Myocardial protective effect of hypothermia during extracorporeal circulation -- by quantitative measurement of myocardial oxygen consumption -.
To evaluate the effect of systemic temperature on myocardial protection during extracorporeal circulation, we quantitatively evaluated the relationship between myocardial oxygen consumption and rectal temperature. Myocardial oxygen consumption during cardiac arrest was calculated via blood gas analysis of venous blood samples collected from the coronary sinus. The rectal temperatures of the patients during extracorporeal circulation ranged from 16.0 degrees C to 33.5 degrees C. The patients were classified into three groups according to their rectal temperature: group I (n=10; rectal temperature: 20.3+/-1.80 degrees C), group II (n=24; rectal temperature: 29.4+/-0.97 degrees C), and group III (n=29; rectal temperature: 31.7+/-0.72 degrees C). The myocardial oxygen consumption of each group was then compared. The average of the myocardial oxygen consumption of all cases was 62.5+/-64.0 O(2) ml/min/100 mm(3) left ventricle volume, and the averages of the individual groups were 26.9+/-28.8 in group I, 72.2+/-71.8 in group II, and 69.3+/-62.6 in group III. There was a significant difference in the oxygen consumption between group I and the other two groups. There was a positive correlation between the rectal temperature and myocardial oxygen consumption, as reflected in the following formula: Y=-0.3 x X +1.10 x X(2)-0.02 x X(3) (Y, myocardial oxygen consumption; X, rectal temperature; R(2)=0.533; P<0.0001). This study suggested that rectal temperature below 22.5 degrees C is advantageous due to the resultant myocardial protection such hypothermia affords.


[Oxidation of aliphatic alcohols and acids by yeasts capable and incapable of growth on n-alkanes].
Yeast cultures, capable and incapable fo growth on hydrocarbons, were tested for their ability to oxidize aliphatic alcohols and acids, intermediate products of n-alkane degradation. The cultures belonging to 7 genera and 13 species did not grow on liquid paraffins and tetradecane. However, they grew on tetradecanol and oxidized aliphatic alcohols and fatty acids, the pattern of oxidation of the substrates being the same as in the case of alkane-oxidizing yeast cultures grown on glucose. None of 45 yeast strains (12 genera and 36 species) which did not grow on paraffin was able to oxidize tetradecane. As follows from this and earlier evidence (Lozinov et al., 1976a), the only reaction typical of yeasts capable of growth on n-alkanes is the oxigenase reaction of their oxidation to alcohols.


Life-threatening expansive sublingual hematoma: a stab wound with lingual artery injury.
Vascular injuries are a constant risk in facial trauma, although bone and soft tissues of the face have provided some protection to the larger blood vessels. However, penetrating injuries usually do not have this type of protection and can damage significant vascular arteries. This article presents a case of a stab wound, which led to airway obstruction arising to a large sublingual hematoma due to lingual artery injury. A healthy 44-year-old man was stabbed in the submandibular region and admitted with an airway obstruction. He was subjected to an emergency tracheotomy and evolved with progressive sublingual edema. Computed tomography (CT) angiography showed a left lingual artery injury with the formation of an expansive hematoma. The CT angiography findings helped to identify the cause of the hematoma and guided the surgery to drain the hematoma after ligation of the lingual artery. The treatment was safely performed as planned and evolved uneventfully. The patient recovered fast and well and presented normal functions 6 months after the treatment. This surgical technique is an effective method for treating such injuries because it can be safely performed when guided by CT angiography. The authors argue that the demand for vascular lesions should be routine in patients who have facial trauma.


The Werner syndrome protein binds replication fork and holliday junction DNAs as an oligomer.
Werner syndrome is an inherited disease displaying a premature aging phenotype. The gene mutated in Werner syndrome encodes both a 3' --> 5' DNA helicase and a 3' --> 5' DNA exonuclease. Both WRN helicase and exonuclease preferentially utilize DNA substrates containing alternate secondary structures. By virtue of its ability to resolve such DNA structures, WRN is postulated to prevent the stalling and collapse of replication forks that encounter damaged DNA. Using electron microscopy, we visualized the binding of full-length WRN to DNA templates containing replication forks and Holliday junctions, intermediates observed during DNA replication and recombination, respectively. We show that both wild-type WRN and a helicase-defective mutant bind with exceptionally high specificity (>1000-fold) to DNA secondary structures at the replication fork and at Holliday junctions. Little or no binding is observed elsewhere on the DNA molecules. Calculations of the molecular weight of full-length WRN revealed that, in solution, WRN exists predominantly as a dimer. However, WRN bound to DNA is larger; the mass is consistent with that of a tetramer.


[Klinefelter syndrome: literature review on using modern methods of assisted reproductive technologies].
The article reviews scientific papers devoted to the problem of reproductive health in men with Klinefelter syndrome (KS). Pathogenesis from a very early age (in utero), the possibility of ensuring biological paternity upon reaching sexual maturity and the risk of chromosomal abnormalities in offspring are discussed. Despite the fact that KS is one of the most common causes of male infertility associated with chromosomal abnormalities, due to the variability of clinical manifestations the proportion of patients identified before puberty did not exceed 10% before the widespread introduction of non-invasive prenatal testing. According to the research results presented in the article, the reproductive potential of males with KS is often already reduced in early childhood. These circumstances should be considered when choosing further patient management tactics.There are few reports on the onset of spontaneous pregnancy in the case of KS, so ensuring biological paternity in this group of patients is often possible only using surgical methods of sperm extraction and assisted reproductive technologies. This article discusses methods like testicular sperm extraction (TESE) and microdissection testicular sperm extraction (mTESE) in terms of their effectiveness and safety for the patient, and the factors influencing the outcome of the operation. The optimal period of these manipulations seems to be the patient's age from 18 to 30 years, although the feasibility of adolescent boys undergoing the aforementioned procedures is highly controversial.The research papers presented in the article suggest that the risk of transmitting chromosomal abnormalities to offspring is rather low, which does not exclude the need for medical and genetic counseling to explain all possible risks to the patient. Preimplantation or intrauterine diagnostics are also deemed necessary.


Emotion dynamics concurrently and prospectively predict mood psychopathology.
Altered emotion dynamics may represent a transdiagnostic risk factor for mood psychopathology. The present study examined whether altered emotion dynamics were associated with bipolar and depressive psychopathology concurrently and at a three-year follow-up. At baseline (n = 138), participants completed diagnostic interviews, questionnaires, and seven days of experience sampling assessments. Four emotion dynamics were computed for negative affect (NA) and positive affect (PA) - within-person variance (variability), mean square of successive differences and probability of acute change (instability), and autocorrelation (inertia). At the three-year follow-up, participants (n = 108) were re-assessed via interviews and questionnaires. NA variability was associated with bipolar spectrum disorders at baseline and follow-up. NA instability predicted depressive symptoms and hypomanic personality at baseline, and bipolar spectrum disorders at the follow-up. NA inertia did not predict diagnoses or symptoms at either assessment. PA inertia predicted hyperthymic temperament at baseline but not follow-up. Notably, NA variability and instability predicted the development of new bipolar spectrum disorders at the follow-up. Consistent with the recruitment strategy and young age of the participants, only 50% had developed diagnosable psychopathology by the time of the follow-up assessment. The present study provided a unique demonstration that altered emotion dynamics differentially predicted bipolar and depressive psychopathology concurrently and prospectively. Emotion dynamics are important to both digital phenotyping and mobile-based interventions as emotional instability offers a measurable risk factor that is identifiable prior to illness onset.


405 nm Light exposure of osteoblasts and inactivation of bacterial isolates from arthroplasty patients: potential for new disinfection applications?
Infection rates after arthroplasty surgery are between 1-4 %, rising significantly after revision procedures. To reduce the associated costs of treating these infections, and the patients' post-operative discomfort and trauma, a new preventative method is required. High intensity narrow spectrum (HINS) 405 nm light has bactericidal effects on a wide range of medically important bacteria, and it reduced bacterial bioburden when used as an environmental disinfection method in a Medical Burns Unit. To prove its safety for use for environmental disinfection in orthopaedic theatres during surgery, cultured osteoblasts were exposed to HINS-light of intensities up to 15 mW/cm2 for 1 h (54 J/cm2). Intensities of up to 5 mW/cm2 for 1 h had no effect on cell morphology, activity of alkaline phosphatase, synthesis of collagen or osteocalcin expression, demonstrating that under these conditions this dose is the maximum safe exposure for osteoblasts; after exposure to 15 mW/cm2 all parameters of osteoblast function were significantly decreased. Viability (measured by protein content and Crystal Violet staining) of the osteoblasts was not influenced by exposure to 5 mW/cm2 for at least 2 h. At 5 mW/cm2 HINS-light is an effective bactericide. It killed 98.1 % of Staphylococcus aureus and 83.2 % Staphylococcus epidermis populations seeded on agar surfaces, and is active against both laboratory strains and clinical isolates from infected hip and knee arthroplasties. HINS-light could have potential for development as a method of disinfection to reduce transmission of bacteria during arthroplasty, with wider applications in diverse surgical procedures involving implantation of a medical device.


Terrestrial contributions to Afrotropical aquatic food webs: The Congo River case.
Understanding the degree to which aquatic and terrestrial primary production fuel tropical aquatic food webs remains poorly understood, and quantifying the relative contributions of autochthonous and allochthonous inputs is methodologically challenging. Carbon and nitrogen stable isotope ratios (δ 13C, δ 15N) can provide valuable insights about contributions of terrestrial resources and trophic position, respectively, but this approach has caveats when applied in typical complex natural food webs.Here, we used a combination of C, N, and H (δ 2H) stable isotope measurements and Bayesian mixing models to estimate the contribution of terrestrial (allochthonous) and aquatic (autochthonous) inputs to fish and invertebrate communities in the Congo River (and some tributaries).Overall, our results show that we gained power to distinguish sources by using a multiple tracer approach and we were able to discriminate aquatic versus terrestrial sources (esp. including hydrogen isotopes). Fish δ 2H values were clearly correlated with their food preferences and revealed a high level of variation in the degree of allochthony in these tropical aquatic communities.At the community level, it is clear that terrestrial C3 plants are an important source fueling the Congo River food web. However, in order to better constrain source contribution in these complex environments will require more robust constraints on stable isotope values of algal and methane-derived C sources.


Meat, meat cooking methods and preservation, and risk for colorectal adenoma.
Cooking meat at high temperatures produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Processed meats contain N-nitroso compounds. Meat intake may increase cancer risk as HCAs, PAHs, and N-nitroso compounds are carcinogenic in animal models. We investigated meat, processed meat, HCAs, and the PAH benzo(a)pyrene and the risk of colorectal adenoma in 3,696 left-sided (descending and sigmoid colon and rectum) adenoma cases and 34,817 endoscopy-negative controls. Dietary intake was assessed using a 137-item food frequency questionnaire, with additional questions on meats and meat cooking practices. The questionnaire was linked to a previously developed database to determine exposure to HCAs and PAHs. Intake of red meat, with known doneness/cooking methods, was associated with an increased risk of adenoma in the descending and sigmoid colon [odds ratio (OR), 1.26; 95% confidence interval (95% CI), 1.05-1.50 comparing extreme quintiles of intake] but not rectal adenoma. Well-done red meat was associated with increased risk of colorectal adenoma (OR, 1.21; 95% CI, 1.06-1.37). Increased risks for adenoma of the descending colon and sigmoid colon were observed for the two HCAs: 2-amino-3,8-dimethylimidazo[4,5]quinoxaline and 2-amino-1-methyl-6-phenylimidazo[4,5]pyridine (OR, 1.18; 95% CI, 1.01-1.38 and OR, 1.17, 95% CI, 1.01-1.35, respectively) as well as benzo(a)pyrene (OR, 1.18; 95% CI, 1.02-1.35). Greater intake of bacon and sausage was associated with increased colorectal adenoma risk (OR, 1.14; 95% CI, 1.00-1.30); however, total intake of processed meat was not (OR, 1.04; 95% CI, 0.90-1.19). Our study of screening-detected colorectal adenomas shows that red meat and meat cooked at high temperatures are associated with an increased risk of colorectal adenoma.


Experimental examination of videodensitometry of large opacifications in digital subtraction angiography.
With the recent introduction of digital radiography the possibility of extracting clinically useful quantitative indices of function has emerged. In digital subtraction angiography (DSA), videodensitometric analysis has been widely applied. An experimental investigation of the usefulness of logarithmically transformed pixel values in DSA images for quantitative densitometry is performed. Dependence on image uniformity, transmittance, scattered radiation and video offset voltages is examined. Results indicate independence of both uniformity and transmittance and dependence on both scattered radiation and offset voltages. The possible use of lead absorbers to derive corrections for contributions from scattered radiation and similar aberrations in each image used for subtraction is also examined. Observations indicate that such corrections can allow accurate videodensitometry.


Robotic thoracic surgery in inflammatory and infective diseases.
Tuberculosis and inflammatory conditions are endemic in India and South-East Asia. They cause intense inflammatory reactions and adhesions, thus making surgical resection difficult. In 2009, we installed an intuitive da Vinci HDSi robot to perform our surgery as a part of a robotic thoracic surgery unit. We reviewed our practice to report the trials and tribulations of starting a robotic thoracic surgery program in an inflammatory and infective disease endemic third-world country. With the success of the multispecialty robotic surgery program, we were able to purchase a second robot with an operating console and a training console. The robot is an additional tool in the armamentarium of the thoracic surgeon. It provides good vision in inflammatory conditions, facilitates dissection of dense adhesions with minimal blood loss, and the ability of the robotic endowrist allows maximum and safe manipulation at the thoracic outlet. Sleeve resection and sleeve lobectomy are technically possible, due to ease of suturing with the robotic platform. Complex resections for tuberculosis, aspergilloma, inflammatory tumours and post-infective bronchiectasis are safer using the robotic thoracic platform. This is our operation of choice in complex thoracic surgery cases.


Quantitative analysis of antithrombin III binding site in low molecular weight heparins by exhausetive heparinases digestion and capillary electrophoresis.
The antithrombin III (ATIII)-binding site, which contains a special 3-O-sulfated, N-sulfated glucosamine residue with or without 6-O-sulfation, is mainly responsible for the anticoagulant activity of heparin. Undergoing the chemical depolymerization process, the preservation of the ATIII-binding site in low molecular weight heparins (LMWHs) are varied leading to the fluctuation of the anticoagulant activity. Herein we report a capillary electrophoresis (CE) method in combination with heparinase digestion and affinity chromatography for the measurement of molar percentage of ATIII-binding site of LMWHs. After exhaustively digesting LMWHs with the mixture of heparinase I, II and III, almost all the resulting oligosaccharide building blocks, including the three 3-O-sulfated tetrasaccharides derived from the ATIII-binding site, were resolved by CE separation. The peak area of each building block permits quantification of the molar percentage of the ATIII-binding site. The peaks corresponding to the 3-O-sulfated tetrasaccharides were assigned based on the linear relationship between the electrophoretic mobilities of the oligosaccharides and their charge to mass ratios. The peak assignment was further confirmed by analysis of the high ATIII affinity fractions, which contains much high 3-O-sulfated tetrasaccharides. With the method, the molar percentage of the ATIII-binding site of enoxaparin from different batches and different manufactures were measured and compared. It was demonstrated that the CE method provides more precise data for assessing the anti-FXa activity than that of the biochemical assay method.


The relationship between arthritis and human parvovirus B19 infection.
In order to evaluate the role of human parvovirus B19 in the etiopathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), synovial fluid and blood specimens were collected at 1-month intervals from 20 patients with early synovitis (ES) and 31 with RA. Blood specimens were also collected from 25 patients with SLE, 25 with osteoarthritis (OA) as the diseased control group, and 50 healthy blood donors (HBD) as the healthy control group. Detection of B19 IgM and B19 IgG were performed by enzyme-linked immunosorbent assay from serum specimens, and B19 DNA was detected by polymerase chain reaction from synovial fluid samples. B19 IgM, B19 IgG, and B19 DNA were found in the three patients of the ES group. Subsequently, two of them were diagnosed with RA and one with SLE. B19 DNA was also detected in the synovial fluid of eight patients in the RA group. Of them, all were positive for B19 IgG and half were positive for B19 IgM. B19 IgM was not detected in either of the control groups. To define the role of B19 in the etiopathogenesis and prognosis of undiagnosed arthritis and other chronic inflammatory diseases such as RA and SLE, we need broader serial and prospective studies based on clinical and laboratory collaboration. In conjunction with case reports, these studies would also serve to detect other possible factors in the etiopathogenesis of chronic inflammatory diseases.


Macrophage MMP10 Regulates TLR7-Mediated Tolerance.
Using an in vivo model of tolerance to TLR7-induced skin inflammation, we found a critical role for macrophage-derived MMP10 in mediating immune hypo-responsiveness. Cutaneous exposure to Imiquimod (IMQ), a TLR7 agonist, induced acute expression of pro-inflammatory factors (IL1β, IL6, CXCL1) and neutrophil influx equally in both wildtype and Mmp10-/- mice. However, whereas subsequent exposure (11 and 12 days later) to IMQ led to marked abrogation of pro-inflammatory factor expression in wildtype mice, Mmp10-/- mice responded similarly as they did to the first application. In addition, the second exposure led to increased expression of negative regulators of TLR signaling (TNFAIP3, IRAK3) and immunosuppressive cytokines (IL10, TGFβ1) in wildtype mice but not in Mmp10-/- mice. In vitro studies demonstrated that prior exposure of IMQ to bone marrow-derived macrophages (BMDM) made wildtype cells refractory to subsequent stimulation but did not for Mmp10-/- macrophages. These findings expand the critical roles MMP10 plays in controlling macrophage activation to indicate that the development of immune tolerance to TLR7 ligand is dependent on this macrophage-derived proteinase.


Revealing the direct effect of individual intercalations on DNA conductance toward single-molecule electrical biodetection.
Monitoring complex interactions of biological systems at the molecular level provides new opportunities to uncover fundamental details of the basic processes of life, of crucial importance to biology, diagnosis and drug discovery. Here, we detailed a reliable single-molecule electrical approach for achieving label-free, ultrasensitive electrical detection of DNA functions, using DNA intercalations by individual EB/SGs as a representative, based on DNA-functionalized molecular junctions. The analysis principle relies on the distortion mechanism of intercalative binding on the structural integrity of DNAs at the single-event level, resulting in significant step-wise changes in DNA charge transport. Such an understanding led to direct, rapid intercalator detection with subfemtomolar sensitivity. This single-molecule electrical approach provides a foundation for future molecular dynamics studies with single-molecule sensitivity, which will lead to direct observation of new effects and fundamental discoveries of the details of the most basic processes of life.


Epidermal growth factor receptor-targeted sonoporation with microbubbles enhances therapeutic efficacy in a squamous cell carcinoma model.
Sonoporation is a drug and gene delivery system using ultrasonication that allows the intracellular delivery of foreign molecules that cannot enter cells under normal conditions. We previously reported that sonoporation with microbubbles (MBs) could achieve effective intracellular drug delivery to human gingival squamous carcinoma Ca9-22 cells. In this study, we developed anti-epidermal growth factor receptor (EGFR) antibody-conjugated MBs (EGFR-MBs) and evaluated their capacity to enhance anti-cancer drug toxicity in vitro and in vivo. We first assessed the effect of sonoporation with EGFR-MBs on Ca9-22 cells by the WST-8 assay, flow cytometry and Hoechst's staining in vitro. Sonoporation and EGFR-MB had a strong cytotoxic effect on Ca9-22 cells with low-dose bleomycin. Furthermore, bleomycin delivery using sonoporation with EGFR-MBs remarkably increased the number of apoptotic cells. We next examined the effect of EGFR-MBs in a murine squamous cell carcinoma model. Bleomycin delivery by sonoporation with EGFR-MBs exhibited remarkable antitumor activity. Together, our results show that EGFR-MBs and ultrasound treatment increases the efficacy and specificity of intracellular drug uptake, suggesting this could be a novel drug-targeting modality for oral squamous cell carcinoma chemotherapy treatment.


TNF-alpha and apoptosis: implications for the pathogenesis and treatment of psoriasis.
TNF-alpha is a key cytokine in innate immune responses and is increased in psoriatic lesions. TNF-alpha has many effects, ranging from inflammation to apoptosis. These effects are reviewed to better understand the role of TNF-alpha as it relates to the pathogenesis and treatment of psoriasis. TNF-alpha increases production of pro-inflammatory molecules (e.g. IL-1, IL-6, IL-8, NF-kappa B, vasoactive intestinal peptide) and adhesion molecules (e.g. intercellular adhesion molecule-1, P-selectin, E-selectin). TNF-alpha promotes apoptosis through binding to the TNF-receptor 1; however, psoriatic lesions are hyperproliferative despite an increase in TNF-alpha. This paradox is partially explained as NF-kappa B activation seems to inhibit TNF-alpha-induced apoptosis. The importance of TNF-alpha and apoptosis in psoriasis is shown through the review of clinical trials using anti-TNF-alpha immunobiologics (e.g. etanercept, infliximab) and apoptosis-inducing treatments that result in clinical improvement of the disease.


[Application of a shuttle avoidance schedule in rats to evaluate a drug-induced auditory impairment (author's transl)].
In attempts to study drug-induced auditory impairment we measured the auditory threshold in rats, using the shuttle box method. The auditory threshold with physical impairment of ears was also measured. The sensitivity of the rats to the auditory response was decreased to about 15dB in cotton-stuffed ears and to about 20dB in pierced eardrums. In this experiment, we used drugs known to be ototoxic; dihydrostreptomycin sulfate, kanamycin sulfate, neomycin sulfate and ethacrynic acid. With successive administration of each drug, the auditory sensitivity in rats decreased. This shuttle box method is easily facilitated and the auditory threshold of many rats can be measured over a short period. This approach may be a useful method for screening ototoxic drugs.


Importance of performing transesophageal echocardiography in acute stroke patients older than fifty.
The purpose of this study was to determine the value of transesophageal echocardiography (TEE) in determining the presence of cardiac manifestations that required anticoagulation in patients presenting with acute stroke. Of 626 consecutive stroke patients who underwent TEE, 188 patients with no obvious etiology for stroke were subcategorized according to age. TEE results were analyzed for cardiac findings suggestive of a cause for embolic stroke, including complex atheromas in the arch/ascending aorta, patent foramen ovale (PFO), atrial septal aneurysm (ASA), and intracavitary thrombi. Data were analyzed using Fisher's exact test. Of 188 patients, 66% (125/188) were older than 50 years and 34% (63/188) were younger than 50 years. The incidence of complex atheroma was 12.8% (16/125) in patients older than 50 years as compared to 0% (0/63) in patients who were younger than 50 years (P = 0.002). In patients older than 50 years, findings that indicated a need for anticoagulation based on TEE results were found in 22.4% (28/125) (atheroma = 16, PFO = 12, ASA = 5, thrombus = 3, PFO + ASA = 1) compared to 14.3% (9/63) (atheroma = 0, PFO = 5, ASA = 2, thrombus = 2, PFO + ASA = 1) in patients younger than 50 years. TEE plays an important role in suspected embolic stroke patients of all age groups. Due to the higher incidence of complex atheromas in patients older than 50 years of age, TEE might be of added importance in identifying the candidates who may benefit from anticoagulation.


Posterior Circulation Ischemic Stroke.
Approximately 20-25% of all acute strokes occur in the posterior circulation. These strokes can be rather difficult to diagnose because they present in such diverse ways, and can easily be mistaken for more benign entities. A fastidious history, physical exam, high clinical suspicion, and appropriate use of imaging are essential for the emergency physician to properly diagnose and treat these patients. Expert stroke neurologist consultation should be utilized liberally.


Local rotational flaps for breast conservation therapy as an alternative to mastectomy.
An anticipated poor cosmetic result has traditionally been deemed a relative contraindication for breast conservation therapy (BCT). We sought to determine whether a local rotational flap could achieve satisfactory cosmesis in patients who were anticipated to have a poor cosmetic result following standard segmental mastectomy but who nevertheless desired BCT. Within the past 3 years, nine patients were treated with BCT using local rotational flap techniques. Their records were reviewed for patient characteristics, pre- and postoperative treatment, disease-free status, and patient satisfaction with cosmesis. The cosmetic outcome following a segmental mastectomy was anticipated to be unacceptable due to the following features: a large previous biopsy cavity with unknown or positive margins (three patients); initial large primary tumors with unknown extent of residual disease following induction chemotherapy (five patients); and pre-existing poor cosmesis (one patient). One patient had refused modified radical mastectomy and had satellitosis from inadequately treated primary tumor (excisional biopsy with positive margins and no further therapy). The median initial tumor size was 2.7 cm (range, 1.5 cm to 5.0 cm). Final resection margins were negative in all patients. Postoperative radiotherapy was given in seven patients; one patient did not receive radiotherapy because of a pre-lupus condition and one did not require radiotherapy because her pathologic diagnosis was Paget's disease without an invasive component. Cosmesis was judged to be good to excellent by eight of nine patients. The patient who refused mastectomy was dissatisfied with cosmesis because of mild asymmetry. With a median follow-up of 24 months, only one patient has developed a local recurrence. Local rotational flaps composed of adjacent breast tissue are an acceptable method of achieving satisfactory cosmesis in selected patients who desire BCT.


The relative bioavailability of diclofenac with respect to time of administration.
The pharmacokinetics of diclofenac after a single oral dose (50 mg) were studied in 10 healthy adults on two occasions separated by 2 weeks, once in the morning (dose administered at 07.00 h) and once in the evening (dose at 19.00 h). Peak serum drug concentrations as well as the area under the drug concentration-time curve were significantly less during the night compared with the day (Cmax: 1886 +/- s.d 901 vs 2791 +/- 1565 ng ml-1 and AUC: 2807 +/- 1376 vs 3681 +/- 1986 ng ml-1 h). However, the time to reach peak concentration (tmax) and the half-life of diclofenac (t1/2) were not significantly different on the two occasions. We suggest that the extent of diclofenac absorption is slightly lower following administration in the evening compared with administration in the morning.


The Ultratrace Determination of Fluoroquinolones in River Water Samples by an Online Solid-Phase Extraction Method Using a Molecularly Imprinted Polymer as a Selective Sorbent.
Fluoroquinolones (FQs) are broad-spectrum antibiotics widely used to treat animal and human infections. The use of FQs in these activities has increased the presence of antibiotics in wastewater and food, triggering antimicrobial resistance, which has severe consequences for human health. The detection of antibiotics residues in water and food samples has attracted much attention. Herein, we report the development of a highly sensitive online solid-phase extraction methodology based on a selective molecularly imprinted polymer (MIP) and fluorescent detection (HPLC-FLD) for the determination of FQs in water at low ng L−1 level concentration. Under the optimal conditions, good linearity was obtained ranging from 0.7 to 666 ng L−1 for 7 FQs, achieving limits of detection (LOD) in the low ng L−1 level and excellent precision. Recoveries ranged between 54 and 118% (RSD < 17%) for all the FQs tested. The method was applied to determining FQs in river water. These results demonstrated that the developed method is highly sensitive and selective.


[Influenza vaccination: which vaccine (author's transl)].
A comparative study of the literature of the past ten years showed that vaccination of horses and ponies against influenza is best done using adjuvant-containing vaccines. Comparable results may probably be obtained by twice inoculating an aquenous vaccine. There are no drawbacks to the use of aluminium-hydroxide as an adjuvant when mineral oil is used as an adjuvant, the first and second vaccinations do not present any problems.


Components and mechanisms of thermal hyperpnea.
The pattern of breathing during a hyperthermia-induced hyperventilation varies across different species. Thermal tachypnea is a first phase panting response adopted during hyperthermia when tidal volume is minimized and the frequency of breathing is maximized. Blood-gas tensions and pH are maintained during this hyperventilation, and the associated heat loss helps the animal regulate its body temperature. A second pattern of breathing adopted in hyperthermia is thermal hyperpnea; this response is the focus of this review. This form of hyperventilation is evident after an increase in core temperature and it is apparent in humans. Increases of tidal volume as well as frequency of breathing are evident during this response that results in a respiratory alkalosis. The cause of thermal hyperpnea is not resolved; evidence of the potential mechanisms underlying this response support that modulators of the response act in either a multiplicative or additive manner with body temperatures. The details of the designs and methodologies of the studies supporting or refuting these two views are discussed. A physiological rationale for thermal hyperpnea is presented in which it is suggested this response serves a heat-loss role and contributes to selective brain cooling in hyperthermic humans. Ongoing research in this area is focused on resolving the mechanisms underlying thermal hyperpnea and its contribution to cranial thermoregulation. The direct application of this research is for the care of febrile and hyperthermic patients.


Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation.
The caspases are a family of at least 10 human cysteine proteases that participate in cytokine maturation and in apoptotic signal transduction and execution mechanisms. Peptidic inhibitors of these enzymes are capable of blocking cytokine maturation and apoptosis, demonstrating their crucial roles in these processes. We have recently discovered that nitric oxide (NO), produced either extracellularly by NO donors or intracellularly by the inducible nitric oxide synthase, prevented apoptosis in hepatocytes. Caspase-3-like activity was found to be inhibited under these conditions. To investigate further the interaction between NO and caspases, we utilized purified human recombinant caspases and examined the effect of NO on enzymatic activities of different caspases. We report here that of the seven caspases studied, all were reversibly inhibited by NO. Dithiothreitol was able to reverse the NO inhibition, indicating direct S-nitrosylation of caspase catalytic cysteine residue by NO. Our results support the concept that NO is an endogenous regulator of caspase activity.


Characterization of verotoxin-encoding phages from Escherichia coli O103:H2 strains of bovine and human origins.
The objectives of this study were to induce and characterize verotoxin-encoding phages from a collection of 91 verotoxin-producing Escherichia coli (VTEC) O103:H2 strains of human and bovine origins. All the strains carried the vt1 gene, and two carried the vt2 gene as well. The phages were induced by UV irradiation and characterized by DNA restriction fragment length polymorphism (RFLP), genome size, morphology, and Q and P genes, characteristic of lambdoid phages. A total of 32 vt-positive phages were induced and isolated from 31 VTEC O103:H2 strains. Thirty phages were vt1 positive, and two were vt2 positive. Ten of the 30 vt1-positive phages (33.3%) were from cattle strains, and 20 (66.6%) were from human strains. The two vt2-positive phages were from human strains. Phages belonged to 21 RFLP profiles, of which 17 were single-phage profiles and 4 were multiple-phage profiles. The estimated genome size of the phages ranged from 34 to 84 kb. Two phages that were examined by electron microscopy possessed hexagonal heads with long tails, and one had an elongated head with a long tail. The Q and P genes were amplified in all 32 phages, and the Q-stxA(1) gene region yielded an amplicon in 19 phages (59.3%). It is concluded that the VTEC O103:H2 strains of human origin were more readily inducible than those of bovine origin and that the genotypic profiles of verotoxin-encoding phages were highly diverse, as revealed by their RFLP profiles.


A risk prediction tool for colorectal cancer screening: a qualitative study of patient and provider facilitators and barriers.
Despite proven effectiveness of colorectal cancer (CRC) screening, at least 35% of screen-eligible adults are not current with screening. Decision aids and risk prediction tools may help increase uptake, adherence, and efficiency of CRC screening by presenting lower-risk patients with options less invasive than colonoscopy. The purpose of this qualitative study was to determine patient and provider perceptions of facilitators and barriers to use of a risk prediction tool for advanced colorectal neoplasia (CRC and advanced, precancerous polyps), to maximize its chances of successful clinical implementation. We conducted qualitative, semi-structured interviews with patients aged 50-75 years who were not current with CRC screening, and primary care providers (PCPs) at an academic and a U.S. Department of Veterans Affairs Medical Center in the Midwest from October 2016 through March 2017. Participants were asked about their current experiences discussing CRC screening, then were shown the risk tool and asked about its acceptability, barriers, facilitators, and whether they would use it to guide their choice of a screening test. The constant comparative method guided analysis. Thirty patients and PCPs participated. Among facilitators were the tool's potential to increase screening uptake, reduce patient risk, improve resource allocation, and facilitate discussion about CRC screening. PCP-identified barriers included concerns about the tool's accuracy, consistency with guidelines, and time constraints. Patients and PCPs found the risk prediction tool useful, with potential to increase uptake, safety, and efficiency of CRC screening, indicating potential acceptability and feasibility of implementation into clinical practice.


Striatal dopamine D₂/D₃ receptor binding in pathological gambling is correlated with mood-related impulsivity.
Pathological gambling (PG) is a behavioural addiction associated with elevated impulsivity and suspected dopamine dysregulation. Reduced striatal dopamine D(2)/D(3) receptor availability has been reported in drug addiction, and may constitute a premorbid vulnerability marker for addictive disorders. The aim of the present study was to assess striatal dopamine D(2)/D(3) receptor availability in PG, and its association with trait impulsivity. Males with PG (n=9) and male healthy controls (n=9) underwent [11C]-raclopride positron emission tomography imaging and completed the UPPS-P impulsivity scale. There was no significant difference between groups in striatal dopamine D(2)/D(3) receptor availability, in contrast to previous reports in drug addiction. However, mood-related impulsivity ('Urgency') was negatively correlated with [11C]-raclopride binding potentials in the PG group. The absence of a group difference in striatal dopamine binding implies a distinction between behavioural addictions and drug addictions. Nevertheless, our data indicate heterogeneity in dopamine receptor availability in disordered gambling, such that individuals with high mood-related impulsivity may show differential benefits from dopamine-based medications.


25-Hydroxyvitamin D 1 alpha- and 24-hydroxylase activities in pig kidney homogenates: effect of vitamin D deficiency.
A method was developed for simultaneous assay of 25-hydroxyvitamin D 1 alpha- and 24-hydroxylase in pig kidney homogenates. The products of these enzymes, 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol, were extracted from the in vitro incubation mixtures, isolated and purified by gel filtration and high-performance liquid chromatography, identified by ultraviolet absorption spectrometry, and high performance liquid chromatography with a second solvent system and quantified relative to authentic standards with a 254-nm detector system. Assay conditions included 12.5 microM substrate (25-hydroxycholecalciferol) concentration and an incubation time of 15 minutes at 37 degrees C, which was on the linear portion of time curves for both enzymes. Maximum enzyme velocity was 1548 pmol/minute per gram kidney tissue for 1 alpha-hydroxylase and 286 pmol/minute per gram kidney tissue for 24-hydroxylase. The apparent Km for pig kidney 25-hydroxyvitamin D 1 alpha-hydroxylase (1 alpha-hydroxylase) was 445 nM and for 25-hydroxyvitamin D 24-hydroxylase (24-hydroxylase) was 833 nM. We also demonstrated the use of this assay in pigs fed a semisynthetic diet with or without vitamin D. Pigs fed vitamin D-deficient diet had a 5- to 10-fold increase in 1 alpha-hydroxylase activity, severe hypocalcemia, low plasma, 1,25-dihydroxycholecalciferol, very low plasma (undetectable) 24,25-dihydroxycholecalciferol concentration, and no detectable 24-hydroxylase activity compared to those fed the vitamin D-replete diet.


French preschool and primary teachers' attitude towards finger counting.
Teachers' beliefs and attitudes are known to guide the type of activities they implement in their classrooms. A traditional conception that finger counting is merely a back-up when children fail to use more sophisticated and efficient strategies could therefore prevent teachers from encouraging children's use of fingers in arithmetic tasks. However, the potential benefit of finger counting for young learners has been recently documented and setting aside its practice within classrooms may hinder children's mathematical skill development. It is therefore important to establish whether there is a discrepancy between teacher's beliefs regarding finger counting and the latest discoveries in this field of research. To this aim, we interrogated 413 teachers from preschool to Grade 5. We found that, despite being generally positive towards finger counting, teachers think that finger counting is typical of children who present math difficulties or lack of confidence, even during the first years of learning. These results are discussed considering what is known and what remains to be determined in the current scientific literature.


Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action.
Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.


Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains.
The evolutionary demand for rapid nerve impulse conduction led to the process of myelination-dependent organization of axons into distinct molecular domains. These domains include the node of Ranvier flanked by highly specialized paranodal domains where myelin loops and axolemma orchestrate the axoglial septate junctions. These junctions are formed by interactions between a glial isoform of neurofascin (Nfasc(NF155)) and axonal Caspr and Cont. Here we report the generation of myelinating glia-specific Nfasc(NF155) null mouse mutants. These mice exhibit severe ataxia, motor paresis, and death before the third postnatal week. In the absence of glial Nfasc(NF155), paranodal axoglial junctions fail to form, axonal domains fail to segregate, and myelinated axons undergo degeneration. Electrophysiological measurements of peripheral nerves from Nfasc(NF155) mutants revealed dramatic reductions in nerve conduction velocities. By using inducible PLP-CreER recombinase to ablate Nfasc(NF155) in adult myelinating glia, we demonstrate that paranodal axoglial junctions disorganize gradually as the levels of Nfasc(NF155) protein at the paranodes begin to drop. This coincides with the loss of the paranodal region and concomitant disorganization of the axonal domains. Our results provide the first direct evidence that the maintenance of axonal domains requires the fence function of the paranodal axoglial junctions. Together, our studies establish a central role for paranodal axoglial junctions in both the organization and the maintenance of axonal domains in myelinated axons.


[Surgery in children and adolescents].
The authors explain in a standardized model of nursing care for children and adolescents durning pre-operative phase, the first part in the global surgical process. This phase commences at the moment a surgical intervention is deemed necessary and finalizes when the child/adolescent is transported to the operating room. The authors perform a systematic and holistic evaluation, using the Gordon Functional Health Patterns. Special emphasis is given to aspects such as the perception-management health pattern, the nutritional-metabolic pattern, the elimination pattern, the exercise-activity pattern, the dream-rest pattern, the self-perception pattern and the adaptation-stress tolerance pattern. They evaluate the perception and responses children of varying ages provide to being separated from parents. They highlight the cultural factors which must be born in mind in order to achieve an adequate evaluation and individualized care. The authors select the Nursing Diagnoses of NANDA, the North American Nursing Diagnosis Association, which most frequently appear in this pre-operative phase: fear/anxiety, risk of aspiration, risk of an alteration in health maintenance, and risk of infection. Finally, the authors describe the nursinginterventions related with these diagnoses.


In vivo effects of head-to-tail 3-alkylpiridinium polymers isolated from the marine sponge Raniera sarai.
Water soluble polymeric 3-alkylpyridinium salts (poly APS; MW 18900 and 5520 Da) were isolated from the marine sponge Raniera sarai. In vitro it strongly inhibited acetyl cholinesterase (AChE) from different species (electric eel, horse serum, human erythrocytes). In our experiments the importance of anti AChE activity in the toxin lethality was evaluated. In vivo experiments were performed on male Wistar rats and ECG, blood pressure and breathing pattern were monitored. After i.v. application of lethal doses of the toxin ECG showed signs of hypo perfusion. Arterial blood pressure fell to mid-circulatory pressure, and breathing stopped after a few breaths At sublethal doses the toxin caused an increase of residual volume, prolongation of expiration, and bradycardia. Patho-anatomical examination revealed that the plugs in lung circulation may cause the death of experimental animals due to cardiorespiratory failure.


Surface plasmon resonance in superperiodic metal nanoslits.
A superperiodic metal nanoslits device is a surface plasmon resonance optical diffraction grating in which each line of the grating consists of an array of finite number metal nanoslits. The metal nanoslits, upon optical excitations, support localized surface plasmon resonance. The superperiod of the nanoslits causes the coherent radiation of the surface plasmon resonance into the far field with angular dispersion. Therefore, localized surface plasmon resonance in the metal nanoslits can be measured with a CCD or a linear photodetector array. In this Letter, we describe a surface plasmon resonance spectral sensor using a superperiodic gold nanoslits array without using an external optical spectrometer.


Cascaded sum-frequency generation and electro-optic polarization coupling in the PPLNOI ridge waveguide.
Quasi-phase matched sum-frequency generation (SFG) and electro-optic (EO) polarization coupling has been realized simultaneously in a periodically poled lithium niobate on insulator (PPLNOI) ridge waveguide. Therefore, utilizing the cascading process, the intensity of sum-frequency conversion can be modulated by applying a transverse electric field. The driving voltage is reduced by using the ridge waveguide structure, and also the frequency conversion efficiency is enhanced. This scheme is proposed to control nonlinear frequency conversion by electric field applying on the lithium niobate on insulator (LNOI) platform. The integration and fast-speed modulation of the configuration may find applications in nonlinear optical processing and communication.


Generation of memory cell-mediated immune responses after secondary infection of mice with pichinde virus.
Pichinde virus (PV), a member of the arenavirus group, was found to elicit strong cell-mediated immune responses in various strains of mice. After primary i.v. inoculation, augmentation of natural killer (NK) cell activity occurred and peaked 3 to 4 days after infection. The NK response was followed by a second peak of cytotoxic activity that was found to be H-2 restricted, virus specific, and mediated by Thy-1.2+, Lyt-2.2+ lymphocytes. This cytotoxic T lymphocyte (CTL) response peaked 7 days post infection. Neutralizing antibodies were not detectable after PV infection of the mice. In light of this, we investigated the generation and kinetics of secondary cell-mediated immune responses after reinjection of homologous virus in vivo. Slight but significant augmentation of NK activity was observed 1 day after secondary virus challenge. As in the primary response, effectors of this NK activity rapidly became sensitive to anti-Thy-1.2 and complement treatment. NK activity rapidly returned to background levels and was followed by an anamnestic CTL response that peaked 4 days after reinjection of the virus. Thus, cell-mediated immune responses appeared more rapidly after secondary challenge in vivo, and the temporal relationship between NK and CTL generation was maintained. Both secondary NK and CTL responses were generated in mice that had been pretreated with cyclophosphamide (CY), suggesting that memory cell-mediated immune responses can be reactivated in vivo without undergoing cell division. In contrast, treatment with CY before primary infection delayed the appearance of virus-induced NK activity and abrogated the generation of H-2-restricted virus-specific CTL. Rechallenge of these CY-treated NK-primed mice resulted in the rapid generation of a secondary NK response that was not followed by either a primary or secondary CTL response. The data suggest that cells mediating a nonspecific effector function may possess specific memory. We discuss our results with respect to possible NK-CTL relationships.


Supplementary vitamin C does not accelerate bone healing in a rat tibia fracture model.
To investigate the role of ascorbic acid supplementation on bone healing after rat tibia fracture. Thirty male Wistar rats were randomly divided into Vitamin C (Group A) and sham (Group B) groups (15 rats each). Group A received 200 mg intraperitoneally per kg per day of ascorbic acid and Group B was given saline 5 ml per kg per day intraperitoneally once a day. The animals were caged in pairs and allowed free access to tap water and a standard rodent chow ad libitum. Fractures were produced manually, they were not stabilized, and unprotected weight-bearing was allowed. At two, four, and six weeks post-fracture, the rats in both groups were anesthetized and sacrificed by cervical dislocation. Callus tissue was dissected, prepared, and analyzed histologically. Histomorphological analysis was performed at six weeks post-fracture and the extent of fracture healing was determined using a five-point scale. There were no histological and histomorphological differences between drug-treated animals and the sham in the three different stages studied. By six weeks post-fracture, the five animals of each group had a complete bone union. Under the studied conditions, intraperitoneal Vitamin C supplementation does not accelerate the fracture healing process after experimental tibia fracture in rats. Level 2, individual study with experimental design.


Population-Based Assessment of Complications Following Surgery for Thyroid Cancer.
As thyroid cancer incidence rises, more patients undergo thyroid surgery. Although postoperative complication rates have been reported in single institution studies, population-based data are limited. To determine thyroid cancer surgery complication rates and identify at-risk populations. Using the Surveillance, Epidemiology, and End Results-Medicare database, we evaluated general complications within 30 days and thyroid surgery-specific complications within 1 year in 27,912 patients who underwent surgery for differentiated or medullary thyroid cancer between 1998 and 2011. Multivariable analyses of patient characteristics associated with postoperative complications were performed. General and thyroid surgery-specific complications. Overall, 1820 (6.5%) patients developed general postoperative complications and 3427 (12.3%) developed thyroid surgery-specific complications. In multivariable analyses, general and thyroid surgery-specific complications were significantly higher in patients >65 years [odds ratio (OR), 2.61; 95% confidence interval (CI), 2.31 to 2.95; OR, 3.12; 95% CI, 2.85 to 3.42], those with a Charlson/Deyo comorbidity score of 1 (OR, 2.40; 95% CI, 1.66 to 3.49; OR, 1.88; 95% CI, 1.53 to 2.31) and ≥2 (OR, 7.05; 95% CI, 5.33 to 9.56; OR, 3.62; 95% CI, 3.11 to 4.25), and those with regional (OR, 1.18; 95% CI, 1.03 to 1.35; OR, 1.31; 95% CI, 1.19 to 1.45) or distant disease (OR, 2.83; 95% CI, 2.30 to 3.47; OR, 1.85; 95% CI, 1.54 to 2.21), respectively. The rates of thyroid cancer surgery complications are higher than predicted, and patients with older age, more comorbidities, and advanced disease are at greatest risk. Efforts to reduce complications are needed.


CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression.
The CD40-CD40 ligand (CD40L) interaction is a key event in the initiation of an adaptive immune response, and as such the therapeutic value of CD40L blockade has been studied in many experimental models of tissue transplantation and autoimmune disease. In rodents, transplantation of allogeneic tissues under the cover of anti-CD40L Abs has resulted in prolonged graft survival but not tolerance. In this report, we show that failure to induce tolerance probably results from the inability of anti-CD40L Abs to prevent graft rejection elicited by the CD8+ T cell subset. When the CD8+ T cell population is controlled independently, using anti-CD8 Abs, then tolerance is possible. Transplantation tolerance induced by anti-CD4 mAbs can often be associated with dominant regulation, manifested as infectious tolerance and linked suppression, both of which are mediated by CD4+ T cells. We show here that CD4+ T cells rendered tolerant using anti-CD40L therapy exhibit the same regulatory property of linked suppression, as demonstrated by their ability to accept grafts expressing third party Ags only if they are expressed in conjunction with the tolerated Ags. This observation of linked suppression reveals a hitherto undocumented consequence of CD40L blockade that suggests the tolerant state is maintained by a dominant regulatory mechanism. Our results suggest that, although anti-CD40L Abs are attractive clinical immunotherapeutic agents, additional therapies to control aggressive CD8+ T cell responses may be required.


Normal and Tumour Tissue mRNA Expressions of Telomerase Complex Genes in Several Types of Cancer.
To investigate the changes in mRNA expression levels of telomerase-related significant proteins in several types of cancer. Human telomerase reverse transcriptase, pontin, reptin and dyskerin expressions were measured in normal and tumour tissues obtained from 26 patients with colorectal, breast and gastric cancers, using the real-time reverse transcriptase-polymerase chain reaction method. For all patients, no significant difference was found in mRNA expressions of human telomerase reverse transcriptase and dyskerin (p>0.05), although their levels in tumour tissues were found to be higher than in normal tissues. However, pontin and reptin mRNA expressions were significantly higher in tumour tissues than in normal tissues (p<0.01). While human telomerase reverse transcriptase showed a high correlation with only pontin (p<0.001) in normal tissues, high positive correlations were observed between human telomerase reverse transcriptase with pontin (p<0.005), reptin (p<0.01) and dyskerin (p<0.01) in tumour tissues. The increased mRNA expressions of all four genes in tumour tissues may suggest a role in cancer development. Correlations of pontin, reptin and dyskerin with human telomerase reverse transcriptase support the hypotheses describing their roles in telomerase complexes.


Comparable Infection Level and Tropism of Measles Virus and Canine Distemper Virus in Organotypic Brain Slice Cultures Obtained from Natural Host Species.
Measles virus (MV) and canine distemper virus (CDV) are closely related members of the family Paramyxoviridae, genus Morbillivirus. MV infection of humans and non-human primates (NHPs) results in a self-limiting disease, which rarely involves central nervous system (CNS) complications. In contrast, infection of carnivores with CDV usually results in severe disease, in which CNS complications are common and the case-fatality rate is high. To compare the neurovirulence and neurotropism of MV and CDV, we established a short-term organotypic brain slice culture system of the olfactory bulb, hippocampus, or cortex obtained from NHPs, dogs, and ferrets. Slices were inoculated ex vivo with wild-type-based recombinant CDV or MV expressing a fluorescent reporter protein. The infection level of both morbilliviruses was determined at different times post-infection. We observed equivalent infection levels and identified microglia as main target cells in CDV-inoculated carnivore and MV-inoculated NHP brain tissue slices. Neurons were also susceptible to MV infection in NHP brain slice cultures. Our findings suggest that MV and CDV have comparable neurotropism and intrinsic capacity to infect CNS-resident cells of their natural host species.


Molecular cloning and nucleotide sequence of the type I beta-lactamase gene from Bacillus cereus.
The gene for the type I beta-lactamase from Bacillus cereus has been cloned in Bacillus subtilis and Escherichia coli. In B. subtilis, penicillinase activity is detected and the enzyme is secreted. In E. coli, the gene confers ampicillin resistance. The cloned insert is 4.3 kb in length and DNA sequencing has revealed the location of the gene, its promoter and signal peptide.


The Development of Cladribine Tablets for the Treatment of Multiple Sclerosis: A Comprehensive Review.
Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers. Due to the molecule's ability to preferentially reduce T and B lymphocytes, it has been developed into an oral formulation for the treatment of multiple sclerosis (MS). The unique proposed mechanism of action of cladribine allows for the therapy to be delivered orally over two treatment-week cycles per year, one cycle at the beginning of the first month and one cycle at the beginning of the second month of years 1 and 2, with the potential for no further cladribine treatment required in years 3 and 4. This review summarizes the clinical development program for cladribine tablets in patients with MS, including the efficacy endpoints and results from the 2-year phase III CLARITY study in patients with relapsing-remitting MS (RRMS), the 2-year CLARITY EXTENSION study, and the phase III ORACLE-MS study in patients with a first clinical demyelinating event at risk for developing MS. Efficacy results from the phase II ONWARD study, in which cladribine tablets were administered as an add-on to interferon-β therapy in patients with RRMS, are also summarized. A review of all safety data, including lymphopenia, infections, and malignancies, is provided based on data from all trials in patients with MS, including the initial parenteral formulation studies. Based on these data, cladribine tablets administered at 3.5 mg/kg over 2 years have been approved across the globe for various forms of relapsing MS. The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review (MP4 279143 kb).


[Anal sphincter rupture during vaginal delivery].
Rupture of the anal sphincter during childbirth is a major cause of faecal incontinence among women, a condition with considerable psychosocial consequences. The reported incidences show large variations, from 0.36% to 24%. Definitions and classifications vary as much. Also, reports on the persisting subjective problems of the women afflicted demonstrate diversity. Over a 2(1/2) year period from January 2000, all women with partial or total rupture of the anal sphincter during delivery were invited to a follow up consultation after 6 months and interviewed about their subjective discomfort. Over the period in question we registered 147 ruptures of the anal sphincter among 6124 vaginal deliveries (2.4%); 109 (1.7%) were partial ruptures, 38 (0.7%) total ruptures. Among the 137 women who came in for a consultation 6 months after delivery, 92 (67%) had no complaints at all. Five women (4%) had some degree of leakage for liquid stools. None of them had incontinence for solid stools. The reported incidence is in keeping with most of the previous registrations in the Nordic countries, but not with those giving the lowest figures. Improved delivery technique might reduce the incidence. The incidence of discomfort and complaints we found at 6 months was lower than expected on the basis of previous reports.


Histopathological study of Schistosoma mansoni infection in the murine model using the PC (Pará) and LILA (Maranhão) strains.
Experimental models of Schistosoma mansoni infections in mammals have contributed greatly in understanding the pathology and pathogenesis of human infection. The absence of earlier reviews regarding specific strains of the Amazon region prompted research, which the main objective was to describe histopathological lesions in different phases of schistosomiasis in a murine model using PC (Pará) and LILA (Maranhão) S. mansoni strains. One hundred and eighty young female albino swiss mice (Mus musculus) were used and were randomly divided into five groups (PC-01, PC-02, LILA-01, LILA-02, and controls), according to the number of cercariae injected and the strain adopted. Animals were sacrificed in predetermined periods (35, 56, 112, 156, and 180 days) in an attempt to follow the evolution of the disease in the histological sections of their tissues at different phases of infection. Our findings were compatible with the data already described by others authors using different strains of S. mansoni, making it possible to identify some peculiarities, which are discussed in this work. In conclusion, the strains of parasite used did not modify the histopathological findings in the tissues of infected mice in any significant way when compared with the results of other studies using different strains.


Associations between Bacillus subtilis sigmaB regulators in cell extracts.
The general stress regulon of Bacillus subtilis is induced by the activation of the sigma(B) transcription factor. Activation of sigma(B) occurs as a consequence of the dephosphorylation of its positive regulator RsbV by one of two phosphatases that respond to either physical or nutritional stress. The physical stress phosphatase (RsbU) requires a second protein (RsbT) for activity. Stress is thought to initiate a process that triggers the release of RsbT from a large inhibitory complex composed of multiple copies of two protein species, RsbR (and/or its paralogues) and RsbS. The stress-derived signal driving RsbT release is unknown, but it fails to develop in B. subtilis lacking either ribosome protein L11 or the ribosome-associated protein Obg. RsbR, RsbS, RsbT, Obg and ribosomes elute in common high-molecular-mass fractions during gel-filtration chromatography of crude B. subtilis extracts. This paper reports the investigation of the basis of this coelution by the examining of associations between these proteins in extracts prepared from wild-type and mutant B. subtilis, and Escherichia coli engineered to express RsbR, RsbS and RsbT. Large RsbR/RsbS complexes, distinct from ribosomes, were detected in extracts of both B. subtilis and E. coli. In E. coli, high-molecular-mass forms of RsbS were less abundant when RsbR was absent, but in B. subtilis, only when both RsbR and its principal paralogues were missing from the extract was this form less abundant. This finding is consistent with the notion that the RsbR paralogues, present in B. subtilis but not E. coli, can substitute for RsbR in such complexes. RsbT was not bound to RsbR/RsbS in any extract that was examined, including one prepared from a B. subtilis strain with an RsbS variant (RsbS59SA) that is believed to continuously associate with RsbT. The high-molecular-mass forms of RsbT were found to be Triton-sensitive and independent of any other B. subtilis protein for their formation. These probably represent RsbT aggregates. The data suggest that the contribution of ribosomes/Obg to sigma(B) activation does not involve formation of a stable association between these proteins and the Rsb complex. In addition, the binding of RsbT to RsbS/RsbR appears to be more labile than the binding between the previously analysed Rsb proteins which form inhibitory complexes. This, and the apparent proclivity of RsbT to aggregate, suggests an inherent instability in RsbT which may play a role in its regulation.


Gene Therapy in Kidney Transplantation: Evidence of Efficacy and Future Directions.
Allograft loss remains a severe clinical problem after kidney transplantation. The molecular mechanism of graft loss is a complex process involving T and/or B cell activation, inflammation responses, autophagy and apoptosis. Since these pathways are involved in immune responses in kidney transplant rejection, application of genetic interference to inhibit specific pathways could present an effective targeted gene therapy method. Recent studies have successfully attempted to use gene therapy to target the key molecules involved in immune responses during transplantation. This strategy has the potential to silence target genes associated with a variety of diseases, including those that trigger allograft loss following organ transplantation. In this review, we have discussed evidence of the clinical applicability of gene therapy in kidney transplantation based on known associations between kidney diseases and genes participating in the underlying mechanisms. The molecules contributing to immune responses and inflammatory injury are further highlighted as potential targets in future clinical therapy for renal transplantation.


The effects of sunshields on red light running behavior of cyclists and electric bike riders.
Bicycles held an important position in transportation of China and other developing countries. As accidents rate involving electronic and regular bicycles is increasing, the severity of the bicycle safety problem should be paid more attention to. The current research explored the effect of sunshields (a kind of affordable traffic facility built on stop line of non-motor vehicle lanes (According to National Standard in China, e-bikes share the non-motor vehicle lane with regular bikes.) which was undertaken to avoid riders suffering from sunlight and high temperature) on diminishing red light running behavior of cyclists and e-bike riders. An observational study of 2477 riders was conducted to record and analyze their crossing behaviors at two sites across the city of Hangzhou, China. Results from logistic regression and analysis of variance indicated a significant effect of sunshield on reducing red light infringement rate both on sunny and cloudy days, while this effect of sunshield was larger on sunny days than on cloudy days based on further analysis. The effect of intersection type in logistic regression showed that riders were 1.376 times more likely to run through a red light upon approaching the intersection without sunshields compared to with sunshields in general. The results of MANCOVA further confirmed that rates of running behaviors against red lights were significantly lower at the intersections with a sunshield than at intersections without sunshields when other factors including traffic flow were statistically controlled. To sum up, it is concluded that sunshields installed at intersections can reduce the likelihood of red light infringement of cyclists and e-bike riders on both sunny and cloudy days. For those areas or countries with a torrid climate, sunshield might be a recommended facility which offers an affordable way to improve the safety of cyclists and e-bike riders at intersections. Limitations of the current sunshield design and current study are also discussed.


The possible influence of breathing patterns on the measurements of breathing frequency.
The breathing frequency is a common parameter to assess the radiation response of the lungs of laboratory rodents. Rats of the strain WAG/Rij which were bred in Hamburg show different breathing patterns which consist of short regular and long irregular breaths. Depending on the breathing pattern, the breathing frequency of untreated animals varies by a factor of three. Although this phenomenon might be strain-specific, it seems noteworthy because it might influence the results obtained after irradiation significantly, especially if breathing frequency is automatically converted into a numerical value.


Dyspnea induced by hemidiaphragmatic paralysis after ultrasound-guided supraclavicular brachial plexus block in a morbidly obese patient.
Hemidiaphragmatic paralysis (HDP) is a frequent complication of the brachial plexus block, caused by unintentional blockade of ipsilateral phrenic nerve. HDP did not rise enough alarm and attention to most anesthesiologists, because most patients with no coexisting comorbid diseases are asymptomatic and able to tolerate it. However, it may cause severe respiratory complication for patients with preexisting compromised cardiorespiratory function. A 67-year-old woman with morbidly obesity was planned to receive opening reduction and internal fixation of right humeral shaft fracture under regional anesthesia considering less respiratory and cardiovascular system interference compared with general anesthesia. After ultrasound guided supraclavicular brachial plexus block, the patient developed severe hypoxia and hypercapnia.Unintentional block of phrenic nerve and diaphragm paralysis was diagnosed by diaphragm ultrasound, which was considered as the main reason of severe hypoxia. It led to a conversion from regional anesthesia to general anesthesia with endotracheal intubation for patient's safety and smooth operation. The unintentional phrenic nerve block leads to a prolonged ventilation time, length of stay in intensive care unit and length of stay in hospital. This case report highlights the risk of diaphragm paralysis in morbidly obese patients. Though new diaphragm sparing brachial plexus block (BPB) methods were developed intended to reduce the risk of HDP, no approaches could absolutely spare phrenic nerve involvement. Therefore, clinicians should always consider the risk of HDP associated with BPBs. For each individual, a detailed preoperative evaluation and sufficient preparation are paramount to avoid serious complications.


The histological changes in the testis, epididymis and prostate gland of the red-bellied tree squirrel, Callosciurus erythraeus, during the growth and reproductive cycle.
The male reproductive glands of the red-bellied tree squirrel, Callosciurus erythraeus, in the infantile, and prepubertal males, as well as sexually functional, degenerating and redeveloping adults were studied histologically. In the infant, testes are characterized with solid seminiferous tubules filled with primordial germ cells and Sertoli cells. Interstitial cells are sparse. The prostate is composed of condensed cell cords grouped into lobules dispersed with interlobular tissues rich in fibroblasts. In the epididymis the highly convoluted tubule is lined with a simple cuboidal or columnar epithelium and thin smooth musculature without. In the prepubertal male, germ cells are engaged actively in mitosis. Primary spermatocytes are readily recognized. Leydig cells appear in groups in the interstitial tissue. In the prostate, cell cords become highly branched and collecting tubules make their appearance. The tubules in the epididymis are enlarged in diameter but their peripheral musculature becomes thinner. In functional males, meiosis is active and bundles of spermatozoa are scattered along the central lumen. Leydig cells have their cytoplasm highly enriched. The prostate is in the secretory phase. The tubule in the epididymis is filled with sperm. In the degenerating adult, meiosis is interrupted and necrotic germ cells are detached from germinal epithelium. In the prostate, secretory and collecting ducts are eventually reduced to condensed lobules separated by interlobular fibrous tissue. The tubule in the epididymis often fills with necrotic germ cells but no sperm. In the redeveloping adult, the histology of the testes, prostate and epididymis is similar to that of the prepubertal male. However, there is more fibrous tissue in the interlobular septa in the prostate gland and thick musculature at the periphery of the tubule in the epididymis.


EU legislation on food and potable water safety which could be potentially applied on board ferries and cruise ships: a comparison with US legislation.
The high number of people moving around by ferries and cruise ships in conjunction with great amounts of food and potable water transported (occasionally overloaded) and consumed by passengers constitute a possible risk for communicable diseases. Another issue of equally great importance is the food handlers who come from diverse origin and have a different mentality, habits, and background. In this paper an attempt is made to present comparatively EU and US legislation that could be potentially applicable to passenger ships food premises and potable water supplies. Moreover, food and water related hazards, not currently covered by EU legislation, were assessed together with US legislation and other guidelines for cruise ships.


Major intestinal complications of radiotherapy. Management and nutrition.
Hospitalization was required in 57 patients for intestinal injuries following radiotherapy for carcinoma of the cervix, endometrium, ovary, bladder, rectum, and other primary sites. Intestinal complications included stenosis, perforation, rectal ulcer, and rectovaginal, ileovaginal, and ileovesical fistula; 27 patients had multiple intestinal complications. Operation was necessary in 33 patients, as follows: bowel resections, 18; colostomy alone, five; adhesiolysis, five; ileocolic bypass, three; and Hartmann's procedure for sigmoid perforation, two. Five anastomotic leaks and six postoperative deaths occurred. Causes of death among the remaining patients included residual cancer (ten), de novo bowel cancer (two), radiation injury (four), and unrelated causes (six). Resection to uninvolved bowel, omental wrap of anterior resection anastomosis, avoidance of unnecessary adhesiolysis, and long-tube orientation seemed to contribute to successful operations. Nutritional support was used for repletion, post-operative fistulas, and short-gut syndrome.


Synovial protease/inhibitor ratios in erosive and nonerosive arthropathies.
Although rheumatoid joint fluids contain numerous polymorphs capable of secreting neutral proteases known to be able to digest cartilage, the high level of inhibitors (mainly alpha 1-antitrypsin and alpha 2-macroglobulin) has always been considered to be more than sufficient to inhibit their activity completely. Consequently little interest has been paid to the potential role of these enzymes in cartilage damage. Four arthropathies of different erosive potential are here compared: spondyloarthropathies, rheumatoid arthritis with and without gold or D-penicillamine therapy, and septic arthritis. The synovial concentration of the inhibitors alpha 1-antitrypsin and alpha 2-macroglobulin has been compared with the polymorph enzyme output, as measured by beta-glucuronidase. Total haemolytic complement, white cell count, and C-reactive protein have also been measured in the joint fluid. The range of white cell count and inhibitors was the same in all 4 groups, while the enzyme output varied substantially from low levels in the spondyloarthropathies to very high levels in the septic joints. The higher the erosive potential of the disease, therefore, the more disadvantageous is the inhibitor/enzyme ratio. It is also pointed out that cartilage has physiochemical properties which facilitate and enhance polymorph enzyme output while severely curtailing the activity of the inhibitors. The observation that synovial fluid is inhibitory in vitro may therefore bear little relationship to the situation at the cartilage surface in vivo.


The acidosis of exogenous phosphate intoxication.
Severe hyperphosphatemia resulting from the use of laxatives and enemas with high levels of phosphate has been the subject of many case reports. These have generally focused on the hypernatremia and hypocalcemia that develop and become life-threatening. Less attention has been paid to the metabolic acidosis of phosphate intoxication. In-depth analysis of a case of severe hyperphosphatemia and review of the literature for cases with sufficient data to permit correlation between the phosphate concentration, acidosis, and anion gap. Marked metabolic acidosis with a large increase in the anion gap was present in our patient. The correlation between these parameters and the plasma phosphate concentration was highly significant. Despite a paucity of data in most case reports, we did uncover other cases of anion gap-positive metabolic acidosis in patients with hyperphosphatemia. Among high-risk patients, including the elderly and debilitated, the presence of metabolic acidosis, hypernatremia, an increased anion gap, and low plasma calcium levels or a prolonged QT interval on the electrocardiogram should raise suspicion of phosphate intoxication.


Laminin-5-enriched extracellular matrix accelerates angiogenesis and neovascularization in association with ePTFE.
The performance of biomedical implant devices is often limited by inappropriate tissue responses associated with synthetic materials used in device construction. Adverse healing responses, in particular the lack of an extensive vascular supply in the peri-implant tissue, are believed to lead to the ultimate failure of many of these medical devices. Accelerated formation of new blood vessels in the peri-implant tissue and within porous polymeric implants is hypothesized to improve the performance of such biomedical implant devices. The current study evaluated the use of cell-mediated, extracellular matrix modification of expanded polytetrafluoroethylene (ePTFE) to increase vessel growth in peri-implant tissue and within the pores of the implants. Discs of ePTFE were modified through cell-mediated matrix deposition using epithelial and endothelial cell lines with variable deposition of collagen types, fibronectin, and laminin types. Cell matrix-modified discs, Matrigel-coated discs, and nonmodified discs were implanted in both the adipose and subcutaneous tissues of the rat. Following a 5-week implant period, samples were removed and evaluated histologically and morphometrically for the presence of blood vessels in the peri-implant tissue and within the pores of the polymer as well as for the presence of activated macrophages and monocytes. A significantly increased presence of activated macrophages and monocytes was associated only with the samples modified with the matrix from a human microvessel endothelial cell line. Increased vessel density was identified in association with those ePTFE samples modified with either the 804-G, HaCaT, or II-4 cell matrices, all of which have extracellular matrices enriched in the protein laminin-5.


Development and Validation of Automated Magnetic Resonance Parkinsonism Index 2.0 to Distinguish Progressive Supranuclear Palsy-Parkinsonism From Parkinson's Disease.
Differentiating progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) is clinically challenging. This study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP-P from PD and to validate its diagnostic performance in two large independent cohorts. We enrolled 676 participants: a training cohort (n = 346; 43 PSP-P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n = 330; 62 PSP-P, 171 PD, and 97 control subjects) from an international research group. We developed a new in-house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP-P from PD and control subjects in both cohorts using receiver operating characteristic curves. The automated MRPI 2.0 showed excellent performance in differentiating patients with PSP-P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC] = 0.93 [95% confidence interval, 0.89-0.98] and AUC = 0.97 [0.93-1.00], respectively) and in the international testing cohort (PSP-P versus PD, AUC = 0.92 [0.87-0.97]; PSP-P versus controls, AUC = 0.94 [0.90-0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP-P and PD in the early stage of the diseases (AUC = 0.91 [0.84-0.97]). A strong correlation (r = 0.91, P < 0.001) was found between automated and manual MRPI 2.0 values. Our study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP-P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP-P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


A model for in vivo analysis of sudomotor sympathetic C-fiber activation and human sweat gland output.
Quantitative assessment of small-fiber peripheral neuropathy often involves an evaluation of the interaction between the C-fiber sudomotor nerve and local sweat rate (SR). Typically, some sort of quantitative sudomotor axon reflex test (QSART) is performed to aid in diagnosing small-fiber dysfunction. The currently used QSART demonstrates only moderate test-retest reliability and therefore limits its usefulness in tracking small-fiber dysfunction. A new experimental model to examine small C-fiber function in the skin using intradermal electrical stimulation and simultaneous monitoring of SR is proposed. Using intradermal electrical stimulation (1.5 and 2.5 mA) and varying stimulus frequency from 0.2 to 64 Hz, a quantitative relationship between the area under the SR-time curve and log10 stimulus frequency is modeled using a four-parameter logistic equation, providing the following parameters: baseline, plateau, EC50, and Hill slope. The model has good to excellent repeatability within the same day (ICC = 0.98), on different days at the same skin site (ICC = 0.80), and when comparing two different skin sites (ICC = 0.78) with a small bias estimate and the line of identity always lying within the 95% limits of agreement. Atropine sulfate (0.1 mg/ml) blocked 90 ± 5% of the electrically induced sweating. Overall, the model provides control over sudomotor nerve activity and a quantitative assessment of SR. Finally, the ability to reproduce the quantitative stimulus-response curve on different days allows for a robust assessment of the relationship between the activation of a sympathetic C-fiber and local SR.NEW & NOTEWORTHY A model for quantitative assessment of C-fiber function in human skin using intradermal electrical stimulation and local sweat rate measurements has been developed. This new electrically induced sweating model is nonpainful and allows for a complete stimulus-response curve plotting the area under the local sweat rate-time curve vs. the log10 stimulus frequency. The model has good reproducibility and should provide a means of assessing the progression of small C-fiber peripheral neuropathy in humans.


Olive Actual "on Year" Yield Forecast Tool Based on the Tree Canopy Geometry Using UAS Imagery.
Olive has a notable importance in countries of Mediterranean basin and its profitability depends on several factors such as actual yield, production cost or product price. Actual "on year" Yield (AY) is production (kg tree-1) in "on years", and this research attempts to relate it with geometrical parameters of the tree canopy. Regression equation to forecast AY based on manual canopy volume was determined based on data acquired from different orchard categories and cultivars during different harvesting seasons in southern Spain. Orthoimages were acquired with unmanned aerial systems (UAS) imagery calculating individual crown for relating to canopy volume and AY. Yield levels did not vary between orchard categories; however, it did between irrigated orchards (7000-17,000 kg ha-1) and rainfed ones (4000-7000 kg ha-1). After that, manual canopy volume was related with the individual crown area of trees that were calculated by orthoimages acquired with UAS imagery. Finally, AY was forecasted using both manual canopy volume and individual tree crown area as main factors for olive productivity. AY forecast only by using individual crown area made it possible to get a simple and cheap forecast tool for a wide range of olive orchards. Finally, the acquired information was introduced in a thematic map describing spatial AY variability obtained from orthoimage analysis that may be a powerful tool for farmers, insurance systems, market forecasts or to detect agronomical problems.


Patient-specific prediction of functional recovery after stroke.
Background and aims Clinical predictive models for stroke recovery could offer the opportunity of targeted early intervention and more specific information for patients and carers. In this study, we developed and validated a patient-specific prognostic model for monitoring recovery after stroke and assessed its clinical utility. Methods Four hundred and ninety-five patients from the population-based South London Stroke Register were included in a substudy between 2002 and 2004. Activities of daily living were assessed using Barthel Index) at one, two, three, four, six, eight, 12, 26, and 52 weeks after stroke. Penalized linear mixed models were developed to predict patients' functional recovery trajectories. An external validation cohort included 1049 newly registered stroke patients between 2005 and 2011. Prediction errors on discrimination and calibration were assessed. The potential clinical utility was evaluated using prognostic accuracy measurements and decision curve analysis. Results Predictive recovery curves showed good accuracy, with root mean squared deviation of 3 Barthel Index points and a R2 of 83% up to one year after stroke in the external cohort. The negative predictive values of the risk of poor recovery (Barthel Index <8) at three and 12 months were also excellent, 96% (95% CI [93.6-97.4]) and 93% [90.8-95.3], respectively, with a potential clinical utility measured by likelihood ratios (LR+:17 [10.8-26.8] at three months and LR+:11 [6.5-17.2] at 12 months). Decision curve analysis showed an increased clinical benefit, particularly at threshold probabilities of above 5% for predictive risk of poor outcomes. Conclusions A recovery curves tool seems to accurately predict progression of functional recovery in poststroke patients.


HLA-DQB1*02 dose effect on RIA anti-tissue transglutaminase autoantibody levels and clinicopathological expressivity of celiac disease.
Celiac disease is an autoimmune enteropathy caused by gluten ingestion in genetically susceptible individuals. Anti-transglutaminase autoantibody (tTGAb) assay is useful to detect candidates undergoing intestinal biopsy. Our aim was to investigate whether the DQB1*02 allele could influence tTGAb titers and the clinicopathological expressivity of the disease. A total of 124 patients with celiac disease, tested for RIA tTGAb at diagnosis, were typed for HLA-DRB1, -DQA1, and -DQB1 genes and divided according to the number of DQB1*02 alleles: group 1, homozygous; group 2, heterozygous; group 3, negative. The mean of tTGAb indexes was significantly higher in group 1 patients than in group 2 (P < 0.02) and group 3 patients (P < 0.01). Patients with at least 1 DQB1*02 allele showed more often a typical CD and diffuse histological lesions than did patients in the other groups. The study demonstrates that tTGAb titers are HLA-DQB1*02 dose dependent, with significantly higher levels in homozygous individuals. Moreover, individuals with at least 1 HLA-DQB1*02 allele tend to have a more expressed clinical and histological form of celiac disease.


Identifying parameter regions for multistationarity.
Mathematical modelling has become an established tool for studying the dynamics of biological systems. Current applications range from building models that reproduce quantitative data to identifying systems with predefined qualitative features, such as switching behaviour, bistability or oscillations. Mathematically, the latter question amounts to identifying parameter values associated with a given qualitative feature. We introduce a procedure to partition the parameter space of a parameterized system of ordinary differential equations into regions for which the system has a unique or multiple equilibria. The procedure is based on the computation of the Brouwer degree, and it creates a multivariate polynomial with parameter depending coefficients. The signs of the coefficients determine parameter regions with and without multistationarity. A particular strength of the procedure is the avoidance of numerical analysis and parameter sampling. The procedure consists of a number of steps. Each of these steps might be addressed algorithmically using various computer programs and available software, or manually. We demonstrate our procedure on several models of gene transcription and cell signalling, and show that in many cases we obtain a complete partitioning of the parameter space with respect to multistationarity.


Corrigendum: Similar outcome with a new anteverted or a straight standard stem: a randomized study of 72 total hip arthroplasties evaluated with clinical variables, radio-stereometry, and DXA up to 2 years.
When we checked our data in our article "Similar outcome with a new anteverted or a straight standard stem: a randomized study of 72 total hip arthroplasties evaluated with clinical variables, radiostereometry, and DXA up to 2 years" by Karin Rilby, Maziar Mohaddes, Emma Nauclér, and Johan Kärrholm, Acta Orthop 2021; 92, Published online October 21, 2021 we noticed that the numbers in Table 7 (Supplementary data) were incorrect. We have not been able to fully reconstruct the reason for this error. We are sorry for this mistake. Even if the corrected numbers are different the overall conclusions will be same and also the statistical significances.


Interreader Reliability of LI-RADS Version 2014 Algorithm and Imaging Features for Diagnosis of Hepatocellular Carcinoma: A Large International Multireader Study.
Purpose To determine in a large multicenter multireader setting the interreader reliability of Liver Imaging Reporting and Data System (LI-RADS) version 2014 categories, the major imaging features seen with computed tomography (CT) and magnetic resonance (MR) imaging, and the potential effect of reader demographics on agreement with a preselected nonconsecutive image set. Materials and Methods Institutional review board approval was obtained, and patient consent was waived for this retrospective study. Ten image sets, comprising 38-40 unique studies (equal number of CT and MR imaging studies, uniformly distributed LI-RADS categories), were randomly allocated to readers. Images were acquired in unenhanced and standard contrast material-enhanced phases, with observation diameter and growth data provided. Readers completed a demographic survey, assigned LI-RADS version 2014 categories, and assessed major features. Intraclass correlation coefficient (ICC) assessed with mixed-model regression analyses was the metric for interreader reliability of assigning categories and major features. Results A total of 113 readers evaluated 380 image sets. ICC of final LI-RADS category assignment was 0.67 (95% confidence interval [CI]: 0.61, 0.71) for CT and 0.73 (95% CI: 0.68, 0.77) for MR imaging. ICC was 0.87 (95% CI: 0.84, 0.90) for arterial phase hyperenhancement, 0.85 (95% CI: 0.81, 0.88) for washout appearance, and 0.84 (95% CI: 0.80, 0.87) for capsule appearance. ICC was not significantly affected by liver expertise, LI-RADS familiarity, or years of postresidency practice (ICC range, 0.69-0.70; ICC difference, 0.003-0.01 [95% CI: -0.003 to -0.01, 0.004-0.02]. ICC was borderline higher for private practice readers than for academic readers (ICC difference, 0.009; 95% CI: 0.000, 0.021). Conclusion ICC is good for final LI-RADS categorization and high for major feature characterization, with minimal reader demographic effect. Of note, our results using selected image sets from nonconsecutive examinations are not necessarily comparable with those of prior studies that used consecutive examination series. © RSNA, 2017.


Positive animal welfare states and encouraging environment-focused and animal-to-animal interactive behaviours.
Affective neuroscience, incorporating neurophysiology and neuropsychology, is providing increasing evidence that certain behaviours of animals may be interpreted in terms of what they are intending to achieve, i.e. their goals. It is also providing evidence that allows inferences to be made about the affective contents of some goal-directed behaviours. These neuroscience-supported inferences are aligned with recommendations based on prior behaviour-based investigations of animals' preferences, aversions and priorities, and these observations together support the cautious use of particular behaviours to infer what the accompanying affects may be. In this review, therefore, some attention is given to negative affects and their relationships to poor animal welfare, but the primary focus is the positive affects animals may experience when they successfully engage in rewarding goal-directed behaviours, encapsulated in the concept of positive affective engagement. The review draws together reports of environment-focused and animal-to-animal interactive behaviours observed in a range of species and under diverse circumstances in order to illustrate the likely widespread occurrence of the positive affects that may accompany them. Particular consideration is given to affects that are potentially associated with some aspects of exploration and food acquisition in stimulus rich or impoverished environments, and to those that may be associated with aspects of the affiliative interactions of bonding or bond affirmation, maternal care, play and sexual activity. It is concluded that animals given the opportunity to engage in such activities may experience some positive affects. However, the intensity of an animal's experience of particular positive affects is likely to range from zero to very high because the associated behaviours occur intermittently, variation may occur during different phases of a goal-directed behaviour, and other positive or negative affects experienced at the same time may have greater impact. As good welfare is achieved both by minimising negative affects and promoting positive ones and as conscious sentient animals may be expected to have an interest in experiencing as little pain and as much pleasure as possible, it is argued that there is an ethical obligation to take practical steps to help them to achieve these outcomes. Such steps would include providing them with opportunities to express more behaviours that are associated with rewarding or satisfying experiences understood in terms of positive affective engagement.


Metabolic effects of the obstructive sleep apnea syndrome and cardiovascular risk.
The obstructive sleep apnea syndrome (OSAS) is characterized by collapse of the upper airway during sleep, recurring apneas, intermittent hypoxemia and daytime somnolence. OSAS is often associated with obesity, and its prevalence is expected to rise due to the obesity epidemics worldwide. OSAS is associated with increased cardiovascular risk which appears to be normalized by treatment with nasal continuous positive airway pressure (nCPAP) during sleep, suggesting an independent role of OSAS in accelerating atherosclerosis. Insulin resistance (IR) and the metabolic syndrome (MetS) are often found in OSAS patients, but the relative role played by OSAS and obesity is still unclear. Both OSAS and MetS may exert negative synergistic effects on the cardiovascular system through multiple mechanisms (hypoxemia, sleep disruption, activation of the sympathetic nervous system, inflammatory activation). Besides nCPAP treatment, pharmacologic interventions to treat obesity and the MetS could improve cardiovascular prevention in OSAS.