Loss of nitric oxide-mediated inhibition of purine neurotransmitter release in the colon in the absence of interstitial cells of Cajal.
Regulation of colonic motility depends on the integrity of enteric inhibitory neurotransmission mediated by nitric oxide (NO), purine neurotransmitters, and neuropeptides. Intramuscular interstitial cells of Cajal (ICC-IM) and platelet-derived growth factor receptor-α-positive (PDGFRα+) cells are involved in generating responses to NO and purine neurotransmitters, respectively. Previous studies have suggested a decreased nitrergic and increased purinergic neurotransmission in KitW/KitW-v (W/Wv ) mice that display lesions in ICC-IM along the gastrointestinal tract. However, contributions of NO to these phenotypes have not been evaluated. We used small-chamber superfusion assays and HPLC to measure the spontaneous and electrical field stimulation (EFS)-evoked release of nicotinamide adenine dinucleotide (NAD+)/ADP-ribose, uridine adenosine tetraphosphate (Up4A), adenosine 5'-triphosphate (ATP), and metabolites from the tunica muscularis of human, monkey, and murine colons and circular muscle of monkey colon, and we tested drugs that modulate NO levels or blocked NO receptors. NO inhibited EFS-evoked release of purines in the colon via presynaptic neuromodulation. Colons from W/Wv, Nos1-/- , and Prkg1-/- mice displayed augmented neural release of purines that was likely due to altered nitrergic neuromodulation. Colons from W/Wv mice demonstrated decreased nitrergic and increased purinergic relaxations in response to nerve stimulation. W/Wv mouse colons demonstrated reduced Nos1 expression and reduced NO release. Our results suggest that enhanced purinergic neurotransmission may compensate for the loss of nitrergic neurotransmission in muscles with partial loss of ICC. The interactions between nitrergic and purinergic neurotransmission in the colon provide novel insight into the role of neurotransmitters and effector cells in the neural regulation of gastrointestinal motility.NEW & NOTEWORTHY This is the first study investigating the role of nitric oxide (NO) and intramuscular interstitial cells of Cajal (ICC-IM) in modulating neural release of purines in colon. We found that NO inhibited release of purines in human, monkey, and murine colons and that colons from KitW/KitW-v (W/Wv ) mice, which present with partial loss of ICC-IM, demonstrated augmented neural release of purines. Interactions between nitrergic and purinergic neurotransmission may affect motility in disease conditions with ICC-IM deficiencies.


[Establishment of a method with real-time reverse transcription-polymerase chain reaction for hepatitis E virus in swine feces and its molecular epidemiology].
Real-time reverse transcription-polymerase chain reaction(real-time RT-PCR) assay based on Taqman and phylogenetic tree were developed for detecting hepatitis E virus in swine feces of pig farms from several provinces and city. Designing prime and probe refering to HEV genotype sequences of Genbank, we developed a Taqman-based real-time RT-PCR assay and nested RT-PCR according to HEV conserved domain after optimizing reaction system, then detected the prevalence of HEV infection of pig farms. The sensitivity of the real-time RT-PCR assay established in this experiment was 19. 9 copies/μL, the amplification efficiency was 92. 9%-109. 1%, there was no cross reaction with Sapovirus, Norovirus and Hepatitis A. A total of 342 samples of swine feces were detected. There were two hundred and ten positive samples, and positive rate was 61. 4%. The positive rate of before-fattening was 56. 6%, and after-fattening was 66. 9%. The positive rate of before and after fattening samples had statistical difference(χ~2=24. 8, P<0. 05). The genotype identification system determined that the positive strains isolated in this study were HEV-4 type, and three subtypes of 4 b, 4 d and 4 h were detected. The pig farms of several provinces and city are contaminated by HEV extensively. The genotypes of the isolated strains are all HEV-4 type. The infection rate and infection subtype of pigs in different provinces and cities are different.


New-onset angina preceding acute myocardial infarction is associated with improved contractile recovery after thrombolysis.
Ischaemic preconditioning reduces myocardial infarct size in animal models. Clinical data suggest that episodes of angina immediately before acute myocardial infarction may be associated with smaller infarct size in man. However, it is unclear whether ischaemic episodes preceding acute myocardial infarction also affect contractile recovery in patients. In this study we investigated the recovery of regional myocardial function after thrombolysis in two groups of patients at their first Q-wave acute myocardial infarction; in one group (n = 42) myocardial infarction occurred unheralded, whereas patients of the second group (n = 48) had experienced new-onset angina in the 48 h that preceded infarction. Echocardiographic analysis of myocardial regional function in the infarct area was done at 2, 24 and 72 h after thrombolysis, and at 1 week, and 1 and 3 months follow-up. Peak level of MB-creatine kinase was significantly lower in patients with new-onset angina (96 +/- 47 as compared with 221 +/- 108 IU.l-1, P < 0.01), as was the area under the MB-creatine kinase curve (1321 +/- 876 as compared to 3879 +/- 1555 U.l-1/36 h, P < 0.01). Hypokinetic segments were fewer in patients with pre-infarction angina. Similarly, wall motion score improved significantly earlier in patients who had new-onset angina before acute myocardial infarction. Thus, contractile recovery was more rapid in patients with previous angina than in those in whom infarction occurred unheralded. Complications during the in-hospital outcome and other variables considered during the 4-week follow-up were similar between groups. Patients who experienced new-onset angina before acute myocardial infarction showed better recovery of regional function after thrombolysis. Our study supports the hypothesis that brief periods of ischaemia immediately before myocardial infarction may precondition the human heart, thus improving contractile recovery.


Dietary methyl donor depletion protects against intestinal tumorigenesis in Apc(Min/+) mice.
Despite recent population data, the influence of dietary folate supplementation on colon cancer risk remains controversial. This study examines the effects of folate deficiency, in combination with choline, methionine, and vitamin B12 depletion, on intestinal tumorigenesis in Apc(Min/+) mice. Methyl donor sufficient (MDS) and deficient (MDD) diets were started at five or 10 weeks of age and tumors evaluated at 16 weeks. MDD suppressed intestinal tumor formation in Apc(Min/+) mice (~80%) when started at five weeks of age. The protective effect was lost when MDD was initiated at 10 weeks of age, indicating an important time dependency on cancer suppression. Concomitant with cancer protection, MDD restricted body weight gain. Therefore, a second study was conducted in which MDS was given ad libitum or pair-fed with MDD. Although small intestinal tumors were reduced 54% in pair-fed MDS mice, MDD caused a further reduction (96%). In colon, although MDD did not affect tumor numbers, tumor size was reduced. Gene expression profiling of normal-appearing colonic mucosa after 11 weeks on MDD identified a total of 493 significantly downregulated genes relative to the MDS group. Pathway analysis placed many of these genes within general categories of inflammatory signaling and cell-cycle regulation, consistent with recently published human data obtained during folate depletion. Further studies are warranted to investigate the complex interplay of methyl donor status and cancer protection in high-risk populations.


Transcript profiling of two potato cultivars during glycoalkaloid-inducing treatments shows differential expression of genes in sterol and glycoalkaloid metabolism.
Steroidal glycoalkaloids (SGA) are sterol-derived neurotoxic defence substances present in several members of the Solanaceae. In the potato (Solanum tuberosum), high SGA levels may render tubers harmful for consumption. Tuber SGA levels depend on genetic factors, and can increase as a response to certain stresses and environmental conditions. To identify genes underlying the cultivar variation in tuber SGA levels, we investigated two potato cultivars differing in their SGA accumulation during wounding or light exposure; two known SGA-inducing treatments. Using microarray analysis coupled to sterol and SGA quantifications, we identified a small number of differentially expressed genes that were associated with increased SGA levels. Two of these genes, encoding distinct types of sterol Δ24-reductases, were by sense/antisense expression in transgenic potato plants shown to have differing roles in sterol and SGA metabolism. The results show that an increased SGA level in potato tubers during both wounding and light exposure is mediated by coordinated expression of a set of key genes in isoprenoid and steroid metabolism, and suggest that differences in this expression underlie cultivar variations in SGA levels. These results may find use within potato breeding and quality assessment.


Interplay between Thermal Stress and Interface Binding on Fracture of WS2 Monolayer with Triangular Voids.
The defect engineering of two-dimensional (2D) materials has become a pivotal strategy for tuning the electrical and optical properties of the material. However, the reliable application of these atomically thin materials in practical devices require careful control of structural defects to avoid premature failure. Herein, a systematic investigation is presented to delineate the complex interactions among structural defects, the role of thermal mismatch between WS2 monolayer and different substrates, and their consequent effect on the fracture behavior of the monolayer. Detailed microscopic and Raman/PL spectroscopic observations enabled a direct correlation between thermal mismatch stress and crack patterns originating from the corner of faceted voids in the WS2 monolayer. Aberration-corrected STEM-HAADF imaging reveals the tensile strain localization around the faceted void corners. Density functional theory (DFT) simulations on interfacial interaction between the substrate (Silicon and sapphire -Al2O3) and monolayer WS2 revealed a binding energy between WS2 and Si substrate is 20 times higher than that with a sapphire substrate. This increased interfacial interaction in WS2 and substrate-aided thermal mismatch stress arising due to difference in thermal expansion coefficient to a maximum extent leading to fracture in monolayer WS2. Finite element simulations revealed the stress distribution near the void in the WS2 monolayer, where the maximum stress was concentrated at the void tip.


Murine models provide insight to the development of non-alcoholic fatty liver disease.
Associated with the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) has become the leading liver disease in North America. Approximately 30 % of patients with NAFLD may develop non-alcoholic steatohepatitis (NASH) that can lead to cirrhosis and hepatocellular carcinoma (HCC). Frequently animal models are used to help identify underlying factors contributing to NAFLD including insulin resistance, dysregulated lipid metabolism and mitochondrial stress. However, studying the inflammatory, progressive nature of NASH in the context of obesity has proven to be a challenge in mice. Although the development of effective treatment strategies for NAFLD and NASH is gaining momentum, the field is hindered by a lack of a concise animal model that reflects the development of liver disease during obesity and the metabolic syndrome. Therefore, selecting an animal model to study NAFLD or NASH must be done carefully to ensure the optimal application. The most widely used animal models have been reviewed highlighting their advantages and disadvantages to studying NAFLD and NASH specifically in the context of obesity.


High-intensity Raf signals convert mitotic cell cycling into cellular growth.
The selection of NIH 3T3 cells expressing a hydroxytamoxifen-inducible c-Raf-1-estrogen receptor fusion protein (c-Raf-1-BxB-ER) in the absence or presence of the inducer results in dramatic differences in the expression levels of the fusion protein. Hydroxytamoxifen-mediated constitutive activation of the Raf signal favors the selection of cells expressing low levels of c-Raf-1-BxB-ER. Cells selected in the absence of hydroxytamoxifen express up to 20 times higher levels of the inducible Raf kinase. Activation of the oncogenic Raf kinase in cells expressing low levels leads to a weak activation of the Raf/Mek/Erk cascade and the induction of S phase in confluent cells. The activation of cells expressing high levels of the kinase leads to a strong persistent signal and inhibits DNA synthesis and mitosis in proliferating cells. The inhibition of DNA synthesis and cell division is presumably due to the elevated expression of the cyclin-dependent kinase inhibitor p21cip1, similar to cells exposed to ionizing radiation. Despite the inhibition of DNA synthesis and mitosis, the constitutive activity of the Raf signaling pathway is still able to initiate cell growth. Activation of the high-intensity Raf signal in arrested serum-starved cells induces cell growth up to a size corresponding to that of M-phase cells in the absence of DNA synthesis. High-intensity Raf signals in proliferating cells consistently lead to an accumulation of cells with the size of M-phase cells and the DNA content of G1 cells or G2-M-phase cells. Therefore, the activation of Raf kinase is sufficient to drive cell growth, even in the presence of high levels of the cyclin-dependent kinase inhibitor p21cip1.


[Pruritus in children].
Itching is usually manifested by scratching. It is lacking before three months of age. The practitioner must determine whether itching is generalised or localised and whether a skin disease is present. The main skin diseases responsible for generalised itching are scabies, atopic dermatitis, urticaria and papular urticaria. When itching is localised, contact dermatitis or pediculosis are usually responsible. Diagnosis rests on careful analysis of symptoms. In patients without skin lesions, an external cause (irritation, environment) or an internal cause (cholestasis, chronic uraemia, lymphoma, drug and psychological problems) should be considered. Therapy should be causal when possible. If not, antihistaminic drugs should be used.


A pilot randomized, controlled trial of the effect of iron depletion on long-term response to alpha-interferon in patients with chronic hepatitis C.
Some studies have suggested that hepatic iron may influence the response to interferon therapy in chronic hepatitis C patients. We conducted this randomized, controlled trial to evaluate the effect of iron depletion on: (1) aminotransferase activity and hepatitis C RNA levels; and (2) response to interferon therapy in 38 patients with elevated alanine aminotransferase levels and who were HCV RNA positive. Seventeen patients underwent a 500-ml phlebotomy every 2 weeks until iron deficiency was achieved. Patients were then started on a 6-month course of alpha-interferon 2b (3 mu tiw). Controls were 21 patients who were monitored for a 6- to 8-week period without phlebotomy prior to interferon therapy. Response to interferon was defined as loss of serum HCV RNA by reverse transcriptase-polymerase chain reaction. Serum HCV RNA was quantitated by bDNA technique. Alanine aminotransferase levels decreased in 15/17 patients after phlebotomy. Mean alanine aminotransferase fell from 156.8 to 89.7 U/l (p=0.008). Changes in iron indices and alanine aminotransferase after phlebotomy were not accompanied by changes in HCV RNA levels. In control patients, neither alanine aminotransferase nor HCV RNA levels changed during the observation period. At the end of 24 weeks of interferon therapy, 7/17 phlebotomized patients had a response, compared to 6/21 control patients (p=ns). After 6 months of follow-up, 5/17 phlebotomized patients remained HCV RNA negative, in contrast to only 1/21 controls (p=0.07). Iron depletion led to a reduction in aminotransferase levels; this was not accompanied by changes in levels of hepatitis C RNA. There may be an improvement in the sustained response to interferon therapy, but this requires confirmation.


Geographic variation in alkaloid production in Conium maculatum populations experiencing differential herbivory by Agonopterix alstroemeriana.
Conium maculatum, a Eurasian weed naturalized in North America, contains high concentrations of piperidine alkaloids that act as chemical defenses against herbivores. C. maculatum was largely free from herbivory in the United States, until approximately 30 yr ago, when it was reassociated via accidental introduction with a monophagous European herbivore, the oecophorid caterpillar Agonopterix alstroemeriana. At present, A. alstroemeriana is found in a continuum of reassociation time and intensities with C. maculatum across the continent; in the Pacific Northwest, A. alstroemeriana can cause severe damage, resulting in some cases in complete defoliation. Studies in biological control and invasion biology have yet to determine whether plants reassociated with a significant herbivore from the area of indigeneity increase their chemical defense investment in areas of introduction. In this study, we compared three locations in the United States (New York, Washington, and Illinois) where C. maculatum experiences different levels of herbivory by A. alstroemeriana to determine the association between the intensity of the interaction, as measured by damage, and chemical defense production. Total alkaloid production in C. maculatum was positively correlated with A. alstroemeriana herbivory levels: plants from New York and Washington, with higher herbivory levels, invested two and four times more N to alkaloid synthesis than did plants from Illinois. Individual plants with lower concentrations of alkaloids from a single location in Illinois experienced more damage by A. alstroemeriana, indicative of a preference on the part of the insect for plants with less chemical defense. These results suggest that A. alstroemeriana may act either as a selective agent or inducing agent for C. maculatum and increase its toxicity in its introduced range.


Joint reconstruction of multiview compressed images.
Distributed representation of correlated multiview images is an important problem that arises in vision sensor networks. This paper concentrates on the joint reconstruction problem where the distributively compressed images are decoded together in order to take benefit from the image correlation. We consider a scenario where the images captured at different viewpoints are encoded independently using common coding solutions (e.g., JPEG) with a balanced rate distribution among different cameras. A central decoder first estimates the inter-view image correlation from the independently compressed data. The joint reconstruction is then cast as a constrained convex optimization problem that reconstructs total-variation (TV) smooth images, which comply with the estimated correlation model. At the same time, we add constraints that force the reconstructed images to be as close as possible to their compressed versions. We show through experiments that the proposed joint reconstruction scheme outperforms independent reconstruction in terms of image quality, for a given target bit rate. In addition, the decoding performance of our algorithm compares advantageously to state-of-the-art distributed coding schemes based on motion learning and on the DISCOVER algorithm.


Nutrition in Pediatric Inflammatory Bowel Disease: From Etiology to Treatment. A Systematic Review.
Nutrition is involved in several aspects of pediatric inflammatory bowel disease (IBD), ranging from disease etiology to induction and maintenance of disease. With regards to etiology, there are pediatric data, mainly from case-control studies, which suggest that some dietary habits (for example consumption of animal protein, fatty foods, high sugar intake) may predispose patients to IBD onset. As for disease treatment, exclusive enteral nutrition (EEN) is an extensively studied, well established, and valid approach to the remission of pediatric Crohn's disease (CD). Apart from EEN, several new nutritional approaches are emerging and have proved to be successful (specific carbohydrate diet and CD exclusion diet) but the available evidence is not strong enough to recommend this kind of intervention in clinical practice and new large experimental controlled studies are needed, especially in the pediatric population. Moreover, efforts are being made to identify foods with anti-inflammatory properties such as curcumin and long-chain polyunsaturated fatty acids n-3, which can possibly be effective in maintenance of disease. The present systematic review aims at reviewing the scientific literature on all aspects of nutrition in pediatric IBD, including the most recent advances on nutritional therapy.


Neuropective constituents from the rhizomes of Abacopteris penangiana.
Two neuropective compounds were isolated from the rhizomes of Abacopteris penangiana, one was a new flavone and the other was a flavanone. Both compounds were firstly separated from natural plant. The isolation work was guided by the antioxidant activity. Both the compounds showed a significant antioxidant activity in vitro and a protective effect on dopamine-induced neurotoxicity in PC12 cells.


Mass and surface fractal in supercritical dried silica aerogels prepared with additions of sodium dodecyl sulfate.
Silica wet gels were prepared from hydrolysis of tetraethoxysilane (TEOS) with additions of sodium dodecyl sulfate (SDS). The surfactant was removed after gelation. Wet gels exhibited mass-fractal structure with mass-fractal dimension D (typically around 2.25) in a length scale extending from a characteristic size ξ (typically about 10 nm) of the mass-fractal domains to a characteristic size a0 (typically between 0.3 and 0.4 nm) of the primary particles building up the fractal domains. ξ increased while D and a0 diminished slightly as the SDS quantity increased. Aerogels with typical specific surface of 1000 m(2)/g and density of 0.20 g/cm(3) were obtained by supercritical drying of the wet gels after washing with ethanol and n-hexane. The pore volume and the mean pore size increased with the increase of the SDS quantity. The aerogels presented most of the mass-fractal characteristics of the original wet gels at large length scales and exhibited at a higher resolution level at about 0.7 nm a crossover to a mass-surface fractal structure, with apparent mass-fractal dimension Dm ∼ 2.4 and surface-fractal dimension Ds ∼ 2.6, as inferred from small-angle X-ray scattering (SAXS) and nitrogen adsorption data.


Effects of iron limitation on adherence and cell surface carbohydrates of Corynebacterium diphtheriae strains.
Iron limitation may cause bacterial pathogens to grow more slowly; however, it may also stimulate these microorganisms to produce greater tissue damage, given that many virulence factors are controlled by the iron supply in the environment. The present study investigated the influence of low iron availability on the expression of proteins and surface sugar residues of two toxigenic strains of Corynebacterium diphtheriae subsp. mitis and evaluated their adherence to human group B erythrocytes and HEp-2 cells. A comparison was made between bacteria grown in (i) Trypticase soy broth (TSB), (ii) TSB treated with dipyridyl to deplete free iron, and (iii) TSB enriched with FeCl(3). The effects of iron concentration on adhesive properties were different for strains 241 and CDC-E8392, of the sucrose-fermenting and non-sucrose-fermenting biotypes, respectively. Iron-limited conditions enhanced interaction of strain 241 with erythrocytes and HEp-2 cells. Inhibition assays suggested the involvement of nonfimbrial protein combination 67-72p on hemagglutination of diphtheria bacilli grown under iron-limited conditions. Conversely, iron limitation inhibited adherence to glass and expression of electron-dense material on the bacterial surface. Lectin binding assays demonstrated a reduction in the number of sialic acid residues and an increase in D-mannose and D-galactose residues on the surfaces of both strains. Thus, iron exerts a regulatory role on adhesive properties of diphtheria bacilli, and low iron availability modulates the expression of C. diphtheriae surface carbohydrate moieties. The significant changes in the degree of lectin binding specific for D-mannose, D-galactose and sialic acid residues may have an effect on binding of host cells. The expression of dissimilar microbial virulence determinants may be coordinately controlled by common regulatory systems. For C. diphtheriae, the present results imply regulation of adherence and slime production as part of a global response to iron-limited environmental conditions that includes derepression of genes for the synthesis of cytotoxin and siderophores and for transport of the Fe(III)-siderophore complexes.


Molecular genetic profiling reveals novel association between FLT3 mutation and survival in glioma.
Recent molecular characterization of gliomas has uncovered somatic gene variation and DNA methylation changes that are associated with etiology, prognosis, and therapeutic response. Here we describe genomic profiling of gliomas assessed for associations between genetic mutations and patient outcomes, including overall survival (OS) and recurrence-free survival (RFS). Mutations in a 50-gene cancer panel, 1p19q co-deletion, and MGMT promoter methylation (MGMT methylation) status were obtained from tumor tissue of 293 glioma patients. Multivariable regression models for overall survival (OS) and recurrence-free survival (RFS) were constructed for MGMT methylation, 1p19q co-deletion, and gene mutations controlling for age, treatment status, and WHO grade. Mutational profiles of gliomas significantly differed based on WHO Grade, such as high prevalence of BRAF V600E, IDH1, and PTEN mutations in WHO Grade I, II/III, and IV tumors, respectively. In multivariate regression analysis, MGMT methylation and IDH1 mutations were significantly associated with improved OS (HR = 0.44, p = 0.0004 and HR = 0.21, p = 0.007, respectively), while FLT3 and TP53 mutations were significantly associated with poorer OS (HR = 19.46, p < 0.0001 and HR = 1.67, p = 0.014, respectively). MGMT methylation and IDH1 mutations were the only significant alterations associated with improved RFS in the model (HR = 0.42, p < 0.0001 and HR = 0.37, p = 0.002, respectively). These factors were then included in a combined model, which significantly exceeded the predictive value of the base model alone (age, surgery, radiation, chemo, grade) (likelihood ratio test OS p = 1.64 × 10-8 and RFS p = 3.80 × 10-7). This study highlights the genomic landscape of gliomas in a single-institution cohort and identifies a novel association between FLT3 mutation and OS in gliomas.


Trastuzumab-polyethylenimine-polyethylene glycol conjugates for targeting Her2-expressing tumors.
In this study, we describe the synthesis and characterization of a conjugate consisting of poly(ethylene glycol 2,000 Da)(10)-graft-poly(ethylene imine 25 kDa) (PEG-PEI) covalently coupled to Trastuzumab (Herceptin) via N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP) for specific gene delivery to Her2-expressing cell lines. The efficiency of DNA condensation was studied using an ethidium bromide exclusion assay and demonstrated negligible differences compared to PEG-PEI. Conjugate complex sizes were determined by dynamic light scattering to be in the range 130-180 nm. zeta potentials at different N/P ratios were close to neutral. Flow cytometry and confocal microscopy revealed efficient binding and uptake of Trastuzumab-PEI-PEG complexes using Her2-positive SK-BR-3 cells. In contrast, binding and uptake into Her2-negative OVCAR-3 cells was negligible. In good correlation with these findings, reporter gene expression using targeted complexes in SK-BR-3 cells was up to sevenfold higher than that of unmodified PEG-PEI complexes. With the use OVCAR-3 cells, no significant difference in expression efficiencies could be observed between conjugate and PEG-PEI complexes. Inhibition experiments with free Trastuzumab showed a significant decrease in reporter gene expression using SK-BR-3 cells but no decrease using OVCAR-3 cells, strongly supporting a specific Her2-receptor-mediated uptake mechanism. Our results suggest that Trastuzumab-PEI-PEG might be a promising new bioconjugate for targeted gene transfer to Her2-positive tumor cells in vivo.


Neoantigen vaccination induces clinical and immunologic responses in non-small cell lung cancer patients harboring EGFR mutations.
Neoantigen (NeoAg) peptides displayed at the tumor cell surface by human leukocyte antigen molecules show exquisite tumor specificity and can elicit T cell mediated tumor rejection. However, few NeoAgs are predicted to be shared between patients, and none to date have demonstrated therapeutic value in the context of vaccination. We report here a phase I trial of personalized NeoAg peptide vaccination (PPV) of 24 stage III/IV non-small cell lung cancer (NSCLC) patients who had previously progressed following multiple conventional therapies, including surgery, radiation, chemotherapy, and tyrosine kinase inhibitors (TKIs). Primary endpoints of the trial evaluated feasibility, tolerability, and safety of the personalized vaccination approach, and secondary trial endpoints assessed tumor-specific immune reactivity and clinical responses. Of the 16 patients with epidermal growth factor receptor (EGFR) mutations, nine continued TKI therapy concurrent with PPV and seven patients received PPV alone. Out of 29 patients enrolled in the trial, 24 were immunized with personalized NeoAg peptides. Aside from transient rash, fatigue and/or fever observed in three patients, no other treatment-related adverse events were observed. Median progression-free survival and overall survival of the 24 vaccinated patients were 6.0 and 8.9 months, respectively. Within 3-4 months following initiation of PPV, seven RECIST-based objective clinical responses including one complete response were observed. Notably, all seven clinical responders had EGFR-mutated tumors, including four patients that had continued TKI therapy concurrently with PPV. Immune monitoring showed that five of the seven responding patients demonstrated vaccine-induced T cell responses against EGFR NeoAg peptides. Furthermore, two highly shared EGFR mutations (L858R and T790M) were shown to be immunogenic in four of the responding patients, all of whom demonstrated increases in peripheral blood neoantigen-specific CD8+ T cell frequencies during the course of PPV. These results show that personalized NeoAg vaccination is feasible and safe for advanced-stage NSCLC patients. The clinical and immune responses observed following PPV suggest that EGFR mutations constitute shared, immunogenic neoantigens with promising immunotherapeutic potential for large subsets of NSCLC patients. Furthermore, PPV with concurrent EGFR inhibitor therapy was well tolerated and may have contributed to the induction of PPV-induced T cell responses.


Exploring a Low-Cost Valorization Route for Amazonian Cocoa Pod Husks through Thermochemical and Catalytic Upgrading of Pyrolysis Vapors.
Ecuador as an international leader in the production of cocoa beans produced more than 300 000 tons in 2021; hence, the management and valorization of the 2 MM tons of waste generated annually by this industry have a strategic and socioeconomic value. Consequently, appropriate technologies to avoid environmental problems and promote sustainable development and the bioeconomy, especially considering that this is a megadiverse country, are of the utmost relevance. For this reason, we explored a low-cost pyrolysis route for valorizing cocoa pod husks from Ecuador's Amazonian region, aiming at producing pyrolysis liquids (bio-oil), biochar, and gas as an alternative chemical source from cocoa residues in the absence of hydrogen. Downstream catalytic processing of hot pyrolysis vapors using Mo- and/or Ni-based catalysts and standalone γ-Al2O3 was applied for obtaining upgraded bio-oils in a laboratory-scale fixed bed reactor, at 500 °C in a N2 atmosphere. As a result, bimetallic catalysts increased the bio-oil aqueous phase yield by 6.6%, at the expense of the organic phase due to cracking reactions according to nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS) results. Overall product yield remained constant, in comparison to pyrolysis without any downstream catalytic treatment (bio-oil ∼39.0-40.0 wt % and permanent gases 24.6-26.6 wt %). Ex situ reduced and passivated MoNi/γ-Al2O3 led to the lowest organic phase and highest aqueous phase yields. The product distribution between the two liquid phases was also modified by the catalytic upgrading experiments carried out, according to heteronuclear single-quantum correlation (HSQC), total correlation spectroscopy (TOCSY), and NMR analyses. The detailed composition distribution reported here shows the chemical production potential of this residue and serves as a starting point for subsequent valorizing technologies and/or processes in the food and nonfood industry beneficiating society, environment, economy, and research.


Para- and Transcellular Transport Kinetics of Nanoparticles across Lymphatic Endothelial Cells.
Lymphatic vessels have received significant attention as drug delivery targets, as they shuttle materials from peripheral tissues to the lymph nodes, where adaptive immunity is formed. Delivery of immune modulatory materials to the lymph nodes via lymphatic vessels has been shown to enhance their efficacy and also improve the bioavailability of drugs when delivered to intestinal lymphatic vessels. In this study, we generated a three-compartment model of a lymphatic vessel with a set of kinematic differential equations to describe the transport of nanoparticles from the surrounding tissues into lymphatic vessels. We used previously published data and collected additional experimental parameters, including the transport efficiency of nanoparticles over time, and also examined how nanoparticle formulation affected the cellular transport mechanisms using small molecule inhibitors. These experimental data were incorporated into a system of kinematic differential equations, and nonlinear, least-squares curve fitting algorithms were employed to extrapolate transport coefficients within our model. The subsequent computational framework produced some of the first parameters to describe transport kinetics across lymphatic endothelial cells and allowed for the quantitative analysis of the driving mechanisms of transport into lymphatic vessels. Our model indicates that transcellular mechanisms, such as micro- and macropinocytosis, drive transport into lymphatics. This information is crucial to further design strategies that will modulate lymphatic transport for drug delivery, particularly in diseases like lymphedema, where normal lymphatic functions are impaired.


Paule-Mandel estimators for network meta-analysis with random inconsistency effects.
Network meta-analysis is used to simultaneously compare multiple treatments in a single analysis. However, network meta-analyses may exhibit inconsistency, where direct and different forms of indirect evidence are not in agreement with each other, even after allowing for between-study heterogeneity. Models for network meta-analysis with random inconsistency effects have the dual aim of allowing for inconsistencies and estimating average treatment effects across the whole network. To date, two classical estimation methods for fitting this type of model have been developed: a method of moments that extends DerSimonian and Laird's univariate method and maximum likelihood estimation. However, the Paule and Mandel estimator is another recommended classical estimation method for univariate meta-analysis. In this paper, we extend the Paule and Mandel method so that it can be used to fit models for network meta-analysis with random inconsistency effects. We apply all three estimation methods to a variety of examples that have been used previously and we also examine a challenging new dataset that is highly heterogenous. We perform a simulation study based on this new example. We find that the proposed Paule and Mandel method performs satisfactorily and generally better than the previously proposed method of moments because it provides more accurate inferences. Furthermore, the Paule and Mandel method possesses some advantages over likelihood-based methods because it is both semiparametric and requires no convergence diagnostics. Although restricted maximum likelihood estimation remains the gold standard, the proposed methodology is a fully viable alternative to this and other estimation methods.


Liver disease in women. Alcohol, autoimmunity, and gallstones.
Some liver diseases, such as autoimmune liver disease, affect women far more often than men. Others, such as alcohol-related disease, progress more rapidly in women than in men. An increased index of suspicion will lead to improved diagnosis and earlier treatment of women with liver disease.


In vitro/in vivo correlations between transdermal delivery of 5-aminolaevulinic acid and cutaneous protoporphyrin IX accumulation and effect of formulation.
Photodynamic therapy (PDT) using topical application of 5-aminolaevulinic acid (ALA) has been widely reported for the treatment of a variety of neoplastic and non-neoplastic cutaneous diseases. Although different formulations containing variable amounts of ALA have been applied in PDT, the dose-response relationships between transdermal ALA delivery and cutaneous protoporphyrin IX (PpIX) accumulation have not been studied. The objectives of this study were to investigate the effect of permeability barrier function, ALA concentration and formulation on the in vitro penetration of ALA through nude mouse skin and cutaneous PpIX formation at 2 h following a 2-h application of ALA to nude mouse skin in vivo, and to delineate the relationships in between. Results demonstrated that variations in barrier integrity, in addition to ALA concentration, profoundly influenced ALA delivery to generate PpIX. Saturable correlations were found to exist between PpIX concentrations in both the epidermis and dermis in vivo and its transdermal flux in vitro, and the relationships were well described by the Emax model. The established correlations based on pure aqueous solutions were applicable to different formulations containing hydroxypropylmethylcellulose as the gelling agent and ethylenediamine tetraacetic acid as the iron chelator. Moreover, incorporation of desferrioxamine, another iron chelator, in the formulation prolonged cutaneous PpIX accumulation in the skin in comparison with 3% ALA aqueous solution, but the peak PpIX levels were not increased. Application of a liposomal formulation resulted in similar prolongation in ALA-induced PpIX accumulation, as well as better epidermal targeting. Knowledge of the dose-response relationships and the effect of formulation is important for designing optimal formulations and treatment schedules for topical ALA-PDT.


Calcium oxalate crystals in breast biopsies. The missing microcalcifications.
Most calcifications detected by mammography and specimen radiography are readily identified by histologic sections stained with hematoxylin and eosin (H&E) or the von Kossa stain. However, calcifications composed of calcium oxalate crystals are not always seen in sections stained with H&E or with von Kossa. To study the incidence of calcium oxalate crystals in breast biopsies, we used polarized light microscopy to review 153 needle-localization breast biopsies. Birefringent crystals were observed in 19 cases (17 benign and 2 malignant), but typical calcium phosphate microcalcifications were revealed by H&E in only 16 of these 19 cases. Multiple H&E sections through the blocks of the remaining three cases did not reveal typical microcalcifications. These crystals did stain with silver nitrate/rubeanic acid with 5% acetic acid pretreatment but failed to stain with von Kossa and alizarin red at pH 4.2. This suggested that they were composed of calcium oxalate. Analytical electron microscopy performed in one of the three cases without typical microcalcifications demonstrated only a calcium peak of energy-dispersive x-ray analysis and an electron-diffraction pattern compatible with calcium oxalate monohydrate. We conclude that discrepancies between the amount of microcalcifications seen on the mammogram or on the x-ray film of the specimen or the paraffin blocks and the amount of microcalcifications seen on the H&E slides may be explained by the presence of calcium oxalate crystals. These crystals are detected with specimen radiography but are not easily seen on H&E slides unless polarized light microscopy is used. Polarized light microscopy and silver nitrate/rubeanic acid with 5% acetic acid pretreatment should be used for breast biopsy specimens when typical microcalcifications are not seen on H&E-stained sections.


MAS1, a gene essential for yeast mitochondrial assembly, encodes a subunit of the mitochondrial processing protease.
We have previously described a yeast mutant (mas1) that accumulates mitochondrial precursor proteins at high temperature and is deficient in the activity of a matrix-localized protease which cleaves presequences from mitochondrial precursor proteins. We have now cloned and sequenced the wild-type MAS1 gene and found that it encodes a subunit of the mitochondrial processing protease, that it is essential for cell viability and that the protein product participates in its own cleavage during import into mitochondria. The MAS1 protein is thus the first genetically defined component of the mitochondrial protein import pathway.


Toxicity of methylglyoxal towards rat enterocytes and colonocytes.
Effect of methylglyoxal, a bacterial metabolic product, on protein, DNA, and RNA synthesis in rat enterocytes and colonocytes was investigated. Results showed that 1 mM methylglyoxal inhibited protein, DNA, and RNA synthesis to the extent of 65-85, 65-80, and 10-20 per cent, respectively, in villus and crypt cells and colonocytes. The inhibitory pattern was similar in these various cell types. The inhibitory effect on protein and DNA synthesis was more marked than that on RNA synthesis. Inclusion of thiol compounds up to 4 mM concentration did not protect the cells from the inhibitory effect of methylglyoxal. No alteration in the level of cellular reduced glutathione and glyoxalase enzyme activity was observed when cells were incubated with 2 mM methylglyoxal. These results suggest that the antiproliferative action of methylglyoxal on eukaryotic cells may be through the inhibition of macromolecular synthesis.


A case of multiple pial arteriovenous fistulas associated with dural arteriovenous fistula.
Pial arteriovenous fistulas (AVFs) are known as rare cerebrovascular lesions. They are composed of >/= 1 arterial feeding vessels and a single draining vein that usually has high perfusion pressure and generally occur in infants. Cases involving adults are very rare and the developmental mechanisms and natural history of these lesions remain unknown. The authors present a case of multiple pial AVFs in an adult in whom the lesions developed after radiosurgical treatment of dural AVFs. Direct disconnection of pial arterial supplies was performed, and the abnormal shunts were successfully eliminated. The authors report the clinical course of this case and discuss the characteristics of and treatment strategy for multiple pial AVFs, reviewing the published literature.


Autoantibodies to keratin in Sjögren's syndrome.
In order to determine which components of the salivary duct cells are recognized by the antisalivary duct antibodies, sera of patients with Sjögren's syndrome were screened for immunoreactivity to keratin by using an ELISA test and a Western blot analysis. The autoantibodies which reacted with keratin were demonstrated in 8 of 9 definite cases of Sjögren's syndrome and in 3 of 6 probable cases, and they reacted with different keratin peptides in each case. The results suggest that the antisalivary duct antibodies include antibodies against keratin, which exists ubiquitously as a cytoskeleton in the salivary gland epithelial cells. Detection of antikeratin antibody might be a useful aid for diagnosis of Sjögren's syndrome.


Effects of MDM4 Gene Regulation by miR-34a on LOVO Cell Proliferation.
This study aims to investigate the effects of regulation of murine double minute protein4 (MDM4) expression by microRNA (miR)-34a on the proliferation of colorectal cancer LOVO cells. Prediction results obtained using a gene microarray showed that MDM4 is a specific miR-34a target gene. The interaction between miR-34a and the 3'-untranslated region (UTR) of MDM4 was detected using a luciferase reporter system. The effect of miR-34a on MDM4 protein expression was detected by Western blotting, and the effect of miR-34a transfection on LOVO cell proliferation was detected using an MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay and flow cytometry. The luciferase activity in LOVO cells after addition of pmirGLO-UTR+miR-34a mimic was only 44% of that obtained with pmirGLO-UTR+miR-34a (p<0.01), and the luciferase activity in LOVO cells after addition of pmir-GLO-mutUTR+miR-34a was 94% of that observed after pmirGLO-UTR+miR-34a addition (p=0.57). These results indicated that miR-34a interacted with the 3'-UTR of MDM4. Results of Western blotting revealed that MDM4 protein expression level in LOVO cells after addition of miR-34a mimic was 29% that of non-treated LOVO cells (p<0.05), indicating that miR-34a negatively regulates MDM4 protein expression. The growth rate of LOVO cells with miR-34a overexpression was significantly reduced compared with that of non-treated LOVO cells (p<0.05), indicating that miR-34a overexpression inhibits LOVO cell proliferation. miR-34a negatively regulates MDM4 gene expression to inhibit LOVO cell proliferation.


It Takes a Village: The Multifaceted Immune Response to Mycobacterium tuberculosis Infection and Vaccine-Induced Immunity.
Despite co-evolving with humans for centuries and being intensely studied for decades, the immune correlates of protection against Mycobacterium tuberculosis (Mtb) have yet to be fully defined. This lapse in understanding is a major lag in the pipeline for evaluating and advancing efficacious vaccine candidates. While CD4+ T helper 1 (TH1) pro-inflammatory responses have a significant role in controlling Mtb infection, the historically narrow focus on this cell population may have eclipsed the characterization of other requisite arms of the immune system. Over the last decade, the tuberculosis (TB) research community has intentionally and intensely increased the breadth of investigation of other immune players. Here, we review mechanistic preclinical studies as well as clinical anecdotes that suggest the degree to which different cell types, such as NK cells, CD8+ T cells, γ δ T cells, and B cells, influence infection or disease prevention. Additionally, we categorically outline the observed role each major cell type plays in vaccine-induced immunity, including Mycobacterium bovis bacillus Calmette-Guérin (BCG). Novel vaccine candidates advancing through either the preclinical or clinical pipeline leverage different platforms (e.g., protein + adjuvant, vector-based, nucleic acid-based) to purposefully elicit complex immune responses, and we review those design rationales and results to date. The better we as a community understand the essential composition, magnitude, timing, and trafficking of immune responses against Mtb, the closer we are to reducing the severe disease burden and toll on human health inflicted by TB globally.


Effect of recombinant IL-1 isomers on fetal and adult islet cell function and replication.
Natural human interleukin and the recombinant human IL-1 alpha and beta isomers were tested for effects on both fetal and adult rat isolated pancreatic islets. IL-1 alpha inhibited both replication and insulin secretion and decreased the insulin content of both islets. In contrast, the beta isomer did not affect fetal islets. It is concluded that the two isomers may have different avidities for the same receptors, or that receptors are expressed at different stages of differentiation.


Ultrasonographic measurement of caudal vena cava to aorta ratio during fluid resuscitation of dogs with spontaneous circulatory shock.
To describe the change in the caudal vena cava to aorta ratio (CVC:Ao) ratio during fluid resuscitation of circulatory shock in dogs and compare these results with those of the physical examination and blood lactate. Perfusion parameters and blood lactate were recorded at admission. An abdominal point-of-care ultrasound protocol was performed, during which the caudal vena cava to aorta ratio was measured on the spleno-renal view. Measurements were performed within 5 minutes before and after a 10 mL/kg crystalloid fluid bolus. Investigators were not blinded to therapeutic interventions. Twenty-nine dogs with physical signs of circulatory shock were enrolled. Caudal vena cava to aorta ratios were below reference interval in 28 of 29 dogs. After bolus administration, median caudal vena cava diameter increased by 0.14 cm (0.69 to 0.83 cm) and median aorta diameter increased by 0.03 cm (0.87 to 0.90 cm) and caudal vena cava to aorta ratio returned to within reference range in 65% of dogs (13/29). Bolus administration was associated with an increase in median caudal vena cava to aorta ratio of 0.10 (95% CI:0.05 to 0.16, P=0.0005). Blood lactate did not change significantly. Heart rate and capillary refill time decreased significantly after fluid bolus (heart rate: estimate=-19 bpm, 95% CI:-30 to -8, P=0.002; capillary refill time: estimate=-1.0 s, 95% CI:-1.3 to -0.7, P < 0.0001). In this population of dogs with circulatory shock, the caudal vena cava to aorta ratio significantly increased after a fluid bolus. Future studies that implement blinding of the outcome assessors are warranted to confirm these findings.


Recombinant Invasive Lactococcus lactis Carrying a DNA Vaccine Coding the Ag85A Antigen Increases INF-γ, IL-6, and TNF-α Cytokines after Intranasal Immunization.
Tuberculosis (TB) remains a major threat throughout the world and in 2015 it caused the death of 1.4 million people. The Bacillus Calmette-Guérin is the only existing vaccine against this ancient disease; however, it does not provide complete protection in adults. New vaccines against TB are eminently a global priority. The use of bacteria as vehicles for delivery of vaccine plasmids is a promising vaccination strategy. In this study, we evaluated the use of, an engineered invasive Lactococcus lactis (expressing Fibronectin-Binding Protein A from Staphylococcus aureus) for the delivery of DNA plasmid to host cells, especially to the mucosal site as a new DNA vaccine against tuberculosis. One of the major antigens documented that offers protective responses against Mycobacterium tuberculosis is the Ag85A. L. lactis FnBPA+ (pValac:Ag85A) which was obtained and used for intranasal immunization of C57BL/6 mice and the immune response profile was evaluated. In this study we observed that this strain was able to produce significant increases in the amount of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6) in the stimulated spleen cell supernatants, showing a systemic T helper 1 (Th1) cell response. Antibody production (IgG and sIgA anti-Ag85A) was also significantly increased in bronchoalveolar lavage, as well as in the serum of mice. In summary, these findings open new perspectives in the area of mucosal DNA vaccine, against specific pathogens using a Lactic Acid Bacteria such as L. lactis.


Protein kinase C activation stimulates calcium transport in adrenal zona glomerulosa cells.
Adrenal zona glomerulosa (ZG) cells produce aldosterone in response to angiotensin II and extracellular potassium through different mechanisms which involve changes in cytosolic free calcium (Cai). Protein kinase C (PKC) activation is part of the angiotensin II signalling cascade but its effects on Cai are unknown. PKC activation with 1 microM phorbol 12-myristate 13-acetate (PMA) and 8 mM Ko significantly increased the rate of calcium influx (P < 0.001). Both the PKC- and the Ko-induced calcium influx occurred via a nifedipine-sensitive pathway. When both were combined, PKC activation and 8 mM Ko were not additive over either agent alone. PKC activation and 8 mM Ko also stimulated calcium efflux (P < 0.01). When combined together PKC activation and 8 mM Ko had additive effects on calcium efflux (P < 0.05). PKC activation did not increase Cai nor the exchangeable calcium pool in contrast to 8 mM Ko which significantly increased both (P < 0.001). Thus, PKC activation in ZG cells induces a pattern of calcium transport characterized by accelerated calcium recycling across the cell membrane without increasing cell calcium content.


The Arabidopsis TETRATRICOPEPTIDE-REPEAT THIOREDOXIN-LIKE (TTL) family members are involved in root system formation via their interaction with cytoskeleton and cell wall remodeling.
Lateral roots (LR) are essential components of the plant edaphic interface; contributing to water and nutrient uptake, biotic and abiotic interactions, stress survival, and plant anchorage. We have identified the TETRATRICOPEPTIDE-REPEAT THIOREDOXIN-LIKE 3 (TTL3) gene as being related to LR emergence and later development. Loss of function of TTL3 leads to a reduced number of emerged LR due to delayed development of lateral root primordia (LRP). This trait is further enhanced in the triple mutant ttl1ttl3ttl4. TTL3 interacts with microtubules and endomembranes, and is known to participate in the brassinosteroid (BR) signaling pathway. Both ttl3 and ttl1ttl3ttl4 mutants are less sensitive to BR treatment in terms of LR formation and primary root growth. The ability of TTL3 to modulate biophysical properties of the cell wall was established under restrictive conditions of hyperosmotic stress and loss of root growth recovery, which was enhanced in ttl1ttl3ttl4. Timing and spatial distribution of TTL3 expression is consistent with its role in development of LRP before their emergence and subsequent growth of LR. TTL3 emerged as a component of the root system morphogenesis regulatory network.


[Patient careers. Facial pain and neuralgias].
The correct diagnosis in patients with facial pain is essential to avoid erroneous diagnostic and therapeutic measures. Trigeminal neuralgia is easily recognized by the typical history given by the patient. Treatment of first choice is carbamazepine. When pharmacological treatment fails, surgical options are available. Tolosa Hunt syndrome is judged to be caused by a granulomatous infiltration in the cavernous sinus, treatment consists in corticosteroids. Painful craniomandibular disorders are often mistaken for 'atypical facial pain'. Atypical facial pain, now called 'persistent idiopathic facial pain' should only be diagnosed after thorough exclusion of all known primary and symptomatic facial pain syndromes. Treatment consists mainly in patient education, in the avoidance of further surgical interventions, and in pharmacotherapy with tricyclic antidepressants. A thorough history and examination are crucial to correctly classify these facial pain syndromes.


[Giant bizarre scrotal leiomyoma].
To review the diagnosis and therapeutic management of scrotal wall smooth muscle tumors by reporting an illustrative case. To emphasize that despite their histological characteristics on presentation, compatible with malignancy, these tumors have a benign behaviour, even when their size is much bigger than the ones found in the review bibliography. 75-year-old male who presented a big, very slowly growing, painless, mobile, hard, not adhered to deep layers, non transilluminating scrotal tumor. Pathology reported a giant bizarre scrotal leiomyoma. We emphasize the atypical characteristics of this case, which despite its compliance with almost all classical criteria establishing the malignant character of tumor lesions has a benign behaviour. It complies with the criterion that, accordingly to reviewed bibliography, seems to be the most important to determine it: the absence of mitosis. We also insist on the importance of an adequate diagnostic approach which guarantees a proper surgical approach, for which we think ultrasound is essential.


Synthesis and structure of heterodinuclear rhodium and iridium borylene complexes.
Herein we report on the synthesis and structural characterization of a representative range of novel heterodinuclear bridging rhodium and iridium borylene complexes. The iridium borylene complexes feature an unusual coordination mode of the borylene ligand. Furthermore, the first instance of a heterodinuclear-bridged borylene compound containing a chromium atom in the three-membered ring is reported.


Sepsis Screening: Combining Early Warning Scores and SIRS Criteria.
Providing effective screening tools to nurses is necessary to improve patient outcomes and health care quality. This research examines if the modification of two electronic health record sepsis screening tools using a combined systemic inflammatory response syndrome (SIRS), modified early warning score (MEWS), and national early warning score (NEWS) criteria improves the recognition of sepsis by nurses. Medical-surgical/telemetry units at a medical center in the Midwest were examined using a quasiexperimental design. Modifications of tool 1 captured 18% more correct classifications of sepsis (odds ratio [OR] = .82, 95% CI = [0.68, 0.98]), triggering for 10% fewer patients, t(1033) = 9.31, p < .001. 95% CI = [0.078, 0.119]. Modifications of tool 2 captured 3 times more correct alerts (OR = .29, 95% CI = [0.24, 0.35]), triggering for 46% fewer patients, t(1033) = 24.38, p < .001. 95% CI = [0.420, 0.493]. The updated criteria showed significant improvement toward correctly identifying sepsis and presents the opportunity to develop an effective tool that balances sensitivity with specificity.


Inhaler Steroid Use Changes Oral and Airway Bacterial and Fungal Microbiome Profile in Asthma Patients.
The full spectrum of bacterial and fungal species in adult asthma and the effect of inhaled corticosteroid use is not well described. The aim was to collect mouthwash and induced sputum samples from newly diagnosed asthma patients in the pretreatment period and in chronic asthma patients while undergoing regular maintenance inhaled corticosteroid therapy, in order to demonstrate the bacterial and fungal microbiome profile. The study included 28 asthmatic patients on inhaler steroid therapy, 25 steroid-naive asthmatics, and 24 healthy controls. Genomic DNA was isolated from induced sputum and mouthwash samples. Analyses were performed using bacterial primers selected from the 16S rRNA region for the bacterial genome and "panfungal" primers selected from the 5.8S rRNA region for the fungal genome. Dominant genera in mouthwash samples of steroid-naive asthmatics were Neisseria, Haemophilus, and Rothia. The oral microbiota of asthmatic patients on inhaler steroid treatment included Neisseria, Rothia, and Veillonella species. Abundant genera in induced sputum samples of steroid-naive asthma patients were Actinomyces, Granulicatella, Fusobacterium, Peptostreptococcus, and Atopobium. Sputum microbiota of asthma patients taking inhaler steroids were dominated by Prevotella and Porphyromonas. Mucor plumbeus and Malassezia restricta species were abundant in the airways of steroid-naive asthma patients. Choanephora infundibulifera and Malassezia restricta became dominant in asthma patients taking inhaled steroids. The oral and airway microbiota consist of different bacterial and fungal communities in healthy and asthmatic patients. Inhaler steroid use may influence the composition of the oral and airway microbiota.


Risk factors for coronary heart disease. Selected recent epidemiological advances.
Several recent advances in our understanding of the epidemiology and prevention of coronary artery disease are presented, highlighting the current status of the 3 major risk factors: blood cholesterol, blood pressure and cigarette smoking. There is a striking analogy between serum cholesterol and diastolic blood pressure in the pattern of the association with coronary heart disease (CHD). Mortality follow-up of the 361,662 middle-aged men screened for the Multiple Risk Factor Intervention Trial (MRFIT) shows that each of these risk factors identifies a large group of patients (the top 15% of the population distribution) who have a 4-fold higher risk of CHD death than those in the bottom 15%, and that each has a continuously rising gradient of risk for people with intermediary levels. The implication from these findings, and from the clinical trial data, is that public health and clinical policies directed at blood cholesterol should be made similar to those that have become widespread for blood pressure in the past 2 decades; i.e. measuring the level periodically in all adults and intervening to prevent CHD in those at highest risk. The public health campaign to reduce cigarette smoking has been bolstered by new evidence on the hazards of ambient smoke. One example comes from the clinical trial cohort of the MRFIT, in which non-smoking men who were married to smoking wives had nearly twice the all-cause mortality rate of non-smoking men who were married to non-smoking wives.(ABSTRACT TRUNCATED AT 250 WORDS)


Analysis of partial 16S rRNA nucleotide sequences of Chlamydia pecorum and C. psittaci.
Partial 16S nucleotide sequences of Chlamydia psittaci isolates S26/3 (abortion), P94/1 (pigeon) and Chlamydia pecorum isolates W73 (enteric) and E58 (encephalomyelitis) were determined. Analysis of these data indicates very high levels of interspecies sequence conservation, with C. psittaci being more closely related to C. pecorum than to C. pneumoniae or C. trachomatis. Restriction enzyme analysis of nucleotide sequences indicated that BslI can be used to clearly distinguish C. psittaci and C. pecorum isolates. Psittacine and non-psittacine (pigeon) avian isolates of C. psittaci were distinguished using MaeI.


Governmental Non-Pharmaceutical Interventions during the COVID-19 Pandemic and the COPD Exacerbation and Respiratory Infection Rate in Patients with Alpha-1 Antitrypsin Deficiency.
During the COVID-19 pandemic the number of hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations was significantly reduced. The reason for this decline is not fully understood. Governmental non-pharmaceutical interventions (NPI's), an increase in community treated exacerbations, or healthcare avoidance by patients, are potential reasons. For the current study, the impact of Dutch governmental NPI's on the COPD exacerbations and respiratory infections rate in patients with severe alpha-1 antitrypsin deficiency (AATD) was analyzed. The patients participated in the NCT04204252 study, a randomized controlled trial evaluating the efficacy and safety of inhaled alpha-1 antitrypsin. Data collected in the time-period from March 2020 until February 2022 was analyzed. In this period the Dutch government imposed variable NPI's to contain the spread of SARS-CoV-2. Patients were required to document their daily symptoms in an electronic diary. The strictness of the governmental NPI's was measured by the COVID-19 Stringency Index. 19 patients participated in this study during the analysis period. A total of 40 respiratory infections and COPD exacerbations occurred. The Spearman's correlation coefficient of the monthly average COVID-19 Stringency Index and respiratory infections and COPD exacerbations rate was -0.316 (p = 0.132). When months known for a low respiratory infection rate were excluded, the correlation coefficient was -0.625 (p = 0.010). This study showed a significant negative correlation between the COPD exacerbations and respiratory infection rate and the COVID-19 Stringency Index in patients with AATD related COPD in the autumn-winter months.


Linkage of the pig main histocompatibility complex and the J blood group system.
Linkage of the main histocompatibility complex (MHC) and the J blood locus was demonstrated in pgis by means of segregation data in families of double back-cross matings. A recombination frequency of 9.82% was estimated. No evidence of close association with the blood group systems A, B, D, E, F, G, H, I, K, L, M, N and O was found.


Metastasis of unknown origin.
Metastasis of unknown origin (MUO) constitutes between 5% and 10% of all noncutaneous cancers. An MUO is defined as a metastatic tumor for which the site of origin is not suggested by thorough history, physical examination, chest x-ray studies, routine blood and urine studies, and histologic evaluation. Two major groups of MUO can be defined: MUO to lymph nodes only (N1-3), and MUO to visceral sites. The prognosis may be quite good for patients with MUO limited to lymph nodes in the mid to high cervical, axillary, and groin areas. However, MUO in other lymph node areas is far more serious, with the possible exception of that in patients with a new syndrome, i.e., "advanced poorly differentiated carcinoma of unknown primary origin." There is some suggestion that these patients may respond to cisplatin-based combination chemotherapy. Patients with MUO to visceral sites have a poor prognosis. However, metastases from some primary tumors are sensitive to chemotherapy and a limited search for these tumors should be undertaken. These tumors include leukemia-lymphoma, germ cell tumors, small cell carcinoma of the lung, adenocarcinomas of the breast, ovary, endometrium, thyroid, or prostate, and possibly adrenal carcinoma. We start by reviewing the biochemical events of metastasis that may be targets for therapy. The importance of a correct tissue diagnosis is then considered, including the role of standard histochemistry, electron microscopy, enzyme histochemistry, and immunohistochemistry. The relatively limited value of radiologic tests in localizing the primary site of origin of the tumor is emphasized, as well as the limited role of currently available biomarkers. We conclude by discussing the treatment of each of the subtypes of MUO.


[Noise-induced hypoacusia in maintenance workers of high voltage electric lines].
Noise-induced hypoacusia continues to represent an important issue in Occupational Medicine in relation to epidemiology, diagnostics, medicolegal issues and occupation related compensation claims. We present the clinical and audiometric findings of 45 maintenance workers of high tension electric lines, undergoing medical surveillance. Noise-induced hearing loss was diagnosed in 49% of cases ("pure" in 27% and mixed--with the concurrence of other causes--in 22% of cases). These unexpected data indicate that electric lines maintenance should be considered a high risk occupation for noise-induced damage, and confirm the need of enforcing current protective laws.


In vivo evidence for unidentified leptin-induced circulating factors that control white fat mass.
Fat transplants increase body fat mass without changing the energy status of an animal and provide a tool for investigating control of total body fat. Early transplant studies found that small pieces of transplanted fat took on the morphology of the transplant recipient. Experiments described here tested whether this response was dependent upon expression of leptin receptors in either transplanted fat or the recipient mouse. Fat from leptin receptor deficient db/db mice or wild-type mice was placed subcutaneously in db/db mice. After 12 wk, cell size distribution in the transplant was the same as in endogenous fat of the recipient. Thus, wild-type fat cells, which express leptin receptors, were enlarged in a hyperleptinemic environment, indicating that leptin does not directly control adipocyte size. By contrast, db/db or wild-type fat transplanted into wild-type mice decreased in size, suggesting that a functional leptin system in the recipient is required for body fat mass to be controlled. In the final experiment, wild-type fat was transplanted into a db/db mouse parabiosed to either another db/db mouse to an ob/ob mouse or in control pairs in which both parabionts were ob/ob mice. Transplants increased in size in db/db-db/db pairs, decreased in db/db-ob/ob pairs and did not change in ob/ob-ob/ob pairs. We propose that leptin from db/db parabionts activated leptin receptors in their ob/ob partners. This, in turn, stimulated release of unidentified circulating factors, which travelled back to the db/db partner and acted on the transplant to reduce fat cell size.


The neurobiology of glia in the context of water and ion homeostasis.
Astrocytes are highly complex cells that respond to a variety of external stimulations. One of the chief functions of astrocytes is to optimize the interstitial space for synaptic transmission by tight control of water and ionic homeostasis. Several lines of work have, over the past decade, expanded the role of astrocytes and it is now clear that astrocytes are active participants in the tri-partite synapse and modulate synaptic activity in hippocampus, cortex, and hypothalamus. Thus, the emerging concept of astrocytes includes both supportive functions as well as active modulation of neuronal output. Glutamate plays a central role in astrocytic-neuronal interactions. This excitatory amino acid is cleared from the neuronal synapses by astrocytes via glutamate transporters, and is converted into glutamine, which is released and in turn taken up by neurons. Furthermore, metabotropic glutamate receptor activation on astrocytes triggers via increases in cytosolic Ca(2+) a variety of responses. For example, calcium-dependent glutamate release from the astrocytes modulates the activity of both excitatory and inhibitory synapses. In vivo studies have identified the astrocytic end-foot processes enveloping the vessel walls as the center for astrocytic Ca(2+) signaling and it is possible that Ca(2+) signaling events in the cellular component of the blood-brain barrier are instrumental in modulation of local blood flow as well as substrate transport. The hormonal regulation of water and ionic homeostasis is achieved by the opposing effects of vasopressin and atrial natriuretic peptide on astroglial water and chloride uptake. In conjuncture, the brain appears to have a distinct astrocytic perivascular system, involving several potassium channels as well as aquaporin 4, a membrane water channel, which has been localized to astrocytic endfeet and mediate water fluxes within the brain. The multitask functions of astrocytes are essential for higher brain function. One of the major challenges for future studies is to link receptor-mediated signaling events in astrocytes to their roles in metabolism, ion, and water homeostasis.


Endoscopic Glucocorticoid Injection for the Treatment of a Refractory Benign Esophageal Stenosis in a Patient With Plummer-Vinson Syndrome.
Plummer-Vinson syndrome (PVS) or Paterson-Brown-Kelly syndrome is a rare clinical condition characterized by the triad of esophageal webs/stenoses, iron-deficiency anemia, and progressively worsening dysphagia. It occurs mostly in Caucasian women in the fourth to seventh decades, particularly in northern countries. Esophageal webs and stenoses can be encountered during endoscopic evaluation for the patient's complaint of dysphagia. Esophageal stenoses are characterized as simple or complex. A stenosis should be considered refractory once the patient has undergone several sequential dilatations within short intervals, optimized treatment for potential underlying causes (eosinophilic esophagitis or acid reflux), and after neuromuscular causes have been excluded. Glucocorticoid injection into a stenosis during an endoscopic dilation session has been proven to be beneficial as the initial treatment modality of refractory nonmalignant esophageal stenoses. We present a case of a 39-year-old woman with refractory esophageal stenosis in the setting of PVS which was successfully treated with serial endoscopic glucocorticoid injections while she received oral iron supplementation. To our knowledge, there are no previous cases of esophageal stenoses associated with PVS in the literature requiring endoscopic glucocorticoid injection for successful resolution.


THE EVOLUTION OF COSTLY MATE PREFERENCES I. FISHER AND BIASED MUTATION.
Fisher's runaway process is the standard explanation of the evolution of exaggerated female preferences. But mathematical formulations of Fisher's process (haploid and additive diploid) show it cannot cause stable exaggeration if female preference carries a cost. At equilibrium female fitness must be maximized. Our analysis shows that evolutionary stable exaggeration of female preference can be achieved if mutation pressure on the male character is biased, that is, mutation has a directional effect. At this equilibrium female fitness is not maximized. We discuss the reasons and evidence for believing that mutation pressure is typically biased. Our analysis highlights the previously unacknowledged importance of biased mutation for sexual selection.


[Effective thrombolytic therapy for calcified cerebral embolism originating from a calcified plaque in the internal carotid artery].
A 72-year-old man was transported to our emergency department after rear-ending another vehicle. He presented with acute left hemispatial neglect, left hemianopsia, and mild left hemiparesis. Computed tomography (CT) on admission showed a calcified embolus in the right middle cerebral artery. After intravenous thrombolytic therapy, the patient showed drastic improvement of neurological deficits. Follow-up CT showed disappearance of embolus, but distal migration of emboli to the downstream of the right middle cerebral artery was seen, sparing the massive territory of the right middle cerebral artery. Carotid duplex sonography and 3-dimensional CT angiography showed a calcified plaque with ulceration at the origin of the right internal carotid artery, representing the presumptive origin of the emboli. We report a rare case of effective intravenous thrombolysis for calcified cerebral embolism from the carotid artery. Further consideration of the mechanism, efficacy, and indication of intravenous thrombolysis for calcified cerebral emboli is needed.


Effect of particle hydrophobicity on the properties of silica particle layers at the air-water interface.
This article describes a study of fumed silica particle layers adsorbed at the air-water interface. We have performed surface pressure, ellipsometry, and Brewster angle microscopy measurements. These determinations were complemented by surface viscoelasticity studies, using capillary waves to measure the compression moduli and an oscillating disc to measure the shear moduli. Our results show a strong influence of the particle hydrophobicity and surface density on the properties of the layers. Under compression-expansion, the particle layers rearrange quasi-instantaneously, and at high density, they buckle and/or collapse. Shear measurements show a transition from viscous to elastic behavior for particles with contact angles close to 90 degrees. The surface compression moduli are quite small and most likely not related to the stability of the foams made with these particles, in contrast to the case of more common surfactant foams.


New positive inotropic substances--true inotropy or peripheral effects?
A large number of chemical substances increase contractility of isolated animal myocardial preparations. Their augmentation is the result of a number of mechanisms which ultimately increase the available calcium for contractile protein coupling. Although there is some research with drugs which activate calcium channels, present clinical research is mainly confined to agents whose major action on contraction is mediated by an increase in myocyte cyclic AMP. Species and age variations in the inotropic effect are common. These agents have additional cardiac effects (e.g. chronotropic, lusitropic) and non-cardiac actions. They are potent vasodilators. In isolated human myocardium obtained from patients without heart failure, they increase contractility at high concentrations. Generally this effect is attenuated in isolated myocardium obtained from patients and animals with chronic cardiac failure. In myocardium from patients with the most severe heart failure, even very high concentrations fail to increase contractility. Part of this attenuation may be due to reduced receptor number (or sensitivity) when the drug's effect is due to receptor-coupled adenylate cyclase activation. However, a reduced ability to produce and/or respond to cyclic AMP itself is suggested by impaired responses to phosphodiesterase inhibitors. In vivo, these agents have frankly harmful effects in patients with near normal cardiac function. Despite increasing contractility indices, they lower blood pressure, raise heart rate and impair myocardial lactate metabolism without increasing cardiac output. In patients with severe heart failure they produce beneficial resting haemodynamic changes; increased cardiac output and reduced filling pressures with only small changes in blood pressure and heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)


Towards evidence-based treatment of thrombotic antiphospholipid syndrome.
Thrombosis in the presence of persistently positive tests for antiphospholipid antibodies is termed thrombotic antiphospholipid syndrome (APS). At present, 'standard' secondary thromboprophylaxis in thrombotic APS is treatment with moderate intensity oral anticoagulants for life after a first venous thrombosis and with high intensity oral anticoagulation after non-embolic ischaemic stroke. These recommendations differ from those applied in the general population, where a restricted period of anticoagulation is common practice after venous thrombosis and antiplatelet drugs are the first choice after ischaemic stroke. From an extensive literature review we conclude that the available data are insufficient to apply a different strategy for secondary thromboprophylaxis in patients with thrombotic APS than the one that holds for the general population.


Radial transport and electron-cyclotron-current drive in the TCV and DIII-D tokamaks.
Calculation of electron-cyclotron-current drive (ECCD) with the comprehensive CQL3D Fokker-Planck code for a TCV tokamak shot gives 550 kA of driven toroidal current, in marked disagreement with the 100-kA experimental value. Published ECCD efficiencies calculated with CQL3D in the much larger, higher-confinement DIII-D tokamak are in excellent agreement with experiment. The disagreement is resolved by including in the calculations electrostatic-type radial transport at levels given by global energy confinement in tokamaks. The radial transport of energy and toroidal current are in agreement.


Assessment of myocardial perfusion in the empty beating porcine heart with laser Doppler flowmetry.
Laser Doppler flowmetry was applied to the empty beating heart of six pigs. Cardiopulmonary bypass was instituted and the preparation allowed continuous and simultaneous measurement of coronary sinus blood flow and local tissue perfusion. An epicardial and an intramuscular probe were used. Significant linear correlation coefficients were obtained between changes of laser Doppler signal and coronary sinus blood flow changes in all seven experiments in four animals (r from 0.71 to 0.94, p less than 0.005) and between laser Doppler signal and changes of extracorporeal bypass in five out of six experiments in four animals (r from 0.82 to 0.99, p less than 0.001). The correlation between coronary sinus flow and bypass flow of four pigs was significant (r from 0.81 to 0.98, p less than 0.001), the coronary flow being about 10% of bypass flow. Muscular activity of the heart contributed to the laser Doppler signal, the magnitude of this "noise level" varying between different experiments even in the same animal. A key question for the applicability of laser Doppler flowmetry to the beating heart is whether it will become possible to discriminate between flow and muscular contribution to the laser Doppler output.


Designing of High-Volume PET/CT Facility with Optimal Reduction of Radiation Exposure to the Staff: Implementation and Optimization in a Tertiary Health Care Facility in India.
Positron emission tomography (PET) has been in use for a few decades but with its fusion with computed tomography (CT) in 2001, the new PET/CT integrated system has become very popular and is now a key influential modality for patient management in oncology. However, along with its growing popularity, a growing concern of radiation safety among the radiation professionals has become evident. We have judiciously developed a PET/CT facility with optimal shielding, along with an efficient workflow to perform high volume procedures and minimize the radiation exposure to the staff and the general public by reducing unnecessary patient proximity to the staff and general public.


Non-marginal jejunal ulcer perforation following Roux-en-Y gastric bypass.
We present a rare case of a jejunal ulcer perforation in the alimentary limb ~15 cm distal to the gastro-jejunal anastomosis on the background of a previous Roux-en-Y gastric bypass (RYGB) 4 months prior to presentation. Marginal ulcer is the most common cause of jejunal perforation following RYGB. However, this is usually confined to the first few centimetres, and the incidence is highest within the first month following surgery. Other risk factors include smoking and non-steroidal anti-inflammatory drug use, Helicobacter pylori infection, trauma, foreign body ingestion, Crohn's disease, typhoid, tuberculosis and malignancy. This case does not possess any of these risk factors and thus represents a unique presentation. Not all jejunal ulcers will present with classical risks factors but still will need to be excluded, given their life-threatening nature. Also, the whole alimentary limb can be susceptible to ulceration; therefore, a thorough investigation of this limb is important to exclude perforation.


Changes in blubber contaminant concentrations in California sea lions (Zalophus californianus) associated with weight loss and gain during rehabilitation.
California sea lions have high levels of persistent organic pollutants (POPs) in their blubber. Animals affected by domoic acid fast and refeed during their rehabilitation. We studied the effect of decreases in total body mass (16 +/- 7% of initial body mass) on blubber POP contaminant concentrations and estimated POP burdens during fasting (12 +/- 5 days) in 19 California sea lions. The effect of refeeding (92 +/- 8% of initial body mass) was also investigated. Significant increases in the concentration of all POPs were found over the mass loss period and decreases during mass gain. A basic mass balance model indicated that the changes did not conform to a simple concentrating and diluting pattern and a proportion of the contaminants were lost from the lipid pool. During mass loss, the lower chlorinated polychlorinated biphenyl congeners, chlordanes, and hexachlorocyclohexanes were lost at a higher rate than the other contaminant classes (particularly polybrominated diphenyl ethers). During mass gain the behavior of all contaminant classes was more consistent with the dilution model. These results indicate the importance of considering the energetic contextwhen sampling blubberfor long-term contaminant monitoring and suggest an initial approach to adjust for such differences.


Bioinformatics Analysis Reveals MicroRNAs Regulating Biological Pathways in Exercise-Induced Cardiac Physiological Hypertrophy.
Exercise-induced physiological cardiac hypertrophy is generally considered to be a type of adaptive change after exercise training and is beneficial for cardiovascular diseases. This study aims at investigating exercise-regulated microRNAs (miRNAs) and their potential biological pathways. Here, we collected 23 miRNAs from 8 published studies. MirPath v.3 from the DIANA tools website was used to execute the analysis, and TargetScan was used to predict the target genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to identify potential pathways and functional annotations associated with exercise-induced physiological cardiac hypertrophy. Various miRNA targets and molecular pathways, such as Fatty acid elongation, Arrhythmogenic right ventricular cardiomyopathy (ARVC), and ECM-receptor interaction, were identified. This study could prompt the understanding of the regulatory mechanisms underlying exercise-induced physiological cardiac hypertrophy.


Physics and chemistry of the solar nebula.
The solar system is thought to have begun in a flattened disk of gas and dust referred to traditionally as the solar nebula. Such a construct seems to be a natural product of the collapse of dense parts of giant molecular clouds, the vast star-forming regions that pepper the Milky Way and other galaxies. Gravitational, magnetic and thermal forces within the solar nebula forced a gradual evolution of mass toward the center (where the sun formed) and angular momentum (borne by a small fraction of the mass) toward the outer more distant regions of the disk. This evolution was accompanied by heating and a strong temperature contrast from the hot, inner regions to the cold, more remote parts of the disk. The resulting chemistry in the disk determined the initial distribution of organic matter in the planets; most of the reduced carbon species, in condensed form, were located beyond the asteroid belt (the 'outer' solar system). The Earth could have received much of its inventory of pre-biological material from comets and other icy fragments of the process of planetary formation in the outer solar system.


Human protein C concentrates for replacement therapy in congenital and acquired protein C deficiency.
The protein C pathway has an important function in regulating and modulating blood coagulation and ensuring patency of the microcirculation. Protein C deficiency leads to macro- or microvascular thrombosis. Hereditary severe protein C deficiency is a life-threatening state with neonatal purpura fulminans. Patients with heterozygous protein C deficiency have an increased risk for thromboembolic events or coumarin-induced skin necrosis. Secondary protein C deficiency occurs during disseminated intravascular coagulation (DIC), sepsis (especially meningococcal sepsis with purpura fulminans), liver failure and vitamin K deficiency. Replacement with protein C concentrates is an established treatment for congenital protein C deficiency. The high-purity, plasma-derived protein C concentrate Ceprotin (Baxter AG, Vienna, Austria) is approved for this indication, but its use in acquired deficiency states is not approved. Several case series demonstrated beneficial effects in infectious purpura fulminans and DIC, but no controlled studies for these indications exist. Protein C concentrate may therefore be given off-label in such cases. Protein C concentrate has an excellent safety profile: no drug interactions, overdose or bloodborne infections, bleeding or prothrombotic complications have been observed. As with all protein preparations, a potential risk of hypersensitivity reactions exists.


Parametric spatial post-filtering utilising high-order circular harmonics with applications to underwater sound-field visualisation.
Beamforming using a circular array of hydrophones may be employed for the task of two-dimensional (2D) underwater sound-field visualisation. In this article, a parametric spatial post-filtering method is proposed, which is specifically intended for applications involving large circular arrays and aims to improve the spatial selectivity of traditional beamformers. In essence, the proposed method is a reformulation of the cross-pattern coherence (CroPaC) spatial post-filter, which involves calculating the normalised cross-spectral density between two signals originating from coincident beamformers. The resulting parameter may be used to sharpen another beamformer steered in the same look-direction, while attenuating ambient noise and interferers from other directions. However, while the original 2D version of the algorithm has been demonstrated to work well with second-order circular harmonic input, it becomes increasingly less suitable with increasing input order. Therefore, the proposed reformulation extends the applicability of CroPaC for much higher orders of circular harmonic input. The method is evaluated with simulated data of a 96-channel circular hydrophone array in three different passive sonar scenarios, where the proposed post-filter is shown to improve the spatial selectivity of both delay-and-sum and minimum-variance distortionless response beamformers.


Heterotopic sites of pleomorphic adenoma.
The majority of the tumours occurring in minor salivary glands are malignant with only 18% being benign. Among the benign tumours, pleomorphic adenoma is the most common. Although it presents more commonly in the parotid and submandibular glands, it can occur at any site where salivary glands reside. Only 6.4% of cases of pleomorphic adenoma occur in minor salivary glands, e.g. palate, cheeks, lips, para-pharyngeal space, etc. It occurs in females in the fourth or fifth decade. It presents as an asymptomatic and slow-growing mass. The treatment of choice is wide local excision due to the high rate of recurrence and malignant potential. We present rare case reports of two patients. The first case is of a young 18 years female presenting with recurrent neck (anterior triangle) swelling and the second case is of a 46-year-old female presenting with lower lip swelling. In both cases, it was a slow-growing mass and asymptomatic. Cytological examination of the lesion revealed the diagnosis of pleomorphic adenoma. It was completely excised with no post-operative complication. Pleomorphic adenoma, although a common benign neoplasm of major salivary glands, should always be kept as a possibility at the locations of minor salivary glands. As pleomorphic adenoma can transform into a malignant counterpart, therefore early diagnosis and treatment of the lesion can prevent further complications. The prognosis of pleomorphic adenoma is excellent. However, a close follow-up of the patient is required due to the high rate of recurrence.


Aggressive growth of epithelial carcinomas following treatment with nucleoside analogues.
Two patients, one with B-cell chronic lymphocytic leukemia (CLL) and one with hairy-cell leukemia (HCL), were treated with immunosuppressive chemotherapy. The patient with CLL was a 54-year-old female, who had had a squamous cell carcinoma (SCC) excised from her forehead 5 months before receiving the first course of fludarabine. During the fludarabine treatment, the patient developed a local SCC relapse and metastases in the neck. The carcinoma was treated by excision and radiotherapy, and further fludarabine treatment was withheld. Nevertheless, the SCC metastasized aggressively and the patient died 3 months after the start of fludarabine treatment, primarily due to respiratory failure. The autopsy revealed heavy SCC infiltrations involving the lungs, pleura, mediastinum, pericardium, and liver. The patient with HCL was a 69-year-old male. At the time of diagnosis of HCL, the patient had two solid tumors in the liver containing poorly differentiated epithelial carcinoma cells of unknown origin. During treatment with 2-chlorodeoxyadenosine (2CdA), the tumors in the liver rapidly spread in multiple intrahepatic metastases, followed by liver failure and death within 1 month. Fludarabine and 2CdA cause a substantial suppression of all lymphocyte subsets, in particular the T-cell line. T-lymphocytes are believed to be responsible for the usually slow growth and the low metastatic rate of the SCC skin lesions. It is therefore assumed that fludarabine and 2CdA in these two cases triggered an exacerbation of both tumors due to the T-cell depletion.


Developing a dementia-specific preference--based quality of life measure (AD-5D) in Australia: a valuation study protocol.
Generic instruments for assessing health-related quality of life may lack the sensitivity to detect changes in health specific to certain conditions, such as dementia. The Quality of Life in Alzheimer's Disease (QOL-AD) is a widely used and well-validated condition-specific instrument for assessing health-related quality of life for people living with dementia, but it does not enable the calculation of quality-adjusted life years, the basis of cost utility analysis. This study will generate a preference-based scoring algorithm for a health state classification system -the Alzheimer's Disease Five Dimensions (AD-5D) derived from the QOL-AD. Discrete choice experiments with duration (DCETTO) and best-worst scaling health state valuation tasks will be administered to a representative sample of 2000 members of the Australian general population via an online survey and to 250 dementia dyads (250 people with dementia and their carers) via face-to-face interview. A multinomial (conditional) logistic framework will be used to analyse responses and produce the utility algorithm for the AD-5D. The algorithms developed will enable prospective and retrospective economic evaluation of any treatment or intervention targeting people with dementia where the QOL-AD has been administered and will be available online. Results will be disseminated through journals that publish health economics articles and through professional conferences. This study has ethical approval.


Computational optical palpation: a finite-element approach to micro-scale tactile imaging using a compliant sensor.
High-resolution tactile imaging, superior to the sense of touch, has potential for future biomedical applications such as robotic surgery. In this paper, we propose a tactile imaging method, termed computational optical palpation, based on measuring the change in thickness of a thin, compliant layer with optical coherence tomography and calculating tactile stress using finite-element analysis. We demonstrate our method on test targets and on freshly excised human breast fibroadenoma, demonstrating a resolution of up to 15-25 µm and a field of view of up to 7 mm. Our method is open source and readily adaptable to other imaging modalities, such as ultrasonography and confocal microscopy.


Differential expression of CD44 during human prostate epithelial cell differentiation.
CD44 is a polymorphic transmembrane glycoprotein that binds hyaluronan and growth factors. Multiple isoforms of the protein can be generated by alternative splicing but little is known about the expression and function of these isoforms in normal development and differentiation. We have investigated the expression of CD44 during normal prostate epithelial cell differentiation. A conditionally immortalized prostate epithelial cell line, Pre2.8, was used as a model system. These cells proliferate at 33C but at 39C stop dividing and undergo changes consistent with early stages of cell differentiation. During the differentiation of these cells, the expression of the CD44 isoform v3-v10 was upregulated. Two layers of epithelial cells can clearly be distinguished in the human prostate, a basal layer expressing keratins 5/14 and a luminal layer expressing keratins 8/18. In prostate tissue the v3-v10 isoform was found predominantly in basal cells but also in keratin 14-negative, keratin 19-positive cells intermediate between the two layers. CD44 v3-v10 was also expressed in other keratin 14-negative prostate tissues, the ejaculatory ducts and prostatic urethra. Therefore, CD44 v3-v10 may be important as a cell surface marker for differentiating cells in the prostate epithelium.


Detection of keratinocyte growth factor (KGF) messenger ribonucleic acid and immunolocalization of KGF in the canine testis.
Keratinocyte growth factor (KGF) was originally discovered in human embryonic lung fibroblasts and is a member of the fibroblast growth factor (FGF) family. Members of the FGF family have been shown to regulate testicular function. However, the recently discovered KGF has not been studied in the testis. KGF has been detected in many other tissues, including the prostate, an organ whose development and function have been associated with presence of the testis. In this study, KGF mRNA was detected in the whole testis using reverse transcription polymerase chain reaction (RT-PCR). The 575-bp KGF-specific product was detected along with a 594-bp β-actin-specific product. To identify the cell types in which KGF mRNA was predominantly expressed, interstitial cells were physically separated from seminiferous tubules. The interstitial cells were then sorted on a discontinuous Percoll gradient and total cellular mRNAs isolated. Using RT-PCR and Southern hybridization with specific cDNA probes, the KGF mRNA was detected in interstitial cells. KGF expression levels were then evaluated semiquantitatively with a competitive RT-PCR assay. KGF expression levels were highest in interstitial cells that equilibrated between 20 and 30% Percoll. Enriched Leydig cells and seminiferous tubules expressed low levels of KGF. Finally, immunohistochemical analysis was performed on canine testes using a rabbit anti-KGF polyclonal antibody. The KGF protein was localized predominantly to peritubular cells of the canine testis. These results suggest that KGF is synthesized in the canine testis.