Discontinuation of empirical antifungal therapy in ICU patients using 1,3-β-d-glucan.
Empirical antifungal therapy in high-risk ICU patients is an attractive strategy, but overuse of antifungal agents is a potential problem. We evaluated if ICU patients at high risk to develop candidaemia identified by a prediction rule could discontinue empirical antifungal therapy on the basis of repeatedly negative 1-3-β-d-glucan (BDG) tests. We conducted a multicentre cohort study in 85 ICU patients receiving antibiotics or with central venous catheter plus two additional factors (dialysis, parenteral nutrition, surgery, pancreatitis or receipt of corticosteroids or other immunosuppressive agents) plus either fever, hypothermia, hypotension, acidosis, elevated C-reactive protein or leucocytosis. Blood cultures (days 1 and 2) and BDG (days 1-3, baseline period) were performed and anidulafungin was given. On day 4, patients with negative blood cultures and BDG discontinued antifungal therapy. Registered in ClinicalTrials.gov (NCT01734525). The incidence of candidaemia was 8.2% in patients selected versus 0.5% in patients without entry criteria (16.9 times higher). Sixty-four patients (75.3%) had baseline positive BDG, including 7 with candidaemia. All 21 patients with baseline negative BDG discontinued anidulafungin on day 4. None developed candidaemia until day 30. Early discontinuation of empirical echinocandin therapy in high-risk ICU patients based on consecutive negative BDG tests may be a reasonable strategy, with great potential to reduce the overuse of echinocandins in ICU patients. Prospective studies with a higher number of patients are needed.


Gender differences in diabetes-related lower extremity amputations.
Diabetes is a major cause of morbidity and mortality in the United States, with much of the economic and social costs related to macrovascular and microvascular complications, such as myocardial infarctions, renal failure, and lower extremity amputations. While racial/ethnic differences in diabetes are well documented, less attention has been given to differences in diabetes outcomes by gender. Does gender influence the rate of diabetes-related lower extremity amputations and/or the rate of mortality after amputation? I reviewed the literature utilizing peer-reviewed publications found through MEDLINE searches. WHERE ARE WE NOW?: Major complex gender differences exist in diabetes-related lower extremity amputations: men are more likely to undergo lower extremity amputations, but women apparently have higher mortality related to these procedures. The reasons for such differences are not entirely clear, but it appears biologic factors may play important roles (increased rates of peripheral vascular disease and peripheral neuropathy in men, interaction between gender and cardiac mortality in women). WHERE DO WE NEED TO GO?: More research is warranted to confirm gender differences in diabetes-related lower extremity amputation mortality and explore underlying mechanisms for the gender differences in lower extremity amputations and its associated mortality. HOW DO WE GET THERE?: Exploring gender disparities in diabetes-related outcomes, such as lower extremity amputations, will need to become a national priority from a research (eg, National Institutes of Health) and policy (eg, Centers for Medicare and Medicaid Services) perspective. Only when we have a better understanding of the causes of such differences can we begin to make strides in addressing them.


Formation of complex natural flavours by biotransformation of apple pomace with basidiomycetes.
Altogether 30 different basidiomycetes were grown submerged in liquid culture media using seven different by-products of the food industry as the only carbon source. Seven fungus/substrate combinations revealed interesting flavour profiles. Culture supernatants of Tyromyces chioneus grown on apple pomace were extracted, and the aroma compounds were analysed by gas chromatography-olfactometry (GC-O). Potent odorants were identified by aroma extract dilution analysis (AEDA), calculation of the odour activity values (OAV), and proven by confection of an aroma model. 3-Phenylpropanal, 3-phenyl-1-propanol, and benzyl alcohol were identified as potent aroma biotransformation products. Headspace solid-phase microextraction gas chromatography mass spectrometry (HS-SPME-GC-MS) experiments showed that 3-phenylpropanal, 3-phenyl-1-propanol, benzyl alcohol, methyl 3-phenylpropionate, methyl 2-phenylacetate, cinnamaldehyde and methyl cinnamate were produced during the cultivation period of eight days. By means of labelling experiments, (E)-cinnamic acid was identified as the precursor of 3-phenylpropanal and 3-phenyl-1-propanol. Basidiomycetes were able to biotransform food by-products to pleasant complex flavour mixtures.


Radiofrequency ablation of lung lesions: practical applications and tips.
Radiofrequency ablation (RFA) therapy is a minimally invasive technique that can be used in the management of inoperable non-small-cell lung cancer and for palliation in selected patients with pulmonary metastases. Surgical resection remains the gold standard of treatment; however, many patients are ineligible due to comorbidities or poor cardiopulmonary reserve. Others may simply decline radical surgical intervention. Alternative treatment options are limited mainly to chemotherapy and external beam radiation. With the development of RFA, a new promising technique has evolved that can be offered to many, as an alternative choice or as part of combination therapy. The published results of RFA for the treatment of primary and secondary lung malignancies are encouraging. This article aims to minimize the learning curve for performing RFA of lung lesions by examining the technical difficulties more commonly encountered and offering practical tips and applications.


Effects of tongxinluo on the neointima formation and expression of inflammatory cytokines in rats after carotid artery balloon injury.
Tongxinluo (TXL) is a traditional Chinese medicine (TCM). It is used to treat coronary heart disease and atherosclerosis. We investigated the effects of TXL on the neointima formation and expression of inflammatory cytokines in rats after carotid artery balloon injury. Male Sprague-Dawley rats were randomly divided into four groups: sham operation group (Sham, n = 15), balloon injury group treated with vehicle (Control, n = 15), TXL low-dose group treated with TXL of 0.5 g/kg/d (TXL-L, n = 15), and TXL high-dose group treated with TXL of 1.0 g/kg/d (TXL-H, n = 15). TXL was given by gavage daily. 14 days after injury', the levels of serum nitric oxide (NO), endothelin-1 (ET-1), monocyte chemoattractant protein-1 (MCP-1), and soluble intercellular adhesion molecule-1 (sICAM-1) were evaluated. The morphology of carotid artery tissue was observed with hematoxylin-eosin staining. Expressions of MCP-1 and ICAM-1 in the artery were detected by real-time polymerase chain reaction (RT-PCR) and western blotting. 14 days after injury, a significant increase in concentrations of serum ET-1, MCP-1, and sICAM-1 (P < 0.05), as well as a significant decrease in NO serum level were observed in rats subjected to artery injury compared to the sham rats (P < 0.05). TXL significantly decreased ET-1, MCP-1 and sICAM-1 serum levels (P < 0.05), whereas significantly increased NO serum level compared with the control (P < 0.05). TXL significantly reduced the neointimal thickening at day14 after injury (P < 0.05). In addition, TXL significantly reduced mRNA and protein expressions of ICAM-1 and MCP-1 in injured artery (P < 0.05). This study demonstrates that TXL is effective in improving endothelial function, attenuating neointimal formation of artery after balloon injury, and reducing expression of inflammatory cytokine MCP-1 and ICAM-1. It may be a useful agent for protecting the artery against injury.


Inferring spatial and signaling relationships between cells from single cell transcriptomic data.
Single-cell RNA sequencing (scRNA-seq) provides details for individual cells; however, crucial spatial information is often lost. We present SpaOTsc, a method relying on structured optimal transport to recover spatial properties of scRNA-seq data by utilizing spatial measurements of a relatively small number of genes. A spatial metric for individual cells in scRNA-seq data is first established based on a map connecting it with the spatial measurements. The cell-cell communications are then obtained by "optimally transporting" signal senders to target signal receivers in space. Using partial information decomposition, we next compute the intercellular gene-gene information flow to estimate the spatial regulations between genes across cells. Four datasets are employed for cross-validation of spatial gene expression prediction and comparison to known cell-cell communications. SpaOTsc has broader applications, both in integrating non-spatial single-cell measurements with spatial data, and directly in spatial single-cell transcriptomics data to reconstruct spatial cellular dynamics in tissues.


Anterior selective scalenectomy for periforaminal exposure in the ventral supraclavicular approach.
Route of choice to access cervical paravertebral lesions with foraminal involvement is the anterolateral corridor with its variants. Main limitation of these techniques is represented by the limited surgical access to periforaminal area due to the bulk generated by the anterior scalene muscle (ASM). Over the years, alternative techniques for ASM surgical management have been developed, which are still today a matter of debate. Most popular include ASM scalene complete section (SCS) and ASM medial detachment (SMD). Authors describe an innovative, minimally invasive muscle section technique, the anterior selective scalenectomy (ASS), which reduces the risk of iatrogenic morbidity and optimizes exposure of periforaminal area in anterolateral cervical routes. A laboratory investigation was conducted. Technique was applied in a surgical setting, and an illustrative case was reported. ASS is a quick and easy technique to perform. It allows optimization of surgical visibility and control on the periforaminal area in the cervical anterolateral corridor. It respects muscle anatomy and vascularization, favoring functional recovery and management of peri-operative pain; it reduces the risk of morbidity on phrenic nerve and pleura. Considering the minimally invasive nature of the technique, it allows for a slightly more limited exposure compared to traditional techniques while ensuring optimal surgical maneuverability on the target area. ASS represents an effective and safe alternative to traditional ASM section techniques for the exposure of periforaminal area in anterolateral cervical routes. It is indicated in case of lesions with paravertebral development and minimal intraforaminal component in the C3-C6 segment.


Intraoperative fluorescence imaging in thoracic surgery.
Intraoperative fluorescence imaging (IFI) can improve real-time identification of cancer cells during an operation. Phase I clinical trials in thoracic surgery have demonstrated that IFI with second window indocyanine green (TumorGlow® ) can identify subcentimeter pulmonary nodules, anterior mediastinal masses, and mesothelioma, while the use of a folate receptor-targeted near-infrared agent, OTL38, can improve the specificity for diagnosing tumors with folate receptor expression. Here, we review the existing preclinical and clinical data on IFI in thoracic surgery.


Feasibility study for remote assessment of cognitive function in multiple sclerosis.
Cognitive impairment is common in multiple sclerosis (MS), and affects employment and quality of life. Large studies are needed to identify risk factors for cognitive decline. Currently, a MS-validated remote assessment for cognitive function does not exist. Studies to determine feasibility of large remote cognitive function investigations in MS have not been published. To determine whether MS patients would participate in remote cognitive studies. We utilized the Modified Telephone Interview for Cognitive Status (TICS-M), a previously validated phone assessment for cognitive function in healthy elderly populations to detect mild cognitive impairment. We identified factors that influenced participation rates. We investigated the relationship between MS risk factors and TICS-M score in cases, and score differences between cases and control individuals. The TICS-M was administered to MS cases and controls. Linear and logistic regression models were utilized. 11.5% of eligible study participants did not participate in cognitive testing. MS cases, females and individuals with lower educational status were more likely to refuse (p<0.001). Cases who did complete testing did not differ in terms of perceived cognitive deficit compared to cases that did participate. More severe disease, smoking, and being male were associated with a lower TICS-M score among cases (p<0.001). The TICS-M score was significantly lower in cases compared to controls (p=0.007). Our results demonstrate convincingly that a remotely administered cognitive assessment is quite feasible for conducting large epidemiologic studies in MS, and lay the much needed foundation for future work that will utilize MS-validated cognitive measures.


Combination of CCR1 mRNA, MCP1, and CA125 measurements in peripheral blood as a diagnostic test for endometriosis.
This study investigated the possible use of CCR1 mRNA measurement in peripheral blood leukocytes in combination with measurements of monocyte chemotactic protein-1 (MCP-1) and CA125 protein in serum as a diagnostic test for endometriosis.The expression of CCR1 mRNA in peripheral blood leukocytes was measured by quantitative real-time polymerase chain reaction. MCP-1 and CA125 levels in serum were determined by ELISA and ECLIA.The ratio of CCR1/HPRT mRNA in peripheral blood of patients with endometriosis and adenomyosis was significantly elevated compared with women without endometriosis. Additionally, serum levels of MCP-1 and CA125 were significantly higher in patients with endometriosis. This method showed a sensitivity of 92.2%, a specificity of 81.6%, a negative predictive value of 83.3%, a positive predictive value of 92.3%, a likelihood ratio of a positive test result of 5.017, and a likelihood ratio of a negative test result of 0.096 to predict the presence or absence of endometriosis.The results imply the potential use of CCR1 mRNA, MCP-1, and CA125 protein measurements for the diagnosis or exclusion of endometriosis.


Two novel antigens associated with group B streptococci identified by a rapid two-stage radioimmunoassay.
A two-stage radioimmunoassay (RIA) has been developed that identifies type-specific antigens on the surfaces of group B streptococci. In addition to detecting the type-specific carbohydrate antigens Ia, Ib, II, and III, the RIA identified four unique antigens reactive with the Centers for Disease Control's c-protein typing antiserum. Analysis of hot-acid extracts by immunoelectrophoresis confirmed that two of these reactivities corresponded to the reported alpha and beta antigens of the c-protein marker. In addition, the identification of two heretofore unidentified antigens, gamma and delta, by the two-stage RIA is detailed in this report. The assay uses intact bacteria and does not require hot-acid extraction, a procedure thus enabling detection of acid-labile antigens in their native unmodified form. The semiquantitative RIA requires less typing reagent than does precipitin testing and is more objective, reproducible, and rapid. The assay described here could be applied to the detection of any cell surface antigen for which a monospecific antiserum is available.


Titanium-prepared platelet-rich fibrin provides advantages on periodontal healing: A randomized split-mouth clinical study.
The aim of this study to evaluate the contributions of titanium-prepared platelet-rich fibrin (T-PRF) combined with open flap debridement (OFD) on biological markers in gingival crevicular fluid (GCF)and periodontal outcomes. Twenty-nine participants with chronic periodontitis were treated either with autologous T-PRF+OFD or OFD alone. GCF growth factor levels and relative receptor activator nuclear factor kappa-B/osteoprotegerin (RANKL/OPG) ratio at baseline and 2, 4, and 6 weeks postoperatively were analyzed, and clinical parameters such as probing depth (PD), relative attachment level (RAL) and gingival margin level (GML) at baseline and 9 months after surgery were compared. The mean PD reduction, RAL gain, and GML change were significantly greater in the OFD+T-PRF sites than in the OFD sites (P = 0.033, P = 0.029, and P = 0.026, respectively). Both groups demonstrated increased growth factor levels at week 2 compared with baseline, followed by reductions at weeks 4 and 6. GCF growth factor levels in the test group were seen at higher concentrations with respect to control group until 6 weeks post-surgery. During this 6-week period, relative RANKL/OPG ratio was found significantly lower in the OFD+T-PRF group compared to the OFD group(P < 0.05). Using T-PRF membrane combined with OFD provided significantly higher concentrations of growth factors and lower RANKL/OPG ratio in GCF for approximately 4 to 6 weeks, and improved periodontal healing compared to conventional flap sites.


Dermatological testing of an emollient-treated menstrual pad with a novel foam absorbent core.
Dermatological testing was used to assess the skin compatibility of a menstrual pad with an emollient-treated surface layer and a novel, polymeric absorbent foam core. The test program included: 1) skin patch tests to assess cumulative skin irritation, 2) human repeat insult patch tests to assess the potential for contact sensitization, and 3) repeated application to the popliteal fossa ("behind-the-knee" test) to assess combined chemical irritation and frictional effects. Studies showed the new product and its components to be as mild to skin as other commercially available materials with no evidence for the induction of delayed contact hypersensitivity. Pads with an emollient-based topsheet finish were milder to the skin than pads with a conventional topsheet finish. The test program provides reassurance that the skin compatibility of the new menstrual pad is similar to that of conventional marketed pads with a history of safe use and consumer acceptance.


Perception v. actual intakes of junk food and sugar-sweetened beverages in Australian young adults: assessed using the mobile food record.
To determine perception v. actual intakes of energy-dense nutrient-poor 'junk food' (JF) and sugar-sweetened beverages (SSB) in young adults, using the mobile food record (mFR). Before-and-after eating images using a 4 d mFR were assessed for standardised 600 kJ (143 kcal) servings of JF and SSB (excluding diet drinks). Participants reported their concern about the health aspects of their diet, perceptions and intentions regarding JF and SSB. Perth, Western Australia. Adults (n 246) aged 18-30 years. The mean (sd) intake of JF+SSB was 3·7 (2·0) servings/d. Women thinking about drinking less SSB consumed more SSB servings/d (1·5 (1·2)) than men (0·7 (0·5); P<0·05) who were thinking about drinking less. Men not thinking about cutting down JF consumed more servings/d (4·6 (2·4)) than women (2·5 (0·7); P<0·01) who were not thinking about cutting down. Those who paid a lot of attention to the health aspects of their diet consumed less JF+SSB than those who took only a bit of notice (P<0·001), were not really thinking much about it (P<0·001) or who didn't think at all about the health aspects of food (P<0·01). Perceptions and attitudes regarding JF and SSB were associated with level of consumption. Those not thinking about cutting down their intake of these foods represent an important target group as they consume more than their peers. Further research is needed to identify how amenable young adults are to changing their intake, particularly given the lack of attention paid to the health aspects of their diet.


[Pathogenesis of osteopathy caused by anticonvulsives (author's transl)].
After a short survey of the recent suggestions of the pathogenesis of osteopathy caused by therapy with anticonvulsives it is demonstrated in the light of 3 case reports that 1. A vitamin D-sensible rickets, which is only due to abnormal living conditions, can develop in severely cerebral-damaged persons if there is no specific vitamin D administration. 2. An "antiepileptic rickets" is spontaneously reversible if the anticonvulsive therapy is stopped. 3. An enzymatic induction due to anticonvulsives is also detectable in the light of morphologic hepatic changes (biopsy, electron microscopy). Hence it follows that there are demands for a specific control of all patients treated with anticonvulsives. It is recommended to carry out a rickets prevention for a selected patient group.


From 'two medicines' to 'One Health' and beyond.
We first review historic and conceptual background to integrative thinking in medicine. Lacking a general theory of 'One Health', we provide an operational definition of 'One Health' and its leverage as: any added value in terms of human and animal health, financial savings or environmental benefit from closer cooperation of human and animal health sectors at all levels of organisation. Examples of such added value of 'One Health' are given from the fields of health systems, nutrition and zoonoses control in Africa and Asia. 'One Health' must become main-stream rather than a new discipline or new association; it should just become normal that practitioners and professionals in the health, animal and environment sectors work together as closely as possible. Current and future challenges in financing clean energy, migration flows, food security and global trade further warrant rethinking of human and animal health services. A conceptual outlook relates health as an outcome of human-environment systems called 'health in social-ecological systems'. The paper ends with an outlook on the operationalisation of 'One Health' and its future potential, specifically also in industrialised countries.


Serotonin receptor agonists in the acute treatment of migraine: a review on their therapeutic potential.
Migraine is an important socioeconomic burden and is ranked the sixth cause of years of life lost because of disability in the general population and the third cause of years of life lost in people younger than 50 years. The cornerstone of pharmacological treatment is represented by the acute therapy. The serotonin (5-hydroxytryptamine [5-HT]) receptor subtype 1B/1D agonists, called triptans, are nowadays the first-line acute therapy for patients who experience moderate-to-severe migraine attacks. Unfortunately, a high percentage of patients are not satisfied with this acute treatment, either for lack of response or side effects. Moreover, their mechanism of action based on vasoconstriction makes them unsuitable for patients with previous cardio- and cerebrovascular diseases and for those with uncontrolled hypertension. Since the introduction of triptans, no other acute drug class has passed all developmental stages. The research for a new drug lacking vasoconstrictive effects led to the development of lasmiditan, a highly selective 5-HT1F receptor agonist with minimized interactions with other 5-HT receptor subtypes. Lasmiditan is considered to be the first member of a new drug category, the neurally acting anti-migraine agent (NAAMA). Phase II and III trials had shown superiority compared to placebo and absence of typical triptan-associated adverse events (AEs). Most of the AEs were related to the central nervous system, depending on the high permeability through the blood-brain barrier and mild to moderate severity. The results of ongoing long-term Phase III trials will determine whether lasmiditan will become available in the market, and then active triptan comparator studies will assess patients' preference. Future studies could then explore the safety during pregnancy and breastfeeding or the risk that overuse of lasmiditan leads to medication overuse headache.


Nutrition and the future of mankind.
Malnutrition is primarily due to poverty, a manifestation of social injustice with inadequate distribution of resources and services within and between countries. By limiting the capability of poor people to improve their economical and social status, malnutrition helps to perpetuate this situation. A change in developmental policies taking more into account the improvement of living conditions of the poor is needed to correct this social problem.


Dual-energy X-ray absorptiometry in early life.
Dual-energy X-ray absorptiometry (DXA) is a safe and quick technique, and requires little cooperation from the patient. DXA has therefore been introduced progressively in paediatrics and neonatology to study bone mineral content and body composition. The limits of DXA are related mainly to accuracy, and it is too early to claim that DXA is a 'gold standard' technique for body composition research. However, DXA appears to be an adequate tool for measuring bone mass and body composition in the clinical setting, and it represents the best technical choice for paediatric use to date.


Phenotyping Superagers Using Resting-State fMRI.
Superagers are defined as older adults with episodic memory performance similar or superior to that in middle-aged adults. This study aimed to investigate the key differences in discriminative networks and their main nodes between superagers and cognitively average elderly controls. In addition, we sought to explore differences in sensitivity in detecting these functional activities across the networks at 3T and 7T MR imaging fields. Fifty-five subjects 80 years of age or older were screened using a detailed neuropsychological protocol, and 31 participants, comprising 14 superagers and 17 cognitively average elderly controls, were included for analysis. Participants underwent resting-state-fMRI at 3T and 7T MR imaging. A prediction classification algorithm using a penalized regression model on the measurements of the network was used to calculate the probabilities of a healthy older adult being a superager. Additionally, ORs quantified the influence of each node across preselected networks. The key networks that differentiated superagers and elderly controls were the default mode, salience, and language networks. The most discriminative nodes (ORs > 1) in superagers encompassed areas in the precuneus posterior cingulate cortex, prefrontal cortex, temporoparietal junction, temporal pole, extrastriate superior cortex, and insula. The prediction classification model for being a superager showed better performance using the 7T compared with 3T resting-state-fMRI data set. Our findings suggest that the functional connectivity in the default mode, salience, and language networks can provide potential imaging biomarkers for predicting superagers. The 7T field holds promise for the most appropriate study setting to accurately detect the functional connectivity patterns in superagers.


Sex-Dependent Effects of Bmal1-Deficiency on Mouse Cerebral Cortex Infarction in Response to Photothrombotic Stroke.
Stroke is a leading cause of disability and death worldwide. There is increasing evidence that occurrence of ischemic stroke is affected by circadian system and sex. However, little is known about the effect of these factors on structural recovery after ischemic stroke. Therefore, we studied infarction in cerebral neocortex of male and female mice with deletion of the clock gene Bmal1 (Bmal1-/-) after focal ischemia induced by photothrombosis (PT). The infarct core size was significantly smaller 14 days (d) as compared to seven days after PT, consistent with structural recovery during the sub-acute phase. However, when sexes were analyzed separately 14 days after PT, infarct core was significantly larger in wild-type (Bmal1+/+) female as compared to male Bmal1+/+ mice, and in female Bmal1+/+, as compared to female Bmal1-/- mice. Volumes of reactive astrogliosis and densely packed microglia closely mirrored the size of infarct core in respective groups. Estradiol levels were significantly higher in female Bmal1-/- as compared to Bmal1+/+ mice. Our data suggests a sex-dependent effect and an interaction between sex and genotype on infarct size, the recruitment of astrocytes and microglia, and a relationship of these cells with structural recovery probably due to positive effects of estradiol during the subacute phase.


Off-planar geometry and structural instability of EDO-TTF explained by using the extended debye polarizability model for bond angles.
The geometry of ethylenedioxy-tetrathiafulvalene, EDO-TTF, plays an important role in the metal-insulator transition in the charge transfer salt (EDO-TTF)(2)PF(6). The planar and off-planar geometrical conformations of the EDO-TTF molecules are explained using an extended Debye polarizability model for the bond angle. The geometrical structure of EDO-TTF is dictated by its four sulfur bond angles and these are, in turn, determined by the polarizability of the sulfur atoms. With Hartree-Fock and second-order Møller-Plesset perturbation theory calculations on EDO-TTF, TTF, H(2)S, and their oxygen and selenium substituted counterparts we confirm this hypothesis. The Debye polarizability model for bond angles relates directly the optimum bond angle with the polarizability of the center atom. Considering the (EDO-TTF)(2)PF(6) material in this light proves to be very fruitful.


Pseudo-asymmetry of cerebral blood flow in arterial spin labeling caused by unilateral fetal-type circle of Willis: Technical limitation or a way to better understanding physiological variations of cerebral perfusion and improving arterial spin labeling acquisition?
In the recently published article, "Unilateral fetal-type circle of Willis anatomy causes right-left asymmetry in cerebral blood flow with pseudo-continuous arterial spin labeling: A limitation of arterial spin labeling-based cerebral blood flow measurements?", it was shown by the method of arterial spin labeling (ASL) that unilateral fetal-type circle of Willis could induce variation of blood flow in cerebellar and posterior cerebral artery territory. We believe that the reported observation, rather than being a limitation, gives several interesting cues for understanding the ASL sequence. In this commentary, we formulate some suggestions regarding the use of ASL in clinical practice, discuss the potential causes of the above-mentioned pseudo-asymmetry and consider future improvements of the ASL technique.


Distinct inter-domain interactions of dimeric versus monomeric α-catenin link cell junctions to filaments.
Attachment between cells is crucial for almost all aspects of the life of cells. These inter-cell adhesions are mediated by the binding of transmembrane cadherin receptors of one cell to cadherins of a neighboring cell. Inside the cell, cadherin binds β-catenin, which interacts with α-catenin. The transitioning of cells between migration and adhesion is modulated by α-catenin, which links cell junctions and the plasma membrane to the actin cytoskeleton. At cell junctions, a single β-catenin/α-catenin heterodimer slips along filamentous actin in the direction of cytoskeletal tension which unfolds clustered heterodimers to form catch bonds with F-actin. Outside cell junctions, α-catenin dimerizes and links the plasma membrane to F-actin. Under cytoskeletal tension, α-catenin unfolds and forms an asymmetric catch bond with F-actin. To understand the mechanism of this important α-catenin function, we determined the 2.7 Å cryogenic electron microscopy (cryoEM) structures of filamentous actin alone and bound to human dimeric α-catenin. Our structures provide mechanistic insights into the role of the α-catenin interdomain interactions in directing α-catenin function and suggest a bivalent mechanism. Further, our cryoEM structure of human monomeric α-catenin provides mechanistic insights into α-catenin autoinhibition. Collectively, our structures capture the initial α-catenin interaction with F-actin before the sensing of force, which is a crucial event in cell adhesion and human disease.


A guide to organizing a multicenter clinical trial.
Multicenter clinical trials are important research tools. Planning a multicenter clinical trial is a long and arduous task that requires substantial preparation time. In this guide, the authors discuss the steps used to plan a multicenter clinical trial. A preplanning phase, which involves formulating and refining a research question and conducting pilot studies, is detailed, and the planning phase, which involves the acquisition of funding to support the coordination and preparation of a multicenter clinical trial, culminating in the submission of an R01 grant, is described. An essential asset to planning a multicenter clinical trial is the fluidity with which all collaborators work together toward a common vision. The philosophy among collaborators should be consensus and commitment and is emphasized by the development of a consensus assisted study protocol. Most important are the recruitment of centers and co-investigators who are dedicated, collaborative, and selfless in the team effort to achieve goals that cannot be reached by a single-center effort.


Clinical pharmacokinetics of nebivolol: a systematic review.
Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC0-∞) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (Cmax) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC0-∞ of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher Cmax, AUC0-∞ and half-life (t1/2) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.


Association between changes in quality of life and mortality in hemodialysis patients: results from the DOPPS.
Cross-sectional health-related quality of life (HR-QOL) measures are associated with mortality in hemodialysis (HD) patients. The impact of changes in HR-QOL on outcomes remains unclear. We describe the association of prior changes in HR-QOL with subsequent mortality among HD patients. A total of 13 784 patients in the Dialysis Outcomes and Practice Patterns Study had more than one measurement of HR-QOL. The impact of changes between two measurements of the physical (PCS) and mental (MCS) component summary scores of the SF-12 on mortality was estimated with Cox regression. Mean age was 62 years (standard deviation: 14 years); 59% were male and 32% diabetic. Median time between HR-QOL measurements was 12 months [interquartile range (IQR): 11, 14]. Median initial PCS and MCS scores were 37.5 (IQR: 29.4, 46.2) and 46.4 (IQR: 37.2, 54.9); median changes in PCS and MCS scores were -0.2 (IQR: -5.5, 4.7) and -0.1 (IQR: -6.8, 5.9), respectively. The adjusted hazard ratio (HR) for a 5-point decline in HR-QOL score was 1.09 [95% confidence interval (CI): 1.06-1.12] for PCS and 1.05 (95% CI: 1.03-1.08) for MCS. Adjusting for the second QOL score, the change was not associated with mortality: HR = 1.01 (95% CI: 0.98-1.05) for delta PCS and 1.01 (95% CI: 0.98-1.03) for delta MCS. Categorizing the first and second scores as predictors, only the second PCS or MCS score was associated with mortality. In our study, only the most recent HR-QOL score was associated with mortality. Hence, the predictive power of a measurement of HR-QOL is not affected by changes in HR-QOL prior to that measurement; more frequent HR-QOL measurements are needed to improve the prediction of outcomes in HD. Further studies are needed to determine the optimal frequency and appropriate instrument to be used for serial measurements.


[Roentgen anatomy of the arteries of the gallbladder (according to intravital angiography)].
Examiniation of 163 series of coeliacograms and 10 series of angiograms of the superior mesentery artery has established thatby a conventional method the gallbladder artery is revealed in 79.1% of observations. The gall-bladder is blood supplied by a solitary or a double artery , or by numerous small vessels (scattered type of blood supply). Distinctive features of the gall-bladder arteries are:the site of their origination, the type of branching, irregular sinous course and false enlargements of the lumen as well as the disposition of arteries and their branches coinciding withthe topographs of the bladder determined in the parenchymatous phase. The main causes preventing determination of the gall-bladder arteries are both insufficiently contrast angiograms andpoor accumulation of the contrast substance in the bladder wall. Superposition of theshade of the enlarged liver is one of the obstacles in determinating the gall-bladder arteries. The author's experience show that the sourses of the gall baldder blood supply can be revealedin most cases in ordinary coeliacograms.


Plasmodium berghei: physiopathological changes during infections in mice.
Using infections of Plasmodium berghei in laboratory mice, the following physiopathological changes were observed during the seven days of the infection: reduction in haematocrit, increases in parasitized erythrocytes, pulmonary oedema, hypothermia, formation of prostaglandin-like substances in the central nervous system, increases and decreases in plasma bradykininogen levels and leucocytosis, as evidenced by neutrophilia, lymphocytosis and monocytosis. We found no changes in total plasma protein levels and albumin/globulin ratio.


The limits of empirical studies on research ethics.
The results of empirical research in psychology and psychiatry are increasingly being used to formulate as well as understand problems at the interface of law and psychiatry. There has been a proliferation of studies, such as the determinants of individual competence or threat to self or others, the results of which are influencing policy and legislative decisions as well as buttressing holdings in court cases. In this article, I explore the issues of interpretation of epidemiological studies, particularly the role of ideological positions on the design and results of empirical findings, the importance of the way data are interpreted, and the role of ideologies in the way research findings are presented to provide support for policy positions. Two levels of analysis are involved in determining the validity of a study. The first addresses the questions of whether the study meets the statistical and epidemiological requirements for reliable results. These include considerations such as the appropriateness of the study design and methods for gathering and interpreting data. The second focuses on the underlying framework of the study. This involves factors such as the perspectives and values of those conducting the study, the explicit and implicit dominating ideologies where they operate, and the extent to which the study is constructed to reaffirm specific ideologies. This level of analysis is essential for disclosing the influences of ideologies on the results of studies and the way in which data are interpreted. In this article, I try to demonstrate through critiques of selected studies that the first stage of analysis is insufficient without an examination of underlying preconceived values to establish the meaningfulness of results.


Uncovering the pharmacology of the G protein-coupled receptor GPR40: high apparent constitutive activity in guanosine 5'-O-(3-[35S]thio)triphosphate binding studies reflects binding of an endogenous agonist.
In cells lacking expression of Ca(2+)-mobilizing G proteins, coexpression of human GPR40 and Galpha(q) allowed medium- and long-chain fatty acids to elevate intracellular [Ca(2+)]. This was also observed when human embryonic kidney (HEK) 293 cells were transfected with a GPR40-Galpha(q) fusion protein. The kinetic of elevation of intracellular [Ca(2+)] slowed with increasing fatty acid chain length, suggesting different ligand on-rates, whereas the addition of fatty acid-free bovine serum albumin reduced signals, presumably by binding the fatty acids. To allow effective ligand equilibration, GPR40-Galpha(q) was used in guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding assays. After expression of GPR40-Galpha(q) in HEK293 cells and membrane preparation basal binding of [(35)S]GTPgammaSinGalpha(q) immunoprecipitates was high and not elevated substantially by fatty acids. However, treatment of membranes with fatty acid-free bovine serum albumin reduced the basal [(35)S]GTPgammaS binding in a concentration-dependent manner and allowed the responsiveness and pharmacology at GPR40 of each of the fatty acids thiazolidinediones and a novel small-molecule agonist to be uncovered. Membranes of rat INS-1E cells that express GPR40 endogenously provided similar observations. The high apparent constitutive activity of GPR40-Galpha(q) was also reversed by a small-molecule GPR40 antagonist, and basal [(35)S]GTPgammaS binding was prevented by the selective Galpha(q)/Galpha(11) inhibitor YM-254890. The current studies provide novel insights into the pharmacology of GPR40 and indicate that G protein-coupled receptors which respond to fatty acids, and potentially to other lipid ligands, can be occupied by endogenous agonists before assay and that this may mask the pharmacology of the receptor and may be mistaken for high levels of constitutive activity.


Radiative cooling: lattice quantization and surface emissivity in thin coatings.
Nanodiamond powder (NDP), multiwall carbon nanotube (MWCNT), and carbon black (CB) were dispersed in an acrylate (AC) emulsion to form composite materials. These materials were coated on aluminum panels (alloy 3003) to give thin coatings. The active phonons of the nanomaterials were designed to act as a cooling fan, termed "molecular fan (MF)". The order of lattice quantization, as investigated by Raman spectroscopy, is MWCNT > CB >> NDP. The enhanced surface emissivity of the MF coating (as observed by IR imaging) is well-correlated to lattice quantization, resulting in a better cooling performance by the MWCNT-AC composite. MF coatings with different concentrations (0%, 0.4%, 0.7%, and 1%) of MWCNT were prepared. The equilibrium temperature lowering of the coated panel was observed with an increase in the loading of CNTs and was measured as 17 degrees C for 1% loading of MWCNT. This was attributed to an increased density of active phonons in the MF coating.


Nasopharyngeal carcinoma in children and adolescents successful role of retrieval therapy.
The nasopharyngeal carcinoma in children and adolescents usually presents in advanced locoregional stages. Seventeen patients, below the age of 18 years, with the diagnosis of nasopharyngeal carcinoma were diagnosed and treated at the National Cancer Institute (NCI), Cairo, Egypt, during the period 1982-1987. These 17 patients were selected from 28 patients of the same age group to whom the diagnosis of nasopharyngeal malignancies were established. This diagnosis was confirmed morphologically and with immunostaining using antibodies against leucocyte common antigen (LCA), epithelial membrane antigen (EMA), cytokeratin and vimentin. Eighty two percent of our patients were in T3 + T4 and 94% had N 1-3 nodal status. The locoregional control was 94% with adequate conventional radiotherapy, while the distant metastasis rate was also high (81%). The 5-year actuarial survival rate was 47 +/- 11% and the survival worsened with the advancement in T stage. However, the present study did not show any influence of N stage on survival. The relatively high survival rate depended mainly upon successful retrieval therapy with radiochemotherapy. This emphasizes the role of combination chemotherapy in the treatment of relapsing nasopharyngeal carcinoma in young patients.


Location of liver metastases reflects the site of the primary colorectal carcinoma.
The present study was designed to investigate whether the different venous return of different locations of colorectal carcinomas affects the lobar distribution of metastases to the liver, due to the "streaming" within the portal vein. The site of the primary colorectal carcinoma was divided into the right- and left hemicolon according to the different venous drainage via the superior and the inferior mesenteric/splenic vein. Both groups were analyzed for the distribution of the metastases in the liver. The anatomic site of the liver metastases was detected by intraoperative exploration and differentiated between the two lobes using the Cantlie line. Out of a total of 178 patients, 109 men and 69 women with 264 metastases were eligible for the study. The ratio of metastases in the right and left hemiliver was 3.6:1 for 35 right-sided primary tumors (p=0.002) compared with 2.1:1 for 143 left-sided primary tumors (p=NS). No significant differences were evident for the sub-analysis of involved liver segments. The results of our study support the existence of the "streaming" effect in the portal vein. Right-sided colon carcinomas predominantly involve the right hemiliver, while left-sided colon carcinomas involve the liver homogeneously, considering the size ratio of the right to left liver lobe, which is about 2:1. Knowledge of streaming may help us to understand the spread of abdominal malignancies and may provide a reference concerning the possible primary site depending on metastatic distribution in the liver.


Coronary artery bypass grafting in type II diabetic patients: a comparison between insulin-dependent and non-insulin-dependent patients at short- and mid-term follow-up.
Diabetes is a well-established risk factor for coronary artery disease, and it is associated with an increased rate of early and late adverse events after myocardial revascularization by coronary artery bypass grafting. A prospective follow-up study was done to evaluate the short-term and mid-term outcomes of type II diabetic patients who had coronary artery bypass grafting at our institution between 1996 and May 1999. A total of 200 patients, 100 insulin-dependent diabetic patients (group I) and 100 non-insulin-dependent diabetic patients (group II), met the inclusion criteria of the study and were included in the clinical follow-up study. The characteristics of the patients of the two groups were similar for baseline clinical angiographic and operative characteristics. In particular, no significant differences in cardiopulmonary bypass and aortic cross-clamping times were noted between the two groups. The number grafts per patient was similar between the two groups. There were no in-hospital deaths, but postoperative complications were different among the two series. In fact, 33% of patients in group I had at least one major complication compared with 20% in group II (p = 0.037). The cumulative number of complications was 148 in group I and 69 in group II, and the mean number of complications per patient was 4.5 and 3.5 in groups I and II, respectively. The major differences in perioperative complication rates were found in the need for prolonged (> 24 hours) ventilation, occurrence of respiratory or renal insufficiency, and mediastinitis. The mean length of stay in the intensive care unit and for total hospitalization were longer in group I than group II (4.3 +/- 2.8 days versus 2.8 +/- 2.7 days [p = 0.010] and 11.1 +/- 2.2 days versus 7.2 +/- 2.4 group II [p < 0.05], respectively). At long-term follow-up, group I patients had a significantly higher mortality rate (29% versus 10%, p < 0.001). Moreover, overall late cardiac and noncardiac complication rates were significantly higher in group I than II (37% versus 22%, p = 0.02). In the multivariate analysis including several preoperative and operative variables, treatment by insulin, advanced age (> 75 years), left ventricular dysfunction (left ventricular ejection fraction < 35%), and complex lesions at coronary angiography (American Heart Association lesion classification type C lesion) were found as independent predictors of increased mortality. Our data show that patients with insulin-dependent type II diabetes who had coronary artery bypass grafting have a significantly higher rate of major postoperative complications with an extremely unfavorable short- and long-term prognosis. Diabetic patients on insulin treatment should be considered high-risk candidates for coronary artery bypass grafting and require intense perioperative and long-term monitoring. Further studies will be necessary to investigate whether such conclusions may be appropriate for newer surgical strategies such as off-pump operation.


Grading Criteria of Anthurium DUS Quantitative Characteristics by Multiple Comparison.
The determination of the grades and interval of quantitative characteristics is an important job while we draft new distinctness, uniformity and stability (DUS) test guidelines. Grading criteria should be adjusted because of the effect of year and site; it is also a key task to establish applicable criteria in the DUS test. Excellent criteria will improve the accuracy of the DUS evaluation. In this study, we analyzed the variability and distribution patterns of nine quantitative characteristics of 251 anthurium varieties. Three methods were used to establish the grade criteria: the two standard deviation methods, the two LSD0.05 methods and the multiple comparison method. The results showed that the coefficient of variation within varieties varied from 6.96% to 10.11%. The quantitative characteristics observed in this study did not follow a normal distribution, except spadix thickness at the middle and spathe size. In most characteristics, the standard deviations and LSD0.05 were similar, except for spathe size. The state interval set by multiple comparison methods for every characteristic was variable, and its mean was about 1.25 times that of the other two methods. The process of establishing grading criteria using the multiple comparison method was simpler, and the criteria were more accurate, with a lower error rate.


Genetic Architecture of Flooding Tolerance in the Dry Bean Middle-American Diversity Panel.
Flooding is a devastating abiotic stress that endangers crop production in the twenty-first century. Because of the severe susceptibility of common bean (Phaseolus vulgaris L.) to flooding, an understanding of the genetic architecture and physiological responses of this crop will set the stage for further improvement. However, challenging phenotyping methods hinder a large-scale genetic study of flooding tolerance in common bean and other economically important crops. A greenhouse phenotyping protocol was developed to evaluate the flooding conditions at early stages. The Middle-American diversity panel (n = 272) of common bean was developed to capture most of the diversity exits in North American germplasm. This panel was evaluated for seven traits under both flooded and non-flooded conditions at two early developmental stages. A subset of contrasting genotypes was further evaluated in the field to assess the relationship between greenhouse and field data under flooding condition. A genome-wide association study using ~150 K SNPs was performed to discover genomic regions associated with multiple physiological responses. The results indicate a significant strong correlation (r > 0.77) between greenhouse and field data, highlighting the reliability of greenhouse phenotyping method. Black and small red beans were the least affected by excess water at germination stage. At the seedling stage, pinto and great northern genotypes were the most tolerant. Root weight reduction due to flooding was greatest in pink and small red cultivars. Flooding reduced the chlorophyll content to the greatest extent in the navy bean cultivars compared with other market classes. Races of Durango/Jalisco and Mesoamerica were separated by both genotypic and phenotypic data indicating the potential effect of eco-geographical variations. Furthermore, several loci were identified that potentially represent the antagonistic pleiotropy. The GWAS analysis revealed peaks at Pv08/1.6 Mb and Pv02/41 Mb that are associated with root weight and germination rate, respectively. These regions are syntenic with two QTL reported in soybean (Glycine max L.) that contribute to flooding tolerance, suggesting a conserved evolutionary pathway involved in flooding tolerance for these related legumes.


Hydrogen-oxidizing methane bacteria. II. Electron microscopy.
Comparison of the fine structure of the methanogenic organism from the culture known as Methanobacillus omelianskii with that of Methanobacterium formicicum revealed a great similarity. Both organisms exhibited a large number of intracytoplasmic membranous elements when stained with phosphotungstic acid. In contrast, no such elements were observed in Methanobacterium ruminantium.


Does inhalation of ultrafine particles cause pulmonary vascular effects in humans?
Inhalation of ambient particulate matter increases the risk of cardiovascular disease. Clinical studies play an important role in elucidating mechanisms for pollutant effects, and in establishing ambient air quality standards. Ultrafine particles (UFP; diameter <100 nm) may be important in the cardiovascular effects of ambient PM, yet there are few clinical studies of UFP health effects. Our laboratory has developed an exposure facility for clinical studies of laboratory-generated UFP. We confirmed previous predictions that UFP <50 nm in diameter deposit in the respiratory tract with a high efficiency, and have shown that exercise or the presence of asthma further increases UFP deposition. UFP exposure with exercise reduced expression of selected adhesion molecules on blood leukocytes, and also decreased the pulmonary diffusing capacity for carbon monoxide. These findings are best explained by UFP effects on pulmonary vascular function. These findings provide a possible mechanism by which inhalation of UFP may contribute to cardiopulmonary health effects in susceptible people.


Importance of brain alterations in spinal cord injury.
Spinal cord injury (SCI) destroys the sensorimotor pathway and blocks the information flow between the peripheral nerve and the brain, resulting in autonomic function loss. Numerous studies have explored the effects of obstructed information flow on brain structure and function and proved the extensive plasticity of the brain after SCI. Great progress has also been achieved in therapeutic strategies for SCI to restore the "re-innervation" of the cerebral cortex to the limbs to some extent. Although no thorough research has been conducted, the changes of brain structure and function caused by "re-domination" have been reported. This article is a review of the recent research progress on local structure, functional changes, and circuit reorganization of the cerebral cortex after SCI. Alterations of structure and electrical activity characteristics of brain neurons, features of brain functional reorganization, and regulation of brain functions by reconfigured information flow were also explored. The integration of brain function is the basis for the human body to exercise complex/fine movements and is intricately and widely regulated by information flow. Hence, its changes after SCI and treatments should be considered.


Determining the Stage of the Estrous Cycle in Female Mice by Vaginal Smear.
Female mice undergo a 3- to 5-d, hormonally controlled estrous cycle. The estrous cycle is divided into different stages, including diestrus, proestrus, estrus, and metestrus. These stages can easily be determined by examining washes or cell smears of the vagina. Determining the stage of the estrous cycle may be important for setting up matings, identifying receptive females for artificial insemination, and analyzing phenotypes of the female reproductive tract.


[Disorders of speech and imagery functioning in children with epilepsy in the right or left cerebral hemisphere as primary loci of lesions].
The paper presents the relationship between the disorders of speech and a drawing. 40 epileptic 5-12 year-old children as well as 9 healthy children (a control group) were examined. There were analysed the disorders of speech, alterations of drawing in children with epilepsy, mechanisms of participation of the right or the left hemisphere in forming of speech and descriptive activity on different stages of ontogenesis and its compensation in dependence on the severity of the disease. In younger preschool age disorders of a speech and deficiency in drawing were determined by the damages of the right hemisphere, while a role of the left hemisphere in such processes increased later.


The Effects of mmW and THz Radiation on Dry Eyes: A Finite-Difference Time-Domain (FDTD) Computational Simulation Using XFdtd.
The importance of investigating the health effects of RF radiation on the cornea cannot be overstated. This study aimed to address this need by utilizing a mathematical simulation to examine the absorption of millimeter wave (mmW) and terahertz (THz) waves by the cornea, considering both normal and pathological conditions. The simulation incorporated variations in tear film thickness and hydration levels, as these factors play a crucial role in corneal health. To assess the impact of RF radiation on the cornea, the study calculated temperature rises, which indicate heating effects for both dry and normal eyes. XFdtd, a widely used commercial software based on the Finite-Difference Time Domain (FDTD) method, was employed to evaluate the radiation absorption and resulting temperature changes. The outcomes of this study demonstrated a crucial finding, i.e., that changes in the water ratio and thickness of the tear film, which are associated with an increased risk of dry eye syndrome, directly impact the absorption of mmW and THz waves by the cornea. This insight provides valuable evidence supporting the interconnection between tear film properties and the vulnerability of the cornea to RF radiation.


[Establishment of skin and joint micro-dialysis sampling method of triptolide in vivo by HPLC-MS/MS].
To detect the concentration of triptolide in skin and joint after percutaneous administration,an HPLC-MS/MS method and skin and joint micro-dialysis( MD) method of triptolide were established in this study. The separation was achieved on triple quadrupole( AB QTRAP4500) and phenomenex-C18( 4. 6 mm×150 mm,5 μm,luna) column with acetonitrile-water with 0. 1% formic acid( 65 ∶35) as the mobile phase at a flow rate of 0. 7 m L·min-1. An electrospray ionization( ESI) source was applied and operated in the positive multiple reaction monitoring( MRM) mode. The fragment ion for triptolide was m/z 361. 1→145. 0. The effects of different perfusion [Ringer's,PBS( p H 7. 4),30% ethanol saline]drug concentrations and flow rates on the recovery rate,as well as the relationship between the recovery rate and the loss rate were determined by incremental( dialysis) and reduction( retrodialysis) methods.The reduction method was applied in the in vivo study to investigate and determine the stability of the probe recovery rate in 10 h. The results of HPLC-MS/MS detection method conformed to the requirements of biological samples. The perfusion fluid was 30% ethanol saline. The recovery rate of skin and joint probes in vitro of triptolide increased within the flow rate of 0. 5-2. 5 μL·min-1. In order to increase the timeliness of data and the accuracy,the flow rate was determined to be 1 μL·min-1,and the sample interval was determined to be 0. 5 h. The recovery rate of triptolide in skin and joint probes in vitro and the loss rate were stable and equal despite of change of triptolide concentration within 10-200 μg·L-1. This indicated that the effect of drug concentration on the MD probe recovery rate was small,and the recovery rate could be replaced by the loss rate. The loss rate in vivo using MD method was measured at 10 h,indicating that the transfer rate of triptolide was stable within 10 h. The established method of triptolide in MD and HPLC-MS/MS can be applied to investigate the kinetic in skin and joint after percutaneous administration of triptolide.


Irreversible thermochromic behavior in gold and silver nanorod/polymeric ionic liquid nanocomposite films.
The novel application of gold and silver nanorods as irreversible thermochromic dyes in polymeric ionic liquid (PIL) nanocomposites is proposed here. These materials have been synthesized by anion exchange of an imidazolium-based PIL in a solution that also contained gold nanorods. This resulted in the entrapment of the nanoobjects within a solid polymer precipitate. In this article, the effect of the temperature was studied in relation to the change of shape and, consequently, color of the gold or silver nanorods within the films. For the nanocomposites studied here, a maximum of two visual thermochromic transitions was observed for gold nanorods and up to three transitions were observed for silver nanorods.


Theta pattern coma, a variant of alpha pattern coma.
Electroencephalograms with a dominant rhythmic areactive 5Hz theta activity are reported in two comatose patients with fatal outcome. This pattern was followed by isoelectric EEG and death in the first patient, who suffered multiple injuries including severe cerebral concussion and later tentorial herniation. The second patient died eight hours after the second EEG recording, both EEGs having shown a very rhythmic 5-6 Hz activity which was maximal anteriorly. He died two days after a severe cerebral hypoxic episode due to acute respiratory failure. Both patients were in their late sixties. It is suggested that the dominant areactive theta activity is a variant of malignant "alpha pattern coma".


Mobilizing positive reinforcement in communities to reduce youth access to tobacco.
A community intervention to mobilize positive reinforcement for not selling tobacco to young people was evaluated. The intervention had five components: (a) mobilization of community support, (b) merchant education, (c) changing consequences to clerks for selling or not selling to those under 18, (d) publicity about clerks' refusals to sell, and (e) feedback to store owners or managers about the extent of their sales to adolescents. A multiple baseline design experiment was conducted, in which two small Oregon communities received the intervention, while two other continued in baseline. Outlets' willingness to sell was assessed repeatedly by teenage volunteers. The intervention significantly reduced the proportion of stores willing to sell. Mobilizing social and material reinforcement for stores not selling tobacco to young people is a viable means of reducing such sales. It may be especially valuable in communities where laws against sales to minors go unenforced.


Amino acids as possible mediators of the intestinal phase of gastric secretion.
In a group of six dogs with Heidenhain pouches, the infusion of a solution of L-amino acids caused identical increases in gastric secretion when given into the jejunum as when administered directly into the portal venous system. Elevations in plasma amino nitrogen were also similar in the two circumstances. In four dogs with Heidenhain pouches and portacaval transposition, a similar infusion caused an identical increase in gastric secretion when given into the jejunum as when given into the peripheral venous system; plasma amino nitrogen levels were almost as high with the jejunal administration as with venous infusion. It is concluded that all, or almost all, of the gastric secretion evoked by amino acids in the canine intestine can be accounted for by the direct effect of absorbed amino acids on parietal cell secretion, with little or no contribution from release of an intestinal hormone.


Tumor programmed cell death ligand 1 expression correlates with nodal metastasis in patients with cutaneous squamous cell carcinoma of the head and neck.
Binding of tumor-expressed programmed cell death ligand 1 (PD-L1) to the programmed cell death 1 (PD-1) surface receptor blocks T-cell activation thereby leading to immune evasion. Tumor PD-L1 expression has been associated with poor outcome in a wide variety of cancers; however, data in cutaneous squamous cell carcinoma (cSCC) are scarce and conflicting. To investigate the relationship of tumor PD-L1 expression with the clinicopathologic features and prognosis of cSCC. PD-L1 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 100 patients with cSCC. Cumulative/dynamic receiver operating characteristic curve was used to determine the optimal PD-L1 threshold. Kaplan-Meier estimators and Cox proportional hazards regression models were also used. On the basis of cumulative/dynamic receiver operating characteristic curves, we defined the cut-off score for PD-L1 expression as ≥25% of tumor cells positively stained. PD-L1 expression was a significant risk factor for nodal metastasis with crude and adjusted hazard ratios of 3.39 (1.71-6.65) and 6.54 (2.28-18.78), respectively. This is a retrospective study limited to cSCC of the head and neck. These findings indicate that tumor PD-L1 expression predicts increased risk for nodal metastasis in patients with cSCC.


Liposomal delivery of hydrophobic weak acids: enhancement of drug retention using a high intraliposomal pH.
Clinical development of highly potent lipophilic neutral camptothecins has been impeded by the poor solubility, stability, and nonspecific toxicity of these compounds. Liposomal encapsulation offers a promising formulation route for tumor site-specific delivery of these novel drug candidates. However, the development of formulation strategies for liposomal loading and retention of hydrophobic drugs such as the neutral camptothecins has been lacking. In the studies presented here, we explored the potential of a trans-bilayer pH gradient strategy for prolonging the liposome retention of DB-67, a novel lipophilic camptothecin that can undergo lactone ring-opening to form a hydrophobic weak acid. The liposome membrane permeability of DB-67 was obtained as a function of pH in aqueous buffers. A permeability model was developed and liposome membrane permeability was shown to be controlled by the fraction of unbound neutral lactone entrapped in the vesicles. Liposome membrane permeability of DB-67 was also studied under physiological conditions. The high membrane partitioning of DB-67 in the intraliposomal microenvironment was found to shift the equilibrium between lactone and carboxylate towards the lactone species resulting in a faster than desired drug release under physiological conditions. The effectiveness of the pH gradient strategy was further reduced under physiological conditions by the rapid loss of trans-membrane pH gradients due to CO(2) uptake. Simulations were conducted to explore the role of membrane binding, intravesicular pH, and carbonate buffer concentration in successful utilization of the pH gradient strategy for hydrophobic weak acids.


Early histopathologic changes after lateral semicircular canal transection and occlusion in guinea pigs.
Occlusion of the semicircular canals has been used in otoneurologic and skull base surgeries with preservation of hearing. In order to understand the role of occlusion in hearing preservation, we observed early histopathologic changes of the lateral semicircular canal following transection and occlusion in guinea pigs. After surgery, the membranous endolymphatic canal was collapsed, and its torn ends were sealed by intramural bone dust in the bony semicircular canal. On the first postoperative day, the endolymphatic canal was expanded to its normal shape, and the sealing at the torn ends was maintained by the bone dust. These findings suggest that occlusion after semicircular canal injuries, by making blind ducts in the membranous endolymphatic canal, is important for the preservation of postoperative hearing.


Molecular requirements involving the human platelet protease-activated receptor-4 mechanism of activation by peptide analogues of its tethered-ligand.
Thrombin is the most potent agonist of human platelets and its effects are primarily mediated through the protease-activated receptors (PARs)-1 and -4. Although PAR-1 has higher affinity for thrombin than PAR-4, both receptors contribute to thrombin-mediated actions on platelets. Recently, a potent and selective PAR-1 antagonist (vorapaxar) was approved for clinical use in selected patients. In contrast, despite the fact that several PAR-4 antagonists have been developed, few of them have been tested in clinical trials. The aim of the present study was to elucidate the molecular requirements involving the PAR-4 mechanism of activation by peptide analogues of its tethered-ligand. Eight synthetic PAR-4 tethered-ligand peptide analogues were synthesized and studied for their agonistic/antagonistic potency and selectivity toward human washed platelet aggregation, using light transmittance aggregometry. In addition, in silico studies were conducted to describe the receptor-peptide interactions that are developed following PAR-4 exposure to the above analogues. To provide a first structure-activity relationship rationale on the bioactivity profiles recorded for the studied analogues, molecular docking was applied in a homology model of PAR-4, derived using the crystal structure of PAR-1. The following peptide analogues were synthesized: AYPGKF-NH2 (1), GYPGKF-NH2 (2), Ac-AYPGKF-NH2 (3), trans-cinnamoyl-AYPGKF-NH2 (4), YPGKF-NH2 (5), Ac-YPGKF-NH2 (6), trans-cinnamoyl-YPGKF-NH2 (7), and caffeoyl-YPGKF-NH2 (8). Peptide (1) is a selective PAR-4 agonist inducing platelet aggregation with an IC50 value of 26.2 μM. Substitution of Ala-1 with Gly-1 resulted in peptide (2), which significantly reduces the agonistic potency of peptide (1) by 25-fold. Importantly, substitution of Ala-1 with trans-cinnamoyl-1 resulted in peptide (7), which completely abolishes the agonistic activity of peptide (1) and renders it with a potent antagonistic activity toward peptide (1)-induced platelet aggregation. All other peptides tested were inactive. Tyr-2, residue, along with its neighboring environment was a key determinant in the PAR-4 recognition mode. When the neighboring residues to Tyr-2 provided an optimum spatial ability for the ligand to enter into the binding site of the transmembrane receptor, a biological response was propagated. These results were compared with the predicted binding poses of small molecule antagonists of PAR-4, denoted as YD-3, ML-354, and BMS-986120. π-π stacking interaction with Tyr-183 appears to be critical and common for both small molecules antagonists and the peptide trans-cinnamoyl-YPGKF-NH2. Conclusively, the lipophilicity, size, and aromatic nature of the residue preceding Tyr-2 are determining factors on whether a human platelet PAR-4 tethered-ligand peptide analogue will exert an agonistic or antagonistic activity.


Evolving tRNA(Sec) for efficient canonical incorporation of selenocysteine.
Bacterial selenocysteine incorporation occurs in response to opal stop codons and is dependent on the presence of a selenocysteine insertion sequence (SECIS) element, which recruits the selenocysteine specific elongation factor and tRNA(Sec) needed to reassign the UGA codon. The SECIS element is a stem-loop RNA structure immediately following the UGA codon and forms part of the coding sequence in bacterial selenoproteins. Although the site specific incorporation of selenocysteine is of great interest for protein engineering, the sequence constraints imposed by the adjoining SECIS element severely limit its use. We have evolved an E. coli tRNA(Sec) that is compatible with the canonical translation machinery and can suppress amber stop codons to incorporate selenocysteine with high efficiency. This evolved tRNA(Sec) allows the production of new recombinant selenoproteins containing structural motifs such as selenyl-sulfhydryl and diselenide bonds.


Influence of Ca2+e on 5-HT2- and alpha 1-induced arterial contraction and phosphoinositide metabolism.
Serotonin and phenylephrine were found to induce contractile responses and inositol phosphate (IP) formation in isolated rat tail artery. Both processes displayed similar concentration dependence in the presence of 2.5 mM external calcium (Ca2+e) and both were respectively inhibited by either ketanserine or prazosin, depending on the agonist used. In the absence of Ca2+e the amines no longer produced a contractile effect. In addition, lack of Ca2+ caused a shift to the right in the dose-response curve for phenylephrine-induced IP formation whereas serotonin-induced IP formation was not affected by changes in Ca2+e. The results suggest that alpha 1- and 5-HT2-induced contractions are quantitatively related to phosphatidylinositol metabolism. Contraction, but not IP formation requires the presence of Ca2+e. Different effects of Ca2+e on phenylephrine- and serotonin-induced IP formation could be related to a differential Ca2+ effect on binding of alpha 1- or 5-HT2 agonists.


Analysis of electrical activity of normal muscle in man at different degrees of voluntary effort.
Electrical activity during voluntary effort was analysed in 33 normal subjects. Parameters of activity measured were number of peaks, mean amplitude, distribution of time intervals and of amplitudes between peaks. Recording from 10 sites evenly distributed over a muscle gave adequate representation of activity; force should be a fixed proportion of maximum rather than constant.


How to promote patients' sleep in hospital.
Rationale and key points Disturbed or disrupted sleep is associated with adverse effects on physical and psychological health. This article explores the importance of promoting patients' sleep in hospital, although some of the principles can be applied to other healthcare settings. Sleep is essential to recovery and well-being, and nurses are well placed to support patients to achieve and sustain sleep. » Sleep has a restorative function and is particularly important in maintaining patients' health and well-being. » Sleep deficit has been linked to obesity, type 2 diabetes, cardiovascular disease and some cancers. » Assessment of patients' sleep routines and patterns, and consideration of environmental factors enables nurses to identify that which assists and limits sleep, and take appropriate action. Reflective activity 'How to' articles can help you update your practice and ensure it remains evidence-based. Apply this article to your practice. Reflect on and write a short account of: » How you think this article will change your practice when promoting sleep in patients in your care. » How you could use this article to educate your colleagues.


Experimental hyperthyroidism increases expression of parathyroid hormone-related peptide and type-1 parathyroid hormone receptor in rat ventricular myocardium of the Langendorff ischaemia-reperfusion model.
Parathyroid hormone-related peptide (PTHrP) is released under ischaemic conditions and it improves contractile function of stunned myocardium. The actions of PTHrP are mediated primarily by the type 1 parathyroid hormone receptor (PTH.1R), while PTHrP and PTH.1R expression levels are increased in ventricular hypertrophy associated with experimental hyperthyroidism. Since chronic administration of thyroxine (T4) improves postischaemic recovery in isolated heart models subjected to ischaemia-reperfusion stress, we tested the hypothesis that experimentally induced hyperthyroidism is associated with elevated expression of PTHrP and PTH.1R in rat myocardium. Hyperthyroid and control male Wistar rats were subjected to ischaemia-reperfusion stress using the Langendorff technique, and the PTHrP and PTH.1R expression was assessed by relative quantitative reverse transcriptase-polymerase chain reaction, Western blot analysis and immunohistochemistry. In the Langendorff model, the recovery of left ventricular developed pressure at the end of the stablization period and 45 min into the reperfusion period was used to assess the cardioprotective actions of T4 administration. Our data show that hyperthyroid animals had increased tolerance to the ischaemia-reperfusion stress and that this was associated with an increase of PTHrP and PTH.1R expression levels compared with those of control animals. In the control animals, the expression of PTHrP was increased 45 min into the reperfusion phase, while the PTH.1R expression pattern was significantly and gradually decreased throughout the ischaemia and reperfusion phases. In the hyperthyroid animals, the PTHrP and PTH.1R expression pattern was significantly higher throughout the ischaemia and reperfusion phases compared with that of control hearts. Our data suggest that increasing levels of PTHrP and PTH.1R expression can mediate, at least in part, the T4 administration-induced cardioprotection in rat ventricular myocardium.


Advances in the nutrition of preterm infants.
The greatly improved survival rate of infants born both preterm and low birth weight (LBW) has led to the subsequent growth and development of these infants becoming an important focus for research. Preterm infants begin life with, or acquire as a result of their prematurity, greater morbidity than term born babies, growth deficits, an increased risk of developmental delay and an increased risk of later adult diseases compared with appropriate for gestational age (AGA) term born babies. Research in recent decades has confirmed that there are marked differences in the nutritional requirements of preterm LBW infants compared with their AGA term born counterparts, both in the neonatal period and probably for all of infancy. In addition to the increased requirement for energy and protein, preterm LBW infants demonstrate a greatly increased requirement for some of the mineral elements, particularly iron, zinc and calcium, when compared with the needs of term AGA infants. In the UK, feeding practices for preterm infants in neonatal units and throughout infancy after hospital discharge are variable and many questions remain as to the optimal nutritional regimen for preterm LBW infants (and for subgroups of these infants) at different stages of infancy. There is some concern that the 2002 World Health Organization recommendations on infant feeding may be applied to all infants, including preterm infants, without consideration of their special nutritional needs, which may further compromise their growth and development. A brief résumé of the work of prominent researchers in the field of preterm infant nutrition in the UK, notably Lucas, Cooke and Fewtrell, is included in the review, together with information from papers published by the authors of the review. The review concludes with a summary of the generally accepted recommendations on feeding preterm LBW infants after hospital discharge and information on some practical help available to the parents of these children and to health workers in the field.


Prevalence of dental anomalies on panoramic radiographs in a population of the state of Pará, Brazil.
Dental anomalies (DAs) are the result of disorders that are able to modify the shape, number, size, and structure of teeth. This study aimed to evaluate the prevalence of DAs using panoramic radiographs in a population of the City of Belém, northern Brazil. In this study, 487 panoramic radiographs were evaluated searching for DAs. Dental records were reviewed for diagnostic confirmation. DAs related to the shape, number, size, and structure of teeth were investigated. Our results showed a DA prevalence of 56.9%. The most prevalent DA was taurodontism, which was present in 27.19% of cases. Root dilaceration was the second most prevalent DA in adults, whereas hypodontia was the second most prevalent DA in children. A total of 13 DAs were found. Dental anomalies were present in over half of the sample, and most of them were related to the shape of the teeth. Although there was a high prevalence of shape-related DAs, these alterations are generally of lower severity, and most do not require specific treatment. However, in 19.25% of cases, DAs were found involving the number, size and structure of the teeth. These DAs should be diagnosed and treated early, avoiding thus more serious complications.


Predictive Factors for Lymph Node Metastasis and the Effect on Survival in Early Gastric Cancer Patients with Radical Gastric Resection.
Selected patients with early gastric cancer (GC) are treated endoscopically. Lymph node metastasis (LNM) in the T1 stage may also be detected during surgical resection for early GC. The aim of this study was to determine factors associated with LNM and the effect on survival. A total of 63 patients with tumor invasion stage T1a or T1b who were operated on for early GC between 2010 and 2018 were included in the study. Parameters were investigated retrospectively to identify predictive factors for LNM and overall survival. Significance was defined with a 2-sided p-value of <0.05. Among the 63 patients, 21 (33.3%) had LNM. Lymphovascular invasion (LVI) (p=0.02) and a high-grade tumor (p=0.02) were significantly associated with LNM. The overall survival rate was 73.0%. The number of patients with LNM was greater among the deceased patients compared with the censored group (p=0.03). The median follow-up time of the entire group was 28 months (range: 12-55 months) while it was 23 months (range: 7-39 months) in the deceased group and 33.5 months (15.5-60 months) in the censored group (p=0.06). The mean survival was 62.36 months in patients with LNM and 71.99 months in those without LNM (p=0.09). The cut-off value determined for the neutrophil-to-lymphocyte ratio (NLR) was 2.33 and it was an effective value in survival analysis (p<0.05). Surgical treatment should be considered for early GC patients with high-grade tumors and cases demonstrating LVI. The overall survival was shorter in patients with a high NLR value and LNM.


Particulate platform for bioluminescent immunosensing.
The present study examines pyruvate kinase-conjugated antibodies for potential use in ELISA applications. The conjugates had an acceptable stability, and the coupling inflicted only minor impairment on the kinase activity. To mimic the setup of an immunoassay under development, a test antigen (BSA) was attached to polystyrene nanoparticles. This arrangement was found to be suitable as solid support for presentation of antigens in sensitive bioluminescence assays. The nanoparticles were well characterized in terms of protein surface load and were used to establish the number of conjugate complexes needed to generate a detectable signal. Under the biochemical conditions employed here, the detection limit of the pyruvate kinase conjugate lies in the femtomole range.


Age-related impairment of mitochondrial matrix aconitase and ATP-stimulated protease in rat liver and heart.
Mitochondrial matrix proteins are sensitive to oxidative inactivation, and oxidized proteins are known to accumulate during ageing. The Lon protease is believed to play an important role in the degradation of oxidized matrix proteins such as oxidized aconitase. We reported previously that an age-related accumulation of altered proteins occurs in the liver matrix of rats and that the ATP-stimulated proteolytic activity, referred as to Lon-like protease activity, decreases considerably in 27 month-old rats, whereas no concomitant changes in the levels of Lon protein expression occur in the liver. Here, we report that this decline is associated with a decrease in the activity of aconitase, an essential Krebs' cycle enzyme. Contrary to what we observed in the liver, the ATP-stimulated protease activity was found to remain constant in the heart mitochondrial matrix during ageing, and the levels of expression of the Lon protease increased in the older animals in comparison with the younger ones. Although the ATP-stimulated protease activity remained practically the same in older animals as in younger ones, a decrease in the level of aconitase activity was still observed. Altogether, these results indicate that matrix proteins, such as the critical enzymes aconitase and Lon protease, are inactivated with ageing and that the effects of ageing vary from one organ to another.


[Mediastinitis caused by odontogenic anaerobic bacteria].
Anaerobic odontogenic mediastinitis appeared to be on the increase. The case described had a favourable outcome. The aetiology and pathology of this disease, the dreadful prognosis of which was a mortality rate of 50%, were discussed. The aggravating factors appeared to be general, these patients presenting a particular predisposition, due to steroids and malnutrition, and anatomical, as the cellulitis spread along cervical fascial planes. The treatment always required was mediastinal surgical drainage by a transcervical approach or by thoracotomy, the association of three antibiotics (a penicillin with an imidazole, an aminoglycoside or a macrolide) and a high energy and nitrogen intake.


In vitro effects of styrene on cytoskeletal apparatus: an immunocytochemical study.
Styrene is known as an organic solvent implicated in neurological disorders occurring in exposed workers. Our studies were focused on the effects of styrene on the cytoskeletal apparatus, involved in several toxic neuropathies. The cultured cells were considered as living systems useful to investigate the mechanisms of cytotoxicity. Preliminary results reported here were obtained on two different epithelial cell lines (CG5 and HEp-2) by immunocytochemical methods. Treatment with styrene at 0.04% and 0.08% for 24 and 48 hours, induced changes in cytoskeletal elements. In particular, styrene seemed to induce a decrease in number of cells adhering to the substrate and some alterations in microtubule assembly. Moreover, a rearrangement of the keratin filaments was observed while styrene did not seem to induce noticeable changes in actin filament network. Data obtained seem to confirm in vitro studies as a useful tool in toxicity assessment of xenobiotic compounds at subcellular levels.


The nonrecurrent inferior laryngeal nerve: review of 33 cases, including two on the left side.
In 6307 cervicotomies for thyroid and parathyroid excision, 33 cases of nonrecurrent inferior laryngeal nerve were identified (0.52%). The anomaly was observed in 31 cases from 4921 dissections on the right side (0.63%) and in two cases from 4673 dissections on the left side (0.04%). Of the 31 patients who were initially seen with this anomaly on the right side, no innominate (brachiocephalic) artery was found; the right common carotid artery was arising directly from the aortic arch. The aberrant subclavian artery could always be felt against the vertebral column behind the esophagus. The two patients with the anomaly on the left side had a right aortic arch associated with situs inversus viscerum. In one case of invasive thyroid carcinoma, the nerve had to be sacrificed. In all of the other patients, postoperative laryngoscopic findings were normal. The nervous anomaly was of vascular anomaly origin in all cases. Predisposing factors for its onset during aortic arch development are discussed. Before surgical treatment, the diagnosis may only be made if vascular anomaly is suspected. Impairment of swallowing is the only clinical symptom to be looked for. The retroesophageal subclavian artery may be detected on chest x-ray films (20%) or by the compression and distortion of the esophagus shown during barium swallow tests (97%). Although rare on the right side and exceptional on the left, an aberrant nonrecurrent pathway for the inferior laryngeal nerve represents a major surgical risk. This is an additional argument in favor of systematic dissection of the inferior laryngeal nerve during thyroid or parathyroid excision.


[Expert consensus on pre-exposure rabies prophylaxis].
Pre-exposure rabies prophylaxis, also known as immunoprophylaxis before exposure to rabies, refers to preventive rabies vaccination for individuals at risk of rabies infection before rabies exposure, which is one of the important strategies for rabies prevention. Pre-exposure rabies prophylaxis can reduce the risk of individual rabies and reduce the cost of post-exposure prophylaxis by establishing an immunologic barrier in advance and the memory immune response after the booster. In view of the current situation that clinicians in China have relatively insufficient knowledge of pre-exposure rabies prophylaxis, the Rabies Prevention and Control Committee of the Chinese Preventive Medicine Association and Animal Injury Treatment Branch of China Association for Disaster and Emergency Rescue Medicine organized domestic experts in relevant fields to write this expert consensus in accordance with the latest guidelines, expert consensus, and the latest clinical evidence. This consensus describes the concept and significance of pre-exposure rabies prophylaxis, immunization procedures and cost-effectiveness respectively, and puts forward recommendations on pre-exposure rabies prophylaxis strategies. It is hoped that this consensus can improve clinicians' understanding of pre-exposure rabies prophylaxis and increase the rate of pre-exposure rabies prophylaxis among people at high risk of exposure in China.


High dose intravenous immunoglobulin repertoire versus anti-D. Disproportions in quantity and quality.
Here we consider certain therapeutic effects that intravenous administration of pooled high dose immunoglobulin and anti-D IgG share. Despite million-fold difference in doses such an effect occurs at least in idiopathic thrombocytopenic purpura (ITP). We postulate that spontaneous bleeding events may remit even when platelet numbers show refractoriness. We also mention the possible sparing of anti-D antibody-coated red blood cell (RBC) destruction and, finally, an acceleration of fibrotic involution. Fc receptors (FcRs) play a central role; beyond the well-established interactions with the immunoglobulin Fc fragment, FcRs are supposed to display special cognitive properties that enable them to pick out the therapeutic molecules from the recipient's IgG pool. Such subtle selection suggests some disarray in the host. On the other hand it may explain why the often-encouraging outcome of IVIG therapy remains unpredictable.


Prophylactic Absorbable Antibiotic Beads for High-risk, Implant-based Prepectoral Reconstruction.
Infections are problematic in postmastectomy implant-based reconstruction with infection rates as high as 30%. Strategies to reduce the risk of infection have demonstrated various efficacies. A prolonged course of systemic, oral antibiotics has not shown evidence-based benefit. Although absorbable antibiotic beads have been described for orthopedic procedures and pressure wounds, their use has not been well studied during breast reconstruction, particularly for prepectoral implant placement. The purpose of this study was to evaluate the selective use of prophylactic absorbable calcium sulfate antibiotic beads during high-risk implant-based, prepectoral breast reconstruction after mastectomy. Patients who underwent implant-based, prepectoral breast reconstruction between 2019 and 2022 were reviewed. Groups were divided into those who received antibiotic beads and those who did not. Outcome variables included postoperative infection at 90 days. A total of 148 patients (256 implants) were included: 15 patients (31 implants) who received biodegradable antibiotic beads and 133 patients (225 implants) in the control group. Patients who received antibiotic beads were more likely to have a history of infection (66.7%) compared with the control group (0%) (P < 0.01). Surgical site infection occurred in 3.2% of implants in the antibiotic bead group compared with 7.6%, but this did not reach statistical significance. The incidence of infection in high-risk patients who have absorbable antibiotic beads placed during the time of reconstruction seems to be normalized to the control group in this pilot study. We present a novel use of prophylactic absorbable antibiotic beads in prepectoral breast implant reconstruction.


Non-toxigenic Clostridioides (Formerly Clostridium) difficile for Prevention of C. difficile Infection: From Bench to Bedside Back to Bench and Back to Bedside.
The beneficial effect of colonization of the gastrointestinal tract by non-toxigenic Clostridioides difficile (NTCD) strains as a preventive of toxigenic C. difficile infection (CDI) has been known since the early 1980s. Investigators in both the USA and United Kingdom demonstrated that prior colonization by randomly selected NTCD strains provided prevention against infection by toxigenic C. difficile in hamsters, albeit with limited durability. In the 1980s two patients with multiply recurrent CDI in the UK were treated with vancomycin followed by NTCD to prevent further recurrences, with one success and one failure. Epidemiologic studies of hospitalized patients using weekly rectal swab cultures demonstrated that asymptomatic colonization of patients by toxigenic C. difficile was much more common than CDI, but also that the rate of asymptomatic NTCD colonization of patients was unexpectedly high. Development of molecular strain typing of C. difficile was instrumental in characterizing different strains of both toxigenic C. difficile and NTCD leading to identification of NTCD strains that were effective human colonizers. These strains were reintroduced in hamsters in the 1990s and shown to prevent CDI efficiently and durably when challenged with epidemic toxigenic C. difficile strains. One strain of NTCD, NTCD-M3, was manufactured under cGMP standards and was demonstrated to be safe in a phase 1 volunteer trial. NTCD-M3 was then tested in a phase 2 double-blind placebo controlled trial for the prevention of recurrent CDI in patients experiencing their first CDI episode or first CDI recurrence. NTCD-M3 was given at doses of 104 or 107 spores per day orally for 7 or 14 days following successful treatment of CDI with vancomycin and/or metronidazole. CDI recurred in 30% of placebo patients and 11% of all NTCD-M3 patients (p = 0.006); recurrence rate for the best dose, 107 spores/d × 7 days, was 5% (p = 0.01 vs. placebo). Detection of colonization predicted prevention success; among the 86 patients who were colonized with NTCD-M3 the recurrence rate was 2% vs. 31% in patients who received NTCD-M3 but were not colonized (p < 0.001). Additional trials of NTCD-M3 for primary prevention of CDI and prevention of CDI recurrence seem warranted by these promising results.


Whose health is it? Views about decision-making and information-seeking from people with HIV infection and their professional carers.
The views of people with HIV and their professional carers about patients' views on involvement in decision-making and information-seeking were studied, using a standardized self-report instrument. Patients and staff reported high levels of desire for patients' involvement in their care, but there were important differences between groups. Staff had higher preference for patients' involvement in decision-making than the patients themselves, while the opposite was the case for information-seeking. There were differences between professional groups and symptomatic and asymptomatic patients, social workers generally reporting higher preference for patients' autonomy, while doctors reported lower levels. Symptomatic patients tended to have lower preference for autonomy than asymptomatic ones. The significance and practical implications of the findings are discussed.


[Design, goals and preliminary results of the first national breast cancer study--the Federal Ministry of Research and Technology study of "small breast cancer"].
In the multicentre trial sponsored by the Federal Ministry for Research and Technology (= BMFT), mastectomy is compared with breast preservation in patients with pT1 NO MO breast cancer. On the basis of that protocol breast preservation can also be performed by smaller institutions thus implementing the health policy programme of effecting new treatment modalities on a broad basis. We can already recognise a substantial improvement in treatment standards applied by the different disciplines in the hospitals involved in the study. Special emphasis is placed on an optimal patient information about the possible treatment modalities involving the patients in the treatment decision. The evaluation of various prognostic factors will result in additional information on the biology of breast cancer. As a consequence, the definition of the group of patients suitable for breast preservation therapy can be clarified further.