Sense of agency: Sensorimotor signals and social context are differentially weighed at implicit and explicit levels.
Sense of agency (SoA) describes the experience of being the author of an action. Cue integration approaches divide SoA into an implicit level, mostly relying on prospective sensorimotor signals, and an explicit level, resulting from an integration of sensorimotor and contextual cues based on their reliability. Integration mechanisms at each level and the contribution of implicit to explicit SoA remain underspecified. In a task of movements with visual outcomes, we tested the effect of social context (contextual cue) and sensory prediction congruency (retrospective sensorimotor cue) over implicit (intentional binding) and explicit (verbal judgments) SoA. Our results suggest that prospective sensorimotor cues determine implicit SoA. At the explicit level, retrospective sensorimotor cues and contextual cues are partly integrated in an additive way, but contextual cues can also act as a heuristic if sensorimotor cues are highly unreliable. We also found no significant association between implicit and explicit SoA.


Photobiomodulation and eccentric exercise for Achilles tendinopathy: a randomized controlled trial.
The common regime of eccentric exercise in use for Achilles tendinopathy is somewhat arduous and compliance issues can arise. This is the first study to investigate the effectiveness of a regime of fewer exercise sessions combined with photobiomodulation for the treatment of Achilles tendinopathy. A double blind randomized controlled trial and intention-to-treat analysis were performed. Eighty participants, 18-65 years with Achilles tendinopathy and symptoms for longer than 3 months, were included in the trial. Participants randomized into one of four groups; 1 (Placebo + Ex Regime 1) or 2 (Laser + Ex Regime 1) or 3 (Placebo + Ex Regime 2) or 4 (Laser + Ex Regime 2). The primary outcome measure was the Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire. Outcomes were collected at baseline, week 4 and week 12. Sixteen participants were lost to follow-up at 12 weeks, 4 of which due to adverse reactions. As per intention to treat, missing data were imputed, 80 participants were included in the final analysis. For VISA-A at 12 weeks, group 4 achieved significant gains over the other 3 groups: group 1 (18.5 [9.1, 27.9]), group 2 (10.4 [1.5, 19.2]), group 3 (11.3 [3.0, 19.6]). There was a moderate effect size in favour of exercise twice per week (7.2 [-1.8, 16.2], ES .7). Twice-daily exercise sessions are not necessary as equivalent results can be obtained with two exercise sessions per week. The addition of photobiomodulation as adjunct to exercise can bring added benefit.


A chain binomial epidemic with asymptomatics motivated by COVID-19 modelling.
Motivated by modelling epidemics like COVID-19, this paper proposes a generalized chain binomial process which integrates two types of infectives, those with symptoms and those without. Testing of infectives and vaccination of susceptibles are then incorporated as preventive protective measures. Our interest relates to the distribution of the state of the population at the end of infection and to the reproduction number [Formula: see text] with the associated extinction condition. The method uses the construction of a family of martingales and a branching approximation for large populations, respectively. A more general branching process for epidemics is also constructed and studied. Finally, some results obtained are illustrated by numerical examples.


Unnatural acts: The transition from Natural Principles to Laws of Nature in Early Modern science.
This paper's aim is to explain the transition that occurred during the Early Modern period, from Principles of Nature to Laws of Nature. Natural Principles are taken to be innate to substances and arise from their natures, while Laws of Nature are external and imposed from without. The paper takes the view that to explain this transition, one needs to examine the history of philosophical theories of substantial action. It argues that during the late Middle Ages and in the Early Modern era, philosophers began to disentangle substantial actions from the nature of substances. This process of disentangling action eventually led to the concept of Laws of Nature, according to which laws compel a body to act in a certain way even though its nature does not.


Essential factors of Sui Zheng Shi Liang strategy in type 2 diabetes treatment assessed by questionnaire.
Sui Zheng Shi Liang strategy (regulating prescription dosage with different syndromes) is an important part of syndrome differentiation and treatment in Traditional Chinese Medicine (TCM). Questionnaires were given to doctors and patients to study the essential factors (indicators and timing) of Sui Zheng Shi Liang strategy in the treatment process of type 2 diabetes (T2DM). Two questionnaires were designed for diabetes patients and their doctors. The questionnaires included the most important indicators for determining the patient's condition, the ability of TCM in treating T2DM, the length of time it takes forTCM to be effective, and when to adjust the prescription dosage. The frequency of answers was calculated, summarized, and analyzed after the survey. Twenty questionnaires from doctors and 90 questionnaires from patients were included in the analysis. Doctors and patients recognized that TCM could decrease blood glucose, improve syndromes, and delay complications. Doctors were mainly concerned about glycosylated hemoglobin, while the patients were concerned about fasting plasma glucose for determining whether treatment was effective. Doctors also paid attention to changes in blood sugar and syndromes 2 weeks after medication was given as the indication to adjust the prescription dosage, while patients were concerned about these factors in 4 weeks. The prescription should be regulated when there are side effects or the medication is ineffective. The essential factor in the treatment process of T2DM in Sui Zheng Shi Liang strategy is that if fasting blood glucose level did not decrease after 4 weeks of treatment, the Chinese medicine prescription should be adjusted.


Altered phosphatidylinositol regulation of mutant inwardly rectifying K+ Kir7.1 channels associated with inherited retinal degeneration disease.
Kir7.1 K+ channel expressed in retinal pigment epithelium is mutated in inherited retinal degeneration diseases. We study Kir7.1 in heterologous expression to test the hypothesis that pathological R162 mutation to neutral amino acids results in loss of a crucial site that binds PI(4,5)P2 . Although R162W mutation inactivates Kir7.1, changes to smaller volume (e.g. Gln) amino acids are tolerated or even enhance function (Ala or Cys). Chemical modification of Kir7.1-R162C confirms that large residues of the size of Trp are incompatible with normal channel function even if positively charged. In addition to R162, K164 (and possibly K159) forms a binding site for the phosphoinositide and is essential for channel activity. R162 substitution with a large, neutral side chain like Trp exerts a dominant negative effect on Kir7.1 activity such that less than one fifth of the full activity is expected in a cell expressing the same amount of mutant and wild-type channels. Mutations in the Kir7.1 K+ channel, highly expressed in retinal pigment epithelium, have been linked to inherited retinal degeneration diseases. Examples are mutations changing Arg 162 to Trp in snowflake vitreoretinal degeneration (SVD) and Gln in retinitis pigmentosa. R162 is believed to be part of a site that binds PI(4,5)P2 and stabilises the open state. We have tested the hypothesis that R162 mutation to neutral amino acids will result in the loss of this crucial interaction to the detriment of channel function. Our findings indicate that although R612W mutation inactivates Kir7.1, changes to smaller volume (e.g. Gln) amino acids are tolerated or even enhance function (Ala or Cys). Cys chemical modification of Kir7.1-R162C confirms that large residues of the size of Trp are incompatible with normal channel function even if positively charged. Experiments titrating the levels of plasma membrane PI(4,5)P2 with voltage-dependent phosphatase DrVSP reveal that, in addition to R162, K164 (and possibly K159) forms a binding site for the phosphoinositide and ensures channel activity. Finally, the use of a concatemeric approach shows that substitution of R162 with a large, neutral side chain mimicking a Trp residue exerts a dominant negative effect on Kir7.1 activity such that less than one fifth of the full activity is expected in heterozygous cells carrying the SVD mutation. Our results suggest that if mutations in the human KCNJ13 gene resulting in the neutralisation of R162 and Kir7.1 malfunction led to retinal degeneration diseases, their severity might depend on the nature of the side chain of the replacing amino acid.


Prostaglandin E2 inhibits proliferation and migration of HTR-8/SVneo cells, a human trophoblast-derived cell line.
Normal placentation requires a highly coordinated control of proliferation, migration and invasiveness of extravillous trophoblast cells. Since prostaglandin E2 is a major prostanoid synthesized by intrauterine tissues and highly involved in pregnancy homeostasis, we examined the possibility that it modulates extravillous trophoblast cell functions. Here, we report the presence of mRNAs for prostaglandin E2 EP2 and EP4 receptor isoforms and of proteins in both first-trimester human chorionic villi and in the human trophoblast-derived HTR-8/SVneo cells. Moreover we found that: (i) this cell line releases prostaglandin E2 and the output is enhanced by interleukin-1beta; (ii) the prostanoid consistently inhibits serum- or epidermal growth factor-induced cell proliferation and also migration. An involvement of cAMP in the prostaglandin E2 antiproliferative action is suggested by the observation that the prostanoid greatly enhances cAMP level in HTR-8/SVneo cells and that forskolin inhibits cell proliferation; moreover the administration of prostaglandin E2 plus forskolin, a condition which evokes a synergistic enhancement of cAMP, induces a major impairment of cell growth. Provided that our data are applicable to the trophoblast tissue in vivo, we suggest that prostaglandin E2 exerts an important control on extravillous trophoblast cell functions, preventing an excessive proliferation and migration.


Differential effects of D-cycloserine and amantadine on motor behavior and D2/3 receptor binding in the nigrostriatal and mesolimbic system of the adult rat.
D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist, respectively. In the present study, we compared the effects of DCS and AMA on dopamine D2/3R binding in the brain of adult rats in relation to motor behavior. D2/3R binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [123I]IBZM as radioligand. Immediately post-challenge, motor/exploratory behavior was assessed for 30 min in an open field. The regional binding potentials (ratios of the specifically bound compartments to the cerebellar reference region) were computed in baseline and post-challenge. DCS increased D2/3R binding in nucleus accumbens, substantia nigra/ventral tegmental area, thalamus, frontal, motor and parietal cortex as well as anterodorsal and posterior hippocampus, whereas AMA decreased D2/3R binding in nucleus accumbens, caudateputamen and thalamus. After DCS, ambulation and head-shoulder motility were decreased, while sitting was increased compared to vehicle and AMA. Moreover, DCS increased rearing relative to AMA. The regional elevations of D2/3R binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of D2/3R binding after AMA indicate increased dopamine in nucleus accumbens, caudateputamen and thalamus. Findings imply that, after DCS, nigrostriatal and mesolimbic dopamine levels are directly related to motor/exploratory activity, whereas an inverse relationship may be inferred for AMA.


Tuning exocytosis for speed: fast and slow modes.
Exocytic fusion reactions triggered by Ca(2+) are widespread in neural, endocrine, exocrine, hemapoetic and perhaps all cell types. These processes exhibit tremendous variation in latencies to fusion following a Ca(2+) rise and in rates of fusion. We review reported differences for synaptic vesicle (SV) and dense-core vesicle (DCV) exocytosis and attempt to identify key features in the molecular mechanisms of docking, priming and fusion of SVs and DCVs that may account for differences in speed.


Effects of chronic furosemide treatment on rat exocrine glands.
It has been suggested that a defective chloride transport is the primary cellular basis for the disease cystic fibrosis (CF). Therefore, the effects of chronic furosemide treatment on the structure and function of rat exocrine glands were investigated. X-ray microanalysis of the submandibular gland showed an increase in the cellular Ca and Mg concentrations, and a decrease in the cellular Cl concentration. Transmission electron microscopy showed intracellular accumulation of mucus and the presence of mucus in acinar and ductal lumina. The volume of saliva secreted by the submandibular gland after pilocarpine stimulation was markedly reduced in furosemide-treated animals; the salivary concentrations of Na and Ca were higher, and that of K was lower, than in control animals. The protein concentration in submandibular saliva was not significantly affected. The response of the submandibular gland to isoproterenol stimulation was reduced in furosemide-treated animals. In the parotid gland, chronic furosemide treatment caused an accumulation of immature zymogen granules in the acinar cells and a decrease in the cellular Cl concentration. In the pancreas, the acinar lumen was dilated and completely filled with secretory material, and the acinar cells contained less Na and somewhat less Cl than in control animals. The chronically furosemide-treated rat shows a number of parallels with other animal models for CF, in particular the chronically reserpinized rat. There is also agreement with the human disease itself.


Landed property as collateral to access credit for housing development in Ghana: The case of Northern Region of Ghana.
Property in the commons, or the Washington Consensus, as it is known in other circles, posits that landed property and access to formal credit are directly related. Whether landed property improves access to formal credit or not has been at the centre of the debate, with varying practical evidence, especially for the Global South. Another related dimension of the debate concerns the implications of family-help-mortgage arrangements using intra-family transfer of land as collateral to support a member's mortgage by placing a charge on the collective property. This paper investigates the use of landed property as collateral to access formal credit from financial institutions for housing development in the Tamale Metropolitan Area (TMA) in the Northern Region of Ghana. The primary research question is: does formal documentation of landed property as collateral help in accessing formal credit for housing development in TMA? The study involves the use of in-depth interviews to investigate the opinions of estate developers, credit officers of universal banks, and land title holders on the relative importance of landed property and access to credit for housing development. The data are analysed by means of thematic content analysis. The findings indicate that even though landed property may contribute to the decision to grant formal credit, it is not a turn-key solution easily accepted in the final lending decision. This study adds to the body of knowledge primarily by evaluating the effects of reforms to increase credit access with landed property as collateral in Ghana, investigating the implications of family-help mortgage arrangements, including the use of intra-family assets as collateral in obtaining loans for investment at the micro-level in Ghana. The paper concludes that while formal documentation of land rights matters in the broad scheme of estate financing, it is not sufficient to bring about more immediate access to credit, especially for those who lack regular or reliable systems of income that could be critical in ensuring the payback of loans contracted using landed property as collateral for housing development.


The treatment of intermediate stage tumours beyond TACE: From surgery to systemic therapy.
Treatment of hepatocellular carcinoma (HCC) is dependent on the stage of the disease. Intermediate stage HCC encompasses the largest subgroup of patients with the disease, and is characterized by substantial heterogeneity. The standard therapeutic approach, transarterial chemoembolization (TACE), is probably over-used and may not be appropriate for all patients with intermediate stage HCC. In patients with extensive tumour bulk, multi-nodular spread or impaired liver function, TACE may not be optimal and other treatments can be considered as a first-line treatment. These include surgery, percutaneous ablation, radioembolization or systemic treatment. In addition, patients who do not achieve complete or partial necrosis (TACE failure) and patients with early recurrence after TACE, should be managed individually, considering systemic treatments usually reserved for advanced disease. In selected cases and in patients who achieve downstaging, radical approaches such as hepatic resection or even liver transplantation can be considered. In this review, we evaluate the current literature for the treatment strategies for patients with intermediate Barcelona Clinic Liver Cancer (BCLC) B stage HCC.


Glucocorticoid maintenance therapy and severe infectious complications in ANCA-associated vasculitis: a retrospective analysis.
To study the impact of glucocorticoid maintenance dose and treatment duration on outcomes in patients with AAV (ANCA-associated vasculitis) with emphasis on infectious complications. A total of 130 AAV patients from two German vasculitis centers diagnosed between August 2004 and January 2019 treated with cyclophosphamide and glucocorticoids for induction therapy and glucocorticoids for maintenance therapy were retrospectively enrolled. We investigated the influence of glucocorticoid maintenance therapy on patient survival, time to relapse, kidney function, infectious complications and irreversible physical damage. The patients were divided into the following groups: patients treated according to the predefined reduction scheme (< 7.5 mg) or patients treated with glucocorticoids ≥ 7.5 mg after 6 months. Compared to patients receiving < 7.5 mg glucocorticoids after 6 months, patients receiving [Formula: see text] 7.5 mg had an increased rate of infectious episodes per patient (1.7 vs. 0.6; p < 0.001), including urinary tract infection (p = 0.007), pneumonia (p = 0.003), opportunistic pneumonia (p = 0.022) and sepsis (p = 0.008). Especially pneumonia during the first 24 months after disease onset [hazard ratio, 3.0 (95% CI 1.5 - 6.1)] led to more deaths from infection (p = 0.034). Glucocorticoid maintenance therapy after 6 months had no impact on relapse rate or patient survival and decline in kidney function was comparable. Glucocorticoid maintenance therapy with [Formula: see text] 7.5 mg after 6 months is associated with more severe infectious complications leading to an increased frequency of deaths from infection. Glucocorticoid maintenance therapy has no effect on time to relapse or patient survival and should therefore be critically revised throughout the aftercare of AAV patients.


Functional Mandibular Reconstruction With Double-Barrel Fibular Flap and Primary Osseointegrated Dental Implants Improve Facial Esthetic Outcome.
Osseointegrated dental implants in fibular free flaps can be used to reconstruct segmental mandibular defects resulting from head and neck resections. The double-barrel fibular flap (DBFF) has been applied as a modified method to overcome insufficient fibular width. This article describes the use of the DBFF with simultaneous dental implant placement as a superior method for esthetic mandibular reconstruction. From 2012 to 2015, 26 patients underwent mandibular reconstruction with a free fibular flap and immediate dental implant placement after segmental mandibulectomies. Twelve patients received the DBFF and the other 14 patients received the conventional single-barrel fibular flap (SBFF). Palatal mucosal grafting was performed when necessary. Functional and esthetic outcomes were evaluated after 31 to 45 months of follow-up. All microvascular fibula transplantations were successful. All patients completed prosthodontic rehabilitation. The mean follow-up of patients after reconstruction was 36.3 months (range, 31 to 45 months). The facial esthetic score was significantly higher in patients treated with the DBFF than with the SBFF after 24 and 30 months (P < .05). There was no significant difference in marginal bone resorption between the DBFF and SBFF groups (P > .05). This 1-stage surgical method is safe and reliable. Use of the DBFF markedly decreased the height discrepancy between the native and new mandible and achieved a better lower face esthetic outcome than the SBFF. Osseointegrated dental implantation was adequate to achieve satisfactory dental rehabilitation in the DBFF group.


Attenuation of ataxia telangiectasia mutated signalling mitigates age-associated intervertebral disc degeneration.
Previously, we reported that persistent DNA damage accelerates ageing of the spine, but the mechanisms behind this process are not well understood. Ataxia telangiectasia mutated (ATM) is a protein kinase involved in the DNA damage response, which controls cell fate, including cell death. To test the role of ATM in the human intervertebral disc, we exposed human nucleus pulposus (hNP) cells directly to the DNA damaging agent cisplatin. Cisplatin-treated hNP cells exhibited rapid phosphorylation of ATM and subsequent increased NF-κB activation, aggrecanolysis, decreased total proteoglycan production and increased expression of markers of senescence, including p21, γH2 AX and SA-ß-gal. Treating cisplatin-exposed hNP cells with an ATM-specific inhibitor negated these effects. In addition, genetic reduction of ATM reduced disc cellular senescence and matrix proteoglycan loss in the progeroid Ercc1-/∆ mouse model of accelerated ageing. These findings suggest that activation of ATM signalling under persistent genotoxic stress promotes disc cellular senescence and matrix homeostatic perturbation. Thus, the ATM signalling pathway represents a therapeutic target to delay the progression of age-associated spine pathologies.


Infection following challenge of the lactating and dry udder of dairy cows with Actinomyces pyogenes and Peptostreptococcus indolicus.
Challenge of 12 mammary glands of cows in mid-lactation with 10(7) colony forming units (cfu) of Peptostreptococcus indolicus on two occasions led to clinical mastitis in only four quarters. The bacteria were rarely recovered and disappeared from the secretion within 14 days. In challenges 7 days prior to drying off eight of 12 quarters became infected and at drying off all quarters challenged became infected. The infections established at drying off persisted well into the dry period. P. indolicus infection was also established in all of 12 dry glands challenged, but usually eliminated at calving or early in the next lactation. Isolation of P. indolicus was accompanied in about one-third of cases by changes in the appearance of the secretion. Intramammary challenge with Actinomyces (formally Corynebacterium) pyogenes led to clinical and subclinical infections in nine of 12 lactating glands and in all of six dry glands. Dry period infections with A. pyogenes were more severe and rarely eliminated even by antibiotic therapy. Infections during lactation were often eliminated either naturally or by antibiotic therapy. Intermittent recovery of A. pyogenes from the lactating mammary gland, without clinical signs of infection, was possible for up to 90 days after challenge. Combined infections with A. pyogenes and P. indolicus were clinically more severe with a higher frequency of systemic involvement. It was shown that in the non-lactating gland an acute mastitis, similar to 'summer mastitis' could be established either by simultaneous inoculation with A. pyogenes and P. indolicus or by subsequent inoculation of quarters excreting P. indolicus with A. pyogenes.


Bifunctional role of pro-inflammatory cytokines after traumatic brain injury.
Pro-inflammatory cytokines play an essential role in maintenance of normal brain function as well as in repair after traumatic brain injuries (TBI). However, massive and uncontrolled release of these cytokines, particularly interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α, can also result in a great deal of additional brain damage. Levels of these cytokines may increase in the brain thousands of times more than do the corresponding levels in serum. Narrative literature review. Outcome and conclusions: Strategies to control the levels of these pro-inflammatory cytokines and to reduce the cytokine-induced brain damage are discussed. There is extensive evidence from experiments in animal models that suppression of cytokines is effective in ameliorating neurologic damage after TBI. However, the efficacy of this approach remains to be proven in patient trials.


The influence of terrorism in tourism arrivals: A longitudinal approach in a Mediterranean country.
This longitudinal study examines the impact that terrorist attacks within a representative group of European countries can have on the tourism demand of a South European country with no record of terrorism attacks. In order to analyze the connections between terrorist attacks and tourists' arrivals, occurred between 2002 and the end of 2016, an Unrestricted Vector Autoregressive model was used for multivariate time series analysis. The main results show that terrorist attacks have a strong impact on tourist arrivals and confirm the existence of terrorism spillover, namely the substitution and generalization effects phenomena.


rac-(E,trans)-4-Bromo-10,10-dimethyl-9,11-dioxabi-cyclo-[6.3.0]undec-4-ene.
In the title compound, a cyclo-octene ring in a twist-boat conformation and a dioxolane ring with a distorted envelope conformation are annulated in a trans configuration. Alternating strands of single enanti-omers build up the crystal. Within the strands, the mol-ecules are connected by weak C-H⋯O hydrogen bonds.


Proximal femoral osteotomy as an adjunct in cementless revision total hip arthroplasty.
Cementless total hip replacement techniques are increasingly used in revision arthroplasty. A major challenge is to achieve implant stability in a femur distorted by a failed arthroplasty. Five patients with aseptic loosening of cemented primary or revision total hip replacements complicated by significant proximal femoral disease, four with marked angular deformity of the femur and one with a subtrochanteric nonunion, were treated successfully with cementless revision arthroplasty combined with proximal femoral osteotomy. At follow-up examination, all femoral and trochanteric osteotomies had healed and D'Aubigne and Postel scores for pain, function, and range of motion had improved. All porous prostheses demonstrated radiographic features consistent with bone ingrowth fixation. No progressive stress shielding has been observed. Concomitant femoral osteotomy to correct anatomic deformity, in association with cementless total hip arthroplasty, results in union of the osteotomy and restoration of hip function.


A full evaluation for the enantiomeric impacts of lactofen and its metabolites on aquatic macrophyte Lemna minor.
Pesticide pollution of surface water represents a considerable danger for the aquatic plants which play very crucial roles in aquatic system such as oxygen production, nutrient cycling, water quality controlling and sediment stabilization. In this work, the toxic effects of the chiral herbicide lactofen and its three metabolites (desethyl lactofen, acifluorfene and amino acifluorfene) to the aquatic plant Lemna minor (L. minor) on enantiomeric level were evaluated. The influences on growth rate, fresh weight, content of photosynthetic pigment, protein and malondialdehyde (MDA) and the activities of antioxidant defense enzymes (catalase (CAT) and superoxide dismutase (SOD)) were measured after 7 days of exposure. L. minor growth was inhibited in the order of (S)-desethyl lactofen > racemic-desethyl lactofen > (R)-desethyl lactofen > racemic-lactofen > (S)-lactofen > (R)-lactofen > acifluorfene > amino acifluorfene, and the IC50 (7d) values showed desethyl lactofen was the most powerful compound which was about twice as toxic as lactofen. The contents of chlorophylls (Chl) and carotenoids (Car) were significantly reduced by the chemicals, while, the levels of protein, MDA and the activity of CAT and SOD enzymes increased in most cases. The obtained results revealed that lactofen and its metabolites had an undesirable effect on L. minor, in terms of physiological and biochemical aspects. Besides, enantioselective toxicity of lactofen and desethyl lactofen to L. minor was observed. The S-enantiomer of desethyl lactofen was more toxic than the corresponding R-enantiomer. Furthermore, racemic lactofen was more toxic than the individual enantiomers. The side effects of pesticide metabolites and the enantioselectivity should be considered in developing optically pure products and risk assessment.


Hunting human disease genes: lessons from the past, challenges for the future.
The concept that a specific alteration in an individual's DNA can result in disease is central to our notion of molecular medicine. The molecular basis of more than 3,500 Mendelian disorders has now been identified. In contrast, the identification of genes for common disease has been much more challenging. We discuss historical and contemporary approaches to disease gene identification, focusing on novel opportunities such as the use of population extremes and the identification of rare variants. While our ability to sequence DNA has advanced dramatically, assigning function to a given sequence change remains a major challenge, highlighting the need for both bioinformatics and functional approaches to appropriately interpret these data. We review progress in mapping and identifying human disease genes and discuss future challenges and opportunities for the field.


Micronodular thymic neoplasms: case series and literature review with emphasis on the spectrum of differentiation.
We report nine cases of micronodular thymoma with lymphoid B-cell hyperplasia and one case of micronodular thymic carcinoma with lymphoid hyperplasia from our institution. For a better understanding of these rare tumors, clinical records, and histological features of these cases were reviewed, with detailed review of additional 64 literature cases of micronodular thymic neoplasms. The joint analysis identified 64 cases of micronodular thymoma with lymphoid B-cell hyperplasia and 9 cases of micronodular thymic carcinoma with lymphoid hyperplasia. Both groups revealed slight male predilection, with male:female ratio of 1.3:1 and 5:4, and occurred at >40 years of age, with a mean of 64 (41-83) and 62 (42-78) years, respectively. Myasthenia gravis was noted in 3/64 (5%) and 1/9 (11%) patients, respectively. Other systemic, disimmune, or hematologic disorders were noted in 6/64 (9%) and 1/9 (11%) patients, respectively. Components of conventional thymoma were reported in 11/64 (17%) micronodular thymomas with lymphoid B-cell hyperplasia, with transitional morphology between the two components in most of them. Cellular morphology was predominantly spindle in micronodular thymoma with lymphoid B-cell hyperplasia when specified (30/43), and epithelioid in micronodular thymic carcinoma with lymphoid hyperplasia (6/9), and cytological atypia was more encountered in the latter. Dedifferentiation/transformation from micronodular thymoma with lymphoid B-cell hyperplasia to micronodular thymic carcinoma with lymphoid hyperplasia seems to occur in a small subset of cases. Three cases of micronodular thymomas with lymphoid B-cell hyperplasia were described with co-existent low-grade B-cell lymphomas. Follow-up data were available for 30 micronodular thymomas with lymphoid B-cell hyperplasia and 6 micronodular thymic carcinomas with lymphoid hyperplasia, with a mean of 47 (0.2-180) months and 23 (3-39) months, respectively. Patients were alive without disease, except for five micronodular thymoma with lymphoid B-cell hyperplasia patients (dead from unrelated causes), and one micronodular thymic carcinoma with lymphoid hyperplasia patient (dead of disease).


Pelvic floor muscle training in radical prostatectomy: a randomized controlled trial of the impacts on pelvic floor muscle function and urinary incontinence.
Pelvic floor muscle training (PFM) training for post-prostatectomy incontinence (PPI) is an important rehabilitative approach, but the evidence base is still evolving. We developed a novel PFM training program focussed on activating fast and slow twitch muscle fibres. We hypothesized that this training, which commenced pre-operatively, would improve PFM function and reduce PPI, when compared to a control group. This randomized trial allocated 97 men (63 ± 7y, BMI = 25.4, Gleason 7) undergoing radical prostatectomy (RP) to either a control group (n = 47) performing low-volume rehabilitation, or an intervention group (n = 50). Both interventions commenced 5 weeks prior to surgery and continued for 12 weeks post-RP. Participants were assessed pre-operatively and at 2, 6 and 12 weeks post-RP using 24 h pad weights, International Prostate Symptom Score (IPSS), Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) and real time ultrasound (RTUS) measurements of PFM function. Following RP, participants in the control group demonstrated a slower return to continence and experienced significantly more leakage (p < 0.05), measured by 24 h pad weight, compared to the intervention group, suggesting an impact of the prehabilitation protocol. PFM function measures were enhanced following RP in the intervention group. Secondary measures (IPSS, EPIC-CP and RTUS PFM function tests) demonstrated improvement across all time points, with the intervention group displaying consistently lower "bothersome" scores. A pelvic floor muscle exercise program commenced prior to prostate surgery enhanced post-surgical measures of pelvic floor muscle function, reduced PPI and improved QoL outcomes related to incontinence. The trial was registered in the Australia New Zealand Clinical Trials Registry and allocated as ACTRN12617001400358. The trial was registered on 4/10/2017 and this was a retrospective registration.


Novel nitrifiers and comammox in a full-scale hybrid biofilm and activated sludge reactor revealed by metagenomic approach.
Biofilms are widely used in wastewater treatment for their particular enhancement of nitrogen removal and other significant advantages. In this study, the diversity and potential functions of nitrogen removal bacteria in suspended activated sludge (AS) and biofilm of a full-scale hybrid reactor were uncovered by metagenomes (∼34 Gb), coupled with PCR-based 454 reads (>33 K reads). The results indicated that the diversity and abundance of nitrifiers and denitrifiers in biofilm did not surpass that in AS, while more nitrification and denitrification genes were indeed found in biofilm than AS, suggesting that the increased nitrogen removal ability by applying biofilm might be attributed to the enhancement of removal efficiency, rather than the biomass accumulation of nitrogen removal bacteria. The gene annotation and phylogenetic analysis results revealed that AS and biofilm samples consisted of 6.0 % and 9.4 % of novel functional genes for nitrogen removal and 18 % and 30 % of new Nitrospira species for nitrite-oxidizing bacteria, respectively. Moreover, the identification of Nitrospira-like amoA genes provided metagenomic evidence for the presence of complete ammonia oxidizer (comammox) with the functional potential to perform the complete oxidation of ammonia to nitrate. These findings have significant implications in expanding our knowledge of the biological nitrogen transformations in wastewater treatment.


[French lawsuits after breast implantation].
Standpoint of surgeon about the french legislation on breast implant surgery in 2005. All possible proceedings in France are listed: Ordinal court (Deontology and professional risks), Civil court (Sharing of the costs and after-effects), Penal court (Personal punishement) and recently National Office on therapeutic hazards. Sinistrality observed in one insurance practice, in France, is described (1999-2004). Preparation of surgeon's defence is described, particulary for the expertal debate, indispensable preliminar before lawsuit in France.


Acute ischemic events after COVID-19 infection in patients undergoing maintenance hemodialysis.
Patients undergoing maintenance hemodialysis have unique risk factors that render them prone to ischemia. To what extent coronavirus infectious disease 2019 (COVID-19) increases this risk is unknown. This retrospective cohort study included incident patients undergoing maintenance hemodialysis from one city in Turkey. A comparison was made between those who developed COVID-19 and those who did not for clinical variables. Independent predictors of acute ischemic complications in the total cohort were assessed using the logistic regression analysis. By the start of the pandemic in Turkey, 33 of 154 (21.4%) patients developed COVID-19. During the 15 months of median follow-up after the start of the pandemic, 16 (10.4%) patients developed acute ischemic complications. These included acute myocardial infarction (n = 10), acute ischemic stroke (n = 4), acute peripheral artery thrombosis (n = 1), and pulmonary thromboembolism (n = 1). Overall, acute ischemic events occurred more commonly in those who experienced COVID-19 (24.2% vs. 6.6%, p = 0.007). Ischemia-free survival was significantly shorter in the COVID-19 group (p = 0.001). In the eight patients with COVID-19, ischemic complications emerged at a median 185 (range 21-306) days after the diagnosis of COVID-19. While age, dialysis vintage, and experience of COVID-19 were found as factors significantly associated with the development of acute ischemic events in univariate analysis, the association between COVID-19 and acute ischemia remained significant in the multivariate regression model (odds ratio 3.99, 95% CI [1.3, 12.13], p = 0.016). During the pandemic, 23 (14.9%) patients died. Overall survival was significantly shorter among those who developed acute ischemic event (p < 0.001). The hazard ratio of acute ischemic event for death was 6.76 (95% CI [2.92, 15.66], p < 0.001). A considerable number of patients undergoing maintenance hemodialysis developed acute ischemic complications weeks to months after the resolution of COVID-19. Hemodialysis patients appear to require specific interventions in order to prevent subsequent acute ischemic events after the resolution of COVID-19.


[Ultrasonography in trauma].
The aim of this paper is to report on the possibilities of ultrasonography of the musculoskeletal system following traumatic injuries. Subsequent to clinical and radiologic examination, ultrasonography is able to confirm the primary diagnosis by dynamic comparison with a minimal expenditure of time and costs. The size, extent, and anatomic topography of tissue lesions are depicted. This paper focuses especially on the diagnosis of fluid within joints and soft tissues, the identification of foreign bodies, the diagnosis and follow-up of fractures, the diagnosis of infections (possibility of sonographically guided puncture), and musculotendinous injuries. Furthermore, the use of ultrasonography for the evaluation of postoperative pain and complications, the preoperative planning of metal removals, and its performance during spinal surgery are discussed. This paper deals with indications and technical tips for sonography as well as methodological limitations and sources of error in the evaluation of ultrasonographic findings.


Couple Interdependence Impacts Alcohol Use and Adherence to Antiretroviral Therapy in Malawi.
In sub-Saharan Africa, harmful alcohol use among male drinkers is high and has deleterious consequences on adherence to antiretroviral therapy (ART), HIV clinical outcomes, and couple relationship dynamics. We conducted in-depth qualitative interviews with 25 Malawian couples on ART to understand how relationships influence adherence to ART, in which alcohol use emerged as a major theme. Almost half of men (40%) reported current or past alcohol use. Although alcohol use was linked to men's non-adherence, women buffered this harm by encouraging husbands to reduce alcohol use and by offering adherence support when men were drinking. Men's drinking interfered with being an effective treatment guardian for wives on ART and also weakened couple support systems needed for adherence. Relationship challenges including food insecurity, intimate partner violence, and extramarital relationships appeared to exacerbate the negative consequences of alcohol use on ART adherence. In this setting, alcohol may be best understood as a couple-level issue. Alcohol interventions for people living with HIV should consider approaches that jointly engage both partners.


Osteoblast adhesion, migration, and proliferation variations on chemically patterned nanocrystalline diamond films evaluated by live-cell imaging.
Cell fate modulation by adapting the surface of a biocompatible material is nowadays a challenge in implantology, tissue engineering as well as in construction of biosensors. Nanocrystalline diamond (NCD) thin films are considered promising in these fields due to their extraordinary physical and chemical properties and diverse ways in which they can be modified structurally and chemically. The initial cell distribution, the rate of cell adhesion, distance of cell migration and also the cell proliferation are influenced by the NCD surface termination. Here, we use real-time live-cell imaging to investigate the above-mentioned processes on oxidized NCD (NCD-O) and hydrogenated NCD (NCD-H) to elucidate cell preference to the NCD-O especially on surfaces with microscopic surface termination patterns. Cells adhere more slowly and migrate farther on NCD-H than on NCD-O. Cells seeded with a fetal bovine serum (FBS) supplement in the medium move across the surface prior to adhesion. In the absence of FBS, the cells adhere immediately, but still exhibit different migration and proliferation on NCD-O/H regions. We discuss the impact of these effects on the formation of cell arrays on micropatterned NCD. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1469-1478, 2017.


New insights into the oxidative damage and antioxidant defense mechanism in Manila clams (Ruditapes philippinarum) exposed to 8:2 polyfluoroalkyl phosphate diester stress.
8:2 perfluoroalkyl phosphate diester (8:2 diPAP) is the main precursor of perfluoroalkyl carboxylic acids, and it has been detected in a wide range of environments. In this study, conventional biochemical and histopathological analyses and transcriptome methods were used to investigate the accumulation and oxidative stress of 8:2 diPAP in Manila clams (Ruditapes philippinarum) as well as the clam's defense mechanisms for the first time. The hepatopancreas was the main target organ for 8:2 diPAP accumulation; the concentration reached 484.0 ± 15.5 ng/g after 7 days of exposure to 10 μg/L of 8:2 diPAP, which was 2-100 times higher than that found in other organs. 8:2 diPAP accumulation resulted in significant lipid peroxidation, and the change in malondialdehyde content was highly correlated with 8:2 diPAP accumulation (r > 0.8). The antioxidant enzymes catalase and peroxidase were significantly activated at 7 days of exposure. Although the levels subsequently returned to normal, this restoration was unable to prevent damage. Histopathological analysis showed that 8:2 diPAP exposure resulted in inflammatory damage to the hepatopancreas, which failed to resolve during the recovery period. Transcriptomic analyses showed that the expression of differentially expressed genes had different degrees of positive/negative correlation with antioxidant indicators, and they were significantly enriched in cell death regulatory pathways such as autophagy, apoptosis, and necrosis. The core factor expression results indicated that 8:2 diPAP exposure induced activation of the organismal autophagy factor followed by a shift towards apoptosis. In addition, pathways related to amino acid metabolism and energy metabolism were involved in determining the cell fate of Manila clams. Overall, these results indicated that 8:2 diPAP induced peroxidation of membrane lipids, disturbed physiological processes, and ultimately initiated programmed cell death in Manila clams. The findings of this study provide new insights into the mechanism of toxicity of 8:2 diPAP exposure in marine bivalves.


Seizure-like episodes and EEG abnormalities in patients with long QT syndrome.
The congenital long QT-syndrome (cLQTS) is characterized by ventricular arrhythmias, syncope and sudden cardiac death. Many LQTS genes are also expressed in the brain and emerging evidence suggest that cardiac channelopathies can also cause epilepsy. The aim of the study is to explore evidence of epilepsy and/or EEG abnormalities in a cohort with a genotyped diagnosis of LQT1 or LQT2. Adult patients were randomly selected from the outpatient clinic and a random sample of healthy controls were recruited from the general population. Ictal semiology was explored in symptomatic patients. A 1 h 64-channel awake EEG was performed and analyzed by visual assessment. Brain connectivity was quantified by Directed Transfer Function (DTF) from the current source density estimate within the theta band (4-7 Hz). Fifteen patients with LQT1, 20 with LQT2 and 20 controls were included. Seventy-one % of the patients reported loss of consciousness (LOC); 44% in combination with convulsions. EEG was abnormal in 34% of patients and 10% of controls (p < 0.05). Two patients had epileptiform or sharp activity. The fronto-parietal DTF connectivity was significantly altered in patients compared to controls (LQT1 p = 2.2 × 10-6, LQT2 p = 0.044). Seizure-like episodes and EEG abnormalities were common in our cohort with cLQTS patients. However, we could not find firm evidence of epilepsy. Our findings reinforce the notion that cLQTS is a cardiocerebral channelopathy. Correct classification of seizures may be challenging to the clinician, but of vital importance for patients.


Genetic and environmental contributions to psychopathological symptoms in adulthood: Clarifying the role of individual and parental risk factors.
Psychopathology-related suicide attempts and deaths are increasing, and the research focus remains on mental disorder in childhood and adolescence. We examined the genetic and environmental contributions to internalizing, externalizing, and general psychopathological distress to clarify the role of individual/parental risk factors for suicide in young adults. Data from 1206 young adults were obtained from a publicly available dataset from the Human Connectome Project. Heritability estimates were analyzed by twin modelling using OpenMx and data from a subsample of 402 monozygotic and dizygotic twins. The estimated prevalence of psychopathological symptoms ranged from 9 to 16%. The heritability of internalizing, externalizing, and general psychopathological distress reached significance, with estimates ranging from 22 to 46%. Shared (common) environments contributed to aggressive behavior (30 %). Determining factors for psychopathological distress (internalizing, externalizing, general) were evaluated using logistic regression analysis. Household income (<$50,000), childhood conduct problems, and maternal drug or alcohol problems were common risk factors of internalizing, externalizing, and general psychopathological distress. Marijuana dependence and maternal anxiety were additional risk factors of externalizing distress. The presence of alcohol and maternal drug or alcohol problems was linked to general psychopathological distress. The results highlight risk factors associated with psychopathological symptoms that should be considered in the early detection of high-risk groups and implementation of family-based interventions. Providing continuous care and/or follow-up in at-risk children and young adults may improve mental health and well-being.


Antigen-independent adhesion of CD4 CD45RA T cells from cord blood.
Antigen-independent adhesion of resting adult CD4+ CD45RO+ T cells to B lymphocytes has been shown to be transient and can be down-regulated by CD4 major histocompatibility complex (MHC) class II molecule interactions. Conversely, adhesion of adult CD4+ CD45RA+ subpopulation to B cells is not regulated by ligands of CD4. We have investigated the regulation of adhesion of cord blood CD45RA+ CD4+ T lymphocytes. In contrast to adult CD45RA+ CD4+ T cells, cord blood CD45RA+ CD4+ T cells were strongly sensitive to the down-regulation of adhesion mediated by the CD4-HLA class II interaction, since adhesion to MHC class II(+) B cells was transient and inhibited by an anti-CD4 antibody. In addition, human immunodeficiency virus gp160, synthetic gp106-derived peptides encompassing a CD4 binding site inhibited conjugate formation between cord blood CD45RA+ CD4+ T cells and B cells. Following activation of the cord blood CD4 T cells by an anti-CD3 antibody, a conversion from a transient to a stable adhesion pattern of cord blood CD4 T cells to B cells occurred in 2 days. The reversal to a transient adhesion occurred at day 8 following anti-CD3 activation in correlation with a complete shift to a CD45RO phenotype of the cord blood CD4 T cells. These data suggest that CD4 T cell adhesion can be developmentally regulated.


A quantitative comparison of a percentile rule with a 2-fold rule for assessing mutagenicity in the Ames assay.
Using a model based on the bivariate normal density function, this paper compares the effectiveness of two commonly employed decision rules for assessing mutagenicity in the standard Ames Salmonella assay. The 2-fold method, which considers a compound significantly mutagenic if its mean number of revertants per plate at any dose is equal to or greater than twice the mean number of revertants per plate in the concurrent control, may be a poor indicator of significant mutagenesis. In the percentile method, the frequency of induced mutations for the test compound is tested against the 95th percentile of the accumulated historical data for the spontaneous mutation frequency. As judged by the higher probability of declaring a compound mutagenic that elevates the reversion rate above background, the percentile rule is more reliable than the 2-fold method.


A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema.
To evaluate the safety and efficacy of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME). Randomized, double-masked, multicenter, dose-ranging, controlled trial. Individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks. Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36. Best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36. One hundred seventy-two patients appeared balanced for baseline demographic and ocular characteristics. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (P = 0.04). A larger proportion of those receiving 0.3 mg gained VAs of > or =10 letters (approximately 2 lines) (34% vs. 10%, P = 0.003) and > or =15 letters (18% vs. 7%, P = 0.12). Mean central retinal thickness decreased by 68 microm with 0.3 mg, versus an increase of 4 microm with sham (P = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both > or =100 microm (42% vs. 16%, P = 0.02) and > or =75 microm (49% vs. 19%, P = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; P = 0.04). All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%/injection; i.e., 1/130 [0.8%] pegaptanib subjects) and was not associated with severe visual loss. In this phase II trial, subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up.


Audiovisual temporal recalibration occurs independently at two different time scales.
Combining signals across the senses improves precision and speed of perception, although this multisensory benefit declines for asynchronous signals. Multisensory events may produce synchronized stimuli at source but asynchronies inevitably arise due to distance, intensity, attention and neural latencies. Temporal recalibration is an adaptive phenomenon that serves to perceptually realign physically asynchronous signals. Recently, it was discovered that temporal recalibration occurs far more rapidly than previously thought and does not require minutes of adaptation. Using a classical audiovisual simultaneity task and a series of brief flashes and tones varying in onset asynchrony, perceived simultaneity on a given trial was found to shift in the direction of the preceding trial's asynchrony. Here we examine whether this inter-trial recalibration reflects the same process as prolonged adaptation by combining both paradigms: participants adapted to a fixed temporal lag for several minutes followed by a rapid series of test trials requiring a synchrony judgment. Interestingly, we find evidence of recalibration from prolonged adaptation and inter-trial recalibration within a single experiment. We show a dissociation in which sustained adaptation produces a large but decaying recalibration effect whilst inter-trial recalibration produces large transient effects whose sign matches that of the previous trial.


Pharmacokinetics of Succinate in Rats after Intravenous Administration of Mexidol.
The pharmacokinetics of succinate was studied in Wistar rats after a single intravenous administration of Mexidol in a dose 100 mg/kg body weight. The concentration of succinate in blood plasma, cytoplasmic and mitochondrial fractions of cells of the cerebral cortex, left-ventricular myocardium, and liver was measured by HPLC-MS/MS. After single intravenous administration of Mexidol, succinate was evenly distributed in organs and tissues and quickly eliminated from the body. The pharmacokinetics of succinate was described by a two-chamber model. An increase in the level of succinate in the cytoplasmic fraction of the liver, myocardium, and cerebral cortex cells and a minor increase in the mitochondrial fraction were observed. The maximum increase in the level of succinate in the cytoplasmic fraction was observed in the liver tissue, a less pronounced elevation was observed in the cerebral cortex and myocardium; no significant differences between the cerebral cortex and myocardium were observed by this parameter.


Aerobactin production of serotyped Escherichia coli from urinary tract infections.
Aerobactin production was examined by a bioassay in 467 Escherichia coli urinary strains from girls. All strains were of known O:K:H serotype. 139, 119 and 112 strains were isolates from pyelonephritis (Py), cystitis (Cy) and asymptomatic bacteriuria (ABU), respectively, and 97 were from fecal samples of healthy girls (FN). The incidence of aerobactin production was significantly higher among Py strains than among ABU and FN strains (P less than 0.001) and also significantly higher than among Cy strains (P less than 0.01). Aerobactin production was associated with serotype, e.g. the majority of O6:K2:H1 strains and of O16:K1:H6 were positive while e.g. the O6:K13:H1 strains were negative. There was no consistent pattern of coappearance of aerobactin and hemolysin.


Determinants of soil carbon- and nitrogen-hydrolyzing enzymes within different afforested lands in central China.
Soil organic matter (SOM) decomposition is regulated by a complex set of enzymes. However, the influences of biotic and abiotic factors on spatial variations of soil enzyme activity (EA) within ecosystems remain unresolved. Here, we measured EA at different locations within two afforested lands (coniferous woodland and leguminous shrubland), and simultaneously collected data on soil physico-chemical, vegetation-related, and microbial properties to identify the determinants of EA spatial patterns. The results showed that soil organic C and total N contents were the predominant abiotic factors in regulating absolute EA (EA per unit of oven-dry soil mass) in both afforested lands, while soil pH was the predominant factor in regulating specific EA (EA per unit of microbial biomass (MB)). However, the predominant biotic factors varied with the afforested type: the root biomass and MB were the determinants of EA in the shrubland, whereas the tree distribution, litter and root biomass, and bacterial biomass were the determinants in the woodland. Vegetation-related factors (i.e., litter and root biomass) indirectly influenced soil EA by regulating the soil abiotic factors. Compared with the MB, microbial community composition had a minor impact on EA. The variance of specific EA (EA per unit of MB or SOM) explained by selected factors was much lower than that of absolute EA. In addition, the enzymatic C/N ratio within ecosystems did not follow a general pattern (1:1) observed at a global scale. Our results provide novel experimental insight into ecosystem-level spatial variability of C and N cycling via enzymes, suggesting that soil abiotic factors are more reliable than biotic factors to reflect EA spatial patterns across afforested systems.


Indocyanine green retention test in cirrhosis and portal hypertension: Accuracy and relation to severity of disease.
Patients with cirrhosis and portal hypertension often develop complications relating to hepatic excretory dysfunction. The standard measurement of the hepatic excretion is the constant infusion indocyanine green clearance (ICGCI ) technique. The ICG 15-min retention test (ICG-r15) is faster, more patient friendly, and cheaper. The aims were to compare the ICG-r15 test with the standard method, to assess relations to patient characteristics and survival, and to assess the ICG-r15 level in healthy control subjects. This study included 68 patients with cirrhosis and portal hypertension (Child class A/B/C:17/37/14). All patients underwent a full liver vein catheterization and hemodynamic evaluation with determination of ICG-r15 and ICGCI as the reference in a subset of 38 patients. Sixteen healthy control subjects were included for compiling a reference interval. The ICG-r15 was increased in the cirrhotic patients with increasing values in parallel with liver dysfunction (15/41/58%) in Child class A/B/C compared with 7% in the controls (P < 0.001). ICG-r15 correlated highly significantly with the ICGCI (r = -0.96, P < 0.0001) and in a multivariate regression analysis with hepatic venous pressure gradient, markers of liver dysfunction and hyperdynamic circulation (P < 0.05-0.005). In the control group, normal reference values ranged from 0% to 13%. In addition, ICG-r15 was significantly related to mortality in the patient group (P = 0.02). Indocyanine green-r15 reflects portal hypertension, the degree of hepatic failure, and survival and may replace the standard ICGCI . A more elaborated reference interval needs to be compiled, and the prognostic value of ICG-r15 should be validated.


Subtotal Epiglottectomy and Ablation of Unilateral Arytenoid Cartilage as Surgical Treatments for Grade III Laryngeal Collapse in Dogs.
Stage III laryngeal collapse is defined as the collapse of the corniculate processes of the arytenoid cartilages and the destructuration of the dorsal portion of the rima glottidis. The primary cause is chronic upper airway obstruction, and the condition is often present in brachycephalic dogs. The treatment is still controversial; the patients are generally treated with a permanent tracheostomy. This article reports the authors' experience with 16 dogs affected by stage III laryngeal collapse treated with subtotal epiglottectomy and the ablation of unilateral arytenoid cartilage. Before the surgery, all of the dogs underwent an effort test to classify the clinical severity of the disease and an endoscopic examination of the airways to determine the stage of severity of the laryngeal collapse. One month after surgery, the effort test was repeated in order to evaluate the clinical outcome. One year after surgery, the owners of 12 patients rated their dogs as follows: excellent in five cases, good in five cases, and fair in two cases. According to this pilot study, epiglottectomy associated with the photoablation of unilateral arytenoid cartilage increases airway flow, and thus may be considered a valid surgical procedure to treat dogs affected by grade III laryngeal collapse.


Involvement of high mobility group box 1 in the activation of C5a-primed neutrophils induced by ANCA.
C5a plays a central role in antineutrophil cytoplasmic antibody (ANCA)-mediated neutrophil recruitment and activation. A previous study showed that C5a played a crucial role in the regulation of high mobility group box 1 (HMGB1) release from human neutrophils. The current study further investigated the interaction between C5a and HMGB1 in ANCA-induced neutrophil activation. The effects of HMGB1 inhibitors on the translocation of ANCA antigens, ANCA-induced respiratory burst and degranulation of C5a-primed neutrophils were tested. We found that blocking HMGB1 decreased C5a-mediated translocation of ANCA antigens, as well as ANCA-induced respiratory burst and degranulation of C5a-primed neutrophils. Further study showed that supernatant of C5a-primed neutrophils, which contained HMGB1, also caused translocation of ANCA antigens of primary neutrophils, whereas blocking HMGB1 decreased the translocation. In conclusion, blocking HMGB1 may attenuate ANCA-induced activation of C5a-primed neutrophils. The interaction between HMGB1 and C5a might play an important role in ANCA-induced neutrophil activation.


Mechanical control of cardiac myofibroblasts.
Fibroblasts produce and turn over collagenous extracellular matrix as part of the normal adaptive response to increased mechanical load in the heart, e.g. during prolonged exercise. However, chronic overload as a consequence of hypertension or myocardial injury trigger a repair program that culminates in the formation of myofibroblasts. Myofibroblasts are opportunistically activated from various precursor cells that all acquire a phenotype promoting excessive collagen secretion and contraction of the neo-matrix into stiff scar tissue. Stiff fibrotic tissue reduces heart distensibility, impedes pumping and valve function, contributes to diastolic and systolic dysfunction, and affects myocardial electrical transmission, potentially leading to arrhythmia and heart failure. Here, we discuss how mechanical factors, such as matrix stiffness and strain, are feeding back and cooperate with cytokine signals to drive myofibroblast activation. We elaborate on the importance of considering the mechanical boundary conditions in the heart to generate better cell culture models for mechanistic studies of cardiac fibroblast function. Elements of the force transmission and mechanoperception apparatus acting in myofibroblasts are presented as potential therapeutic targets to treat fibrosis.


Essential oils of Nigella sativa protects Artemia from the pathogenic effect of Vibrio parahaemolyticus Dahv2.
The anti-Vibrio activity of essential oils (EOs) of nine medicinal plants was tested against 28 Vibrio spp. isolated from diseased Fenneropenaeus indicus. EO of Nigella sativa exhibited anti-Vibrio activity against all Vibrio spp. and greater inhibition was noted for the isolate V2 which was identified as Vibrio parahaemolyticus Dahv2. Further, EO of N. sativa effectively inhibited V. parahaemolyticus Dahv2 with an inhibition zone of 23.9mm at 101.2μgml(-1). Moreover, EO of N. sativa revealed anti-biofilm activity at 101.2μgml(-1) against V. parahaemolyticus Dahv2 and inhibited the growth of V. parahaemolyticus Dahv2 at 100μgml(-1).In vivo experimental infection studies showed that the survival of Artemia spp. infected with V. parahaemolyticus Dahv2 at 1×10(3)cfuml(-1) was only 40%. However, the survival of Artemia spp. was significantly increased after challenge with 100μgml(-1) of EO of N. sativa. EO of N. sativa showed higher anti-oxidant potential and total phenol content than other EOs tested. The anti-oxidant activity of EO of N. sativa was highly correlated to their total phenolic contents (r=0.836, P<0.05). This observation suggests that EO of N. sativa protected the Artemia spp. after experimental infection of V. parahaemolyticus Dahv2.


A linkage group with FRA16B (the fragile site at 16q22.1).
Polymorphic DNA markers located in bands 16q13, 16q21 and 16q22 were examined for recombination with FRA16B, the fragile site at 16q22.100. A tight linkage cluster D16S10-FRA16B-D16S4-HP was established. There were no recombinants (theta = 0.0, z = 8.3) between D16S10 and D16S4, which flank FRA16B. The markers D16S10 and D16S4 are in close proximity on the genetic map and delineate a small chromosomal segment, which contains the distamycin A-inducible fragile site.


Craniofacial morphology in Apert syndrome: a systematic review and meta-analysis.
This meta-analysis aims to compare Apert syndrome (AS) patients with non-AS populations (not clinically or genetically diagnosed) on craniofacial cephalometric characteristics (CCC) to combine publicly available scientific information while also improving the validity of primary study findings. A comprehensive search was performed in the following databases: PubMed, Google Scholar, Scopus, Medline, and Web of Science, an article published between 1st January 2000 to October 17th, 2021. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed to carry out this systematic review. We used the PECO system to classify people with AS based on whether or not they had distinctive CCC compared to the non-AS population. Following are some examples of how PECO has been used: People with AS are labeled P; clinical or genetic diagnosis of AS is labeled E; individuals without AS are labeled C; CCC of AS are labeled O. Using the Newcastle-Ottawa Quality-Assessment-Scale, independent reviewers assessed the articles' methodological quality and extracted data. 13 studies were included in the systematic review. 8 out of 13 studies were score 7-8 in NOS scale, which indicated that most of the studies were medium to high qualities. Six case-control studies were analyzed for meta-analysis. Due to the wide range of variability in CCC, we were only able to include data from at least three previous studies. There was a statistically significant difference in N-S-PP (I2: 76.56%; P = 0.014; CI 1.27 to - 0.28) and Greater wing angle (I2: 79.07%; P = 0.008; CI 3.07-1.17) between AS and control subjects. Cleft palate, anterior open bite, crowding in the upper jaw, and hypodontia occurred more frequently among AS patients. Significant shortening of the mandibular width, height and length is the most reported feature in AS patients. CT scans can help patients with AS decide whether to pursue orthodontic treatment alone or to have their mouth surgically expanded. The role of well-informed orthodontic and maxillofacial practitioners is critical in preventing and rehabilitating oral health issues.


Effects of rhodioloside on the neurological functions of rats with total cerebral ischemia/reperfusion and cone neuron injury in the hippocampal CA1 region.
Rhodioloside, the main effective constituent of Rhodiola rosea, demonstrates antiaging and antioxidative stress functions and inhibits calcium overloading in cells. These functions imply that rhodioloside may exert protective effects on hippocampal neurons after total cerebral ischemia/reperfusion injury. In this study, male Wistar rat models of total cerebral ischemia were constructed and randomly divided into four groups: sham-operation, ischemia/reperfusion, low-dosage, and high-dosage groups. The result showed that rhodioloside treatment reduced the apoptosis rates of hippocampal neurons and the histological grades of cone cells in the hippocampal CA1 region, but neuronal density was significantly increased. Besides, the protein expressions of Bcl-2/Bax and p53 were measured and found Bcl-2/Bax was increased and p53 protein level was reduced. Therefore, rhodioloside might have protective effects on rats with ischemia/reperfusion brain injury.


A cloned cytotoxic T-lymphocyte (CTL) line recognizing a subtype of HLA B27.
The lymphoblastoid cell-line JY (HLA-A2,2;B7,7;C-; DR4,w6) was used to stimulate T cells from donor HG (HLA-A2,w23; B40,w44; Cw4; DRw6,7). Cloned CTL line were obtained by limiting dilution after tertiary stimulation. Strong cytotoxic activity on stimulator cells was found with all CTL clones obtained. One of the clones (HG-31 recognized a subtype of the HLA-B7 antigen. In this paper, we describe another long-term cloned CTL line (HG-61). This line, when tested on a panel of 107 target cells from unrelated individuals, recognized a subtype of HLA-B27 (B27 "K"). There was no significant association with any other HLA antigen. The cloned CTLs were T8+ and their cytotoxic activity could be blocked by the monoclonal antibody W6/32 which recognizes a framework determinant on HLA-A, -B, and -C molecules. In families, reactivity with cells of the CTL line (HG-61) segregated with HLA. It is concluded that the CTL line interacts with an antigenic determinant shared between the HLA-B7 antigen and JY and the subtype of HLA-B27 (B27 "K"), or detects products of a gene closely linked to HLA-B, not revealed by present-day serology.


Facilitation of agonist motoneurons upon initiation of rapid and slow voluntary movements in man.
The time course of facilitation of the agonist motoneurons upon initiation of voluntary ankle dorsiflexion was investigated in eight healthy subjects. The H-reflex and visually guided tracking methods were used for testing the excitability of the motoneuron pool and for controlling the initiation of movement as well as speed and force. Since the onset of voluntary EMG activity (EMG reaction time: EMGvRT) was delayed and/or obscured by test H-reflexes which were evoked very close to the behavioral responses, the subject was instructed to make response movements bilaterally, and EMGvRT was measured on the side without stimulation. In every subject, the EMGvRT was invariably longer in the ramp movement than in the step movement. The onset of H-reflex facilitation prior to EMG onset, which was regarded as indicating the arrival time of the descending motor command to the motoneuron pool, always started earlier in the ramp movement than in the step movement. The difference in facilitation onset between the two tasks was smaller than that in EMGvRT. Since the amplitude of the H-reflex at the onset of the voluntary EMG was equivalent in both movements, the development of H-reflex towards the behavioral EMG onset was more gradual in the ramp movement than in the step movement. The present results demonstrate that the longer reaction time in the slow ramp task depends on 2 factors: delay in the arrival of descending facilitatory impulses to the agonist motoneuron pool, and its slow recruitment thereafter.


Osmotic regulation of neuropeptide Y and its binding sites in the magnocellular hypothalamo-neurohypophysial pathway.
The magnocellular hypothalamo-neurohypophysial system is, via a release of vasopressin from nerve terminals in the neurohypophysis to the peripheral blood, centrally involved in the regulation of body salt and water homeostasis. Furthermore, it has been shown that expression of neuropeptides co-existing with vasopressin or oxytocin in magnocellular neurons is influenced by salt loading. We here report, that neuropeptide Y (NPY)-immunoreactivity, which is normally not observed in the magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei of rats becomes immunohistochemically detectable after salt loading. Using a double-immunohistochemical procedure on the same brain sections, it is shown that NPY is co-existing with either vasopressin or oxytocin in these neurons. Within the neurohypophysis of normal rats, a moderate number of predominantly fine calibered NPY-immunoreactive nerve fibers most often coursing along vessels is observed in addition to a low number of large peptidergic terminals. In salt-loaded rats, however, the number of NPY-immunoreactive neurohypophysial large nerve terminals in apposition to vascular lumina is drastically increased. By using quantitative receptor autoradiography, it is demonstrated that in salt-loaded animals, the number of neurohypophysial NPY binding sites is decreased to nearly undetectable levels (0.054 +/- 0.02 fmol/mg) compared to a very high density of binding sites in normal animals (1.151 +/- 0.15 fmol/mg). This raises evidence that NPY containing hypothalamo-neurohypophysial neurons as well as peripherally released NPY may be involved in the regulation of water homeostasis via NPY receptors in the neurohypophysis.


Blood identification and discrimination between human and nonhuman blood using portable Raman spectroscopy.
Raman spectroscopy is commonly used in chemistry to identify molecular structure. This technique is a nondestructive analysis and needs no sample preparation. Recently, Raman spectroscopy has been shown to be effective as a multipurpose analytical method for forensic applications. In the present study, blood identification and discrimination between human and nonhuman blood were performed by a portable Raman spectrometer, which can be used at a crime scene. To identify the blood and to discriminate between human and nonhuman blood, Raman spectra of bloodstains from 11 species (human, rat, mouse, cow, horse, sheep, pig, rabbit, cat, dog, and chicken) were taken using a portable Raman spectrometer. Raman peaks for blood (742, 1001, 1123, 1247, 1341, 1368, 1446, 1576, and 1619 cm-1) could be observed by the portable Raman spectrometer in all 11 species, and the human bloodstain could be distinguished from the nonhuman ones by using a principal component analysis. This analysis can be performed on a bloodstain sample of at least 3 months old. The portable Raman spectrometer can be used at a crime scene, and this analysis is useful for forensic examination.


Expression of fasciculation and elongation protein zeta-1 (FEZ1) in the developing rat brain.
Fasciculation and elongation protein zeta-1 (FEZ1) is a mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth and fasciculation. Recently, we reported that FEZ1 interacts with Disrupted-In-Schizophrenia 1 (DISC1), a product of the candidate gene for schizophrenia, and that the interaction between these proteins has a role in neurite outgrowth. This time, we investigated the expression of FEZ1 and DISC1 in the developing rat brain using in situ hybridization. Both FEZ1 and DISC1 showed high levels of expression, especially in developing hippocampal neurons. These findings suggest the potential involvement of FEZ1 and DISC1 in the formation of hippocampal neural circuits.


Efficacy and Safety of External-beam Radiation Therapy for Unresectable Primary or Local Recurrent Cholangiocarcinoma.
Treatment options for unresectable cholangiocarcinoma are limited. The aim of the study was to evaluate the clinical outcomes of definitive external-beam radiation therapy (EBRT) for patients with unresectable cholangiocarcinoma. Patients with unresectable primary cholangiocarcinoma, or local recurrent cholangiocarcinoma after primary surgery, without distant metastasis who received definitive EBRT (≥45 Gy) between January 2006 and December 2020 at our Institution were analyzed retrospectively. EBRT was basically performed using conventional fractionation (1.8-2 Gy per fraction). Prophylactic nodal irradiation was not performed. A total of 21 consecutive patients were analyzed: 7 primary and 14 recurrent cases. The median age was 70 (range=38-85) years at initiation of EBRT. A median dose of 54 (range=45-60) Gy comprising 1.8 (range=1.8-3) Gy per fraction was administered to the primary/recurrent local tumor site. The median follow-up period was 21.6 months. The 2-year overall survival, cause-specific survival, progression-free survival, and local recurrence-free rates were 35.7, 35.7, 16.1, and 32.7%, respectively. Long-term local control (>2 years after EBRT) was achieved in 19.0%. Grade 3 toxicities related to EBRT were observed in 4.8% (duodenum hemorrhage). No grade 4 or higher toxicities were observed. Definitive EBRT for unresectable cholangiocarcinoma was feasible and achieved long-term local control in a subset of patients. As the avoidance of local recurrence may lead to the benefits of prolonging biliary patency and subsequently alleviating the need for an invasive procedure for biliary drainage, EBRT could be one sustainable therapeutic option for patients with unresectable cholangiocarcinoma.


Survival after surgery for spinal metastatic disease: a nationwide multiregistry cohort study.
To evaluate survival after surgery and indications for surgery due to spinal metastatic disease. A retrospective longitudinal multiregistry nationwide cohort study. 19 public hospitals in Sweden with spine surgery service, where 6 university hospitals account for over 90% of the cases. 1820 patients 18 years or older undergoing surgery due to spinal metastatic disease 2006-2018 and registered in Swespine, the Swedish national spine surgery registry. Decompressive and/or stabilising spine surgery due to spinal metastatic disease. Survival (median and mean) after surgery. Indications for surgery, types of surgery and causes of death. The median estimated survival after surgery was 6.2 months (95% CI: 5.6 to 6.8) and the mean estimated survival time was 12.2 months (95% CI: 11.4 to 13.1). Neurologic deficit was the most common indication for surgery and posterior stabilisation was performed in 70.5% of the cases. A neoplasm was stated as the main cause of death for 97% of the patients. Both median and mean survival times were well above the generally accepted thresholds for surgical treatment for spinal metastases, suggesting that patient selection for surgical treatment on a national level is adequate. Further research on quality of life after surgery and prognostication is needed.


Is skilled technique characterized by high or low variability? An analysis of high bar giant circles.
There is conflicting evidence as to whether skilled performance is associated with lower or higher movement variability. The effect of skill level and task difficulty on movement variability during gymnastics swinging was investigated. Four male gymnasts ranging in skill from university standard through to international medallist performed 10 consecutive regular giant circles and 10 double straight somersault dismounts preceded by accelerated giant circles while kinematic data were recorded. Joint angle time histories of the hip and shoulder were calculated and the turning points between flexion and extension determined during each giant circle. Standard deviations of the time and magnitude of the angles at each turning point were calculated. The more elite gymnasts were found to have less variability in the mechanically important aspects of technique compared to the less elite gymnasts. The variability in the mechanically important aspects of technique was not statistically different between the two types of giant circles, whereas the more elite gymnasts demonstrated more variability in some of the less mechanically important aspects.


A two-stage cluster sampling method using gridded population data, a GIS, and Google Earth(TM) imagery in a population-based mortality survey in Iraq.
Mortality estimates can measure and monitor the impacts of conflict on a population, guide humanitarian efforts, and help to better understand the public health impacts of conflict. Vital statistics registration and surveillance systems are rarely functional in conflict settings, posing a challenge of estimating mortality using retrospective population-based surveys. We present a two-stage cluster sampling method for application in population-based mortality surveys. The sampling method utilizes gridded population data and a geographic information system (GIS) to select clusters in the first sampling stage and Google Earth TM imagery and sampling grids to select households in the second sampling stage. The sampling method is implemented in a household mortality study in Iraq in 2011. Factors affecting feasibility and methodological quality are described. Sampling is a challenge in retrospective population-based mortality studies and alternatives that improve on the conventional approaches are needed. The sampling strategy presented here was designed to generate a representative sample of the Iraqi population while reducing the potential for bias and considering the context specific challenges of the study setting. This sampling strategy, or variations on it, are adaptable and should be considered and tested in other conflict settings.


Oral UFT (uracil plus futrafur) for neoadjuvant chemotherapy of gastric cancer.
BACKGROUND: Neoadjuvant chemotherapy has become one of the topics of interest in chemotherapy of gastric cancer; the present study assessed the clinical benefits of neoadjuvant chemotherapy with oral uracil and futrafur (UFT) for gastric cancer.METHODS: Between 1991 and 1997, 82 patients with gastric cancer (36 with early and 46 with advanced cancers) received UFT at 300-600 mg/day orally for 1-6 weeks before surgery. Objective responses, histological effects, and postsurgical survival rates were assessed.RESULTS: In 69 of the 82 patients, the objective responses of the primary lesions were assessed by endoscopy or upper gastrointestinal series examination, and 2 complete responses (CR)s, 25 partial responses (PRs), and 42 no changes (NCs) were seen (39.1% response). Histological effects were evaluated in 82 patients, and 2 grade 3, 11 grade 2, 11 grade 1b, 27 grade 1a, and 31 grade 0 effects were seen. A longer period of UFT administration was associated with a CR or PR. However, the objective responses did not correlate with the histological effects. All the patients underwent gastrectomy, and during the median follow-up period of 41 months, 3-year survival rates were 97.1% for pTNM stage 1, 75% for stage 2, 86.7% for stage 3, and 41.6% for stage 4. The survival rates of stage 3 and stage 4 patients were higher than those of the historical controls in our department. However, CR or PR did not correlate with the improvement in survival. Side effects before surgery were not serious; they included slight myelotoxicity, liver dysfunction, and anorexia; however, 3 patients (3.7%) had suture insufficiency, 3 patients (3.7%) had methicillin-resistant Staphylococcus aureus (MRSA) enteritis, and 7 patients (8.5%) had liver dysfunction.CONCLUSIONS: Preoperative chemotherapy for gastric cancer with oral UFT was safe and resulted in a good local response (macro- and microscopically) which may indicate the possibility of improved survival with neoadjuvant chemotherapy with UFT. Furthermore, preoperative chemotherapy with oral UFT is easy and patients can receive this treatment on an outpatient basis.


Chemical tuning of electrochemical properties of Pt-skin surfaces for highly active oxygen reduction reactions.
Pt-skin surfaces were successfully fabricated by the chemical deposition of additional Pt on corrugated Pt-Ni nanoparticles with Pt-skeleton surfaces. Compared to the Pt-skin formed by heat annealing, the chemically-tuned Pt-skin had a higher Pt coordination number and surface crystallinity, which resulted in superior ORR activity and durability.


Pharyngocutaneous fistulas in advanced cancer: closure with musculocutaneous or muscle flaps.
Two hundred cases of head and neck cancer were reviewed and 16 pharyngocutaneous fistulas identified, for an incidence of 6 percent. The fistulas were closed with pectoralis major muscle flaps in four patients, pectoralis musculocutaneous flaps in seven patients, sternocleidomastoid muscle flaps in four patients, and latissimus dorsi flaps in two patients. Four types of fistulas were identified, and flap selection was determined by fistula location. Successful closure was obtained in 15 patients (88 percent), although one patient died from recurrence with a persistent fistula.


Education of parents about paediatric asthma: effects of a protocol on medical consumption.
Asthma is a very common chronic disease among preschool children in primary health care. Research has shown that planned and systematic patient education positively affects the management of asthma by parents. This study focuses on the question of whether an asthma patient education protocol that is used by general practitioners (GPs) has an effect on medical care consumption. The treatment group consisted of 28 GPs, representing 47 asthmatic infants. The control group contained 18 GPs, representing 38 patients. Data were collected from medical records (with a written instrument) for a 12-month period preceding and after the intervention period in which the education protocol was tested. Results indicated that sociodemographic variables and pretest data on asthma severity and medical care utilization were largely comparable for patients in both study groups. Furthermore, the treatment group showed a significantly greater decrease than the control group from pre- to post-test measurement in the number of contacts with the GP and the number of emergency visits to the physician's office.


Oncicola martini sp. n., and other archiacanthocephala of the Chaco Boreal, Paraguay.
Archiacanthocephalans are reported from mammals of Paraguay. Oncicola martini sp. n. is described from Felis geoffroyi. It is most similar to O. lamasi (Freitas et Costa 1964) comb. n., differing in having larger hooks, all except the smallest of which are barbed. Other species recorded are Oncicola oncicola from Felis geoffroyi (new host record), O. paracampanulata from Felis yagouaroundi, O. luehei from Nasua nasua, Oligacanthorhynchus microcephala from Didelphis albiventris, and O. tortuosa from Euphractus sexcinctus (new host and South American records).


Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 2): effect of epinephrine.
The ability of epinephrine to improve the efficacy of epidurally administered drugs is assumed to result from local vasoconstriction and a consequent decrease in drug clearance. However, because drug concentration in the epidural space has never been measured, our understanding of the effect of epinephrine on epidural pharmacokinetics is incomplete. This study was designed to characterize the effect of epinephrine on the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids. Morphine plus alfentanil, fentanyl, or sufentanil was administered epidurally with and without epinephrine (1:200,000) to pigs. Opioid concentration was subsequently measured in the epidural space, central venous plasma, and epidural venous plasma, and these data were used to calculate relevant pharmacokinetic parameters. The pharmacokinetic effects of epinephrine varied by opioid and by sampling site. For example, in the lumbar epidural space, epinephrine increased the mean residence time of morphine but decreased that of fentanyl and sufentanil. Epinephrine had no effect on the terminal elimination half-life of morphine in the epidural space, but it decreased that of fentanyl and sufentanil. In contrast, in the lumbar intrathecal space, epinephrine had no effect on the pharmacokinetics of alfentanil, fentanyl, or sufentanil, but it increased the area under the concentration-time curve of morphine and decreased its elimination half-life. The findings indicate that the effects of epinephrine on the spinal pharmacokinetics of these opioids are complex and often antithetical across compartments and opioids. In addition, the data clearly indicate that the pharmacokinetic effects of epinephrine in spinal "compartments" cannot be predicted from measurements of drug concentration in plasma, as has been assumed for decades.


Sonographic hemodynamic evaluation of spleno-renal shunt using the Valsalva maneuver.
The purpose of this study was to assess the characteristic features of hemodynamic changes in portal venous hypertension with spleno-renal shunt on conventional B-mode and color Doppler imaging before and after the Valsalva maneuver. A total of 11 patients with portal venous hypertension underwent conventional B-mode and color Doppler ultrasound during follow-up examinations. Sonographic imaging of the splenic vein and the left renal vein was performed before and after the Valsalva maneuver. In the six patients with spleno-renal shunt formation, dilated left renal veins were depicted after the Valsalva maneuver. In the five patients without spleno-renal shunt, there was no apparent dilatation of the left renal vein either before or after the Valsalva maneuver. In all six patients with spleno-renal shunt, color flow mapping of the left renal veins was emphasized during the Valsalva maneuver. In the five patients without spleno-renal shunt formation, there were no apparent changes on color flow mapping of the left renal vein before or after the Valsalva maneuver. The sonographic findings of the splenic vein and the left renal vein on conventional B-mode and color Doppler imaging before and after the Valsalva maneuver are useful for diagnosis of spleno-renal shunt and for grading the hemodynamic changes caused by spleno-renal shunt.


Role of beta-endorphin in the regulation of proinflammatory cytokine production by peripheral blood monocytes in vitro.
beta-Endorphin activated interleukin-1beta production in the culture of unfractionated cells with lipopolysaccharide, but had no effect on the synthesis of tumor necrosis factor-alpha and interleukin-6. This peptide produced a slight stimulatory effect on spontaneous production of interleukin-1beta by cultured leukocytes. Opioid receptor blockade with naloxone and naltrindole did not abolish the stimulatory effect of beta-endorphin on interleukin-1beta production. beta-Endorphin did not modulate the synthesis of interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 in a purified fraction of monocytes.


Lifestyle behaviors and sun exposure among individuals diagnosed with skin cancer: a cross-sectional analysis of 2018 BRFSS data.
With the continued increase in skin cancer incidence rates, the population of skin cancer survivors continues to grow. Understanding skin cancer survivors' lifestyle behaviors, including ultraviolet radiation exposure, is important in reducing skin cancer recurrences and improving health outcomes. The objective of this study is to compare the differences in lifestyle behaviors among skin cancer survivors or individuals who currently have skin cancer versus individuals who have never had a skin cancer diagnosis. To investigate these lifestyle behaviors, we performed a cross-sectional analysis comparing lifestyle behaviors in persons diagnosed with skin cancer and those without a history of skin cancer among US citizens using publicly available data from the 2018 Behavior Risk Factor Surveillance System (BRFSS). In total, there were 437,436 respondents. No significant difference existed between the two cohorts in sunburn frequency, use of sun protection, or indoor tanning; in fact, males were more likely to be afflicted with sunburns following diagnosis. Skin cancer survivors were less likely to be current smokers and sedentary. Female survivors were more likely to binge and heavily drink alcohol. Our findings highlight important areas for reducing risk factors, which could reduce the recurrence of skin malignancies in skin cancer survivors. Our study provides insight to lifestyle behaviors among skin cancer survivors. Being aware of these behaviors has the potential to reduce skin cancer recurrence.


Development and evaluation of a simultaneous and efficient quantification strategy for final prostanoid metabolites in urine.
Prostanoids (PNs) play critical roles in various physiological and pathological processes. Therefore, it is important to understand the alternation of PN expression profiles. However, a simultaneous and efficient quantification system for final PN metabolites in urine has not yet been established. Here, we developed and evaluated a novel method to quantify all final PN metabolites. By purification using a reverse phase solid phase extraction (SPE) column, the matrix effects against the final PGD2, PGE2, and PGF2α metabolites were low, and their accuracies were nearly 100%. The matrix effects against the final PGI2 and TXA2 metabolites were high using reverse phase SPE column purification alone. By applying a tandem SPE method that combined reverse phase and ion exchange SPE columns, the matrix effects decreased so that the accuracy was nearly 100%. To validate the reliability of the method, each final metabolite was quantified from mouse urine to which the PNs (PGD2, PGE2, and PGI2) were intravenously administered. As a result, the amounts of PN metabolites were correlated with those of the PNs administered to the blood in a dose-dependent manner. To validate the method using human samples, the urinary metabolites of Crohn's disease (CD, a PN-related disease) patients and healthy individuals were quantified. All five metabolites were successfully quantified. Only final PGE2 metabolite levels were significantly higher in CD patients than those in healthy individuals, so that the urinary metabolite profiles of CD patients is determined. In conclusion, we developed a novel method to quantify all final PN metabolites simultaneously and efficiently and demonstrated the practicality of the method using human CD patient samples.


The immature and the mature myocardium. Responses to multidose crystalloid cardioplegia.
This study was designed to determine whether multidose St. Thomas' Hospital cardioplegic solution is as effective for preservation of the immature myocardium during ischemia as it is for the mature myocardium. An isolated working heart model was used. Sets of six hearts from immature (3 to 4 weeks, 500 gm) and mature (24 weeks, 2 kg) rabbits were subjected to 60, 90, or 120 minutes of ischemia. Myocardial protection consisted of infusion of cardioplegic solution every 30 minutes at 4 degrees C in a dose of 10 ml/kg of animal weight and maintenance of hypothermia at 10 degrees C by immersion in a cold saline bath. The percent recovery of preischemic aortic flow was lower in the immature than the mature hearts after 90 minutes (60.3% +/- 7.4% versus 101.8% +/- 4.3%) and after 120 minutes (57.4% +/- 10.6% versus 91.1% +/- 13.6%) of ischemia (results expressed as mean value +/- standard error of the mean, p less than 0.05). There were no differences between the mature and the immature hearts in the recovery of heart rate, left atrial pressure, mean aortic pressure, or glycogen stores. Adenosine triphosphate levels measured at the end of the experiment were not different from control in the immature hearts subjected to 60 or 90 minutes of ischemia, but did decline after 120 minutes of ischemia (18.5 +/- 0.8, 16.9 +/- 1.3, 16.6 +/- 0.6 versus 12.3 +/- 1.8 mumol/gm dry weight, p less than 0.05). Adenosine triphosphate levels in the mature hearts were lower than control in hearts subjected to 60, 90, and 120 minutes of ischemia (18.0 +/- 1.2 versus 13.6 +/- 1.1, 12.8 +/- 0.9, 13.7 +/- 1.5 mumol/gm dry weight, p less than 0.05). Multidose St. Thomas' Hospital cardioplegia does not provide adequate preservation of hemodynamic function in the immature rabbit heart, even though myocardial high-energy stores are well preserved. Additional work is necessary to clarify the mechanism of this finding and to develop appropriate methods for protection of the immature myocardium.


Sites of urokinase-type plasminogen activator expression and distribution of its receptor in the normal human kidney.
The urokinase-type plasminogen activator (uPA) is secreted into the urine at high concentrations and both the uPA protein and mRNA are present in human renal tissue. Normal kidney tissue also expresses the receptor for uPA. Neither the precise sites of uPA mRNA expression, nor the distribution of the uPA-receptor antigen, have been elucidated in the human kidney. In the present study, the sites of uPA mRNA expression were identified by in situ hybridization, and the cellular localization of both uPA and uPA-receptor was determined by immunohistochemical analysis. High-level uPA mRNA expression was restricted to epithelial cells of the convoluted proximal tubules and the thick ascending limb of Henle's loop (the straight part of the distal tubule). However, uPA immunoreactivity was not confined to sites of uPA mRNA expression, but was present in all segments of the tubular epithelium. Tubular epithelial cells also exhibited a consistent immunoreactivity with uPA-receptor antibody, indicative of a co-localization of the uPA antigen and its receptor in the uriniferous epithelium. We propose that the uPA antigen expression in nephron segments lacking demonstrable endogenous uPA synthesis may be the result of a uPA-receptor-mediated uptake of uPA.