The Potentiation of Anti-Tumor Immunity by Tumor Abolition with Alpha Particles, Protons, or Carbon Ion Radiation and Its Enforcement by Combination with Immunoadjuvants or Inhibitors of Immune Suppressor Cells and Checkpoint Molecules.
The delivery of radiation therapy (RT) for cancer with intent to cure has been optimized and standardized over the last 80 years. Both preclinical and clinical work emphasized the observation that radiation destroys the tumor and exposes its components to the immune response in a mode that facilitates the induction of anti-tumor immunity or reinforces such a response. External beam photon radiation is the most prevalent in situ abolition treatment, and its use exposed the "abscopal effect". Particle radiotherapy (PRT), which has been in various stages of research and development for 70 years, is today available for the treatment of patients in the form of alpha particles, proton, or carbon ion radiotherapy. Charged particle radiotherapy is based on the acceleration of charged species, such as protons or carbon-12, which deposit their energy in the treated tumor and have a higher relative biological effectiveness compared with photon radiation. In this review, we will bring evidence that alpha particles, proton, or carbon ion radiation can destroy tumors and activate specific anti-tumor immune responses. Radiation may also directly affect the distribution and function of immune cells such as T cells, regulatory T cells, and mononuclear phagocytes. Tumor abolition by radiation can trigger an immune response against the tumor. However, abolition alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement abolition to reinforce the anti-tumor immunity to better eradicate residual local and metastatic tumor cells. Various methods and agents such as immunoadjuvants, suppressor cell inhibitors, or checkpoint inhibitors were used to manipulate the immune response in combination with radiation. This review deals with the manifestations of particle-mediated radiotherapy and its correlation with immunotherapy of cancer.


[Syncope in the elderly].
Age-related physiologic changes, a higher prevalence of chronic illness, and concomitant (often multiple) medication account for a higher susceptibility of elderly patients to syncope. Although elderly patients are the largest group with syncope, the causes frequently remain unclear. Multifactorial causes, lack of witnesses, overlap with falls, and additional cognitive impairment often confound the assessment of syncope in the elderly. Thus, strategic investigation is often needed to establish the diagnosis and to unmask the cause. In addition to a comprehensive medical history (by both patient and witnesses), a thorough physical examination including supine and standing blood pressure measurements and a standard 12 lead ECG remain the mainstay of diagnosis. The decision whether additional tests are needed depends on indications whether organic heart disease is present or not. Without evidence of structural heart disease, tilt table testing and studies of autonomic function are the next steps. In contrast, additional cardiac investigation (including invasive studies) is needed in patients with suspected or documented cardiac disease. External or implantable loop recorders represent a significant improvement in the diagnosis of rare episodes of (brady- or tachy)-arrhythmias. Prognosis is determined by the underlying (heart) disease.


Airway bacteria measured by quantitative polymerase chain reaction and culture in patients with stable COPD: relationship with neutrophilic airway inflammation, exacerbation frequency, and lung function.
Potentially pathogenic microorganisms can be detected by quantitative real-time polymerase chain reaction (qPCR) in sputum from patients with COPD, although how this technique relates to culture and clinical measures of disease is unclear. We used cross-sectional and longitudinal data to test the hypotheses that qPCR is a more sensitive measure of bacterial presence and is associated with neutrophilic airway inflammation and adverse clinical outcomes. Sputum was collected from 174 stable COPD subjects longitudinally over 12 months. Microbial sampling using culture and qPCR was performed. Spirometry and sputum measures of airway inflammation were assessed. Sputum was qPCR-positive (>10(6) copies/mL) in 77/152 samples (Haemophilus influenzae [n=52], Moraxella catarrhalis [n=24], Streptococcus pneumoniae [n=19], and Staphylococcus aureus [n=7]). Sputum was culture-positive in 50/174 samples, with 49 out of 50 culture-positive samples having pathogen-specific qPCR bacterial loads >10(6) copies/mL. Samples that had qPCR copy numbers >10(6)/mL, whether culture-positive or not, had increased sputum neutrophil counts. H. influenzae qPCR copy numbers correlated with sputum neutrophil counts (r=0.37, P<0.001), were repeatable within subjects, and were >10(6)/mL three or more times in 19 patients, eight of whom were repeatedly sputum culture-positive. Persistence, whether defined by culture, qPCR, or both, was associated with a higher sputum neutrophil count, lower forced expiratory volume in 1 second (FEV1), and worsened quality of life. qPCR identifies a significant number of patients with potentially bacteria-associated neutrophilic airway inflammation and disease that are not identified by traditional culture-based methods.


Y-box binding protein, YB-1, as a marker of tumor aggressiveness and response to adjuvant chemotherapy in breast cancer.
The Y-box binding protein 1 (YB-1) regulates gene expression through transcription and translation. YB-1 has been shown to be associated with up-regulation of P-glycoprotein (Pgp), an ATP-binding transporter involved in multi-drug resistance. In this study, we determined the prognostic significance of YB-1 and its relationship with Pgp in patients with breast cancer. YB-1 and Pgp expression were evaluated by immunohistochemistry in resected specimens of infiltrative ductal breast cancers from 99 patients and 57 patients respectively and correlated with clinicopathological parameters and adjuvant chemotherapy regimes. The antibody for the YB-1 protein was prepared by injecting a rabbit with a purified recombinant chicken YB1 protein. The relationship between YB-1 and Pgp was also evaluated by a computational approach using the Resonant Recognition Model (RRM). We found that breast tumors which were both estrogen receptor-negative and lymph node positive were associated with high YB-1 expression (P=0.017). In patients who did not receive adjuvant chemotherapy, recurrence risk was reduced in breast cancers having lower YB-1 expression (P=0.034), suggesting that high levels of YB-1 expression in breast cancer is associated with tumor aggressiveness. We were able to demonstrate a direct interaction between YB-1 and Pgp using the computer-based RRM. Interestingly, we found that patients who were on a chemotherapy regime which contained an anthracycline (a Pgp substrate) and subsequently developed recurrence, had a higher YB-1 score compared to patients on the Cyclophosphamide/Methotrexate/5-Fluorouracil regime (P=0.024). YB-1 expression in breast cancer may be a potential marker of chemoresistance and could possibly aid in selection of the appropriate adjuvant chemotherapy regime for breast cancers.


Human kappa chain expression in a lambda phage vector: methods of isolating amplified cDNA affects cloning efficiency.
Three common methods of isolating amplified DNA were evaluated for their effects on cloning efficiency in a phage vector designed to express human kappa chain. The "glass milk" technique gave higher cloning efficiency and protein expression than phenol-chloroform extraction or microfiltration. This shows that the quality of amplified cDNA should be considered when studying the human antibody repertoire using this vector system.


Delaying Middle School and High School Start Times Promotes Student Health and Performance: An American Academy of Sleep Medicine Position Statement.
During adolescence, internal circadian rhythms and biological sleep drive change to result in later sleep and wake times. As a result of these changes, early middle school and high school start times curtail sleep, hamper a student's preparedness to learn, negatively impact physical and mental health, and impair driving safety. Furthermore, a growing body of evidence shows that delaying school start times positively impacts student achievement, health, and safety. Public awareness of the hazards of early school start times and the benefits of later start times are largely unappreciated. As a result, the American Academy of Sleep Medicine is calling on communities, school boards, and educational institutions to implement start times of 8:30 AM or later for middle schools and high schools to ensure that every student arrives at school healthy, awake, alert, and ready to learn.


Prospective Evaluation of Intra-Articular Sodium Hyaluronate Injection in the Ankle.
Viscosupplementation by injection of hyaluronic acid into the ankle can be used to provide pain relief and to delay the need for surgery in patients with osteoarthritis of the ankle. In the present investigation, we prospectively evaluated 50 consecutive patients (25 males and 25 females) undergoing a 3-injection protocol of sodium hyaluronate viscosupplementation in the ankle from January 2014 to January 2015. The Foot and Ankle Outcomes Score was used to compare the patients' pre- and post-treatment opinions about their ankle problems. The mean pretreatment Foot and Ankle Outcomes Score was 48 ± 6.3 (range 25 to 84) and the 6-month post-treatment score was 78 ± 5.8 (range 48 to 100). This difference was statistically significant (p = .003). From our findings in the present prospective cohort study, we have concluded that intra-articular injection of sodium hyaluronate viscosupplementation is a useful conservative therapy for osteoarthritis of the ankle.


[Neurochemical mechanisms of artifical hypobiosis and chemical thermoregulation].
Artificial hypobiosis in rats and rabbits was modelled using ornid which caused the blockade of neurotransmitter release from adrenergic neurons. The data obtained corroborated the hypothesis of the mechanisms of chemical thermoregulation as well as new ways of controlling these processes up to their complete blockade by means of decreasing adrenergic effects in the organism. Warm-blooded animals were transferred into poikilothermic state and then into hypobiosis under any given body temperature. At 18-20 degrees C, metabolism may be decreased to 1/10 of standard values and the state of hypobiosis may be maintained for a prolonged period remaining eversible without application of any drugs activating or blocking physiological functions.


LncRNA EMX2OS Induces Proliferation, Invasion and Sphere Formation of Ovarian Cancer Cells via Regulating the miR-654-3p/AKT3/PD-L1 Axis.
Long noncoding RNA (lncRNA) deregulation is frequent in human ovarian cancers (OCs), but the role of specific miRNAs involved in this disease remains elusive. LncRNA EMX2OS was previously reported to act as an oncogene in human cancers. However, their accurate expression, function and underlying mechanisms in OC are largely unclear. The levels of EMX2OS in OC tissues and cell lines were determined by quantitative real-time PCR, and the function of EMX2OS was then analyzed both in vitro and in vivo. Luciferase assays and immunoprecipitation assays were performed to analyze the association between EMX2OS and miR-654 expression in OC cells. EMX2OS is overexpressed in human ovarian cancer tissues. Knockdown of EMX2OS reduced, while overexpression of EMX2OS enhanced the proliferation, invasion and sphere formation of OC cells. In addition, EMX2OS enhanced tumor growth in an in vivo xenograft model of human OC. We discovered that EMX2OS directly binds to miR-654 and suppresses its expression, thus leading to the upregulation of AKT3, which served as a direct target of miR-654. Moreover, miR-654 inhibited cell proliferation, invasion and sphere formation, and restoration of AKT3 reversed the effects of EMX2OS silencing or miR-654 overexpression. Furthermore, PD-L1 was identified as the key oncogenic component acting downstream of AKT3 in OC cells. Ectopic expression of PD-L1 reversed the anti-cancer functions by EMX2OS knockdown, AKT3 silencing or miR-654 upregulation in OC cells. These results demonstrated that the EMX2OS/miR-654/AKT3/PD-L1 axis confers aggressiveness in ovarian cancer and may represent a therapeutic target for OC metastasis.


Immunofluorescence for detection of antibodies against human cytomegalovirus-induced membrane antigens.
This paper describes an improved method for the in vitro detection of antibodies specifically directed against human cytomegalovirus (CMV)-induced membrane antigens present on the surface of CMV-infected fibroblasts (CMV-MA). Viable cells were found to be essential for specific visualization of CMV-MA staining. The addition of divalent cations (2.6 mM Ca2+ and 2.2 mM Mg2+) and glucose (180 mM) to the incubation and washing buffers improved the viability and morphology of the cells and increased the cell yield at the end of the assay. Clustering of antigen-antibody complexes on the surface of viable CMV-infected cells was prevented by low-temperature incubation (0 to 4 degrees C) rather than by the addition of agents which act on the metabolism of the cell. No interaction with the CMV-induced Fc receptor was observed at 0 degrees C with either human sera or murine monoclonal antibodies. The specificity of the CMV-MA reaction was confirmed by using monoclonal antibodies to CMV nuclear, cytoplasmic, and membrane-associated antigens. Furthermore, a microplate modification of the membrane fluorescence test is described which is suitable for multisample screening purposes. This method can be applied to the determination of anti-CMV-MA antibody titers in human sera and to the screening of hybridoma supernatants for the presence of antibodies with specificity for CMV-MA.


Dipsogenic effect of urea in rats.
Anephric rats injected subcutaneously with urea in isotonic saline drank much more than anephric control animals receiving isotonic saline alone. The pattern of water intake and urine output of normal rats, repeatedly injected with urea solution, was similar to that of rats injected with dipsogenic hypertonic NaCl and quite different from that of rats receiving furosemide. A well-evident dipsogenic effect (unrelated to the urine output) was observed in normal rats repeatedly injected with urea solution and having a rapid rise of serum urea concentrations. On the contrary, in rats receiving a single load of urea and showing first a very rapid increase, then followed by a slow decrease of serum urea concentrations, the dipsogenic effect was present only initially. These results demonstrate that urea exerts a direct dipsogenic action which may be interpreted as a consequence of an osmotic gradient between the extra- and the intracellular fluid. When this is positive, as in the case of a rapid rise of serum urea levels, cell dehydration ensues and thirst is stimulated. On the contrary, when serum urea levels are decreasing and, presumably, when the intra- and the extracellular concentrations of urea are in equilibrium, no cellular dehydration occurs and thirst does not appear.


Alternative pathways in Angiostrongylus cantonensis (Metastrongyloidea: Angiostrongylidae) transmission.
In order to elucidate the infection pathways of third stage larvae (L3) of Angiostrongylus cantonensis, we performed experiments to assess: (i) the shedding of L3 from two species of experimental veronicellid slugs drowned in water and the ratio of emerged larvae, (ii) the transmission of viable L3 from drowned terrestrial gastropods to aquatic snails, and (iii) the transmission of viable L3 between terrestrial snails. Molluscs were experimentally infected by first stage larvae (L1) of A. cantonensis. Significantly more L3 larvae were released from Veronicella cubensis than from Veronicella sloanei. Numerous L3 were observed in the muscular foot, and also in the connective tissue between internal organs. Experimental exposure of P. maculata to L3 of A. cantonensis liberated from other gastropod species led to their infection and the infectivity of larvae after intermediesis was demonstrated by infection of laboratory rats (Rattus norvegicus). The transmission of L3 was observed in three out of four experiment replications and L3 were retrieved from 6 out of 24 Subulina octona snails. The infected synanthropic molluscs represent a key component in the epidemiology of human infections by A. cantonensis. Escape of L3 larvae from bodies of dead snails or slugs and their ability to infect further gastropod hosts (intermediesis) represents a public health risk. Thus, control of molluscs living in peri-domestic environment is an essential part of prevention of human infections.


A comparison of Web page and slide/tape for instruction in periapical and panoramic radiographic anatomy.
Self-guided slide/tape (ST) and web page (WP) instruction in normal radiographic anatomy of periapical and panoramic images is compared using objective test performance and subjective preference of freshman dental students. A class of seventy-four students was divided into a group studying anatomy in periapical images using WP and a group studying similar ST material. In a modified cross-over design the groups switched presentation technologies to learn anatomy in panoramic images. Students completed self-administered on-line quizzes covering WP materials and conventional quizzes for ST material. Students also completed a voluntary survey. Mean quiz performance identifying matched anatomic features in PA (n = 26) and panoramic images (n = 35) was excellent (96.9%) and not different between image types (p = 0.12) or presentation technologies (p = 0.81). Students preferred WP for accessibility, ease of use, freedom of navigation, and image quality (p < .01). Student comfort level with the quiz formats of the two technologies was not different (p = 0.11). Students experienced a higher rate of mechanical and logistical problems with ST than with WP technology. While 71 percent of the students preferred WP technology, this preference appears to be related to ease of use and facilitation of flexible learning styles rather than improved didactic performance.


Popular Dietary Trends' Impact on Athletic Performance: A Critical Analysis Review.
Nutrition fuels optimal performance for athletes. With increased research developments, numerous diets available, and publicity from professional athletes, a review of dietary patterns impact on athletic performance is warranted. The Mediterranean diet is a low inflammatory diet linked to improved power and muscle endurance and body composition. Ketogenic diets are restrictive of carbohydrates and proteins. Though both show no decrements in weight loss, ketogenic diets, which is a more restrictive form of low-carbohydrate diets, can be more difficult to follow. High-protein and protein-paced versions of low-carbohydrate diets have also shown to benefit athletic performance. Plant-based diets have many variations. Vegans are at risk of micronutrient deficiencies and decreased leucine content, and therefore, decreased muscle protein synthesis. However, the literature has not shown decreases in performance compared to omnivores. Intermittent fasting has many different versions, which may not suit those with comorbidities or specific needs as well as lead to decreases in sprint speed and worsening time to exhaustion. This paper critically evaluates the research on diets in relation to athletic performance and details some of the potential risks that should be monitored. No one diet is universally recommend for athletes; however, this article provides the information for athletes to analyze, in conjunction with medical professional counsel, their own diet and consider sustainable changes that can help achieve performance and body habitus goals.


Medical therapy for intracerebral hematoma with the gamma-aminobutyric acid-A agonist muscimol.
No therapy has been rigorously proven effective for intracerebral hematoma, although surgery is frequently used for some types of lobar hemorrhages. Since intracerebral mass causes significant ischemia in surrounding brain, we reasoned that anti-ischemia therapy might improve outcome after experimental hematoma. We stereotaxically injected varying doses of bacterial collagenase into the caudate nucleus of rats. Four hours later we administered intravenously 2 mg/kg muscimol, a potent agonist of the gamma-aminobutyric acid-A receptor (n = 20); 1 mg/kg MK-801, an antagonist of the N-methyl-D-aspartate receptor (n = 17); or saline (n = 28). Forty-eight hours after collagenase injection we rated each animal using a standard rodent neurological examination. The ratings were compared with the amounts of injected collagenase by the quantal bioassay procedure. Brains were then prepared for histomorphometry and brain volumes estimated. We found that the ED50 for collagenase (amount of enzyme that renders 50% of the subjects abnormal) was 0.77 +/- 0.09 U in saline-treated subjects. Treatment with muscimol significantly increased the ED50 to 1.2 +/- 0.21 U, for a potency ratio of 1.55 +/- 0.34 (t = 1.7, P < .05). MK-801 did not affect outcome. Volume of hematoma was significantly correlated with amount of injected collagenase (n = 33, r = .64, P < .001). Volumes of basal ganglia and white matter were significantly reduced by hemorrhage, and muscimol partially ameliorated this. We conclude that muscimol significantly improves neurological outcome after intracerebral hematoma.


An Overdetermined System of Transform Equations in Support of Robust DCE-MRI Registration With Outlier Rejection.
Quantitative hepatic perfusion parameters derived by fitting dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of liver to a pharmacokinetic model are prone to errors if the dynamic images are not corrected for respiratory motion by image registration. The contrast-induced intensity variations in pre- and postcontrast phases pose challenges for the accuracy of image registration. We propose an overdetermined system of transformation equations between the image volumes in the DCE-MRI series to achieve robust alignment. In this method, we register each volume to every other volume. From the transforms produced by all pairwise registrations, we constructed an overdetermined system of transform equations that was solved robustly by minimizing the L1/2-norm of the residuals. This method was evaluated on a set of 100 liver DCE-MRI examinations from 35 patients by examining the area under spikes appearing in the voxel time-intensity curves. The robust alignment procedure significantly reduced the area under intensity spikes compared with unregistered volumes (P<.001) and volumes registered to a single reference phase (P<.001). Our registration procedure provides a larger number of reliable time-intensity curve samples. The additional reliable samples in the precontrast baseline are important for calculating the postcontrast signal enhancement and thereby for converting intensity to contrast concentration. On the intensity ramp, retained samples help to better describe the uptake dynamics, providing a better foundation for parameter estimation. The presented method also simplifies the analysis of data sets with many patients by eliminating the need for manual intervention during registration.


Hereditary gingival fibromatosis.
Hereditary gingival fibromatosis is a rare benign oral condition characterised by slow and progressive enlargement of both maxillary and mandibular attached gingiva. It may develop as an isolated disorder but can feature along with a syndrome. A case of 12 year old female child who presented with generalised severe gingival overgrowth, involving both the arches and covering almost the entire dentition, and had all the teeth remaining invisible within the confinement of gingival tissues. The excess gingival tissue, in this non-syndromic case was removed by conventional gingivectomy using local as well as general anaesthesia. The post-operative result was uneventful and the patient appearance improved considerably. Good aesthetic result was achieved to allow patient to practice oral hygiene measures. After treatment regular recall visits are necessary in order to evaluate oral hygiene and stability of periodontal treatment.


Factors determining penetrance in familial atypical haemolytic uraemic syndrome.
Inherited abnormalities of complement are found in ∼60% of patients with atypical haemolytic uraemic syndrome (aHUS). Such abnormalities are not fully penetrant. In this study, we have estimated the penetrance of the disease in three families with a CFH mutation (c.3643C>G; p. Arg1215Gly) in whom a common lineage is probable. 25 individuals have been affected with aHUS with three peaks of incidence-early childhood (n=6), early adulthood (n=11) and late adulthood (n=8). Eighteen individuals who have not developed aHUS carry the mutation. We estimated penetrance at the ages of 4, 27, 60 and 70 years as both a binary and a survival trait using MLINK and Mendel. We genotyped susceptibility factors in CFH, CD46 and CFHR1 in affected and unaffected carriers. We found that the estimates of penetrance at the age of 4 years ranged from <0.01 to 0.10, at the age of 27 years from 0.16 to 0.29, at the age of 60 years from 0.39 to 0.51 and at the age of 70 years from 0.44 to 0.64. We found that the CFH haplotype on the allele not carrying the CFH mutation had a significant effect on disease penetrance. In this family, we did not find that the CD46 haplotypes had a significant effect on penetrance.


Isolation of microbes from Lake Vostok accretion ice.
Bacteria from seven Lake Vostok accretion and two deep glacial Vostok ice core sections were characterized. The cell concentrations were low, but many of the cells were viable. From the hundreds of cultures, 18 unique bacterial rRNA gene phylotypes were determined. Lake Vostok may contain a complex microbial ecosystem.


Mitofusins modulate the increase in mitochondrial length, bioenergetics and secretory phenotype in therapy-induced senescent melanoma cells.
Cellular senescence is an endpoint of chemotherapy, and targeted therapies in melanoma and the senescence-associated secretory phenotype (SASP) can affect tumor growth and microenvironment, influencing treatment outcomes. Metabolic interventions can modulate the SASP, and an enhanced mitochondrial energy metabolism supports resistance to therapy in melanoma cells. Herein, we assessed the mitochondrial function of therapy-induced senescent melanoma cells obtained after exposing the cells to temozolomide (TMZ), a methylating chemotherapeutic agent. Senescence induction in melanoma was accompanied by a substantial increase in mitochondrial basal, ATP-linked, and maximum respiration rates and in coupling efficiency, spare respiratory capacity, and respiratory control ratio. Further examinations revealed an increase in mitochondrial mass and length. Alterations in mitochondrial function and morphology were confirmed in isolated senescent cells, obtained by cell-size sorting. An increase in mitofusin 1 and 2 (MFN1 and 2) expression and levels was observed in senescent cells, pointing to alterations in mitochondrial fusion. Silencing mitofusin expression with short hairpin RNA (shRNA) prevented the increase in mitochondrial length, oxygen consumption rate and secretion of interleukin 6 (IL-6), a component of the SASP, in melanoma senescent cells. Our results represent the first in-depth study of mitochondrial function in therapy-induced senescence in melanoma. They indicate that senescence increases mitochondrial mass, length and energy metabolism; and highlight mitochondria as potential pharmacological targets to modulate senescence and the SASP.


High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions.
High dietary fructose is a major contributor to insulin resistance and metabolic syndrome, disturbing tissue and organ functions. Fructose is mainly absorbed into systemic circulation by glucose transporter 2 (GLUT2) and GLUT5, and metabolized in liver to produce glucose, lactate, triglyceride (TG), free fatty acid (FFA), uric acid (UA) and methylglyoxal (MG). Its extrahepatic absorption and metabolism also take place. High levels of these metabolites are the direct dangerous factors. During fructose metabolism, ATP depletion occurs and induces oxidative stress and inflammatory response, disturbing functions of local tissues and organs to overproduce inflammatory cytokine, adiponectin, leptin and endotoxin, which act as indirect dangerous factors. Fructose and its metabolites directly and/or indirectly cause oxidative stress, chronic inflammation, endothelial dysfunction, autophagy and increased intestinal permeability, and then further aggravate the metabolic syndrome with tissue and organ dysfunctions. Therefore, this review addresses fructose-induced metabolic syndrome, and the disturbance effects of direct and/or indirect dangerous factors on the functions of liver, adipose, pancreas islet, skeletal muscle, kidney, heart, brain and small intestine. It is important to find the potential correlations between direct and/or indirect risk factors and healthy problems under excess dietary fructose consumption.


Clinical activity after fingolimod cessation: disease reactivation or rebound?
There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS. Patients with relapsing-remitting MS who were treated with fingolimod for at least 6 months and who stopped treatment for reasons that were unrelated to inefficacy were included in the analysis. A total of 100 patients who had discontinued fingolimod were included in the study. Fourteen patients (14%) had a relapse within 3 months after fingolimod discontinuation, and an additional 12 (12%) had a relapse within 6 months. According to this study's criteria, 10 patients (10%) had a severe reactivation. Amongst these patients, five (5%) had a reactivation that was considered to be a rebound. The present study showed that more than 26% of patients are at risk of having a relapse within 6 months after fingolimod discontinuation. Nevertheless, the risk of severe reactivations and rebound is lower than has been previously described.


Immunogenicity of hepatitis B vaccine in patients infected with Schistosoma mansoni.
Because dual infection with Schistosoma mansoni and hepatitis B may lead to severe liver disease, populations living in schistosomiasis-endemic areas might benefit if effectively immunized against hepatitis B. To determine whether a plasma-derived hepatitis B vaccine is immunogenic in patients with schistosomiasis, 32 individuals infected with S. mansoni were given three 20-micrograms doses of Heptavax-B vaccine and treated with praziquantel. Antibody to hepatitis B surface antigen developed in 90.6% of the study subjects after three doses of vaccine. Five patients (15.6%) had a weak response to the vaccine, and three patients (9.4%) failed to develop antibody. A weak or failed response to the vaccine was significantly associated with the presence of hepatosplenomegaly. A plasma-derived vaccine is immunogenic for persons infected with S. mansoni; however, vaccine response is diminished in hepatosplenic schistosomiasis.


Immune stimulating photoactive hybrid nanoparticles for metastatic breast cancer.
A therapeutic technology that combines the phototoxic and immune-stimulating ability of photodynamic therapy (PDT) with the widespread effectiveness of the immune system can be very promising to treat metastatic breast cancer. We speculated that the knowledge of molecular mechanisms of existing multi-component therapies could provide clues to aid the discovery of new combinations of an immunostimulant with a photosensitizer (PS) using a nanoparticle (NP) delivery platform. Therapeutic challenges when administering therapeutic combinations include the choice of dosages to reduce side effects, the definitive delivery of the correct drug ratio, and exposure to the targets of interest. These factors are very difficult to achieve when drugs are individually administered. By combining controlled release polymer-based NP drug delivery approaches, we were able to differentially deliver zinc phthalocyanine (ZnPc) based PS to metastatic breast cancer cells along with CpG-ODN, a single-stranded DNA that is a known immunostimulant to manage the distant tumors in a temporally regulated manner. We encapsulated ZnPc which is a long-wavelength absorbing PS within a polymeric NP core made up of poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG). After coating the outside of the polymeric core with gold NPs (AuNPs), we further modified the AuNP surface with CpG-ODN. In vitro cytotoxicity using 4T1 metastatic mouse breast carcinoma cells shows significant photocytotoxicity of the hybrid NPs containing both ZnPc and CpG-ODN after irradiation with a 660 nm LASER light and this activity was remarkably better than either treatment alone. Treatment of mouse bone marrow derived dendritic cells with the PDT-killed 4T1 cell lysate shows that the combination of PDT with a synergistic immunostimulant in a single NP system results in significant immune response, which can be used for the treatment of metastatic cancer.


Neutrophil activation by Helicobacter pylori.
Helicobacter pylori infection of the stomach is accompanied by a persistent polymorphonuclear leukocyte (PMNL) infiltrate of the mucosa. The aim of this work was to study the activation of human PMNL by substances produced by H pylori. Filtered H pylori conditioned media stimulated a significant PMNL oxidative burst (p less than 0.002). This was equal to 26% of the maximal response stimulated by the PMNL chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP, 1 mumol/l). The response to FMLP was prolonged by the combined presence of complement inactivated human anti-H pylori plasma and conditioned medium (p less than 0.002). High pressure liquid chromatography of an extract of conditioned medium showed a fraction that stimulated PMNL, eluted, and antigenically cross reacted with FMLP. Washed H pylori cells, and those opsonised with complement inactivated human anti-H pylori plasma, did not induce a significant oxidative burst. Opsonized H pylori, however, prolonged the oxidative burst induced by FMLP (p less than 0.02). In conclusion, H pylori synthesizes and secretes a substance, probably FMLP, that may account for the PMNL accumulation that accompanies H pylori infections. Immune complexes composed of H pylori antigen and specific antibody potentiate the PMNL oxidative burst. This combination of H pylori derived products, and host PMNL and antibodies, may be involved in the mucosal damage observed in H pylori associated gastritis.


Enhanced protein breakdown after eccentric exercise in young and older men.
The effects of eccentric exercise on whole body protein metabolism were compared in five young untrained [age 24 +/- 1 yr, maximal O2 uptake (VO2max) = 49 +/- 6 ml.kg-1.min-1] and five older untrained men (age 61 +/- 1 yr, VO2max = 34 +/- 2 ml.kg-1.min-1). They performed 45 min of eccentric exercise on a cycle ergometer at a power output equivalent to 80% VO2max (182 +/- 18 W). Beginning 5 days before exercise and continuing for at least 10 days after exercise, they consumed a eucaloric diet providing 1.5 g.kg-1.day-1 of protein. Leucine metabolism in the fed state was measured before, immediately after, and 10 days after exercise, with intravenous L-[1-13C]leucine as a tracer (0.115 mumol.kg-1.min-1). Leucine flux increased 9% immediately after exercise (P less than 0.011) and remained elevated 10 days later, with no effect of age. Leucine oxidation increased 19% immediately after exercise and remained 15% above baseline 10 days after exercise (P less than 0.0001), with no effect of age. In the young men, urinary excretion of 3-methylhistidine per gram of creatinine did not increase until 10 days postexercise (P less than 0.05), but in the older men, it increased 5 days after exercise and remained high through 10 days postexercise (P less than 0.05), averaging 37% higher than in the young men. These data suggest that eccentric exercise produces a similar increase in whole body protein breakdown in older and young men, but myofibrillar proteolysis may contribute more to whole body protein breakdown in the older group.


Recurrent t(2;2) and t(2;8) translocations in rhabdomyosarcoma without the canonical PAX-FOXO1 fuse PAX3 to members of the nuclear receptor transcriptional coactivator family.
The fusion oncoproteins PAX3-FOXO1 [t(2;13)(q35;q14)] and PAX7-FOXO1 [t(1;13)(p36;q14)] typify alveolar rhabdomyosarcoma (ARMS); however, 20-30% of cases lack these specific translocations. In this study, cytogenetic and/or molecular characterization to include FISH, reverse transcription polymerase chain reaction (RT-PCR), and sequencing analyses of five rhabdomyosarcomas [four ARMS and one embryonal rhabdomyosarcoma (ERMS)] with novel, recurrent t(2;2)(p23;q35) or t(2;8)(q35;q13) revealed that these noncanonical translocations fuse PAX3 to NCOA1 or NCOA2, respectively. The PAX3-NCOA1 and PAX3-NCOA2 transcripts encode chimeric proteins composed of the paired-box and homeodomain DNA-binding domains of PAX3, and the CID domain, the Q-rich region, and the activation domain 2 (AD2) domain of NCOA1 or NCOA2. To investigate the biological function of these recurrent variant translocations, the coding regions of PAX3-NCOA1 and PAX3-NCOA2 cDNA constructs were introduced into expression vectors with tetracycline-regulated expression. Both fusion proteins showed transforming activity in the soft-agar assay. Deletion of the AD2 portion of the PAX3-NCOA fusion proteins reduced the transforming activity of each chimeric protein. Similarly, but with greater impact, CID domain deletion fully abrogated the transforming activity of the chimeric protein. These studies (1) expand our knowledge of PAX3 variant translocations in RMS with identification of a novel PAX3-NCOA2 fusion, (2) show that both PAX3-NCOA1 and PAX3-NCOA2 represent recurrent RMS rearrangements, (3) confirm the transforming activity of both translocation events and demonstrate the essentiality of intact AD2 and CID domains for optimal transforming activity, and (4) provide alternative approaches (FISH and RT-PCR) for detecting PAX-NCOA fusions in nondividing cells of RMS. The latter could potentially be used as aids in diagnostically challenging cases.


[Effect of amino acids and proteins on bacitracin and exoprotease synthesis by Bacillus licheniformis].
Amino acids and proteins were found to produce different effect on the synthesis of bacitracin and exoprotease by Bacillus licheniformis 28 KA depending on the age of the cells. The enzyme synthesis was induced by amino acids and proteins only in the cells at the exponential growth phase. No correlation could be established between the antibiotic and proteolytic activities. The optimal protease synthesis was found in a medium with isoleucine whereas the antibiotic synthesis was optimal in a medium containing no amino acids.


Chronic beetroot juice supplementation attenuates neuromuscular fatigue etiology during simulated soccer match play.
The aim of the present study was to assess the effect of beetroot juice supplementation (BEET) on neuromuscular fatigue etiology during simulated soccer match play. In a randomized, double-blind, crossover design, 13 soccer players completed the Loughborough Intermittent Shuttle Test (LIST). Players received either BEET (2×150 mL; ∼8 mmol/L nitrate) or placebo (PLA) for 7 days (6 days prior to the experimental session and on the day of trial, 2 h before LIST). Neuromuscular assessments were performed at baseline, 45 min (half time: HT), and 90 min (full time: FT) following LIST. Maximal voluntary contraction (MVC) and twitch responses, delivered through electrical femoral nerve stimulation, were used to assess peripheral (quadriceps resting twitch force Qtw,pot) and central fatigue (voluntary activation, VA). Compared with baseline, MVC Qtw,pot and VA values decreased in PLA and BEET conditions at HT and FT (P < 0.05). Compared with PLA, the decrease in MVC and Qtw,pot was significantly attenuated with BEET at HT and FT (P < 0.001). Likewise, BEET attenuated the decrease in VA at HT (P < 0.001, d = 1.3) and FT (P < 0.001, d = 1.5) compared with the PLA condition. Chronic beetroot juice supplementation attenuates neuromuscular fatigue development during simulated soccer matches, and this is due to both central and peripheral factors. Consequently, chronic beetroot may optimize physical performance.


Development and evaluation of a palliative medicine curriculum for third-year medical students.
To assess the impact, retention, and magnitude of effect of a required didactic and experiential palliative care curriculum on third-year medical students' knowledge, confidence, and concerns about end-of-life care, over time and in comparison to benchmark data from a national study of internal medicine residents and faculty. Prospective study of third-year medical students prior to and immediately after course completion, with a follow-up assessment in the fourth year, and in comparison to benchmark data from a large national study. Internal Medicine Clerkship in a public accredited medical school. Five hundred ninety-three third-year medical students, from July 2002 to December 2007. Pre- and postinstruction performance on: knowledge, confidence (self-assessed competence), and concerns (attitudes) about end-of-life care measures, validated in a national study of internal medicine residents and faculty. Medical student's reflective written comments were qualitatively assessed. Required 32-hour didactic and experiential curriculum, including home hospice visits and inpatient hospice care, with content drawn from the AMA-sponsored Education for Physicians on End-of-life Care (EPEC) Project. Analysis of 487 paired t tests shows significant improvements, with 23% improvement in knowledge (F(1,486)=881, p<0.001), 56% improvement in self-reported competence (F(1,486)=2,804, p<0.001), and 29% decrease in self-reported concern (F(1,486)=208, p<0.001). Retesting medical students in the fourth year showed a further 5% increase in confidence (p<0.0002), 13% increase in allaying concerns (p<0.0001), but a 6% drop in knowledge. The curriculum's effect size on M3 students' knowledge (0.56) exceeded that of a national cross-sectional study comparing residents at progressive training levels (0.18) Themes identified in students' reflective comments included perceived relevance, humanism, and effectiveness of methods used to teach and assess palliative care education. We conclude that required structured didactic and experiential palliative care during the clinical clerkship year of medical student education shows significant and largely sustained effects indicating students are better prepared than a national sample of residents and attending physicians.


Zoonotic Diseases from Horses: A Systematic Review.
Background: Worldwide, horses play critical roles in recreation, food production, transportation, and as working animals. Horses' roles differ by geographical region and the socioeconomic status of the people, but despite modern advances in transportation, which have in some ways altered humans contact with horses, potential risks for equine zoonotic pathogen transmission to humans occur globally. While previous reports have focused upon individual or groups of equine pathogens, to our knowledge, a systematic review of equine zoonoses has never been performed. Methods: Using PRISMA's systematic review guidelines, we searched the English literature and identified 233 previous reports of potential equine zoonoses found in horses. We studied and summarized their findings with a goal of identifying risk factors that favor disease transmission from horses to humans. Results: These previous reports identified 56 zoonotic pathogens that have been found in horses. Of the 233 articles, 13 involved direct transmission to humans (5.6%).The main potential routes of transmission included oral, inhalation, and cutaneous exposures. Pathogens most often manifest in humans through systemic, gastrointestinal, and dermatological signs and symptoms. Furthermore, 16.1% were classified as emerging infectious diseases and thus may be less known to both the equine and human medical community. Sometimes, these infections were severe leading to human and equine death. Conclusions: While case reports of zoonotic infections directly from horses remain low, there is a high potential for underreporting due to lack of knowledge among health professionals. Awareness of these zoonotic pathogens, their disease presentation in horses and humans, and their associated risk factors for cross-species infection are important to public health officials, clinicians, and people with recreational or occupational equid exposure.


Dependence of fluence errors in dynamic IMRT on leaf-positional errors varying with time and leaf number.
In d-MLC based IMRT, leaves move along a trajectory that lies within a user-defined tolerance (TOL) about the ideal trajectory specified in a d-MLC sequence file. The MLC controller measures leaf positions multiple times per second and corrects them if they deviate from ideal positions by a value greater than TOL. The magnitude of leaf-positional errors resulting from finite mechanical precision depends on the performance of the MLC motors executing leaf motions and is generally larger if leaves are forced to move at higher speeds. The maximum value of leaf-positional errors can be limited by decreasing TOL. However, due to the inherent time delay in the MLC controller, this may not happen at all times. Furthermore, decreasing the leaf tolerance results in a larger number of beam hold-offs, which, in turn leads, to a longer delivery time and, paradoxically, to higher chances of leaf-positional errors (< or = TOL). On the other end, the magnitude of leaf-positional errors depends on the complexity of the fluence map to be delivered. Recently, it has been shown that it is possible to determine the actual distribution of leaf-positional errors either by the imaging of moving MLC apertures with a digital imager or by analysis of a MLC log file saved by a MLC controller. This leads next to an important question: What is the relation between the distribution of leaf-positional errors and fluence errors. In this work, we introduce an analytical method to determine this relation in dynamic IMRT delivery. We model MLC errors as Random-Leaf Positional (RLP) errors described by a truncated normal distribution defined by two characteristic parameters: a standard deviation sigma and a cut-off value deltax0 (deltaxo approximately TOL). We quantify fluence errors for two cases: (i) deltax0 >> sigma (unrestricted normal distribution) and (ii) deltax0 << sigma (deltax0--limited normal distribution). We show that an average fluence error of an IMRT field is proportional to (i) sigma/ALPO and (ii) deltax0/ALPO, respectively, where ALPO is an Average Leaf Pair Opening (the concept of ALPO was previously introduced by us in Med. Phys. 28, 2220-2226 (2001). Therefore, dose errors associated with RLP errors are larger for fields requiring small leaf gaps. For an N-field IMRT plan, we demonstrate that the total fluence error (if we neglect inhomogeneities and scatter) is proportional to 1/square root of N, where N is the number of fields, which slightly reduces the impact of RLP errors of individual fields on the total fluence error. We tested and applied the analytical apparatus in the context of commercial inverse treatment planning systems used in our clinics (Helios and BrainScan). We determined the actual distribution of leaf-positional errors by studying MLC controller (Varian Mark II and Brainlab Novalis MLCs) log files created by the controller after each field delivery. The analytically derived relationship between fluence error and RLP errors was confirmed by numerical simulations. The equivalence of relative fluence error to relative dose error was verified by a direct dose calculation. We also experimentally verified the truthfulness of fluences derived from the log file data by comparing them to film data.


Ethiopian origin high-risk youth: a cross-cultural examination of alcohol use, binge drinking, and problem behavior.
Alcohol use among underage youth has a major impact on public health, accidents, fatalities, and other problem behaviors. In Israel, alcohol use, binge drinking, and related problem behaviors are a growing concern. The purpose of this study was to examine underserved and underreported Ethiopian origin youth by comparing their substance use patterns and behavior with other high-risk youth. Data were collected from a purposive sample of boys of Ethiopian, former Soviet Union, and Israeli origin who were receiving treatment for drug use. Youth were asked to complete a simply worded self-report questionnaire developed for monitoring substance use and related problem behaviors. Ethiopian youth reported higher rates of family unemployment and public welfare dependence, last 30-day consumption of beer and hard liquor, serious fighting, and achievement decline when in school compared with the other youths. Findings highlight the need for ethno-cultural specific prevention and intervention efforts and further research of this high-risk, underserved group of immigrant origin youth.


Exploring In Vivo Models of Musculoskeletal Frailty: A Comprehensive Systematic Review.
Musculoskeletal frailty-a common and debilitating condition linked to aging and chronic diseases-presents a major public health issue. In vivo models have become a key tool for researchers as they investigate the condition's underlying mechanisms and develop effective interventions. This systematic review examines the current body of research on in vivo models of musculoskeletal frailty, without any time constraints. To achieve this aim, we utilized three electronic databases and incorporated a total of 11 studies. Our investigation delves into varied animal models that simulate specific features of musculoskeletal frailty, including muscle loss, bone density reduction, and functional decline. Furthermore, we examine the translational prospects of these models in augmenting our comprehension of musculoskeletal frailty and streamlining the production of groundbreaking therapeutic approaches. This review provides significant insights and guidance for healthcare researchers and practitioners who aim to combat musculoskeletal frailty, ultimately enhancing the quality of life for older adults and individuals affected by this condition.


The utility of basal serum LH in prediction of central precocious puberty in girls.
The mainstay of distinction between prepubertal girls and girls who are suspected of having central precocious puberty (CPP) is based on gonadotropin measurements after a GnRH stimulation test to evaluate hypothalamic-pituitary-gonadal axis maturity. The objective of this study was to determine whether a single basal gonadotropin measurement carries a useful predictive value in verifying or refuting the diagnosis of CPP. Basal serum LH and FSH were measured by a chemiluminescent immunometric assay in a cohort of girls who had been evaluated for CPP before and after GnRH stimulation test. Peak LH levels higher than 5 IU/l were considered a pubertal response. Eighty girls with suspected breast development before 8 years of age were enrolled to the study, out of whom 42 had CPP. Low basal serum LH (≤0.1 IU/l) was sufficient to rule out the diagnosis of CPP in 94.7% of the 38 prepubertal girls; the sensitivity of basal LH levels for this purpose was only 64%. The basal FSH and the basal LH to FSH ratio achieved less efficient predictive value with 76 and 71% sensitivity and 73 and 86% specificity respectively. A single basal LH measurement may be adequate to confirm but not to refute the presence of CPP in most of the girls who are evaluated for early pubertal signs.


Comparison of LACE and HOSPITAL Readmission Risk Scores for CMS Target and Nontarget Conditions.
This study evaluated the utility and performance of the LACE index and HOSPITAL score with consideration of the type of diagnoses and assessed the accuracy of these models for predicting readmission risks in patient cohorts from 2 large academic medical centers. Admissions to 2 hospitals from 2011 to 2015, derived from the Vizient Clinical Data Base and regional health information exchange, were included in this study (291 886 encounters). Models were assessed using Bayesian information criterion and area under the receiver operating characteristic curve. They were compared in CMS diagnosis-based cohorts and in 2 non-CMS cancer diagnosis-based cohorts. Overall, both models for readmission risk performed well, with LACE performing slightly better (area under the receiver operating characteristic curve 0.73 versus 0.69; P ≤ 0.001). HOSPITAL consistently outperformed LACE among 4 CMS target diagnoses, lung cancer, and colon cancer. Both LACE and HOSPITAL predict readmission risks well in the overall population, but performance varies by salient, diagnosis-based risk factors.


De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.
Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.


Restriction endonuclease studies of hyperplastic outgrowth lines from BALB/cfC3H mouse hyperplastic mammary nodules.
The DNA's isolated from five mouse hyperplastic mammary gland outgrowth lines from BALB/cfC3H mice were digested with the restriction endonucleases PsTI, BamHI, or EcoRI; electrophoresed; and analyzed by Southern blotting and autoradiography. Proviral DNA sequences from the acquired C3H mouse mammary tumor virus were detected in the DNA of all five lines, indicating that they were infected. The DNA of the five hyperplastic lines contained more EcoRI and BamHI mouse mammary tumor virus proviral DNA fragments than did DNA from normal organs, suggesting that the hyperplastic tissues were composed of more homogeneous cell populations than was lactating mammary gland. Each hyperplastic line had unique and reproducible BamHI and EcoRI restriction (integration) patterns which were stable over as many as seven transplant generations. Three sublines, which originated from the same hyperplastic alveolar nodule, had unique integration patterns but also shared several fragments. On the basis of these observations, we propose that mouse mammary "hyperplasias" are clonal dominant premalignant neoplasms.


Comparing hand-held computers and paper diaries for haemophilia home therapy: a randomized trial.
Treatment of severe haemophilia with factor concentrates is by self-infusion in the home. Adherence to record keeping on paper diaries is poor. A randomized-controlled trial compared adherence with record keeping of paper diaries with hand-held computers. Forty-one individuals with severe haemophilia, were randomized to hand-held computers (n = 22) or paper diaries (n = 19) and followed for 6 months. About 86.2% (679 of 788) of infusions by patients in the computer group were in compliance with the data submission schedule compared with only 48.3% (358 of 741) of infusions by patients using paper diaries (P < 0.0001). The time intervals between infusions and the receipt of data were shorter in the computer group (median 0.25 vs. 25 days respectively, P < 0.0001). Reminder phone calls by the clinic were made less frequently to users of hand-held computers than to users of paper diaries (median one vs. five times, P < 0.0001). Accuracy of data was similar for both methods. Compliance with hand-held computers was superior to paper diaries. The clinic received data from hand-held computers mostly on the same day, and nurses could thereby provide clinical advice more effectively. Although hand-held computers did not result in increased accuracy, errors could be detected and corrected more rapidly. Electronic data can more easily be verified, analysed and summarized than that from paper diaries.


A promoter in the novel exon of hPPARgamma directs the circadian expression of PPARgamma.
PPARgamma (peroxisome proliferator-activated receptor gamma) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that regulate the expression of genes associated with lipid metabolism. Herein, we show that expression levels of the novel PPARgamma transcript exhibit circadian oscillation. To study the mechanisms controlling PPARgamma expression, a novel PPARgamma gene promoter was cloned and characterized. We analyzed the novel PPARgamma promoter by luciferase reporter assays and gel shift analysis. Surprisingly, it was not an intron but rather the novel first exon of PPARgamma that was found to have functional minimal promoter activity. Luciferase reporter assays and gel shift assays revealed that the novel first exon is essential for novel PPARgamma promoter activation and that DBP (albumin gene D-site binding protein) and E4BP4 (E4 promoter A binding protein 4) bind directly to D-sites in the novel first exon. Our results demonstrate that the PAR-bZIP (bZIP, basic leucine zipper) family and E4BP4 are the main regulatory factors involved in oscillation of novel PPARgamma expression. This regulatory mechanism clearly differs from that of the circadian expression of PPARalpha.


Molecular analysis of incHI1 antimicrobial resistance plasmids from Salmonella serovar Typhi strains associated with typhoid fever.
The first outbreak of multidrug-resistant (MDR) typhoid fever in Vietnam was in 1993, and by 1995 nearly 90% of cases were MDR. Plasmid HCM1, sequenced in full, is an incHI1 plasmid from Salmonella enterica serovar Typhi strain CT18, isolated in Vietnam in 1993. Restriction analysis shows that pHCM1 shares a restriction fragment length polymorphism (RFLP) pattern with plasmids isolated from the first outbreak and 10 of 17 MDR plasmids isolated from sporadic cases occurring at the same time in Vietnam. A core region of pHCM1 has significant DNA sequence similarity to plasmid R27, isolated in 1961 from S. enterica in the United Kingdom. There are five regions of DNA in pHCM1 which are not present in R27. Two of these are putative acquisition regions; the largest is 34.955 kbp in length and includes sequences of several antibiotic resistance genes and several insertion sequences. The borders of this region are defined by two identical IS10 left elements, associated with an inversion of DNA or with a truncated Tn10 element. The second, smaller region is 14.751 kbp and carries a trimethoprim resistance gene dfr14A cassette associated with a class 1 integrase. In 1993 to 1994, restriction analysis revealed some variations in the structures of Salmonella serovar Typhi MDR plasmids which were mapped to the two putative acquisition regions and three smaller variable regions. In 1996 a single RFLP type, RFLP7, was found to carry the dfrA7 and sul-1 genes, which were not present on R27 or pHCM1. This plasmid type appears to have a selective advantage over other plasmids with the same resistance phenotype.


Fibrin membrane pupillary-block glaucoma after uneventful cataract surgery treated with intracameral tissue plasminogen activator: a case report.
Fibrin pupillary-block glaucoma is a rare complication after cataract surgery. The treatment for this condition is still controversial, since Nd:YAG laser fibrin membranotomy tends to reocclude and laser peripheral iridotomy entails the risk of damaging the corneal endothelium in the presence of corneal edema associated with elevated intraocular pressure. A 62-year-old man with diabetes mellitus developed acute elevation of intraocular pressure with a shallow anterior chamber five days after uneventful cataract surgery. Initially, slit lamp examination provided only limited information due to severe corneal edema. After resolution of corneal edema with systemic glaucoma therapy, a complete fibrin membrane was observed across the pupil by slit lamp examination. Anterior segment optic coherence tomography clearly revealed a thin fibrin membrane covering the entire pupillary space, a shallow anterior chamber, and a deep posterior chamber. The intraocular lens was not observed by anterior segment optic coherence tomography. In contrast, ultrasound biomicroscopy, which has superior penetration depth, was able to visualize the intraocular lens deep in the posterior chamber. Injection of tissue plasminogen activator into the anterior chamber resulted in complete fibrinolysis and released the pupillary block. This case suggests that ocular anterior segment imaging modalities, especially ultrasound biomicroscopy, serve as powerful diagnostic tools to identify mechanisms of acute angle closure glaucoma, which is often accompanied by poor intraocular visibility. This is the first reported case of fibrin pupillary-block glaucoma after cataract surgery successfully treated with intracameral tissue plasminogen activator.


Motions caused by the growth of Bacillus subtilis macrofibres in fluid medium result in new forms of movement of the multicellular structures over solid surfaces.
Bacillus subtilis macrofibres, highly ordered multicellular structures, undergo twisting and writhing motions when they grow in fluid medium as a result of forces generated by the elongation of individual cells. Macrofibres are denser than the fluid medium in which they are cultured, consequently they settle to the bottom of the growth chamber and grow in contact with it. The ramifications of growth on plastic and glass surfaces were examined. Macrofibres were observed to rotate about a vertical axis near the centre of their length in a chiral-specific direction. Right-handed fibres rotated clockwise on plastic surfaces at approximately 4 degrees min(-1), left-handed structures of lower twist rotate anti-clockwise at about half that rate. Very large ball structures produced late in macrofibre formation perched on many small protruding fibres but rotated only when driven by large fibres attached to their periphery. Closer examination showed that fibres made contact with surfaces at only a few points along their length (between 1 and 6 on glass). The regions in contact with the surface changed periodically as a result of rotation of the fibre shaft caused by growth. Every time the weight of a fibre transferred from one contact point to another, each section of the fibre took a small step approximately proportional to its distance from the fibre mid-point. The net result was a rolling of each section over the surface so that the fibre rotation about a vertical axis was produced. Macrofibres also took large steps when part of the structure rose off the floor, swept through an arc in the fluid and then returned to the floor at a new location. The rate of movement during a large step, measured as the change of angle between the moving and stationary portions of the fibre, was 5 degrees s(-1). These observations reveal that the forces derived from helical growth that lead to macrofibre formation also cause characteristic macrofibre motion that differs from classical motility.


[Experimental studies on the earliest echographic manifestations of incipient pancreatitis and pancreatic necrosis].
The earliest echographic manifestations of developing pancreatitis or pancreatic necrosis were studied experimentally in five dogs (Beagles). Fifteen minutes after induction of pancreatitis the pancreas was removed and accurately corresponding histological and sonographic serial sections were prepared. Pancreatic necrosis up to 25% was not apparent sonographically. 50% pancreatic necrosis manifested various echo patterns (low echoes, focal hyperechogenicity). 75% and 100% pancreatic necrosis showed characteristic sonographic appearances of focal-nodular hyperechogenicity on an hypo-echogenic background. The study has shown that sonography is a highly sensitive method for recognizing even the earliest stages of acute necrotizing pancreatitis.


Stepwise occlusion of the carotid arteries of the rat: MRI assessment of the effect of donepezil and hypoperfusion-induced brain atrophy and white matter microstructural changes.
Bilateral common carotid artery occlusion (BCCAo) in the rat is a widely used animal model of vascular dementia and a valuable tool for preclinical pharmacological drug testing, although the varying degrees of acute focal ischemic lesions it induces could interfere with its translational value. Recently, a modification to the BCCAo model, the stepwise occlusion of the two carotid arteries, has been introduced. To acquire objective translatable measures, we used longitudinal multimodal magnetic resonance imaging (MRI) to assess the effects of semi-chronic (8 days) donepezil treatment in this model, with half of the Wistar rats receiving the treatment one week after the stepwise BCCAo. With an ultrahigh field MRI, we measured high-resolution anatomy, diffusion tensor imaging, cerebral blood flow measurements and functional MRI in response to whisker stimulation, to evaluate both the structural and functional effects of the donepezil treatment and stepwise BCCAo up to 5 weeks post-occlusion. While no large ischemic lesions were detected, atrophy in the striatum and in the neocortex, along with widespread white matter microstructural changes, were found. Donepezil ameliorated the transient drop in the somatosensory BOLD response in distant cortical areas, as detected 2 weeks after the occlusion but the drug had no effect on the long term structural changes. Our results demonstrate a measurable functional MRI effect of the donepezil treatment and the importance of diffusion MRI and voxel based morphometry (VBM) analysis in the translational evaluation of the rat BCCAo model.


Oxidative-nitrosative stress as a contributing factor to cardiovascular disease in subjects with diabetes.
In diabetes, clear evidence has emerged for the presence of oxidative-nitrosative stress, which may be a consequence of a glucose-mediated imbalance of systemic antioxidant buffering capacity, coupled with increased production of free radical species. Although multiple metabolic pathways have been identified, which may contribute to oxidative stress in diabetes, the principal pathogenetic pathways and their key down-stream targets remain to be established. Evidence links oxidative stress in particular, to elevations of postprandial glucose and lipids, which also have recently emerged as major risk factors for cardiovascular events. Indeed, considerable evidence suggests that increased oxidative stress in diabetes may play an important role in the development or progression of cardiovascular disease by a number of different mechanisms, including alterations of cardiovascular sympathetic nervous system tone and integrity, elevation of acute phase reactants, disruption of endothelial function and facilitation of myocardial injury. Despite the disappointments of recent large scale clinical trials evaluating the efficacy of antioxidants in cardiovascular disease, many therapeutic agents which have been used successfully in diabetic subjects at high risk for cardiovascular disease have a mechanism of action which includes an antioxidant capacity. Therefore, incorporating an antioxidant action in future therapeutic approaches to combat cardiovascular disease complicating diabetes, appears to remain justified and warrants further evaluation.


van't Hoff-van der Waals osmotic pressure and energy transformers.
We find the van't Hoff relations between osmotic pressure, freezing point depression, and boiling point elevation provide a clue on how, by using salt solutions, one may lower the cost of extracting power from low-grade heat sources. In particular, the ratio of 7 between the heat of evaporation and the heat of freezing of pure water suggests a chemical system that raises 7-fold the temperature difference between heat source and heat sink, while decreasing by the same factor the heat flux. Heat exchangers dominate the cost of heat engines operating upon low-grade heat. Their area for a fixed power output is inversely proportional to the available temperature differential. Herein lies the potential for a great cost reduction. We show that the simple van der Waals concept of a gas of hard elastic spheres suffices to understand the colligative properties of salt solutions, at least up to the concentration of the eutectic composition. This concept enables us to physically interpret the thermodynamic processes during the concentration of salt solutions by evaporation and during the mixing of ice and solid salt hydrates at their eutectic temperature. These are identical to the thermodynamic processes taking place during the isothermal compression and expansion of gases in pumps and in turbines.


Epidemiology and Impact of Spinal Cord Injury in the Elderly: Results of a Fifteen-Year Population-Based Cohort Study.
Although experience suggests a shift in the epidemiology of spinal cord injury (SCI) toward an older demographic, population studies are lacking. We aimed to evaluate (1) how the epidemiology and age profile of SCI have changed over time, and (2) how increased age impacts health outcomes up to 15 years post-injury. A population-based cohort study was performed in Ontario including adults diagnosed with traumatic SCI between 2002 and 2017. Older and younger SCI cohorts were created based on an age cutoff of 65 years. An older cohort of uninjured persons was matched to the older SCI cohort based on age, gender, and comorbidity status. Changes in crude incidence were reported as average annual percentage change (AAPC). Survival, readmissions, and costs were compared between the older and younger SCI cohorts as well as the between the older SCI and older matched uninjured cohorts. The incidence of SCI increased among females (AAPC 2.2; 95% confidence interval [CI] 0.1, 4.3), driven by a marked rise (4%/year) among elderly females (AAPC 4.3; 95% CI 0.1, 4.3). Although no change in incidence was detected for males, there was a trend toward increased incidence among older males (AAPC 1.2; 95% CI -1.3, 3.8). There were a higher proportion of cervical, incomplete, and fall-related injuries in the older than in younger SCI cohorts. Being over 65 years of age was associated with a sixfold increased risk of death (hazard ratio [HR] 5.75; 95% CI 4.72, 7.00). In comparison with the older uninjured cohort, the older SCI cohort had double the risk of death (HR 2.23; 95% CI 2.00, 2.50). Older persons with SCI had higher odds of readmission and higher costs. The incidence of SCI among the elderly is increasing, particularly among women. Prevention through fall reduction and education to improve outcomes are needed.


Master equation approach to friction at the mesoscale.
At the mesoscale friction occurs through the breaking and formation of local contacts. This is often described by the earthquakelike model which requires numerical studies. We show that this phenomenon can also be described by a master equation, which can be solved analytically in some cases and provides an efficient numerical solution for more general cases. We examine the effect of temperature and aging of the contacts and discuss the statistical properties of the contacts for different situations of friction and their implications, particularly regarding the existence of stick-slip.


Lateralized effect of cerebral infarction on spinal fluid monoamine metabolite concentrations in rats.
Using a rat model of stroke, we studied the effect of unilateral middle cerebral artery ligation on cerebrospinal fluid monoamine metabolites at different intervals over a 40-day postoperative period. Male Sprague-Dawley rats were divided into four groups: an unoperated control group (n = 9), a sham-operated group (n = 9), a right middle cerebral artery ligation group (n = 10), and a left middle cerebral artery ligation group (n = 10). One hundred microliters of cerebrospinal fluid were collected percutaneously from the cerebellomedullary cistern just before and 5, 20, and 40 days after the surgical procedure. Monoamine metabolites--3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxy-indoleacetic acid (5-HIAA), and homovanillic acid (HVA)--were measured using high-performance liquid chromatography. MHPG concentration in the right lesion group was significantly depleted from control levels 5, 20, and 40 days after surgery. No such depletion was observed in the left lesion rats. Concentration of 5-HIAA was relatively lower at Days 5 and 20 in the right lesion group than in the left lesion group. HVA concentration did not differ among the groups at any time. Our study has demonstrated a differential effect of unilateral ischemia on cerebrospinal fluid neurochemistry in rats dependent on the cerebral hemisphere involved.


Genetic analysis of vertebral trabecular bone density and cross-sectional area in older men.
We investigated 383 bone candidate genes for associations between single nucleotide polymorphisms and vertebral trabecular volumetric bone mineral density (vBMD) and cross-sectional area (CSA) in 2,018 Caucasian men aged ≥ 65 years. SNPs in TGFBR3, SOST, KL, CALCR, LEP, CSF1R, PTN, GNRH2, FGFR2, and MEPE were associated with vBMD and SNPs in CYP11B1, DVL2, DLX5, WNT4, and PAX7 were associated with CSA in independent study samples (p < 0.005). Vertebral bone mineral density and cross-sectional area are important determinants of vertebral bone strength. Little is known about the specific genetic variants that influence these phenotypes in humans. We investigated the potential genetic variants associated with vertebral trabecular volumetric BMD and CSA measured by quantitative computed tomography. We initially tested for association between these phenotypes and 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes in 862 community-dwelling Caucasian men aged ≥ 65 years in the Osteoporotic Fractures in Men Study. SNP associations were then validated by genotyping an additional 1,156 randomly sampled men from the same cohort. We identified 11 SNPs in 10 genes (TGFBR3, SOST, KL, CALCR, LEP, CSF1R, PTN, GNRH2, FGFR2, and MEPE) that were consistently associated with trabecular vBMD and five SNPs in five genes (CYP11B1, DVL2, DLX5, WNT4, and PAX7) that were consistently associated with CSA in both samples (p < 0.005). None of the SNPs associated with trabecular vBMD were associated with CSA. Our findings raise the possibility that at least some of the loci for vertebral trabecular BMD and bone size may be distinct.


pH effects on BSA-dispersed carbon nanotubes studied by spectroscopy-enhanced composition evaluation techniques.
Dispersion and exfoliation of carbon nanotubes (CNT) by water soluble dispersants such as surfactant, polymer or protein is a key step toward the application of carbon nanotubes in composite materials, biochemical and biomedical applications. Upon dispersion, the solution phase separates into dispersed nanotubes in the supernatant and a precipitate phase including carbonaceous impurities but also nanotubes and dispersants. Yet, simple but accurate tools for measuring the concentrations of the constituents are not available. In most studies a comparison between CNT suspensions is based on ocular observation or on UV-visible measurement of a featureless spectrum at single wavelength. Such measurements are complex since both nanotubes and most dispersants absorb along the whole UV-visible spectrum and an overlap of their signals occurs. In this paper we employ chemometric techniques to evaluate the pH effect on the concentration of both dispersant (protein-bovine serum albumin, BSA) and single-wall nanotube (SWNT) from a full UV-visible spectrum of aqueous solutions. We find strong correlation between the conformation of the protein and its dispersion efficiency.


Simulation Training in the Management of Adverse Contrast Reactions: A Systematic Review.
Simulation-based training has become increasingly prominent within medical education, but its utility within radiology remains underexplored. To appraise the evidence for the effectiveness of simulation on the management of adverse reactions to contrast media. A systematic search of the literature was conducted. Eligible studies recruited radiology residents, provided simulation-based training focused on contrast reaction management, and measured any effectiveness outcome compared with any nonsimulation training or no training. The quality of studies was appraised and outcomes were classified according to Kirkpatrick's hierarchy and the strength of evidence. Out of 146 screened results, 15 articles were included that described 17 studies-3 randomized trials and 14 pretest-posttest studies of hands-on or, less commonly, computer-based simulation. In all 16 studies that assessed knowledge before and after intervention, written test scores improved after simulation. Most studies noted improvements in comfort or confidence managing contrast reactions as well. In all three studies that assessed knowledge after simulation and after didactic lecture as a control, posttest scores were not statistically significantly better in the simulation groups than the lecture groups. Common study limitations included single-group designs, measuring only learning outcomes using unvalidated instruments, modest sample sizes, and limited assessment of long-term retention. Simulation produces subjective improvements and knowledge gain relevant to contrast reaction management. Further research is required to demonstrate superiority of simulation-based contrast reaction management training over traditional didactic lecture-based instruction.


On Anecdote and Antidotes: Poison Trials in Sixteenth-Century Europe.
This article describes the use of poison trials, in which an animal or a condemned criminal was poisoned, to test antidotes in sixteenth-century Europe. In contrast to most drug testing in medieval and early modern Europe, which was gathered in the normal course of therapeutic experience, the poison trial was a contrived, deliberate event. I argue that poison trials had an important function in both medical testing and medical writing in the period between 1524-1580. While poison trials dated back to antiquity, they tended to be described in medieval texts as theoretical possibilities rather than empirical tests that had already occurred. In contrast, early modern physicians conducted poison trials and described them as anecdotes in medical texts. Although physicians did not explicitly separate poison trials from evidence gathered in the course of regular therapeutic experience, they did imbue the outcome of poison trials with considerable epistemological weight.


Scanning electron microscopy of four teleostean retinas.
The morphology of the retinas of the goldeye Hiodon alosoides (fam. Hiodontidae), the brook trout Salvelinus fontinalis (fam. Salmonidae), the yellow perch Perca flavescens and the walleye Stizostedion vitreum (fam. Percidae) was studied by SEM. Semi-thin plastic sections of the same retinas were also examined for comparison. Contrary to observation of earlier authors the goldeye retina was found to possess both rods and cones; in the case of the other three fishes' retinas, present observations correspond to previous ones, adding only details. SEM gives an impressive, three dimensil view of the gross surface features of the retinas. Shrinkage during the processing of the specimens for SEM, while not altering the general topography, does induce artifacts in both plexiform layers.


Value of dynamic clinical and biomarker data for mortality risk prediction in COVID-19: a multicentre retrospective cohort study.
Being able to predict which patients with COVID-19 are going to deteriorate is important to help identify patients for clinical and research practice. Clinical prediction models play a critical role in this process, but current models are of limited value because they are typically restricted to baseline predictors and do not always use contemporary statistical methods. We sought to explore the benefits of incorporating dynamic changes in routinely measured biomarkers, non-linear effects and applying 'state-of-the-art' statistical methods in the development of a prognostic model to predict death in hospitalised patients with COVID-19. The data were analysed from admissions with COVID-19 to three hospital sites. Exploratory data analysis included a graphical approach to partial correlations. Dynamic biomarkers were considered up to 5 days following admission rather than depending solely on baseline or single time-point data. Marked departures from linear effects of covariates were identified by employing smoothing splines within a generalised additive modelling framework. 3 secondary and tertiary level centres in Greater Manchester, the UK. 392 hospitalised patients with a diagnosis of COVID-19. 392 patients with a COVID-19 diagnosis were identified. Area under the receiver operating characteristic curve increased from 0.73 using admission data alone to 0.75 when also considering results of baseline blood samples and to 0.83 when considering dynamic values of routinely collected markers. There was clear non-linearity in the association of age with patient outcome. This study shows that clinical prediction models to predict death in hospitalised patients with COVID-19 can be improved by taking into account both non-linear effects in covariates such as age and dynamic changes in values of biomarkers.


ChAMP: updated methylation analysis pipeline for Illumina BeadChips.
The Illumina Infinium HumanMethylationEPIC BeadChip is the new platform for high-throughput DNA methylation analysis, effectively doubling the coverage compared to the older 450 K array. Here we present a significantly updated and improved version of the Bioconductor package ChAMP, which can be used to analyze EPIC and 450k data. Many enhanced functionalities have been added, including correction for cell-type heterogeneity, network analysis and a series of interactive graphical user interfaces. ChAMP is a BioC package available from https://bioconductor.org/packages/release/bioc/html/ChAMP.html. firstname.lastname@example.com or firstname.lastname@example.com or firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Lager Yeast Design Through Meiotic Segregation of a Saccharomyces cerevisiae × Saccharomyces eubayanus Hybrid.
Yeasts in the lager brewing group are closely related and consequently do not exhibit significant genetic variability. Here, an artificial Saccharomyces cerevisiae × Saccharomyces eubayanus tetraploid interspecies hybrid was created by rare mating, and its ability to sporulate and produce viable gametes was exploited to generate phenotypic diversity. Four spore clones obtained from a single ascus were isolated, and their brewing-relevant phenotypes were assessed. These F1 spore clones were found to differ with respect to fermentation performance under lager brewing conditions (15°C, 15 °Plato), production of volatile aroma compounds, flocculation potential and temperature tolerance. One spore clone, selected for its rapid fermentation and acetate ester production was sporulated to produce an F2 generation, again comprised of four spore clones from a single ascus. Again, phenotypic diversity was introduced. In two of these F2 clones, the fermentation performance was maintained and acetate ester production was improved relative to the F1 parent and the original hybrid strain. Strains also performed well in comparison to a commercial lager yeast strain. Spore clones varied in ploidy and chromosome copy numbers, and faster wort fermentation was observed in strains with a higher ploidy. An F2 spore clone was also subjected to 10 consecutive wort fermentations, and single cells were isolated from the resulting yeast slurry. These isolates also exhibited variable fermentation performance and chromosome copy numbers, highlighting the instability of polyploid interspecific hybrids. These results demonstrate the value of this natural approach to increase the phenotypic diversity of lager brewing yeast strains.


Words we do not say-Context effects on the phonological activation of lexical alternatives in speech production.
There is compelling evidence that context strongly influences our choice of words (e.g., whether we refer to a particular animal with the basic-level name "bird" or the subordinate-level name "duck"). However, little is known about whether the context already affects the degree to which the alternative words are activated. In this study, we explored the effect of a preceding linguistic context on the phonological activation of alternative picture names. In Experiments 1 to 3, the context was established by a request produced by an imaginary interlocutor. These requests either constrained the naming response to the subordinate level on pragmatic grounds (e.g., "name the bird!") or not (e.g., "name the object!"). In Experiment 4, the context was established by the speaker's own previous naming response. Participants named the pictures with their subordinate-level names and the phonological activation of the basic-level names was assessed with distractor words phonologically related versus unrelated to that name (e.g., "birch" vs. "lamp"). In all experiments, we consistently found that distractor words phonologically related to the basic-level name interfered with the naming response more strongly than unrelated distractor words. Moreover, this effect was of comparable size for nonconstraining and constraining contexts indicating that the alternative name was phonologically activated and competed for selection, even when it was not an appropriate lexical option. Our results suggest that the speech production system is limited in its ability of flexibly adjusting and fine-tuning the lexical activation patterns of words (among which to choose from) as a function of pragmatic constraints. (PsycINFO Database Record


Miniature all-solid-state heterostructure nanowire Li-ion batteries as a tool for engineering and structural diagnostics of nanoscale electrochemical processes.
Complex interfacial phenomena and phase transformations that govern the operation of Li-ion batteries require detailed nanoscale 3D structural and compositional characterization that can be directly related to their capacity and electrical transport properties. For this purpose, we have designed model miniature all solid-state radial heterostructure Li-ion batteries composed of LiCoO2 cathode, LiPON electrolyte and amorphous Si anode shells, which were deposited around metallized high-aspect-ratio Si nanowires as a scaffolding core. Such diagnostic batteries, the smallest, complete secondary Li-ion batteries realized to date, were specifically designed for in situ electrical testing in a field-emission scanning electron microscope and/or transmission electron microscope. The results of electrochemical testing were described in detail in a previous publication (Nano Lett., 2012, 12, 505-511). The model Li-ion batteries allow analysis of the correlations between electrochemical properties and their structural evolution during cycling in various imaging, diffraction and spectroscopic modes down to the atomic level. Employing multimode analytical scanning/transmission electron microscopy imaging coupled with correlative multivariate statistical analysis and tomography, we have analyzed and quantified the 3D morphological and structural arrangement of the batteries, including textured platelet-like LiCoO2 nanocrystallites, buried electrode-electrolyte interfaces and hidden internal defects to clarify effects of scaling on a battery's electrochemical performance. Characterization of the nanoscale interfacial processes using model heterostructure nanowire-based Li-ion batteries provides useful guidelines for engineering of prospective nano-sized building blocks in future electrochemical energy storage systems.


Electrochemical Sensor for Detection and Degradation Studies of Ethyl Violet Dye.
In this work, a simple and sensitive electrochemical method was developed to determine ethyl violet (EV) dye in aqueous systems by using square wave anodic stripping voltammetry (SWASV) employing a glassy carbon electrode modified with acidic-functionalized carbon nanotubes (COOH-fCNTs). In square wave anodic stripping voltammetry, EV exhibited a well-defined oxidation peak at 0.86 V at the modified GCE. Impedance spectroscopy and cyclic voltammetry were used to examine the charge transduction and sensing capabilities of the modified electrode. The influence of pH, deposition potential, and accumulation time on the electro-oxidation of EV was optimized. Under the optimum experimental conditions, the limit of detection with a value of 0.36 nM demonstrates high sensitivity of COOH-fCNTs/GCE for EV. After detection, it was envisioned to devise a method for the efficient removal of EV from an aqueous system. In this regard a photocatalytic degradation method of EV using Ho/TiO2 nanoparticles was developed. The Ho/TiO2 nanoparticles synthesized by the sol-gel method were characterized by UV-vis, XRD, FTIR, SEM, and EDX. The photocatalytic degradation studies revealed that basic medium is more suitable for a higher degradation rate of EV than acidic and neutral media. The photodegradation kinetic parameters were evaluated using UV-vis spectroscopic and electrochemical methods. The results revealed that the degradation process of EV follows first-order kinetics.


Adoptive regulatory T-cell therapy preserves systemic immune homeostasis after cerebral ischemia.
Cerebral ischemia has been shown to result in peripheral inflammatory responses followed by long-lasting immunosuppression. Our recent study demonstrated that intravenous delivery of regulatory T cells (Tregs) markedly protected against transient cerebral ischemia by suppressing neutrophil-derived matrix metallopeptidase 9 production in the periphery. However, the effect of Tregs on systemic inflammatory responses and immune status has not been fully characterized. Cerebral ischemia was induced by middle cerebral artery occlusion for 60 minutes in mice or 120 minutes in rats. Tregs were isolated from donor animals by CD4 and CD25 double selection and transferred intravenously to ischemic recipients at 2 hours after middle cerebral artery occlusion. Animals were euthanized on different days after reperfusion. The effects of Tregs on systemic inflammation and immune status were evaluated using flow cytometry, ELISAs, and immunohistochemistry. Systemic administration of purified Tregs raises functional Tregs in the blood and peripheral organs, including spleen and lymph nodes. These exogenous Tregs remain in the blood and peripheral organs for ≥12 days. Functionally, Treg adoptive transfer markedly inhibits middle cerebral artery occlusion-induced elevation of inflammatory cytokines (interleukin-6 and tumor necrosis factor α) in the blood. Furthermore, Treg treatment corrects long-term lymphopenia and improves cellular immune functions after ischemic brain injury. As a result, Treg-treated animals exhibit decreased bacterial loads in the blood during recovery from cerebral ischemic attack. Treg treatment did not exacerbate poststroke immunosuppression. On the contrary, Treg-treated animals displayed improved immune status after focal cerebral ischemia.


3'-coterminal subgenomic RNAs and putative cis-acting elements of Grapevine leafroll-associated virus 3 reveals 'unique' features of gene expression strategy in the genus Ampelovirus.
The family Closteroviridae comprises genera with monopartite genomes, Closterovirus and Ampelovirus, and with bipartite and tripartite genomes, Crinivirus. By contrast to closteroviruses in the genera Closterovirus and Crinivirus, much less is known about the molecular biology of viruses in the genus Ampelovirus, although they cause serious diseases in agriculturally important perennial crops like grapevines, pineapple, cherries and plums. The gene expression and cis-acting elements of Grapevine leafroll-associated virus 3 (GLRaV-3; genus Ampelovirus) was examined and compared to that of other members of the family Closteroviridae. Six putative 3'-coterminal subgenomic (sg) RNAs were abundantly present in grapevine (Vitis vinifera) infected with GLRaV-3. The sgRNAs for coat protein (CP), p21, p20A and p20B were confirmed using gene-specific riboprobes in Northern blot analysis. The 5'-termini of sgRNAs specific to CP, p21, p20A and p20B were mapped in the 18,498 nucleotide (nt) virus genome and their leader sequences determined to be 48, 23, 95 and 125 nt, respectively. No conserved motifs were found around the transcription start site or in the leader sequence of these sgRNAs. The predicted secondary structure analysis of sequences around the start site failed to reveal any conserved motifs among the four sgRNAs. The GLRaV-3 isolate from Washington had a 737 nt long 5' nontranslated region (NTR) with a tandem repeat of 65 nt sequence and differed in sequence and predicted secondary structure with a South Africa isolate. Comparison of the dissimilar sequences of the 5'NTRs did not reveal any common predicted structures. The 3'NTR was shorter and more conserved. The lack of similarity among the cis-acting elements of the diverse viruses in the family Closteroviridae is another measure of the complexity of their evolution. The results indicate that transcription regulation of GLRaV-3 sgRNAs appears to be different from members of the genus Closterovirus. An analysis of the genome sequence confirmed that GLRaV-3 has an unusually long 5'NTR of 737 nt compared to other monopartite members of the family Closteroviridae, with distinct differences in the sequence and predicted secondary structure when compared to the corresponding region of the GLRaV-3 isolate from South Africa.


Reverberation Clutter Suppression Using 2-D Spatial Coherence Analysis.
Diffuse reverberation clutter often significantly degrades the visibility of abdominal structures. Reverberation clutter acts as a temporally stationary haze that originates from the multiple scattering within the subcutaneous layers and has a narrow spatial correlation length. We recently presented an adaptive beamforming technique, Lag-one Spatial Coherence Adaptive Normalization (LoSCAN), which can recover the contrast suppressed by incoherent noise. LoSCAN successfully suppressed reverberation clutter in numerous clinical examples. However, reverberation clutter is a 3-D phenomenon and can often exhibit a finite partial correlation between receive channels. Due to a strict noise-incoherence assumption, LoSCAN does not eliminate correlated reverberation clutter. This work presents a 2-D matrix array-based LoSCAN method and evaluates matrix-LoSCAN-based strategies to suppress partially correlated reverberation clutter. We validated the proposed matrix LoSCAN method using Field II simulations of a 64×64 symmetric 2-D array. We show that a subaperture beamforming (SAB) method tuned to the direction of noise correlation is an effective method to enhance LoSCAN's performance. We evaluated the efficacy of the proposed methods using fundamental and harmonic channel data acquired from the liver of two healthy volunteers using a 64×16 custom 2-D array. Compared to azimuthal LoSCAN, the proposed approach increased the contrast by up to 5.5 dB and the generalized contrast-to-noise ratio (gCNR) by up to 0.07. We also present analytic models to understand the impact of partially correlated reverberation clutter on LoSCAN images and explain the proposed methods' mechanism of image quality improvement.


Nutritional requirements in chronic renal failure and end stage renal disease at the Kenyatta National Hospital.
Since August, 1984 renal replacement therapy with haemodialysis, peritoneal dialysis and renal transplant has been carried out regularly at the renal unit of the Kenyatta National Hospital (KNH). Various nutritional disturbances have been met. Nausea, vomiting and anorexia have been noticed frequently particularly in those on intermittent peritoneal dialysis (IPD). The same problems were experienced in those few patients who were on continuous ambulatory peritoneal dialysis (CAPD). The patients were usually malnourished, the malnutrition being of protein-calorie type. At the start of the programme of renal replacement therapy in 1984, the problems of poor nutrition were worse but are currently improving. At the moment our patients with chronic renal failure (CRF) and end stage renal disease (ESRD) on dialysis are scattered all over the medical and paediatric wards at KNH. This has impeded the smooth surveillance of patients' diets by the few available nutritionists. The review of our performance from 1984-1988 on the nutritional status of patients with CRF and ESRD is an attempt to create a normal dietary cover for patients with the above problems.