Species-specific identification of equine cyathostomes resistant to fenbendazole and susceptible to oxibendazole and moxidectin by macroarray probing.
Cyathostome populations in horses on two farms located in central Italy with a history of fenbendazole (FBZ) resistance were investigated with the Faecal Egg Count Reduction Test to evaluate the susceptibility to oxibendazole and moxidectin. Faecal eggs were collected pre- and post-treatment on each farm and molecularly examined with a Reverse Line Blot (RLB) assay able to unequivocally detect and identify 13 cyathostome species. Resistance to FBZ was confirmed on both farms, while oxibendazole and moxidectin demonstrated 97% and 100% efficacy, respectively. Overall eight species of cyathostomes (Coronocyclus labiatus, Cylicocyclus ashworthi, Cylicocyclus nassatus, Cyathostomum catinatum, Cylicostephanus longibursatus, Cylicostephanus goldi, Cylicostephanus calicatus and Cylicocyclus insigne) were identified in pre-treatment samples. Coronocyclus labiatus and C. goldi were identified after treatment with FBZ while C. calicatus and C. labiatus were shown to be <100% susceptible to oxibendazole. These data confirm that resistance to benzimidazoles is established in cyathostome populations from horse farms in Italy and that they are susceptible to moxidectin. The oxibendazole has been successfully demonstrated for the first time as effective against Italian populations of cyathostomes resistant to other benzimidazoles. The RLB assay herein used showed to be useful to study the distribution of these parasitic populations at species level under field conditions and could represent a powerful tool in broader investigation of drug resistance in horse farms from several countries.


Clinical Trials Overview: From Explanatory to Pragmatic Clinical Trials.
Clinical trials have been the bedrock of research to evaluate the safety and efficacy of new medical, surgical, or other interventions. Traditional "explanatory" clinical trials have aimed to explain a biological cause (new treatment) and effect (patient outcome) while controlling for many factors that might impact the evaluation, such as restricted eligibility criteria, frequent follow-up visits, and multiple clinical and laboratory measures. Despite the benefits of a well-controlled clinical trial, compromises have been made that can limit who might benefit from a new intervention, can increase complexity of the conduct of a trial, or that lead to excessively long durations of trials. An alternative approach to evaluate the effectiveness of an intervention is based on "pragmatic" clinical trials, which consider how an intervention affects a patient's condition in the real world, accounting for how to optimize an intervention within the operations of busy and diverse clinical practices. Although we describe explanatory and pragmatic trial designs as separate approaches, there is a continuum of approaches that intersect. Some key points are the need to maintain scientific rigor, increase efficiency of clinical trials operations, ensure that trial results can be generalized to a broad spectrum of patients, and balance the needs of real-world clinical care. Pragmatic trials can leverage technology and telecommunication strategies of decentralized trials to further reach underrepresented and underserved patients to close the health disparity gaps.


Characterizing primary care for patients with major depressive disorder using electronic health records of a US-based healthcare provider.
Major depressive disorder (MDD) is predominantly managed in primary care. However, primary care providers (PCPs) may not consistently follow evidence-based treatment algorithms, leading to variable patient management that can impact outcomes. We retrospectively analyzed adult patients with MDD seen at Geisinger, an integrated health system. Utilizing electronic health record (EHR) data, we classified patients as having MDD based on International Classification of Disease (ICD)-9/10 codes or a Patient Health Questionnaire (PHQ)-9 score ≥5. Outcomes assessed included time to first visit with a PCP or behavioral health specialist following diagnosis, antidepressant medication switching, persistence, healthcare resource utilization (HRU), and treatment costs. Among the 38,321 patients with MDD managed in primary care in this study, significant delays between diagnosis with antidepressant prescribing and follow-up PCP visits were observed. There was also considerable variation in care following diagnosis. Overall, 34.9% of patients with an ICD-9/10 diagnosis of MDD and 41.3% with a PHQ-9 score ≥15 switched antidepressants. An ICD-9/10 diagnosis, but not moderately severe to severe depression, was associated with higher costs and HRU. More than 75% of patients with MDD discontinued antidepressant medication within 6 months. The study population was comparable with other real-world studies of MDD, but study limitations include its retrospective nature and reliance on the accuracy of EHRs. Management of patients with MDD in a primary care setting is variable. Addressing these gaps will have important implications for ensuring optimal patient management, which may reduce HRU and treatment medication costs, and improve treatment persistence.


Country-specific regulation and international standardization of cell-based therapeutic products derived from pluripotent stem cells.
Currently, many types of cell-based therapeutic products (CTPs) derived from pluripotent stem cells (PSCs) are being developed in a lot of countries, some of which are in clinical trial stages. CTPs are classified differently in different countries and regions. The evaluation of their efficacy, safety, and quality also differs from that for conventional small-molecule drugs and biopharmaceuticals, which reflects the complex properties of living cells and unmet medical needs. Since there are no international guidelines to evaluate CTPs, including PSC-derived products, it is necessary to be aware of differences in relevant laws and regulations in different countries and regions. International consortia are organized and actively working to standardize/harmonize the evaluation methods and regulations to facilitate the development and global distribution of PSC-derived CTPs. In this paper, we outline the regulations related to PSC-derived CTPs in the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use founding regions (US, EU/UK, Japan) and introduce representative consortia working on their standardization.


Triazole-based Zn²⁺-specific molecular marker for fluorescence bioimaging.
Fluorescence bioimaging potential, both in vitro and in vivo, of a yellow emissive triazole-based molecular marker has been investigated and demonstrated. Three different kinds of cells, viz Bacillus thuringiensis, Candida albicans, and Techoma stans pollen grains were used to investigate the intracellular zinc imaging potential of 1 (in vitro studies). Fluorescence imaging of translocation of zinc through the stem of small herb, Peperomia pellucida, having transparent stem proved in vivo bioimaging capability of 1. This approach will enable in screening cell permeability and biostability of a newly developed probe. Similarly, the current method for detection and localization of zinc in Gram seed sprouts could be an easy and potential alternative of the existing analytical methods to investigate the efficiency of various strategies applied for increasing zinc-content in cereal crops. The probe-zinc ensemble has efficiently been applied for detecting phosphate-based biomolecules.


What Socrates drank? Comparative chemical investigation of two Greek Conium taxa exhibiting diverse chemical profiles.
Conium divaricatum, even though exhibiting morphological differences in comparison to its congener of European origin Conium maculatum, is still considered a disputed taxon often referred to as a synonym of the latter. Herein, essential oils of various plant tissues from several populations of both taxa were comparatively investigated, showing distinct chemical profiles. In the case of C. divaricatum, the essential oils were dominated by hydrocarbon esters, among which the main constituents 4'-oxodecyl hexanoate, 4'-oxododecyl hexanoate and 4'-oxooctyl hexanoate were isolated and identified as undescribed natural products. In contrast, the essential oils of C. maculatum were dominated by hydrocarbon alkanes, alkenes and ketones, as well as the polyacetylene (Z)-falcarinol. Even though determination of the total alkaloids content and toxicity assessment against the crustacean Artemia salina did not reveal significant differences, the distinct chemical profiles and the morphological differences observed for both taxa, strongly support their distinction as separate species.


Study on Chemical Components from Derris taiwaniana and Their Lung Epithelial Cell Protect Effects.
The ethanol extract of roots of Derris taiwaniana gave two undescribed compounds, 3,3'-dimethoxy-5'-hydroxystilbene-4-O-β-apiofuranosyl-(1→6)-β-D-glucopyranoside (1) and 4',5-dihydroxy-3'-methoxyisoflavone-7-O-β-apiofuranosyl-(1→6)-β-D-glucopyranoside (2), along with thirty known components. Among them, compounds 14, 16-17, 23, 26-32 were isolated from this genus for the first time. Their structures were established based on physico-chemical properties and spectroscopic data, the lung epithelial cell protective effects were evaluated using NNK-induced MLE-12 cells. Among them, 2α,3α-epoxy-5,7,3',4'-tetrahydroxyflavan-(4β-8-catechin) (30) showed the best significant protective effect, speculated to be the key component of D. taiwaniana that plays a protective role in lung epithelial cells.


Simplified models for gas exchange in the human lungs.
This paper presents a hierarchy of models with increasing complexity for gas exchange in the human lungs. The models span from a single compartment, inflexible lung to a single compartment, flexible lung with pulmonary gas exchange. It is shown how the models are related to well-known models in the literature. A long-term purpose of this work is to study nonlinear phenomena seen in the cardio-respiratory system (for example, synchronization between ventilation rate and heart rate, and Cheyne-Stokes respiration). The models developed in this paper can be regarded as the controlled system (plant) and provide a mathematical framework to link between "molecular-level", and "systems-level" models. It is shown how changes in molecular level affect the alveolar partial pressure. Two assumptions that have previously been made are re-examined: (1) the hidden assumption that the air flow through the mouth is equal to the rate of volume change in the lungs, and, (2) the assumption that the process of oxygen binding to hemoglobin is near equilibrium. Conditions under which these assumptions are valid are studied. All the parameters in the models, except two, are physiologically realistic. Numerical results are consistent with published experimental observations.


Exanthematic diseases during pregnancy and attention-deficit/hyperactivity disorder (ADHD).
Rash causing viral diseases may be transmitted during pregnancy, causing severe congenital disease. Although neurological and psychiatric disorders are common consequences of congenital rubella, children born to women who developed a viral rash during pregnancy do not appear to be at increased risk of these disorders if they were asymptomatic at birth. In a case-control study conducted to evaluate risk factors for ADHD, we found an increased risk of this disorder among children born to women experiencing a viral rash during pregnancy. The viral rash (i.e. measles, varicella, or rubella) was reported by 4 of 71 mothers of children with ADHD and none of the 118 controls' mothers (P<0.01). The difference remained statistically significant after adjusting for potential confounders (i.e. other factors found associated with ADHD, such as gender and familiarity). Although, the viral disease reported by the mothers, in accordance with their physician's diagnosis, did not represent a homogeneous nosological group, the unexpectedly high rate found among ADHD cases' mothers suggest a role for viral diseases occurring during pregnancy in the development of ADHD.


Association between migraine and headache attributed to stroke: a case-control study.
Several studies were carried out to investigate the occurrence of headache attributed to acute stroke in patients with a lifetime history of migraine. In a case-control series of 96 acute stroke patients with a lifetime history of migraine (M+) and 96 stroke patients without (M-), ischemic stroke patients only, without secondary infarction, were selected. The headache attributed to acute ischemic stroke was then analyzed. (M+) patients complained of headache more often than (M-) patients (P < .0001), mainly in the 24 hours before stroke onset (P < .0001). Migraine-like features of headache were recognized in a greater proportion of cases in the (M+) patient group with ischemic stroke (P < .018). A preferential brainstem location of ischemic stroke in (M+) patients emerged compared with (M-) patients (P = .014). The high prevalence of headache attributed to stroke in (M+) patients, in a relevant proportion of cases presenting as a sentinel headache, suggests that cerebral ischemia lowers the threshold for head pain more easily in these "susceptible" patients. The most frequent involvement of the brainstem in (M+) patients with ischemic infarction concurs with recent reports that emphasized a greater headache frequency when cerebral infarctions are localized in this structure or deep brain gray matter.


Tibial nerve neuropathy following medial opening-wedge high tibial osteotomy-case report of a rare technical complication.
A 63-year-old woman developed tibial nerve injury caused by an overlong K wire and 4.5-mm cortical lag screw through the first distal hole below the osteotomy during medial opening-wedge high tibial osteotomy (HTO), leading to a lack of sensation on the sole of the foot with no disturbances in motor functions. The temporary lag screw in the first distal hole below the osteotomy is often inserted by an excessive length in order to compress the potentially fractured opposite cortex. By doing so, posterior neurovascular structures including the tibial nerve and the popliteal vessels can be injured. To avoid this type of injury during medial opening-wedge HTO, proper knee position and appropriate Hohmann retractor position in combination with meticulous insertion of the K wire or screw under fluoroscopic control are essential. In addition, our study reinforces the fact that different presentations of injury to the tibial nerve should be carefully considered in the absence of common diagnostic features, including weakness of the toe flexors and posterior tibial muscle of the leg with intractable pain.


[Contributing factors and control strategies of pine wilt disease].
There are several types of pine wilt diseases with inherent inter-relations. The diseases are closely related with the complex ecological system composed of local environment, pine trees, insect vectors, and pathogenic nematodes and some other microorganisms. Sustainable pest management based on ecology is a potential approach for pine wilt disease control.


Nutritional status and body composition evolution in early post-renal transplantation: is there a female advantage?
Chronic renal failure is associated with metabolic derangements, affecting proteins, amino acids, and lipids. Usually these patients follow a restricted diet. Kidney transplant patients enjoy a recovery of renal function, but their therapeutics may entail significant changes in general metabolism. We compare the anthropometric results during the first 3 months after successful transplant for male and female patients versus a healthy group. Eighteen patients (11 men and 7 women) were studied. Anthropometry was assessed before and at month 1 and month 3 posttransplant including body weight (Wt), body mass index (BMI), triceps (TSF), biceps (BSF), subscapular (SCSF), and suprailiac skinfolds (SISF), midarm circumference (MAC), midarm muscle circumference (MAMC), corrected arm muscle area (CT.AMA), total body muscle mass (MM), body density (D), fat mass (FM), and fat-free mass (FFM). The healthy group was evaluated three times in the first year. Pretransplant men showed lower Wt, BMI, TSF, BSF, SCSF, SISF, MAC, MAMC, CT.AMA, MM, FM and FFM than controls, while women displayed no differences from controls. By the third month, men showed only a partial recovery and women higher TSF and SCSF than controls. Uremic men before transplant displayed undernutrition indices. During the first 3 months posttransplant men showed an incomplete recovery of anthropometric parameters. Quite differently, women started close to normal and had significantly increased body weight and fat content posttransplant. We suggest that nutritional requirements post-kidney grafting may be significantly different among male compared to female patients.


The effect of COVID-19 pandemic on market integration: Evidence from vegetable farmers in Pakistan.
The COVID-19 pandemic exposed the agriculture sector and farming communities to unprecedented risks. This study investigates the impact of the pandemic, identifying the suggestions of community elders for effective resilience via in-depth interviews (IDIs) and Focus Group Discussions (FGDs). We also examine determinants of vegetable farmers' inputs and outputs market participation using a binary logit model. The findings reveal poor business owners' support, difficulties accessing inputs and outputs markets, non-availability/shortage of inputs recommended by extension services, and poor access to mechanizations. Labor shortages, lack of access to agricultural credit, and lack of information on innovations and markets are also barriers to market integration of farming communities in Pakistan. Results of the logit model show that farming experience and support from market owners drive the participation of both the inputs and outputs market. Similarly, ownership of personal vehicles and the availability of farm machinery drive the participation of farmers in outputs markets. Various strategies are suggested to mitigate the risks of the Covid-19 pandemic, including the establishment of inputs and outputs markets, strategies for transportation, access to information, and farm machinery at the local level.


Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity.
The stromal scaffold of the lymph node (LN) paracortex is built by fibroblastic reticular cells (FRCs). Conditional ablation of lymphotoxin-β receptor (LTβR) expression in LN FRCs and their mesenchymal progenitors in developing LNs revealed that LTβR-signaling in these cells was not essential for the formation of LNs. Although T cell zone reticular cells had lost podoplanin expression, they still formed a functional conduit system and showed enhanced expression of myofibroblastic markers. However, essential immune functions of FRCs, including homeostatic chemokine and interleukin-7 expression, were impaired. These changes in T cell zone reticular cell function were associated with increased susceptibility to viral infection. Thus, myofibroblasic FRC precursors are able to generate the basic T cell zone infrastructure, whereas LTβR-dependent maturation of FRCs guarantees full immunocompetence and hence optimal LN function during infection.


Fast-Tracking Patients Through the Diagnostic and Therapeutic Pathways of Intrathoracic Conditions: The Role of Uniportal Video-Assisted Thoracic Surgery.
Fast-tracking patients in surgery has become standard in many hospitals. This allows for a shorter hospital stay and a complete organized pathway for treating patients. The operative trauma has an important role in the patient's recovery, as has the increasing use of minimally invasive procedures. In thoracic surgery, video-assisted thoracic surgery (VATS) procedures are aimed at reducing the operative trauma. One of the latest developments of VATS is represented by the uniportal approach, whose purpose is to reduce postoperative pain and morbidity. This article reviews the current literature and the authors' experience in combining uniportal VATS technique and fast-track surgery.


Recent Advances in Egypt for Treatment of Talar Osteochondral Lesions.
Treatment of osteochondral defects (OCLs) of the talus is a challenging orthopedic surgery. Treatment of talar OCLs has evolved through the 3 "R" paradigm: reconstruction, repair, and replacement. This article highlights current state-of-the-art techniques and reviews recent advances in the literature about articular cartilage repair using various novel tissue engineering approaches, including various scaffolds, growth factors, and cell niches; which include chondrocytes and culture-expanded bone marrow-derived mesenchymal stem cells.


Recent progress in the engineering of C1-utilizing microbes.
The global climate crisis has led to the transition toward the sustainable production of chemicals and fuels with a low carbon footprint. Microbial utilization of one-carbon (C1) substrates, such as carbon dioxide, carbon monoxide, methane, formate, and methanol, may be a promising replacement for the current fossil fuel-based industry. However, natural C1-utilizing microbes are currently unsuitable for industrial applications because of their slow growth and low carbon conversion efficiency, which results in low productivity and yield. Here, we review the recent achievements in engineering C1-utilizing microbes with improved carbon assimilation efficiency and describe the development of synthetic microorganisms by introducing natural C1 assimilation pathways in non-C1-utilizing microbes. Finally, we outline the future directions for realizing the industrial potential of C1-utilizing microbes.


Folding characteristics of membranes in capillary origami.
A study was conducted to understand the effects of membrane shape, thickness, contact angle, surface tension and large deflection on capillary origami. For experiments, square and triangular membranes made of PDMS with various thicknesses and sizes were used to encapsulate different liquids. Models for membranes under pure bending were developed using the energy balance between interfacial energies (liquid-vapor, solid-liquid and solid-vapor energies) and bending energy evaluated by a small-deflection and a large-deflection assumptions. This paper is the first study to consider the large deflection for membranes as well as to include the terms for the wettability of the membrane and its shape. The developed models evaluated an important characteristic length, i.e., elasto-capillary length (LEC), which is proportional to the critical length (Lcritical) below which membranes cannot be closed to encapsulate liquid. The experimental results showed that the large-deflection model can estimate Lcritical more accurately in terms of membrane shape, thickness, contact angle and surface tension for liquids with similar properties to water than the small-deflection model. The developed models should be further improved to extend the applicability to liquids with low surface tension and low contact angle.


Two recessive mutations in FGF5 are associated with the long-hair phenotype in donkeys.
Seven donkey breeds are recognized by the French studbook. Individuals from the Pyrenean, Provence, Berry Black, Normand, Cotentin and Bourbonnais breeds are characterized by a short coat, while those from the Poitou breed (Baudet du Poitou) are characterized by a long-hair phenotype. We hypothesized that loss-of-function mutations in the FGF5 (fibroblast growth factor 5) gene, which are associated with a long-hair phenotype in several mammalian species, may account for the special coat feature of Poitou donkeys. To the best of our knowledge, mutations in FGF5 have never been described in Equidae. We sequenced the FGF5 gene from 35 long-haired Poitou donkeys, as well as from a panel of 67 short-haired donkeys from the six other French breeds and 131 short-haired ponies and horses. We identified a recessive c.433_434delAT frameshift deletion in FGF5, present in Poitou and three other donkey breeds and a recessive nonsense c.245G > A substitution, present in Poitou and four other donkey breeds. The frameshift deletion was associated with the long-hair phenotype in Poitou donkeys when present in two copies (n = 31) or combined with the nonsense mutation (n = 4). The frameshift deletion led to a stop codon at position 159 whereas the nonsense mutation led to a stop codon at position 82 in the FGF5 protein. In silico, the two truncated FGF5 proteins were predicted to lack the critical β strands involved in the interaction between FGF5 and its receptor, a mandatory step to inhibit hair growth. Our results highlight the allelic heterogeneity of the long-hair phenotype in donkeys and enlarge the panel of recessive FGF5 loss-of-function alleles described in mammals. Thanks to the DNA test developed in this study, breeders of non-Poitou breeds will have the opportunity to identify long-hair carriers in their breeding stocks.


Origin, Clinical Characteristics and 30-Day Outcomes of Severe Hematochezia in Cirrhotics and Non-cirrhotics.
The sites of origin, causes and outcomes of severe hematochezia have not been compared between cirrhotics and non-cirrhotics. In cirrhotics versus non-cirrhotics presenting with severe hematochezia, we aimed at (1) identifying the site and etiology of gastro-intestinal bleeding and independent predictors of bleeding from the upper gastrointestinal tract versus small bowel or the colon, (2) comparing 30-day clinical outcomes, and (3) proposing an algorithm for management of severe hematochezia. In this cohort study from two university-based medical centers, 860 consecutive patients with severe hematochezia admitted from 1995 to 2011 were prospectively enrolled with 160 (18.6 %) cirrhotics. We studied (a) general clinical and laboratory characteristics of cirrhotics versus non-cirrhotics, (b) predictors of bleeding sites in each patient group by multiple variable regression analysis, and compared (c) 30-day outcomes, including rebleeding, surgery and deaths. Cirrhosis independently predicted an upper gastrointestinal source of bleeding (OR 3.47; 95 % CI 2.01-5.96) as well as history of hematemesis, melena in the past 30 days, positive nasogastric aspirate, prior upper gastrointestinal bleeding or use of aspirin or non-steroidal anti-inflammatory. The most prevalent diagnoses were esophageal varices (20 %) in cirrhotics and colon diverticular bleeding (27.1 %) in non-cirrhotics. Thirty-day rates of rebleeding, surgical interventions and deaths were 23.1 versus 15 % (P = 0.01), 14.4 versus 6.4 % (P < 0.001), and 17.5 versus 4.1 % (P < 0.001), in cirrhotics versus non-cirrhotics, respectively. Cirrhosis predicted an upper gastrointestinal site of bleeding in patients presenting with severe hematochezia. The 30-day rates of rebleeding, surgery, and death were significantly higher in cirrhotics than in non-cirrhotics.


Physiological Gut Oxygenation Alters GLP-1 Secretion from the Enteroendocrine Cell Line STC-1.
Enteroendocrine cell lines are routinely assayed in simple buffers at ≈20% oxygen to screen foods for bioactives that boost satiety hormone levels. However, in vivo, enteroendocrine cells are exposed to different phases of food digestion and function at low oxygen concentration, ranging from 7.5% in the stomach to 0.5% in the colon-rectal junction. The objective of this study is to investigate the effect of physiologically relevant O2 concentrations of the gut on the production and secretion of the satiety hormone, glucagon-like peptide 1 (GLP-1), from the murine enteroendocrine cell line, secretin tumor cell line (STC-1), in response to dairy macronutrients as they transit the gut. GLP-1 exocytosis from STC-1 cells is influenced by both oxygen concentration and by individual macronutrients. At low oxygen, STC-1 cell viability is significantly improved for all macronutrient stimulations and cyclic adenosine monophosphate levels are dampened. GLP-1 secretion from STC-1 cells is influenced by both the phase of yogurt digestion and corresponding O2 concentration. Atmospheric oxygen at 4.5% combined with upper gastric digesta, which simulates ileum conditions, yields the highest GLP-1 response. This demonstrates the importance of considering physiological oxygen levels and food digestion along gastrointestinal tract for reliable in vitro analysis of gut hormone secretion.


Comparison of fatty acid profile in the chicken meat after feeding with narasin, nicarbazin and salinomycin sodium and phyto-additive substances.
The purpose of this study was an experimental investigation and a statistical evaluation of the influence of various additives in feed mixtures of broiler chickens on fatty acids content and their ratio in breast and thigh muscles. First feed additive consisted of narasin, nicarbasin and salinomycin sodium, and other five additives were of phytogenic origin. In vivo experiment was realized on the poultry experimental station with deep litter breeding system. A total of 300 one-day-old hybrid chickens Cobb 500 divided into six groups were used for the experiment. The experimental period was divided into four phases, i.e. Starter, Grower 1, Grower 2 and Final, according to the application of commercial feed mixture of soy cereal type. Additive substances used in feed mixtures were different for each group. Basic feed mixtures were equal for all groups. Fatty acid profile of breast and thigh muscles was measured by the method of FT IR Nicolet 6700. Investigated additive substances in the feed mixtures did not have statistically significant effect on fatty acid content and omega-6/omega-3 polyunsaturated fatty acid (PUFA) ratio in breast and thigh muscles. Strong statistically significant relation between omega-6 PUFAs and total PUFAs were proved by experiment. A relation between omega-3 PUFAs and total PUFAs was found only in the group with Biocitro additive.


Indeterminate cell lineage of the zebrafish embryo.
We have examined the clonal progeny descended from individual blastomeres injected with lineage-tracer dye in the zebrafish embryo. Blastomeres arising by the same cleavages in different embryos generated clones in which the types and positions of cells were highly variable. Several features of early development were correlated with this diversity in cell fate. There was no fixed relationship between the plane of the first cleavage and the eventual plane of bilateral symmetry of the embryo. By blastula stages the cleavages of identified blastomeres were variable in pattern. Moreover, cell fate was not easily related to the longitudinal and dorsoventral position of the clone in the gastrula. These results establish that single blastomeres can potentially generate a highly diverse array of cell types and that the cell lineage is indeterminate.


Clinical in-situ evaluation of the effect of rubber dam isolation on bond strength to enamel.
To evaluate the effect of rubber dam isolation on shear bond strength of two different adhesive systems to enamel. The mesial, distal, lingual, and vestibular enamel surfaces of thirty human third molars were prepared (total n = 120). A custom splint was made to fit a volunteer's maxilla, holding the specimens in place in the oral cavity. Four composite resin cylinders were bonded to each tooth with one of two bonding agents (OptiBond FL and Prime&Bond active) with or without rubber dam isolation. Shear bond strength was tested in a universal testing machine and failure modes were assessed. Significance level for statistical analyses was set at 5%. All pairwise comparisons revealed statistical differences (p < 0.05). The highest mean shear bond strength values were obtained in rubber dam experimental groups, regardless of the adhesive system. Group OptiBond FL with rubber dam presented the highest mean bond strength values. Fracture modes for specimens bonded without rubber dam isolation were adhesive and cohesive within enamel, while rubber dam experimental groups revealed only cohesive fractures. Absolute isolation with rubber dam increases bond strength to enamel, independent of the adhesive system. The three-step total-etch system OptiBond FL provided significantly higher bond strength values than Prime&Bond active under both experimental conditions. Rubber dam isolation has a significant effect on bond strengths to enamel, independent of the adhesive system. Its application is, therefore, advised whenever adhesive procedures are performed. A filled three-step etch-and-rinse adhesive performed superiorly, with or without rubber dam isolation, when bonding to enamel compared to an isopropanol-based universal adhesive.


Decoding Single Cell Morphology in Osteotropic Breast Cancer Cells for Dissecting Their Migratory, Molecular and Biophysical Heterogeneity.
Breast cancer is a heterogeneous disease and the mechanistic framework for differential osteotropism among intrinsic breast cancer subtypes is unknown. Hypothesizing that cell morphology could be an integrated readout for the functional state of a cancer cell, we established a catalogue of the migratory, molecular and biophysical traits of MDA-MB-231 breast cancer cells, compared it with two enhanced bone-seeking derivative cell lines and integrated these findings with single cell morphology profiles. Such knowledge could be essential for predicting metastatic capacities in breast cancer. High-resolution microscopy revealed a heterogeneous and specific spectrum of single cell morphologies in bone-seeking cells, which correlated with differential migration and stiffness. While parental MDA-MB-231 cells showed long and dynamic membrane protrusions and were enriched in motile cells with continuous and mesenchymal cell migration, bone-seeking cells appeared with discontinuous mesenchymal or amoeboid-like migration. Although non-responsive to CXCL12, bone-seeking cells responded to epidermal growth factor with a morphotype shift and differential expression of genes controlling cell shape and directional migration. Hence, single cell morphology encodes the molecular, migratory and biophysical architecture of breast cancer cells and is specifically altered among osteotropic phenotypes. Quantitative morpho-profiling could aid in dissecting breast cancer heterogeneity and in refining clinically relevant intrinsic breast cancer subtypes.


Medication Burden of Treatment Using Oral Cancer Medications.
With the changes in healthcare, patients with cancer now have to assume greater responsibility for their own care. Oral cancer medications with complex regimens are now a part of cancer treatment. Patients have to manage these along with the management of medications for their other chronic illnesses. This results in medication burden as patients assume the self-management. This paper describes the treatment burdens that patients endured in a randomized, clinical trial examining adherence for patients on oral cancer medications. There were four categories of oral agents reported. Most of the diagnoses of the patients were solid tumors with breast, colorectal, renal, and gastrointestinal. Patients had 1-4 pills/day for oral cancer medications as well as a number for comorbidity conditions (>3), for which they also took medications (10-11). In addition, patients had 3.7-5.9 symptoms and side effects. Patients on all categories except those on sex hormones had 49%-57% drug interruptions necessitating further medication burden. This study points out that patients taking oral agents have multiple medications for cancer and other comorbid conditions. The number of pills, times per day, and interruptions adds to the medication burden that patients' experience. Further study is needed to determine strategies to assist the patients on oral cancer medications to reduce their medication burden.


Age-related morphine kinetics.
The kinetic disposition of morphine was compared in 13 young and 7 older healthy subjects after a single intravenous dose of 10 mg/70 kg morphine. The apparent volume of distribution at steady state in elderly subjects was only half of that in young subjects. This difference was derived from reductions in both central and peripheral kinetic compartment volumes in the older subjects. The beta elimination phase for morphine was more rapid, but its plasma clearance was reduced in older subjects. Calculation of the peripheral compartment morphine concentration for these subjects indicated that drug concentration in this kinetic space was higher in older subjects for 1.5 hr after dosing.


Evaluation and management of perianal abscess and anal fistula: a consensus statement developed by the Italian Society of Colorectal Surgery (SICCR).
Perianal sepsis is a common condition ranging from acute abscess to chronic fistula formation. In most cases, the source is considered to be a non-specific cryptoglandular infection starting from the intersphincteric space. The key to successful treatment is the eradication of the primary track. As surgery may lead to a disturbance of continence, several sphincter-preserving techniques have been developed. This consensus statement examines the pertinent literature and provides evidence-based recommendations to improve individualized management of patients.


Further experience with contrast-enhanced CT in head trauma.
Abnormal contrast enhancement was seen in 196 (39.8%) of 492 CT scans performed on patients for evaluation of head trauma. It proved most helpful in the diagnosis of isodense subdural hematomas and contusions. The advantages of contrast-enhanced CT scans in the evaluation of head trauma more than compensate for the additional time in performing the examination.


The T-cell receptor signalosome: a dynamic structure with expanding complexity.
Signal transduction in T cells is a dynamic process involving a large number of membrane and cytosolic proteins. The TCR macromolecular complex (signalosome) is initiated by receptor occupancy and becomes more elaborate over time. This review describes how 'vertical' displacement mechanisms and lateral coalescence of lipid-raft-associated scaffold proteins combine to form distinct signalosomes, which control signal specificity.


Intravitreal aflibercept for submacular hemorrhage secondary to neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.
To evaluate the efficacy of intravitreal aflibercept monotherapy for submacular hemorrhage secondary to neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). This prospective, phase 4 clinical trial included 29 patients diagnosed with fovea-involving submacular hemorrhage secondary to neovascular AMD (7 patients) or PCV (22 patients). Patients were initially administered 3 monthly aflibercept injections, followed by 1 injection every 2 months. The primary outcome measure was changes in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) during the 56-week study period. Other key outcome measures were the proportion of patients who exhibited changes in BCVA of ≥ 15 ETDRS letters from baseline and changes in central retinal thickness (CRT). The mean size of hemorrhage was 6.2 ± 4.8-disc-diameter area. The mean BCVA significantly improved from 52.9 ± 17.8 ETDRS letters at week 0 (baseline) to 71.8 ± 16.1 letters at week 56 (P < 0.001). At week 56, improvement in BCVA of ≥ 15 letters was noted in 16 patients (55.2%), whereas none of the patients experienced a loss of ≥ 15 letters. The mean CRT significantly decreased from 498.9 ± 194.2 μm at week 0 to 248.3 ± 45.0 μm at week 56 (P < 0.001). During the study period, retinal break developed in one patient. Intravitreal aflibercept administered every 2 months after the 3 initial monthly doses was found to be an effective and safe treatment method for submacular hemorrhage secondary to neovascular AMD.


Non-prescription cannabis use for symptom management amongst women with gynecologic malignancies.
To evaluate interest in and patterns of use of non-prescription cannabis products for symptom management amongst gynecologic cancer patients living in states with legal access to medical and recreational marijuana. Cross-sectional study using a novel 35-question survey distributed to women diagnosed with gynecologic cancer within two academic centers in California and Colorado. The survey queries demographic and disease traits, and both objective and subjective issues surrounding use of cannabis products for symptom management. Surveys were distributed to patients actively receiving treatment or under surveillance. Enrollment began July 16, 2018 and was completed December 1, 2018. Survey return rate was 52.7%. A total of 225 participants met inclusion criteria.Sixty-two percent reported that they have used or would be interested in using cannabis products for symptom management; 60 (26.7%) are using non-prescription cannabis for treatment of cancer related symptoms, and 80 (35.6%) are interested in using cannabis derivatives under direction of their oncologist. Reasons cited for use of cannabis included: pain control (n = 41, 68.3), insomnia (n = 33, 55.0%), anxiety (n = 29, 48.3%), nausea (n = 26, 43.3%), and appetite stimulation (n = 21, 35.0%). Of the women using cannabis products, almost half report decreased prescription narcotic use after initiation of cannabis products (n = 27, 45.0%). Women with gynecologic cancer report a strong interest in the use of non-prescription cannabis products for management of cancer-related symptoms. Practitioners in the field of gynecologic oncology should be aware of the frequency of use of non-prescription cannabis amongst their patients as well as the growing desire for guidance about the use of cannabis derivatives. A substantial number of patients report decreased reliance on opioids when using cannabis derivatives for pain control.


An intrinsically disordered nascent protein interacts with specific regions of the ribosomal surface near the exit tunnel.
The influence of the ribosome on nascent chains is poorly understood, especially in the case of proteins devoid of signal or arrest sequences. Here, we provide explicit evidence for the interaction of specific ribosomal proteins with ribosome-bound nascent chains (RNCs). We target RNCs pertaining to the intrinsically disordered protein PIR and a number of mutants bearing a variable net charge. All the constructs analyzed in this work lack N-terminal signal sequences. By a combination chemical crosslinking and Western-blotting, we find that all RNCs interact with ribosomal protein L23 and that longer nascent chains also weakly interact with L29. The interacting proteins are spatially clustered on a specific region of the large ribosomal subunit, close to the exit tunnel. Based on chain-length-dependence and mutational studies, we find that the interactions with L23 persist despite drastic variations in RNC sequence. Importantly, we also find that the interactions are highly Mg+2-concentration-dependent. This work is significant because it unravels a novel role of the ribosome, which is shown to engage with the nascent protein chain even in the absence of signal or arrest sequences.


Proteoglycans synthesized in vitro by nude and normal mouse peritoneal macrophages.
Peritoneal macrophages from nude mice were found to be functionally similar to 'activated' macrophages from normal mice. The objective of the present study was to characterize the proteoglycans synthesized and secreted in vitro by peritoneal macrophages isolated from nude and normal Balb/c mice and to investigate the relationship between macrophage 'activation' and changes in the proteoglycan patterns. Macrophages obtained by peritoneal lavage were seeded in Petri dishes. After 2 h incubation at 37 degrees C, the adherent cells (macrophages) were exposed to [35S]sulphate for the biosynthetic labelling of proteoglycans. After incubation, the cell and medium fractions were collected and analysed for proteoglycans and glycosaminoglycans. The glycosaminoglycans were identified and characterized by a combination of agarose gel electrophoresis and enzymatic degradation with specific mucopolysaccharidases. It was shown that 3/4 of the total 35S-labelled glycosaminoglycans were in the extracellular compartment after 24-48 h. The macrophages synthesized dermatan sulphate (68%), chondroitin sulphate (7%) and heparan sulphate (25%). Both cell and medium fractions of normal and nude mouse macrophages contained glycosaminoglycans with the same ratios, although the nude mouse macrophages synthesized 2-fold less glycosaminoglycans than the normal mouse macrophages. Lower levels of 35S-proteoglycans were also obtained from in vitro 'activated' macrophages, but the ratios of dermatan sulphate:chondroitin sulphate: heparan sulphate were altered in these cells as compared to the control. Furthermore, all the 35S-macromolecules found in the extracellular compartment of nude and normal control cells were of proteoglycan nature, in contrast to the medium fractions of 'activated' macrophages, which contain both intact proteoglycans and 'free' glycosaminoglycan chains. These results indicate that, at least as regards the proteoglycans and glycosaminoglycans, the nude mouse macrophages are not identical to the 'activated' macrophages from normal mice.


Potentiation of hypericin and hypocrellin-induced phototoxicity by omeprazole.
Hypericin and hypocrellin are potential antiviral and antineoplastic agents with multiple modes of light-induced biological activity connected with a production of singlet oxygen and/or excited-state proton transfer and consequent pH drop formation in the drugs environment. In present work light-induced cytotoxicity of hypericin (1 x 10(-5) - 10(-9) mol) and hypocrellin (1 x 10(-5) - 10(-9) mol) and potentiating effect of omeprazole on human leukemic cell line HL-60 was studied. Under dark condition cultivation none cytotoxicity was observed. The only one exception was hypocrellin in concentration 1 x 10(-5) mol which displayed full cytotoxic effect. However, illumination increased cytotoxic effect of hypericin and hypocrellin, both. Omeprazole, an inhibitor of H+K+-ATPase, has been used for testing the hypothetical pH decreasing effect of hypericin and hypocrellin in their cytotoxic mechanism of action. The results of our experiments have shown that in HL-60 cell line the effect of hypericin and hypocrellin at 1 x 10(-6) mol (both) was significantly potentiated by omeprazole in concentrations 1 x 10(-6) - 10(-9) mol. Our results support the hypothesis that the excited-state proton transfer and the consequent acidification of hypericin and hypocrellin environment could play a role in the biological activity of both agents.


[Heterogeneous selection in a subdivided population with unstable deme sizes].
The influence of small deme sizes oscillations in a one-locus two-allele model is considered. The dependence of frequency deviations from the fluctuation numbers is obtained. The new method of selection coefficients and migration matrix estimation from the deme numbers and the allele frequencies observations is found.


MicroRNAs and their cross-talks in plant development.
Plant development is a complex process influenced by exogenous and endogenous elements. A series of postembryonic developmental events is involved to form the final architecture and contend with the changing environment. MicroRNA (miRNA) is one of endogenous non-coding RNAs, which plays an important role in plant developmental regulation. In this review, we summarized 34 miRNA families that are closely associated with plant development. Among these families, nine are expressed only in specific organs, whereas 20 families are expressed in at least two different organs. It is known that some miRNAs are expressed across most processes of plant growth, while some appear only at particular developmental stages or under special environmental conditions such as drought, waterlogging and short-day time. These miRNAs execute their diverse functions by regulating developmental gene expression levels, interacting with phytohormone signaling response, participating in the biogenesis of ta-siRNAs and affecting the production of miRNAs.


Skeletal status assessed by quantitative ultrasound at the calcaneus in females with bronchial asthma on prolonged corticosteroid therapy.
The aim of the study was to assess skeletal status in bronchial asthma female patients after long-term oral corticosteroid (CS) therapy. Eighty-two female patients (25 with and 57 without fractures; mean age 58.0+/-7.8 years) were compared with 999 females (821 controls without fractures, mean age 58.6+/-7.2 years and 178 females with previous osteoporotic fractures, mean age 57.8+/-7.1 years). Mean age and years since menopause did not differ between patients and controls. The duration of CS therapy was 8.4+/-7.3 years, and daily mean dose equivalent to prednison was 8.8+/-3.5 mg. Skeletal status was evaluated by quantitative ultrasound (QUS) measurements at the heel using the Achilles system (Lunar, USA) which measures speed of sound (SOS (m/s)) and Broadband Ultrasound Attenuation (BUA (dB/MHz)). The Achilles software also calculates a stiffness index (SI (%)). The precision expressed using the root mean square coefficient of variation (RMS_CV%) was: 0.26% for SOS, 4.37% for BUA, and 2.13% for SI. Patients (all, with and without fractures) had significantly lower QUS values than controls without fractures and their values did not differ significantly from controls with fractures. Controls with fractures had significantly lower QUS values than controls without fractures. There was no difference between patients with and without fractures. The duration of the therapy did not influence skeletal variables in any group. Receiver operating characteristic curve (ROC) analysis was performed to assess the discriminatory capability of calcaneal QUS for CS-treated patients by calculating the area under the ROC curve (AUC). AUCs were: 0.70 for SOS, 0.68 for BUA and 0.70 for SI. In females with bronchial asthma on prolonged CS therapy, skeletal status is affected but does not differ from controls with fractures therefore CS therapy seems to be a risk factor for osteoporotic fracture. Calcaneal QUS measurements can be a useful tool in the assessment of CS bone-side effects.


The effect of oxazepam on sleep in normal human volunteers.
The effects of 25 mg of oxazepam, a benzodiazepine with a short half-life and no active metabolites, were compared with placebo in two healthy volunteers in a single-blind polygraphically recorded sleep study. The experiment lasted for 24 nights and recordings were made for 11 nights. It was found that 25 mg oxazepam induced sleep faster than placebo, and that the subjects awoke less often during the treatment period. The total amount of REM-sleep was not affected. However, REM-sleep was shortened during the first part of the night and extended during the latter part of the night. Slow-wave sleep diminished differently in the two subjects, possibly due to interindividual differences in the rate of elimination of oxazepam. The effect on blood pressure was small, and the normal physiological difference between bedtime and morning blood pressure was preserved.


Memokath stents for the treatment of detrusor sphincter dyssynergia (DSD) in men with spinal cord injury: the Princess Royal Spinal Injuries Unit 10-year experience.
Medical records review. To assess the effectiveness of the Memokath (Engineers and Doctors A/S, Denmark) thermosensitive stent as a 'nondestructive' means of reducing bladder outlet resistance by treating detrusor sphincter dyssynergia (DSD) of neurogenic bladder dysfunction associated with spinal cord injury. Spinal Injuries Unit, Sheffield, England. A medical records review was performed to examine our experience of Memokaths over the last 10 years. During this time, 29 patients with spinal cord injury (17 tetraplegic and 12 paraplegic) underwent stenting of the external urethral sphincter either for prevention of dysreflexic symptoms, high residual urine volumes and subsequent urinary tract infection (UTI) or for protection of the upper tracts. A total of 33 stents were inserted into 29 men (25-77 years) with suprasacral spinal cord injury. Initial results showed that the Memokath was effective in almost all for relief of dysreflexic symptoms and elimination of DSD on pressure flow urodynamics. However, to date, 30 of the 33 stents have been removed. The overall mean working life of the Memokath was 21 months. Four stents were removed electively and 23 for complications, which included stent migration (seven) and blockage (14). Single-ended stents were more prone to migration, which was rare after 1 year (1-13 months, median 3 months, mean 5.5 months). Stent blockage by encrustation or prostatic ingrowth did not occur before 12 months (12-45 months, median 30, mean 27.9 months). In selected patients, temporary, thermo-expandable (Memokath) stents are effective in the treatment of DSD. The 'working life' of a Memokath stent is 21 months; however, complications do occur which may necessitate removal. Our overall experience with Memokath stents was disappointing. In future, Memokath stents will only be inserted after careful consideration in patients with prior 'failed' transurethral sphincterotomy or with caution in patients suitable for reconstructive surgery.


Endoscopically observable white nodule caused by distal intramural lymphatic spread of rectal cancer: a case report.
This report describes a case of rectal cancer with endoscopically observable white nodules caused by distal intramural lymphatic spread. A 57-year-old female presented to our hospital with frequent diarrhea and hemorrhoids. Computed tomography showed bilateral ovarian masses and three hepatic tumors diagnosed as rectal cancer metastases, and also showed multiple lymph node involvement. The patient was preoperatively diagnosed with stage IV rectal cancer. Colonoscopy demonstrated that primary rectal cancer existed 15 cm from the anal verge and that there were multiple white small nodules on the anal side of the primary tumor extending to the dentate line. Biopsies of the white spots were performed, and they were identified as adenocarcinoma. The patient underwent Hartmann's procedure because of the locally advanced primary tumor. The white nodules were ultimately diagnosed as being caused by intramural lymphatic spreading because lymphatic permeation was strongly positive at the surrounding area. Small white nodules near a primary rectal cancer should be suspected of being intramural spreading. Endoscopic detection of white nodules may be useful for the diagnosis of distal intramural spread.


Vascular complication of percutaneously placed pigtail ureteral stent.
Ureteral obstruction due to benign and malignant lesions has been managed successfully with percutaneous nephrostomy. With increasing use of percutaneous urinary diversion the attendant complications are becoming obvious. We report a case of an arteriovenous fistula discovered 10 weeks after placement of a double pigtail ureteral stent. Angiographic embolization of the fistula was successful after removal of the stent.


Flagellin enhances NK cell proliferation and activation directly and through dendritic cell-NK cell interactions.
Flagellin, the principal component of bacterial flagella, is a ligand for Toll-like receptor 5 (TLR5) or TLR11 and contributes to systemic inflammation during sepsis through activation of dendritic cells (DCs) and other cells of the innate immune system. Here, we report that flagellin and the TLR4 ligand, lipopolysaccharide (LPS), induced phenotypic and functional maturation of murine bone marrow-derived DCs and enhanced DC accumulation in the draining popliteal lymph node following their footpad injection. It is interesting that flagellin injection enhanced myeloid (CD8alpha(-1)) and plasmacytoid (plasmacytoid DC antigen(+) B220(+)) DC subsets, whereas LPS only increased myeloid DCs in the draining lymph node. In addition, the footpad injection of flagellin or LPS induced significant CD4(+) T cell activation in the draining popliteal lymph node, as judged by increased CD69 or CD25 expression. We illustrate, for the first time, that flagellin also increases natural killer (NK) cell number and activation status in the draining lymph node after footpad injection. Using coculture with enriched carboxy-fluorescein diacetate succinimidyl ester-labeled NK cells, flagellin-treated DCs induce significant NK cell proliferation and activation. In fact, direct treatment of NK cells with flagellin induces a greater increase in cell proliferation than treatment with LPS. In contrast, flagellin treatment of NK cells was not a strong inducer of interferon-gamma (IFN-gamma) production, indicating that NK cell proliferation and IFN-gamma production may be regulated differentially. These data suggest that flagellin is a capable maturation agent for murine myeloid-derived DCs, and flagellin-activated DCs and flagellin itself are potent inducers of NK cell proliferation.


Progress in Utilizing Dynamic Bonds to Fabricate Structurally Adaptive Self-Healing, Shape Memory, and Liquid Crystal Polymers.
Stimuli-responsive structurally dynamic polymers are capable of mimicking the biological systems to adapt themselves to the surrounding environmental changes and subsequently exhibiting a wide range of responses ranging from self-healing to complex shape-morphing. Dynamic self-healing polymers (SHPs), shape-memory polymers (SMPs), and liquid crystal elastomers (LCEs), which are three representative examples of stimuli-responsive structurally dynamic polymers, have been attracting broad and growing interest in recent years because of their potential applications in the fields of electronic skin, sensors, soft robots, artificial muscles, and so on. Recent advances and challenges in the developments toward dynamic SHPs, SMPs, and LCEs are reviewed, focusing on the chemistry strategies and the dynamic reaction mechanisms that enhance the performances of the materials including self-healing, reprocessing, and reprogramming. The different dynamic chemistries and their mechanisms on the enhanced functions of the materials are compared and discussed, where three summary tables are presented: A library of dynamic bonds and the resulting characteristics of the materials. Finally, a critical outline of the unresolved issues and future perspectives on the emerging developments is provided.


Potent inhibition of L-type Ca2+ currents by a Rad variant associated with congestive heart failure.
Ca(2+) influx via L-type voltage-gated Ca(2+) channels supports the plateau phase of ventricular action potentials and is the trigger for excitation-contraction (EC) coupling in the myocardium. Rad, a member of the RGK (Rem, Rem2, Rad, Gem/Kir) family of monomeric G proteins, regulates ventricular action potential duration and EC coupling gain through its ability to inhibit cardiac L-type channel activity. In this study, we have investigated the potential dysfunction of a naturally occurring Rad variant (Q66P) that has been associated with congestive heart failure in humans. Specifically, we have tested whether Rad Q66P limits, or even eliminates, the inhibitory actions of Rad on CaV1.2 and CaV1.3, the two L-type channel isoforms known to be expressed in the heart. We have found that mouse Rad Q65P (the murine equivalent of human Rad Q66P) inhibits L-type currents conducted by CaV1.2 or CaV1.3 channels as potently as wild-type Rad (>95% inhibition of both channels). In addition, Rad Q65P attenuates the gating movement of both channels as effectively as wild-type Rad, indicating that the Q65P substitution does not differentially impair any of the three described modes of L-type channel inhibition by RGK proteins. Thus, we conclude that if Rad Q66P contributes to cardiomyopathy, it does so via a mechanism that is not related to its ability to inhibit L-type channel-dependent processes per se. However, our results do not rule out the possibility that decreased expression, mistargeting or altered regulation of Rad Q66P may reduce the RGK protein's efficacy in vivo.


Spatial variations in vegetation as related to the soil moisture regime over an arid limestone hillside, northern Negev, Israel.
A detailed study of the distribution of plant communities was conducted in an experimental site, located in the arid northern Negev of Israel, where the spatial variation in rainfall, runoff and soil moisture regime are currently being studied. Phytogeographical methods of analysis usually used for studies on a regional scale were applied for a small area extending over 11,325 m2 of a north-facing hillside. Data obtained indicate that the best water regime and a high diversity of plant species are characteristic of a massive limestone rock unit; whereas worse water regimes characterize densely jointed and thinly bedded limestones. Over slopes, developed in a uniform lithology, whose lower part is composed of a colluvial mantle, a gradual downslope worsening of the soil moisture regime is recorded within the colluvium. These changes are well expressed in the distribution of the plant communities and their phytogeographical affinities along the slopes.


Are Masking-Based Models of Risk Useful?
As our understanding of directly observable effects from anthropogenic sound exposure has improved, concern about "unobservable" effects such as stress and masking have received greater attention. Equal energy models of masking such as power spectrum models have the appeal of simplicity, but do they offer biologically realistic assessments of the risk of masking? Data relevant to masking such as critical ratios, critical bandwidths, temporal resolution, and directional resolution along with what is known about general mammalian antimasking mechanisms all argue for a much more complicated view of masking when making decisions about the risk of masking inherent in a given anthropogenic sound exposure scenario.


Quality of life related to oral versus subcutaneous iron chelation: a time trade-off study.
To investigate the utility associated with subcutaneous infusion (deferoxamine) compared with once-daily oral administration (deferasirox) of iron chelation therapy. Interviews using the time trade-off technique were used to estimate preferences (utility) for health states by finding the point at which respondents were indifferent between a longer but lower quality of life (QoL) and a shorter time in full health. Participants (n = 110) were community-based, 51% women, median age 35 years, from four regions in Sydney, Australia. Respondents rated three health states involving equal outcomes for people with thalassemia but with different treatment modalities for iron chelation; an "anchor state" describing a patient receiving iron chelation without administration mode specified, anchor state plus iron chelation via subcutaneous infusion, and anchor state plus iron chelation through once-daily oral medication. On an interval scale between 0 (death) and 1 (full health), median (interquartile range) utility of 0.80 (0.65-0.95) for the anchor state, 0.66 (0.45-0.87) for subcutaneous infusion, and 0.93 (0.80-0.97) for once-daily oral administration was obtained. The mean (median) difference of 0.23 (0.27) between the two treatments was statistically significant (Wilcoxon-signed rank test, P < 0.001). Subcutaneous infusion was associated with a mean (median) utility 0.13 (0.14) lower than the anchor state (P < 0.001), and once-daily oral treatment had a utility 0.10 (0.13) higher (P < 0.001). Community respondents associate oral administration of an iron chelator such as deferasirox with enhanced QoL compared with subcutaneous treatment. Assuming equal safety and efficacy, QoL gains from once-daily oral treatment compared with subcutaneous infusion are significant.


Effect of compliant layers within piezoelectric composites on power generation providing electrical stimulation in low frequency applications.
For patients that use tobacco or have diabetes, bone healing after orthopedic procedures is challenging. Direct current electrical stimulation has shown success clinically to significantly improve bone healing in these difficult-to-fuse populations. Energy harvesting with piezoelectric material has gained popularity in the last decade, but is challenging at low frequencies due to material properties that limit total power generation at these frequencies. Stacked generators have been used to increase power generation at lower voltage levels but have not been widely explored as a load-bearing biomaterial to provide DC stimulation. To match structural compliance levels and increase efficiency of power generation at low frequencies, the effect of compliant layers between piezoelectric discs was investigated. Compliant Layer Adaptive Composite Stacks (CLACS) were manufactured using five PZT discs connected electrically in parallel and stacked mechanically in series with a layer of low modulus epoxy between each disc. The stacks were encapsulated, keeping PZT and overall volume constant. Each stack was electromechanically tested by varying load, frequency, and resistance. As compliant layer thickness increased, power generation increased significantly across all loads, frequencies, and resistances measured. As expected, increase in frequency significantly increased power output for all groups. Similarly, an increase applied peak-to-peak mechanical load also significantly increased power output. The novel use of CLACS for power generation under load and frequencies experienced by typical orthopedic implants could provide an effective method to harvest energy and provide power without the use of a battery in multiple low frequency applications.


Inhibition of striatal dopamine synthesis in rats injected chronically with neuroleptics in their early life.
3H-dopamine synthesis from L-3,5-3H-tyrosine was reduced in striatal slices of 40 days old rats treated during their early life with neuroleptics. Animals were first injected intra-utero with thioproperazine (5 mg/kg) or with the palmitic ester of pipotiazine (32 mg/kg); the thioproperazine-treated rats were then injected every day from day 1 to day 37; the animals injected with the long acting neuroleptic were injected once more with the drug on day 15 after birth.


Ethanol metabolism and hepatotoxicity. Does sex make a difference?
The role of gender as a variable that might affect the metabolism of ethanol and thus the hepatotoxicity of ethanol is evaluated. First, the pharmacodynamics of ethanol are reviewed with particular attention to hormone effects on ethanol absorption and metabolism. Specific differences between males and females relative to ethanol pharmacokinetic parameters are discussed, including gender differences in the volume of distribution and putative hormonal effects on achieved blood alcohol levels. In addition, attention is directed toward the metabolic capacity of alcohol dehydrogenase and the microsomal ethanol-oxidizing system with respect to effects of both sex differences and hormonal manipulations on the activity of these ethanol-metabolizing enzymes. Finally, the studies on the concept of sex-related differences in susceptibility to alcohol hepatotoxicity are examined.


Disturbance and organisms on boulders : II. Causes of patterns in diversity and abundance.
The tops of intertidal boulders on the east coast of Australia may carry a half-dozen algae, while the undersides may support a dozen or more species of sessile animals; mobile forms such as molluscs, crustaceans, and echinoderms are also common. These organisms are disturbed when boulders are moved by waves or buried in sand. Experiments were done to test the hypothesis that these disturbances are responsible for the reduced diversity and abundance of the assemblages on the undersides of small boulders. Boulders on one shore were bolted to the substratum to prevent movement by waves. In two separate experiments on another shore, boulders with and without attached organisms were buried in a few centimetres of sand. All experiments included relevant controls and were done high and low on the shore using rocks of several sizes.The assemblages of algae developing on the tops of all stabilised boulders, regardless of size, were similar to those on boulders free to roll indicating that, in contrast to results elsewhere, disturbance by waves was too infrequent or slight to affect these species. The tops of rocks were also rarely buried in sand and the main influences on the community in this situation were apparently exposure at low-tide and grazing gastropods.More species, however, did settle or survive on the undersides of rocks which were free of sand or could not be moved by waves; thus disturbances were important in this situation. In the absence of disturbance low on the shore, much or all space was occupied and sessile species such as sponges and ascidians overgrew other forms and reduced diversity. This did not happen higher on the shore and here diversity was simply an increasing function of rock-size. Overall disturbance played a similar role in all places - it killed organisms and created free space - but the final effects on the community varied depending upon the species present and the actions of other factors.


The Effect of Chitosan on the Erythrocyte Antioxidant Potential of Lead Toxicity-Induced Rats.
In the present study, the effects of chitosan on erythrocyte malondialdehyde (MDA) and glutathione (GSH) levels and glutathione peroxidase (GSH-Px), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH) enzyme activities in lead toxicity-induced rats were investigated. Twenty-eight male Wistar albino rats were divided into four groups of control (C), lead group (Pb group), lead + chitosan group (Pb + CS group), and chitosan group (CS group). Lead groups were administered 50 mg/kg lead acetate intraperitoneally (ip) for 5 days and chitosan groups were administered 200 mg/kg chitosan for 28 days via gavage. At the end of the study, lead levels were measured in the blood; MDA and GSH levels and GPx, GR, and G6PDH activities were measured in the erythrocyte. It was determined that, in parallel with the increase of full blood lead levels in the Pb group, erythrocyte MDA levels increased significantly, while GSH levels and GSH-Px, GR, and G6PDH activities decreased when compared to those in the C and CS groups (p ˂ 0.05). There was a statistically significant decrease in lead and MDA levels and GSH level and GSH-Px activity increased (p ˂ 0.05) in the Pb + CS group, where chitosan was administered as a protective agent in addition to lead, when compared to the Pb group. There were no differences between the Pb + CS group and the other three groups based on GR and G6PDH activities (p ˃ 0.05). No statistically significant difference was found between the C and CS groups based on the parameters of analysis (p ˃ 0.05). The findings of the present study demonstrated that lead increased oxidative stress by increasing free radical production in erythrocytes, and chitosan was effective in removing the lead from the circulation and enforced the antioxidant defense system.


Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury.
Renal ischemia/reperfusion (I/R) injury contributes to the development of acute kidney injury (AKI). Kidney is the second organ rich in mitochondrial content next to the heart. Mitochondrial damage substantially contributes for AKI development. Mitophagy eliminates damaged mitochondria from the cells to maintain a healthy mitochondrial population, which plays an important role in AKI. Pannexin 1 (PANX1) channel transmembrane proteins are known to drive inflammation and release of adenosine triphosphate (ATP) during I/R injury. However, the specific role of PANX1 on mitophagy regulation in renal I/R injury remains elusive. In this study, we find that serum level of PANX1 is elevated in patients who developed AKI after cardiac surgery, and the level of PANX1 is positively correlated with serum creatinine and urea nitrogen levels. Using the mouse model of renal I/R injury in vivo and cell-based hypoxia/reoxygenation (H/R) model in vitro, we prove that genetic deletion of PANX1 mitigate the kidney tubular cell death, oxidative stress and mitochondrial damage after I/R injury through enhanced mitophagy. Mechanistically, PANX1 disrupts mitophagy by influencing ATP-P2Y-mTOR signal pathway. These observations provide evidence that PANX1 could be a potential biomarker for AKI and a therapeutic target to alleviate AKI caused by I/R injury.


Unintended impact of pharmacovigilance regulatory interventions: A systematic review.
Studies assessing the impact of pharmacovigilance regulatory interventions often focus on the expected (or intended) outcomes, while any possible unintended impact may be overlooked. The update of the Good Pharmacovigilance Practice guideline in 2017 elaborated on impact assessment, emphasizing the need also to assess possible unintended impact. This systematic literature review investigated how often the unintended impact of regulatory interventions was considered in publications of studies investigating pharmacovigilance regulatory interventions in Europe. We conducted a systematic review of the literature on MEDLINE and EMBASE from 1 January 2012 to 28 February 2022 to identify publications that investigated the impact of regulatory interventions in Europe. The primary outcome of the study was the number of publications reporting assessments of unintended impact. In addition, we studied the characteristics of these publications, including the type of outcomes assessed, the analytical methods applied and the type of data used. In total, 96 publications were included in the analysis. The unintended impact of pharmacovigilance regulatory interventions was investigated in 23 of 96 publications (24%). The drug classes most frequently studied in the publications assessing unintended impact of regulatory interventions were oral glucose-lowering drugs (n = 6, 26%), opioids (n = 4, 17%), antidepressants (n = 4, 17%) and antipsychotics (n = 3, 13%). The reported methods to assess the unintended impact were interrupted time series (n = 10, 43%) and descriptive statistics with or without significance testing (n = 2 [9%] and n = 9 [39%], respectively). The outcomes selected for unintended impact assessments included the use of other drugs (n = 16, 70%), health outcomes (n = 8, 35%) and behavioural changes (n = 4, 17%). Most of the publications reported on the use of electronic health record databases (n = 13, 57%) or claims databases (n = 13, 57%), while registries were used in 4 publications (17%). The unintended impact of pharmacovigilance regulatory interventions was reported in only a quarter of identified publications. There was no apparent increase in attention to unintended impact assessments after the update of the Good Pharmacovigilance Practice guidelines.


A national dissemination of an evidence-based self-management program: a process evaluation study.
While evidence exists regarding the effectiveness of many health education interventions, few of these evidence-based programs have been systematically or widely disseminated. This paper reports on the dissemination of one such intervention, the 6-week peer-led Chronic Disease Self-Management Program, throughout a large health-care system, Kaiser Permanente. We describe the dissemination process and, using qualitative analysis of interviews and surveys, discuss the factors that aided and hindered this process and make recommendations for similar dissemination projects. Six years after the beginning of the dissemination process, the program is integrated in most of the Kaiser Permanente regions and is being offered to several thousand people a year.


Monoclonal antibodies evoked by the free oligopeptide (Gly)5 reacting specifically with peptidoglycan from staphylococci.
Murine monoclonal antibodies reactive with the Staphylococcus aureus peptidoglycan (PG) epitope (Gly)5 were obtained using the synthetic oligopeptide (Gly)5 in its free form as immunogen. The selected monoclonal antibodies were of the IgM kappa isotype and reacted specifically with PG from S. aureus and Staphylococcus epidermidis, but gave no reaction with PG from Streptococcus pyogenes, Bacillus subtilis and Micrococcus lysodeikticus. Affinity chromatography showed that the antibodies were reactive with the N-terminus of the (Gly)5 peptide. These monoclonal antibodies can be used for the detection of staphylococcal PG in solution.


[Spirometric reference values in the Bantu population aged 20-70 years in Kinshasa].
Spirometric reference values cannot be extrapolated in the populations, being subject to many environmental and human variables; hence the interest of local studies in this field. This study aims to determine the reference values among healthy adults in Kinshasa. We conducted a cross-sectional study including 7443 subjects (3208 women, 43%). FEV1, FVC, PEF were correlated with anthropometric data. Five age groups were formed and comparisons were made on the basis of sex, age, BMI and of the practice of sporting activity. Differences are evident between the sexes, in terms of FEV1 (3.00 vs 2.21 L), FVC (3.19 vs 2.38) and the PEF (6.8 vs 5.70 L/s); same as for the outer age categories. FEV1 ranged between 2.33 et 4.54 vs 1.93-3.3 L in the age group 20-29 years and 1,76-3,39 vs 1,60 vs 2,53 L in the age group 60-70 years; FVC ranged between 2,44-4,89 vs 1,96-3,56 L and 1,79-3,78 vs 1,66-2,74 L ; PEF ranged between 4,34-12.2 vs 3,62-8.58 L/s and 2.99-6.76 vs 2.99-7.34L/s in the age group 60-70 years. The differences related to gender, age, anthropometric data as well as to the practice of sporting activity are obvious. These results warrant further and more extended investigations and show the relevance of values based on percentiles in the determinantion of a spirometry standard in a given population.


Cancer cell membrane-modified biodegradable mesoporous silica nanocarriers for berberine therapy of liver cancer.
Berberine (Ber) is regarded as a new, active and natural anti-cancer product; however, its clinical application has been limited due to its low aqueous solubility, poor gastrointestinal absorption, short residence time and poor targeting abilities. Hence, we reported a biomimetic nanoparticle as a drug delivery system to surmount these obstacles. We fabricated disulfide (S-S)-bridged mesoporous organosilica nanoparticles (ss-MONs) for Ber loading, which possessed uniform morphology, controllable mesoporous properties, highly-efficient drug loading capacity and superior biocompatibility. More interestingly, ss-MONs exhibited effective biodegradability under glutathione conditions through the breakage of the disulfide bond in ss-MONs, which promoted the Ber release. After coating human liver cancer HepG2 cell membranes (CM) on the surface of ss-MONs, the obtained CM-ss-MONs-Ber enhanced accumulation in liver cancer tissue through homologous targeting and effectively avoiding rapid blood clearance. Our findings indicate that CM-ss-MONs might be desirable drug carriers to promote the clinical use of Ber against liver cancer.


Large- and small-size advantages in sneaking behaviour in the dusky frillgoby Bathygobius fuscus.
Sneaking tactic, a male alternative reproductive tactic involving sperm competition, is generally adopted by small individuals because of its inconspicuousness. However, large size has an advantage when competition occurs between sneakers for fertilization of eggs. Here, we suggest that both large- and small-size advantages of sneaker males are present within the same species. Large sneaker males of the dusky frillgoby Bathygobius fuscus showed a high success rate in intruding into spawning nests because of their advantage in competition among sneaker males in keeping a suitable position to sneak, whereas small sneakers had few chances to sneak. However, small sneaker males were able to stay in the nests longer than large sneaker males when they succeeded in sneak intrusion. This suggests the possibility of an increase in their paternity. The findings of these size-specific behavioural advantages may be important in considering the evolution of size-related reproductive traits.


UV damage and DNA repair in malignant melanoma and nonmelanoma skin cancer.
Exposition of the skin with solar ultraviolet radiation (UV) is the main cause of skin cancer development. The consistently increasing incidences of melanocytic and nonmelanocytic skin tumors are believed to be at least in part associated with recreational sun exposure. Epidemiological data indicate that excessive or cumulative sunlight exposition takes place years and decades before the resulting malignancies arise. The most important defense mechanisms that protect human skin against UV radiation involve melanin synthesis and active repair mechanisms. DNA is the major target of direct or indirect UV-induced cellular damage. Low pigmentation capacity in white Caucasians and rare congenital defects in DNA repair are mainly responsible for protection failures. The important function of nucleotide excision DNA repair (NER) to protect against skin cancer becomes obvious by the rare genetic disease xeroderma pigmentosum, in which diverse NER genes are mutated. In animal models, it has been demonstrated that UVB is more effective to induce skin cancer than UVA. UV-induced DNA photoproducts are able to cause specific mutations (UV-signature) in susceptible genes for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In SCC development, UV-signature mutations in the p513 tumor suppressor gene are the most common event, as precancerous lesions reveal approximately 80% and SCCs > 90% UV-specific p53 mutations. Mutations in Hedgehog pathway related genes, especially PTCH1, are well known to represent the most significant pathogenic event in BCC. However, specific UV-induced mutations can be found only in approximately 50% of sporadic BCCs. Thus, cumulative UVB radiation can not be considered to be the single etiologic risk factor for BCC development. During the last decades, experimental animal models, including genetically engineered mice, the Xiphophorus hybrid fish, the south american oppossum and human skin xenografts, have further elucidated the important role of the DNA repair system in the multi-step process of UV-induced melanomagenesis. An increasing body of evidence now indicates that nucleotide excision repair is not the only DNA repair pathway that is involved in UV-induced tumorigenesis of melanoma and nonmelanoma skin cancer. An interesting new perspective in DNA damage and repair research lies in the participation of mammalian mismatch repair (MMR) in UV damage correction. As MMR enzyme hMSH2 displays a p53 target gene, is induced by UVB radiation and is involved in NER pathways, studies have now been initiated to elucidate the physiological and pathophysiological role of MMR in malignant melanoma and nonmelanoma skin cancer development.


Molecular insights into the transformation of refractory organic matter in landfill leachate nanofiltration concentrates during a flocculation and O3/H2O2 treatment.
During leachate treatment, molecular information regarding the completely removed, partially removed, less-reactive, increased, and produced parts of dissolved organic matter (DOM) remains unknown. This study applied ESI FT-ICR MS to investigate the transformation characteristics of leachate nanofiltration concentrate (NFC) DOM during a combined flocculation-O3/H2O2 process. The NFC contained 5069 compounds in four main classes (CHO, CHON, CHOS, and CHONS compounds). The DOM number decreased to 4489 during flocculation and to 2903 after the O3/H2O2 process. During flocculation, the completely and partially removed DOM was mainly low-oxygen unsaturated and phenolic compounds. Saturated DOM was produced and remained in the flocculated effluent. During the O3/H2O2 process, the completely and partially removed DOM were mainly low-oxygen unsaturated and phenolic compounds that were mainly in a reduced state. Flocculation can remove many (condensed) aromatic compounds, and methylation and hydrogenation reactions occurred during flocculation. In the O3/H2O2 process, dearomatization, demethylation, carboxylation, and carbonylation reactions further achieved the degradation of DOM that was resistant to flocculation. Overall, the combined flocculation-O3/H2O2 process collectively eliminated a broader range of DOM than the single processes could achieve. The results of this study provide an in-depth understanding of DOM transformation in an NFC treatment.


Multimodal therapy of small cell lung cancer in TNM stages I through IIIa.
Since 1977, Innsbruck University Hospital has been employing a multimodal therapy concept for small cell bronchial carcinomas in stages I to IIIa. This concept includes all three treatment forms effective in this tumor, namely, chemotherapy, surgery, and radiotherapy. The therapy scheme is stage-dependent and begins in stages T1-3 N0-1 with lung resection and in stage N2 with chemotherapy. To date, 45 patients have been included in a prospective, nonrandomized (phase II) trial: 7 in TNM stage I, 11 in stage II, and 27 in stage IIIa (6 T3 and 21 N2). The actuarial 5-year survival rate of the entire group (including therapy-related lethality, early recurrences, and protocol violations) is 36%; it is 57% for those in stage I, 28% for those in stage II, and 34% for those in stage IIIa. Median survival time is 18 months. Patients with completed multimodal treatment have a 5-year survival rate of 56% regardless of disease stage. Three patients died of tumor-unrelated causes after 47, 52, and 54 months.


Ethanol alters glutamate but not adenosine uptake in rat astrocytes: evidence for protein kinase C involvement.
Glutamate is the primary excitatory neurotransmitter in brain. By stimulating neuronal activity, glutamate increases cellular energy utilization, enhances ATP hydrolysis and promotes the formation of adenosine. Adenosine has receptor-mediated effects that reduce or oppose the excitatory effects of glutamate. As a possible mechanism for ethanol's ability to inhibit excitatory effects of glutamate and enhance inhibitory effects of adenosine, we tested the hypothesis that ethanol promotes [3H]glutamate uptake and inhibits [3H]adenosine uptake. Using primary cultures of rat astrocytes, we found that acute treatment with ethanol (50 mM, 30 min) inhibited [3H]glutamate uptake and reduced protein kinase C (PKC)-induced stimulation of [3H]glutamate uptake. Prolonged treatment (50 mM, 3 day) with ethanol, however, increased both [3H]glutamate uptake and PKC activity. Contrary to other cell types, neither acute or chronic ethanol exposure affected [3H]adenosine uptake in astrocytes. These data indicate that in rat cortical astrocytes ethanol affects [3H]glutamate uptake but not [3H]adenosine uptake by affecting PKC modulation of transporter activity.


Home blood pressure during normal pregnancy.
To determine values for home blood pressure (HBP) during pregnancy, nurses taught 45 healthy pregnant women to use a HBP method for 1 week before 15 weeks of gestation, between weeks 15 and 27, and after 28 weeks for the last 3 months of gestation. HBP values were significantly lower during the second trimester and higher during the last trimester (102 +/- 8/59 +/- 7*, 101 +/- 8/57 +/- 8*, 105 +/- 8*/62 +/- 9* mm Hg;*P< 0.05) than during other trimesters. Heart rate increased significantly during the pregnancy. The present study suggests upper limits for HBP: 118/73, 117/73, and 121/80 mm Hg, respectively during the 3-month gestational periods. These findings may be helpful in providing clinicians with comparative values so as begin to establish reference values for HBP during pregnancy.


SCFAs improve disease resistance via modulate gut microbiota, enhance immune response and increase antioxidative capacity in the host.
To evaluate the effects of dietary short chain fatty acids (SCFAs) on the intestinal health and innate immunity in crucian carp, a six-week feeding trial was carried out with following treatments: basal diet (BD), basal diet supplementation with 1% sodium acetate (BDSA), basal diet supplementation with 1% sodium propionate (BDSP) and basal diet supplementation with 1% sodium butyrate (BDSB). The results showed dietary BDSA, BDSP and BDSB could protect the host against oxidative stress by improving the activity of certain antioxidative enzymes (T-SOD, GSH-Px and CAT). Additionally, dietary SCFAs could enhance mucosal and humoral immune responses by improving certain innate immune parameters in serum and skin mucus productions (IgM, ACH50 and T-SOD). Furthermore, dietary BDSA and BDSP could up-regulate the expression of immune related genes (TNF-α, TGF-β and IL-8) and tight junction protein genes (occludin and ZO-1). Dietary BDSB could also elevate the expression of IL-8, TGF-β, ZO-1 and Occludin in the midgut. Although dietary differences of SCFAs didn't alter the α-diversity of the intestinal flora, they altered the core microbiota. Finally, the challenge trial showed that dietary basal diet supplementation with SCFAs could protect zebrafish against Aeromonas hydrophila. These results suggest that dietary SCFAs could improve innate immunity, modulate gut microbiota and increase disease resistance in the host, which indicated the potential of SCFAs as immunostimulants in aquaculture.


Sphingolipids and lifespan regulation.
Diseases including cancer, type 2 diabetes, cardiovascular and immune dysfunction and neurodegeneration become more prevalent as we age, and combined with the increase in average human lifespan, place an ever increasing burden on the health care system. In this chapter we focus on finding ways of modulating sphingolipids to prevent the development of age-associated diseases or delay their onset, both of which could improve health in elderly, fragile people. Reducing the incidence of or delaying the onset of diseases of aging has blossomed in the past decade because of advances in understanding signal transduction pathways and cellular processes, especially in model organisms, that are largely conserved in most eukaryotes and that can be modulated to reduce signs of aging and increase health span. In model organisms such interventions must also increase lifespan to be considered significant, but this is not a requirement for use in humans. The most encouraging interventions in model organisms involve lowering the concentration of one or more sphingolipids so as to reduce the activity of key signaling pathways, one of the most promising being the Target of Rapamycin Complex 1 (TORC1) protein kinase pathway. Other potential ways in which modulating sphingolipids may contribute to improving the health profile of the elderly is by reducing oxidative stresses, inflammatory responses and growth factor signaling. Lastly, perhaps the most interesting way to modulate sphingolipids and promote longevity is by lowering the activity of serine palmitoyltransferase, the first enzyme in the de novo sphingolipid biosynthesis pathway. Available data in yeasts and rodents are encouraging and as we gain insights into molecular mechanisms the strategies for improving human health by modulating sphingolipids will become more apparent. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.


Clinical non-effectiveness of clopidogrel use for peripheral artery disease in patients with CYP2C19 polymorphisms: a systematic review.
To conduct a systematic review to identify studies that assessed the association between CYP2C19 polymorphisms and clinical outcomes in peripheral artery disease (PAD) patients who took clopidogrel. We systematically searched Ovid EMBASE, PubMed, and Web of Science from November 1997 (inception) to September 2020. We included observational studies evaluating how CYP2C19 polymorphism is associated with clopidogrel's effectiveness and safety among patients with PAD. We extracted relevant information details from eligible studies (e.g., study type, patient population, study outcomes). We used the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) Tool to assess the risk of bias for included observational studies. The outcomes of interest were the effectiveness and safety of clopidogrel. The effectiveness outcomes included clinical ineffectiveness (e.g., restenosis). The safety outcomes included bleeding and death related to the use of clopidogrel. We identified four observational studies with a sample size ranging from 50 to 278. Outcomes and comparison groups of the studies varied. Three studies (75%) had an overall low risk of bias. All included studies demonstrated that carrying CYP2C19 loss of function (LOF) alleles was significantly associated with reduced clinical effectiveness and safety of clopidogrel. Our systematic review showed an association between CYP2C19 LOF alleles and reduced functions of clopidogrel. The use of CYP2C19 testing in PAD patients prescribed clopidogrel may help improve the clinical outcomes. However, based on the limited evidence, there is a need for randomized clinical trials in PAD patients to test both the effectiveness and safety outcomes of clopidogrel.


Physiological responses and perceived comfort to high-flow nasal cannula therapy in awake adults: effects of flow magnitude and temperature.
Clinical use of heated, high-flow nasal cannula (HFNC) for noninvasive respiratory support is increasing and may have a therapeutic role in stabilizing the upper airway in obstructive sleep apnea (OSA). However, physiological mechanisms by which HFNC therapy may improve upper airway function and effects of different temperature modes are unclear. Accordingly, this study aimed to determine effects of incremental flows and temperature modes (heated and nonheated) of HFNC on upper airway muscle activity (genioglossus), pharyngeal airway pressure, breathing parameters, and perceived comfort. Six participants (2 females, aged 35 ± 14 yr) were studied during wakefulness in the supine position and received HFNC at variable flows (0-60 L/min) during heated (37°C) and nonheated (21°C) modes. Breathing parameters via calibrated Respitrace inductance bands (chest and abdomen), upper airway pressures via airway transducers, and genioglossus muscle activity via intramuscular bipolar fine wire electrodes were measured. Comfort levels during HFNC were quantified using a visual analog scale. Increasing HFNC flows did not increase genioglossus muscle activation despite increased negative epiglottic pressure swings (P = 0.009). HFNC provided ∼7 cmH2O positive airway pressure at 60 L/min in nonheated and heated modes. In addition, increasing the magnitude of HFNC flow reduced breathing frequency (P = 0.045), increased expiratory time (P = 0.040), increased peak inspiratory flow (P = 0.002), and increased discomfort (P = 0.004). Greater discomfort occurred at higher flows in the nonheated versus the heated mode (P = 0.034). These findings provide novel insight into key physiological changes that occur with HFNC for respiratory support and indicate that the primary mechanism for improved upper airway stability is positive airway pressure, not increased pharyngeal muscle activity.NEW & NOTEWORTHY This study evaluated upper airway muscle function, breathing, and comfort across different HFNC flows and temperatures. There were no increases in genioglossus muscle activity at higher flows despite greater negative epiglottic pressure swings. Increasing negative pressure swings was associated with increasing discomfort in the nonheated mode. HFNC was associated with ∼7 cmH2O increase in positive airway pressure, which may be the primary mechanism for upper airway stability with HFNC rather than increases in pharyngeal muscle activity.


Terlipressin for norepinephrine-resistant septic shock.
Norepinephrine-resistant hypotension when associated with septic shock has a high rate of mortality, which might possibly be reduced by infusion of low-dose vasopressin. However, rebound hypotension often arises after treatment is stopped, and the drug usually has to be administered for several days. We report use of terlipressin, a long-acting vasopressin analogue, in eight patients with septic shock who did not respond to corticosteroids and methylene blue. A significant rise in blood pressure that lasted for at least 5 h was seen in all patients after a single bolus, allowing reduction or cessation of norepinephrine administration in seven patients. We were able to discharge four patients from intensive care subsequently. Terlipressin seems to be an effective rescue therapy, which is able to restore blood pressure in patients with catecholamine-resistant septic shock, without obvious complication.


The Cost-Effectiveness of Pregabalin Versus Gabapentin for Peripheral Neuropathic Pain (pNeP) and Postherpetic Neuralgia (PHN) in China.
Postherpetic neuralgia (PHN), a type of peripheral neuropathic pain (pNeP), is the most common complication of herpes zoster. The objective of this analysis was to determine the cost-effectiveness of pregabalin compared with gabapentin in pNeP and PHN in China. We developed a China-localized 12-week simulation model to determine the cost-effectiveness of pregabalin compared to gabapentin in 1000 patients with pNeP and PHN. We utilized a questionnaire of Chinese key opinion leaders to estimate the pre-treatment distribution of pain scores for pNeP and PHN. Treatment outcomes for pregabalin and gabapentin were acquired from the published literature. Treatment with pregabalin lead to 12-week decreases in pain scores of 0.6 (pNeP) and 0.7 (PHN) when compared to patients receiving gabapentin, at an incremental cost per additional day of mild/no pain of $45. The difference in mean days of no or mild pain, moderate pain, and severe pain was 8.8, -5.7, and -3.1, when comparing pregabalin and gabapentin, respectively. Pregabalin had more mean days with a >30% (7.71 days), 40% (8.97 days), and 50% reduction (9.97 days) in pain when compared with gabapentin. In the pNeP scenario, pregabalin was associated with a lower average pain score compared with gabapentin (3.91 vs. 4.55). The difference in mean days of no or mild pain, moderate pain, and severe pain was 9.39, -5.56, and -3.82, when comparing pregabalin and gabapentin, respectively. Pregabalin had more mean days with a >30% (8.77 days), 40% (9.81 days), and 50% reduction (10.55 days) in pain when compared with gabapentin. Pregabalin is an effective treatment for PHN and even for pNeP extensively, but at increased cost. It leads to improved outcomes including lower pain scores and more days with no or mild pain. Pfizer, China.