Educating for collaborative practice: an interpretation of current achievements and thoughts for future directions.
The Edinburgh Declaration, developed in 1998 as a pledge to alter the character of medical education to more effectively meet the needs of society, included a recommendation to increase the opportunity for joint learning between health and health-related professions, as part of the training for teamwork. This article acknowledges achievements since the Declaration in relation to this recommendation, using an umbrella term for the phenomenon, 'educating for collaborative practice', and presents a perspective framed as a series of questions to encourage reflection on future directions. A literature interpretation, informed by philosophical hermeneutics, was conducted using text sets comprising reports and reviews from a section of the international literature since 1988. The interpretation involved: engaging with meanings as presented in the chosen texts; making iterative returns to the texts to explore emerging understanding; and ensuring parts of our understanding from particular texts were fused with complete understanding of the texts as a whole. A lens of appreciative inquiry facilitated acknowledgement of what has been achieved, while being curious about how it could be. Interpretation of the selected literature revealed notable achievements. Areas for further consideration were identified in relation to three themes: establishing shared understanding AND purpose behind use of terminology; being a conduit AND sharing responsibility for change; exploring ways of doing things AND ensuring ongoing inclusivity. Interpreting the current literature on 'educating for collaborative practice' has generated questions for reflection on how it may be otherwise. Readers are encouraged to embrace the tensions inherent in unanswered questions, providing space for communication, initiative and diversity of thought. An ongoing dialogue with the literature is proposed, asking whether educating students for a collective identity in settings where they are learning for and with patients is likely to advance educating for patient-centred collaborative practice.


The contribution of potentially modifiable risk factors to acute ischemic stroke burden - Comparing young and older adults.
Stroke is a leading cause of death and disability. In order to estimate the contribution of five modifiable risk factors to acute ischemic stroke (AIS) incidence in Israel, we conducted a case-control study based on first AIS cases aged 21-90 reported to the Israeli National Stroke Registry during 2014-2015, and controls from a national health survey conducted between 2013 and 2015. We calculated the population attributable risk (PAR) of each risk factor and the combined PAR for all risk factors (hypertension, diabetes, current smoking, obesity and hyperlipidemia), in all study population and by subgroups of young adults (age < 55) and older adults (age ≥ 55). The final analysis included 571, 577 and 500 matched pairs for all study population, young adults and older adults, respectively. Among young adults, current smoking and hypertension were the two most contributing risk factors for AIS, accounting for 33.6% (95% CI 27.3-39.9) and 28.9% (95% CI 22.1-35.7) of AIS cases, respectively. Among older adults, hypertension was the single most contributing risk factor for AIS and diabetes was the second most contributing risk factor for AIS, accounting for 64.9% (95% CI 57.3-72.5) and 25.7% (95% CI 17.5-33.9) of AIS cases, respectively. The combined PAR was significantly lower among young adults (PAR = 67.9%), compared with older adults (PAR = 80.7%). The combined PAR for all study population was 80.1% (95% CI 74.0-86.2), indicating that five common and modifiable risk factors explain ~80% of AIS incidence in Israel. Primary prevention strategies targeting these risk factors have the potential to drastically reduce stroke related morbidity and mortality.


Use of oral isotretinoin to treat acne in the public system: a hospital-based retrospective cohort.
Acne needs to be treated early to prevent negative psychosocial impacts. In severe or moderate forms, which tend to leave scars, oral isotretinoin is the first-line therapy. However, concern about its adverse events, especially in developed countries, delays effective treatment. In contrast, isotretinoin is widely prescribed in Brazilian private clinics. To describe the use of isotretinoin for treating acne in a Brazilian public hospital, and to analyze whether its prescription is effective or belated. Retrospective cohort study in a public hospital. Clinical and therapeutic data were obtained from the medical records of patients who were undergoing or had undergone acne treatment with isotretinoin in this hospital's general dermatology outpatient clinic over the last seven years, up to April 2018. 1526 medical records from patients with acne were analyzed. Isotretinoin was prescribed for 279 patients (18.28%) with mild (1.19%), moderate (57.37%), severe (35.85%) or conglobata (5.57%) forms of acne vulgaris. Sequelae of acne were present at the start of most of these patients' treatment. An initial daily dose of 20 mg was usually prescribed. The average initial dose/weight ratio was 0.33 mg/kg/day. The average total dose/weight ratio was 127.61 mg/kg. There were only a few cases of laboratory abnormalities. Sequelae of acne at the onset of treatment reveal delayed indication of isotretinoin, which can have negative psychosocial impacts on quality of life. Isotretinoin should be indicated early to prevent this. Its use is supported by its lack of laboratory alterations and controllable adverse events.


Stage-specific miRNAs regulate gene expression associated with growth, development and parasite-host interaction during the intra-mammalian migration of the zoonotic helminth parasite Fasciola hepatica.
MiRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression in organisms ranging from viruses to mammals. There is great relevance in understanding how miRNAs regulate genes involved in the growth, development, and maturation of the many parasitic worms (helminths) that together afflict more than 2 billion people. Here, we describe the miRNAs expressed by each of the predominant intra-mammalian development stages of Fasciola hepatica, a foodborne flatworm that infects a wide range of mammals worldwide, most importantly humans and their livestock. A total of 124 miRNAs were profiled, 72 of which had been previously reported and three of which were conserved miRNA sequences described here for the first time. The remaining 49 miRNAs were novel sequences of which, 31 were conserved with F. gigantica and the remaining 18 were specific to F. hepatica. The newly excysted juveniles express 22 unique miRNAs while the immature liver and mature bile duct stages each express 16 unique miRNAs. We discovered several sequence variant miRNAs (IsomiRs) as well as miRNA clusters that exhibit strict temporal expression paralleling parasite development. Target analysis revealed the close association between miRNA expression and stage-specific changes in the transcriptome; for example, we identified specific miRNAs that target parasite proteases known to be essential for intestinal wall penetration (cathepsin L3). Moreover, we demonstrate that miRNAs fine-tune the expression of genes involved in the metabolic pathways that allow the parasites to move from an aerobic external environment to the anerobic environment of the host. These results provide novel insight into the regulation of helminth parasite development and identifies new genes and miRNAs for therapeutic development to limit the virulence and pathogenesis caused by F. hepatica.


Atrial fibrillation.
Atrial fibrillation (AF) is the most common cardiac arrhythmia despite substantial efforts to understand the pathophysiology of the condition and develop improved treatments. Identifying the underlying causative mechanisms of AF in individual patients is difficult and the efficacy of current therapies is suboptimal. Consequently, the incidence of AF is steadily rising and there is a pressing need for novel therapies. Research has revealed that defects in specific molecular pathways underlie AF pathogenesis, resulting in electrical conduction disorders that drive AF. The severity of this so-called electropathology correlates with the stage of AF disease progression and determines the response to AF treatment. Therefore, unravelling the molecular mechanisms underlying electropathology is expected to fuel the development of innovative personalized diagnostic tools and mechanism-based therapies. Moreover, the co-creation of AF studies with patients to implement novel diagnostic tools and therapies is a prerequisite for successful personalized AF management. Currently, various treatment modalities targeting AF-related electropathology, including lifestyle changes, pharmaceutical and nutraceutical therapy, substrate-based ablative therapy, and neuromodulation, are available to maintain sinus rhythm and might offer a novel holistic strategy to treat AF.


Tissue plasminogen activator genetic polymorphisms do not influence tissue plasminogen activator release in patients with coronary heart disease.
To determine if polymorphisms of the tissue plasminogen activator (t-PA) gene influence acute endogenous t-PA release in patients with coronary heart disease (CHD). Forearm blood flow and plasma t-PA concentrations were measured in response to intra-brachial infusion of substance P and sodium nitroprusside in 96 patients with stable CHD. Genotyping was performed using a Taqman polymerase chain reaction assay specifically designed to detect the polymorphisms of interest: (i) Alu-repeat insertion/deletion sequence; (ii) C-->T substitution in an upstream enhancer region (-7351 C/T); (iii) T-->C in exon 6 (20 099 T/C); and (iv) T-->A (27 445 T/A) in intron 10. Substance P and sodium nitroprusside caused dose-dependent increases in forearm blood flow in all patients (P < 0.001 for all) that were independent of the four genetic polymorphisms. Similarly, there were no differences in basal plasma t-PA antigen concentrations or net t-PA release between genotypes. Compared to non-smokers, smokers exhibited impaired substance P-induced vasodilatation (P < 0.001) and t-PA release (P = 0.05). Despite confirming our previous findings in cigarette smokers, we have found no effect of polymorphisms of the t-PA gene on two complementary aspects of endothelial function. We conclude that genetic variation of the t-PA locus is unlikely to have a major influence on acute t-PA release in subjects with established CHD.


Resting-state cerebellar-cerebral networks are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings.
Dysconnectivity hypothesis posits that schizophrenia is a disorder with dysconnectivity of the cortico-cerebellar-thalamic-cortical circuit (CCTCC). However, it remains unclear to the changes of the cerebral connectivity with the cerebellum in schizophrenia patients and unaffected siblings. Forty-nine patients with first-episode, drug-naive schizophrenia patients, 46 unaffected siblings of schizophrenia patients and 46 healthy controls participated in the study. Seed-based resting-state functional connectivity approach was employed to analyze the data. Compared with the controls, the patients and the siblings share increased default-mode network (DMN) seed - right Crus II connectivity. The patients have decreased right dorsal attention network (DAN) seed - bilateral cerebellum 4,5 connectivity relative to the controls. By contrast, the siblings exhibit increased FC between the right DAN seed and the right cerebellum 6 and right cerebellum 4,5 compared to the controls. No other abnormal connectivities (executive control network and salience network) are observed in the patients/siblings relative to the controls. There are no correlations between abnormal cerebellar-cerebral connectivities and clinical variables. Cerebellar-cerebral connectivity of brain networks within the cerebellum are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings. Increased DMN connectivity with the cerebellum may serve as potential endophenotype for schizophrenia.


Gender differences in TRH-stimulated TSH and prolactin in primary degenerative dementia and elderly controls.
We performed thyrotropin-releasing hormone (TRH) stimulation testing in 18 nondepressed patients with primary degenerative dementia (10 M, 8F; average age +/- SD = 68 +/- 7) and 12 elderly controls (7M, 5F; average age +/- SD = 61 +/- 6). Six patients were retested approximately 2 years later. Initial Mini-Mental State Examination scores for patients ranged from 2 to 28 (average +/- SD = 18 +/- 6) and the scores for the control subjects were all equal to 30. Protirelin (500 micrograms) was injected iv and blood was sampled at 0, 15, 30, 45, 60, and 90 min for thyrotropin-stimulating hormone (TSH) and prolactin (PRL). There were no significant differences between patients and controls in baseline T4, T3 uptake, TSH, or PRL. No significant differences were found between patients and controls for either TRH-stimulated TSH or PRL at all time points. Duration of illness, severity of dementia, and severity of depressive symptoms did not correlate significantly with stimulation test results. There were, however, significantly greater responses in stimulated TSH and PRL for women compared with men in both patients and controls. Upon repeat testing (n = 6), TRH-stimulated TSH and PRL were not significantly different from the initial results.


Antioxidants as therapies: can we improve on nature?
Although oxidative damage contributes to many pathologies the use of naturally occurring, small-molecule antioxidants as therapies for these disorders has not been successful. Here I discuss some of the reasons this may be so. Paramount among these are the difficulties in delivering enough of the antioxidant to the intracellular location required to decrease pathological oxidative damage and the challenge of assessing whether the intervention has actually decreased oxidative damage in the patient to a therapeutically useful extent. To develop effective antioxidant therapies the best strategy may be to create new chemical entities designed to detoxify a defined reactive oxygen species-dependent process that underlies a particular pathology, in the same way a conventional drug is designed to modulate a biochemical process, rather than applying antioxidants in an unfocused manner. In developing new antioxidants it will be useful to utilize endogenous processes to activate and recycle the molecules in parallel with the targeting of compounds to cells and organelles in ways that are not limited by the constraints that impair the distribution of endogenous antioxidants. In short, I suggest that the future development of antioxidant therapies should be viewed as an arm of drug development, utilizing focused approaches similar to those of medicinal chemistry and pharmacology, rather than as a branch of nutrition.


The Year Embolectomy Won: a Review of Five Trials Assessing the Efficacy of Mechanical Intervention in Acute Stroke.
Embolectomy with stentriever devices is the newest treatment for acute stroke. Since 1995, treatment of acute stroke has been limited to a 4.5-h window with the use of intravenous tissue plasminogen activator (tPA). Five articles have been published in 2015 with the results supporting the paired treatment of tPA and embolectomy. This has also expanded the treatment window to greater than 4.5 h and produced evidence which will guide selection of patients that will benefit most from this therapy. This article will compare and contrast this most recent evidence.


Vitamin D receptor (VDR) gene polymorphisms and expression profile influence upon the immunological imbalance in Turner syndrome.
Turner syndrome (TS) patients display considerable immune misregulation, and it is hypothesized that Vitamin D (VTD) activity may fluctuate according to Vitamin D receptor (VDR) polymorphisms and/or expression profile. To uncover a possible relationship between VDR genotype and clinical conditions in TS patients, we investigated two functional VDR variants (Cdx-2 and FokI) for allele and genotype frequencies, as well as expression profile in TS individuals versus healthy controls (HC). We performed a genetic association study including 100 TS patients and 116 HC. Genotyping for VDR Cdx-2 G > A (rs11568820) and FokI C > T (rs2228570) was performed using Taqman Genotyping Assays. VDR gene expression was also evaluated in 15 TS and 15 HC, using fluorogenic probes by qPCR. Statistical analyses were performed using nonparametric Mann-Whitney test, with a 5% significance level (p < 0.05) to uncover differences between groups. In addition, we investigated whether shifted VDR mRNA levels were associated with Cdx-2 and FokI variants in TS patients. We detected a significantly higher frequency of T allele (p = 0.006) as well as T/T genotype (p = 0.01) for FokI in TS patients when compared to HC. When assessing VDR expression, we identified a downregulation in TS woman (- 2.84 FC) versus HC (p < 0.001). Furthermore, C/T (11.24 FC; p = 0.01) and T/T (9.20 FC; p = 0.01) FokI genotypes were upregulated when compared to C/C reference genotype. TS patients show different distribution of FokI polymorphism. Downregulation of VDR gene expression may contribute to immunological imbalance in TS.


Improving the therapeutic efficacy of peptides and proteins: a role for polysialic acids.
Peptide and protein drugs are a growing class of therapeutics. However, their effective application in the clinic is compromised by problems, for instance proteolysis in the circulating blood, premature clearance through the kidneys, and immunogenicity. A number of approaches have been used to circumvent such shortcomings including changes in the primary peptide structure, entrapment into nanoparticles (e.g. liposomes) and conjugation to polymers. Polysialylation, namely, conjugation of peptides and proteins to the naturally occurring, biodegradable alpha-(2-->8) linked polysialic acid is a recent development, which promises to be at least as effective as PEGylation but without its potential toxicity. Polysialylation of a range of peptide and protein therapeutics has led to markedly reduced proteolysis, retention of their activity in vivo, prolongation of their half-life in the circulation and reduction in immunogenicity and antigenicity. It is anticipated that polysialylation will lead to a new generation of peptide and protein constructs with significantly improved pharmacological profiles.


The contribution of serum enzymes and carcinoembryonic antigen to the early diagnosis of metastatic colorectal cancer.
The evolution of metastatic colorectal cancer in patients who have had surgical treatment for a primary lesion was studied in relation the progressive changes in the blood levels of carcinembryonic antigen (CEA), to gamma glutamyl transpeptidase (GGT) and routine liver function tests (LFTs). Involvement of the liver could ofter be reliably predicted many weeks in advance of clinical diagnosis while metastases to other sites were less likely to be detected early by this test. The association of the extent of disease with the patterns of biochemical changes is discussed with reference to several illustrative examples.


Harnessing the interparticle J-aggregate induced plasmonic coupling for surface-enhanced Raman scattering.
This report demonstrates that both surface plasmon resonance absorption and surface-enhanced Raman scattering work in concert with plasmonic coupling. The kinetic correlation between the two spectroscopic signatures highlights an effective pathway for harnessing the nanoparticles in solution for a broad range of applications by exploiting the plasmonic and spectroscopic properties.


A service evaluation of patients suspected of Cauda Equina Syndrome referred to accident and emergency departments from a national telephone triage service.
The presentation and management of Cauda Equina Syndrome (CES) remains contentious in medical literature, however it is widely agreed that CES requires emergency medical attention. Physiotherapists will often refer suspected cases to A&E departments for emergency medical review in order to safeguard patient safety. To evaluate the management of patients triaged by a national telephone service referred to A&E for suspected CES. Known escalations (17 cases) from January 2017 to June 2017 from a national telephone triage service referred to A&E with suspected CES were included. 53% of cases with CES symptoms that conformed to the BASS definition of having a requirement for diagnostic imaging were not investigated by MRI scan. The MRI and non-MRI groups had similar group sizes (8 : 9) and mean ages (42.4 years ± 8SD and 45.7 years ± 12SD). Overall, there were more females (11) compared to males (6) referred to A&E. There appears to be significant variability in the management of this cohort of patients once referred to emergency departments. Further guidance is needed as to when watchful waiting is clinically appropriate, and what best practice should be to facilitate safe patient management.


Protease inhibitors prevent the protein kinase A-dependent loss of Rap1 GTPase from the particulate fraction of COS1 cells.
Immunoblotting with a monoclonal Rap1 antibody, we found that elevation of cyclic AMP, with forskolin and IBMX or CPT-cAMP, led to a rapid reduction in the levels of Rap1 protein associated with particulate, nuclear/perinuclear fractions from PC12 and COS1 cells. In contrast, cytoplasmic levels of Rap1 remained constant following cyclic AMP stimulation. To gain independent confirmation that cyclic AMP promoted loss of Rap1 in nuclear/perinuclear fractions we used a polyclonal Rap1 antibody, which gave similar results to the monoclonal antibody. This demonstrated that the loss in Rap1 immunoreactivity was not due to phosphorylation-dependent changes that alter immunorecognition. The reduction in Rap1 levels was blocked by PKA inhibitors and by a Rap1 serine to alanine PKA-phosphorylation site mutant (S180A). Peptide inhibitors of the proteasome, cathespin, and calpain II also inhibited the decrease in Rap1 levels, indicating that proteolytic degradation may contribute to maintaining Rap1 levels in the nuclear/perinuclear fraction of cells.


Integration of biochemical and topographic cues for the formation and spatial distribution of invadosomes in nasopharyngeal epithelial cells.
Invadosomes are invasive protrusions generated by cells which can secrete matrix metalloproteinases for focal digestion of extracellular matrix. They also aid invasive cancer cells in their transmigration through vascular endothelium. However, how the physical and chemical cues in a three-dimensional (3D) system signal the spatial localization of invadosomes remains largely unknown. Here we study the topographic guidance of invadosome formation in invasive nasopharyngeal cells under the stimulation of an inflammatory cytokine, TGF-β1, using engineered gratings with different width and depth. We first report that TGF-β1 can act as an external signal to upregulate the formation of invadosomes with a random distribution on a plane 2D surface. When the cells were seeded on parallel 3D gratings of 5 µm width and 1 µm depth, most of the invadosomes aligned to the edges of the gratings, indicating a topographic cue to the control of invadosome localization. While the number of invadosomes per cell were not upregulated when the cells were seeded on 3D topography, guidance of invadosomes localization to edges is correlated with cell migration directionality on 1 µm deep gratings. Invadosomes preferentially form at edges when the cells move at a lower speed and are guided along narrow gratings. The invadosomes forming at 3D edges also have a longer half-life than those forming on a plane surface. These data suggest that there are integrated biochemical and 3D geometric cues underlying the spatial regulation of invasive structures so as to elicit efficient invasion or metastasis of cells. STATEMENT OF SIGNIFICANCE: Nasopharyngeal cells were integrated with the biological cues and matrix topography to govern the activity and spatial distribution of invadosomes. The biochemical induction of invadosome formation by TGF-β1 in nasopharyngeal cells was observed. When the cells were seeded on parallel 3D gratings, most of the invadosomes aligned to the edges of the gratings due to topographical induced invadosome localization. While the number of invadosomes per cell were not upregulated, guidance of invadosomes localization to edges is correlated with cell migration directionality on 1 µm deep gratings. Invadosomes preferentially form at edges with a higher stability when the cells are guided along narrow gratings. The integrated biochemical and 3D geometric cues could elicit efficient invasion or metastasis of cells.


Doing autoethnographic drugs research: Some notes from the field.
This article is concerned with the processes of doing research with people who use drugs, as someone who has a history of using drugs. It offers a brief introductory review to autoethnographic research methods and how they might be used to enhance the practice of drugs research. Through illustrative examples from the author's own experiences of researching heroin use, the article cautiously makes the case for an increased focus upon our drug-using experiences in drugs research. The positive and negative implications of this for research methods in drug studies are discussed, as well as their potential intersections with drug policy debates.


Two-dimensional Fourier spectrum of QRST integral maps in classification of patients prone to ventricular arrhythmia.
Two-dimensional Fourier spectra of QRST integral maps, obtained by body surface potential mapping, were analyzed to identify subjects prone to ventricular arrhythmia, when they have not been identified by the extrema count method. The diagnostic performance (84.38 percent) of the peak value of the Fourier spectrum as a classifier for subjects prone to ventricular arrhythmia showed an improvement of 3.65 percent over the use of the extrema count method as a classifier.


Reaming versus broaching in cemented hip arthroplasty: mechanical stability in cadaver femora.
We used an experimental hip model to assess the mechanical stability of a hip prosthesis, and compared the femoral medullary canal preparation techniques of reaming and broaching. 15 pairs of cadaveric femora had a simulated replacement, the right femur with a reaming technique and the left with a broaching technique. Both femurs were radiographed to assess component positioning and cement mantle. The femurs were osteotomized 30 days after the procedure. The shear strength of the interface was studied at 4 different levels along an aluminum rod during push-out tests. The overall mean value of the interface failure load was 15% lower with the reaming technique (6.5 kN for the reaming technique versus 7.7 kN for the broaching technique; p = 0.02). Broaching was superior to reaming for the preparation of the femoral canal, and should be used in order to increase primary stability. Further in vivo studies are required to account for factors such as intramedullary pressure, bleeding and surgical variations, which could not be accounted for in our study.


Recurrent facial fibrous histiocytoma.
A case of fibrous histiocytoma required 4 surgical excisions over an 11-year period. The technique of frequent observation and early excision of recurrences is probably the best approach to established histiocytomas. Complete primary excision seems to offer the best chance of definitive cure.


The abnormal cerebellar organization of Weaver and reeler mice does not affect the cellular distribution of three neuronal mRNAs.
We used in situ hybridization of 35S-labeled antisense RNAs to study the cellular distribution of three neuronal mRNAs. We compared the expression of these RNAs in cerebellar Purkinje neurons in wild-type (C57Bl-6J) mice and in two mutants (Weaver and reeler) known to have abnormal cerebellar morphologies. In normal mice, GAD mRNA is present in four sets of neurons in the cerebellar cortex while calbindin mRNA is present only in Purkinje neurons. Proenkephalin mRNA is present in Golgi II neurons as well as in a set of neurons in the deep part of the molecular layer. Despite the dramatic differences in structural organization and inputs of Purkinje neurons in the cerebella of adult Weaver and reeler mice, the expression of these RNAs appears unchanged. These results support the hypothesis that Purkinje cell cytodifferentiation proceeds autonomously after its inception in early embryonic life.


Preparation and in vitro bioactivity of hydroxyapatite/solgel glass biphasic material.
Hydroxyapatite/solgel glass biphasic material has been obtained in order to improve the bioactivity of the hydroxyapatite (OHAp). A mixture of stoichiometric OHAp and the precursor gel of a solgel glass, with nominal composition in mol% CaO-26, SiO2-70, P205-4, has been prepared. The amounts of components used have been selected to obtain a final relationship for OHAp/solgel glass of 60/40 on heating. Two different thermal treatments have been used: (i) 700 degrees C, temperature of solgel glass stabilisation and (ii) 1000 degrees C, lower temperature of hydroxyapatite sintering. The bioactivity of the resulting materials has been examined in vitro by immersion in simulated body fluid at 37 degrees C. The results obtained show that both materials are bioactive. The apatite-like layer grown is greater for the new materials than for the OHAp and the solgel glass themselves.


[Mexiletine, a drug with anti-arrhythmic action. Experimental research on the cardiovascular system].
It was shown experimentally that mexilithene possesses anti-arrhythmic activity with slight depression of sino-carotid baroreceptorial and glomo-carotid and gangliar chemoreceptorial activity and catecholamine uptake. Hypotensive and bradycardizing effects were only noted when high per kg doses were used. The drug did not display vascular alpha- and beta-adrenolytic, anti-muscarinic and anti-histaminic activity.


Could Tailored Chirp Stimuli Benefit Measurement of the Supra-threshold Auditory Brainstem Wave-I Response?
Auditory brainstem responses (ABRs) to broadband clicks are strongly affected by dyssynchrony, or "latency dispersion", of their frequency-specific cochlear contributions. Optimized chirp stimuli, designed to compensate for cochlear dispersion, can afford substantial increase in broadband ABR amplitudes, particularly for the prominent wave-V deflection. Reports on the smaller wave I, however, which may be useful for measuring cochlear synaptopathy, have been mixed. This study aimed to test previous claims that ABR latency dispersion differs between waves I and V, and between males and females, and thus that using wave- and/or sex-tailored chirps may provide more reliable wave-I benefit. Using the derived-band technique, we measured responses from frequency-restricted (one-octave-wide) cochlear regions to energy-matched click and chirp stimuli. The derived-band responses' latencies were used to assess any wave- and/or sex-related dispersion differences across bands, and their amplitudes, to evaluate any within-band dispersion differences. Our results suggest that sex-related dispersion difference within the lowest-frequency cochlear regions (< 1 kHz), where dispersion is generally greatest, may be a predominant driver of the often-reported sex difference in broadband ABR amplitude. At the same time, they showed no systematic dispersion difference between waves I and V. Instead, they suggest that reduced chirp benefit on wave I may arise as a result of chirp-induced desynchronization of on- and off-frequency responses generated at the same cochlear places, and resultant reduction in response contributions from higher-frequency cochlear regions, to which wave I is thought to be particularly sensitive.


Support vector machine-based prediction of MHC-binding peptides.
The use of major histocompatibility complex (MHC) class I binding peptides for immunotherapeutic purposes has shown promising results in recent years. The identification of such peptides mostly starts with predicting MHC-binding peptides, given a protein of interest. An accurate prediction method can reduce the number of peptides that needs to be tested experimentally. This protocol describes in this describes how support vector machines (SVMs) can be used for predicting MHC class I binding peptides. Focus is given on data representation, the concept of cross-validation, and how optimal SVM-specific parameters are obtained.


Case report: Anesthesia management for emergency cesarean section in a patient with dwarfism.
Dwarfism is characterized by short stature. Pregnancy in women with dwarfism is uncommon and cesarean section is generally indicated for delivery. Patients with dwarfism are high-risk population for both general and regional anesthesia, let alone in an emergency surgery. In this case report we present a 27-year-old Chinese puerpera with dwarfism who underwent emergency cesarean section under combined spinal and epidural anesthesia. It is an original case report, which provides instructive significance for anesthesia management especially combined spinal and epidural anesthesia in this rare condition. There was only one former article that reported a puerpera who underwent combined spinal and epidural anesthesia for a selective cesarean section.


Murine germinal center B cells require functional Fms-like tyrosine kinase 3 signaling for IgG1 class-switch recombination.
Switched antibody classes are important for efficient immune responses. Aberrant antibody production to otherwise harmless antigens may result in autoimmunity. The protein kinase fms-like tyrosine kinase 3 receptor (Flt3) has an important role during early B-cell development, but the role of Flt3 in peripheral B cells has not been assessed before. Herein we describe a previously unappreciated role for Flt3 in IgG1 class-switch recombination (CSR) and production. We show that Flt3 is reexpressed on B-cell lymphoma 6(+) germinal center B cells in vivo and following LPS activation of peripheral B cells in vitro. Absence of Flt3 signaling in Flt3 ligand-deficient mice results in impaired IgG1 CSR and accumulation of IgM-secreting plasma cells. On activated B cells, Flt3 is coexpressed and functions in synergy with the common-gamma chain receptor family. B cells from Flt3 ligand-deficient mice have impaired IL-4R signaling, with reduced phosphorylation of signal transducer and activator of transcription (Stat) 6, and demonstrate a failure to initiate CSR to IgG1 with low expression of γ1 germ-line transcripts, resulting in impaired IgG1 production. Thus, functional synergy between Flt3 and IL-4R signaling is critical for Stat-mediated regulation of sterile γ1 germ-line transcripts and CSR to IgG1.


Molecular phylogenetic analysis of the coccidian cephalopod parasites Aggregata octopiana and Aggregata eberthi (Apicomplexa: Aggregatidae) from the NE Atlantic coast using 18S rRNA sequences.
The coccidia genus Aggregata is responsible for intestinal coccidiosis in wild and cultivated cephalopods. Two coccidia species, Aggregata octopiana, (infecting the common octopus Octopus vulgaris), and A. eberthi, (infecting the cuttlefish Sepia officinalis), are identified in European waters. Extensive investigation of their morphology resulted in a redescription of A. octopiana in octopuses from the NE Atlantic Coast (NW Spain) thus clarifying confusing descriptions recorded in the past. The present study sequenced the 18S rRNA gene in A. octopiana and A. eberthi from the NE Atlantic coast in order to assess their taxonomic and phylogenetic status. Phylogenetic analyses revealed conspecific genetic differences (2.5%) in 18S rRNA sequences between A. eberthi from the Ria of Vigo (NW Spain) and the Adriatic Sea. Larger congeneric differences (15.9%) were observed between A. octopiana samples from the same two areas, which suggest the existence of two species. Based on previous morphological evidence, host specificity data, and new molecular phylogenetic analyses, we suggest that A. octopiana from the Ria of Vigo is the valid type species.


Poor adherence to guidelines for long-term oxygen therapy (LTOT) in two Italian university hospitals.
Long-term oxygen therapy (LTOT) improves survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxemia. Adherence to LTOT guidelines is problematic, both because efficacy has been demonstrated only in specific groups of COPD patients, and because it implies high costs. Introduces treatment high costs. The aim of our study was to examine retrospectively the adherence to LTOT guidelines in a sample of medical records of patients prescribed LTOT between January 2005 and December 2006 in two Italian university hospitals (Ferrara and Modena). Out of a total of 191 medical records of patients prescribed LTOT, only 157 had adequate clinical data considering the three main criteria for appropriateness (arterial blood gas and/or pulse oximetry measurement, oxygen administration, smoking status). Out of these 157 patients, only 73 (46.5 %) fulfilled all three criteria recommended by the guidelines. Adherence was higher for LTOT prescribed by pulmonologists compared to internists. This survey showed that the adherence to LTOT guidelines in a sample of medical records of patients prescribed LTOT is poor. Considering the high costs and the impact on the patients' quality of life of LTOT, these results suggest that the adherence should be carefully monitored.


Growth-associated protein-43 immunohistochemical and ultrastructural changes in jaw muscle spindles of the rat following loss of occlusion.
The effects of complete loss of occlusion on the structural and functional status of these muscle spindles were investigated by immunohistochemistry either for protein gene product 9.5 (PGP 9.5) or growth-associated protein-43 (GAP-43) by light and electron microscopy. All the upper molars of 4-week-old Wistar rats were extracted and the erupted portions of the upper and lower incisors of the same animals were cut-off at the level of the interdental papilla every other day. In a control group, immunoreactivity for GAP-43 was positive in the developing annulospiral endings of 2-week-old rats, but was not detected in any of the muscle spindles after 3 weeks of age. At 4 weeks of age, the PGP 9.5 immunostained spindles had well-differentiated annulospiral endings. Ultrastructurally, these afferent endings showed lenticular or circular profiles in cross-sections, and were differentially indented into the intrafusal-fibres. The inner surfaces of the terminals formed rather smooth myoneural junctions, while the outer surfaces were covered only by basal lamina continuous with that of the underlying intrafusal muscle fibres. After the experimental elimination of occlusal contact, GAP-43 immunoreactivity reappeared in some nerve endings of muscle spindles by 3 days, and persisted for at least 28 days. During this period, the afferent-terminals exhibited various fine structural abnormalities such as irregular outlines and invaginated neuromuscular interfaces. Some sensory-terminal (ST) profiles were completely engulfed by intrafusal-fibres. However, GAP-43 expression and ultrastructural alterations became undetectable within a week of the end of incisal cutting and the recovery of incisal-contact. These data indicate that remodelling of nerve terminals in muscle spindles, as assessed by GAP-43 expression and ultrastructural changes, occurs soon after a loss of occlusion, and ceases if incisal-contact is restored. It is concluded that possible changes in jaw muscle function, as well as a sudden loss of proprioceptive sensory input from the periodontal mechanoreceptors of molars and incisors, induce the structural reorganisation of nerve terminations in jaw muscle spindles that is associated with the appearance and disappearance of GAP-43 immunoreactivity.


Extent of Lung Involvement and Serum Cryptococcal Antigen Test in Non-Human Immunodeficiency Virus Adult Patients with Pulmonary Cryptococcosis.
Serum cryptococcal antigen (CrAg) test is the most used noninvasive method to detect cryptococcal infection. However, false-negative CrAg test is not uncommon in clinical practice. Then, the aim of this study was to investigate the factors associated with false-negative CrAg test among non-human immunodeficiency virus (HIV) adult patients with pulmonary cryptococcosis and its clinical features. One hundred and fourteen non-HIV adult patients with pulmonary cryptococcosis, proven by biopsy, were retrospectively reviewed. Finally, 85 patients were enrolled; 56 were CrAg positive (CrAg+ group) and 29 were negative (CrAg- group). It was a cross-sectional study. Then, baseline characteristics, underlying diseases, clinical symptoms, laboratory findings, and chest radiological findings were reviewed and analyzed. Chi-square test was used to analyze categorical variable. Odds ratio (OR) was used to measure correlation. Student's t- test was obtained to analyze continuous variable. No difference in baseline characteristics, underlying diseases, clinical symptoms, and laboratory findings were found between two groups (P > 0.05 in all). Nevertheless, diffuse extent lesion was 82.1% in CrAg+ group and 10.3% in CrAg- group (χ2 = 40.34, P < 0.001; OR = 39.87). Among patients with limited pulmonary involvement, a negative serum CrAg does not preclude the diagnosis of pulmonary cryptococcosis. However, among patients with extensive pulmonary involvement, serum CrAg is a useful diagnostic tool for pulmonary cryptococcosis. Furthermore, we also noticed that the untypical and mild presentations with extensive pulmonary lesion might be the features of pulmonary cryptococcosis, which needs further investigation.


Population-Based Results in the Management of Sinonasal and Ventral Skull Base Malignancies.
Population-based cancer registries allow for data collection on the scale of large populations, outside the limits of a single institution, and facilitate study of rare entities. The SEER database has been used to study more than 7000 cases encompassing a wide variety of relatively rare sinonasal malignant histologies. Clinically useful parameters have been gleaned from these analyses. Important limitations, such as omission of chemotherapy data, surgical approach used, type of radiation administered, and selection and confounding bias, should be considered. Nevertheless, population-based analyses yield readily generalizable and clinically relevant information regarding the management of sinonasal malignancies for the practicing clinician.


Liver resection without blood transfusion.
A personal series of 58 liver resections was reviewed to identify technical factors minimizing blood transfusions. We identified a concept of vascular isolation prior to parenchymal division (VIP) which used singularly or in combination the following methods of vascular control: parenchymal compression, Pringle maneuver, hepatic venous tourniquet, hilar division, hepatic vein division, and Heaney maneuver. VIP significantly decreased the need for transfusion; of 34 patients with VIP only 2 (6 percent) required transfusion, whereas of 24 patients without VIP, 18 (75 percent) required transfusion (p less than 0.001).


Performance characteristics of a fan filter unit (FFU) in mitigating particulate matter levels in a naturally ventilated classroom during haze conditions.
The performance of a low-cost fan filter unit (FFU) in mitigating hazardous particulate matter (PM) levels in a naturally ventilated school classroom is presented. The FFU can be considered as a simplified mechanical ventilation and air-conditioning system without heating and cooling functions. The FFU improves indoor air quality through introduction of cleaned outdoor air to flush out internally generated heat and moisture and reducing infiltration by maintaining indoor pressurization. Indoor particle number concentrations were reduced between 85% and 95%. The particle removal performance (PRFFFU ) of the FFU is determined and incorporated into the augmented façade penetration factor (Paug ). A case-specific recursive dynamic mass balance model is used to characterize the infiltration factor (FINF ), deposition rate (K), and the penetration efficiency (Paug ) from continuously monitored indoor and outdoor mass concentration levels. Computed "Paug " (0.07, 0.09, and 0.13) and "FINF " (0.06, 0.08, and 0.11), respectively, for PM10, PM2.5, and PM1 suggest that exposure to PM was significantly reduced indoors. The effectiveness of the FFU for reduced "FINF " and "Paug " may be attributed to its superior filtration, dilution, and exfiltration mechanisms. In comparison with alternative PM mitigation solutions, the FFU is effective, affordable, and sustainable.


How are early maladaptive schemas and DSM-5 personality traits associated with the severity of binge eating?
The present study aimed to (a) assess and compare personological traits and early maladaptive schemas (EMSs) of obese women with and without binge eating disorder (BED) and (b) identify the variables associated with the binge severity. One hundred women (55 BED-obese and 45 non-BED-obese) completed psychopathological and personological self-report questionnaires. A forward stepwise linear regression analysis was performed to assess variables associated with binge eating severity. Not only psychopathological but also personological differences were evident between BED and non-BED-obese women. BED severity was significantly associated with depressivity, emotional deprivation, and defectiveness. Our preliminary findings suggest that BED patients exhibit some EMSs that could be linked to the construct of emotional neglect and specific personological traits closely related to depressive dimensions, emotional lability, and impulsivity. In particular, binge severity is associated with the pervasiveness of depressogenic cognitive schemas, as well as those of emotional deprivation and defectiveness.


A study on the chemical stability of cholesterol-lowering drugs in concomitant simple suspensions with magnesium oxide.
Difficulty in taking solid medicines is a common issue particularly for the elderly because of a decline in swallowing function, also known as dysphagia. For patients with such a dysfunction, a simple suspension method, in which solid medicines are disintegrated and suspended using warm water, has been developed and widely used in Japanese clinical settings. However, there is little information on drug stability in the simple co-suspension of multiple formulations especially including acidic or alkaline ones. In this study, the chemical stability of typical cholesterol-lowering drugs was investigated in a simple co-suspension with alkaline magnesium oxide (MgO) which is frequently used as a laxative or antacid in Japan. A cholesterol-lowering drug (one tablet) was soaked with or without MgO in warm water (55°C), and the vessel was left at room temperature for 10 min or 5 h. The suspensions prepared were then analyzed by high-performance liquid chromatography. Degradation products were analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry for the structural elucidation. In the simple co-suspension with MgO, no significant degradation was observed for atorvastatin or pravastatin, while a significant decrease of the recovery from the co-suspension was observed for rosuvastatin after 5 h. On the other hand, simvastatin and ezetimibe co-suspended with MgO were partially degraded to simvastatin acid and a pyran compound, respectively. A simple co-suspension with MgO is feasible for atorvastatin, pravastatin, and rosuvastatin, although the rosuvastatin tablet should not be left soaking for a long time. Further it is inadvisable to suspend simvastatin or ezetimibe together with MgO because of their partial degradation.


The diagnosis of post-cholecystectomy cystic duct fistula utilizing endoscopic retrograde cholangiopancreatography.
A patient developed persistent right upper quadrant pain and tenderness following cholecystectomy. An endoscopic retrograde cholangiopancreatogram showed leakage of bile through the cystic duct remnant into the subhepatic space. The endoscopic retrograde cholangiopancreatographic findings (ERCP) are described.


Concurrent collagenous colitis and multiple ileal carcinoids.
A case of collagenous colitis in a patient with ileal carcinoid is described. Considerable fibrofatty thickening of the small bowel mesentery was present. The association of these findings appears to be unprecedented. Further observations are required to ascertain that collagenous colitis is one of the protean manifestations of carcinoid tumor.


Nordic walking training and nutritional supplementation in pre-frail older Indians: an open-labelled experimental pre-test and post-test pilot study to develop intervention model.
Identifying and treating people in a pre-frail state may be an effective way to prevent or delay frailty and preserve their functional capacity. This study aimed to assess the efficacy of, and compliance with, a 12 week individualized nutritional supplementation (INS) and Nordic walking (NW) program in pre-frail older Indians. The primary measure is physical performance, as indicated by Fried's Frailty scale. Other measures include: cognition, as indicated by the Hindi Mental Status Examination; mood, by the Geriatric Depression Scale; and nutritional status, by the Mini Nutritional Assessment. This is an open-labeled experimental pre-test and post-test study, which took place from October 2012 to December 2014. The study was approved by Institute Ethics committee (IEC/NP-350/2012/RP-26/2012) at the All India Institute of Medical Sciences (AIIMS), New Delhi. Participants were sixty-six pre-frail elderly, who were randomly allocated into three subgroups, namely: A (NW only), B (INS only), and C (NW and INS). One-way ANOVA was used to statistically assess differences in baseline characteristics for quantitative variables, with the Chi-Square/Fischer exact test utilized for qualitative variables. Paired t-tests were used to assess pre and post intervention difference within the group for quantitative variables, with McNemar's Chi-Square test used for qualitative variables. Kruskal Wallis test was used to assess significant intervention effects among the groups. A p-value < 0.05 was considered as statistically significant. There was significant effect of intervention in gait speed in group A (p = 0.001) and C (p = 0.002), but not in group B (p = 0.926). While there was no significant change in grip strength in Group A (p = 0.488) and B (p = 0.852), a statistically significant increase was observed in group C (p = 0.013). Mood significantly improved in group B (p = 0.025) and C (p = 0.021). No significant difference was noted in cognitive status across groups. Following the interventions, a total of 18.18% of pre-frail participants were classified as non-frail. Combining NW and INS provides a simple, pragmatic intervention with efficacy in the management of functionally vulnerable older adults, and allows their maintained independence. Future studies should replicate this readily applicable intervention in a larger cohort with a longer follow-up period. Clinical Trial Registry-India CTRI/2016/05/006937 [Registered on: 16/05/2016]; Trial was Registered Retrospectively.


Effect of CNT over structural properties of SAPO-34 in MTO process: Experimental and molecular simulation studies.
The hierarchical silicoaluminophosphate (SAPO-34) catalyst was synthesized using the mixtures of diethylamine (D) and butylamine (B) as a structure-directing agent (SDA), and carbon nanotube (CNT) as a secondary template in the hydrothermal method. The catalysts were characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), N2 physisorption, and temperature-programmed desorption of ammonia (NH3-TPD) techniques and evaluated for the catalytic activity in the Methanol to Olefins (MTO) process. The results showed that the use of CNT as the secondary template improved the hierarchical structure of SAPO-34 due to increasing the external surface area and mesoporosity and decreasing the particle size and as a result, made better the performance of the prepared SAPO-34 zeolite in the MTO process. Among all the prepared samples, the CNT-B-D catalyst synthesized by mixing three templates displayed the highest ethylene and propylene selectivity of 49% and 34%, respectively. Also, using CNT in the synthesis of samples increased the catalytic stability. In addition, pure, binary, and ternary adsorption isotherms and diffusivities of the main products and reactants over the SAPO-34 were investigated by theoretical measurements, because sorption and diffusion affect the catalyst stability and C2-C3 selectivity in the MTO reaction. The higher diffusion rate of ethylene leads to following the aromatic-based cycle in the MTO process.


Renal tumor in developing countries: 142 cases from a single institution at Shanghai, China.
The clinical management of children with renal tumors including Wilms' tumor, clear cell sarcoma, rhabdoid tumor and other renal tumors in our center was designed according to the National Wilms' Tumor Study Group protocols. A total of 142 consecutive patients who had been diagnosed as having renal tumors at Shanghai Children's Medical Center were reviewed retrospectively in the period of December 1998 and September 2012. Diagnosis and treatment were decided by a multidisciplinary team including oncologists, surgeons, pathologists and sub-specialized radiologists. The median age of the patients at the time of diagnosis was 27 months. The tumor stages of the patients were as follows: stage I 24.6%, stage II 23.2%, stage III 32.3%, stage IV 14.1%, and stage V 5.6%. Favorable histology was diagnosed in 80.3%, anaplasia in 4.2%, clear cell sarcoma in 9.8%, rhabdoid tumor in 4.9%, and other renal tumors in 0.7% of the patients. The event-free and overall 5-year survival rates were 80% and 83%, respectively. Tumor relapse and progress was seen in 25 patients (17.6%). The median relapse time was 6 months (range: 2-37 months). Seven relapsing patients were retreated and four of them got second complete remission (three in stage II, one in stage I). A multi-disciplinary team work model is feasible in developing countries, and the renal tumors protocols basically from developed countries are safe in developing countries.


The pathogenesis of turkey origin reoviruses in turkeys and chickens.
Avian reoviruses that have been shown to be genetically distinct from chicken origin reoviruses were isolated from commercial turkey flocks in the Southeastern US and Texas that were experiencing enteritis. The pathogenesis of these turkey origin reoviruses (TRVs) was evaluated in commercial and specific pathogen free (SPF) turkey poults and SPF chickens. Mortality, clinical disease, gross lesions, microscopic lesions and body weights were observed. TRVs replicated poorly and did not cause disease in chickens. Clinical disease induced by the TRV isolates, characterized by diarrhoea and depression, was mild in both SPF and commercial origin poults. Several TRV isolates caused moderate to severe bursal atrophy in poults. Additionally, each of the TRV isolates caused significant body weight decreases in SPF and/or commercial poults as compared with sham inoculates. Molecular characterization of the isolates revealed that the TRVs and chicken origin reoviruses had identical electropherotype profiles.


Anatomical meningo-orbital band evaluation and clinical implications: a cadaveric dissection study.
The meningo-orbital band (MOB) is a dural structure which runs around the superior orbital fissure (SOF) tethering the frontotemporal basal dura to the periorbita, through the SOF. MOB division is important to expose and remove the anterior clinoid process, to access to proximal carotid artery and cavernous sinus area. The aim of this study was to measure how the MOB could be safely incised without cranial nerves and cavernous sinus injuries. Anatomical dissections and extradural exposure of the anterior clinoid process was performed on 20 cadavers (40 sides). Measurement of the MOB thickness was performed before its incision, after dura propria dissection, and retraction off the inner cavernous membrane, to expose the cranial nerves. We analyzed 20 cadaveric formalin-fixed heads injected with colored silicone, 11 man and 9 women of Caucasian race. The average length of a safe incision of the MOB was 10.6±1.1 mm on the right side, and 10.65±1.09 mm on the left side. In our study the average length of a safe incision of the MOB was 10.6±1.1 mm. Thus, the incision length of the MOB should not exceed 9 mm; the peeling of the anterior cavernous sinus and of the SOF, dissecting the two layers of the dura throughout the incision of the MOB, is a useful technique to avoid cranial nerves and cavernous sinus lesions.


Combination of Quadruple Antegrade and Retrograde In Situ Stent-Graft Laser Fenestration in the Management of a Complex Abdominal Aortic Aneurysm.
We report a case of juxtarenal abdominal aortic aneurysm-anatomically unsuitable for conventional endovascular repair because of narrow distal aorta-successfully treated by endovascular repair facilitated by in situ laser fenestration. An aortic stent graft was inserted to exclude a juxtarenal aneurysm: under image fusion guidance, antegrade in situ laser fenestration allowed to perfuse superior mesenteric artery and both renal arteries. After complementary insertion of an extended aortouni-iliac stent graft, retrograde in situ laser fenestration was performed to perfuse the contralateral left iliac artery, in order to overcome a narrow distal aorta. Postoperative course was uneventful. Six month's CT showed an excluded aneurysm, patency of the inserted stents and the absence of endoleak. In situ laser fenestration seems to be an effective solution for endovascular therapy of complex juxtarenal aneurysms. In this case of narrow distal aorta it was a suitable alternative to overcome endovascular aneurysm repair anatomical restrictions and to prevent other additional open surgical interventions.


Data on nephroprotective effect of all-trans retinoic acid in early diabetic nephropathy.
Data showed in this report are related to the research article entitled "All-trans retinoic acid ameliorates inflammatory response mediated by TLR4/NF-кB during the initiation of diabetic nephropathy" by Sierra-Mondragon et al. (2018) [1]. Diabetic nephropathy (DN) has become the main cause of renal failure. Inflammatory molecules such as cytokines, chemokines and growth factors play a key role in DN-induced renal injury Pichler et al. (2016) [2]. Results illustrate the effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the renal alterations related to diabetes, among them glomerular and tubular dysfunction, and its effect on renal inflammation in different nephron segments: glomeruli, proximal and distal tubules in an initial stage of DN. Data were obtained by physical-biochemical measurements and Western blot assays performed on isolated glomeruli, proximal and distal tubules from rat kidneys.


Metabolomic profiling of M. speciosa champ at different growth stages.
Millettia speciosa Champ (M. speciosa) is an edible food and folk medicine and extracts from its roots exhibit a hepatoprotective effect. However, its metabolic growth process and the best harvest time have not been reported. This study systematically evaluated the metabolomic profiling of M. speciosa root extracts at different growth stages through the UPLC-Q-TOF-MS, nuclear magnetic resonance (NMR) and An orthogonal partial least squares-discriminant analysis (OPLS-DA). The results revealed there were significant differences among extracts from six ages of M. speciosa, and 110 compounds were identified. Pharmacological studies showed that 5-year and 20-year old M. speciosa roots may exhibit higher fat-lowering effects, while 5-year-old (M.s-5Y) showed better hepatoprotective activity in high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) mice. Hence, our study suggested that M.s-5Y may have potent efficacy in ameliorating NAFLD, which might be useful in determining the optimum time to harvest M. speciosa.


[Evaluation of the antibacterial effect of passive nanoimpregnation of tooth root dentin by real-time PCR].
Assessment of antibacterial properties of a new intracanal paste based on calcium hydroxocuprate (CHC) and silver nanoparticles hydrosol for passive root impregnation. The study included 55 teeth with 69 root canals belonging patients with chronic apical periodontitis. The main group, including 44 root canals, was filled with a new paste based on CHC and silver nanoparticles for 7 days after preparation and irrigation. In the control group, 25 root canals were sealed with an aqueous paste of calcium hydroxide for 14 days. The presence of the endodontic microorganisms was evaluated by real-time PCR. Further analysis showed that the amount of the DNA, common for P. gingivalis, T. forsythia and T. denticola, after treatment was less in the main group, where the new paste was applied. These results were significant at the p=0.05 level (p=0.005, p=0.006, p=0.003 according to each mentioned bacterial sample). No significant differences were found between the groups in the number of genome equivalents specific for P. intermedia and F. nucleatum (p=0.543, p=0.554). These findings suggest that the new method of passive root impregnation with the CHC and silver nanoparticles paste may be an effective method for the treatment of chronical apical periodontitis.


Cognitive and anatomic double dissociation in the representation of concrete and abstract words in semantic variant and behavioral variant frontotemporal degeneration.
We examine the anatomic basis for abstract and concrete lexical representations in semantic memory by assessing patients with focal neurodegenerative disease. Prior evidence from healthy adult studies suggests that there may be an anatomical dissociation between abstract and concrete representations: abstract words more strongly activate the left inferior frontal gyrus relative to concrete words, while concrete words more strongly activate left anterior-inferior temporal regions. However, this double dissociation has not been directly examined. We test this dissociation in two patient groups with focal cortical atrophy in each of these regions, the behavioral variant of Frontotemporal Degeneration (bvFTD) and the semantic variant of Primary Progressive Aphasia (svPPA). We administered an associativity judgment task for abstract and concrete words, where subjects select which of two words is best associated with a given target word. Both bvFTD and svPPA patients were significantly impaired in their overall performance compared to controls. While controls treated concrete and abstract words equally, we found a category-specific double dissociation in patients' judgments: bvFTD patients showed a concreteness effect (CE), with significantly worse performance for abstract compared to concrete words, while svPPA patients showed reversal of the CE, with significantly worse performance for concrete over abstract words. Regression analyses also revealed an anatomic double dissociation: The CE is associated with inferior frontal atrophy in bvFTD, while reversal of the CE is associated with left anterior-inferior temporal atrophy in svPPA. These results support a cognitive and anatomic model of semantic memory organization where abstract and concrete representations are supported by dissociable neuroanatomic substrates.


Effect of phytochemical-filled microcapsules with antifungal activity on material properties and dimensional accuracy of denture base resin for three-dimensional printing.
Studies on the material properties and dimensional accuracy of three-dimensionally (3D) printed denture base containing microcapsules with antifungal phytochemicals are lacking. Two types of phytochemicals (phytoncide A and B) with antifungal activity were microencapsulated. The 3D-printed denture base specimens with minimum and maximum effective concentrations of microcapsules (6 and 8 wt% for phytoncide A; 15 and 25 wt% for phytoncide B) were prepared. The morphological changes of C. albicans on 3D-printed denture base with microcapsules was microscopically observed. The degree of conversion of 3D-printed denture base with microcapsules investigated. The microhardness and flexural strength values were also measured to evaluate the mechanical properties of 3D-printed denture bases. The dimensional accuracy (trueness) of the specimens with microcapsules was measured as root-mean-square values (RMS) for the whole, upper, and side surfaces of the specimens as well as their total height. For the degree of conversion, microhardness, and flexural strength values, the Kruskal-Wallis analysis and a post-hoc comparison using Mann-Whitney U test was performed. For the analysis of trueness (RMS), the one-way analysis of variance and a post-hoc comparison using Tukey's method was conducted (α = 0.05). At both maximum and minimum effective concentrations of microcapsules, cell surface disruption or membrane breakdown of fungal cells were observed in the specimens. The groups with microcapsules (both phytoncide A- and B-filled) showed significantly lower microhardness and elastic modulus values than the control group (all, P = 0.001). For the trueness, all the RMS values of the whole, upper, and side surfaces of the specimens with microcapsules were less than 100 µm, although significantly higher than those without (all, P = 0.001). The mean flexural strength values of the groups with phytoncide A-filled microcapsule were higher than 65 MPa, not statistically different from that of the control group (all, P > 0.05). However, the groups with phytoncide B-filled microcapsules showed significantly lower values than the control (all, P = 0.001). Within the limitations of this in-vitro study, the 3D-printed denture base containing 6 wt% of phytoncide A-filled microcapsules was clinically acceptable in terms of antifungal activity, dimensional accuracy, and flexural strength.


Renal adenocarcinoma metastasizing to contralateral renal pelvis.
Ureteric metastases from renal adenocarcinoma are uncommon and occur predominantly in the residual ipsilateral ureteric stump. We report on a patient with renal adenocarcinoma metastasizing to the contralateral renal pelvis and the clinical problems involved.


BRCA2 germline mutation in a woman with uterine serous papillary carcinoma--case report.
Recently, a high incidence of BRCA1 cancer predisposing mutation was described among patients with Uterine Serous Papillary Carcinoma (USPC). A BRCA2 germline mutation in a USPC patient has never been reported. A 65-year-old Ashkenazi Jewish woman was diagnosed with USPC Stage III A. The patient family history included a mother with ovarian carcinoma, a maternal aunt who had breast carcinoma that was diagnosed at an early age, an additional maternal aunt who suffered from gastric carcinoma, and the patient's sister who had duodenal carcinoma. The patient was found to be a carrier of the germline BRCA2 cancer predisposing mutation (6174delT). We report the first case of a BRCA2 mutation in a USPC patient. A strong family history of breast and ovarian cancer with the presence of the BRCA2 germline mutation is an additional hint for the possible association between BRCA cancer predisposing mutations and USPC.


Association of Taxane Type With Patient-Reported Chemotherapy-Induced Peripheral Neuropathy Among Patients With Breast Cancer.
Understanding the detailed symptom spectrum of chemotherapy-induced peripheral neuropathy (CIPN) could facilitate shared decision-making and promote early intervention. To compare the symptom spectrum of patient-reported CIPN associated with nab-paclitaxel, paclitaxel, and docetaxel treatments among patients with breast cancer. This prospective cohort study was conducted at 9 medical centers across China from 2019 to 2021. Participants included hospitalized women diagnosed with invasive breast cancer, assessed with overlap propensity score weighting. Data were analyzed from from December 2021 to May 2022. Treatment with nab-paclitaxel-, paclitaxel-, or docetaxel-based regimens. Patient-reported CIPN on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire: CIPN 20-item instruments, consisting of sensory, motor, and autonomic scales. Multiple regression models were adjusted for baseline patient, tumor, and treatment characteristics. Of 1234 participants, the mean (SD) age was 50.9 (10.4) years, and 295 patients (23.9%) received nab-paclitaxel, 514 patients (41.7%) received paclitaxel, and 425 patients (34.4%) received docetaxel. The nab-paclitaxel group mostly reported numbness in hands or feet related to sensory symptoms (83 patients [81.4%]), while the paclitaxel and docetaxel groups reported mainly motor (eg, weakness in legs: 60 patients [47.2%] in the paclitaxel group; 52 patients [44.4%] in the docetaxel group) and autonomic (eg, blurred vision: 58 patients [45.7%] in the paclitaxel group; 51 patients [43.6%] in the docetaxel group) symptoms. Patients reported motor symptoms earlier than sensory abnormalities, with a median of 0.4 (95% CI, 0.4-2.3) weeks in the nab-paclitaxel group, 2.7 (95% CI, 1.7-3.4) weeks in the paclitaxel group, and 5.6 (95% CI, 3.1-6.1) weeks in the docetaxel group. After overlap propensity score weighting and compared with the nab-paclitaxel group, the risks of patient-reported CIPN were lower in the paclitaxel (hazard ratio [HR], 0.59 [95% CI, 0.41-0.87]; P = .008) and the docetaxel (HR, 0.65 [95% CI, 0.45-0.94]; P = .02) groups. Similarly, patients who received paclitaxel (HR, 0.44 [95% CI, 0.30-0.64]; P < .001) or docetaxel (HR, 0.52 [95% CI, 0.36-0.75]; P < .001) reported less sensory discomfort compared with those who received nab-paclitaxel. However, the risk of patients in the paclitaxel or docetaxel groups reporting motor (paclitaxel: HR, 0.76 [95% CI, 0.52-1.11]; P = .15; docetaxel: HR, 0.69 [95% CI, 0.47-1.01]; P = .05) and/or autonomic (paclitaxel: HR, 1.00 [95% CI, 0.68-1.49]; P = .98; docetaxel: HR, 0.88 [95% CI, 0.59-1.30]; P = .52) symptoms was not lower than that in the nab-paclitaxel group. In this cohort study of women with invasive breast cancer, nab-paclitaxel was associated with more severe CIPN than either paclitaxel or docetaxel. In addition to sensory symptoms, the risk of motor and autonomic abnormalities was not low among these 3 taxanes, and patients-reported motor symptoms even earlier than sensory symptoms. These findings may facilitate early detection and intervention for CIPN in taxane treatments for breast cancer.


Optimization of extraction process of 15 bioactive compounds from Qing Fei Yi Huo tablets using response surface methodology.
Qing Fei Yi Huo tablets (QFYHT) can relieve the clinical symptoms of acute bronchitis, and is widely prescribed in China. However, the quality standard of QFTHT lacks quantitative assessment. Therefore, it is crucial to develop an effective method for the extraction and analyses of its bioactive components.This study aimed to optimize the ultrasonic extraction of QFYHT and establish a method for the simultaneous quantification of 15 components. Box-Behnken Design (BBD) experiment was employed with three factors (solvent volume, extraction time and ultrasonic power) to optimize the extraction conditions, and the total content of 15 components was measured by high-performance liquid chromatography-diode array detector (HPLC-DAD) method. The total extracted content of 15 components was the highest when 100% methanol was used as the solvent, and the solvent volume was 22 mL, extraction time was 30 min and ultrasonic power was 350 w. The 15 components showed a good linear relationship (r ≥ 0.9998) within a concentration range. The precision, stability and repeatability of this method were satisfactory, and the average recovery rates ranged from 98.08% ∼ 102.87%. These findings demonstrate that optimization of extraction conditions by RSM can significantly improve the ultrasonic extraction rate of the 15 bioactive components of QFYHT. The quantification method is simple, accurate, reliable and practical, and can provide reference for improving the quality control of QFYHT.


Women's views of the climacteric at the time of low menopausal hormone use, Estonia 1998.
This study examined women's opinions about the climacteric and hormone therapy (HT) after menopause and compared women's and physicians' opinions in a country of low-HT use. In 1998, a postal questionnaire was sent to a random sample of 2000 Estonian 45-64-year-old women; 69% (n=1312) responded. In 1999, a postal questionnaire was sent to a random sample of 500 Estonian gynaecologists and general practitioners; 68% (n=342) responded. Mean age at menopause was 49.8 years (S.D. 4.0), and there was no difference by socioeconomic classes or by age in self-rated health. Ten percent of women reported having used HT, with 3% currently using it. Most women reported some symptoms, with vasomotor symptoms more frequently reported by 50-54 years old; women most often reported tiredness (48%). Half of the women but under a fifth of physicians considered the climacteric a normal phase of life. Women's awareness about HT was low and about half had no opinion on its health effects. Half of the women had visited a gynaecologist, older women less so. Women with contacts with health care were more aware of HT. Women reported symptoms by age-group as similarly found in high-HT use countries and it verifies that many symptoms experienced were not due to menopause. As in other low-HT use countries, women were unfamiliar with HT and their attitudes were traditional, although physicians' attitudes were more positive. Estonian women seemed to have escaped the period of the preventive use of HT.


Acceptance of contraceptives among women who had an unsafe abortion in Dar es Salaam.
To assess the need for post-abortion contraception and to determine if women who had an unsafe abortion will use a contraceptive method to avoid repeated unwanted pregnancies and STDs/HIV. Women attending Temeke Municipal Hospital, Dar es Salaam, after an unsafe abortion or an induced abortion performed at the hospital (n=788) were counselled about contraception and the risk of contracting STDs/HIV. A free ward-based contraceptive service was offered and the women were asked to return for follow-up. Participants (90%) accepted the post-abortion contraceptive service. Of these, 86% stated they were still using contraception 1-6 months after discharge. Initially, 55% of the women accepted to use condoms either alone or as part of double protection. After 1-6 months this proportion had dropped to 18%. Single women were significantly more likely to use condoms. High-quality contraceptive service counselling can induce women to use contraception after having had an unsafe abortion. The results of our study are encouraging and should be used to convince policy makers of the need to implement such services at municipal level to reduce the number of repeated unsafe abortions.


Acute effects of neuromuscular electrical stimulation on cortical dynamics and reflex activation.
Superimposing neuromuscular electrical stimulation (NMES) on voluntary muscle contractions has shown the potential to improve motor performance even more than voluntary exercise alone. Nevertheless, the neurophysiological and neurocognitive mechanisms underlying this technique are still unclear. The aim of this study was to investigate the acute responses in spinal excitability and brain activity following three conditions: NMES superimposed on isometric contractions (NMES + ISO), passive NMES, and voluntary isometric contractions (ISO). Each condition involved 15 intermittent ankle plantar-flexions at submaximal level. Before and after each condition, tibial nerve stimulation was used to elicit H-reflexes, which represent a measure of spinal excitability, and somatosensory evoked potentials (SEPs), which index the activity of subcortical and cortical somatosensory areas. H-reflex amplitudes increased after NMES + ISO and decreased after passive NMES compared with baseline values, whereas they remained unaltered after ISO. Subcortical lemniscal activity remained unaltered after the three conditions. Activity in both primary and secondary somatosensory cortices (S1 and S2) increased after NMES + ISO and decreased after the ISO condition, whereas no differences emerged after NMES. At later stages of S2 processing, ISO induced no changes in cortical activity, which, conversely, increased after NMES and NMES + ISO. These findings indicate that the beneficial effects of NMES may be mediated by potentiation of the reflex pathways at the spinal level. At the brain level, peripheral input representation in the brain stem was not influenced by the experimental conditions, which, conversely, altered cortical activity by affecting synaptic efficiency through the somatosensory pathway.NEW & NOTEWORTHY Neuromuscular electrical stimulation superimposed on voluntary contractions (NMES+) is effective to improve motor performance in several populations. Here, we investigated the changes in cortical activation and reflex response following three acute conditions, including NMES+. Our results show that NMES+ has a greater excitatory effect at both spinal and cortical levels compared with passive stimulation and voluntary exercise alone. These results open up original perspectives for the implementation of NMES+ in neurorehabilitation and training environments.


The activated factor X-antithrombin III reaction rate: a measure of the increased thrombotic tendency induced by estrogen-containing oral contraceptives in rabbits.
Estrogen-containing compounds are thrombogenic in man. The extent of thrombosis is dose-related, but a measure of this thrombogenicity is not currently available. Evidence is presented, using an animal model of venous thrombosis, that impaired Xa inhibitory activity (the rate of reaction between Xa and antithrombin III) correlates with the development of thrombosis initiated by thrombin in rabbits receiving an oral contraceptive compound. The responses in the clotting assay and in the extent of thrombosis are dose-related. The hypercoagulable state induced by oral contraceptives can be completely reversed by trace amounts of heparin.


Black Phosphorus-New Nanostructured Material for Humidity Sensors: Achievements and Limitations.
The prospects of using nanostructured black phosphorus for the development of humidity sensors are considered. It was shown that black phosphorus has a set of parameters that distinguish it from other two-dimensional (2D) materials such as graphene, silicone, and dichalcogenides. At the same time, an analysis of shortcomings, limiting the use of black phosphorus as a humidity sensitive material in devices aimed for market of humidity sensors, was also conducted.


Perspectives on antiviral drug development.
The 21st International Conference on Antiviral Research provided novel insights and approaches to drug discovery across a wide array of virologic fields. Topics ranged from the chemical synthesis of new compounds against the human immunodeficiency virus (HIV) to the long-term use of established drugs against influenza. A session on novel targets for HIV therapy focused on the importance of Apobec3G, LEDGF/p75 and other cellular factors as innovative ways to control infection. New targets for hepatitis B and C viruses were surveyed. There were also discussions as to how the development of new antiviral compounds might lead to novel mechanisms of drug resistance by HIV, herpesviruses and hepatitis viruses. These covered such issues as transmission dynamics, viral fitness, the acquisition of differential resistance patterns depending on viral subtype, and clinical outcomes. Drug efficacy, toxicity, patient adherence, treatment interruption and the importance of generic drugs in resource-poor settings were also extensively discussed. These topics will all play a pivotal role in drug development and the management of viral infections in the years to come.


Evaluation of three alternatives cost-effective culture media for Mycobacterium tuberculosis detection and drug susceptibility determination using the microscopic observation drug susceptibility (MODS) assay.
Tuberculosis phenotypic detection assays are commonly used in low-resource countries. Therefore, reliable detection methods are crucial for early diagnosis and treatment. The microscopic observation drug susceptibility (MODS) assay is a culture-based test to detect Mycobacterium tuberculosis and characterize drug resistance in 7-10 days directly from sputum. The use of MODS is limited by the availability of supplies necessary for preparing the enriched culture. In this study, we evaluated three dry culture media that are easier to produce and cheaper than the standard one used in MODS [1]: an unsterilized powder-based mixed (Boldú et al., 2007) [2], a sterile-lyophilized medium, and (Sengstake et al., 2017) [3] an irradiated powder-based mixed. Mycobacterial growth and drug susceptibility were evaluated for rifampin, isoniazid, and pyrazinamide (PZA). The alternative cultures were evaluated using 282 sputum samples with positive acid-fast smears. No significant differences were observed in the positivity test rates. The positivity time showed high correlations (Rho) of 0.925, 0.889, and 0.866 between each of the three alternative media and the standard. Susceptibility testing for MDR and PZA showed an excellent concordance of 1 compared to the reference test. These results demonstrate that dry culture media are appropriate and advantageous for use in MODS in low-resource settings.


Studies on the morphologic alterations of axonal membraneous organelles in neurofilamentous neuropathies.
Alterations in the membraneous organelles were studied in two experimental neuropathies: 2,5-hexanedione (2,5-HD) and beta,beta'-iminodiproprionitrile (IDPN), both of which exhibit massive neurofilamentous accumulation. The membranous organelles were stained using the diaminobenzidine potassium ferrocyanide (DPF) method. In 2,5-HD, where there is a progressive impairment of fast axoplasmic transport, studies of the smooth endoplasmic reticulum (SER) revealed a fragmentation and disruption of the continuity of the longitudinally oriented interconnecting tubules and a significant increase in the number of free vesicles. In IDPN, where studies of fast transport have been normal, the longitudinal orientation of the smooth SER tubules was not disturbed although channels of longitudinally oriented tubules of SER were clustered with microtubules and mitochondria. This study suggests that in 2,5-HD the accumulation of vesicles in association with fragmentation and disorganization of the SER is one of the morphologic correlates of the impaired fast anterograde transport system.


Systematic topology optimization of solid-solid phononic crystals for multiple separate band-gaps with different polarizations.
Phononic crystals (PnCs) have attracted considerable interest due to their unique and outstanding band-gap characteristics. In many applications, it is desirable to have a unit cell with specific band-gaps. The distribution of elastic materials within a unit cell has significant effect on the band-gaps, which is extremely difficult to be determined without systematic synthesis method. In this paper, topology optimization techniques are utilized to obtain two-dimensional (2D) square lattice PnCs with maximized relative band-gaps between multiple consecutive bands. The optimization follows two-stage design process using Genetic algorithms (GAs) in combination with finite element method (FEM). Three numerical examples are given to optimize 2D steel/epoxy PnCs in one-eighth symmetry for coupled mode, shear mode and mixed mode respectively. The results show that the optimized PnCs with different band-gaps, which can easily be found by the developed method, have different materials layout, and the PnCs with the lowest order band-gap are simple lattice and have the highest value of application in noise reduction and vibration isolation. Some optimized PnCs with higher order band-gaps have the same lattice as those with the lowest order band-gap, and whose absolute band-gaps are inversely proportional to the minimum feature size of primitive cells.


Can ankle imbalance be a risk factor for tensor fascia lata muscle weakness?
Risk factors that can determine knee and ankle injuries have been investigated and causes are probably multifactorial. A possible explanation could be related by the temporary inhibition of muscular control following an alteration of proprioceptive regulation due to the ankle imbalance pathology. The purpose of our study was to validate a new experimental set up to quantify two kinesiologic procedures (Shock Absorber Test (SAT) and Kendall and Kendall's Procedure (KKP)) to verify if a subtalus stimulus in an ankle with imbalance can induce a non-appropriate response of controlateral tensor fascia lata muscle (TFL). Fifteen male soccer players with ankle imbalance (AIG) and 14 healthy (CG) were tested after (TEST) before (NO-TEST) a manual percussion in subtalus joint (SAT). A new tailor-made device equipped with a load cell was used to quantify TFL's strength activation in standardized positions. Two trials for each subject were performed, separated by at least one 4-min resting interval. In NO-TEST conditions both AIG and CG showed a progressive adaptation of the subject to the force imposed by operator. No reduction in mean force, mean peak force, and muscle force duration (p>0.5). AIG presented significant differences (mean difference 0.92+/-0.46 s; p=0.000) in muscle force duration in TEST conditions. Our results indicated that "wrong" proprioceptive stimuli coming from the subtalus joint in AIG might induce inhibition in terms of duration of TFL muscle altering the knee stability. This kinesiological evaluation might be useful to prevent ankle and knee injuries.


[Juvenile xanthogranuloma of the corneoscleral limbus: report of a patient and review of the literature].
Juvenile xanthogranuloma is an uncommon benign skin disease primarily affecting infants and young children. Ocular involvement is rare and most often affecting the iris. Isolated xanthogranulomas of the corneoscleral limbus are reported in the literature in only a few patients. A 10-year-old boy presented in October 1993 with a yellow solid tumor at the limbus of his left eye. The other ocular and extraocular structures were normal. Furthermore, he showed a preauricular nodular skin lesion. We suspected a dermoid of the corneoscleral limbus and performed an excision of the tumor. Histological examination revealed a juvenile xanthogranuloma. The tumor had regrown to its original size 2 months after excision. Treatment with topical corticosteroids resulted in an acceptable but incomplete regression of the tumor. Juvenile Xanthogranulomas of the corneoscleral limbus are rare tumors. The majority of previously reported cases showed a recurrence of the tumor at the original site after simple excision. In the case of unsuccessful therapy with topical corticosteroids a lamellar graft is recommended.


Tragic Choices and the Virtue of Techno-Responsibility Gaps.
There is a concern that the widespread deployment of autonomous machines will open up a number of 'responsibility gaps' throughout society. Various articulations of such techno-responsibility gaps have been proposed over the years, along with several potential solutions. Most of these solutions focus on 'plugging' or 'dissolving' the gaps. This paper offers an alternative perspective. It argues that techno-responsibility gaps are, sometimes, to be welcomed and that one of the advantages of autonomous machines is that they enable us to embrace certain kinds of responsibility gap. The argument is based on the idea that human morality is often tragic. We frequently confront situations in which competing moral considerations pull in different directions and it is impossible to perfectly balance these considerations. This heightens the burden of responsibility associated with our choices. We cope with the tragedy of moral choice in different ways. Sometimes we delude ourselves into thinking the choices we make were not tragic (illusionism); sometimes we delegate the tragic choice to others (delegation); sometimes we make the choice ourselves and bear the psychological consequences (responsibilisation). Each of these strategies has its benefits and costs. One potential advantage of autonomous machines is that they enable a reduced cost form of delegation. However, we only gain the advantage of this reduced cost if we accept that some techno-responsibility gaps are virtuous.


Pharmacy Education; Competency and Beyond.
Competency-based curricula are the dominant approach in the education of healthcare professionals around the world today [...].


[Hyperthermic effect of a trypsin inhibitor in rats and rabbits].
The influence of intraventricular and intravenous administration of trypsin inhibitor (from soya-bean) on the body temperature was studied in experiments on unanesthetized rats and rabbits. It was established that the substance provoked a steady and prolonged hyperthermia in rats and rabbits, attenuated by pre-administration of sodium salicylate. Hyperthermia was accompanied by a significant decrease in the content of PGE2 in the hypothalamus. The results suggest than inhibition of certain trypsin-like serine proteases in thermoregulatory centres may be one of the factors responsible for the development of fever.


In Vitro and In Vivo Behaviour of In Complexes of TTHA, TTHA-Bis(Butylamide) and TTHA-Bis(Glucamide): Stability, Biodistribution and Excretion Studied by Gamma Imaging.
Aiming at radiopharmaceutical application, (111)In(3+) complexes of the polyaminocarboxylates TTHA, TTHA-bis(butylamide) and TTHA-bis(glucamide) were investigated. The in vitro stability of (111)In(TTHA)(3-) and (111)In(TTHA-bis(butylamide)(-) was evaluated by measuring the exchange of (111)In(3+) from the complexes to transferrin and the results were compared with those for (111)In(DTPA)(2-). We also performed biodistribution studies of the three (111)In(3+) complexes by gamma-imaging in Wistar rats and by measuring the radioactivity in their organs. TTHA and its derivatives seem to have similar in vivo biodistribution with prevailing renal excretion.


Endocrine assays to predict preterm delivery.
Advances in the understanding of the endocrine and hormonal mechanisms involved in normal and abnormal labor have led to clinical research into the roles of hormones and cytokines in preterm labor. This article reviews the current status of assays for estriol, activin, corticotropin-releasing hormone, interleukin-6, and relaxin as predictors of preterm labor and delivery.


The neurotensin analog xenopsin excites nigral dopamine neurons.
The electrophysiological effects of neurotensin (NT), its analog xenopsin, and the fragment NT-(1-8) on the activity of dopaminergic neurons in rat substantia nigra slices were compared. Xenopsin and NT produced a concentration-dependent increase in the firing rate. The mean firing rate was increased by 58.5% with xenopsin (0.1 microM) and 49.1% with NT (0.1 microM). NT-(1-8) was inactive at this concentration. Dopamine (100 microM) inhibited firing in these neurons by 54.7%. These data provide evidence that xenopsin mimics the physiological effects of NT.


Vancomycin covalently bonded to titanium beads kills Staphylococcus aureus.
Periprosthetic infections are life-threatening complications that occur in about 6% of medical device insertions. Stringent sterile techniques have reduced the incidence of infections, but many implant patients are at high risk for infection, especially the elderly, diabetic, and immune compromised. Moreover, because of low vascularity at the site of the new implant, antibiotic prophylaxis is often not effective. To address this problem, we designed a covalent modification to titanium implant surfaces to render them bactericidal. Specifically, we aminopropylated titanium, a widely used implant material and extended a tether by solid phase coupling of ethylene glycol linkers, followed by solid phase coupling of vancomycin. Vancomycin covalently attached to titanium still bound soluble bacterial peptidoglycan, reduced Staphylococcus aureus colony-forming units by 88% +/- 16% over 2 hr, and retained antibacterial activity upon a repeated challenge.


Transcriptome-Wide Analysis of Human Liver Reveals Age-Related Differences in the Expression of Select Functional Gene Clusters and Evidence for a PPP1R10-Governed 'Aging Cascade'.
A transcriptome-wide analysis of human liver for demonstrating differences between young and old humans has not yet been performed. However, identifying major age-related alterations in hepatic gene expression may pinpoint ontogenetic shifts with important hepatic and systemic consequences, provide novel pharmacogenetic information, offer clues to efficiently counteract symptoms of old age, and improve the overarching understanding of individual decline. Next-generation sequencing (NGS) data analyzed by the Mann-Whitney nonparametric test and Ensemble Feature Selection (EFS) bioinformatics identified 44 transcripts among 60,617 total and 19,986 protein-encoding transcripts that significantly (p = 0.0003 to 0.0464) and strikingly (EFS score > 0.3:16 transcripts; EFS score > 0.2:28 transcripts) differ between young and old livers. Most of these age-related transcripts were assigned to the categories 'regulome', 'inflammaging', 'regeneration', and 'pharmacogenes'. NGS results were confirmed by quantitative real-time polymerase chain reaction. Our results have important implications for the areas of ontogeny/aging and the age-dependent increase in major liver diseases. Finally, we present a broadly substantiated and testable hypothesis on a genetically governed 'aging cascade', wherein PPP1R10 acts as a putative ontogenetic master regulator, prominently flanked by IGFALS and DUSP1. This transcriptome-wide analysis of human liver offers potential clues towards developing safer and improved therapeutic interventions against major liver diseases and increased insights into key mechanisms underlying aging.


Evaluation of the delivered activity of yttrium-90 resin microspheres using sterile water and 5 % glucose during administration.
The purpose of this study is to evaluate the impact of switching from sterile water to 5 % glucose (G5W) for the administration of yttrium-90 ((90)Y)-resin microspheres on the total activity of (90)Y administered (expressed as a proportion of the prescribed/calculated activity), as well as the number of cases of stasis and the reported incidence of discomfort during the selective internal radiation therapy (SIRT) procedure. In December 2013, we switched from sterile water to G5W for the administration of SIRT using (90)Y resin microspheres in all patients. This retrospective observational single-center case series describes our experience in the months preceding and after the switch. Apart from the change in administration medium, the protocol for SIRT was otherwise identical. One hundred and four SIRT procedures were performed on 78 patients (45 male, mean age: 63 years, range: 31-87 years) with either unresectable hepatocellular carcinoma, cholangiocarcinoma, or chemorefractory liver-dominant metastatic cancer. Compared with sterile water, the whole prescribed activity was administered in significantly more procedures with G5W: 85 vs. 22 %; p < 0.0001. A significantly higher proportion of the calculated activity was administered with G5W: 96.1 ± 11.0 % vs. 77.4 ± 24.3 % (p < 0.0001). G5W procedures were also associated with a significantly lower incidence of stasis (28 vs. 11 % procedures; p = 0.02) and mild-to-moderate upper abdominal pain during the procedure (1.8 vs. 44 % procedures; p < 0.0001). Replacing sterile water with isotonic G5W during administration favorably impacts on the safety of SIRT, eliminates and/or minimizes flow reductions and stasis/reflux during administration of (90)Y resin microspheres, improves percentage activity delivered, and reduces peri-procedural pain.


Real-world adherence, persistence, and in-class switching during use of dipeptidyl peptidase-4 inhibitors: a systematic review and meta-analysis involving 594,138 patients with type 2 diabetes.
Medication adherence and persistence are important determinants of treatment success in type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis evaluated the real-world adherence, persistence, and in-class switching among patients with T2DM prescribed dipeptidyl peptidase-4 (DPP4) inhibitors. MEDLINE, EMBASE, Cochrane Library, PsychINFO, and CINAHL were searched for relevant observational studies published in the English language up to 20 December 2019. This was supplemented by manual screening of the references of included papers. Random-effects meta-analysis was performed. Thirty-four cohort studies involving 594,138 patients with T2DM prescribed DPP4 inhibitors from ten countries were included. The pooled proportion adherent (proportion of days covered (PDC) or medication possession ratio (MPR) ≥ 0.80) was 56.9% (95% confidence interval [CI] 49.3-64.4) at one year and 44.2% (95% CI 36.4-52.1) at two years. The proportion persistent with treatment decreased from 75.6% (95% CI 71.5-79.5) at six months to 52.8% (95% CI 51.6-59.8) at two years. No significant differences in adherence and persistence were observed between individual DPP4 inhibitors. At one year, just 3.2% (95% CI 3.1-3.3) of patients switched from one DPP4 inhibitor to another. Switching from saxagliptin and alogliptin to others was commonest. Adherence to and persistence with DPP4 inhibitors is suboptimal but similar across all medications within the class. While in-class switching is uncommon, saxagliptin and alogliptin are the DPP4 inhibitors most commonly switched. Interventions to improve treatment adherence and persistence among patients with T2DM prescribed DPP4 inhibitors may be warranted.