Effects of UV irradiation with one minimal erythema dose on human afferent skin lymph in vivo.
Ultraviolet (UV) irradiation of the skin induces complex local and systemic immunomodulatory reactions. The biological effects of UV irradiation on human skin derived afferent lymph however are unknown. The aim of this study was to examine the effects of a single combined UV-A and UV-B irradiation with 1 minimal erythema dose (MED) on human skin derived lymph in vivo. After cannulation of a superficial lymph vessel on the lower leg, lymph flow and cell output per hour were determined before and for 6 days after UV irradiation of the lymph draining skin area in 5 volunteers. Furthermore, expression of CD1a, CD4, CD8, CD28, CD54, CD80, CD86 and HLA-DR on migrating lymph cells and cytokine levels (IL-1alpha, IL-1beta, IL-2, IL-6, IL-8, IL-10, IL-13, TNF-alpha and IFN-gamma) in the afferent lymph were analyzed by cytofluorometry and ELISA. After UV irradiation a small initial enhancement in the daily lymph flow per hour was noticed in correlation with the slight erythematous skin reaction. Following resolution of the skin reaction, a delayed increase in cell output in correlation with an additional peak in the lymph flow was found between the 4th and 6th day after UV irradiation. However, no changes in the expression of CD1a, CD4, CD8, CD28, CD54, CD80, CD86 and HLA-DR on migrating lymph cells were detectable. Interestingly, in parallel to the increased lymph flow and cell output, only elevated IL-8 protein levels were reproducibly detected in the afferent lymph after UV irradiation. Furthermore, using immunohistochemistry positive staining for IL-8 was found on migrating mononuclear lymph cells. In conclusion, our data demonstrate that a single UV irradiation of the skin with 1 minimal erythema dose leads to a delayed enhancement of lymph flow, number of migrating lymph cells and cytokine levels of IL-8. Moreover, we provide evidence that migrating lymph cells, besides resident epidermal and dermal cells, may contribute to the detected levels of IL-8 in the afferent lymph.


Plasma zonulin correlates with cardiac dysfunction and poor physical performance in patients with chronic heart failure.
An aberrant intestinal permeability is often associated with systemic inflammation and cardiovascular diseases accompanied by compromised physical performance. However, the link between these complications is poorly defined. Here we investigated the potential association of zonulin, a regulator of intestinal permeability, with ischemic and non-ischemic heart failure (HF) and, associated physical disability. The investigation including echocardiography, short physical performance battery (SPPB) and measurement of plasma zonulin and c-reactive protein (CRP), was performed in 59 HF patients and an equal number of healthy controls. As expected, the left ventricular end-systolic dimension (LVESD) was significantly higher, which was accompanied by a significantly lower LV ejection fraction (EF) in the HF patients compared to controls. The levels of plasma zonulin and CRP was profoundly elevated in both ischemic (P < 0.0001) and non-ischemic (P < 0.01) HF patients. Interestingly, LVESD positively (r2 = 0.156, P = 0.001) and LVEF negatively (r2 = 0.186, P = 0.0006) correlated with the level of zonulin in HF patients. The SPPB scores for balance, chair sit-to-stand (STS), gait speed (GS), and hand grip strength (HGS) were consistently compromised in HF patients. Moreover, LVESD was negatively (r2 = 0.118, P = 0.007), and there was trend of positive correlation of LVEF (r2 = 0.05, P = 0.08) with the SPPB scores for balance. Consistently, zonulin levels was negatively correlated with SPPB scores for balance (r2 = 0.176, P = 0.0009), STS (r2 = 0.120, P = 0.001) and HGS (r2 = 0.085, P = 0.02). Chronic cardiac complications induce the level of plasma zonulin, which predicts the cardiac remodeling and dysfunction and physical performance in patients with chronic HF.


Plasma catecholamines in children.
Plasma catecholamine concentrations in 46 children of various ages were determined by a sensitive radioenzymatic assay. Noradrenaline levels were found to be in the same range as in adults, whereas adrenaline levels in a few of the children were abnormally high.


Modelling and quantifying tomorrow's risks from natural hazards.
Understanding and modelling future risks from natural hazards is becoming increasingly crucial as the climate changes, human population grows, asset wealth accumulates, and societies become more urbanised and interconnected. This need is recognised by the 2015-2030 Sendai Framework for Disaster Risk Reduction, which emphasises the importance of preparing for the disasters that our world may face tomorrow through strategies/policies that aim to minimise uncontrolled development in hazardous areas. While the vast majority of natural-hazard risk-assessment frameworks have so far focused on static impacts associated with current conditions and/or are influenced by historical context, some authors have sought to provide decision makers with risk-quantification approaches that can be used to cultivate a sustainable future. This Review documents these latter efforts, explicitly examining work that has modelled and quantified the individual components that comprise tomorrow's risk, i.e., future natural hazards affected by climate change, future exposure (e.g., in terms of population, land use, and the built environment), and the evolving physical vulnerabilities of the world's infrastructure. We end with a discussion on the challenges faced by modellers in determining the risks that tomorrow's world may face from natural hazards, and the constraints these place on the decision-making abilities of relevant stakeholders.


Regulation of gene expression by stop codon recoding: selenocysteine.
The regulation of gene expression at the translational level not only allows for rapid changes in specific protein levels but also provides an opportunity to alter codon specificity. For the incorporation of selenocysteine (Sec) into protein, the UGA codon is transformed from one that signals translation termination to one specific for Sec. This review provides a look at Sec incorporation from the perspective of the individual steps involved in protein synthesis: initiation, elongation and termination. The roles of the factors known to be required for Sec incorporation are considered in the context of each step in translation including structural modeling of the differences between the standard elongation factor eEF1A and the Sec-specific counterpart, eEFSec.


Urban human settlements' resilience measurement and characteristics and their mechanism model in China.
This study introduces the principle of resilience into the study of human settlements. In this study, a comprehensive evaluation model of urban human settlements' resilience based on the provincial region of China was constructed using the Driver-Pressure-State-Impact-Response framework. The spatio-temporal evolution characteristics of urban human settlements' resilience was explored. The influencing factors were analysed by geographical detectors, and the driving mechanism was constructed. Results show that the following. (1) The resilience level of human settlements in China continued to increase, and the resilience level of each province and city changed significantly. The overall clustering effect showed a tendency to fluctuate and weaken. The distribution of cold spot areas became less and less, and the hot spots were moving from northeast China to southeast China. (2) Significant differences existed in the intensity of the impact of different indicators on the resilience system. The value of the impact factor showed an overall upward trend, and the number of key impact factors increased. (3) Improving the ability of scientific and technological innovation, accelerating the transformation and upgrading of the regional economy, increasing the training of talents and making financial inclination in scientific and technological development and industrial pollution control were all important ways for developing and maintaining the resilience of urban human settlements. This study not only introduces a new evaluation of urban human settlements from the perspective of resilience but also explores key impact indices and driving mechanisms, which provides new ideas for studying urban human settlements.


Role of clinical parameters for predicting the cause of upper gastrointestinal bleeding.
Upper gastrointestinal bleeding (UGIB) has been classified into portal and non-portal hypertension (PHT) bleeding causes. Differentiating the two major categories of UGIB is therefore important for selection of the appropriate empirical treatment. To evaluate the potential of certain clinical parameters for predicting the cause of UGIB. The records of patients with UGIB who underwent endoscopy within 72 hours of diagnosis were retrospectively examined for the clinical parameters. Potential predictive factors for categorizing the cause of UGIB were identified by univariate and multivariate analysis. One hundred forty six UGIB patients were enrolled in the present study. One hundred nine patients had non-PHT bleeding and 37 patients were PHT bleeding. Multivariate analysis identified three independent factors for predicting PHT bleeding, presence of signs of chronic liver disease or PHT (Odds ratio (OR) 51.1, p < 0.05), presence of underlying cirrhosis (OR 28.4, p < 0.05) and an initial hematocrit < 30% (OR 12.7, p < 0.05). A presentation with coffee ground vomitus was the only factor that indicated a reduced possibility of PHT bleeding (OR 0.1, p < 0.05). The presence of underlying cirrhosis, signs of chronic liver disease or portal hypertension and an initial hematocrit < 30% were significantly correlated with PHT bleeding while the presentation of coffee ground vomitus indicated a less likely chance of PHT bleeding.


Affordability, availability and tolerability of anti-seizure medications are better predictors of adherence than beliefs: Changing paradigms from a low resource setting.
Anti-seizure medication (ASM) non-adherence contributes to treatment gap and increases mortality and morbidity associated with epilepsy. Beliefs about medications are considered better predictors of ASM non-adherence than clinico-demographic factors. We aimed to look into ASM non-adherence rates among adults with epilepsy (AWE), identify the contributing barriers and determine whether medication beliefs were more powerful predictors than clinico-demographic factors. This was a cross-sectional study of AWE receiving ASMs. Participants (n = 304) were assessed by validated questionnaires, for non-adherence (8-item Morisky Medication Adherence Scale) and perceptions of ASMs (Beliefs about Medicines Questionnaire) along with clinico-demographic details. Our group with high literacy and low-income had a high non-adherence rate (55 %) despite having positive beliefs (Mean necessity-concern differential [NCD] = 2.86). Among the beliefs, ASM non-adherence was significantly associated with ASM-concern (t = 4.23, p < 0.001) and NCD (t = -4.11, p < 0.001). Stepwise multiple linear regression analysis showed that non-adherence was significantly associated with per-capita income (β -0.215, p < 0.001), ASM side effects (β 0.177, p = 0.001), high seizure frequency (β 0.167, p = 0.002), ASM availability (β -0.151, p = 0.004), ASM costs (β -0.134, p = 0.013 and NCD (β -0.184, p = 0.001). NCD accounted for 2.9 % of the variance in non-adherence whereas the other clinico-demographic variables together accounted for 14.6 %. We describe a paradigm shift in AWE with high non-adherence to ASMs, wherein clinico-demographic variables emerge as better predictors of non-adherence than beliefs. High literacy facilitates the perception of need for ASMs whereas costs and side effects hamper adherence.


A pre-mRNA-associating factor links endogenous siRNAs to chromatin regulation.
In plants and fungi, small RNAs silence gene expression in the nucleus by establishing repressive chromatin states. The role of endogenous small RNAs in metazoan nuclei is largely unknown. Here we show that endogenous small interfering RNAs (endo-siRNAs) direct Histone H3 Lysine 9 methylation (H3K9me) in Caenorhabditis elegans. In addition, we report the identification and characterization of nuclear RNAi defective (nrde)-1 and nrde-4. Endo-siRNA-driven H3K9me requires the nuclear RNAi pathway including the Argonaute (Ago) NRDE-3, the conserved nuclear RNAi factor NRDE-2, as well as NRDE-1 and NRDE-4. Small RNAs direct NRDE-1 to associate with the pre-mRNA and chromatin of genes, which have been targeted by RNAi. NRDE-3 and NRDE-2 are required for the association of NRDE-1 with pre-mRNA and chromatin. NRDE-4 is required for NRDE-1/chromatin association, but not NRDE-1/pre-mRNA association. These data establish that NRDE-1 is a novel pre-mRNA and chromatin-associating factor that links small RNAs to H3K9 methylation. In addition, these results demonstrate that endo-siRNAs direct chromatin modifications via the Nrde pathway in C. elegans.


The effect of exercise on cytokine concentration in equine autologous conditioned serum.
Autologous conditioned serum (ACS) is a commonly administered intra-articular treatment for the management of osteoarthritis in athletic horses. To investigate the influence of exercise on the concentration of cytokines in a non-commercial method of ACS production. Non-randomised cross over design. Whole blood was obtained from eight healthy Standardbred horses immediately prior to, 1 h and 24 h following a single bout of exhaustive exercise. Blood was processed using a non-commercial method of ACS production. Fluorescent microsphere immunoassay (FMIA) analysis was performed to quantify Interleukin 1 receptor antagonist (IL-1Ra), Interleukin-10 (IL-10), Interleukin 1β (IL-1β) and tumour necrosis factor α (TNF-α) concentrations at each time point. Mixed effect repeated measures analysis of variance (ANOVA) was used to compare the pre-exercise and post-exercise cytokine concentrations. Significance was set at P < 0.05. A reduced concentration of IL-1Ra (median 584.4, IQR 81.9-5098 pg/ml, p = 0.004) and an increased concentration of TNF-α (11.92, 9.28-39.75 pg/ml, P = .05) at 1 h post-exercise were observed when compared with baseline values (IL-Ra 7349, 1272-10 760 pg/ml; TNF TNF-α 11.16, 8.36-32.74 pg/ml). No difference in cytokine concentrations of IL-10 or IL-1β were found between any of the time points. The large biological variability and small sample size represents limitations of this study. These results suggest that a single bout of intense exercise can reduce the concentration of the anti-inflammatory cytokine IL-1Ra and increase the concentration of the pro-inflammatory cytokine TNF-α, reducing the 'anti-inflammatory' cytokine composition of ACS. Our findings suggest that collection of blood for ACS production should be performed no sooner than 24 h following a single episode of intense exercise.


Minimally-invasive technique for transforaminal lumbar interbody fusion (TLIF).
Minimal access surgical techniques have been described for diskectomy and laminectomy procedures performed through tubular exposures. Tubular exposures, however, restrain visibility to a fixed diameter and require co-axial instrument manipulation. An independent blade retractor system has been developed to overcome the obstacles of working through a tube. Decompression and circumferential fusion can be accomplished through this minimal access exposure via a combination of laminectomy and transforaminal lumbar interbody fusion (TLIF) coupled with minimally invasive pedicle screw fixation. Herein, we describe a minimally-invasive technique for TLIF exposure. Illustrations, intraoperative photographs, and fluoroscopic images supplement this technique. We found that the described minimally-invasive system provides comparable exposure to the traditional-open techniques with the benefits of minimally-invasive techniques. Additionally, it does not have the added constraints of a tubular system. We were able to perform TLIFs without any additional complications. Minimal access decompression and TLIF can be performed safely and effectively using this minimally-invasive system. Besides the retractor system, no additional specialized instruments are required. An operative microscope is not required, in fact, all our cases were performed using operative loupes. The light attachment provides superb visbility without the discomfort of having to wear a headlight. Thus far we have found no added risks or complications using this system. We are currently working on long-term analysis and follow-up to further evaluate this system's efficacy.


Articular Cartilage Lesions Pathomechanism, Diagnosis, Epidemiology, Possibilities for Conservative Treatment.
Osteoarthritis, which is the most common joint disorder, is one of major reasons for hospitalizations and one of the greatest burdens to health care systems. Osteoarthritis has a complex etiology, but lesions of articular cartilage are a major risk factor. These lesions are often encountered in young active people and usually remain asymptomatic for a long time. Depending on the extent of injury, chondral lesions can be managed conservatively or surgically. An important factor influencing the effectiveness of conservative treatment is the morphology and location of injury. Conservative treatment should be based on patient education and rehabilitation, and supported by pharmacotherapy.


Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation.
The risk of osteoporotic fracture with dabigatran use in patients with nonvalvular atrial fibrillation (NVAF) is unknown. To investigate the risk of osteoporotic fracture with dabigatran vs warfarin in patients with NVAF. Retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with NVAF from 2010 through 2014 and prescribed dabigatran or warfarin were matched by propensity score at a 1:2 ratio with follow-up until July 31, 2016. Dabigatran or warfarin use during the study period. Risk of osteoporotic hip fracture and vertebral fracture was compared between dabigatran and warfarin users using Poisson regression. The corresponding incidence rate ratio (IRR) and absolute risk difference (ARD) with 95% CIs were calculated. Among 51 496 patients newly diagnosed with NVAF, 8152 new users of dabigatran (n = 3268) and warfarin (n = 4884) were matched by propensity score (50% women; mean [SD] age, 74 [11] years). Osteoporotic fracture developed in 104 (1.3%) patients during follow-up (32 dabigatran users [1.0%]; 72 warfarin users [1.5%]). Results of Poisson regression analysis showed that dabigatran use was associated with a significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per 100 person-years; ARD per 100 person-years, -0.68 [95% CI, -0.38 to -0.86]; IRR, 0.38 [95% CI, 0.22 to 0.66]). The association with lower risk was statistically significant in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per 100 person-years; ARD per 100 person-years, -3.15 [95% CI, -2.40 to -3.45]; IRR, 0.12 [95% CI, 0.04 to 0.33]), but not in those without a history (0.6 vs 0.7 per 100 person-years; ARD per 100 person-years, -0.04 [95% CI, 0.67 to -0.39]; IRR, 0.95 [95% CI, 0.45 to 1.96]) (P value for interaction, <.001). Among adults with NVAF receiving anticoagulation, the use of dabigatran compared with warfarin was associated with a lower risk of osteoporotic fracture. Additional study, perhaps including randomized clinical trials, may be warranted to further understand the relationship between use of dabigatran vs warfarin and risk of fracture.


Nail plate combination in fractures of the distal femur in the elderly: A new paradigm for optimum fixation and early mobilization?
Distal femoral fractures in elderly or osteoporotic patients constitute a challenging injury, especially in the settings of fracture comminution or periprosthetic fractures. A recent trend in the treatment of these difficult injuries is the double fixation with a nail and a plate, a strategy that comes with advantages including faster weight-bearing and lower risk for non-union. Although biomechanical studies have demonstrated the superiority of nail-plate constructs, there is a paucity in the literature regarding the indications and results of treatment. A review of the literature to date was carried out to identify which group of patients would benefit the most from this type of reconstruction and to evaluate the clinical outcomes.


Improved delivery of inhaled steroids to the large and small airways.
The reformulation of asthma medications with non-ozone depleting propellants such as hydrofluoroalkane-134a (HFA) has provided the opportunity to apply new knowledge and inhaler technology to improve significantly the delivery of aerosol drugs to the respiratory tract. Beclomethasone dipropionate (BDP), the most commonly prescribed inhaled corticosteroid for asthma therapy, is effective therapy; however currently available chlorofluorocarbon (CFC)-BDP metered dose inhalers typically deliver no more than 10% of the inhaled drug to the lungs with the remainder deposited in the oropharynx. Compared with an average particle size of 3.5-4.0 microns for CFC-BDP, the new HFA-BDP formulation has an average particle size of 1.1 microns and a respirable fraction of approximately 60%. The lung deposition of 99mTc-radiolabelled HFA-BDP has been investigated in healthy volunteers and patients with asthma. Results showed that the HFA-BDP formulation reverses the pattern of distribution seen with CFC-BDP products, delivering most of the dose of inhaled steroid directly to the lungs rather than to the oropharynx and gut where it may lead to unwanted side-effects. As such, HFA-BDP is likely to achieve equivalent efficacy to existing CFC-BDP formulations with lower doses and with reduced potential for local adverse effects.


Dermal collagen fibrils are hybrids of type I and type III collagen molecules.
It has been suggested that dermal collagen fibrils with 67-nm periodicity consist of hybrids of type I and type III collagens. This is based on the assumption that all these banded fibrils are coated with type III collagen regardless of their diameter. However, conclusive evidence for this form of hybridization is lacking. In order to clarify this problem dermal collagen fibrils were disrupted into microfibrils using 8 M urea. Single and double indirect immunoelectron microscopy showed type III collagen at the periphery of intact collagen fibrils but no labeling with type I collagen antibodies, suggesting that the epitopes for this collagen were masked. Disrupted collagen fibrils revealed type I collagen throughout the fibril except for the periphery which was coated with type III collagen. Almost no type III collagen was noted in the interior of the collagen fibrils. Since type III collagen is present only at the periphery it suggests that this collagen has a different role than type I collagen and may have a regulatory function in fibrillogenesis.


Phenytoin: an evaluation of several potential teratogenic mechanisms.
The effect of pharmacological doses of phenytoin (DPH) administered for a maximum of 28 days was studied in pregnant and nonpregnant rats as well as in 14- and 21-day fetuses. The following parameters were monitored in the adult rats: maximal electroshock seizures, serum DPH and folate, liver microsomal P-450, and 14C-DPH tissue distribution. 14C-DPH distribution was also evaluated in fetal tissues. Pregnant animals demonstrated an increase in anticonvulsant activity as well as increased serum concentrations of DPH throughout pregnancy and on the 7th post-partum day. Brain concentrations of DPH increased during pregnancy but had returned to the values in the nonpregnant group at the 7th post-partum day. Liver microsomal P-450 was decreased in pregnant animals receiving DPH at days 7 and 14 of pregnancy. Serum folate also decreased at day 14 of pregnancy in animals receiving DPH. Fetal tissue binding of DPH appeared to be related to serum concentrations of the drug at day 14. Teratogenic effects of DPH could be related to the increased serum and tissue concentrations of the drug observed during pregnancy as well as its effect on serum folate at day 14 of gestation.


Tin(II) Chloride-Catalyzed Direct Esterification and Amidation of tert-Butyl Esters Using α,α-Dichlorodiphenylmethane Under Mild Conditions.
A practical one-pot synthesis of esters and amides from tert-butyl esters via acid chloride was developed. Reactions of tert-butyl esters with α,α-dichlorodiphenylmethane as the chlorinating agent and SnCl2 as catalyst-generated acid chloride intermediates in situ were subsequently used in reactions with a variety of alcohols and amines to afford the corresponding esters and amides in high yields under mild reaction conditions. This catalytic synthetic procedure offers an effective strategy for the facile esterification and amidation of tert-butyl esters.


Corticosteroids and immunomodulators: postoperative infectious complication risk in inflammatory bowel disease patients.
Many patients with inflammatory bowel disease receive corticosteroids and 6-mercaptopurine/azathioprine during elective bowel surgery. We investigated the postoperative infection risk for patients undergoing elective bowel surgery who were receiving corticosteroids and/or 6-mercaptopurine/azathioprine before surgery compared with patients not receiving these medications. A retrospective cohort study was conducted on 159 patients with inflammatory bowel disease who underwent elective bowel surgery. There were 56 patients receiving corticosteroids alone, 52 patients receiving 6-mercaptopurine/azathioprine alone or with corticosteroids, and 51 patients receiving neither corticosteroids nor 6-mercaptopurine/azathioprine. Postoperative infectious complications to time of discharge were categorized into major and minor complications. Patients receiving corticosteroids had an adjusted odds ratio for any and major infectious complications of 3.69 (95% confidence interval [CI], 1.24-10.97) and 5.54 (95% CI, 1.12-27.26), respectively. The adjusted odds ratio for patients receiving 6-mercaptopurine/azathioprine for any and major infectious complications was 1.68 (95% CI, 0.65-4.27) and 1.20 (95% CI, 0.37-3.94), respectively. Preoperative use of corticosteroids in patients with inflammatory bowel disease who are undergoing elective bowel surgery is associated with an increased risk of postoperative infectious complications. 6-Mercaptopurine/azathioprine alone and the addition of 6-mercaptopurine/azathioprine for patients receiving corticosteroids was not found to significantly increase the risk of postoperative infectious complications.


Inflammation, the complement system and the diseases of aging.
Inflammation is characteristic of neurodegenerative diseases of aging. Neuropathological evidence of activated microglia and activated astrocytes in lesioned areas, combined with epidemiological evidence of sparing of Alzheimer's disease (AD), Parkinson's disease (PD) and age-related macular degeneration (AMD) in long-term users of anti-inflammatory agents, indicates that inflammation is autodestructive of neurons. Locally produced autodestructive molecules include the membrane attack complex (MAC) of complement and oxygen-free radicals. Stimulation is provided by a variety of inflammatory cytokines. Agents which reduce the intensity of inflammation should have broad spectrum application in degenerative diseases of aging.


Recent advances in MRI technology: Implications for image quality and patient safety.
Recent advances in MRI technology are presented, with emphasis on how this new technology impacts clinical operations (better image quality, faster exam times, and improved throughput). In addition, implications for patient safety are discussed with emphasis on the risk of patient injury due to either high local specific absorption rate (SAR) or large cumulative energy doses delivered during long exam times. Patient comfort issues are examined as well.


The conditional relationship between renewable energy and environmental quality in sub-Saharan Africa.
This paper complements existing literature by assessing the conditional relationship between renewable energy and environmental quality in a sample of 40 African countries for the period 2002 to 2017. The empirical evidence is based on fixed effects regressions and quantile fixed effects regressions. The findings from both estimation techniques show that renewable energy consistently decreases carbon dioxide (CO2) emissions. Moreover, the negative effect is a decreasing function of CO2 emissions or the negative effect of renewable energy on CO2 emissions decreases with increasing levels of CO2 emissions. In other words, countries with higher levels of CO2 emissions consistently experience a less negative effect compared with their counterparts with lower levels of CO2 emissions. Policy implications are discussed.


Human endopeptidase (THOP1) is localized on chromosome 19 within the linkage region for the late-onset alzheimer disease AD2 locus.
A cDNA encoding the rat endopeptidase 24.15 was used to determine the chromosomal localization of the respective human gene. Hybridization to DNA from human-rodent somatic cell hybrids assigned the human gene to chromosome 19. Fluorescence in situ hybridization on human metaphase chromosomes localized the human endopeptidase 24.15 to 19q13.3.


Performance of Leghorn type hens fed two levels of energy and a synthetic estrogen during the growing period.
Feeding of an estrogen, dienestrol diacetate, at 352 mg/kg of diet to December-hatched White Leghorn type pullets, from 16 to 20 wk of age, caused onset of production to be delayed approximately 3 wk. The dietary dienestrol diacetate also resulted in increased body weights at 30 and 46 wk in one experiment. Hens receiving the estrogen laid significantly (P less than .05) heavier but fewer eggs during most of the production year than did those fed diets without the estrogenic compound. The addition of 2.2% fat to diets of pullets from 0 to 20 wk of age failed to influence their performance in the layer house.


Synergy Between Expert and Machine-Learning Approaches Allows for Improved Retrosynthetic Planning.
When computers plan multistep syntheses, they can rely either on expert knowledge or information machine-extracted from large reaction repositories. Both approaches suffer from imperfect functions evaluating reaction choices: expert functions are heuristics based on chemical intuition, whereas machine learning (ML) relies on neural networks (NNs) that can make meaningful predictions only about popular reaction types. This paper shows that expert and ML approaches can be synergistic-specifically, when NNs are trained on literature data matched onto high-quality, expert-coded reaction rules, they achieve higher synthetic accuracy than either of the methods alone and, importantly, can also handle rare/specialized reaction types.


Generalist-Specialist Collaboration in Primary Care for Frail Older Persons: A Promising Model for the Future.
The complex care needs of frail older persons living at home is a major challenge for health care systems worldwide. One possible solution is to employ a primary care physician (PCP) with additional geriatric expertise. In the Netherlands, elderly care physicians (ECPs), who traditionally work in nursing homes, are increasingly encouraged to utilize their expertise within primary care. However, little is known about how PCPs and ECPs collaborate. Therefore, we aimed to unravel the nature of the current PCP-ECP collaboration in primary care for frail older persons, and to identify key concepts for success. A qualitative multiple case study with semistructured interviews. A selection of 22 participants from 7 "established collaboration practices" within the primary care setting in the Netherlands, including at least 1 ECP, 1 PCP, and 1 other health care professional for every included established collaboration practice. Transcripts of individual interviews were analyzed using largely double and independent open and axial coding, and formulation of themes and subthemes. Data analysis revealed 4 key concepts for success: (1) clarification of roles and expectations (ie, patient-centered care and embedding in existing care networks), (2) trust, respect, and familiarity as drivers for collaboration (ie, mutual trust through knowing each other and having shared goals); (3) framework for regular communication (ie, structural meetings and a shared vision); and (4) government, payer, and organization support (ie, financial support and emphasis on the collaboration's urgency by organizations and national policy makers). For a successful generalist-specialist collaboration, health care professionals need to invest in building relationships and mutual trust, and incorporating their efforts in the existing care networks to guarantee patient-centeredness. When provided with reimbursement and appreciation, this collaboration is a promising change in general practice to improve the care and outcomes of frail older persons.


Nanozymes: Versatile Platforms for Cancer Diagnosis and Therapy.
Natural enzymes usually suffer from high production cost, ease of denaturation and inactivation, and low yield, making them difficult to be broadly applicable. As an emerging type of artificial enzyme, nanozymes that combine the characteristics of nanomaterials and enzymes are promising alternatives. On the one hand, nanozymes have high enzyme-like catalytic activities to regulate biochemical reactions. On the other hand, nanozymes also inherit the properties of nanomaterials, which can ameliorate the shortcomings of natural enzymes and serve as versatile platforms for diverse applications. In this review, various nanozymes that mimic the catalytic activity of different enzymes are introduced. The achievements of nanozymes in different cancer diagnosis and treatment technologies are summarized by highlighting the advantages of nanozymes in these applications. Finally, future research directions in this rapidly developing field are outlooked.


Comparison of model-free Lorentzian and spinlock model-based fittings in quantitative CEST imaging of acute stroke.
CEST MRI detects complex tissue changes following acute stroke. Our study aimed to test if spinlock model-based fitting of the quasi-steady-state (QUASS)-reconstructed equilibrium CEST MRI improves the determination of multi-pool signal changes over the commonly-used model-free Lorentzian fitting in acute stroke. Multiple three-pool CEST Z-spectra were simulated using Bloch-McConnell equations for a range of T1 , relaxation delay, and saturation times. The multi-pool CEST signals were solved from the simulated Z-spectra to test the accuracy of routine Lorentzian (model-free) and spinlock (model-based) fittings without and with QUASS reconstruction. In addition, multiparametric MRI scans were obtained in rat models of acute stroke, including relaxation, diffusion, and CEST Z-spectrum. Finally, we compared model-free and model-based per-pixel CEST quantification in vivo. The spinlock model-based fitting of QUASS CEST MRI provided a nearly T1 -independent determination of multi-pool CEST signals, advantageous over the fittings of apparent CEST MRI (model-free and model-based). In vivo data also demonstrated that the spinlock model-based QUASS fitting captured significantly different changes in semisolid magnetization transfer (-0.9 ± 0.8 vs. 0.3 ± 0.8%), amide (-1.1 ± 0.4 vs. -0.5 ± 0.2%), and guanidyl (1.0 ± 0.4 vs. 0.7 ± 0.3%) signals over the model-free Lorentzian analysis. Our study demonstrated that spinlock model-based fitting of QUASS CEST MRI improved the determination of the underlying tissue changes following acute stroke, promising further clinical translation of quantitative CEST imaging.


Synergistic rotavirus and Escherichia coli diarrheal infection of mice.
Experimental or naturally acquired subclinical infections with rotavirus caused a significant increase in mortality of infant mice after challenge with enterotoxigenic Escherichia coli B44.


The influence of orthotic devices and vastus medialis strength and timing on patellofemoral loads during running.
To use a musculoskeletal model and simulation of running to examine: (1) the influence of two commonly prescribed treatments for patellofemoral pain (vastus medialis oblique strengthening and orthoses) and (2) the functional significance of timing differences between vastus medialis oblique and vastus lateralis on lateral patellofemoral joint loads. A three-dimensional musculoskeletal model of the lower extremity was used to simulate running at 4 m/s. Repetitive and excessive joint loading is often associated with overuse injuries that require clinical treatments to reduce pain and restore function. Affecting one in four runners, patellofemoral pain is one of the most common injuries in running. Although conservative treatments have been reported to successfully treat patellofemoral pain, the effectiveness is often based on subjective or empirical data, which have generated disagreement on the most effective treatment. Nine subject specific running simulations were generated and experiments were performed by applying the treatments and timing differences to the nominal simulations. Both treatments significantly reduced the average patellofemoral joint load and the vastus medialis strengthening also significantly reduced the peak patellofemoral joint load. In addition, when the vastus medialis oblique timing was delayed and advanced relative to the vastus lateralis timing, a significant increase and decrease in the joint load was observed, respectively, during the loading response.Conclusions. Increasing vastus medialis oblique strength yielded more consistent results across subjects than the orthosis in reducing patellofemoral joint loads during running. The effect of orthoses was highly variable and sensitive to the individual subject's running mechanics. Vastus medialis oblique activation timing is an important determinant of lateral patellofemoral joint loading during the impact phase. These findings indicate that a reduction in patellofemoral pain may be achieved through techniques that selectively increase the vastus medialis oblique strength. Therefore, future studies should be directed towards identifying such techniques. Additionally, the functional significance of timing differences between the vastus medialis oblique and vastus lateralis is an important consideration in patellofemoral pain treatment and orthoses may be beneficial for some patients depending on their running mechanics.


Norepinephrine metabolism and clinical response to dextroamphetamine in hyperactive boys.
The 24-hour urinary catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol, normetanephrine, and metanephrine were measured in 23 hyperactive boys and 13 matched healthy controls. The hyperactive children excreted lower MHPG and higher NM (low MHPG/NM ratio) amounts than in controls. The administration of d-amphetamine in the dose of 0.5 mg/kg body weight divided over two doses daily for two weeks decreased MHPG excretion in the hyperactive children. When the hyperactive children group was divided into drug responders and nonresponders according to their pre- and post-treatment scores on the Conners Teacher Questionnaire, d-amphetamine administration decreased MHPG excretion in the responders and did not change it in the nonresponders. Percent decrease in MHPG excretion correlated significantly with percent change in the hyperactivity factor of the questionnaire on the Spearman Rank Order Correlation Coefficient. Pretreatment urinary metabolites did not differentiate the responders from nonresponders. It is suggested that a relationship between CNS norepinephrine metabolism and hyperactivity exists and that d-amphetamine may achieve its therapeutic action in hyperactive children by altering CNS NE metabolism.


Renal dysfunction and ischemic heart disease mortality in a hypertensive population.
While recent studies indicate that renal dysfunction may be predictive of all-cause mortality and cardiovascular disease (CVD) outcomes in hypertensive individuals, there has been little attention to the specific association of ischemic heart disease (IHD) mortality and renal function. This study examines the relationship between IHD mortality and baseline glomerular filtration rate (GFR) (estimated by the Cockcroft and Gault formula) among treated hypertensive subjects. A prospective cohort study of participants in a worksite-based antihypertensive treatment program in New York City (1981-1999). We studied 9929 subjects who had at least 6 months follow-up (mean 9.6 years) with a baseline serum creatinine. IHD death outcomes (n=343) ascertained from the National Death Index. Multivariate Cox proportional hazard models were constructed adjusting for known cardiovascular risk factors. Mean GFR of the cohort was 91.6 ml/min per 1.73 m. Those with lower GFR were more likely to be older, female, White, report a history of cardiovascular disease, have higher cholesterol and blood urea nitrogen values, and lower hemoglobin and body mass index than those with highest GFR. After adjustment for known cardiovascular risk factors, the risk of IHD death increased progressively as the GFR decreased. Hazard ratio for IHD mortality for each 10-unit reduction of estimated GFR below the normal threshold of >or=90 ml/min per 1.73 m was 1.33 (95% confidence interval 1.17, 1.50; P<0.001). The results of this study suggest an independent inverse association between estimated GFR and IHD mortality among treated hypertensive individuals.


Comparison of T suppressor factors from tumour-bearing mice and mice immunized with a monoclonal anti-idiotypic antibody.
Certain dosage schedules of a monoclonal anti-idiotypic antibody (related to a murine bladder carcinoma) were found to induce suppressor factor production by syngeneic mice. This suppressor factor resembled the factor from tumour-bearing mice with respect to idiotype specificity, possession of molecular markers (reactive with anti-IJ and B16G antibodies) and production by Lyt2+IJ+ T cells in spleen cell cultures. The two factors differed with respect to Igh restriction in an in vitro assay (leucocyte adherence inhibition) and ability to suppress the induction of delayed-type hypersensitivity to tumour antigen.


Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation.
Preterm infants having immature lungs often require respiratory support, potentially leading to bronchopulmonary dysplasia (BPD). Conventional BPD rodent models based on mechanical ventilation (MV) present outcome measured at the end of the ventilation period. A reversible intubation and ventilation model in newborn rats recently allowed discovering that different sets of genes modified their expression related to time after MV. In a newborn rat model, the expression profile 48 h after MV was analyzed with gene arrays to detect potentially interesting candidates with an impact on BPD development. Rat pups were injected P4-5 with 2 mg/kg lipopolysaccharide (LPS). One day later, MV with 21 or 60% oxygen was applied during 6 h. Animals were sacrified 48 h after end of ventilation. Affymetrix gene arrays assessed the total gene expression profile in lung tissue. In fully treated animals (LPS + MV + 60% O(2)) vs. controls, 271 genes changed expression significantly. All modified genes could be classified in six pathways: tissue remodeling/wound repair, immune system and inflammatory response, hematopoiesis, vasodilatation, and oxidative stress. Major alterations were found in the MMP and complement system. MMPs and complement factors play a central role in several of the pathways identified and may represent interesting targets for BPD treatment/prevention.Bronchopulmonary dysplasia (BPD) is a chronic lung disease occurring in ~30% of preterm infants born less than 30 wk of gestation (1). Its main risk factors include lung immaturity due to preterm delivery, mechanical ventilation (MV), oxygen toxicity, chorioamnionitis, and sepsis. The main feature is an arrest of alveolar and capillary formation (2). Models trying to decipher genes involved in the pathophysiology of BPD are mainly based on MV and oxygen application to young mammals with immature lungs of different species (3). In newborn rodent models, analyses of lung structure and gene and protein expression are performed for practical reasons directly at the end of MV (4,5,6). However, later appearing changes of gene expression might also have an impact on lung development and the evolution towards BPD and cannot be discovered by such models. Recently, we developed a newborn rat model of MV using an atraumatic (orotracheal) intubation technique that allows the weaning of the newborn animal off anesthesia and MV, the extubation to spontaneous breathing, and therefore allows the evaluation of effects of MV after a ventilation-free period of recovery (7). Indeed, applying this concept of atraumatic intubation by direct laryngoscopy, we recently were able to show significant differences between gene expression changes appearing directly after MV compared to those measured after a ventilation-free interval of 48 h. Immediately after MV, inflammation-related genes showed a transitory modified expression, while another set of more structurally related genes changed their expression only after a delay of 2 d (7). Lung structure, analyzed by conventional 2D histology and also by 3D reconstruction using synchrotron x-ray tomographic microscopy revealed, 48 h after end of MV, a reduced complexity of lung architecture compared to the nonventilated rat lungs, similar to the typical findings in BPD. To extend these observations about late gene expression modifications, we performed with a similar model a full gene expression profile of lung tissue 48 h after the end of MV with either room air or 60% oxygen. Essentially, we measured changes in the expression of genes related to the MMPs and complement system which played a role in many of the six identified mostly affected pathways.


Human telomerase and alpha-methylacyl-coenzyme A racemase in prostatic carcinoma. A comparative immunohistochemical study.
Human telomerase detected by in situ hybridization has been demonstrated to be a useful tool for the diagnosis of malignancy and has also been tested by reverse transcriptase-polymerase chain reaction in several tumors such as hepatic cell carcinoma, melanoma, colonic carcinoma, gastric carcinoma, biliary carcinoma, breast carcinoma, mesothelioma, lung carcinoma, female tract carcinoma, and prostatic carcinoma. A monoclonal antibody (clone Tel-24) that allows for the detection of human telomerase reverse transcriptase (hTERT) in paraffin blocks of archival material has recently been developed. Carcinomas of cervix, endometrium, and breast have been studied by this method, but its value in prostatic carcinoma has not been explored; for that reason, we studied benign and malignant prostatic lesions by immunohistochemistry using paraffin embedded tissue. The aim of the study was to define the sensitivity and specificity of hTERT in prostate cancer, in comparison with alpha-methylacyl-coenzyme A racemase (AMACR) (P504-S). Fifty-five specimens of diverse prostatic lesions were selected for study (43 needle biopsies and 12 transurethral resections); there were 61 malignancies (47 infiltrating carcinomas and 14 high-grade prostatic intraepithelial neoplasias [PIN]) and 29 benign lesions (10 basal cell hyperplasias, 12 nodular hyperplasias, 4 chronic prostatitis, and 3 atrophic glands). Signal for hTERT nucleolar was detected in 31 of 47 infiltrating adenocarcinomas, in 11 of 14 PIN, and in none of 27 benign lesions (sensitivity, 71%; specificity, 100%). Diffuse cytoplasmic positivity for AMACR was found in 37 of 41 infiltrating adenocarcinomas, in 7 of 7 PIN, and in 6 of 22 benign lesions (sensitivity, 91%; specificity, 72%). These results indicate that hTERT is highly specific of malignancy, with no false-positive cases; however, it had lower sensitivity than AMACR.


How does collegial support increase retention of registered nurses in homecare nursing agencies? a qualitative study.
Collegial workplace support has been linked to higher registered nurse (RN) retention in various clinical settings. In Japan, homecare agencies experience high RN turnover. The purpose of this study was to develop a conceptual framework to describe how perceived support from colleagues affects RNs' decision to remain in an agency. A qualitative research method based on grounded theory was used. Participants were RNs with at least 4 years of experience at the same homecare agency. Participants were theoretically sampled via managers of 12 homecare nursing agencies. Semi-structured interviews and supplementary participant observations were conducted. Data were analyzed using a constant comparative technique, and the process of how workplace support affected participants' decision to remain at their agency was clarified. In total, 26 RNs were interviewed, 23 of whom were observed in their practice setting. Participants' perception of support from colleagues was framed as being "encouraged to grow in one's own way", which comprised practicing with protected autonomy in an insight-producing environment. Participants reported that they were able to practice with protected autonomy, receiving 1) mindful monitoring, 2) semi-independent responsibility, 3) help as needed, and 4) collegial empathy and validation. RNs also felt supported in an insight-producing environment by 1) enlightening dialogue, 2) being set for one's next challenges, and 3) being able to grow at one's own pace. Reportedly, these were defining characteristics in their decision to continue working in their agencies. For RNs to willingly stay at a homecare nursing agency, it is essential that they are able to practice with protected autonomy in an insight-producing environment that encourages them to grow in their own way. Further research is needed to explore ways to create and enhance such environments to lower RN turnover.


Palmitoylethanolamide stimulates phagocytosis of Escherichia coli K1 and Streptococcus pneumoniae R6 by microglial cells.
The ability of microglial cells to phagocytose bacteria after stimulation with the endocannabinoid palmitoylethanolamide (PEA) was studied in vitro. PEA increased the phagocytosis of unencapsulated Streptococcus pneumoniae R6 and encapsulated Escherichia coli K1 by murine microglial cells significantly after 30 min of microglial stimulation. This suggested that stimulation of microglial cells by PEA can increase the resistance of the brain against CNS infections.


Cough reflex responses during pulmonary C-fibre receptor activation in anesthetized rabbits.
We investigated the changes induced by pulmonary C-fibre receptor activation in the cough reflex evoked by mechanical stimulation of the tracheobronchial tree in pentobarbitone anesthetized, spontaneously breathing rabbits. Phrenic nerve and abdominal muscle activities were monitored along with tracheal and arterial blood pressures. The activation of pulmonary C-fibre receptors by means of right atrial injection of phenylbiguanide (PBG) caused the pulmonary chemoreflex characterized by tachypnea, bradycardia and hypotension. During the pulmonary chemoreflex, the time components (total cycle duration, inspiratory and expiratory times) of the cough motor pattern significantly decreased, whereas no consistent changes in peak phrenic and abdominal activity, peak tracheal pressure and number of coughs evoked by each stimulation trial were observed. At variance with previous findings in cats and dogs, the results show that tracheobronchial cough is not significantly reduced in the rabbit during PBG-induced chemoreflex. This study is the first to provide evidence supporting the hypothesis that the time components of the cough motor pattern are, to some extent, dependent upon the timing characteristics of the ongoing respiratory activity and suggests a novel mechanism leading to cough depression.


TumorML: Concept and requirements of an in silico cancer modelling markup language.
This paper describes the initial groundwork carried out as part of the European Commission funded Transatlantic Tumor Model Repositories project, to develop a new markup language for computational cancer modelling, TumorML. In this paper we describe the motivations for such a language, arguing that current state-of-the-art biomodelling languages are not suited to the cancer modelling domain. We go on to describe the work that needs to be done to develop TumorML, the conceptual design, and a description of what existing markup languages will be used to compose the language specification.


Role of FXR in Liver Inflammation during Nonalcoholic Steatohepatitis.
About 15-25% of patients with simple steatosis of non-alcoholic fatty liver disease progresses to non-alcoholic steatohepatitis (NASH), and the underlying mechanism for this progression has not been elucidated. NASH ultimately could progress to cirrhosis, an irreversible condition. Farnesoid X receptor (FXR) has been studied for its role in modulating inflammation, and the expression of FXR is down-regulated during NASH development. FXR deficiency has shown to progress and exacerbate NASH development, and FXR activation has been protective against liver inflammation associated with NASH. The expression of factors in both the adaptive and innate immune response in the liver are regulated in a FXR-dependent and -independent manner. Therefore, understanding key signaling pathways of liver inflammation in NASH is important to determine essential components that predispose, progress, or exacerbate NASH. FXR has been identified as a therapeutic target for NASH to prevent liver inflammation.


Multiple intravesical linear staples identified during surveillance cystoscopy after laparoscopic nephroureterectomy.
Laparoscopic nephroureterectomy has faced technical criticism secondary to the unknown effects of urine-exposed intravesical or intraureteral staples. Although not reported, staples exposed to urine theoretically create a nidus for encrustation and stone formation. We present a case of a 66-year-old man after left laparoscopic ureterectomy for ureteral malignancy. Surveillance cystoscopy at 6 months revealed a nearly complete intravesical titanium staple line without encrustation. Successful transurethral removal of all staples with standard cystoscopic graspers revealed no immediate, or delayed, sequelae.


Results of a feasibility randomized controlled trial (RCT) of the Toolkit for Optimal Recovery (TOR): a live video program to prevent chronic pain in at-risk adults with orthopedic injuries.
Orthopedic injuries are the leading cause of hospital admissions in the USA, and many of these patients transition into chronic pain. Currently, there are no evidence-based interventions targeting prevention of chronic pain in patients with orthopedic injuries. We iteratively developed a four-session intervention "The Toolkit for Optimal Recovery" (TOR) which we plan to subsequently test for efficacy in a phase III hybrid efficacy-effectiveness multi-site clinical trial. In order to prevent methodological weaknesses in the subsequent trial, we conducted a feasibility pilot to evaluate the TOR delivered via secure live video versus usual care (UC) in patients with orthopedic injuries from an urban, level I trauma clinic, who screen in as at risk for chronic pain and disability. We tested the feasibility of recruitment, acceptability of screening, and randomization methods; acceptability of the intervention, treatment adherence, and treatment fidelity; satisfaction with the intervention; feasibility of the assessment process at all time points; acceptability of outcome measures for the definitive trial; and within-treatment effect sizes. We aimed to recruit 50-60 participants, randomize, and retain them for ~ 4 months. Assessments were done electronically via REDCap at baseline, post-intervention (approximately 5 weeks after baseline), and 3 months later. We followed procedures we intend to implement in the full-scale hybrid efficacy-effectiveness trial. We recruited 54 participants and found that randomization and data collection procedures were generally acceptable. The majority of participants were white, educated, and employed. Warm hand-off referrals were more effective than research assistants directly approaching patients for participation without their providers' engagement. Feasibility of recruitment, acceptability of screening, and randomization were good. Satisfaction with the program, adherence to treatment sessions, and treatment fidelity were all high. There were no technical issues associated with the live video delivery of the TOR. There was minimal missing data and outcome measures were deemed appropriate. Effect sizes for improvement after participation in TOR were moderate to large. There were many lessons learned for future trials. This study provided evidence of the feasibility of the planned hybrid efficacy-effectiveness trial design when implemented at our home institution. Establishing feasibility of the intervention and study procedures at other trauma centers with more diverse patient populations and different clinical practices is required before a multi-site phase III efficacy-effectiveness trial. ClinicalTrials.gov ID: NCT03405610. Registered on January 28, 2018-retrospectively registered.


The appearance in TEM of proteoglycan predentine is fixation dependant.
The appearance of proteoglycans visualized on thin sections with alcian blue was compared in rat incisor predentine fixed either in aqueous aldehyde solutions or by anhydrous methods (acrolein vapours or rapid freezing-freeze substitution). The granular or branched chain-like structures detected after aqueous fixation probably resulted from precipitation or shrinkage of an expanded amorphous gel observed only after anhydrous fixation. In predentine, morphological interactions between proteoglycans and collagen fibres may be also artefactual.


Regional and species differences in endogenous prostaglandin biosynthesis by brain homogenates.
Endogenously formed prostaglandins (PGs) D2, E2 and F2 alpha were determined in homogenates of brain regions from rat, guinea-pig, rabbit and cat, using gas-chromatography-mass spectrometry. The main PGs formed in the brain regions of the rat were PGD2, in the guinea-pig PGD2 and PGF2 alpha, in the rabbit PGF2 alpha and in the cat PGE2. Brain regions from the same animal species showed the same pattern of PG formation. They varied, however, in the amount of total PGs formed, the limbic system and the cerebral cortex being highest and cerebellum lowest.


Geochemical signatures of acidic drainage recorded in estuarine sediments after an extreme drought.
Extreme prolonged drought over south-eastern Australia a decade ago (the Millennium Drought, 1996-2010) triggered extensive acid sulfate soil oxidation and associated acidification. Whilst the significant release of metal-enriched drainage has been documented during this event, the fate of these elements in receiving systems is still largely unknown. Here we investigate the spatial distribution, chemical partitioning, and potential bioavailability of S, Fe, Mn, Al, trace metals (V, Cr, Co, Ni, Cu, Pb) and rare earth elements in the surficial sediments of Lake Albert, South Australia; a system that received prolonged (2007-2011) acidic drainage during the Millennium Drought. The highest concentrations of all metals (Enrichment Factors ranging from 1.06-1.97) were observed in the sediments closest to shorelines where sulfidic material were oxidised, generating metal-enriched acidic drainage. Localised enrichment indicates metals have not been completely redistributed across the system following their initial deposition by physical (wind-driven resuspension) or chemical (diagenetic and redox changes) processes. Based on selective extraction data, these metals are likely partitioned as discrete sulfides (Pb) or are with organic material (V, Cr, Cu, Pb, REEs), Fe monosulfides (V, Co, Ni), or pyrite (Co, Ni, Pb). Lake-wide enrichment of trace metals Cr (mean concentration 57 ppm), Ni (39 ppm), Cu (36 ppm), and Pb (24 ppm) relative to other Lower Murray River sites is also evident, suggesting that metal contamination associated with acidic drainage is not restricted to near-source sites. Importantly, the mobilisation, transport, and accumulation of metals is controlled by sediment transport pathways and system hydrology and will thus function differently under varying states of geomorphology, climate, and anthropogenic modification. Our study shows that extreme drought is recorded as a lasting geochemical signature in estuarine sediments, demonstrating that metal and rare earth element geochemistry provides insights into the distribution and behaviour of contaminants mobilised into dynamic, anthropogenically altered estuaries.


Effects of an anti-exospore monoclonal antibody on microsporidial development in vitro.
In this study we evaluated the effects of the anti-microsporidial exospore monoclonal antibody 3B6, recognizing 3 Encephalitozoon species, Encephalitozoon intestinalis (Syn. Septata intestinalis), Encephalitozoon cuniculi, and Encephalitozoon hellem on microsporidial growth in vitro. Pre-treatment of spores for 24 h with mAb 3B6 resulted in 21-29% fewer infected host cells 4 days after inoculation of the cultures compared to cultures pre-treated with medium or an irrelevant isotype control mAb (P < 0.001). Fewer intracellular spores (1.2 +/- 0.2) in infected cells were found when mAb 3B6 was present in cultures compared to cultures with medium alone (4.3 +/- 0.8) or an irrelevant isotype control mAb (4.2 +/- 0.9; P < 0.001). This decrease appeared not to be dependent on time of exposure, mAb concentration, or presence of complement. It is concluded that antibodies, particularly those directed to potential neutralizing-sensitive epitopes on spores, may have a role in the control of microsporidial growth in vitro.


Renal cysts in premature children: occurrence in a family with polycystic kidney disease.
Discrete but typical renal lesions, probably representing the first stage of familial adult-type polycystic kidney disease, were found in two premature still-born daughters of a woman whose family had many cases of this autosomal dominant disease. Apparently, enough cysts were present to form polycystic kidneys of adult size solely by cyst dilation, without additional cyst formation.


Integration of transdermal chemistry and network pharmacology to decipher the mechanism of ShexiangZhuifeng analgesic plaster to treat rheumatoid arthritis.
Transdermal patches are an effective form of treatment for rheumatoid arthritis (RA), and they have a number of benefits, including patient compliance, accessibility, and low systemic toxicity. ShexiangZhuifeng Analgesic Plaster (SZAP), a patch made up of many traditional medicines, has been successfully utilized in numerous clinical trials to treat RA. However, information about anti-RA processes and transdermal active components is still emerging. Our objectives were to identify the transdermal active components of SZAP and investigate its anti-RA mechanisms, primarily focused on joint inflammation. The collagen-induced arthritis (CIA) rats were created first, and then the arthritis score, Paw thickness, and morphology feature of joint synovial were assessed after 7 days of therapy with SZAP. Moreover, the Franz diffusion cell and UPLC-MS technologies were combined to identify and measure the transdermal active ingredients of SZAP. Furthermore, network pharmacology was utilized to anticipate the putative the mechanism of SZAP for treating RA. Finally, the results of network pharmacology were validated using LPS-induced RAW 264.7 cells and CIA rats. SZAP significantly reduced paw thickness, arthritic score and pathological characteristics of joint synovitis in (CIA) rats. Additionally, 12 transdermal active components of SZAP were identified, and network pharmacology prediction results suggested that SZAP may alleviate joint synovial inflammation by blocking the Akt/mTOR/HIF-1 pathway. Our investigations' findings demonstrated that SZAP dramatically reduced the concentrations of excess cytokines (IL6, VEGF, and TNF-α), as well as the protein overexpression of the AKT/mTOR/HIF- pathway (HIF-1, p-AKT, and p-mTOR), whereas its anti-inflammation effect was reversed once AKT or mTOR was activated. By blocking the AKT/mTOR/HIF-1 pathway, SZAP can lessen the release of inflammatory mediators, which reduces joint synovial inflammation associated with RA. The pharmacological evaluation of TCM transdermal drug delivery formulations like SZAP may be amenable to the integration of transdermal chemistry and network pharmacology approaches.


Galantamine (Reminyl) delays cardiac ventricular repolarization and prolongs the QT interval by blocking the HERG current.
Galantamine is a reversible inhibitor of acetylcholinesterase and an allosteric-potentiating ligand of the nicotinic acetylcholine receptors. It is used for treating mild-to-moderate Alzheimer's disease. Interestingly, QT interval prolongation on the electrocardiogram (ECG), malignant ventricular arrhythmias and syncope have been reported with galantamine. Our objective was to evaluate the effects of galantamine on cardiac ventricular repolarization. Three sets of experiments were undertaken: 1) Whole cell patch-clamp experiments: HERG- or KCNQ1+KCNE1-transfected cells were exposed to galantamine 0.1-1000 μmol/l (n=25 cells, total) to assess drug effect on HERG and KCNQ1+KCNE1 currents. 2) Langendorff perfusion experiments: Isolated hearts from male Hartley guinea pigs (n=9) were exposed to galantamine 1 μmol/l to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). 3) Cardiac telemetry experiments: Guinea pigs (n=7) implanted with wireless transmitters were injected a single intraperitoneal (i.p.) dose of galantamine 3mg/kg and 24h ECG recordings were made. 1) The estimated IC(50) for galantamine on HERG current was 760.2 μmol/l. Moreover, galantamine 10 μmol/l had a small inhibiting effect on KCNQ1+KCNE1 current (12.17 ± 2.19% inhibition, n=10 cells). 2) While pacing at cycle lengths of 150, 200 or 250 ms, galantamine 1 μmol/l prolonged MAPD(90) by respectively 5.1 ± 1.6 ms, 9.4 ± 1.9 ms and 12.1 ± 2.1 ms. 3) Galantamine 3 mg/kgi.p. caused a maximal 11.9 ± 2.7 ms prolongation of the corrected QT (QTc). Galantamine is a weak HERG blocker. This contributes to its mild QT-prolonging effect. Patients could be at risk of cardiac proarrhythmia during drug overdosage or interactions involving cytochrome 2D6 drug-metabolizing enzyme.


Proinflammatory cytokines and procalcitonin in children with acute pyelonephritis.
This prospective study, performed in 76 children with a urinary tract infection (UTI), evaluates the diagnostic value of procalcitonin (PCT) and proinflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) in children with acute pyelonephritis documented by dimercaptosuccinic acid scintigraphy (DMSA). Renal parenchymal involvement was assessed by (99m )Tc-DMSA scintigraphy within 7 days of admission. The diagnosis of acute pyelonephritis was confirmed only in patients with reversible lesions on scintigraphy. According to DMSA scan results, patients were divided into two groups, lower UTI or acute pyelonephritis. In acute pyelonephritis, serum PCT level was found to be significantly higher than it is in the lower UTI (p <0.001). Also, significantly higher serum proinflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) levels were detected in those with acute pyelonephritis than those with lower UTI (p <0.001). We conclude that both serum PCT and proinflammatory cytokine levels may be used as accurate markers for diagnosis of acute pyelonephritis.


Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF.
Enhanced osteoblast-dependent osteoclastogenesis due to inhibition of Wnt/beta-catenin signaling in bone morphogenic protein (BMP)-driven osteoprogenitors has been repeatedly implicated in the natural history of cancer-associated osteolytic lesions, but the mechanism of this bone loss is poorly understood. We examined the impact of secreted Wnt inhibitors from the Dickkopf (Dkk) family on pluripotent mesenchymal cells undergoing BMP2-induced osteoblastic differentiation. We found that Dkk1 and -2 restored the Wnt3a-dependent reduction of alkaline phosphatase (ALP), Osterix and p53, indicating that mitigated Wnt/beta-catenin signaling promotes certain aspects of early osteoblastogenesis through the BMP-p53-Osterix-ALP axis. Dkk1 and -2 increased the expression of the osteoclast differentiation factors, receptor activator of NF-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), upon stimulation with Wnt3a/1,25-dihydroxyvitamine D3 and Wnt3a/BMP2, respectively. The decoy receptor of RANKL, osteoprotegerin (OPG), was down regulated under the latter conditions. These findings indicated that Dkk1 and -2 facilitate osteoclastogenesis by enhancing RANKL/RANK and M-CSF/c-Fms interactions. Dkk4 weakly shared activities of Dkk-1 and -2, whereas Dkk3 was ineffective. Our results suggest that inhibited Wnt/beta-catenin signaling in BMP2-induced osteoprogenitors in vivo promotes, on balance, the heightened formation of osteoclasts. Focally increased Dkk1 production by tumor cells in the bone may thus lead to focal bone loss.


Optical diffraction tomography and image reconstruction to measure host cell alterations caused by divergent Plasmodium species.
Malaria is a life-threatening infectious disease caused by parasites of the genus Plasmodium. Understanding the biological features of various parasite forms is important for the optical diagnosis and defining pathological states, which are often constrained by the lack of ambient visualization approaches. Here, we employ a label-free tomographic technique to visualize the host red blood cell (RBC) remodeling process and quantify changes in biochemical properties arising from parasitization. Through this, we provide a quantitative body of information pertaining to the influence of host cell environment on growth, survival, and replication of P. falciparum and P. vivax in their respective host cells: mature erythrocytes and young reticulocytes. These exquisite three-dimensional measurements of infected red cells demonstrats the potential of evolving 3D imaging to advance our understanding of Plasmodium biology and host-parasite interactions.


Patterns of family management of childhood chronic conditions and their relationship to child and family functioning.
Understanding patterns of family response to childhood chronic conditions provides a more comprehensive understanding of their influence on family and child functioning. In this paper, we report the results of a cluster analysis based on the six scales comprising the Family Management Measure (FaMM) and the resulting typology of family management. The sample of 575 parents (414 families) of children with diverse chronic conditions fell into four patterns of response (Family Focused, Somewhat Family Focused, Somewhat Condition Focused, Condition Focused) that differed in the extent family life was focused on usual family routines or the demands of condition management. Most (57%) families were in either the Family Focused or Somewhat Family Focused pattern. Patterns of family management were related significantly to family and child functioning, with families in the Family Focused and Somewhat Family Focused patterns demonstrating significantly better family and child functioning than families in the other two patterns.


What triggers selective daily mobility among older adults? A study comparing trip and environmental characteristics between observed path and shortest path.
Interest is growing in neighborhood effects on health beyond individual's home locations. However, few studies accounted for selective daily mobility bias. Selective mobility of 470 older adults (aged 67-94) living in urban and suburban areas of Luxembourg, was measured through detour percentage between their observed GPS-based paths and their shortest paths. Multilevel negative binomial regression tested associations between detour percentage, trips characteristics and environmental exposures. Detour percentage was higher for walking trips (28%) than car trips (16%). Low-speed areas and connectivity differences between observed and shortest paths vary by transport mode, indicating a potential selective daily mobility bias. The positive effects of amenities, street connectivity, low-speed areas and greenness on walking detour reinforce the existing evidence on older adults' active transportation. Urban planning interventions favoring active transportation will also promote walking trips with longer detours, helping older adults to increase their physical activity levels and ultimately promote healthy aging.


Changes in macromolecular movement accompany organogenesis in thin cell layers of Torenia fournieri.
A range of fluorescently labelled probes of increasing molecular weight was used to monitor diffusion via the symplast in regenerating thin cell layer (TCL) explants of Torenia fournieri. An increase in intercellular movement of these molecules was associated with the earliest stages of vegetative shoot regeneration, with the movement of a 10 kDa dextran (FD 10000) observed between epidermal cells prior to the appearance of the first cell divisions. A low frequency of dextran movement in thin cell layers maintained under non-regenerating conditions was also observed, indicating a possible wound induced increase in intercellular movement. Dextran movement between epidermal cells reached a peak by day 4 of culture and then declined as cell division centres (CDCs) formed, became meristematic regions and finally emerged as adventitious shoots. Within CDCs, testing with small fluorescent probes (CF: carboxyfluorescein, mw 376 Da and F(Glu)3: fluorescein-triglutamic acid, mw 799 Da) revealed a mosaic of cell isolation and regions of maintained symplastic linkage. Within shoots, surface cells of the presumptive apical meristem permitted the intercellular movement of 10 kDa dextrans but epidermal cells of the surrounding leaf primordia did not permit dextran movement. In some cases, intercellular movement of CF was maintained within leaf primordia. Symplastic movement of labelled dextrans during regeneration in Torenia thin cell layers represents a significant increase in the basal size exclusion limit (SEL) of this tissue and reveals the potential for intercellular trafficking of developmentally related endogenous macromolecules.


Influence of natural exposure on castor oil based polyurethane reinforced with waste tire rubber.
Waste tire rubber (WTR) has been extensively generated worldwide due to mobility needs growth. About 1.5 billion units are generated annually, constantly discharged in the environment with a few reusability alternatives. Therefore, rubber recovery methods and these residues' transformation into a cost-effective product have gained attention. Aiming to minimize the usage of fossil resources and contributes to a circular economy, it was analyzed the usage of WTR particles (5-20% by weight) in castor oil-based polyurethane foams under natural aging to promote a holistic view of all factors involved in the performance of the foams. Morphological, thermal, chemical, and mechanical properties were determined before and after exposure to open air to observe the impact of photo-oxidation and hydrolysis. The increase in viscosity of pre-polymer during the rubber loading produced greater density foams with smaller cell sizes than neat PU, in which the average cell size increased after the weathering. The rubber contributes to enhancing the compressive behavior in the non-exposed samples. After exposure, the results suggest that degradation may act to increase the crosslinking density even with the presented structural changes such as yellowing and voids. Regarding thermal stability, the rubber promotes a slight decay in the ability to resist a heat flow before and after weathering. Still, the char yield increased, showing a possibility of better fire retardancy for composites. FTIR and UV-vis showed chemical structure changes as Photo-Fries network rearrangement, Norrish I random chain scission, and Norrish II β-scission. Besides, UV-vis revealed the maximum absorbance in the UVB region, showing that the PU reinforced by WTR can be a promising material for civil coatings.


Intraductal Papillary Neoplasm of the Bile Duct: Radiological Diagnosis of a Rare Entity: Case Series.
Intraductal papillary neoplasm of the bile duct (IPNB) is a rare bile duct neoplasm characterized by an intraluminal papillary growth pattern in bile ducts and is considered a biliary counterpart of intraductal papillary mucinous neoplasm of the pancreas. We report here two cases. (1) A case of a 34-year-old woman who presented with complaints of pain in the abdomen, jaundice, and pruritus. Further radiological investigations revealed the possibility of an IPNB, which was confirmed on histopathology. (2) A case of a 61-year-old man who was a known case of Barrett's esophagus and presented with complaints of right upper abdomen and jaundice. Radiological investigations and histopathology further confirmed the diagnosis of an IPNB involving the extrahepatic bile ducts. The purpose of this article is to highlight the role of computed tomography (CT) and magnetic resonance imaging in reaching this challenging diagnosis. Although the diagnosis is not straightforward, imaging plays a great role in raising the possibility of an IPNB. The correct preoperative diagnosis is necessary for accurate surgical planning and resection. Jain K. Intraductal Papillary Neoplasm of the Bile Duct: Radiological Diagnosis of a Rare Entity: Case Series. Euroasian J Hepato-Gastroenterol 2023;13(1):28-31.


Effect of cholesterol-rich diet on the susceptibility of rodent malarial parasites to chloroquine chemotherapy.
Mice were fed a cholesterol-rich diet and then subsequently infected with chloroquine-sensitive strains of either Plasmodium berghei or P. chabaudi. Chloroquine therapy, which was started 24 hours post-infection and continued for 3-4 days, was significantly less effective in cholesterol-fed animals compared to controls. The consequences of these findings to the resistance of P. falciparum in man to chloroquine, are discussed.


Partial characterization of endothelin-converting enzyme activity in human serum lipoproteins.
Endothelin (ET)-1 is an endothelium-derived vasoconstrictor and mitogen peptide generated from an intermediate form (big ET-1) by endothelin-converting enzyme(s) (ECE). In this study, we partially characterized ECE activity in human serum lipoprotein fraction. By gel filtration chromatography, lipoprotein ECE activities consisted of three major components: the first and the second peak eluted in the positions of very low density lipoprotein (VLDL) and low density lipoprotein (LDL), respectively, while the third peak eluted earlier than that of high density lipoprotein (HDL), whose apparent molecular weight (550 kDa) was similar to that of apolipoprotein B (apo B). Both VLDL/LDL-associated and free ECE fractions were similarly inhibited by metalloproteinase and serine proteinase inhibitors. Free ECE fraction was precipitable with dextran sulphate and manganese ion in the same manner as lipoprotein ECE. Apo B purified by high performance liquid chromatography had the same ECE activity as lipoprotein ECE, whose activity was removed after immunoprecipitation with polyclonal anti-apo B antibody. Our data suggest that ECE activity in human serum lipoproteins may be associated with an apo B-like component, although it needs to be characterized completely.


Barbary partridge meat quality as affected by Hermetia illucens and Tenebrio molitor larva meals in feeds.
A partial substitution (25 or 50%) of dietary protein with Tenebrio molitor (TM) and Hermetia illucens (HI) meals as protein sources in the diet of Barbary partridge (Alectoris barbara) has been tested in terms of raw and cooked meat quality. Twelve partridges per feeding group (control - SBM, HI25, HI50, TM25 and TM50) were slaughtered. The peeled carcasses of the HI25, HI50, TM25 and TM50 groups were heavier than those of the SBM group, both raw and cooked. The pH, color and shear force of the raw meat were not affected to any greater extent by the diet, whereas the presence of insect meal seemed to increase the yellowness index of the cooked meat. The proximate composition was unaffected by both the species and the level of insect meal, although the fatty acid profile was changed considerably. The HI and TM groups had significantly higher C18:1n-9 and lower C16:0 contents than SBM. Furthermore, Hermetia illucens, added as 50% of the dietary protein, induced a significant increase in C12:0 and C16:1n-7. As a result, the highest AI and TI were obtained for the HI50 diet (0.38 and 0.75, respectively), whereas the TM groups both had intermediate AI values (around 0.35) and the lowest TI (0.67). Finally, the cholesterol content of the birds was not affected by insect inclusion in the feeds.


Impact of fracture-prone implantable cardioverter defibrillator leads on long-term patient mortality.
The long-term relationship between fracture-prone implantable cardioverter-defibrillator (ICD) leads and poor prognosis remains unclear in Japanese patients. We conducted a retrospective review of the records of 445 patients who underwent implantation of advisory/Linox leads (Sprint Fidelis, 118; Riata, nine; Isoline, 10; Linox S/SD, 45) and non-advisory leads (Endotak Reliance, 33; Durata, 199; Sprint non-Fidelis, 31) between January 2005 and June 2012 at our hospital. The primary outcomes were all-cause mortality and ICD lead failure. The secondary outcomes were cardiovascular mortality, heart failure (HF) hospitalization, and the composite outcome of cardiovascular mortality and HF hospitalization. During the follow-up period (median, 8.6 [4.1-12.0] years), there were 152 deaths: 61 (34%) in patients with advisory/Linox leads and 91 (35%) in those with non-advisory leads. There were 32 ICD lead failures: 27 (15%) in patients with advisory/Linox leads and five (2%) in those with non-advisory leads. Multivariate analysis for ICD lead failure demonstrated that the advisory/Linox leads had a 6.65-fold significantly greater risk of ICD lead failure than non-advisory leads. Congenital heart disease (hazard ratio 2.51; 95% confidence interval 1.08-5.83; p = .03) could also independently predict ICD lead failure. Multivariate analysis for all-cause mortality demonstrated no significant association between advisory/Linox leads and all-cause mortality. Patients who have implanted fracture-prone ICD leads should be carefully followed up for ICD lead failure. However, these patients have a long-term survival rate comparable with that of patients with non-advisory ICD leads in Japanese patients.


Plasma Exosomal MiRNAs Expression Profile in Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis: Case-Control Study and Analysis of Potential Functions.
To explore an expression profile in plasma exosomal miRNAs of mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE + HS) patients and investigate the associated clinical significance and putative pathways involved. Plasma exosomal miRNAs were measured in six mTLE + HS patients who were confirmed with pre-surgical stereo-electroencephalography and six without hippocampal sclerosis (mTLE-HS) using Illumina HiSeq 2500. Then six dysregulated miRNAs were chosen for validation in an independent sample of 18 mTLE + HS patients and 18 mTLE-HS controls using RT-qPCR. Receiver operating characteristic curve was conducted to evaluate the diagnostic value of miRNAs in HS. Bioinformatic analyses were conducted to reveal in which pathways these miRNAs were involved. We revealed that a total of 42 exosomal miRNAs were differentially expressed in mTLE + HS. Among them, 25 were increased and 17 decreased. After validation, hsa-miR-129-5p, -214-3p, -219a-5p, and -34c-5p were confirmed as being upregulated, while hsa-miR-421 and -184 were significantly downregulated in mTLE + HS. Moreover, hsa-miR-184 had the best diagnostic value for discriminating mTLE + HS with 88.9% sensitivity and 83.3% specificity. These six miRNAs regulated several genes from neurotrophin-, hippo-, p53-, TGF- beta-, HIF- 1-, mTOR-related pathways. Six miRNAs were dysregulated in mTLE + HS patients and targeted several genes. This result might facilitate pathological mechanistic studies of miRNAs in HS and represent potential diagnostic biomarkers. These provided the rationale for further confirmation studies in larger cohorts of prospective patients.


Households contaminated by environmental tobacco smoke: sources of infant exposures.
To examine (1) whether dust and surfaces in households of smokers are contaminated with environmental tobacco smoke (ETS); (2) whether smoking parents can protect their infants by smoking outside and away from the infant; and (3) whether contaminated dust, surfaces, and air contribute to ETS exposure in infants. Quasi-experiment comparing three types of households with infants: (1) non-smokers who believe they have protected their children from ETS; (2) smokers who believe they have protected their children from ETS; (3) smokers who expose their children to ETS. Homes of smokers and non-smokers. Smoking and non-smoking mothers and their infants < or = 1 year. ETS contamination as measured by nicotine in household dust, indoor air, and household surfaces. ETS exposure as measured by cotinine levels in infant urine. ETS contamination and ETS exposure were 5-7 times higher in households of smokers trying to protect their infants by smoking outdoors than in households of non-smokers. ETS contamination and exposure were 3-8 times higher in households of smokers who exposed their infants to ETS by smoking indoors than in households of smokers trying to protect their children by smoking outdoors. Dust and surfaces in homes of smokers are contaminated with ETS. Infants of smokers are at risk of ETS exposure in their homes through dust, surfaces, and air. Smoking outside the home and away from the infant reduces but does not completely protect a smoker's home from ETS contamination and a smoker's infant from ETS exposure.


NP-induced biophysical and biochemical alterations of rat testicular Sertoli cell membranes related to disturbed intracellular Ca(2+) homeostasis.
Nonylphenol (NP) is a representative endocrine disruptor that has an adverse effect on male reproduction and posses direct hazard to Sertoli cells, but the mechanism remains incompletely elucidated. In the present study, based on the structural comparability and high affinity between NP and membrane phospholipid molecules, we tested the hypothesis that entrance of NP into Sertoli cells would alter membrane biophysical characteristics and biochemical functions. First, we used gas chromatography-mass spectrometry (GC-MS) to investigate the distribution and pharmacokinetics of NP in Sertoli cells with the result revealing that NP could penetrate plasma membrane of Sertoli cells. Meanwhile, Sertoli cells treated with NP exhibited abnormal membrane potential; that is an early depolarization following short treatment and hyperpolarization after longer treatment with the highest concentration of NP. Studies on the membrane dynamics indicated that the NP exposure rendered increased membrane fluidity and decreased microviscosity and molecular order. The result of lactate dehydrogenase (LDH) leakage assay demonstrated that NP increased membrane permeability in time-dose-dependent manners. Atomic force microscopic (AFM) imaging was applied to examine the membrane topography, and the images showed that NP treatment caused disturbance of membrane topography. The activities of plasma membrane Ca(2+)-ATPase, Ca(2+)-Mg(2+)-ATPase and Na(+)-K(+)-ATPase were also changed following NP exposure. However, FSH receptor as an important membrane protein was not significantly altered. All the above changes led to the disturbed intracellular Ca(2+) homeostasis which was an important signal triggering apoptosis. Hence, cellular membranes represented a plausible target for NP-induced cytotoxicity.


Angiosarcoma treated with radiotherapy: impact of tumor type and size on outcome.
Angiosarcoma is a rare and highly malignant vascular neoplasm. The purpose of this study was to elucidate the tumor characteristics and evaluate the efficacy of radiotherapy (RT) for angiosarcoma. Thirty patients with angiosarcoma (20 males and 10 females, age range 4-89 years, median 66) who received RT from 1986 to 1999 were enrolled in the study. Twenty-four patients had angiosarcoma of the face and scalp (AFS), and 6 patients had angiosarcomas at other sites. AFS was classified into two categories (according to the macroscopic features): nodular AFS (14 patients) and endophytic AFS (10 patients). The median prescribed irradiation dose was 68 Gy. Surgery had been previously performed in 9 patients, and adjuvant immunotherapy using recombinant interleukin-2 (rIL-2) was combined during and after RT in 20 patients. Univariate analyses and calculation of survival by Kaplan-Meier methods were performed. Local tumor control was obtained in 17 patients (57%). However, 7 (47%) of them developed distant metastases. The median survival time for all patients was 8 months (7 months for AFS), and the 13-year overall survival rate was 25% (20% for AFS). Twenty-one patients died of angiosarcoma, with the cause of death local failure in 7 patients, distant failure in 7, and both in 7. Tumor type and size were found to be significant prognostic factors (p = 0.004 and p = 0.007, respectively), and age, total amount of rIL-2, gender, radiation dose, and surgery were not. Six patients (4 with nodular AFS and 2 with angiosarcoma in other parts) survived >2 years. No patient with endophytic AFS survived >2 years. Ten patients (33%) died of respiratory failure secondary to pulmonary metastases. High-dose rIL-2 administration suppressed the occurrence of distant metastases (p = 0.006). Two patients developed radiation dermatitis (Radiation Therapy Oncology Group Grade 4). RT, combined with complete resection or adjuvant rIL-2 immunotherapy, could be a promising treatment strategy, leading to prolonged survival in patients with angiosarcoma.


Fabiana imbricata Ruiz et Pav. (Solanaceae), a review of an important Patagonian medicinal plant.
Fabiana imbricata (Solanaceae) is a Patagonian medicinal plant with a long tradition of use. The aim of this review is to provide an integrative overview of the traditional uses, chemistry, bioactivity and chemical profiling of the crude drug. The information was collected from scientific databases searching with the keywords Fabiana imbricata, Fabiana species, Fabiana (Solanaceae) and includes local literature and books. The indications of use reported in literature show little variation from the data published as early as 1889. The chemical studies showed a rich diversity in metabolites including phenolics, coumarins, flavonoids, phenylpropanoids, terpenes, alkaloids and sugars. Bioactivity studies supported the traditional use as diuretic and also the potential of the crude drug as a gastroprotective agent. The plant can be used as a source of compounds with effect on gastric ulcers and shows enzyme inhibitory activity. While the germination rate of the plant is very low, protocols were developed for the rapid in vitro propagation of the species. The toxicity of the crude drug extracts was low and did not show clastogenic effect in human lymphocytes. Further research is needed to disclose the potential of the F. imbricata sesquiterpenes on other relevant biological targets.


Prevention of adjuvant arthritis in rats by a nonapeptide from the 65-kD mycobacterial heat-shock protein.
Adjuvant arthritis in Lewis rats is a model of T cell-mediated autoimmune arthritis resembling human rheumatoid arthritis. A nonapeptide from the 65-kD heat-shock protein of Mycobacterium bovis BCG, amino acid sequence 180-188, has been described to carry the dominant immunogenic epitope(s) for both arthritis-protective and arthritogenic T cell clones. Here we demonstrate that immunizations with the synthetic nonapeptide completely protected rats against adjuvant arthritis induced by M. tuberculosis. Interestingly, deletion of the N-terminal threonine of the nonapeptide resulted in loss of the protective activity. Pretreatments with the nonapeptide resulted in an immune response to the nonapeptide and to M. tuberculosis. After immunizations with the synthetic nonapeptide, only low titres of nonapeptide-specific antibodies were produced, whereas a significant cellular immune response to the nonapeptide was observed. In addition, the protection was transferable to naive rats by spleen T cells. These findings document the requirement of a T cell-specific immune response to the dominant epitope of the 65-kD mycobacterial heat-shock protein for the protection against adjuvant arthritis and suggest the feasibility of immune intervention in autoimmune arthritis through the use of synthetic peptides.


Longitudinal relationship between chronic kidney disease and distribution of cerebral microbleeds in patients with ischemic stroke.
Chronic kidney disease (CKD) has been reported to be independently associated with cerebral microbleeds (CMB). Since both glomerular afferent arterioles and cerebral perforating arteries are strain vessels, CKD and CMB may share similar dynamic changes. To clarify whether CKD and CKD progression are related to the distribution and evolution of CMB in patients with ischemic stroke. We retrospectively examined the data from the CASISP study. 500 patients with ischemic stroke were analyzed. The number and distribution of CMB were assessed using Microbleed Anatomical Rating Scale. Renal function was evaluated by the estimated glomerular filtration rate (eGFR) and proteinuria. 51 (10.2%) and 158 (31.6%) had decreased eGFR (<60ml/min/1.73m(2)) and CMB at baseline, respectively; 31 (6.6%) and 84 (16.8%) had CKD and CMB progression. Decreased eGFR at baseline (OR=1.533, 95% CI: 1.111-2.114; p=0.009), proteinuria (OR=1.778, 95% CI: 1.026-3.083; p=0.040), CKD progression (OR=2.004, 95% CI: 1.191-3.370; p=0.009) and history of hypertension (OR=2.084, 95% CI: 1.241-3.49; p=0.005) were independently associated with the presence of deep or infratentorial CMB at follow-up. CMB progression in deep or infratentorial area was more frequent in patients with CKD progression than those without (29.0% versus 13.1%, p=0.028). Logistic regression analyses showed that CKD progression (OR=2.577, 95% CI: 1.393-4.769; p=0.003) was independently associated with the progression of deep or infratentorial CMB. CKD and CKD progression are independently associated with presence and evolution of deep or infratentorial CMB, but not lobar CMB.


Wheat-Free and Nutritious Bread and 'Coricos' Made with Mesoamerican Ancestral Corn, Amaranth, Sweet Potato and Chia.
People with wheat-related disorders require wheat-free and good quality baked goods. We prepared wheat-free bread and cookies (coricos) with flour blends of corn, amaranth, orange sweet potato and chia. Sweet potato flour or puree and amaranth flour were prepared and their properties evaluated. Blends were optimized for dough hardness and cohesiveness by response surface methodology, with a central composite rotatory design. Bread was prepared with optimal blends plus 1.2% chia mucilage, and alternatively used sweet potato puree. The optimized blend was 57:34:9 (corn:amaranth:sweet potato flours). Coricos were made with the blend instead of only corn as traditionally. Chemical composition, texture profile, fiber, and gluten content of the products were analyzed. The breads' crust was uniform, crunchy and golden, and the crumb was homogeneous, with 41% specific volume and 60% size of the wheat bread. Coricos presented a darker golden color than those of 100% corn. Protein content was similar (~ 12% d.w.) between the blend and wheat breads, with better chemical score for the blend one. Blend bread and coricos had 2-4% more dietary fiber and higher content of bioactive compounds than their wheat or corn counterparts. Blend bread was comparable to its counterpart in chewiness while coricos were softer. Gluten content was < 20 ppm in blend products; therefore, in addition to nutritional quality, they are safe for people with wheat-related disorders.


Risk factors for early bacterial infections in liver transplantation.
Our aim was to determine perioperative risk factors for early bacterial infection after liver transplantation. Retrospectively examining medical records using Centers for Disease Control and Prevention (CDC) definitions to identify nosocomial infections, we analyzed data on 367 adult patients. The incidence of infection was 37.3% (n = 137): namely, surgical site (n = 74; 20.2%) [corrected], blood stream (n = 64; 17.4%), pulmonary (n = 49; 13.4%), urinary system (n = 26; 7.1%). Significant risk factors within the first 30 days were as follows: deceased donor, Model for End-Stage Liver Disease (MELD) >20, albumin level <2.8 g/dL, intraoperative erythrocyte transfusion >6 U, intraoperative fresh frozen plasma >12 U, bilioenteric anastomosis, postoperative intensive care unit stay >6 days, and postoperative length of stay >21 days. Significant risk factors detected within the first 90 days were as follows: MELD >20, preoperative length of stay >7 days, reoperation, postoperative length of intensive care unit stay >6 days, and postoperative length of stay >21 days. Variability was observed in risk factors according to localization of infection. As a result, except for MELD, type of donor, and biliary anastomosis, the others are preventable factors for early bacterial infection. In addition, the same risk factors showed variability according to the site of infection.