Evolutionary history of the retinoblastoma gene from archaea to eukarya.
The retinoblastoma gene product (Rb protein) has a role in progression through the cell cycle, regulating the activities of several transcription factors such as E2F. Since its functional loss results in impaired differentiation in the nervous, hematopoietic, and muscular systems, the Rb protein is very important for cell regulation in multicellular eukaryotes. To gain an insight into the evolutionary history of the Rb gene, I have compared the amino acid sequences of Rb proteins in multicellular eukaryotes and unicellular organisms including yeast, archaeotes, and viruses. Two short amino acid sequences, in the N-terminal and pocket A regions of human Rb protein, found to be well conserved, also in a single protein of Saccharomyces cerevisiae. These sequences were also found in proteins of two archaeotes, Archaeoglobus fulgidus and Methanococcus jannaschii. Further, the most conserved sequence in the pocket B region among multicellular eukaryotic Rb proteins was also conserved in several poxviruses. From these data, I conclude that the pocket A and B regions, backbones of the Rb protein, are derived from different organisms, respectively, the ancestors of archaeote and poxvirus, and that the ancestral pocket B region has been lost during evolutionary history of unicellular eukaryotes.


Experimental conditions can obscure the second high-affinity site in LeuT.
Neurotransmitter:Na(+) symporters (NSSs), the targets of antidepressants and psychostimulants, recapture neurotransmitters from the synapse in a Na(+)-dependent symport mechanism. The crystal structure of the NSS homolog LeuT from Aquifex aeolicus revealed one leucine substrate in an occluded, centrally located (S1) binding site next to two Na(+) ions. Computational studies combined with binding and flux experiments identified a second substrate (S2) site and a molecular mechanism of Na(+)-substrate symport that depends upon the allosteric interaction of substrate molecules in the two high-affinity sites. Here we show that the S2 site, which has not yet been identified by crystallographic approaches, can be blocked during preparation of detergent-solubilized LeuT, thereby obscuring its crucial role in Na(+)-coupled symport. This finding points to the need for caution in selecting experimental environments in which the properties and mechanistic features of membrane proteins can be delineated.


An experimental search strategy retrieves more precise results than PubMed and Google for questions about medical interventions.
Objective. We compared the precision of a search strategy designed specifically to retrieve randomized controlled trials (RCTs) and systematic reviews of RCTs with search strategies designed for broader purposes. Methods. We designed an experimental search strategy that automatically revised searches up to five times by using increasingly restrictive queries as long at least 50 citations were retrieved. We compared the ability of the experimental and alternative strategies to retrieve studies relevant to 312 test questions. The primary outcome, search precision, was defined for each strategy as the proportion of relevant, high quality citations among the first 50 citations retrieved. Results. The experimental strategy had the highest median precision (5.5%; interquartile range [IQR]: 0%-12%) followed by the narrow strategy of the PubMed Clinical Queries (4.0%; IQR: 0%-10%). The experimental strategy found the most high quality citations (median 2; IQR: 0-6) and was the strategy most likely to find at least one high quality citation (73% of searches; 95% confidence interval 68%-78%). All comparisons were statistically significant. Conclusions. The experimental strategy performed the best in all outcomes although all strategies had low precision.


Affordable oral proinsulin bioencapsulated in plant cells regulates blood sugar levels similar to natural insulin.
Diabetes Mellitus is a silent epidemic affecting >500 million, which claimed 6.7 million lives in 2021, a projected increase of >670% in <20 years old in the next two decades but insulin is unaffordable for the large majority of the globe. Therefore, we engineered proinsulin in plant cells to facilitate oral delivery. Stability of the proinsulin gene and expression in subsequent generations, after removal of the antibiotic-resistance gene, was confirmed using PCR, Southern and western blots. Proinsulin expression was high (up to 12 mg/g DW or 47.5% of total leaf protein), stable up to one year after storage of freeze-dried plant cells at ambient temperature and met FDA regulatory requirements of uniformity, moisture content and bioburden. GM1 receptor binding, required for uptake via gut epithelial cells was confirmed by pentameric assembly of CTB-Proinsulin. IP insulin injections (without C peptide) in STZ mice rapidly decreased blood glucose level leading to transient hypoglycemia, followed by hepatic glucose compensation. On the other hand, other than the 15-min lag period of oral proinsulin (transit time required to reach the gut), the kinetics of blood sugar regulation of oral CTB-Proinsulin in STZ mice was very similar to naturally secreted insulin in healthy mice (both contain C-peptide), without rapid decrease or hypoglycemia. Elimination of expensive fermentation, purification and cold storage/transportation should reduce cost and increase other health benefits of plant fibers. The recent approval of plant cell delivery of therapeutic proteins by FDA and approval of CTB-ACE2 for phase I/II human clinical studies augur well for advancing oral proinsulin to the clinic.


Ethylene production by ascocarps of Elaphomyces species.
Ascocarps of the hypogaean fungus Elaphomyces spp. from some Swedish forest stands were examined for production of ethylene. Significant amounts were produced by mature ascocarps of E. asperulus and E. granulatus. E. muricatus, which was found only in juvenile or immature stages, did not produce ethylene. None of the ascocarps studied were infected by Cordyceps. The ecological role of the ethylene production by the ascocarps is shortly discussed.


Breast size, bra fit and thoracic pain in young women: a correlational study.
A single sample study was undertaken to determine the strength and direction of correlations between: a) breast size and thoracic spine or posterior chest wall pain; b) bra fit and thoracic spine or posterior chest wall pain and; c) breast size and bra fit, in thirty nulliparous women (18-26 years), with thoracic spine or posterior chest wall pain, who wore bras during daytime. Pain (Short Form McGill Pain Questionnaire), bra size (Triumph International), bra fit (Triumph International). Most (80%) women wore incorrectly sized bras: 70% wore bras that were too small, 10% wore bras that were too large. Breast size was negatively correlated with both bra size (r = -0.78) and bra fit (r = -0.50). These results together indicate that large breasted women were particularly likely to be wearing incorrectly sized and fitted bras. Negligible relationships were found between pain and bra fit, and breast size and pain. Menstrual cycle stage was moderately positively correlated with bra fit (r = 0.32). In young, nulliparous women, thoracic pain appears unrelated to breast size. Bra fit is moderately related to stage of menstrual cycle suggesting that this research may be somewhat confounded by hormonal changes or reproductive stage. Further research is needed to clarify whether there is a relationship between breast size or bra fit and thoracic pain in women during times of hormonal change.


MARCKS is a downstream effector in platelet-derived growth factor-induced cell motility in activated human hepatic stellate cells.
Myristoylated alanine-rich protein kinase c substrate (MARCKS) has been suggested to be implicated in cell adhesion, secretion, motility and mitogenesis through regulation of the actin cytoskeletal structure. In the present study, a possible link between MARCKS and the platelet-derived growth factor (PDGF) signaling pathway was investigated in activated human hepatic stellate cells (hHSC), critical regulators of hepatic fibrogenesis. PDGF-BB stimulation resulted in a bi-directional movement of MARCKS that coincided with the phosphorylation of MARCKS and the activation of both PKCepsilon and PKCalpha. Biochemical inhibition of PKC kinase activity and small interfering RNA (siRNA) against PKCepsilon demonstrated that PKCepsilon is indispensable for PDGF-BB-induced MARCKS phosphorylation and cell migration. Immunoprecipitation studies revealed an association between MARCKS and the PDGFbeta-receptor, while the PDGFbeta-receptor and PKCalpha associated with focal adhesion kinase (FAK). Transient transfection with MARCKS DNA plasmid remarkably reduced PDGF-BB stimulated cell motility. In contrast, siRNA against MARCKS increased cell migration in RNAi treated cells in comparison to the scrambled control cells. In conclusion, the present study indicates that MARCKS play a major key role in PDGF-BB-induced chemotaxis in activated hHSC.


Drug reaction with eosinophilia and systemic symptoms (DRESS): clinicopathological study of 45 cases.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and severe adverse drug reaction. Large detailed studies of histopathological features of DRESS are sparse and suggest an association between keratinocyte damage and the severity of visceral involvement. To describe the dermatopathological features in a large series of DRESS and their possible association with clinical features and the severity of the disease. A retrospective analysis of the clinicobiological and dermatopathological features in a monocentric cohort of patients with DRESS. From January 2005 to January 2013, 45 patients were validated as probable or definite cases of DRESS. The median age was 64 years (range 3-87). The most frequent clinical and biological features included: fever ≥38.5°C (95%), facial oedema (72%), enlarged lymph nodes (51%), visceral involvement (75%), blood eosinophilia (97%) and atypical lymphocytes (82%). Severe DRESS occurred in 24% and a fatal outcome in 6% of patients. Histopathological analysis showed that no specific histopathological pattern was characteristic for DRESS. However, several changes in different cutaneous compartments were observed in 2 of 3 of cases. Spongiosis (55%) and keratinocyte damage (53%) were the most common epidermal changes. Spongiosis was associated with non-severe DRESS (P = 0.041) whereas confluent keratinocyte necrosis correlated with severe DRESS (P = 0.011). Vascular changes were frequent (88%). A moderate dermal perivascular lymphocytic infiltrate was invariably present, containing eosinophils, neutrophils and/or atypical lymphocytes in 57% of cases. Epidermal changes are indicative for the severity of DRESS.


Pharmacologic inhibition of experimentally induced SLE-like deposition of immunoglobulins in skin nuclei.
Binding of autologous immunoglobulins to epidermal nuclei can be induced in mice sensitized to ultraviolet-irradiated DNA following total body uv irradiation. The lesions, which resemble those observed in human systemic lupus erythematosus (SLE), are characterized histologically by the accumulation of polymorphonuclear (PMN) cells at different skin sites. In the present investigation this experimental model has been employed to study whether currently used anti-inflammatory (chloroquine, hydrocortisone, indomethacin) and polyvalent antiprotease (trasylol) drugs can either abolish or reduce the development of this murine pathology. The results of this study demonstrate that while trasylol, chloroquine, and indomethacin are able to inhibit, with variable effectiveness, the experimental skin lesions, hydrocortisone does not manifest any therapeutic activity.


Nanoengineered disposable sensor fabricated with lanthanum stannate nanocrystallite for detecting animal feed additive: Ractopamine.
Ractopamine (RA) has been at the forefront of feed additives as a nutrient repartitioning mediator that recuperates the growth rate, decreases animal fat, and guarantees food safety. However, inappropriate and abusive usage of RA to enhance economic efficiency can negatively impact the environment-animal-human interactions. Therefore, the call for monitoring and quantifying RA is highly desired. In this work, the potentiality of La2Sn2O7 as an electrode modifier on the surface of the portable screen-printed carbon electrode (SPCE) was examined for its precision, disposability, and ability to detect RA. The superior electrocatalytic activity of the fabricated La2Sn2O7/SPCE fortifies its standpoints by displaying a wide linear working range of 0.01-501.2 µM, an enhanced sensitivity, a better stability, a lower LOD of 0.86 nM, and an increased selectivity toward the detection of RA. Furthermore, the investigation of the constructed electrochemical sensor with real-time food samples underpins its practicality and feasibility.


The characterization of dynamic susceptibility effects.
Understanding and quantifying dynamic susceptibility contrast, which arises from compartmentalized magnetic field perturbers (e.g., deoxyhemoglobin, contrast agents) that affect the water around them, formed the basis of a significant part of the author's fMRI-related research in the early 90's. This short note describes how the scientific work used to help understand and quantify dynamic injections of contrast agents, primarily designed for clinical MRI, was adapted to help quantify and explain BOLD imaging.


Microvessel density for melanoma prognosis.
Two-hundred and four accessible cases of malignant melanoma from the Grampian region of Scotland, collected over a period of 4 years, were studied for standard prognostic indicators for comparison with microvessel density. The range of tumour thickness varied from in-situ melanoma to 14.8 mm. Microvessel density was assessed using the Chalkley technique on sections immunostained with CD31 antibody to identify endothelium. Vessel counts were performed in the peritumoral host tissue of all specimens. Strong correlation was observed between microvessel density at the tumour edge and tumour thickness (P < 0.001). Multifactorial regression analysis confirms Chalkley estimation as a reliable predictor of the risk of recurrence of melanoma (P < 0.005). The predictive value was found to be superior to the Breslow score, for tumours more than 2 mm thick. Microvessel assessment of primary melanoma using the Chalkley score technique provides reliable prognostic information on the risk of recurrence of the tumour, particularly for melanomas deeper than 2 mm. It remains to be seen whether this methodology can predict response to novel anti-angiogenic therapies currently entering trials.


Treatment-induced lesions in newly diagnosed glioblastoma patients undergoing chemoradiotherapy and heat-shock protein vaccine therapy.
Treatment-induced lesions represent a great challenge in neuro-oncology. The aims of this study were (i) to characterize treatment induced lesions in glioblastoma patients treated with chemoradiotherapy and heat-shock protein (HSP) vaccine and (ii) to evaluate the diagnostic accuracy of diffusion weighted imaging for differentiation between treatment-induced lesions and tumor progression. Twenty-seven patients with newly diagnosed glioblastoma treated with HSP vaccine and chemoradiotherapy were included. Serial magnetic resonance imaging evaluation was performed to detect treatment-induced lesions and assess their growth. Quantitative analysis of the apparent diffusion coefficient (ADC) was performed to discriminate treatment-induced lesions from tumor progression. Mann-Whitney U-test and receiver operating characteristic (ROC) curves were used for analysis. Thirty-three percent of patients developed treatment-induced lesions. Five treatment-related lesions appeared between end of radiotherapy and the first vaccine administration; 4 lesions within the first 4 months from vaccine initiation and 1 at 3.5 years. Three patients with pathology proven treatment-induced lesions showed a biphasic growth pattern progressed shortly after. ADC ratio between the peripheral enhancing rim and central necrosis showed an accuracy of 0.84 (95% CI 0.63-1) for differentiation between progression and treatment-induced lesions. Our findings do not support the iRANO recommendation of a 6-month time window in which progressive disease should not be declared after immunotherapy initiation. A biphasic growth pattern of pathologically proven treatment-induced lesions was associated with a dismal prognosis. The presence of lower ADC values in the central necrotic portion of the lesions compared to the enhancing rim shows high specificity for detection of treatment-induced lesions.


Two novel anticancer compounds with minimum cardiotoxic property.
Although two novel synthesized compounds with tri-aryl structures; 3-(4-chlorophenyl)-5-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1,2,4-oxadiazole (A) and 3,5-bis-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1,2,4-oxadiazole (B) have been previously demonstrated to possess remarkable anti-breast cancer activity, their cardiotoxicity remains a major concern due to their mechanism of action. To address this concern, we assessed the ability of these compounds to cause toxicity towards H9c2 cardiomyocytes as an in vitro model of cardiotoxicity. Cytotoxic activity of both compounds was explored in vitro on H9c2 cells using MTT assay. Annexin V/PI method, intracellular ROS determination and mitochondrial membrane potential assay were applied to elucidate the mechanism of action of the cell death. MTT assay revealed a concentration- and time-dependent cardiotoxicity. Findings of apoptosis by double staining with annexin V and propidium iodide divulged no cell death including apoptosis and necrosis at the concentration that were effective to inhibit cancer cells proliferation (10 μM) at 24 and 48 h. Furthermore, flow cytometric measurement of membrane potential and ROS determination using DCFH-DA verified the safe concentration of the compounds against H9c2 cells with no cardiotoxic effect. However, the higher concentration of the compounds could induce cell death through ROS-mediated mitochondrial dysfunction. Altogether, the results represented two novel chemical molecules possessing anti-breast cancer activity with minimum cardiac side effect.


Dialogue between centrosomal entrance and exit scaffold pathways regulates mitotic commitment.
The fission yeast scaffold molecule Sid4 anchors the septum initiation network to the spindle pole body (SPB, centrosome equivalent) to control mitotic exit events. A second SPB-associated scaffold, Cut12, promotes SPB-associated Cdk1-cyclin B to drive mitotic commitment. Signals emanating from each scaffold have been assumed to operate independently to promote two distinct outcomes. We now find that signals from Sid4 contribute to the Cut12 mitotic commitment switch. Specifically, phosphorylation of Sid4 by NIMAFin1 reduces Sid4 affinity for its SPB anchor, Ppc89, while also enhancing Sid4's affinity for casein kinase 1δ (CK1δ). The resulting phosphorylation of Sid4 by the newly docked CK1δ recruits Chk2Cds1 to Sid4. Chk2Cds1 then expels the Cdk1-cyclin B antagonistic phosphatase Flp1/Clp1 from the SPB. Flp1/Clp1 departure can then support mitotic commitment when Cdk1-cyclin B activation at the SPB is compromised by reduction of Cut12 function. Such integration of signals emanating from neighboring scaffolds shows how centrosomes/SPBs can integrate inputs from multiple pathways to control cell fate.


Robustness of five different visual assessment methods for the evaluation of hindlimb lameness based on tubera coxarum movement in horses at the trot on a straight line.
The evaluation of hindlimb lameness remains a major challenge in everyday clinical practice. In the absence of clear guidelines, veterinarians use different visual assessment methods for this task whose robustness is unknown. Determination of the robustness of five visual hindlimb lameness assessment methods based on the comparison of left and right tuber coxae movement. Validated mathematical hindlimb lameness model based on experimental data from the literature. Vertical movement of left (LTC) and right (RTC) tuber coxae was simulated for the range of common hindlimb lameness movement patterns that horses present within practice. Lameness severity ranged from sound to moderately lame (0% to 60% motion asymmetry). The scenarios of a pelvis held tilted and asymmetrical pelvic roll were included to reflect possible adaptations in pelvic rotation. Across all conditions, the outcomes for five different visual assessment methods based on comparative tubera coxarum movement were quantified, including hip hike, -drop and range of motion. The robustness of each assessment method was established through comparison to sacrum-based overall motion asymmetry as the ground truth. Tubera coxarum-based lameness assessment was highly sensitive to all the unique lameness patterns and changes in pelvic rotation which a lame horse may adopt. None of the five visual lameness assessment methods was 100% robust across all conditions tested. For everyday clinical practice, comparing the upward movement amplitude of the RTC before right hind foot contact and of the LTC before left hind foot contact (Hip_hike_diff) would be the most robust single tubera coxarum-based visual assessment method. In the absence of published data regarding the frequency of different movement patterns and hip rotation adaptations in clinical practice, this study cannot indicate the proportion of assessments that would be incorrect for a given visual assessment method. Using a single tubera coxarum-based visual hindlimb lameness assessment method may lead to incorrect clinical judgement. Therefore, using multiple assessment methods would be beneficial to substantiate impressions.


Inhibition of cuneate neurones: its afferent source and influence on dynamically sensitive "tactile" neurones.
1. Responses were recorded in decereberate, unanaesthetized cats from individual cuneate neurones in order to determine firstly, the afferent sources of inhibition on cuneate neurones and secondly, the influence of afferent-induced inhibition on those response features of dynamically sensitive tactile neurones which determine their capacity to code information about parameters of tactile stimuli.2. For all cuneate neurones which displayed afferent-induced inhibition from areas surrounding or within their excitatory receptive field (71% of the sample) it was consistently found that 300 Hz vibration at low amplitudes (< 25-50 mum) which selectively engages Pacinian corpuscles was an effective source of inhibition. In contrast, steady indentation which activates slowly adapting tactile afferents was quite ineffective, as was low frequency vibration (30 Hz) at amplitudes of < 50-100 mum. The latter stimulus can be used to engage rapidly adapting receptors either within glabrous skin (presumed to be Meissners corpuscles) or in association with hair follicles. It is concluded that afferents from Pacinian corpuscles are the dominant or exclusive source of afferent-induced inhibition of cuneate neurones.3. For dynamically sensitive neurones responsive to low frequency cutaneous vibration (30 Hz) there was a reduction in the slope of stimulus-response relations with afferent-induced inhibition, but no expansion of the range of stimulus amplitudes over which the neurone responded.4. The influence of afferent-induced inhibition on the phase-locking of impulse activity to a cutaneous vibratory wave form was examined by constructing post-stimulus time histograms and cycle histograms. Measures of dispersion of impulse activity around the preferred point of firing in the vibratory waveform indicated that the capacity of individual cuneate neurones to code information about the frequency of the cutaneous vibration was not systematically changed in the presence of afferent-induced inhibition.


A Simple and Efficient Approach for the Synthesis of 2-Aminated Quinazoline Derivatives via Metal Free Oxidative Annulation.
A simple and efficient approach for the synthesis of 2-aminoquinazoline derivatives in moderate to good yields. This reaction employs mild reaction conditions, is metal-free and utilizes readily available starting materials making it a more viable reaction for the scale up synthesis and ligand diversity. Notably, this methodology allows the synthesis of 2-aminoquinazolines using a free amine or cyclic amine enabling structural diversity and good atom economy.


Behavioural genetics of childhood disorders.
After a general introduction into genetic risk factors for child psychiatric disorders, four specific child psychiatric disorders with a strong genetic component, namely, Autism Spectrum Disorders, Attention Deficit / Hyperactivity Disorder, Nocturnal Enuresis, and obesity, are discussed in detail. Recent evidence of linkage, candidate gene, and genome-wide association studies are presented. This chapter ends with a prospectus on further research needs.


The use of end-quintile comparisons to identify under-servicing of the poor and over-servicing of the rich: a longitudinal study describing the effect of socioeconomic status on healthcare.
To demonstrate the use of end-quintile comparisons in assessing the effect of socio-economic status on hospital utilisation and outcomes in Western Australia. Hospital morbidity records were extracted from the WA Data Linkage System for the period 1994-99, with follow-up to the end of 2000. Multivariate modelling was used to estimate the effect of socio-economic status on hospital admission rates, average and total length of stay (LOS), cumulative incidence of readmission at 30 days and one year, and case fatality at one year. The study demonstrated higher rate ratios of hospital admission in the more disadvantaged quintiles: rate ratios were 1.31 (95% CI 1.25-1.37) and 1.32 (1.26-1.38) in the first quintile (most disadvantaged) and the second quintile respectively, compared with the fifth quintile (most advantaged). There was a longer total LOS in the most disadvantaged quintile compared with quintile 5 (LOS ratio 1.24; 1.23-1.26). The risk of readmission at 30 days and one year and the risk of death at one year were also greater in those with greater disadvantage: the hazard ratios for quintiles 1:quintile 5 were 1.07 (1.05-1.09), 1.17 (1.16-1.18) and 1.10 (1.07-1.13) respectively. In contradiction to the trends towards higher hospital utilisation and poorer outcomes with increasing social disadvantage, in some MDC's the rate ratio of quintile 1:quintile 2 was less than 1, and quintile 4:quintile 5 was greater than 1. For all surgical admissions the most disadvantaged had a significantly lower admission rate than the second quintile. This study has shown that the disadvantaged within Western Australia are more intensive users of hospital services but their outcomes following hospitalisation are worse, consistent with their health status. Instances of overuse in the least disadvantaged and under use in the most disadvantaged have also been identified.


Effect of Transcatheter Arterial Chemoembolization Combined with Argon-Helium Cryosurgery System on the Changes of NK Cells and T Cell Subsets in Peripheral Blood of Hepatocellular Carcinoma Patients.
Hepatocellular carcinoma (HCC) is one of the most aggressive tumors in humans. T lymphocytes and natural killer (NK) cells are the body's first line of defense to prevent tumor cell growth. Previous studies have demonstrated that transcatheter arterial chemoembolization (TACE) combined with argon-helium cryosurgery system (AHCS) can effectively treat liver cancer. However, the mechanism of the treatment is unclear yet. In the current study, we investigated the effects of TACE combined with AHCS on the changes of T cell subsets and NK cells in peripheral blood of HCC. Our data show that alpha-fetoprotein (AFP) levels in peripheral blood were significantly up-regulated in HCC patients before treatment when compared with healthy people and reduced after TACE combined with AHCS treatment (P < 0.01). In addition, we found that CD4+ cells and NK cells decreased (P < 0.05) and CD8+ cells increased (P < 0.05) in HCC patients when compared with healthy people. After treatment, the CD4+ cells, CD4+/CD8+ ratio, and NK cells were dramatically increased in HCC patients (P < 0.05). In contrast, CD8+ cells were significantly decreased (P < 0.05). TACE combined with AHCS treatment significantly prolonged 1-year survival rate of HCC patients and did not show significant side effects. Taken together, our data indicate that TACE combined with AHCS treatment improves patients' immune system. It is a feasible and effective therapeutic method for HCC patients.


Cost comparison of nephron-sparing treatments for cT1a renal masses.
Treatment options for small renal tumors have evolved from radical nephrectomy (RN) to partial nephrectomy (PN), thermal ablation, or active surveillance. With the advancement of techniques, costs differences are unclear. The objective of this study is to compare the 6-month costs associated with nephron-sparing procedures for cT1a renal tumors. We performed a review of patients diagnosed with a solitary cT1a renal mass who underwent surgical treatment from June 2008 to May 2011. Open partial nephrectomy (OPN), robot-assisted partial nephrectomy (RLPN), laparoscopic radio-frequency ablation (LRFA), or computed tomography guided radio frequency ablation (CTRFA) was performed on 173 patients. Cost data were collected for surgical costs, associated hospital stay, and the 6-month postoperative period. Patients underwent surgery, including 52 OPN, 48 RLPN, 44 LRFA, and 29 CTRFA. Median total costs associated were $17,018, $20,314, $13,965, and $6,475, for OPN, RLPN, LRFA, and CTRFA, respectively. When stratified by approach differences were noted for total cost (P < 0.001), operating room (OR) time (P < 0.001), surgical supply (P < 0.001), and room and board (P < 0.001) in univariable analysis. Multivariable linear regression (R(2) = 0.966) showed surgical approach (P = 0.007), length of stay (P < 0.001), and OR time (P < 0.001) to be significant predictors of total cost. However, tumor size (P = 0.175), and Charlson comorbidity index (P = 0.078) were not statistically significant. Six-month cost of nephron-sparing surgery is lowest with radio frequency ablation (RFA) by either laparoscopic or computed tomography (CT)-guided approach compared to RLPN and OPN. As oncologic and safety outcomes improve and become comparable in all nephron-sparing surgery (NSS) approaches, cost of each procedure will start to play a stronger role in the clinical and healthcare policy setting.


Accuracy of the Hospital Anxiety and Depression Scale as a screening tool in cancer patients: a systematic review and meta-analysis.
The Hospital Anxiety and Depression Scale (HADS) is the most extensively validated scale for screening emotional distress in cancer patients. However, thresholds for clinical decision making vary widely across studies. A meta-analysis was conducted with the aim of identifying optimal, empirically derived cut-offs. PubMed, Embase, and PsycINFO databases were searched for studies that compared the HADS total and its subscale scores against a semi-structured or structured clinical interview as a reference standard with regard to its screening efficacy for any mental disorders and depressive disorders alone. Separate pooled analyses were conducted for single or two adjacent thresholds. A total of 28 studies (inter-rater agreement, κ = 0.86) were included. The best thresholds for screening for mental disorders were 10 or 11 on the HADS total (sensitivity 0.80; specificity 0.74), 5 on the HADS depression subscale (sensitivity 0.84; specificity 0.50), and 7 or 8 on the HADS anxiety subscale (sensitivity 0.73; specificity 0.65). Respective thresholds for depression screening were 15 for the HADS total (sensitivity 0.87; specificity 0.88), 7 for the HADS depression subscale (sensitivity 0.86; specificity 0.81), and 10 or 11 for the HADS anxiety subscale (sensitivity 0.63; specificity 0.83). The HADS anxiety subscale performed worse than the total and the depression subscales for both indicators. Diagnostic accuracy varied widely by threshold but was consistently superior for depression screening than for screening of any mental disorder.


Production of porcine interleukin-2 and its biological and antigenic relationships with human interleukin-2.
A lymphokine obtained from PHA-stimulated porcine blood leukocytes was found to induce the growth of IL2-dependent murine cells: this factor was therefore considered as the porcine lymphokine analogous to IL2. PHA was found to induce higher amounts of IL2 than Con A. Preculture of porcine PBL or addition of indomethacin enhanced IL2 production, suggesting the existence of a prostaglandin-mediated inhibition of IL2 production in fresh PBL cultures. Porcine IL2 could also promote the growth of activated porcine cells whereas it was inactive on human lymphoblastoid cells. A neutralizing polyclonal anti-human IL2 antiserum was also unable to neutralize porcine IL2. These results indicate therefore, that no biological and antigenic cross-reactivities are demonstrable between human and porcine IL2.


Effects of breed and wintering diet on growth, puberty and plasma concentrations of growth hormone and insulin-like growth factor 1 in heifers.
Twenty-five Brangus (BR) and 15 Angus (AN) heifers were used to study the effects of breed and wintering diet on average daily gain (ADG), onset of puberty and plasma concentrations of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Wintering diets (fed for 107 days beginning November 15) consisted of the following: 1) native grass hay (NGH), 2) ammoniated NGH, 3) NGH plus cottonseed meal, 4) Diet 3 plus corn and 5) Diet 4 plus monensin. After wintering, heifers were transferred to ryegrass pasture for 70 days. Mean ADG during the wintering phase were -.20, -.10, .17, .29 and .39 kg for heifers fed Diets 1 through 5, respectively (P less than .01). ADG was greater (P less than .05) for BR than for AN heifers. Plasma concentrations of GH were higher (P less than .05) in heifers fed Diets 1 and 2 than in heifers fed Diets 3, 4 or 5. Plasma concentrations of IGF-1 were lowest in heifers fed Diet 1 and highest in heifers fed Diets 4 and 5. During ryegrass grazing, GH concentrations were similar for all groups. However, concentrations of IGF-1 were higher (P less than .05) in heifers fed Diets 3, 4 and 5 than in heifers fed Diets 1 and 2. Age at puberty (onset of cyclic progesterone concentrations) was greatest in heifers fed Diet 1 and lowest in heifers fed Diet 5. Weight at puberty was not affected (P greater than .10) by wintering diet but was greater (P less than .01) in BR than in AN heifers. Therefore, negative ADG appears to be associated with elevated plasma GH concentrations in heifers, and plasma IGF-1 concentration appears to be a more accurate indication of nutritional status than plasma concentrations of GH.


Distribution of degeneration of cholinergic neurons in the septum following axotomy in different portions of the fimbria-fornix: a correlation between degree of cell loss and proximity of neuronal somata to the lesion.
The degree of cell loss of immunohistochemically stained cholinergic neurons was quantitatively compared in equivalent regions of the septum in three groups of animals with lesions transecting their axons at different levels in the fimbria-fornix (FF). Locations of different septal regions and of FF lesions were defined according to their distances from fixed anatomical reference points. Individual animals all exhibited a gradient of cholinergic cell loss, such that the severity of cell loss diminished progressively in the rostral and ventral directions as the distance from the lesion increased beyond a certain point. Comparison of animals with FF lesions in different locations showed that this gradient of cell loss shifts in the caudo-rostral and dorso-ventral directions within the septal complex in direct relation to the proximity of the axotomizing FF lesion. These findings suggest that among septal cholinergic neurons there is a fixed spatial relationship between the distance of neuronal somata from an axotomizing FF lesion and the likelihood of neuronal loss in response to axotomy. This relationship could not be defined precisely using the material studied, but simple geometrical calculations showed that within 2500 microns of the lesion cell loss is always pronounced (less than 30 per cent detectable cells vs controls) and beyond 4000 microns cell loss is generally not severe (greater than 80 per cent detectable cells). Between these two distances cell loss diminishes in a gradiated manner. Thus, relatively small differences (1 mm) in the location of FF lesions can lead to marked differences in the severity of degeneration observed in certain equivalent regions of the septum. The findings have implications both for attempts to understand the causes underlying retrograde neuronal degeneration and for studies investigating means of preventing retrograde degeneration of cholinergic septal neurons.


The Influence of Fat Grafting on Breast Imaging after Postmastectomy Reconstruction: A Matched Cohort Analysis.
Fat grafting to the reconstructed breast may result in the development of benign lesions on physical examination, prompting further investigation with imaging and biopsy. The aim of this study was to assess the influence of fat grafting on the incidence of imaging and biopsies after postmastectomy reconstruction. Patients who underwent autologous or implant-based reconstruction following mastectomy from 2010 to 2018 were identified. Those receiving fat grafting as part of their reconstructive course were propensity matched 1:1 to those that did not with body mass index, reconstruction timing, and reconstruction type as covariates in a multivariable logistic regression model. A total of 186 patients were identified, yielding 93 propensity-matched pairs. Fat-grafted patients had higher incidences of palpable masses (38.0 percent versus 18.3 percent; p = 0.003) and postreconstruction imaging (47.3 percent versus 29.0 percent; p = 0.01), but no significant difference in the number of biopsies performed (11.8 percent versus 7.5 percent; p = 0.32). Imaging was predominately interpreted as normal (Breast Imaging-Reporting and Data System 1, 27.9 percent) or benign (Breast Imaging-Reporting and Data System 2, 48.8 percent), with fat necrosis being the most common finding [n = 20 (45.5 percent)]. No demographic, oncologic, reconstructive, or fat grafting-specific variables were predictive of receiving postreconstruction imaging on multivariate analysis. Fat grafting was not associated with decreased 5-year overall survival or locoregional recurrence-free survival. Fat grafting to the reconstructed breast is associated with increased incidences of palpable masses and subsequent postreconstruction imaging with benign radiographic findings. Although the procedure is oncologically safe, both patients and providers should be aware that concerning physical examination findings can be benign sequelae of fat grafting and may lead to increased imaging after breast reconstruction. Therapeutic, III.


Near-Infrared Self-Assembled Hydroxyl Radical Generator Based on Photoinduced Cascade Electron Transfer for Hypoxic Tumor Phototherapy.
The hydroxyl radical (•OH) is an extremely potent reactive oxygen species that plays a crucial role in photooxidations within the realm of hypoxic tumor therapy. However, the current methods for •OH photogeneration typically rely on inorganic materials that require UV/vis light excitation. Consequently, photogenerators based on organic molecules, especially those utilizing near-infrared (NIR) light excitation, are rare. In this study, the concept of photoinduced cascade charge transfer (PICET), which utilizes NIR heavy-atom-free photosensitizers (ANOR-Cy5) to generate •OH is introduced. The ANOR-Cy5 photosensitizer, with its flexible hydrophobic structure, enables the formation of nanoparticles in aqueous solutions through molecular assembly. PICET involves a symmetry-breaking charge separation-induced localized charge-separated state, transitioning to a delocalized charge-separated state, which governs the efficiency of •OH generation. Thanks to the oxygen-independent nature of •OH generation and its robust oxidative properties, the ANOR-Cy5-based photosensitizer demonstrates highly effective photoinduced anti-cancer effects, even under severely hypoxic conditions. This discovery emphasizes the potential for achieving •OH photogeneration using a single organic molecule through the engineering of molecular self-assembly, thereby opening up new possibilities for phototherapy and beyond.


Development of a Modified-Release Formulation of Lovastatin Targeted to Intestinal Methanogens Implicated in Irritable Bowel Syndrome With Constipation.
There is growing evidence that methane production, predominantly by Methanobrevibacter smithii, in the intestines is a cause of constipation, pain, and bloating in irritable bowel syndrome with constipation (IBS-C). M smithii resides primarily in the large intestine but can also colonize the small intestine. In vitro studies found that the prodrug lactone form of lovastatin, found in cholesterol-lowering drugs, inhibited methane production in stool samples from patients with IBS-C. However, the cholesterol-lowering lovastatin β-hydroxyacid was ineffective at inhibiting methane production in this system. A considerable amount of lovastatin is converted to hydroxyacid in the stomach and is absorbed. It was hypothesized that galenic innovations could protect lovastatin from the stomach and allow release in 2 strategic locations, the duodenum and the ileocecal region, to reach M smithii. The desired release profile was achieved by developing an oral dosage form containing lovastatin and coated with 2 different enteric polymers that enabled a pH-dependent "dual pulse" drug release. Combinations of the 2 coated tablets were encapsulated together to deliver the desired amount of lovastatin to the targeted intestinal locations. The capsules have been tested in vitro and in vivo and show promise in treating IBS-C.


Rapid Utilization of Telehealth in a Comprehensive Cancer Center as a Response to COVID-19: Cross-Sectional Analysis.
The emergence of the coronavirus disease (COVID-19) pandemic in March 2020 created unprecedented challenges in the provision of scheduled ambulatory cancer care. As a result, there has been a renewed focus on video-based telehealth consultations as a means to continue ambulatory care. The aim of this study is to analyze the change in video visit volume at the University of California, San Francisco (UCSF) Comprehensive Cancer Center in response to COVID-19 and compare patient demographics and appointment data from January 1, 2020, and in the 11 weeks after the transition to video visits. Patient demographics and appointment data (dates, visit types, and departments) were extracted from the electronic health record reporting database. Video visits were performed using a HIPAA (Health Insurance Portability and Accountability Act)-compliant video conferencing platform with a pre-existing workflow. In 17 departments and divisions at the UCSF Cancer Center, 2284 video visits were performed in the 11 weeks before COVID-19 changes were implemented (mean 208, SD 75 per week) and 12,946 video visits were performed in the 11-week post-COVID-19 period (mean 1177, SD 120 per week). The proportion of video visits increased from 7%-18% to 54%-72%, between the pre- and post-COVID-19 periods without any disparity based on race/ethnicity, primary language, or payor. In a remarkably brief period of time, we rapidly scaled the utilization of telehealth in response to COVID-19 and maintained access to complex oncologic care at a time of social distancing.


Latent autoimmune diabetes in adults (LADA) should be less latent.
'Latent autoimmune diabetes in adults' (LADA) is the term coined to describe adults who have a slowly progressive form of autoimmune or type 1 diabetes that can be treated initially without insulin injections. The diagnosis of LADA is currently based on three clinical criteria: (1) adult age at onset of diabetes; (2) the presence of circulating islet autoantibodies, which distinguishes LADA from type 2 diabetes; and (3) insulin independence at diagnosis, which distinguishes LADA from classic type 1 diabetes. The prevalence of LADA in adults presenting with non-insulin-requiring diabetes is approximately 10%. Recognition of LADA expands the concept and prevalence of autoimmune diabetes, but LADA remains poorly understood at both a clinical and research level. In this perspective, we review the nomenclature, diagnostic criteria, genetics, pathology and therapy of LADA, to arrive at recommendations that might advance knowledge and management of this form of diabetes.


Drought periods driving bioinvasion on hard substrates at a tropical estuary, Eastern Brazil.
During drier periods estuarine salinization can stimulate the colonization of marine organisms and further bioinvasion, therefore, may cause future ecological change. In this sense, we applied the Rapid Assessment Surveys (RAS) on natural and artificial hard substrates during the most intense drought period (between 2014 and 2016) since 1950, in a tropical estuary in Eastern Brazil. Through the estuary salinization the ascidian Didemnum psammatodes overgrow the dominant native taxa; this dominance taxa shift provided suitable habitat favorable for invasion of Ophiothela mirabilis across the estuary. Even the invasion starts on artificial substrates, the higher resilience of natural substrates were not enough to enable the establishment of invasive species. This baseline is the first evidence of bioinvasion influenced by climate change drought periods in tropical estuaries in South America, which is a great advance for the development of management strategies to mitigate this and future climate change scenarios.


Spatial approximations of network-based individual level infectious disease models.
Often, when modeling infectious disease spread, the complex network through which the disease propagates is approximated by simplified spatial information. Here, we simulate epidemic spread through various contact networks and fit spatial-based models in a Bayesian framework using Markov chain Monte Carlo methods. These spatial models are individual-level models which account for the spatio-temporal dynamics of infectious disease. The focus here is on choosing a spatial model which best predicts the true probabilities of infection, as well as determining under which conditions such spatial models fail. Spatial models tend to predict infection probability reasonably well when disease spread is propagated through contact networks in which contacts are only within a certain distance of each other. If contacts exist over long distances, the spatial models tend to perform worse when compared to the network model.


Preoperative natural killer cell activity as a prognostic factor for distant metastasis following surgery for colon cancer.
To determine whether preoperative natural killer (NK) cell activity has any prognostic significance in colon cancer patients. The study population consisted of 140 patients with colon cancer. NK cell activity was determined within 2 weeks before surgery in 128 patients and at the time of diagnosis in the remaining 12 patients who either did not undergo surgery or who underwent palliative surgery only. Disease progression and postoperative prognosis were examined in relation to NK cell activity. Decreases in NK cell activity did not necessarily correspond to tumor stage. In curatively operated stage I-III diseases, preoperative NK cell activity of 20% or less correlated with poor survival. Lower activity was also associated with metachronous distant metastases but not with local recurrences. In particular, more than half the stage III patients with attenuated NK cell activity developed metastases. Multivariate analysis indicated that attenuated NK cell activity was a significant parameter for predicting distant metastasis following curative surgery for colon cancer. Preoperative NK cell activity has a significant prognostic value in curatively operated colon cancer, particularly for the development of metachronous distant metastasis in stage III patients.


Laminin-α2 Chain-Deficient Congenital Muscular Dystrophy: Pathophysiology and Development of Treatment.
Laminin-211 is a major constituent of the skeletal muscle basement membrane. It stabilizes skeletal muscle and influences signal transduction events from the myomatrix to the muscle cell. Mutations in the gene encoding the α2 chain of laminin-211 lead to congenital muscular dystrophy type 1A (MDC1A), a life-threatening disease characterized by severe hypotonia, progressive muscle weakness, and joint contractures. Common complications include severely impaired motor ability, respiratory failure, and feeding difficulties. Several adequate animal models for laminin-α2 chain deficiency exist and analyses of different MDC1A mouse models have led to a significant improvement in our understanding of MDC1A pathogenesis. Importantly, the animal models have been indispensable tools for the preclinical development of new therapeutic approaches for laminin-α2 chain deficiency, highlighting a number of important disease driving mechanisms that can be targeted by pharmacological approaches. In this chapter, I will describe laminin-211 and discuss the cellular and molecular pathophysiology of MDC1A as well as progression toward development of treatment.


Targeting RyR Activity Boosts Antisense Exon 44 and 45 Skipping in Human DMD Skeletal or Cardiac Muscle Culture Models.
Systemic delivery of antisense oligonucleotides (AO) for DMD exon skipping has proven effective for reframing DMD mRNA, rescuing dystrophin expression, and slowing disease progression in animal models. In humans with Duchenne muscular dystrophy treated with AOs, low levels of dystrophin have been induced, and modest slowing of disease progression has been observed, highlighting the need for improved efficiency of human skipping drugs. Here, we demonstrate that dantrolene and Rycals S107 and ARM210 potentiate AO-mediated exon skipping of exon 44 or exon 45 in patient-derived myotube cultures with appropriate mutations. Further, dantrolene is shown to boost AO-mediated exon skipping in patient-derived, induced cardiomyocyte cultures. Our findings further validate the ryanodine receptors (RyR) as the likely target responsible for exon skip boosting and demonstrate potential applicability beyond exon 51 skipping. These data provide preclinical support of dantrolene trial as an adjuvant to AO-mediated exon-skipping therapy in humans and identify a novel Rycal, ARM210, for development as a potential exon-skipping booster. Further, they highlight the value of mutation-specific DMD culture models for basic discovery, preclinical drug screening and translation of personalized genetic medicines.


Muscle control in chronic tic disorders.
EMG was recorded in nine subjects suffering from chronic tic disorder. Six subjects suffered asymmetrical tics and three had symmetrical tics. EMG in tic-affected and contralateral nonaffected sites was recorded at rest, during a baseline period, and at postbiofeedback training. All subjects received 2-4 biofeedback training sessions aimed at enhancing their ability to control levels of muscle contraction in both affected and nonaffected sites. All nine subjects met the criterion of discriminating unaided between levels of 0, 25%, 50%, and 75% of their fullest contraction. Five of the six people with asymmetrical tics showed lower resting EMG on the affected side at baseline, but EMG significantly increased in tic-affected but not nonaffected muscles after exercises aimed at enhancing muscle control. Six subjects reported a clinically significant > or = 40% decrease in tic frequency. The reflexlike quality of tic muscles can modified by biofeedback training and this constitutes a useful and relatively quickly acquired aid to tic management.


Alternative pre-mRNA splicing in Drosophila spliceosomal assembly factor RNP-4F during development.
The 5'- and 3'-UTR regions in pre-mRNAs play a variety of roles in controlling eukaryotic gene expression, including translational modulation. Here we report the results of a systematic study of alternative splicing in rnp-4f, which encodes a Drosophila spliceosomal assembly factor. We show that most of the nine introns are constitutively spliced, but several patterns of alternative splicing are observed in two pre-mRNA regions including the 5'-UTR. Intron V is shown to be of recent evolutionary origin and is infrequently spliced, resulting in generation of an in-frame stop codon and a predicted truncated protein lacking a nuclear localization signal, so that alternative splicing regulates its subcellular localization. Intron 0, located in the 5'-UTR, is subject to three different splicing decisions in D. melanogaster. Northern analysis of poly(A+) mRNAs reveals two differently sized rnp-4f mRNA isoforms in this species. A switch in relative isoform abundance occurs during mid-embryo stages, when the larger isoform becomes more abundant. This isoform is shown to represent intron 0 unspliced mRNA, whereas the smaller transcript represents the product of alternative splicing. Comparative genomic analysis predicts that intron 0 is present in diverse Drosophila species. Intron 0 splicing results in loss of an evolutionarily conserved stem-loop constituting a potential cis-regulatory element at the 3'-splice site. A model is proposed for the role of this element both in 5'-UTR alternative splicing decisions and in RNP-4F translational modulation. Preliminary evidences in support of our model are discussed.


The essential dynamics of thermolysin: confirmation of the hinge-bending motion and comparison of simulations in vacuum and water.
Comparisons of the crystal structures of thermolysin and the thermolysin-like protease produced by B. cereus have recently led to the hypothesis that neutral proteases undergo a hinge-bending motion. We have investigated this hypothesis by analyzing molecular dynamics simulations of thermolysin in vacuum and water, using the essential dynamics method. This method is able to extract large concerted atomic motions of biological importance from a molecular dynamics trajectory. The analysis of the thermolysin trajectories indeed revealed a large rigid body hinge-bending motion of the N-terminal and C-terminal domains, similar to the motion hypothesized from the crystal structure comparisons. In addition, it appeared that the essential dynamics properties derived from the vacuum simulation were similar to those derived from the solvent simulation.


Association of Meckel's diverticulum and Crohn's disease.
A significant association between Meckel's diverticulum and Crohn's disease has been suggested in the clinical literature. Ten patients with entities demonstrated radiographically as well as cases reported in the literature were analyzed to determine the relevance of this association to radiologic evaluation. The Meckel's diverticulum in most cases was an incidental finding whereas the Crohn's disease usually accounted for the patient's clinical symptoms. Recognition of this association should prevent unnecessary laparotomy for an incidental Meckel's diverticulum and improve the radiographic diagnosis of coexistent Crohn's disease.


Chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy.
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), also known as NIH Category III Prostatitis is a highly prevalent syndrome with significant impact on quality of life. As a heterogeneous syndrome, there exists no 'one size fits all' therapy with level 1 evidence to guide therapy. This often leads to a nihilistic approach to patients and clinical outcomes are poor. In this review, we examine the evidence for CP/CPPS therapies and discuss our technique of clinical phenotyping combined with multimodal therapy. Review of Medline articles with terms 'non-bacterial prostatitis', 'abacterial prostatitis' and 'chronic pelvic pain syndrome'. Many individual therapies have been evaluated in the treatment of CP/CPPS; antibiotics, anti-inflammatory medications (including bioflavonoids), neuromodulators, alpha blockers, pelvic floor physical therapy and cognitive behavior therapy. Each of these has been found to have varying success in alleviating symptoms. UPOINT is a system of clinical phenotyping for CP/CPPS patients that has 6 defined domains, which guide multimodal therapy. It has been validated to correlate with symptom burden and therapy guided by UPOINT leads to significant symptom improvement in 75-84% of patients based on three independent studies. CP/CPPS is a heterogeneous condition and, much like with prostate cancer, optimal therapy can only be achieved by classifying patients into clinically meaningful phenotypic groups (much like TNM) and letting the phenotype drive therapy.


Chloroquine stripping of HLA antigens from neutrophils without removal of neutrophil specific antigens.
Chloroquine stripping removes HLA antigens from neutrophils without damage to neutrophil specific antigens. This offers, for the first time, a simple procedure for the demonstration of neutrophil specific antibodies in sera that also contain HLA antibodies.


Sensitivity enhancement for evanescent-wave sensing using cavity-ring-down ellipsometry.
We demonstrate a method to increase the sensitivity of the s-p phase shift under total internal reflection (TIR) for optical sensing. This is achieved by the introduction of two simple dielectric layers to the TIR surface of a fused silica prism. The enhanced sensitivity is demonstrated using evanescent-wave cavity-ring-down-ellipsometry by measuring the refractive index of liquid mixtures and by studying the adsorption of polymers to the TIR surface of the fused silica prism.


Clinical use of antimicrobial pharmacodynamic profiles to optimise treatment outcomes in community-acquired bacterial respiratory tract infections: application to telithromycin.
Despite the revolutionary introduction of antibiotic therapy in the post-World War II era, primary care physicians continue to struggle with the issue of optimal treatment strategies for bacterial infection and the growing problem of antimicrobial resistance. The aggressive use of potent agents as first-line therapy maximises the potential for successful eradication of bacterial pathogens and slowing of the development of drug-resistant strains. Therapeutic drug monitoring and quantitative assessment of antibacterial potency are not always feasible in daily practice, but the pharmacodynamic profiles of antibacterials - which integrate pharmacokinetic profiles and microbiological properties - can be used to predict clinical success. Telithromycin possesses pharmacodynamic characteristics that make this novel ketolide an optimal choice for the empirical management of community-acquired respiratory tract infections.


[Consensus statement haemorrhoidal disease].
Haemorrhoidal disease belongs to the most common benign disorders in the lower gastrointestinal tract. Treatment options comprise conservative as well as surgical therapy still being applied arbitrarily in accordance with the surgeon's expertise. The aim of this consensus statement was therefore to assess a stage-dependent approach for treatment of haemorrhoidal disease to derive evidence-based recommendations for clinical routine. The most common methods are discussed with respect of haemorrhoidal disease in extraordinary conditions like pregnancy or inflammatory bowel disease and recurrent haemorrhoids. Tailored haemorrhoidectomy is preferable for individualized treatment with regard to the shortcomings of the traditional Goligher classification in solitary or circular haemorrhoidal prolapses.


Enhanced full-inversion-based ultrasound elastography for evaluating tumor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer.
An enhanced ultrasound elastography technique is proposed for early assessment of locally advanced breast cancer (LABC) response to neoadjuvant chemotherapy (NAC). The proposed elastography technique inputs ultrasound radiofrequency data obtained through tissue quasi-static stimulation and adapts a strain refinement algorithm formulated based on fundamental principles of continuum mechanics, coupled with an iterative inverse finite element method to reconstruct the breast Young's modulus (E) images. The technique was explored for therapy response assessment using data acquired from 25 LABC patients before and at weeks 1, 2, and 4 after the NAC initiation (100 scans). The E ratio of tumor to the surrounding tissue was calculated at different scans and compared to the baseline for each patient. Patients' response to NAC was determined many months later using standard clinical and histopathological criteria. Reconstructed E ratio changes obtained as early as one week after the NAC onset demonstrate very good separation between the two cohorts of responders and non-responders to NAC. Statistically significant differences were observed in the E ratio changes between the two patient cohorts at weeks 1 to 4 after treatment (p-value < 0.001; statistical power greater than 97%). A significant difference in axial strain ratio changes was observed only at week 4 (p-value = 0.01; statistical power = 76%). No significant difference was observed in tumor size changes at weeks 1, 2 or 4. The proposed elastography technique demonstrates a high potential for chemotherapy response monitoring in LABC patients and superior performance compared to strain imaging.


Rare causes of gastric outlet obstruction in children.
Gastric outlet obstruction (GOO) presenting beyond the newborn period is a relatively rare condition, when infantile hypertrophic pyloric stenosis (IHPS) is excluded. This report describes the clinical features, evaluation and management of 18 patients with GOO which was not caused by IHPS. The sex, age, and main presenting features were recorded on admission. Hemoglobin estimation, serum chemistry and blood gas analysis were also assessed in these patients. The diagnosis was confirmed with gastrointestinal barium, B ultrasound, gastroscopy, or at surgery. Some of them underwent gastroscopy with biopsy sampling for rapid urease test or histologic examination with Giemsa stains for Helicobacter pylori. Thirteen patients had peptic ulcer disease, of which six were successfully treated with medications. While the other seven needed operative management which included Heineke-Mikulicz pyloroplasty, gastroduodenostomy or gastrojejunostomy, respectively. All the patients who had Heineke-Mikulicz pyloroplasty or gastrojejunostomy developed bile reflux gastritis that could be alleviated with omeprazol. None of the patients developed dumping syndrome, failing to thrive, or anemia. Three children with antral diaphragm recovered without any complications by diaphragm excision with Heineke-Mikulicz pyloroplasty. The pylorus was compressed by fibrotic band in one 30-month boy, and he recovered uneventfully with Heineke-Mikulicz pyloroplasty during 10-year follow-up. Gastric outlet obstruction secondary to ingestion of sulfuric acid was noted in one patient, and he was successfully treated with gastroduodenostomy. Our data suggests that the satisfactory results could be expected in children with GOO with different therapeutic modalities based on the specific cause and degree of obstruction.


Bioluminescence imaging in Paracoccidioides spp.: a tool to monitor the infectious processes.
The genus Paracoccidioides comprises the species complex causing paracoccidioidomycoses (PCM). These fungi are a serious public health problem due to the long-term drug therapy, follow-up treatment, and frequent sequelae generated by the infection, such as pulmonary fibrosis. In this sense, the objective of this work was to generate bioluminescent reporter strains of Paracoccidioides spp. harboring a thermostable, red-shifted luciferase gene under the control of different constitutive promoters. The strains were generated by the integration of a species-specific codon-optimized luciferase gene upon actin or enolase promoter's control. The insertion of the constructs in Paracoccidioides brasiliensis and Paracoccidioides lutzii yeast cells were performed through Agrobacterium tumefaciens-mediated transformation. The results demonstrated the presence of several transformants harboring the luciferase gene. These transformants were further confirmed by the expression of luciferase and by the presence of the hygromycin resistance gene. Moreover, the luciferase activity could be detected in in vitro bioluminescence assays and in vivo models of infection. In general, this work presents the methodology for the construction of bioluminescent strains of Paracoccidioides spp., highlighting potential promoters and proposing an in vivo model, in which those strains could be used for the systemic study of PCM.


Growth kinetics and competition--some contemporary comments.
Results of competition experiments with one growth-limiting factor under idealized experimental conditions have been reported extensively, and usually provide ample support for the conclusion that 'complete competitors cannot coexist'. However, under conditions of multiple substrate limitation and discontinuous or alternating supply of nutrients, coexistence of species is quite common. Since such patterns of nutrient supply may be expected to prevail in many natural environments the mechanisms ruling the survival and growth of bacteria under such conditions need to be understood. However, it appears that surprisingly little is known of the physiological state of individual competing species grown in mixed cultures. Unfortunately, basic information such as the actual concentration of limiting nutrients is lacking in most cases. But perhaps the recent development of new and powerful techniques to explore the physiological properties even of individual cells will further stimulate studies into the mechanisms behind the competitiveness of microbial species.


Concept and application of ideal protein for pigs.
Knowledge about the amino acid requirements and the response of pigs to the amino acid supply is essential in feed formulation. A deficient AA supply results in a reduction in performance while an oversupply is costly and leads to excessive nitrogen excretion with a potentially negative environmental impact. Amino acid requirements are determined to a large extent by the protein deposition in the body and, for lactating sows, by the protein exported in the milk. The concept of ideal protein was developed more than 50 years ago and refers to a protein with an amino acid profile that exactly meets the animal's requirement so that all amino acids are equally limiting for performance. Because Lys typically is the first-limiting amino acid, the ideal amino acid profile is often expressed relative to Lys. Although the ideal protein profile is often assumed to be constant for a given production stage, (small) changes in the ideal protein profile can occur within a production stage. This can be caused by changes in the relative contribution of the different components of amino acid requirements during the productive life on the animal (e.g. changes in the relative contribution of growth and maintenance). Amino acids requirements can be determined experimentally using dose-response studies. The design of the study, the chosen response criterion, and the statistical model affect the requirement estimate. Although considerable experimental work has been carried out to determine the requirements for Lys, Met, Thr, and Trp in growing pigs (and to a lesser extent in sows), little is known about the requirements for the other essential amino acids. Experimental dose-response studies generally focus on the requirement and less on the overall response (i.e. what are the consequences of an amino acid deficiency?). This latter aspect is, to some extent, accounted for in modelling approaches that quantify the response of the animal to the amino acid supply in a dynamic way. The paper describes the origin of ideal protein and illustrates how fundamental concepts of amino acid nutrition have been integrated in practical modeling approaches for the nutrition of growing pigs and sows.


Attentional coding for three-dimensional objects and two-dimensional shapes. Differential interference effects.
The role played by the attentional mechanisms that enable dominance of relevant objects over distractor objects was investigated by measuring changes in the kinematics of the reach-to-grasp movement. Subjects reached towards three-dimensional (3D) stimuli while attention was diverted towards distracting information consisting of either two-dimensional (2D) projected shapes or 3D objects. Movement kinematics were influenced to a greater degree when a secondary task was performed involving a 3D object rather than a 2D projected shape. When the distractor was 3D, both the reaching and the grasping components were altered but, when it was 2D only, the reaching component was modified. It is suggested that, when attention is directed towards a distractor, it is associated with interference in the kinematics of the action towards the target. Further, the nature and dimensions of the distractor selectively influence the reach or the grasp component of a prehension movement.


Spatial distribution and the performance of individual plants in a natural population of Silene dioica.
1) A natural population of the perennial herb Silene dioica was mapped at intervals over the course of a year. The 'space available' to each plant was estimated by a Thiessen polygon, defined by the position of the plant's neighbours. 2) Germination and recruitment of seedlings appeared to be unrelated to the position of individuals with respect to their neighbours. 3) Various measures of plant growth were strongly correlated with polygon area in some seasons, suggesting that competition was occurring between individuals for spatially distributed resources. Plasticity allowed plants to exploit the available area, regardless of polygon shape or the number of neighbours defining a polygon. 4) In the early spring phase of seedling establishment, growth appeared to be enhanced and seedlings lived longer when they were close to neighbours. In late spring this effect was replaced by the more rapid growth of individuals in the larger polygons, i.e. with more distant neighbours. This sequence of events is consistent with the onset of competition for resources in late spring. 5) These effects were observed despite heterogeneity in the environment and variation in individual response.


Increased plasma phospholipase-A2 activity in schizophrenic patients: reduction after neuroleptic therapy.
Phospholipase-A2 (PLA2) is a key enzyme in the metabolism of phospholipids, and it may play an important role in neuronal function and neuronal plasticity. We determined the activity of PLA2 in the plasma of 20 drug-free schizophrenic patients, 6 nonschizophrenic psychiatric patients, and 21 healthy controls. Schizophrenic patients showed significantly higher plasma PLA2 activity than controls, and higher than our nonschizophrenic patients. Seventy percent of the schizophrenics had enzyme activity higher than the highest value from the control group. The increased plasma PLA2 activity in schizophrenics was reduced to the level of the controls after 3 weeks of neuroleptic treatment. These findings warrant further study for possible implications of this increased PLA2 activity in the etiopathology of schizophrenia.


Difference Between HPV-Positive and HPV-Negative Non-Oropharyngeal Head and Neck Cancer: Texture Analysis Features on CT.
To identify the specific texture parameter that shows significant differences between human papillomavirus (HPV)-positive (HPV) and HPV-negative (HPV) non-oropharyngeal carcinoma (non-OPC) using texture analysis. Forty-six patients of non-OPC patients (oral cavity, larynx, and hypopharynx) with known HPV status, who underwent contrast-enhanced computed tomography for initial staging, were retrospectively reviewed. Segmentations of the primary lesion were manually performed, and an in-house developed texture analysis program extracted 42 texture features from each segmented volume. A t test was used to evaluate differences between HPV and HPV non-OPCs (P < 0.05). Sixteen texture parameters, including 5 histogram features (P ≤ 0.03), 3 gray-level co-occurrence matrix features (P ≤ 0.02), 1 gray-level run-length feature (P = 0.009), 2 gray-level gradient matrix features (P ≤ 0.02), and 5 Law features (P ≤ 0.04), showed significant differences. Texture analysis demonstrated significant differences between HPV and HPV non-OPCs on computed tomography images, which may have a potential to prove morphologic feature differences among HPV-related tumors.


Modification of human serum albumin with N-(2,5-dinitro-4-fluorophenyl)-4-amino-2,2,6,6-tetramethyl-piperidinooxy radical.
Human serum albumin has been treated with the spin-labeling reagent indicated in the title. Ultraviolet spectral studies of the protein so modified suggest that reaction takes place at lysine and tyrosine sidechains; kinetic experiments indicate that there are two especially reactive amino groups of the protein which are preferentially modified. Evidence is presented that these groups include the one acetylated by aspirin (Lys-199) or those arylated by 2.6-dinitro-4-trifluoromethylbenzenesulfonate. Esr experiments show that bound spin labels have about the same correlation time expected for overall tumbling of the protein; ESR observations indicate that molecular freedom near the spin labels is not increased when the protein is transferred to 8 M urea.


Androgens are neuroprotective in the dentate gyrus of adrenalectomized female rats.
Neuroprotective effects of androgens have not been well-characterized, but there is evidence that 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) has anti-seizure effects. To further examine androgens' neuroprotective effects, testosterone (T), dihydrotestosterone (DHT), 3 alpha-diol (1.0 mg/kg SC daily), or sesame oil vehicle was administered to adrenalectomized or sham-operated, young, female Long Evans rats (N = 52). After seven days, animals were perfused and trunk blood was collected for radioimmunoassay of plasma corticosterone and androgens. No pyknotic cells were seen in the dentate of the sham-operated animals or those animals that had incomplete adrenalectomies (n = 20); however, cresyl violet and TUNEL stains revealed pyknotic cells in the granule layer of the dentate gyrus of adrenalectomized rats (n = 28). Testosterone, DHT, or 3 alpha-diol significantly reduced the number of pyknotic cells in the dentate gyrus compared to vehicle administered, adrenalectomized rats. Steroid-administered animals had levels of T, DHT, or 3 alpha-diol within physiological concentrations. These findings suggest that T, DHT, or 3 alpha-diol may have neuroprotective effects via a common mechanism of action.


The presence or absence of phenolglycosides in Salix (Salicaceae) leaves and the level of dietary specialisation of some of their herbivorous insects.
European Salix species fall into at least 2 groups on the nature of the secondary compounds in their leaves. Some species such as S. nigricans, S. purpurea and S. fragilis contain phenolglycosides in their leaves. Additionally, there are species such as S. alba, S. caprea and S. cinerea with leaves containing no phenolglycosides.Using published food plant list for the weevils, the sawflies and the caterpillars of the British moth, I tried to see if the presence or absence of phenolglycosides in the willow leaves is related to the degree of dietary specialisation of the insects feeding on these leaves.The results show that the Salix with phenolglycosides tend to be the food of the specialised herbivores and to be avoided by generalist. Conversely, Salix without phenolglycosides tend to be eaten by more generalist insects and are avoided by the more specialised.Moreover, the faunas of the different Salix species with phenolglycosides in their leaves are more similar to each other than to the faunas of the Salix species having no phenolglycosides in their leaves.


Comparision of how old age psychiatry and general adult psychiatry services meet the needs of elderly people with functional mental illness: cross-sectional survey.
There is little research evidence as to whether general adult psychiatry or old age psychiatry should look after old people with enduring mental illness. To compare the extent to which general adult and old age psychiatric services meet the needs of older people with enduring mental illness. A total of 74 elderly patients with functional psychiatric disorders were identified by reviewing the notes of patients over the age of 60 living in a defined inner urban catchment area. Data were collected on the morbidity and needs of the sample. Needs were assessed using the Elderly Psychiatric Needs Schedule (EPNS). The participants in contact with old age psychiatry had significantly fewer unmet needs compared with those in contact with general adult psychiatry (2.8 v. 5.6, t = 2.2, P<0.03). Total needs were not significantly different between those managed by old age and general adult services (8.0 v. 6.5 respectively, t = 1.2, P = 0.2). This study found that old age psychiatry services were better placed to meet the needs of elderly people with mental illness. This finding supports the need for a separate old age psychiatry service.


Static and Dynamic External Fixation are Equally Effective for Unstable Elbow Fracture-Dislocations.
To compare the clinical outcomes of static versus dynamic external fixation for elbow fracture-dislocations with persistent instability after surgical management. Comparative, retrospective review. Two tertiary referral upper-extremity centers. Twenty-four elbows requiring external fixation for persistent elbow instability within 90 days of surgical management of an elbow fracture-dislocation. Static and dynamic external fixation was used in 16 and 8 patients, respectively, for a median of 39 days (interquartile range, 33-48 days). Elbow range of motion, complications, and revision surgeries. Immediately after static and dynamic external fixation removal, there was no difference in elbow extension [33 degrees ± 16 degrees vs. 41 degrees ± 13 degrees, mean difference (MD) 7 degrees, 95% confidence interval (CI) -6 degrees-22 degrees] or flexion (114 degrees ± 35 degrees vs. 118 degrees ± 11 degrees, MD 4 degrees, 95% CI -23 degrees-132 degrees), respectively. At last follow-up, static and dynamic external fixation groups had no difference in elbow extension (27 degrees ± 13 degrees vs. 24 degrees ± 10 degrees, MD -3 degrees, 95% CI -15 degrees-7 degrees) or flexion (129 degrees ± 12 degrees vs. 128 degrees ± 14 degrees, MD -1 degree, 95% CI -13 degrees-10 degrees), respectively. Static and dynamic external fixation groups had no difference in complications [7 (44%) vs. 5 (63%), difference 19%, 95% CI -23%-54%] or revision surgeries [6 (38%) vs. 4 (50%), difference 13%, 95% CI -27%-49%]. No difference in range of motion, complications, and revision surgeries was detected after static versus dynamic external fixation of persistently unstable elbow fracture-dislocations. Due to ease of application, static external fixation is our preferred treatment for these injuries. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


A comparison of intranasal dexmedetomidine for sedation in children administered either by atomiser or by drops.
Intranasal dexmedetomidine has been used successfully for sedation in children. A mucosal atomisation device delivers an atomised solution to the nasal mucosa which facilitates rapid and effective delivery of medication to the systemic circulation. We compared intranasal delivery of dexmedetomidine in a dose of 3 μg.kg(-1) by either atomiser or drops from a syringe in children < 3 years old undergoing transthoracic echocardiography. Two hundred and seventy-nine children were randomly assigned to one or other group. One hundred and thirty-seven children received dexmedetomidine by atomiser and 142 by drops. The successful sedation rate was 82.5% (95% CI 75.3-87.9%) and 84.5% (95% CI 77.7-89.5%) for atomiser and drops, respectively (p = 0.569). Sedation tended to be less successful in older children (p = 0.028, OR 0.949, 95% CI 0.916-0.983). There were no significant complications. We conclude that both modes of dexmedetomidine administration are equally effective, although increasing age of the child was associated with a decreased likelihood of successful sedation.


Gaming strategies within a green supply chain considering consumers' concern about the greenness and conformance quality of products.
With the growing demand for green development, providing green and conformance quality improved products for sustainable growth and industrial upgrading is essential. However, the related literature rarely considers the improvement of product conformance quality in green supply chain management. This paper incorporates both into a framework for addressing the problem. We analyze the optimal strategies of a manufacturer responsible for conformance quality of product and greenness improvement and a retailer responsible for product marketing in a supply chain under four contracts: full cooperation, price-only contract, two-part tariff, and marketing cost-sharing. The results show that full cooperation and two-part tariffs lead to the same and highest product quality, greenness, overall profit, and social welfare, but full cooperation is difficult to achieve in the supply chain. For the profit-maximizing manufacturer and retailer, the manufacturer most prefers two-part tariff contracts, while the retailer prefers marketing cost-sharing because both achieve the highest profit in the preferred contract. In addition, under the price-only contract, the conformance quality of product and greenness is the lowest, and the profit levels for manufacturers and retailers are the lowest. In all four cases, increased environment and quality awareness contribute to improved product greenness and conformance quality, leading to higher profits for the manufacturer and retailer and higher social welfare.


Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus.
Several guidelines are available for identification and management of patients with Gaucher disease, but the most recent guideline was published in 2013. Since then, there have been significant advances in newborn screening, phenotypic characterization, identification of biomarkers and their integration into clinical practice, and the development and approval of new treatment options. Accordingly, the goal of this Delphi consensus exercise was to extend prior initiatives of this type by addressing issues related to newborn screening, diagnostic evaluations, and treatment (both disease directed and adjunctive). The iterative Delphi process involved creation of an initial slate of statements, review by a steering committee, and three rounds of consensus development by an independent panel. A preliminary set of statements was developed by the supporting agency based on literature searches covering the period from 1965 to 2020. The Delphi process reduced an initial set of 185 statements to 65 for which there was unanimous support from the panel. The statements supported may ultimately provide a framework for more detailed treatment guidelines. In addition, the statements for which unanimous support could not be achieved help to identify evidence gaps that are targets for future research.


Usefulness of EUS-guided fine needle aspiration biopsy in the diagnosis of suspected or recurring lymphoproliferative disorders.
EUS-guided fine needle aspiration biopsy (EUS-FNAB) of deep-seated lymphadenopathy is proposed to identify lymphoproliferative disorders when no superficial lesion is accessible. We analyzed prospectively collected data of 115 EUS-FNABs from 73 thoracic or abdomino-pelvic targets in 52 patients with suspected lymphoproliferative disorders (LPDs) between January 2005 and May 2011 from a single institution. Conventional histology and immunohistochemistry procedures were performed on samples. No complications were recorded. An LPD was identified in 29 cases and ruled out in 21 cases. In 2 cases the analysis was negative, but an LPD was identified using a secondary procedure. For the identification of LPDs irrespective of subtype, this procedure has positive and negative predictive values of 100% and 91.3% respectively, with 93.6% sensitivity and 100% specificity. In 31 patients finally diagnosed with LPDs, an accurate diagnosis meeting the 2008 World Health Organization classification criteria was established in 21 (68%) cases, success being significantly associated with target size above 30 mm in multivariate analysis (odds ratio 7.47; p = 0.05). EUS-FNAB of deep-seated lymphadenopathy with conventional morphological assessment appears to have a high diagnostic value for LPD identification and can obviate invasive surgery. A sub-classification was possible in two thirds of the cases.


Expression of acid phosphatase-beta-galactosidase hybrid proteins prevents translocation by depleting a soluble factor.
We have shown that hybrid proteins composed of the yeast repressible acid phosphatase (PHO5) and bacterial beta-galactosidase (lacZ) interfere with secretion of native acid phosphatase (Wolfe, P. B. (1988) J. Biol. Chem. 263, 6908-6915). We now report that PHO5-LacZ hybrid proteins have a more general effect on secretion and prevent translocation of several secreted proteins. Translocation of both the mating pheromone alpha-factor and the vacuolar protease carboxypeptidase Y is partially blocked when PHO5-LacZ hybrids are expressed. Cell fractionation and protease sensitivity indicate that alpha-factor and carboxypeptidase Y accumulate in precursor form on the cytoplasmic surface of the endoplasmic reticulum. Indirect immunofluorescence with antibody directed against beta-galactosidase supports the localization of hybrid proteins to the endoplasmic reticulum. Analysis of the hybrid protein phenotype in vivo and in vitro suggests that the hybrid proteins deplete a soluble factor required for efficient translocation across the endoplasmic reticulum. First, a decrease in the expression of a hybrid protein in vivo decreases its effect on translocation. Second, an in vitro translation/translocation reaction, prepared from a hybrid-bearing strain, is deficient in its ability to translocate prepro-alpha-factor across yeast microsomal membranes. This deficiency is complemented by addition of cytosol prepared from wild type cells. Finally, the hybrid protein phenotype is shown to be independent of the requirement for SSA gene products.


The solvatochromic effects of side chain substitution on the binding interaction of novel tricarbocyanine dyes with human serum albumin.
The effects of solvatochromism on protein-ligand interactions have been studied by absorbance and near-infrared laser induced fluorescence (NIR-LIF) spectroscopy. The utility of three novel classes of cyanine dyes designed for this purpose illustrates that the affinity interactions of ligands at the hydrophobic binding pockets of Human Serum Albumin (HSA) are not only dependent on the overall hydrophobic characteristics of the molecules but are highly influenced by the size of the ligands as well. Whereas changes to the chromophore moiety exhibited slight to moderate changes to the hydrophobic nature of these molecules, substitution at the alkyl indolium side chain has enabled us to vary the binding affinity towards serum albumin. Substitution at the indolium side chain among an ethyl to butyl group results in improved binding characteristics and an almost three-fold increase in affinity constant. In addition, replacement of the ethyl side chain with a phenylpropyl group also yielded unique solvotachromic patterns such as increased hydrophobicity and subsequent biocompatibility with the HSA binding regions. Ligand interaction was however inhibited by steric hindrance associated with the bulky phenyl ring system thus affecting the increased binding that could be realized from the improved hydrophobic nature of the molecules. This characteristic change in binding affinity is of potential interest to developing a methodology which reveals information on the hydrophobic character and steric specificity of the binding cavities.


PLA-based nature-inspired architecture for bone scaffolds: A finite element analysis.
The implantation of bio-degradable scaffolds is considered as a promising approach to address the repair of bone defects. This article aims to develop a computational approach to study the mechanical behaviour, fluid dynamic, and degradation impact on polylactic acid scaffolds with nature-inspired design structures. Scaffold design is considered to be one of the main factors for the regulation of mechanical characteristics and fluid flow dynamics. In this article, five scaffolds with different nature-inspired architectures have been designed within a specific porosity range. Based on finite element analysis, their mechanical behaviour and computational fluid dynamic study are performed to evaluate the respective properties of different scaffolds. In addition, diffusion-governed degradation analysis of the scaffolds has been performed to compute the total time required for the scaffold to degrade within a given environment. Based on the mechanical behaviour, the Spider-web architecture scaffold was found to have the least deformation, and also the lowest value of equivalent stress and strain. The Nautilus Shell architecture scaffold had the highest value of equivalent stress and strain. The permeability of all the scaffolds was found to meet the requirement of the cancellous bone. All computational fluid dynamics (CFD) results of wall shear stress are in line with the requirement for cell differentiation. It was observed that the Spider-web architecture scaffold had undergone the slowest degradation, and the Giant Water Lily architecture scaffold experienced the fastest degradation.


Rhythmic and electrophysiological study after dynamic cardiomyoplasty.
To question the possible proarrhythmic effects of cardiomyoplasty (CMP), six adult goats were submitted to rhythmic and electrophysiological (EP) study 15 days before and 8 months after a posteroanterior clockwise CMP procedure using Medtronic Cardiomyostimulator (CMS) (SP1005) and electrodes (SP5528) and completion of a progressive stimulation protocol. Pre and postoperative screening included a surface ECG, 24-hour Holter monitoring, high amplitude and filtered QRS averaging, and invasive EP study performed in the postoperative period with the CMS "ON" and "OFF." One-hour Holter recording with desynchronization of the CMS was obtained. Comparison of pre and postoperative ECG and rhythmic data showed no significant difference. High amplitude QRS averaging did not evidence meeting the usual criteria of late potentials. EP values were stable in both conditions and the aggressive EP program did not show evidence of increased susceptibility to arrhythmias. Asynchronous cardiomyostimulation did not induce arrhythmias. Our data strongly suggest that provided meticulous surgical technique is used, CMP does not significantly interfere with the electrical characteristics of the normal goat heart. The procedure, despite the disturbances it provokes, does not seem to be arrhythmogenic. The function of the CMS was always appropriate, even under stressful EP conditions.


What motivated the Industrial Revolution: England's libertarian culture or affluence per se?
What impelled the Industrial Revolution's spectacular economic growth? Life History Theory, Baumard argues, explains how England's world-supreme affluence psychologically fostered innovation; moreover, wherever similar affluence abounds, a "civilizing process" bringing enlightenment and democracy is apt to evolve. Baumard insightfully analyzes a "constellation of affluence" but proffers somewhat whiggish history given England's prior and unique proto-capitalist culture of economic liberty and individualism.


Aerobic sludge granulation in shale gas flowback water treatment: Assessment of the bacterial community dynamics and modeling of bioreactor performance using artificial neural network.
Flowback water from shale gas extraction is highly saline and comprises complex organic substances, thereby posing a significant challenge for the environmental management of the unconventional natural gas industry. In this work, an aerobic granular sludge (AGS) method was successfully used for the treatment of flowback water from shale gas extraction. The formed AGS had a diameter of 0.25-2.0 mm and the total sludge volume index was 23.40 mL g-1. The AGS efficiently removed COD, NH4+-N and TN by 70.1%, 92.1%, and 59.2%, respectively. The bacterial communities responsible for the removal of nitrogen and degradation of organics were enriched in AGS. The dynamics of contaminant removal was further explained with a three-layered artificial neural network model. The results showed that the initial concentration of COD, TDS, NH4+-N and TN governed the contaminants' removal. As for operating parameters, aerating time showed a strong effect on NH4+-N and TN removal, whereas settling time impacted the COD removal.


Male fertility and sexual function after spinal cord injury.
Spinal cord injury has an enormous impact upon the sexual relationship of a man and his partner. Erection may be partial or absent, orgasm altered or impossible, and fertility severely impaired. New understanding of the physiology of sexual function and improved treatment can enable most cord-injured men to achieve erections suitable for sexual satisfaction. Modern methods of sperm collection and fertility treatment mean that many can also be fathers. The best results are obtained by a team approach involving rehabilitation and reproductive medicine clinicians, nurses, spinal cord injury specialists and counselors with the cord-injured man and his partner. Erections can be achieved by drugs, such as sildenafil, that block phosphodiesterase 5, prolonging the action of nitric oxide with resultant smooth muscle relaxation. Intracavernosal prostaglandin E1 and mechanical systems, such as vacuum pumps and constriction rings, are also effective. Sexual gratification can be promoted in the context of an understanding relationship in which the cord-injured person can gain pleasure from pleasing his partner and also from his partner's exploration of erotogenic areas not affected by the spinal cord injury. An emphasis on the broader view of sexuality in relationships allows for a continuance and strengthening of bonds between the couple. Vibration ejaculation or electroejaculation can be used to collect semen. For a limited period in the acute phase, usually for about 6-12 days after injury, normal semen can be obtained by electroejaculation from some cord-injured men. With chronic spinal cord injury the semen is of variable quality. Some patients have necrospermia, which may be improved by regular ejaculation. Others have poor quality semen or spermatogenic disorders and, in this situation, in vitro fertilization techniques must be used to achieve parenthood. Trials of assisted ejaculation help individualize cost-effective management of the infertility.


Resolution of conformation equilibria in linear peptides by circular dichroism in cryogenic solvents.
The circular dichroism spectra of the synthetic peptide antigen, 209-222 of the surface glycoprotein of the rabies virus were recorded as a function of solvent composition and over the temperature range of +60 degrees C to -135 degrees C; beta-III and beta-II reverse turn conformations were found to exist in TFE/H2O (3:1) at room temperature and in ethanediol/H2O (2:1) below -110 degrees C respectively. Evidence, from comparison of observed and calculated spectra, is given to support the existence of a conformational equilibrium between a beta-II and a beta-III reverse turn. These data can serve as a basis for synthetic vaccine development and understanding the nature of polypeptide chain folding.


Eye closure sensitivity in juvenile myoclonic epilepsy and its effect on prognosis.
To investigate eye closure sensitivity (ECS) in the EEGs of patients diagnosed with juvenile myoclonic epilepsy (JME) and its relationship to prognosis. We included 76 JME patients with a minimum follow-up of one year and evaluated a total of 254 EEGs to obtain evidence of ECS. The patients were grouped according to their response to treatment, and these subgroups were compared in relation to ECS and other clinical and EEG features. There were 12 patients (15.8%) with poor prognosis who showed resistance to appropriate anti-epileptic drug treatment, 15 (19.7%) patients with pseudo-resistance, and 49 (64.5%) patients with good prognosis. The EEGs of only four of the patients displayed pure ECS (5.3%), and only one of these exhibited poor prognosis. Furthermore, 11 patients (14.5%) had both ECS and photosensitivity, and two of these patients exhibited poor prognosis. Thus, neither pure ECS nor ECS with photosensitivity correlated with poor prognosis. A family history of epilepsy and focal findings on the EEG was correlated with poorer prognosis. ECS is a rare EEG finding in JME and does not appear to be a marker for poor prognosis.


Inhibitory effects of gallic acid and quercetin on UDP-glucose dehydrogenase activity.
We have examined polyphenols as potential inhibitors of UDP-glucose dehydrogenase (UGDH) activity. Gallic acid and quercetin decreased specific activities of UGDH and inhibited the proliferation of MCF-7 human breast cancer cells. Western blot analysis showed that gallic acid and quercetin did not affect UGDH protein expression, suggesting that UGDH activity is inhibited by polyphenols at the post-translational level. Kinetics studies using human UGDH revealed that gallic acid was a non-competitive inhibitor with respect to UDP-glucose and NAD+. In contrast, quercetin showed a competitive inhibition and a mixed-type inhibition with respect to UDP-glucose and NAD+, respectively. These results indicate that gallic acid and quercetin are effective inhibitors of UGDH that exert strong antiproliferative activity in breast cancer cells.