Feeding patterns of full-term and preterm infants at forty weeks postconceptional age.
Little research exists that addresses the differences in feeding skills between preterm (PT) infants at term and full-term (FT) infants. The purpose of this study was to quantify and examine the differences in sucking abilities of PT infants when measured at 40 weeks postconceptional age (PCA) and newly born FT infants. The sample consisted of 213 infants who were divided into three groups on the basis of their gestational age at birth (24-29 wk, 30-32 wk, and 38-42 wk). The Kron Nutritive Sucking Apparatus (KNSA) was used to examine the microstructure of sucking and feeding behaviors. There were significant differences among the three groups in several of the sucking variables: number of bursts (p = .005), intersuck interval (p = .0212), sucks per burst (p = .0003), suck width (p < .0001), intersuck width (p < .0001), mean maximum pressure (p < .0001), and intersuck width/interburst width (p = .02). The findings from this study demonstrate the importance of both maturation at birth and experience as factors influencing feeding behaviors.


Effect of Matrix Metallopeptidase 13 on the Function of Mouse Bone Marrow-derived Dendritic Cells.
Dendritic cells are professional antigen-presenting cells found in an immature state in epithelia and interstitial space, where they capture antigens such as pathogens or damaged tissue. Matrix metallopeptidase 13 (MMP-13), a member of the collagenase subfamily, is involved in many different cellular processes and is expressed in murine bone marrow-derived dendritic cells (DCs). The function of MMP-13 in DCs is not well understood. Here, we investigated the effect of MMP-13 on DC maturation, apoptosis, and phagocytosis. Bone marrow-derived dendritic cells were obtained from C57BL/6 mice. One short-interfering RNA specific for MMP-13 was used to transfect DCs. MMP-13-silenced DCs and control DCs were prepared, and apoptosis was measured using real-time polymerase chain reaction and Western blotting. MMP-13-silenced DCs and control DCs were analyzed for surface expression of CD80 and CD86 and phagocytosis capability using flow cytometry. Compared to the control DCs, MMP-13-silenced DCs increased expression of anti-apoptosis-related genes, BAG1 (control group vs. MMP-13-silenced group: 4.08 ± 0.60 vs. 6.11 ± 0.87, P = 0.008), BCL-2 (control group vs. MMP-13-silenced group: 7.54 ± 0.76 vs. 9.54 ± 1.29, P = 0.036), and TP73 (control group vs. MMP-13-silenced group: 4.33 ± 0.29 vs. 5.60 ± 0.32, P = 0.001) and decreased apoptosis-related genes, CASP1 (control group vs. MMP-13-silenced group: 3.79 ± 0.67 vs. 2.54 ± 0.39, P = 0.019), LTBR (control group vs. MMP-13-silenced group: 9.23 ± 1.25 vs. 6.24 ± 1.15, P = 0.012), and CASP4 (control group vs. MMP-13-silenced group: 2.07 ± 0.56 vs. 0.35 ± 0.35, P = 0.002). Protein levels confirmed the same expression pattern. MMP-13-silenced groups decreased expression of CD86 on DCs; however, there was no statistical difference in CD80 surface expression. Furthermore, MMP-13-silenced groups exhibited weaker phagocytosis capability. These results indicate that MMP-13 inhibition dampens DC maturation, apoptosis, and phagocytosis.


The two faces of metallothionein in carcinogenesis: photoprotection against UVR-induced cancer and promotion of tumour survival.
Metallothionein is a multi-functional protein that protects the host against toxic heavy metals. Under stressful situations it can protect against oxidative damage, contribute to tissue repair, modulate immune responses and limit inflammatory processes. Recently, metallothionein's role in ultraviolet radiation (UVR)-induced injury has been investigated. These studies have shown that when metallothionein is upregulated following exposure to UVR, it can protect against UVR-induced damage and the subsequent development of skin cancer. We propose that this initial protection is achieved through its anti-oxidant role resulting in reduced oxidative stress, reduced apoptosis, reduced NFkappaB activation and enhanced repair of DNA damage. However, once UVR-induced neoplasia has occurred, the cancer cells can hijack metallothionein's protective functions, resulting in increased tumour progression and malignancy. These two discordant sets of attributes are context-dependent, and represent the two faces of metallothionein.


HLA-A amino acid polymorphism and delayed kidney allograft function.
Delayed allograft function (DGF) is a common adverse event in postrenal transplantation. The etiology of DGF is thought to include both nonimmunologic (donor age, cold ischemia time, and recipient race) and immunologic factors. We examined the association of DGF with amino acid mismatches at 66 variable sites of the HLA-A molecule in a prospective cohort study of 697 renal transplant recipients of deceased donors. Using a multivariate logistic regression model adjusted for nonimmunologic risk factors, we show that combinations of a few amino acid mismatches at crucial sites of HLA-A molecules were associated with DGF. In Caucasian recipients, a mismatch at position 62, 95, or 163, all known to be functionally important within the antigen recognition site, was associated with an increased risk for DGF. Furthermore, a decreased risk for DGF was associated with a mismatch at HLA-A family-specific sites (149, 184, 193, or 246), indicating that evolutionary features of HLA-A polymorphism separating HLA-A families and lineages among donor-recipient pairs may correlate with the magnitude of alloreactivity influencing the development of DGF. These findings suggest that amino acid polymorphisms at functionally important positions at the antigen recognition site of the HLA-A molecule have a significant influence on DGF.


Classic and emergent indicators for the assessment of human iron status.
Iron deficiency is the leading cause of anemia, a significant global public health problem. Different methods exist for assessing iron nutritional status, including laboratory tests that focus on storage, transportation, and iron functional compartment parameters. Classical markers such as bone marrow, serum iron, ferritin, hemoglobin, erythrocyte parameters, transferrin, transferrin receptors, and zinc protoporphyrin are discussed in this review. Additional parameters calculated from these indicators, including transferrin saturation, ferritin index and Thomas plot, and some emergent parameters such as hepcidin, erythroferrone, and low hemoglobin density are also discussed. There is no a single indicator for assessing iron nutritional status. Therefore, the use of more than one indicator may be the best practice to obtain the correct diagnosis, also considering the influence of inflammation/infection on many of these indicators. The constant validation of the current parameters, the improvement of assessment methods, and the identification of new indicators will be the key to refine the assessment of iron nutritional status and the right choice of treatment for its improvement.


Photon Versus Proton Beam Therapy for T1-3 Squamous Cell Carcinoma of the Thoracic Esophagus Without Lymph Node Metastasis.
We compared treatment outcomes and toxicities of photon radiotherapy versus proton beam therapy (PBT) and evaluated radiation field effects for T1-3 squamous cell carcinoma of the thoracic esophagus (EC) without lymph node metastasis. Medical records of 77 patients with T1-3N0M0 thoracic EC treated with radiotherapy between 2011 and 2019 were retrospectively analyzed. Among these patients, 61 (79.2%) individuals had T1 EC. The initial clinical target volume encompassed the whole esophagus with or without supraclavicular and/or abdominal lymph nodes (extended-field radiotherapy; 67 patients, 87.0%) or the area 3-5 cm craniocaudally and 1-2 cm radially from the gross tumor volume (involved-field radiotherapy; 10 patients, 13.0%). The final clinical target volume included margins of at least 1 cm from the gross tumor volume, with total radiation doses of 50-66 (median, 66) cobalt gray equivalent. Three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and PBT were used in twenty-four, five, and forty-eight patients, respectively. Concurrent chemotherapy was administered to 17 (22.0%) patients overall and only five (8.0%) T1 patients. PBT showed significantly lower lung and heart radiation exposure in mean dose, V5, V10, V20, and V30 than photon radiotherapy. The median follow-up for all patients was 46 (interquartile range, 22-72) months. The 5-year progression-free survival and overall survival rates were 56.5 and 64.9%, respectively, with no significant survival difference between photon radiotherapy and PBT. In patients with T1 EC, 5-year progression-free survival and overall survival rates were 62.6 and 73.5%, respectively. Extended-field radiotherapy using modern radiotherapy techniques without chemotherapy showed satisfactory clinical outcomes for lymph node-negative T1 EC.


[Anticoagulants and dental extractions].
Dental extractions in patients under platelet antiaggregant or anticoagulant therapy pose the problem of risk benefit between stopping or carrying on treatment. The difficulties of reequilibrating the INR after a heparin relay have led surgeons and cardiologists to look for alternative solutions. Different means of local haemostasis using products with haemostatic properties or not, or the use of sutures or glues, have given encouraging results but there is too much uncertainty for systematic recommendations to practicians responsible for dental extractions in these patients. The authors propose a technique which has the advantages of associating systematically different methods, making bleeding complications very unusual, without interrupting anticoagulant or antiaggregant therapy.


The influence of preoperative urodynamic parameters on clinical results in patients with benign prostatic hyperplasia after transurethral resection of the prostate.
To identify the urodynamic parameters affecting the clinical outcomes of transurethral resection of the prostate(TURP) surgery for patients with benign prostatic hyperplasia(BPH) by multifactor analysis and establish a regression model with diagnostic values. The medical records of patients who underwent TURP surgery for BPH between December 2018 and September 2021 were collected from the urology department of the Second Affiliated Hospital of Kunming Medical University, Kunming, China. The patients' clinical data and urodynamic parameters were collected before surgery. The urodynamic parameters affecting surgical efficacy were identified by multifactor analysis, and a regression model with diagnostic values was established and evaluated. A total of 201 patients underwent TURP, of whom 144 had complete preoperative urodynamic data. Each urodynamic factor was subjected to multifactor analysis, and the bladder contractility index (BCI), bladder outflow obstruction index (BOOI), bladder residual urine, and bladder compliance (BC) were found to be independent influence factors on the efficacy of TURP in patients with BPH. The diagnostic value of the regression model was analyzed by receiver operating characteristics (ROC) analysis, and it was found that the AUC = 0.939 (95% CI 0.886-0.972), for which the sensitivity and specificity were 95.19% and 80%, respectively. The regression model had high diagnostic sensitivity and specificity in predicting the efficacy of surgery, and the diagnostic value was higher than that of individual urodynamic factors. Therefore, BCI, BOOI, bladder residual urine, and BC should be considered as independent influence factors on the efficacy of TURP surgery for BPH.


Large deformation of red blood cell ghosts in a simple shear flow.
Red blood cells are known to change shape in response to local flow conditions. Deformability affects red blood cell physiological function and the hydrodynamic properties of blood. The immersed boundary method is used to simulate three-dimensional membrane-fluid flow interactions for cells with the same internal and external fluid viscosities. The method has been validated for small deformations of an initially spherical capsule in simple shear flow for both neo-Hookean and the Evans-Skalak membrane models. Initially oblate spheroidal capsules are simulated and it is shown that the red blood cell membrane exhibits asymptotic behavior as the ratio of the dilation modulus to the extensional modulus is increased and a good approximation of local area conservation is obtained. Tank treading behavior is observed and its period calculated.


Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the far-reaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.


Cunninghamella bertholletiae infection associated with deferoxamine therapy.
Cunninghamella bertholletiae, an uncommon cause of human infection, has been reported with increasing frequency in recent years. C. bertholletiae belongs to the order Mucorales and produces infections similar to those produced by the other agents of mucormycosis. Infections with this group of organisms have typically been seen either in patients with diabetes mellitus or in those receiving chemotherapy. Recent reports of mucormycosis in dialysis patients receiving deferoxamine for iron or aluminum overload have raised the possibility that deferoxamine therapy is a risk factor for mucormycosis. A case of C. bertholletiae infection in a patient receiving deferoxamine for iron overload unrelated to hemodialysis was investigated in detail, and possible explanations for this patient's infection were assessed.


Remodeling the Microenvironment before Occurrence and Metastasis of Cancer.
Tumorigenesis and progression of cancer are complex processes which transformed cells and stromal cells interact and co-evolve. Intrinsic and extrinsic factors cause the mutations of cells. The survival of transformed cells critically depends on the circumstances which they reside. The malignant transformed cancer cells reprogram the microenvironment locally and systemically. The formation of premetastatic niche in the secondary organs facilitates cancer cells survival in the distant organs. This review outlines the current understanding of the key roles of premalignant niche and premetastatic niche in cancer progression. We proposed that a niche facilitates survival of transformed cells is characteristics of senescence, stromal fibrosis and obese microenvironment. We also proposed the formation of premetastatic niche in secondary organs is critically influenced by primary cancer cells. Therefore, it suggested that strategies to target the niche can be promising approach to eradicate cancer cells.


Neuromotor response of the leg muscles following a supine, stand retraining with/without neuromuscular electrical stimulation training intervention for individuals with SCI: A case series.
The goal of this paper is to study the effects of supine and stand retraining (SRT) interventions with and without multi muscle neuromuscular electrical stimulation (NMES) on the neuromuscular EMG responses of the leg muscles for individuals with motor complete SCI during walking on a body-weight support (BWS) treadmill. The main outcome variables were EMG amplitude, integrated EMG and co-contraction indices (co-excitation and co-activation) collected during a 10-minute walking treadmill trial. Data was analyzed for the first, fifth and tenth minute of walking. Results showed that both Supine+NMES and SRT+NMES interventions increased spatial-temporal aspects of muscle activity (mean EMG amplitude and integrated EMG) of lower limb muscles. SRT+NMES (loading) showed greater gains in the proximal anterior leg compartments. On the contrary, SRT without NMES (SRT only) exhibited deterioration of activity within the same muscle groups. Co-contraction indices increased for both post-NMES interventions suggesting that task-specificity of training is important to achieve the fundamental reciprocal firing known to able-bodied gait. These results show that combination of NMES+loading during passive rhythmic gait will induce neuroplasticity in the lower limbs that ultimately provides a potential effective means to recover gait in individuals with SCI.


Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers.
Neutrophils are well characterized as mediators of peripheral tissue damage in lupus, but it remains unclear whether they influence loss of self-tolerance in the adaptive immune compartment. Lupus neutrophils produce elevated levels of factors known to fuel autoantibody production, including IL-6 and B cell survival factors, but also reactive oxygen intermediates, which can suppress lymphocyte proliferation. To assess whether neutrophils directly influence the progression of autoreactivity in secondary lymphoid organs (SLOs), we characterized the localization and cell-cell contacts of splenic neutrophils at several stages in the progression of disease in the NZB/W murine model of lupus. Neutrophils accumulate in SLO over the course of lupus progression, preferentially localizing near T lymphocytes early in disease and B cells with advanced disease. RNA sequencing reveals that the splenic neutrophil transcriptional program changes significantly over the course of disease, with neutrophil expression of anti-inflammatory mediators peaking during early-stage and midstage disease, and evidence of neutrophil activation with advanced disease. To assess whether neutrophils exert predominantly protective or deleterious effects on loss of B cell self-tolerance in vivo, we depleted neutrophils at different stages of disease. Neutrophil depletion early in lupus resulted in a striking acceleration in the onset of renal disease, SLO germinal center formation, and autoreactive plasma cell production. In contrast, neutrophil depletion with more advanced disease did not alter systemic lupus erythematosus progression. These results demonstrate a surprising temporal and context-dependent role for neutrophils in restraining autoreactive B cell activation in lupus.


Mucocutaneous manifestations in inflammatory bowel disease.
The aim of this study was to evaluate the prevalence and features of the major cutaneous manifestations (erythema nodosum [EN] and pyoderma gangrenosum [PG]) and to determine the associations between cutaneous manifestations and other extraintestinal manifestations in patients with inflammatory bowel disease (IBD). The mucocutaneous manifestations of patients with IBD were studied between December 2002 and June 2007. All patients underwent a detailed whole body examination by a gastroenterologist and dermatologist. In all, 352 patients were included in this study; 34 patients (9.3%) presented with at least 1 major cutaneous manifestation. The prevalence of EN (26 patients) and PG (8 patients) in IBD was 7.4% and 2.3%, respectively. EN was more common in Crohn's disease (16/118) than ulcerative colitis (10/234) (P = 0.002). EN was found to be related to disease activity of the bowel (P = 0.026). The prevalence of arthritis was significantly higher in the IBD patients with EN (11/26) than in IBD patients without EN (53/326) (P = 0.006). Arthritis was more common in IBD patients with PG (7/8) than in IBD patients without PG (57/344) (P = 0.00). IBD patients with PG were significantly more likely to have uveitis (1/8) compared with IBD patients without PG (5/344) (P = 0.017). We found the prevalence of 2 important cutaneous manifestations to be 9.3% in IBD in Turkish patients. EN was found to be more common in Crohn's disease and is associated with an active episode of bowel disease and peripheral arthritis. In addition, PG was connected with uveitis and peripheral arthritis.


A National Survey of Job Satisfaction and Workload Among Emergency Medicine (EM) Residency Faculty.
Faculty workload, and its relation to job satisfaction, has not been well studied in Emergency Medicine (EM). Methods: A cross-sectional survey was conducted among EM physician faculty at 49 residency programs across the United States. We collected information on clinical and non-clinical (education, administration, and research) workload, demographics, and EM department characteristics, as well as job satisfaction measured using the Global Job Satisfaction (GJS) scale. Comparisons were made using Wilcox signed rank tests. Multivariable associations with job satisfaction were assessed in a regression model. Of 1,791 surveys sent, 265 were completed. The quantity of contracted clinical and non-clinical hours was lower than the actual clinical (difference (95% confidence interval (CI)): 2.7 (1.5-4.1)) and non-clinical hours (6.0 (3.8-8.8)) worked. Respondents preferred a distribution of 50% clinical work. However, the actual percentage was 62% (difference (95% CI): 14.4% (10.8%-17.6%)). Identifying as core faculty and required logging of non-clinical hours were associated with improved job satisfaction while increased percentage of time spent in the clinical and administrative domains were associated with significant declines. The estimated actual work performed by EM physician faculty is greater than contracted and misaligned with their preferred type of work, the latter of which is associated with decreased job satisfaction. Improved job satisfaction and faculty retention might be achieved by increasing the percentage of time devoted to education and research, by increasing the core faculty contingent and by implementing tracking of non-clinical efforts.


The treatment of failed rotator cuff repairs.
Results following surgical management of failed rotator cuff tears are clearly inferior to those obtained in the treatment of primary repairs. Conservative management may be the treatment of choice in selected patients with failed rotator cuff repairs. The primary goal for revision rotator cuff surgery should be relief of pain, not improvement in function. If the level of pain is manageable, and the patient is functioning with respect to activities of daily living, additional surgery may not be helpful. As there are multiple etiologies associated with failure of the initial repair, each patient should be carefully evaluated on an individual basis to determine if a subsequent procedure would be appropriate. Repeat repair is more likely to succeed in patients with an intact and functioning deltoid, an intact lateral portion of the acromion, and good quality of rotator cuff tissue. Conversely, patients who have had a lateral or radical acromionectomy, a detached or nonfunctioning deltoid, or poor quality of remaining rotator cuff tissue are less likely to have a successful result after repeat repair. It is evident that some of the factors associated with failure are avoidable. As the best chance for a successful result is at the time of the primary repair, the following points will briefly review these factors. The skin incision should be made in the flexion creases which are perpendicular to the deltoid fibers. The deltoid origin should be meticulously protected during the repair and lateral or radical acromionectomy should not be performed. Adequate anterior acromioplasty is essential for removal of the impingement lesion and to prevent subsequent wear on the repaired cuff tendon. The acromioclavicular joint should be evaluated preoperatively and treated as indicated at the time of the surgery. Adequate release of adhesions and mobilization of rotator cuff tissue should be performed using the coracohumeral ligament release and interval slide when necessary. The rotator cuff should be repaired to bone using tendon to bone sutures and/or secure suture anchors. In large and massive tears, there appears to be a role for the reattachment of the coracohumeral ligament. Early phase I range of motion should be initiated following rotator cuff repair and early resistance exercise with weights should be avoided.


Validation of the International Consultation on Incontinence Questionnaire-Vaginal Symptoms (ICIQ-VS) in two south- Asian languages.
The multifaceted nature of pelvic floor disorders means that a systematic evaluation is required for optimal treatment outcome. It is also generally acknowledged that a valid tool is necessary to objectively assess symptoms reported by affected women. The International Consultation on Incontinence Questionnaire-Vaginal Symptoms (ICIQ-VS) questionnaire was translated to Sinhala and Tamil and a validation study carried out among women attending gynecology clinics at North Colombo Teaching Hospital, Ragama, and the district general hospitals Mannar and Vavuniya. Content validity was assessed by the level of missing answers, which was < 4% and 2% for each item in Sinhala and Tamil, respectively. Construct validity was assessed by the ability of the questionnaire to differentiate between patients and controls. Both differentiated patients from controls on vaginal symptoms score (VSS) (p < 0.001), sexual symptoms score (SSS) (p < 0.01), and quality of life (QoL) (p < 0.001). There was a strong positive correlation between Pelvic Organ Prolapse Quantification (POP-Q) scores and VSS (Sinhala r s = 0.64, p < 0.001, Tamil r s = 0.65, p < 0.001), and QoL (Sinhala r s = 0.49, p < 0.001, Tamil r s = 0.60, p < 0.001). Internal consistency as assessed using Cronbach's coefficient alpha: 0.78 (0.76-0.78) and 0.83 (0.80-0.84) in Sinhala and Tamil, respectively. Test-retest reliability was assessed by weighted kappa scores (Sinhala 0.58-0.88 and Tamil 0.76-0.90). Both questionnaires were sensitive to change and showed that VSS and QoL improved following surgery (Wilcoxon matched-pairs signed-rank test p < 0.001). The validated Sinhala and Tamil translations of ICIQ-VS will be useful for assessing vaginal and sexual symptoms among women speaking Sinhala and Tamil.


K+ currents generated by NMDA receptor activation in rat hippocampal pyramidal neurons.
Long lasting outward currents mediated by Ca2+-activated K+ channels can be induced by Ca2+ influx through N-methyl-D-aspartate (NMDA)-receptor channels in voltage-clamped hippocampal pyramidal neurons. Using specific inhibitors, we have attempted to identify the channels that underlie these outward currents. At a holding potential of -50 mV, applications of 1 mM NMDA to the soma of cultured hippocampal pyramidal neurons induced the expected inward currents. In 44% of cells tested, these were followed by outward currents (average amplitude 60 +/- 7 pA) that peaked 2.5 s after the initiation of the inward NMDA currents and decayed with a time constant of 1.4 s. In 43% of those cells exhibiting an outward current, SK channel inhibitors, UCL 1848 (100 nM) and apamin (100 nM) abolished the outward current. In the remainder of the cells, the outward currents were either insensitive or only partly inhibited (44 +/- 4%) by 100 nM UCL 1848. In these cells, the outward currents were reduced by the slow afterhyperpolarization (sAHP) inhibitors, muscarine (3 microM; 43 +/- 9%), UCL 1880 (3 microM; 34 +/- 10%), and UCL 2027 (3 microM; 57 +/- 6%). Neither the BK channel inhibitor, charybdotoxin (100 nM), nor the Na+/K+ ATPase inhibitor, ouabain (100 microM), reduced these outward currents. Irrespective of the pharmacology, the time course of the outward current did not differ. Interestingly, no correlation was observed between the presence of a slow apamin-insensitive afterhyperpolarization and an outward current insensitive to SK channel blockers following NMDA-receptor activation. It is concluded that an NMDA-mediated rise in [Ca2+]i can result in the activation of apamin-sensitive SK channels and of the channels that underlie the sAHP. The activation of these channels may, however, depend on their location relative to NMDA receptors as well as on the spatial Ca2+ buffering within individual neurons.


Depression in patients with Parkinson's disease: impact on functioning.
Depression is a frequently observed neuropsychiatric phenomenon in Parkinson's disease (PD) and it has been lately considered as a manifestation of such disease. The aim of the study was to investigate the relationship between depression and clinical aspects of PD and to assess the impact of the co-occurrence of such condition on the burden imposed by PD. Fifty outpatients diagnosed with idiopathic PD according to the London Brain Bank criteria were examined. PD was evaluated using Hoehn & Yahr staging (H&Y), United Parkinson's Disease Rating Scale (UPDRS) and Schwab & England (S&E) functional capacity evaluation. A semi-structured clinical interview was used. The diagnosis of PD was made by neurologist experts on movement disorders, and the diagnosis of depression was made by a psychiatrist, according to the ICD-10 diagnostic criteria. Depressive symptoms were additionally measured using the Montgomery-Asberg Depression Scale. The analysis of quantitative data was performed using descriptive statistics, univariate linear regression, T-Student Test and ANOVA. Seventeen (34%) patients were diagnosed as clinically depressed and, when compared to the non-depressed ones, presented the following results: H&Y: 3.2 vs. 2.8; UPDRS total: 75.7 vs. 65.3; S&E: 53.5% vs. 65.8% and PD duration: 114.4 months vs. 125.8 months. Depressed patients showed more advanced staging (H&Y), a more severe global clinical condition (UPDRS) and also a greater decrease in their functional capacity (S&E). These data reinforce the hypothesis that depression is associated to poorer functioning in patients with PD.


Brain-Imaging Mechanisms on Female Abdominal Obesity Treated by "Shu-Mu" Acupoint Catgut Embedding and Compatibility Relation: Study Protocol for a 12-Week Randomized Controlled Trial.
Acupoint catgut embedding (ACE) has been proven to be effective and safe in the treatment of obesity, but few studies have been conducted involving its central mechanisms. Our previous study has demonstrated the effectiveness of Shu-Mu ACE in the treatment of abdominal obesity (AO). However, the neurological mechanism of Shu-Mu ACE for weight loss has not yet been elucidated. The mechanism of the combination of the Shu and Mu acupoints may be related to the central integrative effects of the brain. This paper aims to explore the potential neural mechanisms of Shu-Mu ACE in female patients with AO. A total of 100 eligible female AO patients and 20 healthy female subjects will be recruited for this study. 100 AO patients will be randomly allocated to five groups: Shu-Mu ACE (Group A), Shu ACE (Group B), Mu ACE (Group C), sham ACE (Group D), and waiting-list (Group E). Treatment will be administrated once every two weeks for 12 weeks. The body mass index (BMI), waist circumference (WC), Visual Analog Scales (VAS) of appetite, Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS) will be utilized to evaluate the clinical efficacy. Outcomes will be assessed at baseline and at each time point of treatment. Multimodal MRI will be performed at baseline and after 12-week treatment and the results will be used to investigate the neural mechanisms of ACE for obesity. Neurological changes and clinical data will be analysed for correlation. This study hypothesized that Shu-Mu ACE therapy has a synergistic effect and may treat AO by modulating the neuropathological alterations in the brain. Our findings will demonstrate the neurological mechanism of AO treated by "Shu-Mu" Acupoint Catgut Embedding and compatibility relation. This trial is registered at the Chinese Clinical Trial Registration Center (No. ChiCTR2100048920).


Regulation of plant immunity via small RNA-mediated control of NLR expression.
Plants use different receptors to detect potential pathogens: membrane-anchored pattern recognition receptors (PRRs) activated upon perception of pathogen-associated molecular patterns (PAMPs) that elicit pattern-triggered immunity (PTI); and intracellular nucleotide-binding leucine-rich repeat proteins (NLRs) activated by detection of pathogen-derived effectors, activating effector-triggered immunity (ETI). The interconnections between PTI and ETI responses have been increasingly reported. Elevated NLR levels may cause autoimmunity, with symptoms ranging from fitness cost to developmental arrest, sometimes combined with run-away cell death, making accurate control of NLR dosage key for plant survival. Small RNA-mediated gene regulation has emerged as a major mechanism of control of NLR dosage. Twenty-two nucleotide miRNAs with the unique ability to trigger secondary siRNA production from target transcripts are particularly prevalent in NLR regulation. They enhance repression of the primary NLR target, but also bring about repression of NLRs only complementary to secondary siRNAs. We summarize current knowledge on miRNAs and siRNAs in the regulation of NLR expression with an emphasis on 22 nt miRNAs and propose that miRNA and siRNA regulation of NLR levels provides additional links between PTI and NLR defense pathways to increase plant responsiveness against a broad spectrum of pathogens and control an efficient deployment of defenses.


GENETICS AND INTELLIGENCE: A REVIEW.
A survey of the literature of the past 50 years reveals remarkable consistency in the accumulated data relating mental functioning to genetic potentials. Intragroup resemblance in intellectual abilities increases in proportion to the degree genetic relationship.


Antigastric autoantibodies and gastric secretory function in Helicobacter pylori-infected patients with duodenal ulcer and non-ulcer dyspepsia.
Autoantibodies against epitopes located at the canaliculi of human parietal cells occur in about 30% of Helicobacter pylori-infected patients. This has led to the hypothesis that gastric secretory function could be inhibited by anticanalicular autoantibodies in H. pylori gastritis. Forty-four H. pylori-infected patients with and without duodenal ulcers were screened for anticanalicular autoantibodies by means of immunohistochemistry. Plasma gastrin levels and basal and maximal gastric acid output were determined. Fasting gastrin levels were significantly increased in the group with anticanalicular autoantibodies. In the group of patients with non-ulcer dyspepsia the presence of anticanalicular autoantibodies was significantly correlated with an impaired basal acid secretion. Antigastric autoimmunity in H. pylori gastritis seems to be relevant for gastric hyposecretion either directly by inhibiting the proton pump or indirectly through the development of gastric mucosa atrophy.


[Genitourinary diseases mortality in mercury miners].
To study the mortality due to genitourinary diseases in mercury miners. 3.998 workers exposed to mercury in Minas de Almadén y Arrayanes S.A. were studied. The follow-up period was a century, since 1,895 to 1,994. It was completed assessing the vital status and the basic cause of death, in case of fatalities. Standardized Mortality Ratios by age, sex and calendar period were calculated. Expected deaths were obtained from age, sex and calendar period specific rates for the Spanish and Castilla-La Mancha populations. A significant increase in mortality due to genitourinary diseases was found (CIE-9 codes 580 to 629), being significant with respect to the total population for nephritis, nephrotic syndrome and nephrosis, with SMR of 1.69 an 95% CI 1.18 to 2.34. Mortality excesses due to nephritis, nephrotic syndrome and nephrosis were higher in the metallurgy workers than in miners. A Poisson multivariate regression detected a positive trend in the mortality due to nephritis and nephrosis associated to the exposure length, with the risk increasing fivefold after 30 years of exposure to mercury. This paper shows an excess in the mortality due to genitourinary diseases, specially in nephritis, nephrotic syndrome and nephrosis, whose estimation and significance increases when compared to the population of Castilla-La Mancha.


Alterations of the Erythrocyte Membrane during Sepsis.
Erythrocytes have been long considered as "dead" cells with transport of oxygen (O(2)) as their only function. However, the ability of red blood cells (RBCs) to modulate the microcirculation is now recognized as an important additional function. This capacity is regulated by a key element in the rheologic process: the RBC membrane. This membrane is a complex unit with multiple interactions between the extracellular and intracellular compartments: blood stream, endothelium, and other blood cells on the one hand, and the intracytoplasmic compartment with possible rapid adaptation of erythrocyte metabolism on the other. In this paper, we review the alterations in the erythrocyte membrane observed in critically ill patients and the influence of these alterations on the microcirculatory abnormalities observed in such patients. An understanding of the mechanisms of RBC rheologic alterations in sepsis and their effects on blood flow and on oxygen transport may be important to help reduce morbidity and mortality from severe sepsis.


Risk and reward: extending stochastic glycaemic control intervals to reduce workload.
STAR is a model-based, personalised, risk-based dosing approach for glycaemic control (GC) in critically ill patients. STAR provides safe, effective control to nearly all patients, using 1-3 hourly measurement and intervention intervals. However, the average 11-12 measurements per day required can be a clinical burden in many intensive care units. This study aims to significantly reduce workload by extending STAR 1-3 hourly intervals to 1 to 4-, 5-, and 6-hourly intervals, and evaluate the impact of these longer intervals on GC safety and efficacy, using validated in silico virtual patients and trials methods. A Standard STAR approach was used which allowed more hyperglycaemia over extended intervals, and a STAR Upper Limit Controlled approach limited nutrition to mitigate hyperglycaemia over longer intervention intervals. Extending STAR from 1-3 hourly to 1-6 hourly provided high safety and efficacy for nearly all patients in both approaches. For STAR Standard, virtual trial results showed lower % blood glucose (BG) in the safe 4.4-8.0 mmol/L target band (from 83 to 80%) as treatment intervals increased. Longer intervals resulted in increased risks of hyper- (15% to 18% BG > 8.0 mmol/L) and hypo- (2.1% to 2.8% of patients with min. BG < 2.2 mmol/L) glycaemia. These results were achieved with slightly reduced insulin (3.2 [2.0 5.0] to 2.5 [1.5 3.0] U/h) and nutrition (100 [85 100] to 90 [75 100] % goal feed) rates, but most importantly, with significantly reduced workload (12 to 8 measurements per day). The STAR Upper Limit Controlled approach mitigated hyperglycaemia and had lower insulin and significantly lower nutrition administration rates. The modest increased risk of hyper- and hypo-glycaemia, and the reduction in nutrition delivery associated with longer treatment intervals represent a significant risk and reward trade-off in GC. However, STAR still provided highly safe, effective control for nearly all patients regardless of treatment intervals and approach, showing this unique risk-based dosing approach, modulating both insulin and nutrition, to be robust in its design. Clinical pilot trials using STAR with different measurement timeframes should be undertaken to confirm these results clinically.


Control of oxidative metabolism in volume-overloaded rat hearts: effect of propionyl-L-carnitine.
The objective of the present work was the assessment of metabolic events responsible for the improvement of hemodynamic function of volume-overloaded hearts from rats receiving propionyl-L-carnitine. A severe cardiac hypertrophy was induced in 2-mo-old rats by surgical opening of an aortocaval communication. Three months later, during in vitro perfusions with 1.2 mM palmitate, 11 mM glucose, and 10 IU/l insulin, the mechanical performance and overall energy turnover (myocardial O2 consumption) of hypertrophied rat hearts were significantly decreased under conditions of moderate and high workloads. These changes in cardiac energetics paralleled the decrease in total tissue carnitine content and alterations in exogenous palmitate oxidation. The oxidative utilization of glucose was also slightly depressed in volume-overloaded hearts while steady-state glycolysis rates increased, especially in hearts subjected to high mechanical loads. This slowing of metabolic pathways involved in acetyl-CoA generation resulted in decreased NADH availability and in an apparent substrate limitation of oxidative phosphorylation suggested by a failure of cytosolic unbound ADP to drive respiration. Long-term administration of propionyl-L-carnitine normalized the degree of reduction of mitochondrial pyridine nucleotides and improved the kinetics of mitochondrial ATP production in volume-overloaded hearts. The resulting acceleration of energy turnover was essentially related to improved oxidative utilization of glucose, but steady-state palmitate oxidation rates also increased in severely hypertrophied hearts. This concomitant acceleration of glucose and palmitate oxidation may be related to the particular experimental conditions (high exogenous palmitate concentrations, elevated workloads) used in this study. We assume that the increase in intracellular carnitine, together with a stimulation of acetyl-CoA demands related to high workloads, creates conditions that are compatible with the simultaneous relief of pyruvate dehydrogenase and carnitine palmitoyltransferase I. The resulting increase in the rate of steady-state ATP production improves, in turn, the mechanical activity of volume-overloaded hearts.


Improved bowel care with a polyethylene glycol based bisacadyl suppository.
To test its effectiveness for bowel care in myopathy patients, a bisacodyl suppository based in polyethylene glycol (PEGBS) was compared with a conventional bisacodyl suppository based in hydrogenated vegetable oil (HVOBS). Nineteen patients with upper motor neuron paralysis received 57 HVOBS and 114 PEGBS trials in a crossover design. The average time for complete bowel evacuation was 2.4 (range 1.0 to 4.5) hours with HVOBS and 1.1 (range 0.3 to 1.8) hours with PEGBS. Three patients later discontinued the PEGBS because of cramps or fecal incontinence. The remaining 16 patients continued to use PEGBS for three years and 15 reported a sustained savings in time. It is concluded that the replacement of HVOBS with PEGBS will reduce bowel care time in myelopathy patients by about half.


A molecular dynamics simulation study of the electric double layer and capacitance of [BMIM][PF6] and [BMIM][BF4] room temperature ionic liquids near charged surfaces.
A molecular dynamics simulation study of electric double layer (EDL) structure and differential capacitance (DC) of two 1-butyl-3-methylimidazolium (BMIM)-based room temperature ionic liquids, i.e. [BMIM][BF4] and [BMIM][PF6], has been conducted on basal and prismatic graphite as well as (001) and (011) gold electrode surfaces. The influence of the electrode surface and electrolyte structure on electrode capacitance and EDL structure are discussed. For a given electrode surface both the [BMIM][BF4] and [BMIM][PF6] electrolytes generate very similar DC and EDL structures. The DC for these ionic liquids in contact with atomically flat surfaces (i.e. basal graphite and (001)Au) shows very small variations within the electrolyte chemical stability potential window and fluctuates around an average value of ∼5 μF cm(-2). On atomically more corrugated surfaces (i.e., Au(011) and prismatic graphite) the DC shows more variation with electrode potential and depends on the correspondence between dimensions of the surface roughness and electrolyte ion sizes. The trends and dependencies obtained for DC are used to discriminate between mutually contradictory experimental data reported in the literature for related systems.


Imidazole-4,5-dicarboxamide derivatives with antiproliferative activity against HL-60 cells.
A series of N,N'-disubstituted imidazole-4,5-dicarboxamides (I45DCs) were prepared and tested in order to determine their antiproliferative activity against HL-60 cells. The design of the I45DCs was based in part on the structures of trisubstituted purines complexed with cyclin dependent kinase 2 (cdk2), a protein important in regulating the G1/S transition in the cell cycle, and the intramolecular hydrogen bond in I45DCs that predisposes the conformation to one that mimics substituted adenosines. A majority of the I45DCs in this study inhibit proliferation of HL-60 cells as measured by an MTS mitochondrial functional assay with IC50's in the 2.5-25 microM range. The SAR of the I45DCs is consistent with anticipated hydrogen bonding interactions in the ATP-binding site of cdk2. Thus, the I45DCs represent a useful scaffold for anticancer lead discovery that is both readily accessible and easily diversified.


Photocaged Nanoparticle Sensor for Sensitive MicroRNA Imaging in Living Cancer Cells with Temporal Control.
Sensitive imaging of microRNA in living cells is of great value for disease diagnostics and prognostics. While signal amplification-based strategies have been developed for imaging low-abundance disease-relevant microRNA molecules, precise temporal control over sensor activity in living cells still remains a challenge, and limits their applications for sensing microRNA concentration dynamics. Herein, we report a class of photocaged nanoparticle sensors for highly sensitive imaging of microRNA in living cells with temporal control. The sensor features a DNA-templated gold nanoparticle-quantum dot satellite nanostructure which is temporarily inactivated by a photocaged DNA mask. Upon UV light irradiation, the sensor restores its activity for catalytic sensing of microRNA in living cells via entropy-driven two-step toehold-mediated strand displacement reactions. We show that the sensor exhibits quick response to UV light, robust intracellular stability, and high specificity and sensitivity for the microRNA target. On the basis of this strategy, precise control over sensor activity is achieved using an external light trigger, where on-demand sensing could be potentially performed with spatiotemporal control.


In vitro differentiation of cord blood unrestricted somatic stem cells expressing dopamine-associated genes into neuron-like cells.
An intensive study is underway to evaluate different potential candidates for cell therapy of neurodegenerative disorders such as Parkinson's disease (PD). Availability and lower immunogenicity compared to other sources for stem cell therapy such as bone marrow have made human umbilical cord blood stem cells a considerable source for cell therapy. The present study aimed to investigate differentiation of recently introduced pluripotent cord blood stem cells, known as unrestricted somatic stem cells (USSCs), into cells with neural features in serum-withdrawal medium. Using reverse transcription polymerase chain reaction and immunocytochemistry assays, we have shown the expression of neuron-specific genes following a 2week treatment of USSCs in serum-withdrawal induction medium. In addition, we have found that USSCs and USSC-derived neuron-like cells express transcripts of genes associated with development and/or survival of dopaminergic mesencephalic neurons including En1, En2, Nurr1, Ptx3, Pax2, Wnt1 and Wnt3a. The expression of dopamine-associated genes suggests that these cells may be potential candidates to be used for cell therapy of PD.


The "four quadrants" approach to clinical ethics case analysis; an application and review.
In 1982, Jonsen, Siegler and Winslade published Clinical Ethics, in which they described the "four quadrants" approach, a new method of analysing clinical ethics cases. Although the book is now in its 6th edition, a literature search has revealed only one academic paper demonstrating the method at work. This paper is an attempt to start filling this gap. As a way of describing and testing the approach, I apply the four quadrants method to a detailed clinical ethics case. The analysis is interspersed with reflections on the method itself. It is hoped that this experiment will encourage ethicists and clinicians to devote more attention to this neglected approach.


[Effects of vitamin A on formation of aminoacyl-tRNA].
The melting temperature and hyperchromia of intestine mucosa tRNA preparations and the effect of inactivating factors on aminoacyl-tRNA-synthetase activity were studied at the stage of hypovitaminosis and under deep A-avitaminosis. It is shown that in the aminoacylation reaction, aminoacyl-tRNA-synthetase is a component more sensitive to vitamin A deficiency.


Self-Reported Sleep Quality, Duration, and Health-Related Quality of Life in Older Chinese: Evidence From a Rural Town in Suzhou, China.
To determine the associations of self-reported sleep quality and duration with health-related quality of life (HRQOL) in older Chinese. We analyzed community-based cross-sectional data of 5,539 individuals aged 60 years and older in the Weitang Geriatric Disease Study. Information of sleep quality and duration were self-reported through participants' responses to predefined questions; HRQOL data were collected by using the European Quality of Life-5 Dimensions (EQ-5D). We estimated the associations of sleep quality and duration with the EQ-5D index and visual analog scale (VAS) scores using linear regression models. The associations between sleep quality and duration and EQ-5D-detected health problems were modeled using logistic regression. In multiple linear models adjusting sociodemographic factors, health conditions, and lifestyle habits, both EQ-5D index and VAS scores declined with deterioration of sleep quality. The coefficients for poor and intermediate sleep quality were -0.053 (95% confidence interval [CI]:-0.065, -0.042) and -0.022 (95% CI: -0.030, -0.013), respectively, in relation to EQ-5D index score. They were -5.2 (95% CI: -6.7, -2.4) and - 3.8 (95% CI: -4.9, -2.7) in modeling the EQ-5D VAS score. HRQOL declined as sleep duration decreased below 7.01 hours or exceeded 8.01 hours, though most of the associations did not reach statistical significance. In multiple logistic models, poor sleep quality was associated with problems of mobility, pain/discomfort, and anxiety/ depression; short sleep duration was associated with mobility problems. Poor sleep quality and extreme sleep durations appeared to be negatively associated with HRQOL in older Chinese adults.


Method Matters: Exploring Alkoxysulfonate-Functionalized Poly(3,4-ethylenedioxythiophene) and Its Unintentional Self-Aggregating Copolymer toward Injectable Bioelectronics.
Injectable bioelectronics could become an alternative or a complement to traditional drug treatments. To this end, a new self-doped p-type conducting PEDOT-S copolymer (A5) was synthesized. This copolymer formed highly water-dispersed nanoparticles and aggregated into a mixed ion-electron conducting hydrogel when injected into a tissue model. First, we synthetically repeated most of the published methods for PEDOT-S at the lab scale. Surprisingly, analysis using high-resolution matrix-assisted laser desorption ionization-mass spectroscopy showed that almost all the methods generated PEDOT-S derivatives with the same polymer lengths (i.e., oligomers, seven to eight monomers in average); thus, the polymer length cannot account for the differences in the conductivities reported earlier. The main difference, however, was that some methods generated an unintentional copolymer P(EDOT-S/EDOT-OH) that is more prone to aggregate and display higher conductivities in general than the PEDOT-S homopolymer. Based on this, we synthesized the PEDOT-S derivative A5, that displayed the highest film conductivity (33 S cm-1) among all PEDOT-S derivatives synthesized. Injecting A5 nanoparticles into the agarose gel cast with a physiological buffer generated a stable and highly conductive hydrogel (1-5 S cm-1), where no conductive structures were seen in agarose with the other PEDOT-S derivatives. Furthermore, the ion-treated A5 hydrogel remained stable and maintained initial conductivities for 7 months (the longest period tested) in pure water, and A5 mixed with Fe3O4 nanoparticles generated a magnetoconductive relay device in water. Thus, we have successfully synthesized a water-processable, syringe-injectable, and self-doped PEDOT-S polymer capable of forming a conductive hydrogel in tissue mimics, thereby paving a way for future applications within in vivo electronics.


Distinct Leishmania infantum Strains Circulate in Humans and Dogs in the Emilia-Romagna Region, Northeastern Italy.
Human leishmaniasis is an emerging problem in Italy and is on the increase in the Emilia-Romagna region, northeastern part of the country. Nevertheless, studies dealing with the molecular characterization of Leishmania spp. circulating in these areas are limited. In the present work, we explored the genetic polymorphism of Leishmania isolates from 28 cases of canine leishmaniasis and three cases of human visceral leishmaniasis (VL), which occurred in 2013-2014 in the Emilia-Romagna region. The characterization was carried out in comparison with nine human isolates of Leishmania from other VL endemic Italian regions and two reference strains. Nucleic acid from 31 Leishmania-positive phlebotomine sandfly pools, sampled in 2012-2013 in the Emilia-Romagna region, were also evaluated. DNA amplification and sequencing of the ribosomal internal transcribed spacer-1 and of a repetitive nuclear region on chromosome 31 were carried out for genotyping. Two size polymorphic targets were also analyzed by PCR, the cpb E/F-gene and the k26-gene. Altogether, the analysis showed the circulation of different Leishmania infantum genotypes in the Emilia-Romagna region: two genotypes found in dogs from public kennels were similar to VL isolates from other Italian regions, whereas a third genotype was detected in VL cases of the Emilia-Romagna region and in all but one of the sandfly pools. The combined molecular tools applied in this study can constitute a helpful support for parasite tracking (e.g., in outbreak investigations) and for a better understanding of the epidemiological evolution of leishmaniasis in northeastern Italy.


International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Annual Meeting (May 17-20, 2021 - Virtual Meeting).
COVID-19 has pushed us to think differently about health and its delivery, and following the declaration of pandemic by the World Health Organization (WHO), value chains have been largely broken and must be rebuilt and redesigned. COVID-19 brought the whole world to a standstill, and its impact on overall healthcare utilization and cost trends is undeniable; as such, the importance of public health expertise and health economics outcomes research (HEOR) to support and inform public health cannot be overstated. The virtual International Society for Pharmacoeconomics and Outcomes Research (ISPOR) meeting brought together experts and leaders in the HEOR field to explore topics that will shape healthcare decision making over the coming decades and to consider the useful lessons learnt from COVID-19 and how these will impact healthcare decisions in the post-COVID-19 era.


Purinergic Regulation of Neutrophil Function.
Purinergic signaling, which utilizes nucleotides (particularly ATP) and adenosine as transmitter molecules, plays an essential role in immune system. In the extracellular compartment, ATP predominantly functions as a pro-inflammatory molecule through activation of P2 receptors, whereas adenosine mostly functions as an anti-inflammatory molecule through activation of P1 receptors. Neutrophils are the most abundant immune cells in circulation and have emerged as an important component in orchestrating a complex series of events during inflammation. However, because of the destructive nature of neutrophil-derived inflammatory agents, neutrophil activation is fine-tuned, and purinergic signaling is intimately involved in this process. Indeed, shifting the balance between P2 and P1 signaling is critical for neutrophils to appropriately exert their immunologic activity. Here, we review the role of purinergic signaling in regulating neutrophil function, and discuss the potential of targeting purinergic signaling for the treatment of neutrophil-associated infectious and inflammatory diseases.


An animal model of atherosclerotic plaque disruption and thrombosis in rabbit using pharmacological triggering to plaques induced by perivascular collar placement.
Limited availability of suitable animal model of plaque disruption and thrombosis has hampered the study of mechanism and preclinical evaluation of plaque-stabilizing therapies. This study aims to develop an animal model of atherosclerotic plaque disruption and thrombosis in rabbit femoral artery. Silastic collars were placed around the bilateral femoral arteries of rabbits, which had been fed with atherogenic diet for 7 days. After 28 days on the same diet, the rabbits received pharmacological triggering by intraperitoneal injection of Russell's viper venom (RVV, 0.15 mg/kg) followed by intravenous injection of histamine (0.02 mg/kg), and the animals were then processed for imageological and histological examinations. Perivascular collar placement of the femoral artery in high-cholesterol-fed rabbits for 28 days induced marked intimal hyperplasia, which was a lipid- and collagen-rich lesion that contained substantial amount of macrophages and smooth muscle cells. Subsequent histological analysis showed that the pharmacological triggering evoked plaque disruption and platelet- and fibrin-rich thrombi in the collared femoral arteries. We demonstrated, for the first time, a rabbit model of plaque disruption and thrombosis induced by the combination of perivascular collar placement, RVV, and histamine injections. This model can be rapidly formed, easily operated, and site controlled.


CYP1B1 enhances the resistance of epithelial ovarian cancer cells to paclitaxel in vivo and in vitro.
Ovarian cancer (OC) is the most frequent cause of mortality among gynecological malignancies, with a 5-year survival rate of approximately 30%. The standard regimen for OC therapy includes a platinum agent combined with a taxane, to which the patients frequently acquire resistance. Resistance arises from the oxidation of anticancer drugs by CYP1B1, a cytochrome P450 enzyme overexpressed in malignant OC. The aim of the present study was to determine the role of CYP1B1 expression in the drug resistance of OC to the taxane, paclitaxel (PTX). Immunohistochemical staining was used to assess CYP1B1 expression in a panel of ovarian samples (53 primary cancer samples, 14 samples of metastastic cancer, 30 benign tumor samples and 19 normal tissue samples). Semi-quantitative RT-PCR was also performed to determine CYP1B1 expression in several OC cell lines. Finally, we used proliferation and toxicity assays, as well as a mouse xenograft model using nude mice to determine whether α-naphthoflavone (ANF), a CYP1B1 specific inhibitor, reduces resistance to PTX. CYP1B1 was overexpressed in the samples from primary and metastatic loci of epithelial ovarian cancers. In some cell lines, PTX induced CYP1B1 expression, which resulted in drug resistance. Exposure to ANF reduced drug resistance and enhanced the sensitivity of OC cells to PTX in vitro and in vivo. The expression profile of CYP1B1 suggests that it has the potential to be a useful diagnostic marker and prognostic factor for malignant OC. The inhibition of CYP1B1 expression by specific agents may provide a novel therapeutic strategy for the treatment of patients resistant to PTX and may improve the prognosis of these patients.


Rich structural chemistry in new alkali metal yttrium tellurites: three-dimensional frameworks of NaYTe4O10, KY(TeO3)2, RbY(TeO3)2, and a novel variant of hexagonal tungsten bronze, CsYTe3O8.
Pure polycrystalline phases and single crystals of four new quaternary alkali metal yttrium tellurites, NaYTe4O10, KY(TeO3)2, RbY(TeO3)2, and CsYTe3O8, have been prepared by solid-state and hydrothermal reactions using A2CO3 (A = Na, K, Rb, and Cs), Y(NO3)3·6H2O, Y2O3, and TeO2 as starting reagents. X-ray diffraction analyses suggest that NaYTe4O10 exhibits a highly symmetric three-dimensional (3D) framework consisting of YO8 square antiprisms and chains of TeO4 polyhedra. Within the framework, six- (6-) and eight-membered ring (8-MR) channels are observed. KY(TeO3)2 and RbY(TeO3)2 are isostructural to each other and reveal another 3D framework with structures containing YO6 octahedra and TeO3 trigonal pyramids with 4-MR and 12-MR channels. CsYTe3O8 shows a hexagonal tungsten bronze (HTB)-like topology composed of hexagonal tungsten oxide-like layers of TeO4 polyhedra and YO6 octahedral linkers with 3-MR and 6-MR channels. Thermal analyses, elemental analyses, and spectroscopic characterizations, such as UV-vis diffuse reflectance and infrared spectra, are presented, as are local dipole moment calculations for the constituent asymmetric polyhedra TeO3 and TeO4.


The role of lifetime periods in the organisation of episodic memories.
Research on the nature of episodic memory associations has suggested that episodic memories are associated by conceptual knowledge, where memories cluster around the same content (e.g. memories about the same people) or general-event knowledge, where memories cluster around extended events (e.g. a holiday in London), repeated events (e.g. Sunday walks in the park), or causally related events (i.e. where one event leads to another). Research has also suggested that episodic memories are associated by lifetime periods (e.g. when I was in high school), where memories cluster within lifetime periods. However, it is unclear whether episodic memories can be associated solely by lifetime periods, or if such associations are subordinate to conceptual or general-event associations. To answer this question, we reanalysed a large sample of involuntary memory chains (Mace, J. H., Clevinger, A. M., & Bernas, R. S. (2013). Involuntary memory chains: What do they tell us about autobiographical memory organisation? Memory, 21, 324-335). The results of this analysis suggested that lifetime periods associations are subordinate to conceptual and general-event associations, as lifetime periods were found to cluster within the latter two associations. The potential functions of this organisation are discussed.


Allergy to human seminal plasma: a presentation of six cases.
Six women had symptoms of immediate type allergic reactions such as localized oedema, urticaria and pruritus elicited at, or soon after intercourse. All had positive skin prick tests with dilutions of human seminal plasma. The symptoms failed to appear when the women's partners used a condom an intercourse. None of the women had IgE antibodies in serum against human seminal plasma when tested with the radioallergosorbent test. This type of allergic reaction is easily overlooked.


A keystone avian predator faces elevated energy expenditure in a warming Arctic.
Climate change is transforming bioenergetic landscapes, challenging behavioral and physiological coping mechanisms. A critical question involves whether animals can adjust behavioral patterns and energy expenditure to stabilize fitness given reconfiguration of resource bases, or whether limits to plasticity ultimately compromise energy balance. In the Arctic, rapidly warming temperatures are transforming food webs, making Arctic organisms strong models for understanding biological implications of climate change-related environmental variability. We examined plasticity in the daily energy expenditure (DEE) of an Arctic seabird, the little auk (Alle alle) in response to variability in climate change-sensitive drivers of resource availability, sea surface temperature (SST) and sea ice coverage (SIC), and tested the hypothesis that energetic ceilings and exposure to mercury, an important neurotoxin and endocrine disrupter in marine ecosystems, may limit scope for plasticity. To estimate DEE, we used accelerometer data obtained across years from two colonies exposed to distinct environmental conditions (Ukaleqarteq [UK], East Greenland; Hornsund [HS], Svalbard). We proceeded to model future changes in SST to predict energetic impacts. At UK, high flight costs linked to low SIC and high SST drove DEE from below to above 4 × basal metabolic rate (BMR), a proposed energetic threshold for breeding birds. However, DEE remained below 7 × BMR, an alternative threshold, and did not plateau. Birds at HS experienced higher, relatively invariable SST, and operated above 4 × BMR. Mercury exposure was unrelated to DEE, and fitness remained stable. Thus, plasticity in DEE currently buffers fitness, providing resiliency against climate change. Nevertheless, modeling suggests that continued warming of SST may promote accelerating increases in DEE, which may become unsustainable.


How Health Consciousness and Health Literacy Influence Evaluative Responses to Nutrient-Content Claimed Messaging for an Unhealthy Food.
Guided by the theoretical frameworks of the "health halo effect" and consumer expertise, this research was undertaken to determine how two individual factors, health consciousness and health literacy, differentially influence evaluations of nutrient-content claimed messaging for an unhealthy food (i.e., chocolate) and whether such evaluations are moderated by the reading of the food's Nutrition Facts Label displaying different serving sizes. The research found that health consciousness positively influenced evaluative responses to unhealthy food messaging, and that the positive influence persisted following the reading of a Nutrition Facts label listing a large quantity of unhealthy ingredients per serving size. In contrast, health literacy negatively influenced perceived healthiness and purchase intention when the nutrition label communicated a higher serving size, indicating that subjective and objective expertise work differently. The results advance understanding of the information processing of nutrient-claimed unhealthy foods, and suggest implications for food marketing communication and public health policy.


Scaling and Structural Properties of Juvenile Bull Kelp (Nereocystis luetkeana).
Bull kelp (Nereocystis luetkeana), the only canopy-forming kelp in the Salish Sea, provides primary production in the nearshore subtidal environment and serves as an important habitat for economically and ecologically important species. An annual species, each year juvenile bull kelp sporophytes must grow from the hydrodynamically more benign benthos to the water column, where they experience substantial drag at the surface. Because of the differences in morphology and ecology across life stages, and the fact that previous work has focused mainly on adult bull kelp, we tested whether morphology and structural properties change with stipe length, investigating scaling of both juvenile (stipe length < 40 cm) and mature (stipe length > 40 cm) kelp, and testing how juvenile stipes fail. Juvenile bull kelp grow proportionally (isometric growth) when young, but lengthen more quickly than would be predicted by bulb size (negative allometry) at maturity. Based on our data, the predicted breakpoint between isometric and allometric growth occurred at about 33 cm, likely approximately one to two weeks of growth. Cross-sectional area of the stipe, force to failure, work to failure, and stiffness (Young's modulus) all grow more slowly than would be predicted based on length, while maximum stress and toughness increase more quickly than predicted. There is no change in extensibility over the size range we tested, suggesting that this material property does not change with stipe length. The differences in biomechanics between juvenile and adult kelp are likely a response to the varied hydrodynamic environments experienced during the annual life cycle, which highlights the importance of studying organisms across life stages.


The therapeutic effect of chelidonic acid on ulcerative colitis.
Chelidonic acid (CA), a constituent of Chelidonium majus L., has many pharmacological effects, including mild analgesic and antimicrobial effects. However, the effects of CA on intestinal inflammation and the molecular mechanisms responsible are poorly understood. The aim of this study was to investigate the protective effects of CA against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). Mice treated with DSS displayed obvious clinic signs, such as, body weight loss and a shortening of colon length, but the administration of CA attenuated both of these signs. Additionally, CA was found to regulate levels of interleukin-6 and tumor necrosis factor-α in serum. In colonic tissues, prostaglandin E(2) (PGE(2)) production levels and cyclooxygenase-2 (COX-2) and hypoxia induced factor-1α (HIF-1α) expression levels were increased by DSS, but CA attenuated increases in COX-2 and HIF-1α levels. These results provide novel insights into the pharmacological actions of CA and its potential use for the treatment of intestinal inflammation.


Haemodynamic and humoral effects of oral perindopril, an angiotensin converting enzyme inhibitor, in man.
The tolerance to and dynamic effects of 1 week's oral treatment with the angiotensin converting enzyme inhibitor, perindopril, were assessed in a placebo controlled, parallel group study in 36 normotensive males. The daily dose of perindopril was 1, 2, 4, 8 or 16 mg. The drug was well tolerated and produced no change in routine haematology or serum biochemistry tests. Dose related inhibition of plasma angiotensin converting enzyme was observed. Perindopril 16 mg produced 90% inhibition 4 h after dosing and 60% after 24 h. A dose related rise in plasma renin activity followed doses of 4 mg and over. The renin remained above the normal range for 24 h. Perindopril caused a modest lowering of plasma aldosterone levels but had no effect on plasma adrenaline or noradrenaline levels. Standing diastolic blood pressure was lowered, particularly with 16 mg daily of perindopril but only a slight rise in heart rate occurred. Perindopril appears to be a well tolerated inhibitor of plasma angiotensin converting enzyme, with predictable effects on the renin angiotensin system and blood pressure. An appropriate dose range for further study would appear to be 4 to 16 mg daily.


Maternal Macronutrient Consumption and the Developmental Origins of Metabolic Disease in the Offspring.
Recent research aimed at understanding the rise in obesity and cardiometabolic disease in children suggests that suboptimal maternal nutrition conditions organ systems and physiological responses in the offspring contributing to disease development. Understanding the mechanisms by which the macronutrient composition of the maternal diet during pregnancy or lactation affects health outcomes in the offspring may lead to new maternal nutrition recommendations, disease prevention strategies and therapies that reduce the increasing incidence of cardiometabolic disease in children. Recent mechanistic animal model research has identified how excess fats and sugars in the maternal diet alter offspring glucose tolerance, insulin signaling and metabolism. Maternal nutrition appears to influence epigenetic alterations in the offspring and the programming of gene expression in key metabolic pathways. This review is focused on experimental studies in animal models that have investigated mechanisms of how maternal consumption of macronutrients affects cardiometabolic disease development in the offspring. Future research using "-omic" technologies is essential to elucidate the mechanisms of how altered maternal macronutrient consumption influences the development of disease in the offspring.


Successful management of visceral Klippel-Trenaunay-Weber syndrome with the antifibrinolytic agent tranexamic acid (cyclocapron): a case report.
Klippel-Trenaunay-Weber syndrome (KTWS) is a rare, congenital disorder characterized by vascular nevus formation, deep venous thrombosis, varicosities, and hypertrophy of affected tissues. A patient with known thrombosis of his splanchnic circulation and visceral KTWS presented with life-threatening hemorrhage from rectosigmoid varices. Portosystemic shunting was not feasible. Endoscopic sclerosis, variceal ligation, and proctocolectomy were not possible due to the size and number of the varices. Previous treatment with epsilon-aminocaproic acid had been unsuccessful and complicated by thrombophlebitis. Conservative treatment with blood transfusions, cryoprecipitate, fresh frozen plasma, vitamin K, propanolol, and somatostatin analog failed to stop the bleeding. The patient was given the antifibrinolytic agent, tranexamic acid, with cessation of his hemorrhage. Serial thromboelastograms confirmed improved reaction time, coagulation time, clot formation rate, and maximum amplitude. We conclude that tranexamic acid may be a useful adjunct in the medical treatment of high-risk patients with KTWS and other vascular nevi complicated by coagulopathy.


[When pharmacists administered anesthesia].
Using the examples of several operations undertaken in Bordeaux, the author shows that pharmacists acted as anesthesiologists with the use of chloroform very soon after the first such usage on a patient in Edinburgh (1847). One such was J.-J. Fauré (1799-1869), otherwise known as the author of numerous works on chemical analysis.


Polyketide chain length control by chain length factor.
Bacterial aromatic polyketides are pharmacologically important natural products. A critical parameter that dictates product structure is the carbon chain length of the polyketide backbone. Systematic manipulation of polyketide chain length represents a major unmet challenge in natural product biosynthesis. Polyketide chain elongation is catalyzed by a heterodimeric ketosynthase. In contrast to homodimeric ketosynthases found in fatty acid synthases, the active site cysteine is absent from the one subunit of this heterodimer. The precise role of this catalytically silent subunit has been debated over the past decade. We demonstrate here that this subunit is the primary determinant of polyketide chain length, thereby validating its designation as chain length factor. Using structure-based mutagenesis, we identified key residues in the chain length factor that could be manipulated to convert an octaketide synthase into a decaketide synthase and vice versa. These results should lead to novel strategies for the engineered biosynthesis of hitherto unidentified polyketide scaffolds.


[Not Available].
In 1686 the Zeeland Chamber of the West Indian Company undertook a serious effort to establish a colony on the Wild Coast at the Pomeroon. The Wild Coast, a territory described as stretching from the Amazon to the Orinoco river, was of growing significance for the trade in pharmaceutical and technical products of the Guyana country: dyes, letterwood, balsam of copaiba, tobacco, sugar, vanilla beans and carape oil. The expedition consisted of the ship 'De Vrijheyt' which was dispatched from Flushing with the new commander Jacob de Jongh, his family, some soldiers and the surgeon David van Cassel aboard. The latter could rely on a surgeon chest with 103 medicines. The new Pomeroon colony however quickly collapsed. Mortality due to dysentery and malaria was high and the lack of leadership led to faulty discipline. The list of medicines used to combat diseases is reviewed in this article. Antimony takes an important place in the assortment and theriac was used for its anti-inflammatory activity.


Backs to the future? Reflections on women, ageing and nursing.
There is now a certain amount of evidence to support the contention that ageism is not only rife amongst the population at large, but also amongst many of those who care for older people in a professional capacity. Given that many of these professionals are women caring for other women -- and nursing is a prime example -- this should at the very least give us serious cause for concern. This paper explores the relationship between 'ageing women' and 'old women' from the point of view of personal and professional attitudes and practices. It examines the proposition that until we, as women, fully explore and understand our own attitudes towards ageing and old age, we cannot work in ways which are truly beneficial and empowering for the older women in our care. The purpose of the paper is threefold. First, it reviews what is a relatively limited body of literature and research on this topic. Second, it reports on the preliminary findings from an exploratory study examining the attitudes of female nurses to their own ageing. Finally, it reflects further on the issues raised and considers some of the ways in which we can begin to address and confront the challenges which being 'ageing women' and 'aged women' in late 20th century Britain presents.


Effect of hemoglobin concentration variation on the accuracy and precision of glucose analysis using tissue modulated, noninvasive, in vivo Raman spectroscopy of human blood: a small clinical study.
Tissue modulated Raman spectroscopy was used noninvasively to measure blood glucose concentration in people with type I and type II diabetes with HemoCue fingerstick measurements being used as reference. Including all of the 49 measurements, a Clarke error grid analysis of the noninvasive measurements showed that 72% were A range, i.e., clinically accurate, 20% were B range, i.e., clinically benign, with the remaining 8% of measurements being essentially erroneous, i.e., C, D, or E range. Rejection of 11 outliers gave a correlation coefficient of 0.80, a standard deviation of 22 mg/dL with p<0.0001 for N=38 and places all but one of the measurements in the A and B ranges. The distribution of deviations of the noninvasive glucose measurements from the fingerstick glucose measurements is consistent with the suggestion that there are at least two systematic components in addition to the random noise associated with shot noise, charge coupled device spiking, and human factors. One component is consistent with the known variation of fingerstick glucose concentration measurements from laboratory reference measurements made using plasma or whole blood. A weak but significant correlation between the deviations of noninvasive measurements from fingerstick glucose measurements and the test subject's hemoglobin concentration was also observed.


Laparoscopic removal of migrated intrauterine device embedded in intestine.
The intrauterine device (IUD) is a popular family planning method worldwide. Some of the complications associated with insertion of an IUD are well described in the literature. The frequency of IUD perforation is estimated to be between 0.05 and 13 per 1000 insertions. There are many reports of migrated intrauterine devices, but far fewer reports of IUDs which have penetrated into the small intestine. Herein we report a case of perforated intrauterine device embedded in the small intestine. By using a wound protector retraction device, and fashioning the anastomosis extra-corporeally, we were able to more easily perform this laparoscopically. This left the patient with a quicker recovery, and a better cosmetic result. IUD perforation into the peritoneal cavity is a known complication, and necessitates close follow-up. Most, if not all, should be removed at the time of diagnosis. In the majority of previously reported cases, removal was done through laparotomy. Even in cases where removal was attempted laparoscopically, many were later converted to laparotomy. Surgeons should be aware of different techniques, including using a wound protector retraction device, in order to facilitate laparoscopic removal.


Epidemiology of urinary tract infections and vesico-ureteral reflux in children.
The purpose of this study was to assess the incidence of symptomatic urinary tract infection (U.T.I.) and malformations, such as vesico-ureteral reflux (V.U.R.), in the Trieste area. Data were collected in the framework of a survey based on the application of a protocol on urinary infections between 1979 and 1983. The U.T.I. incidence was found to be 1.38% of the 0-14-year-old residents, with a higher frequency in females (2.36%) than in males (0.46%). As regards V.U.R., the incidence in the population studied turned out to be 0.25%, with a females/males ratio of 4:1. Striking differences in incidence data were observed according to the age of U.T.I. and V.U.R. diagnosis and to the infection level (cystitis or pyelonephritis). The incidence of renal scarring resulted to be extremely low, which can be ascribed to the early diagnosis in our cases.


Specialist surgical training in Papua New Guinea: the outcomes after 10 years.
Surgical training commenced in 1975, the year that Papua New Guinea (PNG) gained independence. The training involves a 4-year programme leading to a Master of Medicine (MMed), awarded by the University of Papua New Guinea. In the past 30 years just over 50 general surgeons have graduated. There have also been 9 graduates in the area of ear nose and throat, 10 in ophthalmology and 2 in oral surgery. The subspecialization of general surgeons began in 1994 with four trainees, two orthopaedic, one head and neck and one urological. The model used was to develop specialist skills over 2-3 years only qualified (MMed) general surgeons so that their ability to carry out general surgical procedures and work in a remote hospital was not lost. The different specialties required different balances of in-country and out-of-country training depending on the local ability to provide training in PNG. An important sponsor has been the PNG National Department of Health, which has funded the training posts by using existing general surgical positions and covering the loss of manpower while surgeons are training overseas, sometimes for up to 2 years. Medical education and tertiary health service projects, funded by Aus-Aid, have also contributed significantly to the teaching and training. These projects have provided visiting specialists to teach and hospital attachments for national surgeons to train in Australasia. Various individual surgeons and their specialist societies in Australasia have also provided invaluable support. Three surgeons have been recipients of the Rowan Nicks scholarship. Twelve surgeons have been awarded a specialist diploma and a further five are in training. The posting of national specialist surgeons to Port Moresby has resulted in all modules of the General surgery MMed programme being taught by Papua New Guineans, which would have been hard to imagine back in 1993. The MMed is now a sustainable programme and can be provided without external support. National surgeons carry out a wide range of specialist procedures, formerly carried out only by visiting teams. They are also able to make outreach visits within PNG and specialist visits to neighbouring Pacific Island countries.


Application of 99mTc-UBI 29-41 scintigraphy in knee periprosthetic infection diagnosis.
In recent years, the use of total knee arthroplasty (TKA) is considered a safe and cost-effective orthopedic procedure for alleviating the chronic pain and treatment of progressive osteoarthritis. This procedure may have some complications including periprosthetic infection as the most serious and aseptic loosening as the most common one. Differentiating between these entities is important because each has a different therapeutic approach. This study was conducted to investigate the ability of 99mTC-UBI scan to distinguish septic from aseptic loosening in a painful knee prosthesis. 34 patients with painful knee prostheses were included. The 99mTC-UBI scan was done immediately after IV administration of 99mTC-UBI in early dynamic and 30-minute static images. Time-activity curve (TAC) was drawn for all patients and target to non-target ratio (T/NT) was calculated on 30-minute images. The final diagnosis was confirmed by surgical findings, microbiologic culture results or active clinical follow up. Using TAC analysis, 24 99mTC-UBI scans were considered negative and 10 positive for an infectious process. Sensitivity, specificity, negative and positive predictive values were 56 %, 80 %, 83 %, and 50 %, respectively. T/NT ratio analysis on 30-minute static images demonstrated 9 positive and 25 negative patterns, with a cut off value of 1.83 for the T/NT ratio. The sensitivity, specificity, negative and positive predictive values, and accuracy of this test modality were all 100 %. Our findings show 99mTc-UBI scan is an excellent clinical diagnostic test for differentiating septic from aseptic loosening of the knee prostheses with perfect sensitivity and specificity. Highly accurate results were obtained only 30 minutes after injection.


Effect of ribavirin on epididymal sperm count in rat.
Ribavirin (1-beta-D-ribofuranosyl-1, 2, 4-triazole-3-Carboxamide) is a potent inhibitor of inosine monophosphate dehydrogenase, used widely as an antiviral drug. Although it has been reported as a teratogen, its effect on spermatogenesis is not known. Male Wistar rats were segregated into 24 groups of 5 in each. Six groups were treated with water, 6 groups with 20 mg/kg, another 6 groups with 100 mg/kg and remaining 6 groups with 200 mg/kg for 5 days at intervals of 24 h (i.p.). Animals were anaesthetized at 14, 28, 35, 42, 70 and 105 days following the last exposure, laparatomy was conducted, epididymis was removed, minced in 1 ml phosphate buffered saline (PBS, pH 7.2), filtered and stained with 1% aqueous eosin Y. An aliquot was taken in haemocytometer, diluted in PBS and charged into Neubauer's chamber. Spermatozoa were counted in 8 squares except the central, and multiplied by 5 x 10(4). Data were analysed by Mann-Whitney "U" test. Ribavirin significantly decreased the sperm count in a dose and time dependent pattern and showed a recovery by day 105 except at 200 mg/kg. Ribavirin is reversibly cytotoxic to germ cells and decreases the production of spermatozoa.


[The informativeness of 2-month surveys of food consumption in private households].
All-year surveys of the food consumption in private households are very laborious. They may be simplified by shortening the period of time covered by the survey. 712 surveys taken in 1974 led to the conclusion that surveys covering only two months (April and August) permit to make statements the validity of which is but slightly inferior to that of an all-year survey. Of the 45 food groups considered, only 5 (potatoes, fresh vegetables, fresh fruit, tropical and subtropical fruit, and sugar) play an important role as to the selection of suitable months for such a survey.


Prostaglandin E(2) induces breast cancer related aromatase promoters via activation of p38 and c-Jun NH(2)-terminal kinase in adipose fibroblasts.
Aromatase is the key enzyme for estrogen biosynthesis. A distal promoter, PI.4, maintains baseline levels of aromatase in normal breast adipose tissue. In contrast, malignant breast epithelial cells secrete prostaglandin E(2) (PGE(2)), which stimulates aromatase expression via proximal promoters PI.3/PII in a cyclic AMP (cAMP)- and protein kinase C (PKC)-dependent manner in adjacent breast adipose fibroblasts (BAF), leading to increased local concentrations of estrogen. Although an effective treatment for breast cancer, aromatase inhibitors indiscriminately abolish estrogen synthesis in all tissues, causing major side effects. To identify drug targets to selectively block aromatase and estrogen production in breast cancer, we investigated PGE(2)-stimulated signaling pathways essential for aromatase induction downstream of cAMP and PKC in human BAFs. Here, we show that PGE(2) or its surrogate hormonal mixture dibutyryl cAMP (Bt(2)cAMP) + phorbol diacetate (PDA) stimulated the p38, c-jun NH(2)-terminal kinase (JNK)-1, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathways. Inhibition or small interfering RNA-mediated knockdown of p38 or JNK1, but not ERK, inhibited PGE(2)- or Bt(2)cAMP + PDA-induced aromatase activity and expression via PI.3/PII. Conversely, overexpression of wild-type p38alpha or JNK1 enhanced PGE(2)-stimulated aromatase expression via PII. PGE(2) or Bt(2)cAMP + PDA stimulated c-Jun and activating transcription factor-2 (ATF2) phosphorylation and binding to the PI.3/PII region. Specific activation of protein kinase A (PKA) or EPAC with cAMP analogues stimulated p38 and JNK1; however, only PKA-activating cAMP analogues induced aromatase expression. The PKC activator PDA effectively stimulated p38 and JNK1 phosphorylation but not aromatase expression. Taken together, PGE(2) activation of p38 and JNK1 via PKA and PKC is necessary for aromatase induction in BAFs, and p38 and JNK1 are potential new drug targets for tissue-specific ablation of aromatase expression in breast cancer.


A multi-center clinical study comparing Sansure Magb and CAP/CTM HBV tests in the quantitative detection of HBV DNA.
As the most reliable means of diagnosing hepatitis (HBV) infection and predicting the prognosis of HBV-related chronic liver disease, the COBAS AmpliPrep/COBAS TaqMan real-time polymerase chain reaction (PCR) (CAP/CTM) assay provides a highly sensitive and accurate method for quantifying HBV DNA. However, the high cost of the COBAS reagents is prohibitive in many developing countries. Thus, we compared the Sansure magnetic bead (Magb) assay, a novel technology developed by a Chinese company, with the CAP/CTM assay. The reproducibility and sensitivity of the Sansure Magb assay were first validated using HBV DNA reference samples. Next, the quantitative results for the two assays using 635 blood samples collected from chronic hepatitis B patients and 10 healthy controls were compared. The Sansure Magb assay showed high reproducibility and was at least as sensitive and specific as the CAP/CTM assay. Among the patient samples, 407 tested positive by both methods, with 386 (94.84%) showing quantitative differences of less than 1 log unit and 21 (5.16%) showing quantitative differences of between 1 and 2 log units. The results from the assays were closely correlated. Bland-Altman plot analysis showed that only 6.6% of the data points fell outside the 95% limits of agreement, which suggests that the differences between methods are clinically acceptable. This study demonstrates that the Sansure Magb assay is highly sensitive and reproducible. Based on its reduced cost, the Sansure Magb assay may be more applicable than the CAP/CTM assay for HBV diagnosis in developing countries such as China.


Thermodynamic Characterization of Hydration Sites from Integral Equation-Derived Free Energy Densities: Application to Protein Binding Sites and Ligand Series.
Water molecules play an essential role for mediating interactions between ligands and protein binding sites. Displacement of specific water molecules can favorably modulate the free energy of binding of protein-ligand complexes. Here, the nature of water interactions in protein binding sites is investigated by 3D RISM (three-dimensional reference interaction site model) integral equation theory to understand and exploit local thermodynamic features of water molecules by ranking their possible displacement in structure-based design. Unlike molecular dynamics-based approaches, 3D RISM theory allows for fast and noise-free calculations using the same detailed level of solute-solvent interaction description. Here we correlate molecular water entities instead of mere site density maxima with local contributions to the solvation free energy using novel algorithms. Distinct water molecules and hydration sites are investigated in multiple protein-ligand X-ray structures, namely streptavidin, factor Xa, and factor VIIa, based on 3D RISM-derived free energy density fields. Our approach allows the semiquantitative assessment of whether a given structural water molecule can potentially be targeted for replacement in structure-based design. Finally, PLS-based regression models from free energy density fields used within a 3D-QSAR approach (CARMa - comparative analysis of 3D RISM Maps) are shown to be able to extract relevant information for the interpretation of structure-activity relationship (SAR) trends, as demonstrated for a series of serine protease inhibitors.


Effect of Diclofenac and Simvastatin on Bone Defect Healing-An In Vivo Animal Study.
Non-steroidal, anti-inflammatory drugs and statins are two widely prescribed drug classes that affect bone formation. The aim of this study was to elucidate the effect of diclofenac and simvastatin in artificial bone defect healing. One hundred and forty-four male Wistar rats were used, and the specimens were divided into groups, with respect to the route of drug administration and the type of defect healing (with or without collagen membrane), and subgroups, with respect to the study duration (2, 4 or 8 weeks). Diclofenac was intramuscularly administered while simvastatin was administered both systemically and locally. Animals were euthanized and specimens were histomorphometrically analyzed to evaluate the percentage of new bone formation (%). Bone healing that occurred without any intervention developed more steadily than that of all other groups. Diclofenac exerted a clear, direct inhibitory effect on bone healing and its systemic administration should be avoided. The systemic administration of simvastatin was related to severe myopathy, while the solvent for the local administration of simvastatin seemed to play significant role in bone growth, as simvastatin, when it is administered intraperitoneally in a DMSO solution, appeared to promote bone healing. Local administration may have a significant impact on bone healing and it should be further investigated with the type of solvent or carrier that is used, which both may play a significant role in bone repair induction.


Pattern-recognition techniques with haplotype analysis in pharmacogenomics.
Single nucleotide polymorphisms (SNPs) can be used in clinical association studies to determine the contribution of genes to drug efficacy. However, it would be extremely inefficient to test all the 10 million common SNPs for an association study. Here we review haplotype analysis and pattern-recognition techniques to systematically select candidate SNPs for candidate-gene association studies in pharmacogenomics. First, we survey linkage disequilibrium methods to identify tag SNPs and explore the use of haplotypes as genetic markers that are correlated and associated with drug efficacy. Secondly, we investigate pattern-recognition algorithms and statistical analyses to assess drug efficacy based on SNPs and other factors. Finally, we study pattern-recognition approaches to evaluate the epistasis among genes and SNPs. These techniques may provide tools for clinical association studies and help find genes/SNPs involved in responses to therapeutic drugs or adverse drug reactions.


Erythema multiforme following vaccination in an infant.
Erythema multiforme is a cutaneous reaction pattern precipitated by varied agents, notably herpes simplex and drugs. It predominantly occurs in adolescents and young adults but may be seen at other ages also. While vaccination is rarely a precipitating factor for erythema multiforme, it may occasionally be seen in infants and children. We report here a case of a two month-old infant with lesions of erythema multiforme minor appearing after two weeks following vaccination for DPT, Hepatitis B and influenza.


Salivary Gland Cancers: Biology and Systemic Therapy.
Salivary gland tumors are a relatively rare and heterogeneous group of tumors with variable pathologic and phenotypic characteristics. The lack of clinical outcomes data and randomized controlled trials pertaining to them makes it difficult to formulate definitive treatment protocols that could help with making decisions regarding choice of therapy. Most studies involving systemic chemotherapy have not shown promising patient outcome results. With recent advances in molecular technology, however, it is now possible to identify specific genetic alterations and biomarkers as possible targets for therapeutic purposes. For example, in mucoepidermoid carcinomas, one of the most common types of malignant salivary gland tumors, a commonly seen genetic translocation [t(11;19)(q21;p13), which involves the CRTC1 and MAML2 genes] has been found to be associated with improved survival, making it a possible prognostic marker. Also, this translocation gives rise to a fusion protein that appears to render tumors highly sensitive to epidermal growth factor receptor (EGFR) inhibition. However, the results of phase II trials of EGFR inhibitors-as well as other targeted agents--in salivary gland tumors have been disappointing: there has been some disease stabilization but no objective responses. There remains a need for well-designed prospective clinical studies to improve management of these tumors.