible with this schema in terms of grouping and order, (b) compatible only in terms of grouping (category order was changed), and (c) incompatible, not matching the model in terms of either grouping or order. Memory for medication information increased with the compatibility of the instructions to the model. Elders also preferred the more compatible instructions. The findings suggest that elders possess a schema for taking medication, which they use to understand and recall medication instructions.


Posttraumatic headache: recent progress.
Posttraumatic headache (PTH) attributed to mild traumatic brain injury is common and debilitating. In up to one-half of those with acute PTH, the PTH becomes persistent (PTH), enduring for longer than 3 months. The high incidence and persistence of PTH necessitate research into PTH pathophysiology and treatment. In this review, recent developments regarding the diagnostic criteria for PTH, the pathophysiology of PTH, and PTH treatment are discussed. International Classification of Headache Disorders 3 diagnostic criteria for PTH attributed to head trauma require that 'a headache of any type' starts within 7 days of a head injury. PTH is considered 'persistent' when it endures for more than 3 months. Preclinical and human PTH research suggest multiple pathophysiologic mechanisms including genetic influences, neuroinflammation, increased release and inadequate clearance of neuropeptides and neurotransmitters, mast cell degranulation, and brain structural and functional remodeling. Even when it has a phenotype similar to a primary headache, data suggest that PTH is distinct from primary headaches. There is a lack of high-quality evidence for the acute or preventive treatment of PTH. However, results from published studies of conventional headache therapies and newer therapies, such as calcitonin gene-related peptide mAbs and transcranial magnetic stimulation, justify the current and future randomized controlled trials. Evidence points towards a complex pathophysiology for PTH that is at least partially distinct from the primary headaches. Although properly conducted clinical trials of PTH treatment are needed, existing work has provided important data that help to plan these clinical trials. Current and future investigations will help to identify PTH mechanisms, predictors for PTH persistence, therapeutic targets, and evidence-based treatment options.


Weather and arthritis symptoms.
In a one month prospective, double blind study of 70 patients (35 with rheumatoid arthritis [RA], 35 with osteoarthritis [OA]), severity of rheumatic symptoms was compared to changes in daily weather conditions using a visual analogue scale. The majority of patients (62%) believed that various aspects of weather aggravated their symptoms. There was no difference in age, sex, diagnosis or perceived symptom severity between weather sensitive and weather insensitive patients. No significant correlation was found between symptoms of any patient group or individual and any of 13 combinations of weather features. These results suggest that contrary to the belief of the majority of patients with RA or OA external weather conditions do not significantly influence the day-to-day symptoms of arthritis.


High density of fox and cat faeces in kitchen gardens and resulting rodent exposure to Echinococcus multilocularis and Toxoplasma gondii.
The faeces of the red fox, Vulpes vulpes (Linnaeus), and the domestic cat, Felis catus (Linnaeus), can be responsible for spreading eggs of Echinococcus multilocularis Leuckart, 1863 and oocysts of Toxoplasma gondii (Nicolle et Manceaux, 1908) into the environment. The accidental ingestion of these eggs or oocysts, through consumption of raw fruits or vegetables grown in or in contact with contaminated soil, can lead to alveolar echinococcosis (AE) or toxoplasmosis in humans. The present study provides a quantitative assessment of the faecal deposition by foxes and cats in kitchen gardens where fruits and vegetables are grown and its consequences for zoonosis transmission. The density of definitive host faeces is considered as one of the main factors in infection risk for intermediate hosts. The density of fox and cat faeces, as well as the prevalence of both AE and toxoplasmosis in rodent populations (contaminated by ingestion of eggs or oocysts), were compared within and outside kitchen gardens. Our results showed that the mean density of fox faeces did not significantly differ between kitchen gardens and habitat edges (0.29 ± 0.04 faeces/m2 vs 0.22 ± 0.02 faeces/m2), the latter being known as an area of high fox faeceal densities. The density of cat faeces was significantly higher within the kitchen garden than outside (0.86 ± 0.22 faeces/m2 vs 0.04 ± 0.02 faeces/m2). The sampled kitchen gardens might therefore be considered as possible hotspots for both fox and cat defecation. Of the 130 rodents trapped, 14% were infected by at least one species of fox or cat intestinal parasite. These rodents were significantly more often infected when they were exposed to a kitchen garden. These results suggest that the deposit of fox and cat faeces in kitchen gardens would significantly impact the risk of human exposure to E. multilocularis and T. gondii. and should be prevented using effective means.


Children's speech as a source of data toward the measurement of psychological states.
A measurement of psychological states, based on the objective content analysis of small samples of speech, has undergone thorough reliability and constructvalidation studies for individuals in the age range 17-70. The present report is a first step in the extension of this method to children ages 6-16. It has involved a descriptive analysis of the frequency of use of various verbal content categories of 109 schoolchildren, roughly stratified for grade. Percentile scores have been obtained for such content analysis scales as anxiety, hostility outward, hostility inward, ambivalent hostility, social alienation-personal disorganization, cognitive impairment, human relations, hope, and achievement strivings. Comparisons are made between these children's scores on such measures and similar scores obtained from adults. Sex differences and developmental trends are examined.


Micropolarizer using anodized alumina with implanted metallic columns: theoretical analysis.
A theoretical evaluation has been made of the optical loss of anodically oxidized alumina with implanted metallic columns. It has been shown that microcolumns arranged in the alumina film give rise to an optical loss that strongly depends on the direction of polarization. A loss difference between two polarizations, horizontal and vertical to the column axis, is larger than 10 dB/microm in the infrared. Therefore the metal implanted alumina is expected to be an efficient polarizer with large extinction ratio and low insertion loss.


MR fluoroscopy in vascular and cardiac interventions (review).
Vascular and cardiac disease remains a leading cause of morbidity and mortality in developed and emerging countries. Vascular and cardiac interventions require extensive fluoroscopic guidance to navigate endovascular catheters. X-ray fluoroscopy is considered the current modality for real time imaging. It provides excellent spatial and temporal resolution, but is limited by exposure of patients and staff to ionizing radiation, poor soft tissue characterization and lack of quantitative physiologic information. MR fluoroscopy has been introduced with substantial progress during the last decade. Clinical and experimental studies performed under MR fluoroscopy have indicated the suitability of this modality for: delivery of ASD closure, aortic valves, and endovascular stents (aortic, carotid, iliac, renal arteries, inferior vena cava). It aids in performing ablation, creation of hepatic shunts and local delivery of therapies. Development of more MR compatible equipment and devices will widen the applications of MR-guided procedures. At post-intervention, MR imaging aids in assessing the efficacy of therapies, success of interventions. It also provides information on vascular flow and cardiac morphology, function, perfusion and viability. MR fluoroscopy has the potential to form the basis for minimally invasive image-guided surgeries that offer improved patient management and cost effectiveness.


CYP2C8 exists as a dimer in natural membranes.
CYP2C8 with a modified N-terminal sequence (2C8H) crystallizes as a dimer, but it is not known whether native CYP2C8 exists as a dimer in natural membranes. We have examined the organization of 2C8H and CYP2C8 expressed in bacterial membranes and mammalian endoplasmic reticulum membranes, respectively, by cysteine scanning and cross-linking or oxidation of sulfhydryl groups. In both forms of CYP2C8, cross-linked dimers were observed that were eliminated by mutation of Cys-24 in the linker region. Introduction of individual cysteines in the N-terminal 21-amino acid membrane-spanning signal anchor resulted in a pattern of cross-linking consistent with an α-helical structure for the signal anchor. In the linker region, cross-linking was observed for cysteine substituted at residues 22, 23, or 24, just before three Arg residues, indicating close apposition of the two linker sequences despite the neighboring positive charges. Introduction into the F-G loop region of cysteine pairs optimally located for cross-linking based on the crystal structure resulted in cross-linked dimers in the Cys-24 mutant. Deletion of the signal anchor sequence eliminated cross-linking mediated by Cys-24 or by cysteines introduced in the F-G loop regions, indicating that the signal anchor interaction is required for stable dimer formation. These results indicate that the signal anchor sequence and the F-G loop region form interfaces for CYP2C8 intermolecular interactions in natural membranes.


Cost and cost-effectiveness of switching from stavudine to tenofovir in first-line antiretroviral regimens in South Africa.
Most first-line antiretroviral therapy regimens in Africa include stavudine (d4T), despite the high incidence of toxicities related to it. We estimated the cost and cost-effectiveness of switching from d4T to tenofovir disoproxil fumarate (TDF) in South Africa. A model was developed to estimate the proportion of patients in a hypothetical cohort who experienced d4T- and TDF-related events over the 2 years after antiretroviral therapy initiation. Transition probabilities, event and drug costs, and utility losses were estimated from primary data and the literature. Outcomes included incremental cost, incremental cost-effectiveness ratio per quality-adjusted life year gained, and threshold prices for TDF. After 2 years, 82.5% of the d4T scenario cohort remained on d4T, 16.6% had switched to AZT, 0.8% had died, and 414 events that did not lead to a drug change had occurred. In the TDF scenario, 97.5% of the cohort remained on TDF. At a baseline cost of TDF of $17.00/month, the incremental cost of the TDF scenario was $128/patient/year and the incremental cost-effectiveness ratio was $9007 per quality-adjusted life year gained. The change to TDF would be cost neutral for the government at a price of $6.17/month and highly cost effective at a price of $12.94/month. At a TDF price of $17.00/month, savings on d4T toxicity management will offset roughly 20% of the higher price of TDF. The price of TDF would have to fall substantially to make the change cost neutral for South Africa in budgetary terms, but it would be highly cost effective at a price only slightly less than what is currently available.


Meis1 programs transcription of FLT3 and cancer stem cell character, using a mechanism that requires interaction with Pbx and a novel function of the Meis1 C-terminus.
Meis1 is a homeodomain transcription factor coexpressed with Hoxa9 in most human acute myeloid leukemias (AMLs). In mouse models of leukemia produced by Hoxa9, Meis1 accelerates leukemogenesis. Because Hoxa9 immortalizes myeloid progenitors in the absence of Meis1 expression, the contribution of Meis1 toward leukemia remains unclear. Here, we describe a cultured progenitor model in which Meis1 programs leukemogenicity. Progenitors immortalized by Hoxa9 in culture are myeloid-lineage restricted and only infrequently caused leukemia after more than 250 days. Coexpressed Meis1 programmed rapid AML-initiating character, maintained multipotent progenitor potential, and induced expression of genes associated with short-term hematopoietic stem cells (HSCs), such as FLT3 and CD34, whose expression also characterizes the leukemia-initiating stem cells of human AML. Meis1 leukemogenesis functions required binding to Pbx, binding to DNA, and a conserved function of its C-terminal tail. We hypothesize that Meis1 is required for the homing and survival of leukemic progenitors within their hematopoietic niches, functions mediated by HSC-specific genes such as CD34 and Fms-like tyrosine kinase 3 (FLT3), respectively. This is the first example of a transcription factor oncoprotein (Meis1) that establishes expression of a tyrosine kinase oncoprotein (FLT3), and explains their coexpression in human leukemia. This cultured progenitor model will be useful to define the genetic basis of leukemogenesis involving Hoxa9 and Meis1.


Long-term dental visiting patterns and adult oral health.
To date, the evidence supporting the benefits of dental visiting comes from cross-sectional studies. We investigated whether long-term routine dental visiting was associated with lower experience of dental caries and missing teeth, and better self-rated oral health, by age 32. A prospective cohort study in New Zealand examined 932 participants' use of dentistry at ages 15, 18, 26, and 32. At each age, routine attenders (RAs) were identified as those who (a) usually visited for a check-up, and (b) had made a dental visit during the previous 12 months. Routine attending prevalence fell from 82% at age 15 to 28% by 32. At any given age, routine attenders had better-than-average oral health, fewer had teeth missing due to caries, and they had lower mean DS and DMFS scores. By age 32, routine attenders had better self-reported oral health and less tooth loss and caries. The longer routine attendance was maintained, the stronger the effect. Routine dental attendance is associated with better oral health.


Plasma membrane H⁺ -ATPase regulation is required for auxin gradient formation preceding phototropic growth.
Phototropism is a growth response allowing plants to align their photosynthetic organs toward incoming light and thereby to optimize photosynthetic activity. Formation of a lateral gradient of the phytohormone auxin is a key step to trigger asymmetric growth of the shoot leading to phototropic reorientation. To identify important regulators of auxin gradient formation, we developed an auxin flux model that enabled us to test in silico the impact of different morphological and biophysical parameters on gradient formation, including the contribution of the extracellular space (cell wall) or apoplast. Our model indicates that cell size, cell distributions, and apoplast thickness are all important factors affecting gradient formation. Among all tested variables, regulation of apoplastic pH was the most important to enable the formation of a lateral auxin gradient. To test this prediction, we interfered with the activity of plasma membrane H⁺ -ATPases that are required to control apoplastic pH. Our results show that H⁺ -ATPases are indeed important for the establishment of a lateral auxin gradient and phototropism. Moreover, we show that during phototropism, H⁺ -ATPase activity is regulated by the phototropin photoreceptors, providing a mechanism by which light influences apoplastic pH.


High disease impact of myotonic dystrophy type 2 on physical and mental functioning.
The aim of the study was to investigate health status in patients with myotonic dystrophy type 2 (DM2) and determine its relationship to pain and fatigue. Data on health status (SF-36), pain (MPQ) and fatigue (CIS-fatigue) were collected for the Dutch DM2 population (n = 32). Results were compared with those of sex- and age-matched adult-onset myotonic dystrophy type 1 (DM1) patients. In addition, we compared the obtained scores on health status of the DM2 group with normative data of the Dutch general population (n = 1742). Compared to DM1, the SF-36 score for bodily pain was significantly (p = 0.04) lower in DM2, indicating more body pain in DM2. DM2 did not differ from DM1 on any other SF-36 scales. In comparison to the Dutch population, DM2 patients reported lower scores (indicating worse clinical condition) on the physical functioning, role functioning-physical, bodily pain, general health, vitality, social functioning, and role functioning-emotional scales (p < 0.01 on all scales). The difference was most profound for the physical functioning scale. In the DM2 group the severity of pain was significantly correlated with SF-36 scores for bodily pain (p = 0.003). Fatigue was significantly correlated with the SF-36 scores for role functioning-physical (p = 0.001), general health (p = 0.02), and vitality (p = 0.02). The impact of DM2 on a patients' physical, psychological and social functioning is significant and as high as in adult-onset DM1 patients. From the perspective of health-related quality of life, DM2 should not be considered a benign disease. Management of DM2 patients should include screening for pain and fatigue. Symptomatic treatment of pain and fatigue may decrease disease impact and help improve health status in DM2, even if the disease itself cannot be treated.


cDNA-AFLP reveals genes differentially expressed during the hypersensitive response of cassava.
SUMMARY The tropical staple cassava is subject to several major diseases, such as cassava bacterial blight, caused by Xanthomonas axonopodis pv. manihotis. Disease-resistant genotypes afford the only practical solution, yet despite the global importance of this crop, little is known about its defence mechanisms. cDNA-AFLP was used to isolate cassava genes differentially expressed during the hypersensitive reaction (HR) of leaves in response to an incompatible Pseudomonas syringae pathovar. Seventy-eight transcript-derived fragments (TDFs) showing differential expression (c. 75% up-regulated, 25% down-regulated) were identified. Many encoded putative homologues of known defence-related genes involved in signalling (e.g. calcium transport and binding, ACC oxidases and a WRKY transcription factor), cell wall strengthening (e.g. cinnamoyl coenzyme A reductase and peroxidase), programmed cell death (e.g. proteases, 26S proteosome), antimicrobial activity (e.g. proteases and beta-1,3-glucanases) and the production of antimicrobial compounds (e.g. DAHP synthase and cytochrome P450s). Full-length cDNAs including a probable matrix metalloprotease and a WRKY transcription factor were isolated from six TDFs. RT-PCR or Northern blot analysis showed HR-induced TDFs were maximally expressed at 24 h, although some were produced by 6 h; some were induced, albeit more slowly, in response to wounding. This work begins to reveal potential defence-related genes of this understudied, major crop.


Bacterial hemerythrin domain-containing oxygen and redox sensors: Versatile roles for oxygen and redox signaling.
Hemerythrin is an oxygen-binding protein originally found in certain marine invertebrates. Oxygen reversibly binds at its non-heme diiron center, which consists of two oxo-bridged iron atoms bound to a characteristic conserved set of five His residues, one Glu residue, and one Asp residue. It was recently discovered that several bacteria utilize hemerythrin as an oxygen- and redox-sensing domain in responding to changes in cellular oxygen concentration or redox status, and immediately adapt to these environmental changes in order to maintain important physiological processes, including chemotaxis and c-di-GMP synthesis and degradation. This Mini Review focuses on the recent progress made on structural and functional aspects of these emerging bacterial hemerythrin domain-containing oxygen and redox sensors, revealing characteristic features of this family of proteins.


Biogenesis and etiology of distal anastomotic intimal hyperplasia.
Distal anastomotic intimal hyperplasia (DAIH) is a viable biologic entity composed of a multi-interlamination of cells and extracellular matrix. Cell transformation and orientation characterize the dynamic process of this 80-130 cell structure. Morphologic similarity exists in the cytoarchitecture of DAIH irrespective of the graft material. Compliance mismatch is not a cause of DAIH, but it enhances the formation. The geometry of the unnatural distal end-to-side anastomosis is predisposed to turbulent flow and DAIH formation. Prevention of DAIH is dependent on pharmacologic suppression of subendothelial smooth muscle proliferation and synthesis of extracellular matrix.


Advising caution in studying seasonal oscillations in crime rates.
Most types of crime are known to exhibit seasonal oscillations, yet the annual variations in the amplitude of this seasonality and their causes are still uncertain. Using a large collection of data from the Houston and Los Angeles Metropolitan areas, we extract and study the seasonal variations in aggravated assault, break in and theft from vehicles, burglary, grand theft auto, rape, robbery, theft, and vandalism for many years from the raw daily data. Our approach allows us to see various long term and seasonal trends and aberrations in crime rates that have not been reported before. We then apply an ecologically motivated stochastic differential equation to reproduce the data. Our model relies only on social interaction terms, and not on any exigent factors, to reproduce both the seasonality, and the seasonal aberrations observed in our data set. Furthermore, the stochasticity in the system is sufficient to reproduce the variations seen in the seasonal oscillations from year to year. Researchers should be very careful about trying to correlate these oscillations with external factors.


Integration of virtual and high throughput screening in lead discovery settings.
In the last decade mass screening strategies became the main source of leads in drug discovery settings. Although high throughput (HTS) and virtual screening (VS) realize the same concept the different nature of these lead discovery strategies (experimental vs theoretical) results that they are typically applied separately. The majority of drug leads are still identified by hit-to-lead optimization of screening hits. Structural information on the target as well as on bound ligands, however, make structure-based and ligand-based virtual screening available for the identification of alternative chemical starting points. Although, the two techniques have rarely been used together on the same target, here we review the existing prominent studies on their true integration. Various approaches have been shown to apply the combination of HTS and VS and to better use them in lead generation. Although several attempts on their integration have only been considered at a conceptual level, there are numerous applications underlining its relevance that early-stage pharmaceutical drug research could benefit from a combined approach.


Voltage modulates the effect of μ-receptor activation in a ligand-dependent manner.
Various GPCRs have been described as being modulated in a voltage-dependent manner. Opioid analgesics act via activation of μ receptors in various neurons. As neurons are exposed to large changes in membrane potential, we were interested in studying the effects of depolarization on μ receptor signalling. We investigated potential voltage sensitivity of μ receptors in heterologous expression systems (HEK293T cells) using electrophysiology in combination with Förster resonance energy transfer-based assays. Depolarization-induced changes in signalling were also tested in physiological rat tissue containing locus coeruleus neurons. We applied depolarization steps across the physiological range of membrane potentials. Studying μ receptor function and signalling in cells, we discovered that morphine-induced signalling was strongly dependent on the membrane potential (VM ). This became apparent at the level of G-protein activation, G-protein coupled inwardly rectifying potassium channel (Kir 3.X) currents and binding of GPCR kinases and arrestin3 to μ receptors by a robust increase in signalling upon membrane depolarization. The pronounced voltage sensitivity of morphine-induced μ receptor activation was also observed at the level of Kir 3.X currents in rat locus coeruleus neurons. The efficacy of peptide ligands to activate μ receptors was not (Met-enkephalin) or only moderately ([D-Ala2 , N-Me-Phe4 , Gly5 -ol]-enkephalin) enhanced upon depolarization. In contrast, depolarization reduced the ability of the analgesic fentanyl to activate μ receptors. Our results indicate a strong ligand-dependent modulation of μ receptor activity by the membrane potential, suggesting preferential activity of morphine in neurons with high neuronal activity.


Surgical treatment of diseases of the nail.
Nail disorders and diseases are common enough that the primary care physician should be familiar with and capable of performing surgical procedures necessary to treat them. The anatomy of the nail should be well understood. The physician should have access to specialized instruments that are necessary for proper nail surgery and should be familiar with the various techniques of anesthesia and postoperative care that will lead to the best result. Finally, the physician needs to be aware of those instances when a nail disorder is best treated conservatively or when a better result can be obtained with the proper surgical procedure.


Influence of saline on temperature profile of laser lithotripsy activation.
We established an ex vivo model to evaluate the temperature profile of the ureter during laser lithotripsy, the influence of irrigation on temperature, and thermal spread during lithotripsy with the holmium:yttrium-aluminum-garnet (Ho:YAG) laser. Two ex vivo models of Ovis aries urinary tract and human calcium oxalate calculi were used. The Open Ureteral Model was opened longitudinally to measure the thermal profile of the urothelium. On the Clinical Model, anterograde ureteroscopy was performed in an intact urinary system. Temperatures were measured on the external portion of the ureter and the urothelium during lithotripsy and intentional perforation. The lithotripsy group (n=20) was divided into irrigated (n=10) and nonirrigated (n=10), which were compared for thermal spread length and values during laser activation. The intentional perforation group (n=10) was evaluated under saline flow. The Ho:YAG laser with a 365 μm laser fiber and power at 10W was used (1J/Pulse at 10 Hz). Infrared Fluke Ti55 Thermal Imager was used for evaluation. Maximum temperature values were recorded and compared. On the Clinical Model, the external ureteral wall obtained a temperature of 37.4°C±2.5° and 49.5°C±2.3° (P=0.003) and in the Open Ureteral Model, 49.7°C and 112.4°C with and without irrigation, respectively (P<0.05). The thermal spread along the external ureter wall was not statically significant with or without irrigation (P=0.065). During intentional perforation, differences in temperatures were found between groups (opened with and without irrigation): 81.8°±8.8° and 145.0°±15.0°, respectively (P<0.005). There is an increase in the external ureteral temperature during laser activation, but ureteral thermal values decreased when saline flow was applied. Ureter thermal spread showed no difference between irrigated and nonirrigated subgroups. This is the first laser lithotripsy thermography study establishing the framework to evaluate the temperature profile in the future.


Effects of medical interventions on suicidal behavior. Introduction.
Knowledge of effective means of preventing suicide, based on research evidence, is strikingly limited, but there are indications that specific treatments may reduce suicidal risk in patients with major affective disorders. An international symposium was held in Miami, Fla., February 26-28, 1998, to discuss current knowledge of the Effects of Medical Interventions on Suicidal Behavior. Participant experts prepared summary reports of their contributions. Participants considered what is known about the effects of medical treatments on suicidal risk, as well as proposed approaches to future research. This supplement summarizes the proceedings of the symposium. The symposium strongly supported the proposition that suicide is amenable to ethical scientific investigation, suggested that evidence supporting suicide risk-reduction can be developed, and strongly encouraged studies to test the effects of specific interventions on suicidal risk. It also encouraged greater efforts at public and professional education to understand suicide as a result of mood and other psychiatric disorders, and to improve their early recognition and enhance timely access to effective treatment by the psychiatric and general medical community.


Lectin-induced phosphatidylinositol metabolism in lymphocytes is potentiated by macrophages.
The generation and hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) have been shown to occur early after the stimulation of a variety of cells and to trigger an array of responses, including proliferation in lymphocytes. In this study we examined the requirement for macrophages in the production and metabolism of PIP2 in lectin-stimulated lymph node lymphocytes. When lymph node cells (LNC) were stimulated by the mitogenic lectin, Con A, a two- to threefold increase in [3H]inositol-labeled PIP2 occurred within 15 min, followed by a decrease to the level of unstimulated cells by 30 min. In addition, there was also a two- to threefold increase in the accumulation of [3H]inositol-labeled inositol monophosphate (IP) 30 min after the addition of lectin. However, when the LNC were depleted of macrophages by adherence to plastic and passage over cotton columns before the addition of Con A, the PIP2 response was not seen and the IP accumulation was reduced by 40%. The macrophage-depleted, Con A-stimulated cultures failed to synthesize DNA. [3H]TdR incorporation was only 15% of that of Con A-stimulated unseparated LNC cultures. Soluble IL-2 production was also depressed to 20% of that observed in macrophage-containing cultures. Furthermore, when macrophages (2%) were added to the macrophage-depleted cultures, PIP2 production, IP accumulation, and [3H]TdR incorporation were restored to levels observed in the stimulated unseparated LNC cultures. The addition of IL-1 or the phorbol ester 12-O-tetradecanoylphorbol-13-acetate in combination with Con A also restored both [3H]TdR incorporation and IL-2 synthesis in macrophage-depleted cultures. However, they did so without a detectable increase in phosphatidylinositol metabolism. Collectively, these data suggested that the production and degradation of PIP2 in Con A-stimulated lymphocytes was potentiated by the presence of macrophages.


[Effect of diet on the formation of chyme and the rate of absorption of nutrients during active digestion].
In dogs with multiple fistulae the rate of absorption of nutrients from enteral lumen using different nutrient mixtures, revealed that the composition of chyme at the entrance into small intestine is homeostased within a certain range of values differing from the diet. A considerable increase of some nutrient in the diet leads to an increase of its content in the chyme and to considerable acceleration of absorption from the gastroduodenal part.


Glycoengineering of human IgG1-Fc through combined yeast expression and in vitro chemoenzymatic glycosylation.
The presence and precise structures of the glycans attached at the Fc domain of monoclonal antibodies play an important role in determining antibodies' effector functions such as antibody-dependent cell cytotoxicity (ADCC), complement activation, and anti-inflammatory activity. This paper describes a novel approach for glycoengineering of human IgG1-Fc that combines high-yield expression of human IgG1-Fc in yeast and subsequent in vitro enzymatic glycosylation, using the endoglycosidase-catalyzed transglycosylation as the key reaction. Human IgG1-Fc was first overproduced in Pichia pastoris. Then the heterogeneous yeast glycans were removed by Endo-H treatment to give the GlcNAc-containing IgG1-Fc as a homodimer. Finally, selected homogeneous glycans were attached to the GlcNAc-primer in the IgG1-Fc through an endoglycosidase-catalyzed transglycosylation, using sugar oxazolines as the donor substrates. It was found that the enzymatic transglycosylation was efficient with native GlcNAc-containing IgG1-Fc homodimer without the need to denature the protein, and the reaction could proceed to completion to give homogeneous glycoforms of IgG1-Fc when an excess of oligosaccharide oxazolines was used as the donor substrates. The binding of the synthetic IgG1-Fc glycoforms to the FcgammaIIIa receptor was also investigated. This novel glycoengineering approach should be useful for providing various homogeneous, natural or synthetic glycoforms of IgG1-Fc for structure-function relationship studies, and for future clinical applications.


Functional evaluation in young patients undergoing orthopedical interceptive treatment.
The aim of this study is to examining the activity of jaw muscles through electromyograph and electrognatograph in children with unilateral posterior cross-bite and functional lateral shift before and after rapid palatal expansion, and to find out a relationship between the results. The sample included 71 children (35 females and 36 males; range: 6-10 years) with unilateral posterior crossbite and functional mandibular lateral shift in mixed dentition. Superficial Electromiographic activity coming from the muscles areas (anterior temporalis and masseters) and electrognatographic exam were obtained before (T0) and after rapid palatal expansion (T1) and after a follow-up period of 6 months (T2). A significant increase was found in the value of activity index between T0, T1 and T2 in all the analyzed muscles both in rest position and during the exercises of the different acquisitions, at the end of the active phase of the rapid palatal expansion. The evaluation of EMG activity after rapid palatal expansion is important to confirm the adaptation of the neuromuscular system to the new occlusal condition. In this study, the muscular activity was increased after therapy producing important changes in muscular tone.


Characterization of human DSPG3, a small dermatan sulfate proteoglycan.
PG-Lb is a small dermatan sulfate proteoglycan that has been previously characterized in chicken. In the developing limb, chick PG-Lb appears to be exclusively expressed in the zone of flattened chondrocytes. We have cloned and sequenced the human homolog to chick PG-Lb from two human chondrocyte cDNA libraries and a human chondrocyte RNA sample. The human homolog has been named DSPG3, as it is the third member of the small dermatan sulfate proteoglycan family to be identified and characterized along with biglycan (PG-I) and decorin (PG-II). DSPG3 maps to chromosome 12q21 and is composed of 1515 nucleotides of cDNA that code for a 322-amino-acid protein. The protein contains three potential glycosaminoglycan attachment sites, two N-glycosylation sites, a poly- glutamic acid stretch, and six cysteines. By Northern analysis, we have demonstrated that DSPG3 is expressed in cartilage, as well as ligament and placental tissues.


Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer.
Consolidation durvalumab improved overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiotherapy (CRT) in the PACIFIC trial; however, pneumonitis was increased with durvalumab. We sought to examine real-world outcomes with the PACIFIC paradigm, especially factors associated with pneumonitis, using a multi-institutional review. Patients with LA-NSCLC treated with CRT followed by durvalumab from January 2017-February 2019 were identified at 2 institutions. We characterized demographics, tumor factors, radiotherapy, and duration of durvalumab. We examined pneumonitis outcomes including re-challenge success, with secondary endpoints of progression-free survival (PFS) and OS. Thirty-four patients were included with median follow-up of 12 months (range, 3 to 20 months); 94% had stage III disease. The cumulative grade >2 pneumonitis rate was 26.5% with 2 patients developing grade 3 pneumonitis and no grade 4/5 events. Median time to pneumonitis after RT was 2.4 months (range, 0 to 4.9 months). Pneumonitis management included median prednisone dose of 60 mg for median taper of 6 weeks with durvalumab held for median of 4.5 weeks (range, 2 to 8 weeks); 70% of pneumonitis patients received durvalumab re-challenge, with pneumonitis recurring in 14% of patients. 3-month and 6-month pneumonitis-free-survival were 76.9% and 73.6%, respectively; 9- and 12-month OS were 96% (75.1-99.8%), 86.6% (63.5-95.5%), respectively; 9- and 12-month PFS were 68% (47.5-82.5%), 48.7% (25.3-68.3%). Pneumonitis development did not significantly impact PFS or OS (P>0.05). Among LA-NSCLC patients treated with CRT followed by consolidation durvalumab, more than 25% developed symptomatic pneumonitis. In this small case series, pneumonitis did not appear to negatively impact survival, and durvalumab re-challenge appeared feasible after pneumonitis treatment with steroids.


Genetic, molecular, and functional analysis of Streptococcus faecalis R plasmid pJH1.
Streptococcus faecalis JH1 contains two conjugative plasmids, pJH1, an R plasmid that codes for resistance to kanamycin, streptomycin, erythromycin, and tetracycline, and pJH2, a hemolysin-bacteriocin plasmid. Strain JH1 was used as an antibiotic resistance donor in conjugation experiments with two plasmid-free S. faecalis recipient strains, JH2-2 and OG1-RF1. Plasmid pJH1 was purified from one transconjugant, DL77, and subjected to restriction endonuclease analyses. Five restriction enzymes, EcoRI, XbaI, BamHI, SalI, and XhoI, yielding 10, 9, 3, 2, and 2 fragments, respectively, were used to determine the size (80.7 kilobases) of pJH1 and to construct a restriction endonuclease map of the plasmid. Twenty-eight percent of the antibiotic-resistant transconjugants examined expressed only part of the resistance pattern (Kmr Smr Emr Tcr) associated with pJH1, that is, they were resistant to kanamycin, streptomycin, and erythromycin; to erythromycin and tetracycline; or to erythromycin or to tetracycline only. Most of these strains also produced hemolysin and bacteriocin, and several contained a hybrid plasmid consisting of pJH2 and specific segments of pJH1 DNA. Several of these hybrid plasmids, as well as a deletion derivative of pJH1 that coded for resistance to tetracycline but not to kanamycin, streptomycin, or erythromycin, were purified and used to confirm the arrangement of restriction endonuclease fragments on the pJH1 map and to locate the resistance determinants on this map.


Microvessel density as a prognostic factor in penile squamous cell carcinoma.
To examine the potential effect of tumor-induced angiogenesis in squamous cell carcinoma of the penis as a possible prognostic factor. Immunohistochemistry was preformed to detect microvessels in tumor samples of 64 patients with squamous cell carcinoma of the penis. We used a monoclonal mouse antibody directed against CD34 antigen. Only 61 (30 with and 31 without metastasis) patients had good staining properties and were included. After immunostaining, the entire tumor section was scanned microscopically at low power (× 40) to identify hot spots within the tumor and at its periphery. Individual tumor microvessels were then counted under high power (× 200) to obtain a vessel count in a defined area, and the mean of the 3 highest microvessel counts was taken as the microvessel density (MVD). Microvessel counting was performed using a computer-aided image analysis system. The nodal status was based on histopathologic examination or an uneventful follow-up ≥ 2 years. The 5-year overall survival (OAS) was 75% and 30 % for those with high and low peritumoral MVD, respectively (log rank P = 0.01). No difference was noticed within the tumor with regard to high (5-year OAS of 65.03%) and low (5-year OAS of 60.56%) intratumoral MVD (log rank P = 0.99). The mean intratumoral MVD was 32.35 (3.16), 37.94 (3.35), and 62.66 (5.47) in T1, T2, and T3 respectively (ANOVA P = 0.0006), with increasing tendency. The mean peritumoral MVD was 55.91 (5.60), 56.8 (4.00), and 78.86 (8.71), respectively (P = 0.06). No correlation between MVD lymph node status and tumor grade was seen (P > 0.05). In our group of patients, a high peritumoral MVD was associated with a better 5-year OAS. However, for a reliable and reproducible assessment of tumor angiogenesis in penile squamous cell carcinoma, validation procedures and quality control protocols are mandatory.


Formation of the apical pole of epithelial (Madin-Darby canine kidney) cells: polarity of an apical protein is independent of tight junctions while segregation of a basolateral marker requires cell-cell interactions.
The time course of development of polarity of an apical (184-kD) and a basolateral (63-kD) plasma membrane protein of Madin-Darby canine kidney cells was followed using semiquantitative immunofluorescence on semithin (approximately 0.5-micron) frozen sections and monoclonal antibody probes. The 184-kD protein became highly polarized to the apical pole within the initial 24 h both in normal medium and in 1-5 microM Ca2+, which results in well-spread, dome-shaped cells, lacking tight junctions and other lateral membrane interactions. In contrast, the basolateral 63-kD membrane protein developed full polarity only after incubation in normal Ca2+ concentrations for greater than 72 h, a time much longer than that required for the formation of tight junctions (approximately 18 h) and failed to polarize in 1-5 microM Ca2+. These results demonstrate that intradomain restriction mechanisms independent of tight junctions, such as self-aggregation or specific interactions with the submembrane cytoskeleton, participate in the regionalization of at least some epithelial plasma membrane proteins. The full operation of these mechanisms depends on the presence of normal cell-cell interactions in the case of the basolateral 63-kD antigen but not in the case of the apical 184-kD protein.


Ratio model for suprathreshold hue-increment detection.
We use psychophysical techniques to investigate the neural mechanisms subserving suprathreshold chromatic discrimination in human vision. We address two questions: (1) How are the postreceptoral detection mechanism responses combined to form suprathreshold chromatic discriminators? and (2) How do these discriminators contribute to color perception? We use a pedestal paradigm in which the subject is required to distinguish between a pedestal stimulus and the same pedestal added to a chromatic increment (the test). Our stimuli are represented in a cardinal space, in which the axes express the responses of the three postreceptoral detection mechanisms normalized relative to their respective detection thresholds. In the main experiment the test (a hue increment) was fixed in the direction orthogonal to the pedestal in our cardinal space. We found that, for high pedestal contrasts, the test threshold varied proportionally with the pedestal contrast. This result suggests the presence of a hue-increment detector dependent on the ratio of the outputs from the red-green and blue-yellow postreceptoral detection mechanisms. The exception to this was for pedestals and tests fixed along the cardinal axes. In that case detection was enhanced by direct input from the postreceptoral mechanism capable of detecting the test in isolation. Our results also indicate that discrimination in the red-green/luminance and blue-yellow/luminance planes exhibits a behavior similar to discrimination within the isoluminant plane. In the final experiment we observed that thresholds for hue-increment identification (e.g., selecting the bluer of two stimuli) are also governed by a ratio relationship. This finding suggests that our ratio-based mechanisms play an important role in color-difference perception.


Tollip is a mediator of protein sumoylation.
Tollip is an interactor of the interleukin-1 receptor involved in its activation. The endosomal turnover of ubiquitylated IL-1RI is also controlled by Tollip. Furthermore, together with Tom1, Tollip has a general role in endosomal protein traffic. This work shows that Tollip is involved in the sumoylation process. Using the yeast two-hybrid technique, we have isolated new Tollip partners including two sumoylation enzymes, SUMO-1 and the transcriptional repressor Daxx. The interactions were confirmed by GST-pull down experiments and immunoprecipitation of the co-expressed recombinants. More specifically, we show that the TIR domain of the cytoplasmic region of IL-1RI is a sumoylation target of Tollip. The sumoylated and unsumoylated RanGAP-1 protein also interacts with Tollip, suggesting a possible role in RanGAP-1 modification and nuclear-cytoplasmic protein translocation. In fact, Tollip is found in the nuclear bodies of SAOS-2/IL-1RI cells where it colocalizes with SUMO-1 and the Daxx repressor. We conclude that Tollip is involved in the control of both nuclear and cytoplasmic protein traffic, through two different and often contrasting processes: ubiquitylation and sumoylation.


Malaria-specific and nonspecific activation of CD8+ T cells during blood stage of Plasmodium berghei infection.
Cerebral malaria is one of the severe complications of Plasmodium falciparum infection. Studies using a rodent model of Plasmodium berghei ANKA infection established that CD8(+) T cells are involved in the pathogenesis of cerebral malaria. However, it is unclear whether and how Plasmodium-specific CD8(+) T cells can be activated during the erythrocyte stage of malaria infection. We generated recombinant Plasmodium berghei ANKA expressing OVA (OVA-PbA) to investigate the parasite-specific T cell responses during malaria infection. Using this model system, we demonstrate two types of CD8(+) T cell activations during the infection with malaria parasite. Ag (OVA)-specific CD8(+) T cells were activated by TAP-dependent cross-presentation during infection with OVA-PbA leading to their expression of an activation phenotype and granzyme B and the development to functional CTL. These highly activated CD8(+) T cells were preferentially sequestered in the brain, although it was unclear whether these cells were involved in the pathogenesis of cerebral malaria. Activation of OVA-specific CD8(+) T cells in RAG2 knockout TCR-transgenic mice during infection with OVA-PbA did not have a protective role but rather was pathogenic to the host as shown by their higher parasitemia and earlier death when compared with RAG2 knockout mice. The OVA-specific CD8(+) T cells, however, were also activated during infection with wild-type parasites in an Ag-nonspecific manner, although the levels of activation were much lower. This nonspecific activation occurred in a TAP-independent manner, appeared to require NK cells, and was not by itself pathogenic to the host.


[In vitro experimentation of a new model of radial flow bioreactor containing isolated hepatocytes].
Hepatocyte based artificial liver support systems are under investigation to support acute liver failure patients. The main purpose of such systems is to serve as a bridge to liver transplantation, or to promote spontaneous liver recovery. Limitation in mass-transfer capacity makes hollow-fiber bioreactors unsuited for long-term functioning of hybrid devices. We developed a novel radial-flow bioreactor in which the fluid perfuses the module from the center to the periphery, after having diffused through a space occupied by a three-dimensional structure filled with the hepatocytes. Five grams of freshly isolated porcine hepatocytes were seeded into uncoated, woven-non woven, hydrophilic polyester fabric, overlaid by two polyethersulfone membranes. Liver cells were perfused with 37 degrees C-warm, oxygenated, serum-free tissue culture medium, in which NH4Cl and Lidocaine were added at the final concentration of 1 mM and 60 micrograms/ml, respectively. Ammonium chloride removal, urea synthesis, monoethylglycinexylide (MEGX), pO2, pCO2, and pH were measured throughout the 14 day duration of the study. In a separate set of experiments, a scaled-up version of the radial flow bioreactor containing 150 grams of cells was perfused for 7 h with recirculating human plasma and MEGX production was monitored. During the 2 weeks of the study, an increasing production of urea was paralleled by constant ammonium removal. MEGX concentration after Lidocaine addition increased throughout the 14 days of perfusion with tissue culture medium, as well as after 7 hour perfusion with human plasma. Under transmission and scanning electron microscopy cells appeared attached to the polyester and one to each other, displaying ultrastructural features typical of functioning hepatocytes. Our study showed that liver cells were metabolically active when perfused into the radial-flow bioreactor. This configuration allowed close contact between media, or plasma, and cells at a physiological flow rate, by equalizing the concentration of the perfusing components, including O2, throughout the module. Our results suggest a potential use of this system for temporary extracorporeal liver support in acute hepatic failure patients.


Unfolded protein response in keratinocytes: impact on normal and abnormal keratinization.
The unfolded protein response (UPR) is a signaling pathway from the endoplasmic reticulum (ER) to the nucleus that protects cells from stress caused by misfolded or unfolded proteins. As such, ER stress is an ongoing challenge for all cells, given the central biologic importance of secretion as part of normal physiologic functions. Mild UPR is activated by mild ER stress, which occurs under normal conditions. Abnormal UPR is activated by severe ER stress, which occurs under pathological conditions. Abnormal UPR activation is associated with a number of diseases, including diabetes mellitus and Alzheimer's disease. Within skin tissues, keratinocytes in the epidermis are especially dependent upon a mild UPR for normal differentiation in the course of their differentiation into secretory cells in the uppermost granular layers. Association between abnormal UPR activation and hereditary keratoses, including Darier's disease, keratosis linearis with ichthyosis congenita and keratoderma syndrome, erythrokeratoderma variabilis, and ichthyosis follicularis with atrichia and photophobia syndrome, have been elucidated recently. This review describes the UPR in normal and abnormal keratinization and discusses the regulation of abnormal UPR activation by chemical chaperones as a potential treatment for one of the hereditary keratoses.


RAPID METHOD OF DETERMINING COAGULASE ACTIVITY DURING STAPHYLOCOCCAL BACTERIOPHAGE TYPING.
The plate test, a modification of the slide test described by Cadness-Graves was developed for the rapid identification of coagulase-positive staphylococci in conjunction with bacteriophage typing. An evaluation of 1,145 cultures by three coagulase-determination methods, the slide, tube, and plate tests, indicates that the plate test is as accurate as the slide tests, and the plate test agrees 97.7% with the tube test.


Celastrol, a plant-derived triterpene, induces cisplatin-resistance nasopharyngeal carcinoma cancer cell apoptosis though ERK1/2 and p38 MAPK signaling pathway.
Developing resistance to chemotherapeutic drugs has become a major problem in the management of nasopharyngeal carcinoma (NPC). To overcome this issue, use of natural plant products as chemosensitizers is gaining importance at a fast pace. The present study was designed to evaluate the cytotoxic effect and mode of action of a natural pentacyclic triterpenoid, celastrol, on cisplatin-resistant NPC cells. Study results revealed that celastrol treatment significantly reduced the viability of NPC cells in dose and time dependent manners, as compared to untreated control cells. The cytotoxic effect of celastrol was mediated by cell cycle arrest at G2/M phase and induction of intrinsic and extrinsic apoptotic pathways. With further analysis, we observed that celastrol-induced activation of caspases was accompanied by increased phosphorylation of MAPK pathway proteins, p38, ERK1/2. Taken together, our observation provides a novel insight on use of a natural plant product, celastrol, in the management of chemoresistant NPC.


An optical-axis freezing stage for laser-scanning microscopy of broad ice-water interfaces.
This article presents a method to view a dynamic ice interface along the axis of ice growth using a laser-scanning microscope. A deep liquid volume is chilled from below so that ice growth is directed upward toward the microscope objective. The interface is made visible by rejection of fluorescent dye from the solid phase into the liquid. Images of the interface morphology in water with solutes of interest to cryobiology illustrate the imaging capability. These images are processed to quantify the lamellar structure of the ice interface. The optical-axis cryostage provides advantages over horizontal arrangements because (1) immersion objectives enhance, rather than disturb, the desired thermal gradient, and (2) features in the ice interface are not confined within a narrow capillary tube or microscope slide. This arrangement loses some of the thermal control found in planar freezing stages, and the dynamic, refractive interface presents challenges to confocal microscopy.


Vagotomy decreases the neuronal activities of medulla oblongata and alleviates neurogenic inflammation of airways induced by repeated intra-esophageal instillation of HCl in guinea pigs.
Neuronal activity in the medulla oblongata and neurogenic inflammation of airways were investigated in a guinea pig model induced by repeated intra-esophageal instillation of hydrochloric acid (HCl) after vagotomy. Unilateral vagotomy was performed in the vagotomy group, while a sham-operation was performed in the sham group. Operation was not conducted in sham control group. Airway inflammation was observed with hematoxylin and eosin (HE) staining. C-fos protein was measured by immunohistochemistry (IHC) and Western blot (WB). Substance P was examined by IHC and enzyme-linked immuno sorbent assay (ELISA). Airway microvascular permeability was detected by evans blue dye (EBD) fluorescence. Inflammation of airway was observed in the trachea and bronchi after chronic HCl perfusion into the lower esophagus, and was alleviated after unilateral vagotomy. C-fos expression in the medulla oblongata was lower in the vagotomy group compared to the sham control and sham groups. Substance P-like immunoreactivity (SP-li), concentration and microvascular leakage in airway were lower in the vagotomy group than that in the other groups. Our results suggest that vagotomy improved neurogenic inflammation of airways and decreased neuronal activities, the afferent nerves and neurons in medulla oblongata may be involved in neurogenic inflammation of airways mediated by esophageal-bronchial reflex.


Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation.
The extensive exploitation of the antitumor effect of donor lymphocytes infused after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is limited by the risk of graft-versus-host disease (GvHD). To overcome this limitation, we investigated the therapeutic potential of donor lymphocytes engineered with the suicide gene thymidine kinase of herpes simplex virus (TK) in 23 patients experiencing recurrence of hematologic malignancies after allo-HSCT. Long-term follow-up of infused patients included analysis of engraftment of genetically engineered lymphocytes, in vivo assessment of antitumor effect, and control of GvHD by ganciclovir. All 17 patients evaluable for engraftment and graft-versus-leukemia (GvL) had circulating TK(+) cells detectable beginning at a median time of 18 days. Eleven patients (65%) experienced a substantial clinical benefit resulting in 6 (35%) complete remissions and 5 (29%) partial responses. The antitumor effect tightly correlated with the in vivo expansion of TK(+) cells. Seven patients received ganciclovir, resulting in elimination of TK(+) cells and effective and selective treatment of GvHD. Immunization against HSV-TK was observed in 7 patients but did not preclude an effective GvL. These data validate the feasibility, safety, and efficacy of TK(+) cells in the context of allografting and represent the basis for a broader application of this technology.


Physical health problems after childbirth and maternal depression at six to seven months postpartum.
To investigate the relationship between maternal physical and emotional health problems six to nine months after childbirth. Statewide postal survey, incorporating the Edinburgh Postnatal Depression Scale, distributed to women six to seven months after childbirth, with telephone interview follow up of a sub-sample of participants at seven to nine months postpartum. The postal survey was distributed to all women who gave birth in a two-week period in Victoria, Australia in September 1993, except those who had a stillbirth or known neonatal death. Follow up interviews were conducted with respondents to the postal survey who provided contact details and expressed interest in participating in further research selected to recruit three groups of equivalent size according to scores on the Edinburgh Postnatal Depression Scale: a low scoring group (< 9); a borderline group (9-12); and a group with scores indicating probable depression (> or = 13). The response rate to the postal survey was 62.5% (n = 1,336). Respondents were representative of the total sample in terms of mode of delivery, parity and infant birthweight; young women, single women and women of non-English speaking background were under-represented. The participation rate in telephone follow up interviews was: 89.1% (n = 204), comprising 66 women with an Edinburgh Postnatal Depression Scale score of < 9; 72 women scoring 9-12; and 66 scoring > or =13. The point prevalence of depression at six to seven months postpartum was 16.9% (225/1,331, 95% CI 14.9-18.9%). Physical and related health problems associated with significantly increased odds of depression at six to seven months were: tiredness (OR 3.42 [2.2-5.3]); urinary incontinence (OR 2.23 [1.5-3.4]); back pain (OR 2.20 [1.6-3.0]); sexual problems (OR 2.16 [1.6-3.0]); more coughs, colds and minor illnesses than usual (OR 2.78 [1.9-4.1]); bowel problems (OR 1.93 [1.3-2.9]) and relationship difficulties (OR 3.88 [2.8-5.4]). At follow up, three physical health factors were associated with statistically significant linear trends with poorer levels of emotional wellbeing. These were: tiredness (chi2 for linear trend = 12.38, P < 0.001); urinary incontinence (chi2 for linear trend = 5.63, P = 0.02); and more minor illnesses than usual (chi2 for linear trend = 7.94, P = 0.005). The study confirms a link between maternal emotional wellbeing and physical health and recovery in the postnatal period and has important implications for clinical practice. Strategies for encouraging greater disclosure of physical and emotional health problems, assessment of the physical health of recent mothers presenting with depression, and emotional health of recent mothers presenting with other morbidity should be high priorities for all health professionals in contact with mothers in the year following childbirth.


Role of NADPH oxidase-2 and oxidative stress in children exposed to passive smoking.
This study explored oxidative stress, nicotinamide adenine dinucleotide phosphate oxidase-2 (Nox2) activity and endothelial function in children exposed or not to passive smoking. Compared with controls (n=57), Nox2 activity and isoprostanes were higher in children exposed to passive smoking (n=57); conversely, nitric oxide (NO) bioavailability and flow-mediated dilation were lower in children exposed to passive smoking. A bivariate analysis showed that Nox2 activity correlated with flow-mediated dilation, NO bioavailability and isoprostanes. A multivariate analysis showed that Nox2 activity was significantly associated with serum isoprostanes and cotinine levels; flow-mediated dilation was associated with isoprostanes and carotid intima-media thickness.In children exposed to passive smoking, Nox2-derived oxidative stress is upregulated and inversely associated with impaired artery dilation.


Clinical and pathological profile of 73 patients with lung carcinoma: is the picture changing?
A prospective study was undertaken to study the clinical features and pathological cell type of primary lung carcinoma in our institute. Seventy three patients were included in the study over a period of three years. These were investigated according to a study protocol which included a detailed history regarding the onset and progress of the disease, smoking habits, x-ray chest, computed tomography of the chest and upper abdomen, and flexible bronchoscopy with brushings and biopsy. 32.85% of patients were non-smokers. The male-female ratio was 4.2:1. Male sex, age > 50 years and history of smoking are still a risk factor for lung carcinoma. Tobacco smoking of 20 pack-years or more is significantly associated with the incidence of squamous cell carcinoma compared to other cell types. Adenocarcinoma (28.8%) was the most common cell type observed. It was also the most common cell type in central location (32.8%). Adenocarcinoma was the most common cell type diagnosis amongst females (50%) and non-smokers (43.5%). Computed tomography done in 47 patients diagnosed additional eleven patients with rib or vertebral metastases in addition to the three diagnosed by chest roentgenology. Computed tomography diagnosed significant mediastinal lymphadenopathy in 16 patients in whom mediastinal lymphadenopathy was not suspected on chest roentgenology. Computed tomography confirmed liver metastases in four patients diagnosed by ultrasonography and additionally in three more patients. Bronchial brushing cytology yielded positive results in 51.72% of central tumours and 40% in peripheral tumors. Yield of endobronchial biopsy was 59% and transbronchial biopsy was sixty percent. At presentation 74.1% patients with non-small cell carcinoma were inoperable and in case of small cell carcinoma 75% had extensive disease. Fiberoptic bronchoscopy with brushings and biopsy, and computed tomography of the chest and upper abdomen are useful investigations in the diagnosis of lung carcinoma.


Eighteen-month follow-up on the treatment of urinary schistosomiasis with a single dose of metrifonate.
Egg excretion of school children with urinary schistosomiasis treated with a single 10 mg/kg dose of metrifonate was monitored over a period of 18 months. At 18 months 68.8% of infected children showed a greater than 90% reduction in egg excretion and 23.7% had ceased excreting eggs. During the study period 25% of children with no evidence of infection at the start of the trial had become infected, while 45.5% of children apparently cured by the metrifonate treatment had recommenced egg excretion. The evidence suggested that reinfection rather than recovery of adult worms was responsible. Children with scanty or light infections, in general, showed increasing egg excretion rates during the following period, while those with heavy or severe infections showed a sustained reduction. In view of this, single dose metrifonate may be a useful approach to mass treatment in a schistosomiasis control program, resulting in significant reduction in egg excretion in those most likely to be important sources of transmission.


Selected indigestible oligosaccharides affect large bowel mass, cecal and fecal short-chain fatty acids, pH and microflora in rats.
Certain indigestible oligosaccharides may benefit gastrointestinal tract health via fermentation and proliferation of desirable bacterial species. The purpose of this study was to elucidate effects of selected oligosaccharides on cecal and fecal short-chain fatty acid (SCFA) concentration, pH, total large bowel wet weight and wall weight, and gut microbiota levels in rats. Fifty male Sprague-Dawley rats were randomly assigned to one of five treatments: 1) control diet; 2) control diet + 5% microcrystalline cellulose (5% CC); 3) control diet + 5% CC + 6% fructooligosaccharides; 4) control diet + 5% CC + 6% oligofructose; or 5) control diet + 5% CC + 6% xylooligosaccharides. The control diet consisted of (dry matter basis) 20% protein, 65% carbohydrate, 10.5% fat, vitamin and mineral mixes. The duration of the study was 14 d. The oligofructose- and fructooligosaccharide-containing diets resulted in higher cecal butyrate concentrations compared with the control, cellulose and xylooligosaccharide diets. Generally, total cecal SCFA pools were higher while pH was lower from ingesting oligosaccharide-containing diets compared with control or cellulose diets. Cecal total weight and wall weight were higher from oligosaccharide consumption, whereas colonic total wet weight was higher for rats consuming xylooligosaccharides compared with other treatments; colon wall weight was unaffected by treatments. Cecal bifidobacteria and total anaerobes were higher whereas total aerobes were lower in rats fed oligosaccharide diets compared with those fed the control diet. Cecal lactobacilli levels were unaffected by treatment. Dietary incorporation of fermentable, indigestible oligosaccharides, by providing SCFA, lowering pH, and increasing bifidobacteria, may be beneficial in improving gastrointestinal health.


Treatment with ascorbic acid and α-tocopherol modulates oxidative-stress markers in the spinal cord of rats with neuropathic pain.
Vitamin E (vit. E) and vitamin C (vit. C) are antioxidants that inhibit nociception. The effect of these vitamins on oxidative-stress markers in the spinal cord of rats with chronic constriction injury (CCI) of the sciatic nerve is unknown. This study investigated the effect of intraperitoneal administration of vit. E (15 mg·kg-1·day-1) and vit. C (30 mg·kg-1·day-1), given alone or in combination, on spinal cord oxidative-stress markers in CCI rats. Adult male Wistar rats weighing 200-250 g were divided equally into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve), which received injections of vitamins or vehicle (saline containing 1% Tween 80) for 3 or 10 days (n=6/each group). The vitamins prevented the reduction in total thiol content and the increase in superoxide-anion generation that were found in vehicle-treated CCI rats. While nitric-oxide metabolites increased in vehicle-treated CCI rats 3 days after surgery, these metabolites did not show significant changes in vitamin-treated CCI rats. In all rats, total antioxidant capacity and hydrogen-peroxide levels did not change significantly. Lipid hydroperoxides increased 25% only in vehicle-treated CCI rats. These changes may contribute to vit. C- and vit. E-induced antinociception, because scavenging reactive oxygen species seems to help normalize the spinal cord oxidative status altered by pain.


Beyond accuracy: creating a comprehensive evidence base for TB diagnostic tools.
The need for a strong and comprehensive evidence base to support decision making with regard to the implementation of new and improved diagnostic tools and approaches has been highlighted by a number of stakeholders; these include members of the New Diagnostics Working Group (NDWG) and the Subgroup for Introducing New Approaches and Tools of the Stop TB Partnership. To compile such evidence in a systematic manner, we have developed an impact assessment framework (IAF) which links evidence on inputs to outcomes. The IAF comprises five interconnected layers: effectiveness analysis, equity analysis, health systems analysis, scale-up analysis and policy analysis. It can be used by new diagnostics developers and other interested research teams to collect as much policy-relevant data as possible prior to, during and after the demonstration phase of tool development. The evidence collated may be used by international and national policy makers to support adoption, implementation and scale-up decisions. The TREAT TB (Technology, Research, Education and Technical Assistance for TB) initiative uses the IAF in its operational research and field evaluations of new tools and approaches for TB diagnosis. It has also been incorporated into the NDWG's recent publication: 'Pathways to better diagnostics for tuberculosis: a blueprint for the development of TB diagnostics'. This article describes the IAF and the process of improving it and suggests next steps in overcoming the challenges in its implementation.


Crop beta-glucanase activity limits the effectiveness of a recombinant cellulase used to supplement a barley-based feed for free-range broilers.
1. The supplementation of diets rich in soluble polysaccharides with microbial cellulases and hemicellulases decreases digesta viscosity and promotes broiler performance. 2. In contrast, recent experiments suggest that polysaccharidases are ineffective for improving the nutritive value of pasture biomass used by free-range broilers. However, the feasibility of using cellulases and hemicellulases to improve the utilisation of cereal-based feeds by pastured poultry remains to be established. 3. A study was undertaken to investigate the capacity of a recombinant cellulase from Clostridium thermocellum to improve the nutritive value of a barley-based feed for free-range pastured broilers of the RedBro Cou Nu x RedBro M genotype. 4. The results show that supplementation of a barley-based diet with a recombinant beta-glucanase had no effect on the performance of free-range broilers, foraging in legume-based diets from d 28 to 56. In addition, the results confirm that the lack of effect of the recombinant enzyme in improving the nutritive value of the barley-based feed does not result from enzyme proteolysis or inhibition in the gastrointestinal tract. 5. Significantly, beta-glucanase activity was identified in the crop of non-supplemented animals. The data suggest that endogenous cellulases originated both from the barley-based feed and from the crop microflora. 6. The results presented here suggest that in older birds of slow-growing genotypes associated with free-range production systems, previously unknown sources of beta-glucanases, such as the feed and microbial symbiotic microflora, can affect the effectiveness of exogenous enzymes added to the feed.