Paraneoplastic and idiopathic autoimmune neurologic disorders: approach to diagnosis and treatment.
Autoimmune neurology is a rapidly emerging new subspecialty that encompasses the diagnosis and treatment of neurologic disorders with an autoimmune (paraneoplastic or noncancer-associated) basis. The last decade has seen a dramatic rise in the discovery of neural-specific autoantibodies and their target antigens. Laboratory testing, on a service basis, is now available for most of these neural-specific autoantibodies and they serve as diagnostic markers, in some instances directing the physician toward specific cancer types (e.g., N-methyl-d-aspartate receptor antibodies for teratoma; CRMP5-IgG for small-cell cancer) and assisting in therapeutic decision making. Antibodies targeting intracellular proteins (nuclear and intracytoplasmic enzymes, transcription factors, and RNA binding proteins) serve as markers of cytotoxic effector T-cell-mediated injury and are generally poorly responsive to immunotherapy. By contrast, antibodies targeting plasma membrane proteins that are extracellular and accessible (neurotransmitter receptors, ion channels, water channels, and channel-complex proteins) may act as pathogenic effectors and often imply immunotherapy responsiveness. Magnetic resonance imaging, electrophysiologic studies, functional imaging, and neuropsychologic evaluations provide objective evidence of neurologic dysfunction by which the success of immunotherapy may be measured.


Plasticity in shoot development: a biophysical view.
The construction and spacing of leaves can be analysed in terms of the direction of reinforcement in the walls of the organ surface. In general, growth is at right angles to the reinforcement. When, however, tissues are actively stretched by adjacent organs they apparently take on, by cell activity, reinforcement which lies in the direction of stretch. Thus reinforcement can dictate extension direction; extension direction, when imposed on a tissue, may dictate reinforcement direction. This proposed two-way relationship has been used to model the activity of shoot meristems. It produces biophysically plausible schemes for the progressive development of various leaf structures and for the cyclical revision of apical structure seen in various types of phyllotaxis.


Genetic Encoding of para-Pentafluorosulfanyl Phenylalanine: A Highly Hydrophobic and Strongly Electronegative Group for Stable Protein Interactions.
SF5Phe, para-pentafluorosulfanyl phenylalanine, is an unnatural amino acid with extreme physicochemical properties, which is stable in physiological conditions. Here we present newly developed aminoacyl-tRNA synthetases that enable genetic encoding of SF5Phe for site-specific incorporation into proteins in high yields. Owing to the SF5 moiety's dichotomy of strong polarity and high hydrophobicity, the unnatural amino acid forms specific and strong interactions in proteins. The potential of SF5Phe in protein research is illustrated by (i) increasing the binding affinity of a consensus pentapeptide motif toward the β subunit of Escherichia coli DNA polymerase III holoenzyme by mutation of a phenylalanine to a SF5Phe residue, (ii) site-specifically adhering β-cyclodextrin to the surface of ubiquitin, and (iii) selective detection of 19F-19F nuclear Overhauser effects in the Escherichia coli peptidyl-prolyl cis/trans-isomerase B following mutation of two phenylalanine residues in the core of the protein to SF5Phe. With increasing use of the SF5 moiety in pharmaceutical chemistry, this general method of functionalizing proteins with SF5 groups opens unique opportunities for structural biology and in vivo studies.


An unusual combination of relapsing and cholestatic hepatitis A in childhood.
Clinical variants of hepatitis A include the prolonged, relapsing and cholestatic forms. Here, the first childhood case of hepatitis A, with a combination of the relapsing and cholestatic forms is presented, a 14-year old boy. In the first phase of the illness, while the AST and ALT levels were declined, th total and direct bilirubin and GGT were increased. The patient was thought to have the cholestatic form of hepatitis A. Du to intense pruritus and high bilirubin levels, ursodeoxycholic acid (UDCA) therapy was started. On the 17th day, the decreased AST and ALT levels began to increase, reaching levels as high as 484 U/L and 862 U/L, respectively. The UDCA treatment was stopped on the 64th day. On the 164th day, all his laboratory parameters were within normal limits, but the anti-HAV IgM was still positive.


Fatty acid profiling and oxidative stability of biscuits available in the market of the city of Ludhiana, India.
India has occupied third position in biscuit manufacturing with an average production of 1.95 million tonnes. The major ingredients in biscuit manufacturing are refined wheat flour, sugar and fat. Fat to be used must be chosen carefully as it affects quality of final product in terms of fatty acid composition and oxidative stability. Therefore, the present work was planned to study fatty acid profile of highly consumed baked products of biscuit family such as biscuits and cookies available in market. The study was carried out to do fatty acid profiling of a range of highly consumed baked products of biscuit family as a primary objective and also, to determine oxidative stability of these products by analysing peroxide value and free fatty acid content. The most commonly consumed packaged and unpackaged bakery products were selected and were bought from the local market of Ludhiana city on the basis of a survey conducted on 200 subjects. The selected products were analysed for fatty acid composition and oxidative stability using standard methods. Fatty acid profiling of 22 bakery products of biscuit family was done. Palmitic acid was the most abundant among all fatty acids in packaged and unpackaged samples. Peroxide value of all the products even after storage period of three months was found below the permissible limits (< 10 meq/kg). Free fatty acids value of all the products also did not cross acceptable level of 0.5 percent. Out of total selected eight brands, six were national and two were international. Amount of palmitic acid was higher in the products belonging to local brands.


Sites of tau important for aggregation populate {beta}-structure and bind to microtubules and polyanions.
The aggregation of the microtubule-associated tau protein and formation of "neurofibrillary tangles" is one of the hallmarks of Alzheimer disease. The mechanisms underlying the structural transition of innocuous, natively unfolded tau to neurotoxic forms and the detailed mechanisms of binding to microtubules are largely unknown. Here we report the high-resolution characterization of the repeat domain of soluble tau using multidimensional NMR spectroscopy. NMR secondary chemical shifts detect residual beta-structure for 8-10 residues at the beginning of repeats R2-R4. These regions correspond to sequence motifs known to form the core of the cross-beta-structure of tau-paired helical filaments. Chemical shift perturbation studies show that polyanions, which promote paired helical filament aggregation, as well as microtubules interact with tau through positive charges near the ends of the repeats and through the beta-forming motifs at the beginning of repeats 2 and 3. The high degree of similarity between the binding of polyanions and microtubules supports the hypothesis that stable microtubules prevent paired helical filament formation by blocking the tau-polyanion interaction sites, which are crucial for paired helical filament formation.


Pertussis epidemic--Washington, 2012.
Since mid-2011, a substantial rise in pertussis cases has been reported in the state of Washington. In response to this increase, the Washington State Secretary of Health declared a pertussis epidemic on April 3, 2012. By June 16, the reported number of cases in Washington in 2012 had reached 2,520 (37.5 cases per 100,000 residents), a 1,300% increase compared with the same period in 2011 and the highest number of cases reported in any year since 1942. To assess clinical, epidemiologic, and laboratory factors associated with this increase, all pertussis cases reported during January 1-June 16, 2012, were reviewed. Consistent with national trends, high rates of pertussis were observed among infants aged <1 year and children aged 10 years. However, the incidence in adolescents aged 13-14 years also was increased, despite high rates of vaccination with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine, suggesting early waning of immunity. The focus of prevention and control efforts is the protection of infants and others at greatest risk for severe disease and improving vaccination coverage in adolescents and adults, especially those who are pregnant. Pertussis vaccination remains the single most effective strategy for prevention of infection.


Mechanism of the bisphosphatase reaction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase probed by (1)H-(15)N NMR spectroscopy.
The histidines in the bisphosphatase domain of rat liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase were labeled with (15)N, both specifically at N1' and globally, for use in heteronuclear single quantum correlation (HSQC) NMR spectroscopic analyses. The histidine-associated (15)N resonances were assigned by correlation to the C2' protons which had been assigned previously [Okar et al., Biochemistry 38, 1999, 4471-79]. Acquisition of the (1)H-(15)N HSQC from a phosphate-free sample demonstrated that the existence of His-258 in the rare N1' tautomeric state is dependent upon occupation of the phosphate binding site filled by the O2 phosphate of the substrate, fructose-2,6-bisphosphate, and subsequently, the phosphohistidine intermediate. The phosphohistidine intermediate is characterized by two hydrogen bonds involving the catalytic histidines, His-258 and His-392, which are directly observed at the N1' positions of the imidazole rings. The N1' of phospho-His-258 is protonated ((1)H chemical shift, 14.0 ppm) and hydrogen bonded to the backbone carbonyl of Gly-259. The N1' of cationic His-392 is hydrogen bonded ((1)H chemical shift, 13.5 ppm) to the phosphoryl moiety of the phosphohistidine. The existence of a protonated phospho-His-258 intermediate and the observation of a fairly strong hydrogen bond to the same phosphohistidine implies that hydrolysis of the covalent intermediate proceeds without any requirement for an "activated" water. Using the labeled histidines as probes of the catalytic site mutation of Glu-327 to alanine revealed that, in addition to its function as the proton donor to fructose-6-phosphate during formation of the transient phosphohistidine intermediate at the N3' of His-258, this residue has a significant role in maintaining the structural integrity of the catalytic site. The (1)H-(15)N HSQC data also provide clear evidence that despite being a surface residue, His-446 has a very acidic pK(a), much less than 6.0. On the basis of these observations a revised mechanism for fructose-2,6-bisphosphatase that is consistent with all of the previously published kinetic data and X-ray crystal structures is proposed. The revised mechanism accounts for the structural and kinetic consequences produced by mutation of the catalytic histidines and Glu-327. It also provides the basis for a hypothetical mechanism of bisphosphatase activation by cAMP-dependent phosphorylation of Ser-32, which is located in the N-terminal kinase domain.


Ground and excited state exciton polarons in monolayer MoSe2.
Monolayer transition metal dichalcogenide semiconductors, with versatile experimentally accessible exciton species, offer an interesting platform for investigating the interaction between excitons and a Fermi sea of charges. Using hexagonal boron nitride encapsulated monolayer MoSe2, we study the impact of charge density tuning on the A and B series of exciton Rydberg states, including A:1s, A:2s, B:1s, and B:2s. The doping dependence of the A:2s state provides an opportunity to examine such interactions with greatly reduced exciton binding energy and more spatially diffuse structures, and we found that the impact of the Fermi sea becomes much more dramatic compared to the A:1s state. Using photoluminescence upconversion, we verify that the B:2s exciton state displays similar behavior when interacting with the Fermi sea despite being well above the bare bandgap in energy. Photoluminescence and reflection spectra of the A:1s state show clear evidence that the interaction of the exciton with a Fermi sea is best described by the exciton-polaron model, rather than a trion model. Our experimental results demonstrate that overall features of charge interaction are quite generic and highly robust, offering key insights into the dressed many body states in a Fermi sea.


Impact of smoking, alcohol consumption, and NSAID use on risk for and phenotypes of eosinophilic esophagitis.
There are few data exploring modifiable risk factors for eosinophilic esophagitis (EoE). We aimed to determine if smoking, alcohol consumption, and nonsteroidal anti-inflammatory drug (NSAID) use were risk factors for EoE, and to assess their impact on EoE phenotypes and treatment outcomes. We performed a case-control study analyzing data collected from a prospective cohort of adults undergoing upper endoscopy for symptoms of esophageal dysfunction. Incident EoE cases were diagnosed via consensus guidelines. Exposure data were collected via standardized patient questionnaire. Follow-up assessments for cases were made after treatment, with histologic response defined as <15 eosinophils per high-power field (eos/hpf). Exposures were compared between EoE cases and controls, among EoE cases with and without fibrostenosis, and among EoE responders and nonresponders. A total of 115 cases and 225 controls were analyzed. Cases were less likely to have ever smoked cigarettes (23% vs. 47%, P < 0.001) or currently use NSAIDs (17% vs. 40%, P < 0.001) compared to controls. These relations persisted after multivariate analysis. Although alcohol use was more common among cases (75% vs. 51%, P < 0.001), the effect was abrogated after multivariate analysis. Smoking, alcohol, and NSAID use were not associated with the fibrostenotic phenotype. There was a trend toward improved histologic response among EoE patients concomitantly using NSAIDs (87% vs. 63%, P = 0.08; aOR 6.97 (95% CI: 0.81-60.3). In conclusion, NSAID and smoking were inversely associated with EoE compared to endoscopy-based controls. Alcohol use was more prevalent in the EoE cases, although not an independent risk factor. Concomitant NSAID use may improve treatment response and is worthy of future study.


Yopo, ethnicity and social change: a comparative analysis of Piaroa and Cuiva yopo uset.
Most Orinocoan ethnic groups, including the Cuiva and the Piaroa, use yopo, a hallucinogenic snuff derived from the seeds of the Anadenanthera peregrina tree. This study contrasts Piaroa and Cuiva attitudes toward and uses of yopo in light of ongoing processes of social change. We do not believe that these sociocultural forces will lead to a phasing out of yopo in Piaroa and Cuiva life. However, we demonstrate how, in nearby communities, a combination of historical and ethical contingencies lead to very different patterns and understanding of drug use. Yopo is strongly associated with the performance of narratives central to each ethnic group's cosmology and identity. Cuiva yopo consumption is also a means of resisting persecution and asserting the right to a just reality. Piaroa attitudes towards yopo are affected by the interplay of shamanic ethical principles and missionary activity, and are sometimes paradoxical: yopo is the reason for harm and the means of salvation; required by shamans to create the future and yet regarded by many laypeople as a relic of the past. We identify persecution, local responses to missionary activity, and shamanic ethics as key factors affecting the evolution of hallucinogen use by Amazonian ethnic groups.


Pembrolizumab-Induced Meningoencephalitis: A Brain Autopsy Case.
Encephalitis is very rare, but often fatal immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). A 65-year-old Japanese woman was admitted to our hospital because of general fatigue, chillness and high-grade fever for 4 days, 8 months after the initiation of the first-line pembrolizumab monotherapy for metastatic pulmonary adenocarcinoma. On the hospital day 3, she suddenly presented delirium and uncontrollable impaired consciousness. Although the magnetic resonance imaging (MRI) did not suggest a diagnosis of encephalitis and meningitis, the spinal fluid showed abnormally elevated levels of protein (317.6 mg/L) and cell count (197 cells/µL) with increased mononuclear cells (93%). An empirical and intravenous administration of acyclovir in doses of 10 mg/kg body weight every 8 h and steroid pulse therapy in dose of 1 g/body/day from the hospital day 5 until her death failed to improve her conditions. She died on the hospital day 8. The postmortem autopsy showed viable cancer cells in the metastatic tumor in the left occipital lobe and in the spinal fluids. However, many inflammatory cells infiltration in the meninges and perivascular cuffing were prominent especially in the brain stem and medial part of the temporal lobe. Infiltrating lymphocytes in the meninges and parenchyma of the brain stem were mainly composed of cluster of differentiation (CD)8-positive lymphocytes. For irAE encephalitis, early recognition of early signs and symptoms and subsequent early therapeutic intervention are necessary. It is important for oncologists to keep in mind of the possible adverse effects of immunotherapies on the nervous system.


[Reproduction, distribution and abundance of the fish Pseudupeneus grandisquamis (Perciformes: Mullidae), in the Gulf of Tehuantepec, Mexico].
As result of its biological and ecological strategies, Pseudupeneus grandisquamis is a dominant species in the demersal community of the Gulf of Tehuantepec, Mexico. Our main objective was to understand these strategies with respect to distribution, abundance and reproduction. We analyzed 5,175 individuals representing partial collections from five oceanographic expeditions between 1989 and 1990. It is a typical demersal marine species, with a wide distribution on the continental shelf. The highest abundance of P. grandisquamis occurs in March and November, around the 40 m isobath, facing the Superior-Inferior lake systems and Mar Muerto Lagoon. Reproduction occurred during all of the months studied, particularly from August to October, corresponding to the rainy season, when the salinity and temperature is lower. The presence of juveniles, principally in November and March, suggests a long period of recruitment; they are distributed mainly in the Superior-Inferior Lagoons, which serves as a nursery area where they remain until they are adults. The total female to male sex ratio was nearly 1:1 throughout the year. The maximum total length was 213 mm and the size at first maturity was 138 mm TL. The high abundance and reproduction occur when the gulf has a high level of ecological production, in accordance with the dynamics of the system, where the influence of coastal lagoons is important. Protection strategies for the area above the continental shelf of the Gulf of Tehuantepec are recommended for the estuary processes and for the reproduction and rearing of a large number of species, including P. grandisquamis.


Prevalence, clinical characteristics, and outcomes associated with eccentric versus concentric left ventricular hypertrophy in heart failure with preserved ejection fraction.
Although concentric remodeling (CR) and concentric hypertrophy (CH) are common forms of left ventricular (LV) remodeling in heart failure with preserved ejection fraction (HFpEF), eccentric hypertrophy (EH) can also occur in these patients. However, clinical characteristics and outcomes of EH have not been well described in HFpEF. We prospectively studied 402 patients with HFpEF, divided into 4 groups based on LV structure: normal geometry (no LV hypertrophy [LVH] and relative wall thickness [RWT] ≤0.42); CR (no LVH and RWT >0.42); CH (LVH and RWT >0.42); and EH (LVH and RWT ≤0.42). We compared clinical, laboratory, echocardiographic, invasive hemodynamic, and outcome data among groups. Of 402 patients, 48 (12%) had EH. Compared with CH, patients with EH had lower systolic blood pressure and less renal impairment despite similar rates of hypertension. After adjustment for covariates, EH was associated with reduced LV contractility compared with CH: lower LVEF (β coefficient = -3.2; 95% confidence interval [CI] -5.4 to -1.1%) and ratio of systolic blood pressure to end-systolic volume (β coefficient = -1.0; 95% CI -1.5 to -0.5 mm Hg/ml). EH was also associated with increased LV compliance compared with CH (LV end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg β coefficient = 14.2; 95% CI 9.4 to 19.1 ml). Despite these differences, EH and CH had similarly elevated cardiac filling pressures and equivalent adverse outcomes. In conclusion, the presence of EH denotes a distinct subset of HFpEF that is pathophysiologically similar to HF with reduced EF (HFrEF) and may benefit from HFrEF therapy.


The influence of various endocrine disruptors on the reproductive system.
Various stimulants (VS) are chemicals that disrupt the endocrine system - endocrine homeostasis of the reproductive system - which also known as endocrine-disrupting chemicals (EDCs). These substances are found in the human body, in both the blood and urine, amniotic fluid, or, among others, the adipose tissue. This article presents the current state of knowledge of the effect of EDCs and additional factors such as smoking, alcohol consumption, and cannabis on the gonads. The article is an overview of the impact of EDCs and their mechanism of action, with particular emphasis on gonads, based on databases such as PubMed, EMBASE and Google Scholar, and Web of Science available until May 2022. The impact of human exposure to bisphenol A (BPA) is not fully understood, but it has been shown that phthalates show a negative correlation in anti-androgenic activity in the case of men and women for the anti-Müllerian hormone (AMH). Smoking cigarettes and passive exposure to tobacco have a huge impact on the effects of endocrine disorders in both women and men, especially during the reproductive time. Also, the use of large amounts of cannabinoids during the reproductive years can lead to similar disorders. It has been documented that excessive alcohol consumption leads to disturbed function of the hypothalamus-pituitary-gonadal axis (HPG). Excess caffeine consumption may adversely affect male reproductive function, although this is not fully proven. Therefore, the following publication presents various stimulants (BPA, phthalates, nicotine, alcohol, cannabis) that disrupt the function of the endocrine system and, in particular, affect the function of the gonads.


Deciphering the True Immunologic Risk in Renal Transplantation in Patients With HIV.
Since 1995, rates of end-stage renal disease have risen dramatically in patients living with HIV infection. However, given the concern for higher rates of acute rejection in this patient population, the immunologic threat posed by HIV infection is a specter clinicians must continually confront. Living donor transplantation may negate this risk; this study aims to assess the benefit of living donor transplantation in this population and to ascertain the immunologic risk faced by patients who are HIV-infected. The 2021 UNOS database was queried, and all HIV-infected kidney transplant recipients since 1987 were identified. Recipients were stratified based on deceased (DDKT) vs living (LDKT) donor status. Overall survival, allograft survival, acute rejection, panel reactive antibody (PRA) percentage, and crossmatch positivity were compared between groups. One thousand two hundred twenty-six patients underwent DDKT, and 304 patients underwent LDKT. Living donor kidney transplantation demonstrated greater overall survival (P = .045) and graft survival (P < .001). However, no difference in acute rejection was noted between the cohorts, and no difference in overall or graft survival was evident based on PRA percentage. Crossmatch positive status did not negatively affect graft survival. Patients with HIV undergoing LDKT fared better than those undergoing DDKT. Nevertheless, patients at higher immunologic risk-elevated PRA% and crossmatch positivity-did not experience graft loss at a higher rate than patients at lower immunologic risk. These results were valid in both DDKT and LDKT cohorts. These findings suggest that infection with HIV does not overtly increase patients' immunologic risk, and concerns surrounding transplantation in this population may be overestimated.


Dihydropyridine actions on calcium currents of frog sympathetic neurons.
Dihydropyridines (DHPs) generally have little effect on whole-cell calcium currents of neurons, even at concentrations far higher than those effective on muscle. Either neuronal calcium currents are much less sensitive to DHPs, or only a small proportion of the current is DHP-sensitive. We find that DHP agonists and antagonists act at low concentration on calcium currents in frog sympathetic neurons but that the effects are small even at optimal concentrations. The half-maximal dose (EC50) of the agonist Bay K 8644 is approximately 50 nM, and the effect of Bay K 8644 is blocked by 50% at approximately 300 nM nifedipine, from a holding potential of -80 mV. Nifedipine is more effective from a holding potential of -50 mV. These results suggest the presence of an L-type calcium current, with DHP sensitivity similar to L-currents in cardiac muscle. The predominant (greater than 90%) calcium current in frog sympathetic neurons is a DHP-resistant N-type current. However, high concentrations of DHPs (10 microM) partially block N-type calcium current, as well as voltage-dependent sodium and potassium currents.


Low-loss amorphous silicon wire waveguide for integrated photonics: effect of fabrication process and the thermal stability.
Hydrogenated amorphous silicon (a-Si:H) wire waveguides were fabricated by plasma-enhanced chemical vapor deposition and anisotropic dry etching. With the optimized fabrication process, the propagation losses of as low as 3.2 ± 0.2 dB/cm for the TE mode and 2.3 ± 0.1 dB/cm for the TM mode were measured for the 200 nm (height) × 500 nm (width) wire waveguides at 1550 nm using the standard cutback method. The loss becomes larger at shorter wavelength (~4.4 dB/cm for TE and ~5.0 dB/cm for TM at 1520 nm) and smaller at longer wavelength (~1.9 dB/cm for TE and ~1.4 dB/cm for TM at 1620 nm). With the waveguide width shrinking from 500 nm to 300 nm, the TM mode loss keeps almost unchanged whereas the TE mode loss increases, indicating that the predominant loss contributor is the waveguide sidewall roughness, similar to the crystalline silicon waveguides. Although the a-Si:H and the upper cladding SiO2 were both deposited at 400°C, the propagation loss of the fabricated a-Si:H wire waveguides starts to increase upon furnace annealing under atmosphere at a temperature larger than 300°C: ~13-15 dB/cm after 400°C/30 min annealing and >70 dB/cm after 500°C/30 min annealing, which can be attributed to hydrogen out-diffusion. Even higher temperature (i.e., >600°C) annealing leads to the propagation loss approaching to the polycrystalline silicon counterparts (~40-50 dB/cm) due to onset of a-Si:H solid-phase crystallization.


Methylation, sugar puckering and Z-form status of DNA from a heavy metal-acclimated freshwater Gordonia sp.
Heavy metal acclimation of bacteria is of particular interest in many aspects. It could add to our understanding of adaptation strategies applied by bacteria, as well as help us in devising ways to use such adaptive bacteria for bioremediation. In this study, we have explored the changes in the DNA of an aquatic Gordonia sp. acclimated to silver, cadmium, and lead. We have measured the changes in the DNA extracted from the acclimated bacteria by using ATR-FTIR coupled with unsupervised and supervised pattern recognition algorithms. Although whole-cell FTIR studies do reveal nucleic acid changes, the special care should be taken when considering marker nucleic acid bands in such spectra, as various other cell or tissue constituents also yield IR bands in the same region. An FTIR study on isolated DNA can be used to avoid this problem. The IR spectral profiles of the DNA molecules revealed significant changes in the backbone and sugar conformations of upon acclimation. We then further analyzed the DNA's global cytosine-methylation patterns of the heavy metal-acclimated bacteria. We aimed to find out whether epigenetic mechanisms operate in bacteria for survival and growth in inhibitory heavy metal concentrations or not. We found hypermethylation in Cd acclimation but hypomethylation for both Pb and Ag in Gordonia sp. Our results imply that changes in the conformational and methylation states of DNA seem to let bacteria to thrive in otherwise inhibitory conditions and mark the involvement of epigenetic modulation in acclimation processes.


The evaluation of homophobia in an Italian sample.
Homophobia has not been systematically studied by Italian social scientists. This study was an initial investigation of the nature of homophobia among Italians, using an Italian version of a scale measuring the construct, and investigated personality and other factors related to homophobia. We examined (1) whether a male military personnel group had more homophobic attitudes than a group of comparably aged male university students; (2) whether personal characteristics and personality factors were correlated with homophobia; and (3) whether there were gender differences in homophobia between male and female university students. Male officers of the Italian Marine Corps were compared to male university students of the same age with respect to homophobia and personality characteristics. In addition, a sample of male university students was compared to female students. The instruments used were the Italian versions of the Modern Homophobia Scale (MHS) and the 16 Personality Factor Inventory (16 PF). Results showed significantly higher homophobia among the military personnel than among male students. Consistent with previous research, male university students demonstrated more negative attitudes towards gay and lesbian people than female students.


[Primary Prophylactic Administration of Pegfilgrastim in FOLFIRINOX Therapy for Locally Advanced Pancreatic Carcinoma].
FOLFIRINOX therapy has a high response rate for pancreatic carcinoma, but has serious adverse effects. FOLFIRINOX therapy was administered to 11 patients with locally advanced pancreatic carcinoma at our hospital. We investigated the usefulness of primary prophylactic administration of pegfilgrastim(PegG). In the group receiving PegG, as well as with onset of neutropenia and thrombocytopenia, febrile neutropenia was reduced. Rates of anorexia and fatigue were also lower than in those who did not receive PegG. The PegG group maintained a high average relative dose intensity, as well as a high response rate. Primary prophylactic administration of PegG in FOLFIRINOX therapy is valid for pancreatic carcinoma.


Cimetidine-associated exacerbation of cutaneous lupus erythematosus.
A patient with systemic lupus erythematosus (SLE) had new LE skin lesions develop following the initiation of cimetidine, a drug that is known to influence a variety of cellular functions. The temporal relationship between the onset of cutaneous LE with the ingestion of cimetidine is reported to alert others to the possibility that this H2 receptor antagonist may exacerbate cutaneous disease activity in patients with LE.


Body Mass Index, Genetic Susceptibility, and Risk of Complications Among Individuals with Crohn's Disease.
Obesity is associated with systemic and intestine-specific inflammation and alterations in gut microbiota, which in turn impact mucosal immunity. Nonetheless, a specific role of obesity and its interaction with genetics in the progression of Crohn's disease (CD) is unclear. We conducted a cross-sectional study of patients with CD enrolled in Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM). Information on diagnosis of CD and its complications were collected and confirmed through review of medical records. A genetic risk score was calculated using previously reported single-nucleotide polymorphisms-associated genome-wide with CD susceptibility. We used logistic regression to estimate the effect of body mass index (BMI) and its interaction with genetic risk on risk of CD complications. Among 846 patients with CD, 350 required surgery, 242 with penetrating disease, 182 with stricturing disease, and 226 with perianal disease. There were no associations between obesity (BMI ≥ 30 kg/m2) and risk of perianal disease, stricturing disease, or surgery. Compared with normal-weight individuals with BMI < 25 kg/m2, obesity was associated with lower risk of penetrating disease (odds ratio [OR = 0.56; 95% confidence interval [CI], 0.31-0.99). This association persists among a subgroup of participants with available BMI before development of penetrating disease (OR = 0.40; 95% CI, 0.16-0.88). There were no interactions between BMI and genetic risk score on risk of CD complications (all P interaction > 0.28). Our data suggest that obesity does not negatively impact long-term progression of CD, even after accounting for genetic predisposition.


Brooklawnia cerclae gen. nov., sp. nov., a propionate-forming bacterium isolated from chlorosolvent-contaminated groundwater.
Two novel facultatively anaerobic bacterial strains, BL-34(T) and BL-35, isolated from groundwater contaminated by a mixture of chlorosolvents were characterized using a polyphasic approach. The two strains exhibited essentially identical taxonomic features except for a vitamin B(12) requirement by strain BL-35 for optimal growth. Phylogenetically, the isolates were affiliated with members of the family Propionibacteriaceae and were placed in a phylogenetic branch adjacent to, but distinct from, those of the genera Propionimicrobium, Propionibacterium, Luteococcus, Propioniferax and Tessaracoccus. The cells of the novel strains were Gram-positive, non-motile, non-spore-forming pleomorphic rods. They produced catalase but not oxidase, and nitrate reduction did not occur in peptone/yeast extract/glucose medium. Propionate and acetate were the predominant products of glucose fermentation. Fermentation occurred in the presence of 1,2-dichloroethane and 1,1,2-trichloroethane at concentrations up to at least 9.8 mM. The genomic DNA G+C content was 67.5-67.9 mol%. Menaquinone MK-9(H(4)) was the predominant respiratory quinone and meso-diaminopimelic acid was present in the cell-wall peptidoglycan layer. The major cellular fatty acids were C(15 : 0) and anteiso-C(15 : 0). On the basis of the results obtained in this study, strains BL-34(T) and BL-35 should be classified within a novel taxon, for which the name Brooklawnia cerclae gen. nov., sp. nov. is proposed. The type strain of Brooklawnia cerclae is BL-34(T) (=LMG 23248(T)=NRRL B-41418(T)). An additional strain, BL-35 (=LMG 23249=NRRL B-41419), was also characterized.


Neuraxial Anesthesia Reduces Lymphatic Flow: Proof-of-Concept in First In-Human Study.
Dilation of lymphatic vessels may contribute to iatrogenic dissemination of cancer cells during surgery. We sought to determine whether neuraxial anesthesia reduces regional lymphatic flow. Using nuclear lymphoscintigraphy, 5 participants receiving spinal anesthesia for brachytherapy had lower extremity lymph flow at rest compared with flow under conditions of spinal anesthesia. Six limbs were analyzed. Four limbs were excluded because of failure to demonstrate lymph flow (1 patient, 2 limbs), colloid injection error (1 limb), and undiagnosed deep vein thrombosis (1 limb). All analyzed limbs showed reduced lymph flow washout from the pedal injection site (range 62%-100%) due to neuraxial anesthesia. Lymph flow was abolished in 3 limbs. We report proof-of-concept that neuraxial anesthesia reduces lymphatic flow through a likely mechanism of sympathectomy.


Comparison of mechanomyography and acceleromyography for the assessment of rocuronium induced neuromuscular block in myotonic dystrophy type 1.
We measured acceleromyography and mechanomyography simultaneously with monitoring of rocuronium-induced neuromuscular block in four patients with myotonic dystrophy type 1. Furthermore, we compared neuromuscular block measures from these patients with those from normal controls from previous studies. In myotonic dystrophy type 1 patients, the dose-response curve obtained with acceleromyography was steeper and right-shifted compared with that obtained using mechanomyography. However, the effective doses to produce 95% neuromuscular block determined with both acceleromyography and mechanomyography were similar to each other and to values found in normal patients. In the three myotonic dystrophy type 1 patients with mild to moderate disease, times to recovery from block were similar to those observed in normal controls. In both patients and normal controls, neuromuscular block recovered faster with acceleromyography. However, in one patient with severe muscle wasting, recovery of neuromuscular block was prolonged. We conclude that mechanomyography and acceleromyography cannot be used interchangeably to monitor neuromuscular block in myotonic dystrophy type 1 patients.


Dynamic EGFR-Ras signalling in Drosophila leg development.
In Drosophila, as in many other animals, EGFR-Ras signalling has multiple developmental roles from oogenesis to differentiation. In leg development, in particular, it has been described to be responsible for the establishment of distal leg fates in a graded manner. Here, we investigate the patterns of expression of activators of EGFR-Ras signalling, as well as some of the effectors, in order to better understand the patterning of the distal leg, and to investigate further roles of this signalling pathway. These patterns, together with genetic data obtained by different mutant conditions for EGFR-Ras members and transgene expression, suggest two rounds of signalling in leg development. Early, the EGFR ligand Vein is the main player in distal leg patterning, possibly supported later by another ligand activated by Rhomboid. Later, in a second wave of signalling when all the proximal-distal leg fates have been specified, domains of EGFR/Ras activation appear inside each leg segment to regulate Notch-mediated joint development, and also some organs such as tendons and sensory organs. This second wave relies on a ligand activated by Rhomboid.


Acute renal failure due to traumatic rhabdomyolysis.
Between 1990 and 1993, we studied 14 cases of acute renal failure due to prolonged muscular exercise (e.g., squat jumping, sit-ups) and blunt trauma inflicted by law enforcement personnel using sticks or leather belts. None of the patients had a prior history of myopathy, neuropathy, or renal disease. All were critically ill and required renal support in the form of dialysis. Although the morbidity was high, 13 of the patients recovered normal renal function. One patient expired due to sepsis.


[40 years of silicone breast implants].
It is estimated that approximately 50,000 Norwegian women have silicone breast implants following breast augmentation or breast reconstruction. Their numbers are growing and doctors will more often be confronted with the health problems related to these implants. This review is based on information retrieved from Medline and our clinical experience. The modern silicone breast implant is the product of four decades of development. The ongoing debate on health problems associated with the implants has been a vibrant stimulator for research, but a causal relationship between implants and the development of breast cancer and autoimmune defects has not been found. The implants are not, however, without complications; more research is required in order to improve the implants and for quality assurance of treatment and follow up.


Stereospecific interaction of tocainide with the cardiac sodium channel.
The antiarrhythmic action of type I antiarrhythmic drugs may be mediated via binding of the drugs to a receptor associated with the cardiac sodium channel. This suggested that the effects of type I drugs might be stereospecific. We measured the effect of the tocainide stereoisomers (which have stereospecific antiarrhythmic effects) on conduction time and on radioligand binding to the cardiac sodium channel. The concentration-dependent effects of the individual enantiomers of tocainide on interventricular conduction time measured during constant rate ventricular pacing at 350 msec were assessed in 47 isolated perfused rabbit heart preparations. Significant increases (p less than 0.05) in conduction time occurred for both R-(-)-tocainide (75 microM, 10 +/- 5 msec) and S-(+)-tocainide (150 microM, 4 +/- 1 msec). R-(-)-Tocainide was more potent than the S-(+)-tocainide in prolonging conduction time (p less than 0.05). This stereospecific prolongation of conduction time suggested a stereospecific interaction with the sodium channel. The affinities of the enantiomers for the channel were measured with a radioligand binding assay using [3H]batrachotoxinin benzoate and freshly isolated cardiac myocytes. Both enantiomers inhibited [3H]batrachotoxin benzoate binding, but the IC50 (+/- SD) values were different: R-(-)-tocainide 184 +/- 8 microM; S-(+)-tocainide, 546 +/- 37 microM (p less than 0.003). Tocainide isomers are stereospecific in terms of prolonging conduction time and in binding to the sodium channel. The stereospecific electrophysiologic effects of tocainide may result from binding to a receptor associated with the cardiac sodium channel.


Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease.
A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S(1'), S(1), and S(2) enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.


Economic Impact of Tobacco Price Increases Through Taxation: A Community Guide Systematic Review.
Tobacco use is a leading cause of preventable death in the U.S. and around the world. Increasing tobacco price through higher taxes is an effective intervention both to reduce tobacco use in the population and generate government revenues. The goal of this paper is to review evidence on the economic impact of tobacco price increases through taxation with a focus on the likely healthcare cost savings and improvements in employee productivity. The search covered studies published in English from January 2000 to July 2012 and included evaluations of national, state, and local policies to increase the price of any type of tobacco product by raising taxes in high-income countries. Economic review methods developed for The Guide to Community Preventive Services were used to screen and abstract included studies. Economic impact estimates were standardized to summarize the available evidence. Analyses were conducted in 2012. The review included eight modeling studies, with seven providing estimates of the impact on healthcare costs and three providing estimates of the value of productivity gains. Only one study provided an estimate of intervention costs. The economic merit of tobacco product price increases through taxation was determined from the overall body of evidence on per capita annual cost savings from a conservative 20% price increase. The evidence indicates that interventions that raise the unit price of tobacco products through taxes generate substantial healthcare cost savings and can generate additional gains from improved productivity in the workplace.


Effect of Aerobic Exercise Training on Ventilatory Efficiency and Respiratory Drive in Obese Subjects.
Obese patients show a decline in exercise capacity and diverse degrees of dyspnea in association with mechanical abnormalities, increased ventilatory requirements secondary to the increased metabolic load, and a greater work of breathing. Consequently, obese patients may be particularly predisposed to the development of respiratory muscle fatigue during exercise. The aim of this study was to assess inspiratory muscle performance during incremental exercise in 19 obese male subjects (body mass index 41 ± 6 kg/m2) after aerobic exercise training using the noninvasive, inspiratory muscle tension-time index (TT0.1). Measurements performed included anthropometric parameters, lung function assessed by spirometry, rate of perceived breathlessness with the modified Borg dyspnea scale (0-10), breathing pattern, maximal exercise capacity, and inspiratory muscle performance with a breath-by-breath automated exercise metabolic system during an incremental exercise test. TT0.1 was calculated using the equation, TT0.1 = P0.1/PImax × TI/Ttot (where P0.1 represents mouth occlusion pressure, PImax is maximal inspiratory pressure, and TI/Ttot is the duty cycle). At rest, there was no statistically significant difference for spirometric parameters and cardiorespiratory parameters between pre- and post-training. At maximal exercise, the minute ventilation, the rate of exchange ratio, the rate of perceived breathlessness, and the respiratory muscle performance parameters were not significantly different pre- and post-training; in contrast, tidal volume (P = .037, effect size = 1.51), breathing frequency (P = .049, effect size = 0.97), power output (P = .048, effect size = 0.79), peak oxygen uptake (P = .02, effect size = 0.92) were significantly higher after training. At comparable work load, training induces lower minute ventilation, mouth occlusion pressure, ratio of occlusion pressure to maximal inspiratory pressure, TT0.1, and rate of perceived breathlessness. Aerobic exercise at ventilatory threshold can induce significant improvement in respiratory muscle strength, maximal exercise capacity, and inspiratory muscle performance and decreased dyspnea perception in obese subjects.


Chylous ascites due to signet ring cell gastric adenocarcinoma.
"Chylous ascites is a rare presentation of peritoneal effusion. The signet ring cell gastric adenocarcinoma is also relatively rare presentation of gastric cancer. We present a quite rare case of chylous ascites associated with signet ring cell gastric adenocarcinoma. a 47-years-old Caucasian man presented to our emergency department with abdominal distention. The abdominal ultra-sound showed high volume ascites and the diagnostic paracentesis revealed milk-like peritoneal fluid rich in triglycerides. He was underwent to medium chain triglycerides based diet, total parenteric diet and treatment with somatostatin without response. Due to presented digestive hemorrhagic events, upper digestive endoscopy was performed and revealed signet ring cells gastric adenocarcinoma on biopsy. The patient died in disseminated intravascular coagulation context. chylous asicites is a rare presentation of ascites and it may be associated with abdominal neoplasm. The prompt diagnosis is important for optimize the etiology evaluation and therapeutically approach."


Enhancement of subtle density differences of the lung parenchyma on CT.
Several pulmonary conditions are characterized by the finding of areas of decreased attenuation relative to adjacent normal lung parenchyma on computed tomography. In particular, the identification of areas of the lung affected by small airways disease is difficult as the reduction in lung density is subtle and the regions are poorly marginated. This paper presents a novel wavelet analysis technique which increases the conspicuity of differences between normal and abnormal lung parenchyma.


The Impact of Survivorship Care Planning on Patients, General Practitioners, and Hospital-Based Staff.
In 2005, the Institute of Medicine recommended that all cancer patients receive a survivorship care plan (SCP). Despite widespread support, few centers have routinely implemented them. Understanding of their impact is limited. The aims of this study were to examine the impact of SCP delivery on patients and healthcare professionals at an Australian comprehensive cancer center and determine enablers and barriers to implementation. Six groups were surveyed: (1) patients who had received SCPs; (2) nurse coordinators using SCPs, (3) general practitioners (primary care, GPs) of patients who had received SCPs, (4) clinical service chairs, (5) heads of allied health, and (6) nurse coordinators not using SCPs (nonengaged nurse coordinators). Groups 1 to 3 completed written questionnaires. Groups 4 to 6 participated in semistructured interviews. Fifty patients, 7 nurse coordinators, 18 GPs, 7 clinical service chairs, 4 heads of allied health, and 8 nonengaged nurse coordinators participated. Eighty-seven percent of patients considered the SCP to be very or somewhat useful; 50% felt it helped them understand their cancer experience. All engaged nurse coordinators reported SCPs to be very or somewhat useful, and 86% believed SCPs improved communication with GPs. General practitioners felt SCPs were very or somewhat useful (67%) and wished to receive SCPs for future patients (83%). Organizational and clinical leadership, multidisciplinary engagement, resourcing, and timing of SCP delivery were considered critical enablers. Patients and healthcare professionals support the use of SCPs; however, they are resource intensive and require significant organizational support. Nurses are instrumental to SCP implementation. Attention to enablers and barriers is important for successful implementation.


A qualitative exploration of resilience in pre-adolescent AIDS orphans living in a residential care facility.
This article presents the findings of a study among a small group of South African AIDS orphans living in a residential care facility, Lebone Land. The research was conducted between June and September 2006. A qualitative, exploratory study consisting of in-depth, semistructured interviews with eight children and seven key informants aimed to identify and investigate developmental assets operating in the children's lives to help them cope amid exposure to adversities. The findings indicate that the developmental assets that facilitate coping and foster resilience in these children relate to four main components: external stressors and challenges, external supports, inner strengths and interpersonal and problem-solving skills. Emerging key themes relate to the experience of illness, death, poverty and violence, as well as the important roles of morality, social values, resistance skills, religion and faith in assisting these children in defining their purpose in life. To this end, constructive use of time, commitment to learning, goal-setting, problem-solving ability and self-efficacy are fundamental in the children's attainment of their future projections. Therefore, qualities such as optimism, perseverance and hope seem to permeate the children's process of recovery. Strong networks of support, particularly friendships with other children, also seem to contribute to developing and sustaining resilience.


Modeling of caffeine release from crosslinked water-swellable gelatin and gelatin-maltodextrin hydrogels.
Research from this group has recently led to the development of a genipin-crosslinked gelatin gel that may be used as a controlled release matrix for bioactive compounds. This study presents a model that simulates the release of entrapped caffeine from the hydrogel and the ingress of water into these gels. Fick's second law of diffusion is used to describe the water penetration and bioactive release in the system. To validate the model, caffeine release experiments from the gel were carried out. The predicted bioactive release profiles are in very good agreement with experimental data at different gel compositions. The model may also be used for a wide range of bioactive molecules and hydrogels with different cylindrical dimensions.


[Serotonin and hypothalamic control of hunger: a review].
This paper reviews involvement of the serotonergic system in the control of food intake and satiety. It is of great interest to understand the relevance of this system for physiological control of energy balance and obesity. Over 35 years of research suggest that serotonin (5-HT) plays an important role in satiety. Thus, the serotonergic system has been a viable target for weight control. The 5-HT has control over hunger and satiety through different receptors with distinct functions. The 5-HT2C receptor may be more important in the relationship between food intake and energy balance. This review will discuss the mechanisms of the serotonergic system involved in the control of food intake and satiety.


Characteristic structural features of fibrous rings and their connexion with the human cardiac conduction system.
In surgical treatment of acquired defects of mitral, aortic, and tricuspid valves, in many instances severe disturbances of cardiac conduction are observed. With due regard to the individual and typical anatomical features of human heart, the author investigated the structures of fibrous rings and triangles and their interrelationships with the cardiac conduction system. The material studied consisted of 230 hearts obtained from persons aged 20-80 years. The author assumes that within the heart cavity "dangerous zones" have to bbe singled out, whose traumatization in heart surgery may produce a disturbance of elements of the conduction system. The "dangerous zones" are situated at the base of the right-side surface of the interatrial septum above the fibrous ring of the septal cusp of the tricuspid valve, along the base of the membranous segment of the interventricular septum, in front of the posterior fibrous triangle, and at the fibrous ring encircling the bases of the posterior and right aortic semilunar valves.


Loss of growth arrest DNA damage genes expression in oral melanomas.
29 oral melanomas were stained immunohistochemically for the GADD34, GADD45 and GADD153. GADD34 was found in 5/29 melanomas and its expression did not exceed 21%, averaging 4.1% of melanoma cells. GADD45 was observed in 8/29 oral melanomas and cell positivity averaged 2.8%. GADD153 was found in 2/29 melanomas and the percentage of positive cells ranged between 0 and 31%, averaging 1.2%. Not one significant correlation between GADD genes in oral melanomas was found. Loss of GADD gene expression and lack of correlation between them show advanced disturbances in their cooperation, leading to a high genetic instability of oral melanoma cells.


Experimental evolution of pseudogenization and gene loss in a plant RNA virus.
Viruses have evolved highly streamlined genomes and a variety of mechanisms to compress them, suggesting that genome size is under strong selection. Horizontal gene transfer has, on the other hand, played an important role in virus evolution. However, evolution cannot integrate initially nonfunctional sequences into the viral genome if they are rapidly purged by selection. Here we report on the experimental evolution of pseudogenization in virus genomes using a plant RNA virus expressing a heterologous gene. When long 9-week passages were performed, the added gene was lost in all lineages, whereas viruses with large genomic deletions were fixed in only two out of ten 3-week lineages and none in 1-week lineages. Illumina next-generation sequencing revealed considerable convergent evolution in the 9- and 3-week lineages with genomic deletions. Genome size was correlated to within-host competitive fitness, although there was no correlation with virus accumulation or virulence. Within-host competitive fitness of the 3-week virus lineages without genomic deletions was higher than for the 1-week lineages. Our results show that the strength of selection for a reduced genome size and the rate of pseudogenization depend on demographic conditions. Moreover, for the 3-week passage condition, we observed increases in within-host fitness, whereas selection was not strong enough to quickly remove the nonfunctional heterologous gene. These results suggest a demographically determined "sweet spot" might exist, where heterologous insertions are not immediately lost while evolution can act to integrate them into the viral genome.


Natriuretic peptides, respiratory disease, and the right heart.
It is well-recognized that atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are raised in conditions with ventricular volume and pressure overload. In addition to this established role in left ventricular congestive cardiac failure, there is good evidence that BNP has a diagnostic role in right ventricular (RV) dysfunction and pulmonary arterial hypertension (PAH). For example, BNP levels can be used to differentiate between dyspneic patients with pure respiratory defects and those with RV dysfunction. Studies in patients with PAH have demonstrated significant correlations between BNP levels and mean pulmonary arterial pressure as well as pulmonary vascular resistance. Additionally, BNP has a prognostic role in patients with RV pressure overload and pulmonary hypertension, and it offers a noninvasive test that can be used to guide therapy in patients with PAH. However, although measured plasma proBNP levels are raised in conditions with RV overload, its biological significance is still not well-understood. In this article, we review the general physiologic and potential therapeutic role of natriuretic peptides in respiratory disease, RV dysfunction, and PAH. Furthermore, we assess the various clues toward natriuretic peptide action coming from laboratory studies. ANP and BNP knockout mice develop cardiac fibrosis and hypertrophy. Potentiation of the natriuretic pathway has been shown to reduce cardiac hypertrophy and PAH. This is likely to take place as a result of increased intracellular cyclic guanosine monophosphate levels and subsequent pulmonary vasorelaxant activity. In view of this evidence, there may be a rationale for the therapeutic use of recombinant BNP or neutral endopeptidase inhibitors under conditions of RV dysfunction and PAH.


Classification of Muscle-Invasive Bladder Cancer Based on Immunogenomic Profiling.
There is a significant heterogeneity in the immunotherapeutic responsiveness of each muscle-invasive bladder cancer (MIBC) patient. In our research, we aimed to identify a novel classification of MIBC based on immunogenomic profiling that may facilitate the reasonable stratification of prognosis and response to immunotherapy. The single-sample gene-set enrichment analysis (ssGSEA) was used to analyze the RNA-seq data of 29 important immune signatures from TCGA. Unsupervised hierarchical clustering was performed to identify an immunogenomic classification of MIBC. Then, we assessed the features of the classification in prognosis, immune infiltration, tumor-infiltration lymphocytes, HLA genes, and PD-L1 expression level. A total of 399 MIBC samples were included and three subtypes named Immunity_High, Immunity_Medium, and Immunity_Low were identified. The Immunity_High had a significant advantage in overall survival over the Immunity_Medium and Immunity_Low (p = 0.046 and p = 0.024). From Immunity_Low to Immunity_High, immune cell infiltration and stromal content showed an upward trend (p < 0.001). Meanwhile, Immunity_High was associated with a significantly higher proportion of TILs including dendritic cells resting, macrophages M1, mast cells resting, T cells CD4 memory activated, and T cells CD8+. And the expression levels of all HLA genes and PD-L1 of Immunity_High were the highest, consistent (p < 0.001). Two hundred ninety eight MIBC patients treated with immunotherapy from the IMvigor210 were included to form an independent validation cohort to verify the robustness of immunogenomic classification and the ability to predict the response to immunotherapy. This classification had potential clinical implications for predicting prognosis and immunotherapeutic responsiveness of MIBC patients.


"Disease knowledge index" and perspectives on reproductive issues: A nationwide study on 398 women with autoimmune rheumatic diseases.
The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age. We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18-55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149). At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A "Disease Knowledge Index" (DKI) was created to investigate the degree of patients' information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning. Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication.


Anatomy of the Dorsum of the Foot and Its Relevance for Nonsurgical Cosmetic Procedures.
Operative procedures to enhance the aesthetic appearance of the feet are associated with risks. Minimally invasive procedures to volumize the dorsum of the foot are to this point not described. The present study investigates the safety and efficacy of such procedures in a retrospective clinical, anatomical, and ultrasound-based study. A total of 106 feet from 53 female patients (mean age, 64.1 ± 8.3 years) were investigated retrospectively after the injection of a commercially available calcium hydroxylapatite product using a single-entry proximal-to-distal fanning injection technique. Anatomical dissections in 20 fresh, nonembalmed feet from 10 human body donors (mean age, 83.1 ± 8.8 years) were dissected, and 20 feet from 10 healthy volunteers (mean age, 26.5 ± 6.2 years) were examined by ultrasound imaging to help guide conclusions. Aesthetic outcome after 3 months was graded by the patients as 4, connoting good improvement (range, 3 to 5). No allergic reactions or other types of adverse events were documented. The layered anatomy of the dorsum of the foot was confirmed by anatomical dissections and ultrasound imaging as follows: skin, dorsal superficial fatty layer, dorsal superficial fascia, dorsal intermediate fatty layer, superficial lamina of the dorsal deep fascia, dorsal deep fatty layer, and deep lamina of the dorsal deep fascia. Minimally invasive injections of soft-tissue filler in the dorsum of the foot can provide an alternate solution to enhance the aesthetic appearance of feet. The present study provides support for the safety and efficacy of volumizing procedures using a 22-gauge, 50-mm, blunt-tip cannula. Therapeutic, IV.


[Special challenges in the highest-elevation acute-care hospital in Europe].
Oberengadin Hospital in Samedan is faced with particular challenges, as the highest-elevation acute-care hospital in Europe (1750 m = 5,740 ft above sea level). The factors responsible for this are elevation-related and meteorological/climatic influences, as well as seasonal variations in Südbünden's demographic structure due to tourism.


Pump implantation for intrathecal baclofen infusion after laparotomy for necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) and spastic cerebral palsy are both familiar complications of prematurity. Children who are otherwise candidates for intrathecal baclofen infusion occasionally have long, transverse, right midabdominal laparotomy incisions from past management of NEC, and these incisions may interfere with selection of a site for pump implantation. Successful pump implantation immediately beneath a laparotomy incision was accomplished using a modification of the popular subfascial technique.


Nematicidal activity of fluensulfone against some migratory nematodes under laboratory conditions.
The fluoroalkenyl fluensulfone, known to have strong nematicidal activity against Meloidogyne spp. (root-knot nematodes), was evaluated in vitro and in soil against the migratory nematodes Bursaphelenchus xylophilus, Aphelenchoides besseyi, Aphelenchoides fragariae, Ditylenchus dipsaci, Pratylenchus penetrans, Pratylenchus thornei and Xiphinema index. B. xylophilus and D. dipsaci were not immobilised by 48 h in vitro exposure to up to 16 mg L(-1) of fluensulfone. A. besseyi and A. fragariae were affected by 8 mg L(-1) , the highest concentration used for these nematodes. More than 60% of P. penetrans and P. thornei were immobilised by 4 mg L(-1) of fluensulfone; however, exposure of P. penetrans to the compound prior to inoculation did not affect their root penetration ability. The immobilisation rate of X. index was increased by 48 h exposure to even 1.0 mg L(-1) of fluensulfone. Incorporation of over 2 mg L(-1) of fluensulfone into the soil reduced populations of P. penetrans and P. thornei before and after planting lettuce and chickpea respectively. The efficacy of fluensulfone against the tested nematodes was the same or higher than that of fenamiphos in most cases. A. besseyi, A. fragariae, B. xylophilus and D. dipsaci were tolerant to fluensulfone and fenamiphos. P. penetrans, P. thornei and X. index were affected by fluensulfone, but nematicidal activity was much lower than that reported for root-knot nematodes.


VP7 serotype-specific glycoprotein of OSU porcine rotavirus: coding assignment and gene sequence.
With a reassortant from a cross of human rotavirus DS-1 (serotype 2) and OSU (serotype 5) it was determined that the OSU major neutralization glycoprotein antigen (VP7) was encoded by gene segment 9. A full-sized cloned cDNA copy of the OSU gene 9 was produced and sequenced. Hybridization of such labelled cDNA with the corresponding segment of a reassortant DS-1 X OSU virus confirmed the coding assignment. Comparison of the deduced amino acid sequence of the VP7 of OSU with those previously determined for five other rotavirus strains, representing four distinct serotypes, revealed some hydrophilic regions that exhibited significant homology and other hydrophilic domains with greater amino acid divergence. In one of the latter hydrophilic domains each of the five serotypes had a distinct amino acid substitution at residue 146, suggesting that it may be involved in serotype specificity.


Effect of amorolfine (Ro 14-4767/002) on in vitro phagocytosis and intracellular killing of Candida albicans by human neutrophils.
The effect of amorolfine (Ro 14-4767/002) on phagocytosis and intracellular killing of Candida albicans blastospores was determined in human neutrophil monolayer assays. At 0.2, 2 and 5 micrograms/ml amorolfine did not have any significant inhibitory or enhancing effect on phagocytosis whether following simultaneous addition of blastospores and drug to the neutrophils, prior treatment of neutrophils for 2 h before addition of blastospores or prior treatment of blastospores for 2 h. Simultaneous addition of amorolfine resulted in a significant increase in killing at all concentrations. This increase was not significantly enhanced by either preincubation of neutrophils or blastospores for 2 h with the drug.


Very Low Temperature CO Oxidation over Atomically Precise Au25 Nanoclusters on MnO2.
Atomically precise Au25 nanoclusters have garnered significant interest in the field of heterogeneous catalysis due to their remarkable activity and selectivity. However, for the extensively studied reaction of low-temperature CO oxidation, their performance has not been competitive compared to other known gold nanocatalysts. To address this, we deposited Au25(SR)18 (R = CH2CH2Ph) nanoclusters onto a manganese oxide support (Au25/MnO2), resulting in a very stable and highly active catalyst. By optimizing the pretreatment temperature, we were able to significantly enhance the performance of the Au25/MnO2 catalyst, which outperformed most other gold catalysts. Impressively, 100% conversion of CO was achieved at temperatures as low as -50 °C, with 50% conversion being reached below -70 °C. Furthermore, the existence of ligands could also influence the negative apparent activation energy observed at intermediate temperatures. Analysis using X-ray photoelectron spectroscopy (XPS), scanning transmission electron microscopy (STEM), and X-ray diffraction (XRD) techniques indicated that the Au25 nanoclusters remained stable on the catalyst surface even after pretreatment at high temperatures. In-situ modulation excitation spectroscopy (MES) spectra also confirmed that the Au cluster was the active site for CO oxidation, highlighting the potential of atomically precise Au25 nanoclusters as primary active sites at very low temperatures.


Evaluation of the efficiency, trueness, and clinical application of novel artificial intelligence design for dental crown prostheses.
The unique structure of human teeth limits dental repair to custom-made solutions. The production process requires a lot of time and manpower. At present, artificial intelligence (AI) has begun to be used in the medical field and improve efficiency. This study attempted to design a variety of dental restorations using AI and evaluate their clinical applicability. Using inlay and crown restoration types commonly used in dental standard models, we compared differences in artificial wax-up carving (wax-up), artificial digital designs (digital) and AI designs (AI). The AI system was designed using computer calculations, and the other two methods were designed by humans. Restorations were made by 3D printing resin material. Image evaluations were compared with cone beam computed tomography (CBCT) by calculating the root mean squared error. Surface truth results showed that AI (68.4 µm) and digital-designed crowns (51.0 µm) had better reproducibility. Using AI for the crown reduced the time spent by 400% (compared to digital) and 900% (compared to wax-up). Optical microscopic and CBCT images showed that AI and digital designs had close margin gaps (p < 0.05). The margin gap of the crown showed that the wax-up group was 4.1 and 4.3 times greater than those of the AI and digital crowns, respectively. Therefore, the utilization of artificial intelligence can assist in the production of dental restorations, thereby enhancing both production efficiency and accuracy. It is expected that the development of AI can contribute to the reproducibility, efficiency, and goodness of fit of dental restorations.


Effects of β-hydroxy-β-methyl butyrate on working memory and cognitive flexibility in an animal model of aging.
Normal aging results in cognitive decline and nutritional interventions have been suggested as potential approaches for mitigating these deficits. Here, we used rats to investigate the effects of short- and long-term dietary supplementation with the leucine metabolite β-hydroxy-β-methyl butyrate (HMB) on working memory and cognitive flexibility. Beginning ∼12 months of age, male and female Long-Evans rats were given twice daily access to sipper tubes containing calcium HMB (450 mg/kg) or vehicle (285 mg/kg calcium lactate) in a sucrose solution (20% w/v). Supplementation continued for 1 or 7 months (middle- and old-age (OA) groups, respectively) before testing began. Working memory was assessed by requiring rats to respond on a previously sampled lever following various delays. Cognitive flexibility was assessed by training rats to earn food according to a visual strategy and then, once acquired, shifting to an egocentric response strategy. Treatment with HMB improved working memory performance in middle-age (MA) males and OA rats of both sexes. In the cognitive flexibility task, there was a significant age-dependent deficit in acquisition of the visual strategy that was not apparent in OA males treated with HMB. Furthermore, HMB ameliorated an apparent deficit in visual strategy acquisition in MA females. Together, these findings suggest that daily nutritional supplementation with HMB facilitates learning and improves working memory performance. As such, HMB supplementation may mitigate age-related cognitive deficits and may therefore be an effective tool to combat this undesirable feature of the aging process.


Peroxisome proliferation in Foraminifera inhabiting the chemocline: an adaptation to reactive oxygen species exposure?
Certain foraminiferal species are abundant within the chemocline of marine sediments. Ultrastructurally, most of these species possess numerous peroxisomes complexed with the endoplasmic reticulum (ER); mitochondria are often interspersed among these complexes. In the Santa Barbara Basin, pore-water bathing Foraminifera and co-occurring sulfur-oxidizing microbial mats had micromolar levels of hydrogen peroxide (H(2)O(2)), a reactive oxygen species that can be detrimental to biological membranes. Experimental results indicate that adenosine triphosphate concentrations are significantly higher in Foraminifera incubated in 16 microM H(2)O(2) than in specimens incubated in the absence of H(2)O(2). New ultrastructural and experimental observations, together with published results, lead us to propose that foraminiferans can utilize oxygen derived from the breakdown of environmentally and metabolically produced H(2)O(2). Such a capability could explain foraminiferal adaptation to certain chemically inhospitable environments; it would also force us to reassess the role of protists in biogeochemistry, especially with respect to hydrogen and iron. The ecology of these protists also appears to be tightly linked to the sulfur cycle. Finally, given that some Foraminifera bearing peroxisome-ER complexes belong to evolutionarily basal groups, an early acquisition of the capability to use environmental H(2)O(2) could have facilitated diversification of foraminiferans during the Neoproterozoic.


Doxorubicin treatment in vivo activates caspase-12 mediated cardiac apoptosis in both male and female rats.
We investigated in vivo the chemotherapeutic anthracycline agents doxorubicin and its ability to activate mitochondrial-mediated, receptor-mediated and endoplasmic/sarcoplasmic reticulum-mediated apoptosis transduction pathways in cardiac tissue from male and female rats. We administered a single low dose of doxorubicin (10 mg/kg of body weight, i.p.) and then isolated mitochondrial and cytosolic proteins one and four days later from the heart. Caspase-3 protein content and caspase-3 activity were significantly increased after day four of doxorubicin treatment in both male and female rats. However, while males had DNA fragmentation at day one but not day four following doxorubicin administration, females showed no significant increase in DNA fragmentation at either time. Caspase-12, localized in the SR, is considered a central caspase, and its activation by cleavage via calpain indicates activation of the SR-mediated pathway of apoptosis. Cleaved caspase-12 content and calpain activity significantly increased after day four of doxorubicin treatment in both sexes. In the mitochondrial-mediated pathway, there were no significant treatment effects observed in cytosolic cytochrome c and cleaved (active) caspase-9 in either sex. In control rats (saline injection), glutathione peroxidase (GPX) activity and hydrogen peroxide (H2O2) production were lower in females compared to males. Doxorubicin treatment did not significantly affect H2O2, GPX activity or ATP production in isolated mitochondria in either sex. Female rats produced significantly lower levels of H2O2 production one day after doxorubicin treatment, whereas male rats produced significantly less mitochondrial H2O2 four days after doxorubicin treatment. The receptor-mediated pathway (caspase-8 and c-FLIP) showed no evidence of being significantly activated by doxorubicin treatment. Hence, doxorubicin-induced apoptosis in vivo is mediated by the SR to a greater extent than other apoptotic pathways and should therefore be considered for targeted therapeutic interventions. Moreover, no major sex differences exist in apoptosis signaling transduction cascade due to doxorubicin treatment.


Fast algorithm to determine optical properties of a turbid medium from time-resolved measurements.
After analytical expressions for the time-resolved reflectance are introduced from the diffusion approximation under the three most commonly used boundary conditions, a novel algorithm is demonstrated for determining the reduced scattering and the absorption coefficients from time-resolved reflectance (or backscatter) measurements at two positions on the surface of biotissue. The algorithm is straightforward and fast and involves only some simple mathematical operations, avoiding complicated iterative nonlinear fitting to the time-resolved curve. The derived reduced scattering coefficient is not affected by whatever boundary condition is applied. The algorithm was verified with time-resolved data from the Monte Carlo model. Both a semi-infinite medium and a turbid slab medium were tested. In contrast to the nonlinear fitting method, this algorithm allows both the scattering and the absorption coefficients to be determined to a high accuracy.


Skin cornification proteins provide global link between ROS detoxification and cell migration during wound healing.
Wound healing is a complex dynamic process characterised by a uniform flow of events in nearly all types of tissue damage, from a small skin scratch to myocardial infarction. Reactive oxygen species (ROS) are essential during the healing process at multiple stages, ranging from the initial signal that instigates the immune response, to the triggering of intracellular redox-dependent signalling pathways and the defence against invading bacteria. Excessive ROS in the wound milieu nevertheless impedes new tissue formation. Here we identify small proline-rich (SPRR) proteins as essential players in this latter process, as they directly link ROS detoxification with cell migration. A literature-based meta-analysis revealed their up-regulation in various forms of tissue injury, ranging from heart infarction and commensal-induced gut responses to nerve regeneration and burn injury. Apparently, SPRR proteins have a far more widespread role in wound healing and tissue remodelling than their established function in skin cornification. It is inferred that SPRR proteins provide injured tissue with an efficient, finely tuneable antioxidant barrier specifically adapted to the tissue involved and the damage inflicted. Their recognition as novel cell protective proteins combining ROS detoxification with cell migration will provide new venues to study and manage tissue repair and wound healing at a molecular level.


[Serotonin as a neurotrophic factor in the fetal brain: binding, capture and release in centers of axonal growth].
Currently serotonin (5-HT) is recognized as one of the classic neurotransmitters in the adult brain. Results from our laboratory have suggested a trophic role of 5-HT in the fetal brain. Stimulation of 5-HT synthesis during gestation with its precursor, L-tryptophan, has shown the existence of biosynthetic machinery for this amine in the fetal brain. Attempts to demonstrate directly a molecular recognizing system for 5-Ht in the fetal brain have not been conclusive until now. We have profited of a special preparation of axonal growth cones (AGC) derived from neuroblasts of the rat fetal brain. In this neuronal structures actively differentiating we were able to demonstrate a high-affinity and saturable uptake system for 5-HT and the possibility of a regulated release of the amine. In postnatal AGC the 5-Ht uptake has similar kinetics to the adult, whereas fetal AGC have a transitional uptake kinetics with a higher Vmax for the amine. Also in these structures we demonstrated, directly, for the first time, a specific binding system for (3H) 5-HT, saturable, reversible and of high affinity. Altogether, these results strongly support the hypothesis of an important trophic role of 5-HT during neurogenesis.


Lymphocytic thyroiditis in beagle dogs in a breeding colony: findings of serum autoantibodies.
Three serum autoantibodies against antigens of the thyroid gland were detected by the indirect immunofluorescence in a Beagle dog breeding colony. The anti-thyroglobulin autoantibody was present in 10.0%, the anti-microsomal antigen autoantibody was present in 24.6%, and the anti-nuclear substance autoantibody in 10.8% of examined sera, respectively. Only the presence of anti-thyroglobulin autoantibodies could be correlated with histologic findings of the lymphocytic thyroiditis in the same colony.


Magnetized inulin by Fe3O4 as a bio-nano adsorbent for treating water contaminated with methyl orange and crystal violet dyes.
Current work focuses on fabricating a new bio-nano adsorbent of Fe3O4@inulin nanocomposite via an in-situ co-precipitation procedure to adsorb methyl orange (MO) and crystal violet (CV) dyes from aqueous solutions. Different physical characterization analyses verified the successful fabrication of the magnetic nanocomposite. The adsorbent performance in dye removal was evaluated by varying initial dye concentration, adsorbent dosage, pH and temperature in 5110 mg/L, 0.10.8 g/L, 111 and 283-338 K, respectively. Due to the pH of zero point of charge and intrinsic properties of dyes, the optimum pHs were 5 and 7 for MO and CV adsorption, respectively. The correlation of coefficient (R2) and reduced chi-squared value were the criteria in order to select the best isotherm and kinetics models. The Langmuir model illustrated a better fit for the adsorption data for both dyes, demonstrating the maximum adsorption capacity of 276.26 and 223.57 mg/g at 338 K for MO and CV, respectively. As well, the pseudo-second-order model showed a better fitness for kinetics data compared to the pseudo-first-order and Elovich models. The thermodynamic parameters exhibited that the dye adsorption process is endothermic and spontaneous, which supported the enhanced adsorption rate by increasing temperature. Moreover, the nanocomposite presented outstanding capacity and stability after 6 successive cycles by retaining more than 87% of its initial dye removal efficiency. Overall, the magnetized inulin with Fe3O4 could be a competent adsorbent for eliminating anionic and cationic dyes from water.


Intracranial germinoma associated with Down's syndrome. Report of 2 cases.
It is well known that Down's syndrome is sometimes associated with leukemia. However, there have been only a few case reports of a relationship between Down's syndrome and brain tumors. We report 2 cases with histological diagnoses of germinoma. The 1st case was a 10-year-old boy with Down's syndrome complaining of seizure and left hemiparesis. Computed tomographic (CT) scan and magnetic resonance imaging (MRI) showed a mass lesion in the right basal ganglia and thalamus. Histological examination indicated two cell pattern germinomas. The 2nd case was a 20-year-old man with Down's syndrome complaining of headache and vomiting. CT scan and MRI showed a pineal region tumor with marked hydrocephalus. Surgical specimens showed typical germinoma. Only 13 cases of brain tumors associated with Down's syndrome have been reported. A higher incidence of germ cell tumors seems to be related to chromosomal abnormalities.


Comparison of milk consumption and its contribution to total sugar intake in South African and other schoolchildren.
Mean daily milk, lactose and energy intakes were measured in groups of South African school pupils of 9-16 years. Recommended dietary allowances (RDA) were not reached by any of the groups. In comparison, groups of Canadian, Nigerian and German schoolchildren of similar ages fell into two categories, namely high milk consumers and low milk consumers. Lactose and energy intakes for high consumers were 77% of the RDA, compared with 30-40% for low consumers. The lactose contribution to daily energy intake for Canadian children was 10.7% and for South African groups about 5%. Thus for South African children lactose contribution to total sugar intake may be half that of Canadian children. Exact proportions need to be defined.


Topochemical synthesis of cation ordered double perovskite oxynitrides.
Topochemical nitridation in ammonia at moderate temperatures of cation ordered Sr2FeWO6 produces new antiferromagnetic double perovskite oxynitrides Sr2FeWO6-xNx with 0 < x ≤ 1. Nitrogen introduction induces the oxidation of Fe2+ to Fe3+ and decreases TN from 38 K (x = 0) to 13 K for Sr2FeWO5N which represents the first example of a double perovskite oxynitride with both high cationic order and nitrogen content. This synthetic approach can be extended to other cation combinations expanding the possibility of new materials in the large group of double perovskites.


Amnestic mild cognitive impairment: structural MR imaging findings predictive of conversion to Alzheimer disease.
Mild cognitive impairment (MCI) is considered by many to be a prodromal phase of Alzheimer disease (AD). We used voxel-based morphometry (VBM) to find out whether structural differences on MR imaging could offer insight into the development of clinical AD in patients with amnestic MCI at 3-year follow-up. Twenty-four amnestic patients with MCI were included. After 3 years, 46% had progressed to AD (n = 11; age, 72.7 +/- 4.8 years; women/men, 8/3). For 13 patients (age, 72.4 +/- 8.6 years; women/men, 10/3), the diagnosis remained MCI. Baseline MR imaging at 1.5T included a coronal heavily T1-weighted 3D gradient-echo sequence. Localized gray matter differences were assessed with VBM. The converters had less gray matter volume in medial (including the hippocampus) and lateral temporal lobe, parietal lobe, and lateral temporal lobe structures. After correction for age, sex, total gray matter volume, and neuropsychological evaluation, left-sided atrophy remained statistically significant. Specifically, converters had more left parietal atrophy (angular gyrus and inferior parietal lobule) and left lateral temporal lobe atrophy (superior and middle temporal gyrus) than stable patients with MCI. By studying 2 MCI populations, converters versus nonconverters, we found atrophy beyond the medial temporal lobe to be characteristic of patients with MCI who will progress to dementia. Atrophy of structures such as the left lateral temporal lobe and left parietal cortex may independently predict conversion.


The mechanisms of inactivation of sulfite oxidase by periodate and arsenite.
The inactivation of sulfite oxidase, a molybdoenzyme containing the Mo cofactor, by arsenite and periodate was investigated. In contrast to ferricyanide (Gardlik, S., and Rajagopalan, K.V. (1991) J. Biol. Chem. 266, 4889-4895), neither of these reagents causes oxidation of the pterin ring of the Mo cofactor. Instead, inactivation by these reagents appears to involve attack on sulfhydryl groups at the active site of the enzyme. The inactivation of sulfite oxidase by arsenite was shown to be dependent on the presence of O2 and on the enzymatic oxidation of arsenite to arsenate. The inactivation was preventable by the presence of sulfite, or by the use of cytochrome c as the electron acceptor instead of O2. It is concluded that inactivation by arsenite is the result of arsenite displacement of Mo during enzymatic oxidation of arsenite to arsenate, when Mo transiently breaks its bond to protein or molybdopterin sulfhydryl(s) in order to provide a site for transfer of electrons to O2. Data indicate that arsenite is properly oriented to displace Mo only once every 20,800 turnovers, thus accounting for the slow rate of inactivation by this reagent. Inactivation of sulfite oxidase by periodate is believed to occur as the result of direct attack of periodate on the thiolate ligands of Mo, either those of the protein and/or molybdopterin, leading to Mo loss. Treatment of enzyme with even low levels of periodate resulted in loss of Mo and both sulfite:cytochrome c and sulfite:O2 activities. Molybdopterin of periodate-inactivated enzyme retained the ability to reconstitute nitrate reductase apoprotein in nit-1 extracts and the ability to reduce dichlorophenolindophenol, indicating that the pterin ring had not been oxidized.


1-D elasticity assessment in soft solids from shear wave correlation: the time-reversal approach.
One-channel time-reversal (TR) experiments allow focalization of waves in reverberant cavities. According to the Rayleigh criterion, the focal spot width is directly related to the wavelength and therefore depends on the mechanical properties of the medium. Thus, the general idea of this work is to extract quantitative estimations of these mechanical properties using a time-reversal approach based on cross-correlations of the wave field. An external source creates mechanical waves in the audible frequency range. One component of the vectorial field is measured along a line as function of time with signal processing developed in the field of 1-D elastography. The shear wavelength information is deduced from these mechanical waves using spatiotemporal correlations and interpreted in the frame of the time-reversal symmetry. The impact of wave attenuation in soft solids is reduced using a spatial average of the correlation field. The result is shown to be suitable for global elasticity estimation. The advantage is that the technique is almost independent of the source kind, shape, and time excitation function. This robustness as regard to shear wave source allows translation of this technique to applications in the medical field, including deep or moving organs.


Deletion of the Parkin co-regulated gene causes defects in ependymal ciliary motility and hydrocephalus in the quakingviable mutant mouse.
The quakingviable mouse (qkv) is a spontaneous recessive mouse mutant with a deletion of approximately 1.1 Mb in the proximal region of chromosome 17. The deletion affects the expression of three genes; quaking (Qk), Parkin-coregulated gene (Pacrg) and parkin (Park2). The resulting phenotype, which includes dysmyelination of the central nervous system and male sterility, is due to reduced expression of Qk and a complete lack of Pacrg expression, respectively. Pacrg is required for correct development of the spermatozoan flagella, a specialized type of motile cilia. In vertebrates, motile cilia are required for multiple functions related to cellular movement or movement of media over a stationary cell surface. To investigate the potential role of PACRG in motile cilia we analysed qkv mutant mice for evidence of cilial dysfunction. Histological and magnetic resonance imaging analyses demonstrated that qkv mutant mice were affected by acquired, communicating hydrocephalus (HC). Structural analysis of ependymal cilia demonstrated that the 9 + 2 arrangement of axonemal microtubules was intact and that both the density of ciliated cells and cilia length was similar to wild-type littermates. Cilia function studies showed a reduction in ependymal cilial beat frequency and cilial mediated flow in qkv mutant mice compared with wild-type littermate controls. Moreover, transgenic expression of Pacrg was necessary and sufficient to correct this deficit and rescue the HC phenotype in the qkv mutant. This study provides novel in vivo evidence that Pacrg is required for motile cilia function and may be involved in the pathogenesis of human ciliopathies, such as HC, asthenospermia and primary ciliary dyskinesia.


Advances in mesenchymal stem cell-based strategies for cartilage repair and regeneration.
Significant research efforts have been undertaken in the last decade in the development of stem cell-based therapies for cartilage repair. Among the various stem cell sources, mesenchymal stem cells (MSCs) demonstrate great promise and clinical efficacy in cartilage regeneration. With a deeper understanding of stem cell biology, new therapeutics and new bioengineering approaches have emerged and showed potential for further developments. Of note, there has been a paradigm shift in applying MSCs for tissue regeneration from the use of stem cells for transplantation to the use of stem cell-derived matrix and secretome components as therapeutic tools and agents for cartilage regeneration. In this review, we will discuss the emerging role of MSCs in cartilage regeneration and the most recent advances in development of stem cell-based therapeutics for cartilage regeneration.


Drinking water quality management progress in Ontario, two decades after Walkerton.
Following the waterborne disease outbreak in Walkerton, Ontario, the province made significant efforts to implement recommendations of the public inquiry that resulted. As Ontario reformed its drinking water sector, other jurisdictions were advancing risk-based quality management frameworks for drinking water, including the World Health Organization (WHO) through its water safety plan (WSP) framework. Two decades after the Walkerton tragedy, this paper seeks to: (i) evaluate alignment of Ontario's Drinking Water Quality Management Standard (DWQMS) with the WSP framework (ii) review readily available data for evidence that Ontario's DWQMS implementation has improved drinking water safety and promoted a preventive approach through risk-based quality management. Our study found strong alignment between the Ontario DWQMS and WSP frameworks, with supporting programmes and risk assessment procedures present. Analysis of available regulatory data revealed abundant reporting of water quality and adverse incidents in municipal water systems. However, performance data were publicly available, the use of percentage scores for water quality testing obscures the details of system performance and water safety. Reports describing the DWQMS plan and audit results were difficult to obtain and not standardized. There is a need to develop mechanisms to ensure continual improvement of the DWQMS.