Inhibition of Naja naja venom enzymes by the methanolic extract of Leucas aspera and its chemical profile by GC-MS.
The present investigation was aimed at evaluating the anti-ophidian properties of ethnomedicinal herb Leucas aspera against Indian cobra, Naja naja venom enzymes. Methanolic extract of Leucas aspera was evaluated, in vitro, for its ability to inhibit the major enzyme activities of Naja naja venom including protease, phospholipase A2, hyaluronidase and hemolytic factors. The type of phytochemicals present in the extract was analyzed. Also, the major phytoconstituents in the extract was determined by gas chromatography-mass spectrometry (GC-MS). Venom protease and hyaluronidase activities (two isoforms) were completely (100%) neutralized by the L. aspera methanolic extract at ratio of 1:50 w/w (venom: plant extract) and venom hemolytic activity was also completely neutralized at a ratio of 1:80 w/w by the plant extract. However, the extract failed to neutralize phospholipase A2 activity even at the highest concentration used. Phytochemical analysis revealed the presence of alkaloids, acidic compounds, flavonoids, steroids and cardiac glycosides in the extract. GC-MS analysis indicated that a total of 14 compounds were present in the extract. The major bioactive constituents were found to be 6-octadecenoic acid (32.47%), n-hexadecanoic acid (25.97%), and 17-octadecen-14-yn-1-ol (14.22%) along with the minor constituents, sitosterol (2.45%) and stigmasterol (2%), which was previously reported to exhibit antivenom activity. The results obtained demonstrate for the first time that the methanolic extract of Leucas aspera possesses anti-venom activity and could be considered as a potential source for the anti-ophidian metabolites.


The relationship of marital status to survival from melanoma.
As an indirect test of the hypothesis that prior pregnancy has a favorable influence on prognosis in melanoma, the relation of marital status to survival among melanoma patients was examined in data gathered by the Connecticut Tumor Registry, 1935--1973. Compared to women who had never been married, ever-married women with the disease had a slightly increased survival rate, but the difference was not statistically significant. If a difference between parous and nulliparous women in survival from melanoma truly exists, it is probably a small one, and could be due to differences in characteristics other than childbearing.


Inhibition of monosaccharide transport in the intact rat liver by stevioside.
The transport and metabolism of D-glucose and D-fructose in the isolated perfused rat liver and the influence of stevioside and its derivatives were investigated. The transport parameters were measured by the multiple indicator dilution technique. The maximal exchange rate of D-glucose was 700 mumol X min-1 X ml-1 and the Km was 38 mM. Stevioside and its derivatives (isosteviol and steviolbioside) inhibited D-glucose and D-fructose transport across the cell membrane. The half-maximal effect at 1 mM D-glucose occurred at 0.8 mM stevioside. The inhibitory action of stevioside was of mixed type. Isosteviol was more potent than stevioside (half-maximal effect at 0.4 mM), whereas steviolbioside was less active (50% inhibition at 2.5 mM). Stevioside was without effect on D-glucose metabolism, except for transient changes in D-glucose release, reflecting changes in the intracellular concentration. D-Fructose consumption, however, was specifically affected (half-maximal effect at 2.8 mM), as well as all parameters depending on D-fructose transformation (D-glucose production, L-lactate and pyruvate production, and extra oxygen uptake). In livers releasing D-glucose from endogenous glycogen, strong inhibition of transport increased the intracellular to extracellular D-glucose concentration ratio (Ci/Ce). The control values of Ci/Ce, representing an average over the total intracellular water space, were always smaller than unity. The latter observation may indicate that D-glucose does not have access to the whole intracellular water space.


Self-supervision assisted multimodal remote sensing image classification with coupled self-looping convolution networks.
Recently, remote sensing community has seen a surge in the use of multimodal data for different tasks such as land cover classification, change detection and many more. However, handling multimodal data requires synergistically using the information from different sources. Currently, deep learning (DL) techniques are being religiously used in multimodal data fusion owing to their superior feature extraction capabilities. But, DL techniques have their share of challenges. Firstly, DL models are mostly constructed in the forward fashion limiting their feature extraction capability. Secondly, multimodal learning is generally addressed in a supervised setting, which leads to high labelled data requirement. Thirdly, the models generally handle each modality separately, thus preventing any cross-modal interaction. Hence, we propose a novel self-supervision oriented method of multimodal remote sensing data fusion. For effective cross-modal learning, our model solves a self-supervised auxiliary task to reconstruct input features of one modality from the extracted features of another modality, thus enabling more representative pre-fusion features. To counter the forward architecture, our model is composed of convolutions both in backward and forward directions, thus creating self-looping connections, leading to a self-correcting framework. To facilitate cross-modal communication, we have incorporated coupling across modality-specific extractors using shared parameters. We evaluate our approach on three remote sensing datasets, namely Houston 2013 and Houston 2018, which are HSI-LiDAR datasets and TU Berlin, which is an HSI-SAR dataset, where we achieve the respective accuracy of 93.08%, 84.59% and 73.21%, thus beating the state of the art by a minimum of 3.02%, 2.23% and 2.84%.


Development of a comprehensive spectral library of sildenafil and related active analogues using LC-QTOF-MS and its application for screening counterfeit pharmaceuticals.
The abuse or misuse of forged erectile-dysfunction drugs, containing phosphodiesterase type 5 inhibitors (e.g. sildenafil), is a serious issue globally. Therefore, the detection of sildenafil and related active analogues in counterfeit pharmaceuticals or the differentiation between counterfeit and authentic drugs has been performed with a variety of analytical techniques. Recently, a liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS)-based in-house library, consisting of accurate mass ion fragmentation information and retention times, was effectively applied to screen a large number of compounds in field of forensic toxicology. However, a comprehensive LC-QTOF-MS spectral library of sildenafil and related active analogues has not yet been reported. In the present study, a spectral library of 40 compounds of sildenafil and related analogues was developed with accurate mass spectra and retention times using LC-QTOF-MS, and applied to screen nine marketed counterfeit products. The in-house library successfully identified sildenafil, dimethylsildenafil, hydroxyhomosildenafil, demethylhongdenafil, pseudovardenafil and vardenafil in the samples. Our LC-QTOF-MS-based spectral library search is considered a powerful approach for identifying sildenafil and related active analogues in counterfeit pharmaceuticals.


Unpredictable, intermittent access to sucrose or water promotes increased reward pursuit in rats.
Reward uncertainty can sensitize reward pathways, promoting increased reward-seeking and -taking behaviours. This is relevant to human conditions such as pathological gambling, eating disorders and drug addiction. In the context of addiction, preclinical self-administration procedures have been developed to model the intermittency of human drug use. These intermittent-access (IntA) procedures involve intermittent but predictable access to drug during self-administration sessions. However, human drug use typically involves intermittent and unpredictable drug access. We introduce a new procedure modeling unpredictable, intermittent access (UIntA) to a reinforcer, and we compare it to procedures that provide predictable reinforcer availability; continuous (ContA) or intermittent (IntA) access. Female rats self-administered water or liquid sucrose in daily hour-long sessions. IntA and ContA rats had access to a fixed volume of water or sucrose (0.1 ml), under a fixed ratio 3 schedule of reinforcement. IntA rats had predictable 5-min reinforcer ON and 25-min reinforcer OFF periods. ContA rats had 60 min of reinforcer access during each session. For UIntA rats, variation in the length of ON and OFF periods (1, 5 or 9 min/period), response requirement (variable ratio 3 schedule of reinforcement), reinforcer probability (50%) and quantity (0, 0.1 or 0.2 ml) introduced reward uncertainty. Following 14 daily self-administration sessions, UIntA rats showed the highest levels of responding for water or sucrose under progressive ratio conditions, responding under extinction conditions, and cue-induced reinstatement of sucrose seeking. Thus, unpredictable, intermittent reward access promotes increased reward pursuit. This has implications for modeling addiction and other disorders of increased reward seeking.


Unfolding and Folding of the Three-Helix Bundle Protein KIX in the Absence of Solvent.
Electron capture dissociation was used to probe the structure, unfolding, and folding of KIX ions in the gas phase. At energies for vibrational activation that were sufficiently high to cause loss of small molecules such as NH3 and H2O by breaking of covalent bonds in about 5% of the KIX (M + nH)(n+) ions with n = 7-9, only partial unfolding was observed, consistent with our previous hypothesis that salt bridges play an important role in stabilizing the native solution fold after transfer into the gas phase. Folding of the partially unfolded ions on a timescale of up to 10 s was observed only for (M + nH)(n+) ions with n = 9, but not n = 7 and n = 8, which we attribute to differences in the distribution of charges within the (M + nH)(n+) ions. Graphical Abstract .


Altered hypothalamic monoamine metabolism and pituitary prolactin regulation in female spontaneously hypertensive rats.
Prolactin (PRL) secretion after aromatic amino acid decarboxylase inhibition with NSD-1015 was significantly elevated in female spontaneously hypertensive rats (SHR) as compared to normotensive (WKY) controls. Although basal PRL levels tended to be elevated in SHR rats, the differences were not significant. In vitro PRL secretion was also significantly elevated in the SHR rats as compared to the WKY rats, but the SHR rats were more responsive to the inhibitory effects of dopamine (DA). Despite changes in pituitary PRL secretion and DA response, there was no apparent difference in tubero-infundibular DA activity between the two rat strains. Hypothalamic serotonin levels were elevated in SHR rats, but metabolism did not appear to be significantly changed based on measurements of 5-hydroxytryptophan accumulation after NSD-1015 treatment.


Point-of-care C-reactive protein and Xpert MTB/RIF Ultra for tuberculosis screening and diagnosis in unselected antiretroviral therapy initiators: a prospective diagnostic accuracy study.
Tuberculosis (TB), a major cause of death in people living with HIV (PLHIV), remains challenging to diagnose. Diagnostic accuracy data are lacking for promising triage tests, such as C-reactive protein (CRP), and confirmatory tests, such as sputum and urine Xpert MTB/RIF Ultra (Ultra), and urine LAM, without prior symptom selection. 897 PLHIV initiating antiretroviral therapy were consecutively recruited in settings with high TB incidence, irrespective of symptoms. Participants were offered sputum induction, with a liquid culture reference standard. First, we evaluated point-of-care CRP testing on blood, compared to the World Health Organization (WHO)-recommended four-symptom screen (W4SS) for triage (n=800). Second, we evaluated Xpert MTB/RIF Ultra (Ultra) versus Xpert MTB/RIF (Xpert) for sputum-based confirmatory testing (n=787), with or without sputum induction. Third, we evaluated Ultra and Determine LF-LAM for urine-based confirmatory testing (n=732). CRP and number of W4SS symptoms had areas under the receiver operator characteristic curve of 0.78 (95% confidence interval 0.73, 0.83) and 0.70 (0.64, 0.75), respectively. For triage, CRP (≥10 mg/l) has similar sensitivity to W4SS [77% (68, 85) vs. 77% (68, 85); p>0.999] but higher specificity [64% (61, 68) vs. 48% (45, 52); p<0.001]; reducing unnecessary confirmatory testing by 138 per 1000 people and the number-needed-to-test from 6.91 (6.25, 7.81) to 4.87 (4.41, 5.51). Using sputum, which required induction in 31% (24, 39) of people, Ultra had higher sensitivity than Xpert [71% (61, 80) vs. 56% (46, 66); p<0.001] but lower specificity [98% (96, 100) vs. 99% (98, 100); p<0.001]. The proportion of people with ≥1 positive confirmatory result detected by Ultra increased from 45% (26, 64) to 66% (46, 82) when induction was done. Programmatically-done haemoglobin, triage test combinations, and urine tests showed comparatively worse performance. Among ART-initiators in a high burden setting, CRP is a more specific triage test than W4SS. Sputum induction improves yield. Sputum Ultra is a more accurate confirmatory test than Xpert. SAMRC (MRC-RFA-IFSP-01-2013), EDCTP2 (SF1401, OPTIMAL DIAGNOSIS), NIH/NIAD (U01AI152087). Evidence before this study: Novel triage and confirmatory tests are urgently needed for TB, especially in key risk groups like PLHIV. Many TB cases do not meet World Health Organization (WHO)-recommended four-symptom screen (W4SS) criteria despite accounting for significant transmission and morbidity. W4SS also lacks specificity, which makes onward referral of triage-positive people for expensive confirmatory testing inefficient and hampers diagnostic scale-up. Alternative triage approaches like CRP have promise, but have comparatively little data in ART-initiators, especially when done without syndromic preselection and using point-of-care (POC) tools. After triage, confirmatory testing can be challenging due to sputum scarcity and paucibacillary early-stage disease. Next generation WHO-endorsed rapid molecular tests (including Xpert MTB/RIF Ultra; Ultra) are a standard-of-care for confirmatory testing. However, there are no supporting data in ART-initiators, among whom Ultra may offer large sensitivity gains over predecessors like Xpert MTB/RIF (Xpert). The added value of sputum induction to augment diagnostic sampling for confirmatory testing is also unclear. Lastly, the performance of urine tests (Ultra, Determine LF-LAM) in this population requires more data.Added value of this study: We evaluated repurposed and new tests for triage and confirmatory testing using a rigorous microbiological reference standard in a highly vulnerable high-priority patient population (ART-initiators) regardless of symptoms and ability to naturally expectorate sputum. We showed POC CRP triage is feasible, performs better than W4SS, and that combinations of different triage approaches offer no advantages over CRP alone. Sputum Ultra has superior sensitivity to Xpert; often detecting W4SS-negative TB. Furthermore, without induction, confirmatory sputum-based testing would not be possible in a third of people. Urine tests had poor performance. This study contributed unpublished data to systematic reviews and meta-analyses used by the WHO to inform global policy supporting use of CRP triage and Ultra in PLHIV.Implication of all the available evidence: POC CRP triage testing is feasible and superior to W4SS and, together with sputum induction in people who triage CRP-positive should, after appropriate cost and implementation research, be considered for roll-out in ART-initiators in high burden settings. Such people should be offered Ultra, which outperforms Xpert.


Ultrastructural identification of substance P immunoreactive neurons in the main olfactory bulb of the hamster.
The neurons containing substance P immunoreactivity in the main olfactory bulb of the hamster are located in the glomerular layer. Their cell bodies lie in the periglomerular region and contain spherical or ovoid nuclei which lack invaginations of the nuclear membrane and tend to be positioned eccentrically in the cell body. Dendrites of these neurons extend throughout the periglomerular region and project into the glomerular neuropil. Within the glomerular neuropil, processes with substance P immunoreactivity contain agranular, spherical synaptic vesicles. Primary olfactory axons, and processes of uncertain origin which contain pleomorphic synaptic vesicles, form synaptic contacts with substance P immunoreactive processes. These ultrastructural findings confirm that the substance P immunoreactive neurons are external tufted cells. Their likely physiological properties are considered in relation to the synaptic organization in the glomerular layer of the main olfactory bulb and to the other putative neurotransmitters or neuromodulators located in this layer.


Prevalence and associations of the metabolic syndrome among patients prescribed clozapine.
There is increasing concern that the use of second-generation antipsychotic medications in schizophrenia is associated with the development of metabolic syndrome. This study assessed the prevalence and clinical associations of metabolic syndrome among patients receiving clozapine within the catchment area of a mental health service in the west of Ireland. A total of 84 patients (96% response rate) taking clozapine were interviewed and thoroughly investigated using physical assessments, comprehensive laboratory testing and review of medical records. Of the patients, 46.4% taking clozapine fulfilled the criteria for metabolic syndrome. Male gender, high body mass index, high insulin level and receiving a concomitant antipsychotic medication were significantly associated with the presence of metabolic syndrome. Almost half of the patients receiving clozapine have metabolic syndrome and are consequently at risk of cardiovascular morbidity and mortality. Such patients should be closely monitored in order to facilitate interventions, which could alleviate the adverse health consequences of this syndrome.


Genetic approaches to autonomic dysreflexia.
Autonomic dysreflexia is a potentially life-threatening condition in which episodic hypertension occurs after injuries above the mid-thoracic segments of the spinal cord. Despite the seriousness of this condition, little is known of the molecular mechanisms that lead to its development. The completed sequencing of the mouse genome, its dense genetic map, and the large repository of engineered and spontaneous mouse mutants, make the mouse an ideal model organism in which to study the molecular mechanisms underlying autonomic dysreflexia. We subjected two wild-type strains of mice, 129Sv and C57BL/6, and one spontaneous mouse mutant, Wallerian degeneration slow (Wld s), to spinal cord transection and clip-compression injury. We found that the incidence of autonomic dysreflexia is greatly reduced, compared to spinal cord-transected wild-type mice, in Wld s mice after both injury paradigms and in 129Sv and C57BL/6 that have undergone the clip-compression injury. We also found that the amplitude of the dysreflexic response was greater in cord-compressed 129Sv than in C57BL/6 mice. These results implicate axonal degeneration as an important source of signals that trigger the development of autonomic dysreflexia and are discussed in the context of mouse genetics, interstrain differences and possible molecular mechanisms underlying autonomic dysreflexia after spinal cord injury.


Antihypertensive efficacy of cetamolol: a dose-titrated study.
This double-blind, placebo-controlled, randomized multicenter study evaluated the antihypertensive efficacy and safety of cetamolol hydrochloride in 108 patients diagnosed as having mild to moderate hypertension. After a placebo lead-in period, patients received either cetamolol 5-10-15 mg/d (low dose), cetamolol 15-25-50 mg/d (high dose), or placebo, once daily for four weeks. Patients began at the lowest dose and were titrated to higher doses based on the first two assessments of diastolic blood pressure and heart rate, which were conducted each week after double-blind treatment was dispensed. After four weeks of treatment 82.4%, 81.3%, and 93.3% of the low-dose group, high-dose group, and placebo group, respectively, were titrated to the maximum dose level. After four weeks of treatment and 24 hours since the patient's last dose, both cetamolol groups showed a significantly greater (P less than or equal to .05) reduction in supine systolic/diastolic blood pressure (-18.1 +/- 2.3/-9.2 +/- 1.5 mm Hg [low dose] and -17.3 +/- 2.3/-8.3 +/- 1.6 mm Hg [high dose]) than the placebo group (-9.9 +/- 2.5/-3.5 +/- 1.7 mm Hg). In general, the changes in standing (stabilized) systolic and diastolic blood pressure were similar to those seen in supine measurements. Significantly more patients receiving cetamolol than those receiving placebo showed a "good response" (a decrease in diastolic blood pressure of 10 mm Hg or more or measuring less than 90 mm Hg with a decrease of at least 4 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)


Targeted genome editing in the rare actinomycete Actinoplanes sp. SE50/110 by using the CRISPR/Cas9 System.
The application of genome editing technologies, like CRISPR/Cas9 for industrially relevant microorganisms, is becoming increasingly important. Compared to other methods of genetic engineering the decisive factor is that CRISPR/Cas9 is relatively easy to apply and thus time and effort can be significantly reduced in organisms, which are otherwise genetically difficult to access. Because of its many advantages and opportunities, we adopted the CRISPR/Cas9 technology for Actinoplanes sp. SE50/110, the producer of the diabetes type II drug acarbose. The functionality of genome editing was successfully shown by the scarless and antibiotic marker-free deletion of the gene encoding the tyrosinase MelC, which catalyzes the formation of the dark pigment eumelanin in the wild type strain. The generated ΔmelC2 mutant of Actinoplanes sp. SE50/110 no longer produces this pigment and therefore the supernatant does not darken. Furthermore, it was shown that the plasmid containing the gene for the Cas9 protein was removed by increasing the temperature due to its temperature-sensitive replication. The precision of the intended mutation was proven and possible off-target effects caused by the genome editing system were ruled out by genome sequencing of several mutants.


Replicating instabilities in yeast: occurrence in different mutational systems.
Following mutagenesis of yeast cells with nitrosoguanidine, primary mosaic colonies exhibiting prototrophic/auxotrophic phenotypes were obtained. Upon replating of these primary mosaics, numerous secondary mosaics were present in the progeny. This study shows that replicating instabilities occur at many different loci within the Schizosaccharomyces pombe genome. In addition, the ade-1 gene of Saccharomyces cerevisiae (causing red pigmentation) was used to show that the phenomenon also occurs in this yeast.


Changes and clinical correlation of diffusion tensor imaging parameters of compressed spinal cord and nerve root in patients with cervical spondylosis.
Diffusion tensor imaging (DTI) was used to quantitatively study the characteristics of the related spinal cord and nerve root compression parameters in patients with cervical spondylosis (CS), and diffusion tensor tractography (DTT) was used to visualize the spinal cord and nerve root and analyze their relevance to clinical evaluation. A total of 67 patients with CS and 30 healthy volunteers received 3.0 T magnetic resonance imaging. Cervical DTI and DTT were performed in all the participants, where the b value of DTI was set at 800 s/mm2. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of the spinal cord and cervical nerve roots were measured by using DTI. Patients with CS were scored according to the modified Japanese Orthopedic Association (mJOA) score. In all the participants, the spinal cord and cervical nerve roots were clearly visible by DTT. Compared to the healthy volunteers, the FA values were significantly decreased and ADC values were significantly increased in patients with CS. mJOA score was significantly correlated with the DTI index (ADC and FA) values. Receiver operator characteristic curve analysis revealed that FA and ADC could identify mild, moderate, and severe CS. DTI parameters of cervical spinal cord and nerve root compression are associated with the clinical evaluation of patients with CS and may be helpful in assessing the severity of CS.


Insights on the pathogenesis of type 2 diabetes as revealed by signature genomic classifiers in an African American population in the Washington, DC area.
African Americans (AA) in the United States have a high risk of type 2 diabetes mellitus (T2DM) and suffer from disparities in the prevalence, mortality, and comorbidities of the disease compared to other Americans. The present study aimed to shed light on the molecular mechanisms of disease pathogenesis of T2DM among AA in the Washington, DC region. We performed TaqMan Low Density Arrays (TLDA) on 24 genes of interest that belong to three categories: metabolic disease and disorders, cancer-related genes, and neurobehavioural disorders genes. The 18 genes, viz. ARNT, CYP2D6, IL6, INSR, RRAD, SLC2A2 (metabolic disease and disorders), APC, BCL2, CSNK1D, MYC, SOD2, TP53 (Cancer-related), APBA1, APBB2, APOC1, APOE, GSK3B, and NAE1 (neurobehavioural disorders), were differentially expressed in T2DM participants compared to controls. Our results suggest that factors including gender, smoking habits, and the severity or lack of control of T2DM (as indicated by HbA1c levels) were significantly associated with differential gene expression. APBA1 was significantly (p-value <0.05) downregulated in all diabetes participants. Upregulation of APOE and CYP2D6 genes and downregulation of the INSR gene were observed in the majority of diabetes patients. Tobacco smoking and gender were significantly associated with case-control differences in expression of the APBA1 and APOE genes (connected with Alzheimer's disease) and the INSR and CYP2D6 (associated with metabolic disorders). The results highlight the need for more effective management of T2DM and for tobacco smoking cessation interventions in this community, and further research on the associations of T2DM with other disease processes, including cancer and neurobehavioral pathways.


Multiplex MQMAS NMR of quadrupolar nuclei.
A multiplex phase cycling method (N. Ivchenko et al., J. Magn. Reson. 160 (2003) 52-58) has been used to record two-dimensional MQMAS spectra with a very short phase cycling. A straightforward procedure has been developed to easily process the data. Combining this Multiplex approach and the new Soft-Pulse-Adding-Mixing (SPAM) method considerably increases the signal-to-noise ratio of the conventional MQMAS experiment. The Multiplex acquisition procedure is much simpler than the echo/anti-echo method recently proposed, and has been applied with success to record (87)Rb spectra of RbNO(3) and (27)Al 3Q and 5Q MQMAS NMR of microporous aluminophosphate AlPO(4)-14.


Problem-solving strategies and manifest brain asymmetry.
The dichhaptic stimulation procedures developed by Witelson (1974) for the study of brain lateralization in children were modified and extended for use with adults. Consistent with findings in children, an overall left hand advantage was found under conditions of simultaneous or dichhaptic stimulation, although it was not found under conditions of monohaptic stimulation. The major purpose of the study was to determine whether in adults hand differences (assumed to reflect hemisphere utilization) could be influenced by the use of differential problem-solving strategies. Half the Ss were instructed to approach the haptic learning and recognition problems in a "sequential" or "analytic" manner, and half to approach them in a "holistic" or "Gestalt" manner. The results indicated that the degree of left hand superiority was indeed influenced by this manipulation, although it is to be noted that the actual basis of the effect is unclear. The results were consistent with the idea that brain lateralization must be defined, not strictly by tasks, but by strategies used by subjects to perform the tasks used to detect and study that lateralization. It is suggested that this immensely complicates the issue of interpreting the origin and basis of individual and group differences in laterality effects.


Kinetics of the in vivo labeling of the acyl groups of rabbit lung phosphatidylcholine and disaturated phosphatidylcholine.
The kinetics of labeling of lung phosphatidylcholine and disaturated phosphatidylcholine were studied for periods from 0.75--120 min following intravenous injection of radiolabeled palmitic acid and choline into 3-day-old rabbits. The labeled palmitic acid was cleared rapidly from plasma, and rapidly appeared with identical incorporation kinetics in both phosphatidylcholine and disaturated phosphatidylcholine. The 2-acyl positions of both phosphatidylcholine and disaturated phosphatidylcholine were labeled preferentially soon after [14C]palmitic acid injection. The specific activities of palmitic acid in the 2-acyl positions of phosphatidylcholine and disaturated phosphatidylcholine 0.75 min after injection of labeled palmitic acid were 3.4 and 1.9 times, respectively, the specific activities of palmitic acid in the 1-acyl positions. By 120 min the label had randomized between the 1-acyl and 2-acyl positions, and the kinetics of that randomization were defined for both phosphatidylcholine and disaturated phosphatidylcholine. Choline did not pulse label lung phosphatidylcholine or disaturated phosphatidylcholine. The choline label appeared with equal specific activities in both phosphatidylcholine and disaturated phosphatidylcholine. Thus no analysis of the de novo synthesized product via the CDP-choline pathway was possible.


A Successful Renal Transplantation Case After Stem Cell Transplantation.
Renal transplantation is the most effective treatment method for end-stage renal disease (ESRD). However, new treatment modalities are being investigated, such as immunotoleration, to avoid the acute and chronic side effects of immunosuppressant drugs. We report a case in which a man had undergone allogenic stem cell transplantation from his brother 16 years ago due to chronic myeloid leukemia, and who then developed ESRD due to arterial hypertension and underwent renal transplantation (Rtx) from the same brother. The patient was followed up without immunosuppression due to full chimerism.


Psychiatric nursing consultation: the use of an inservice model to assist nurses in the grief process.
This paper proposes that death is a situation which nurses face on a daily basis. Anxiety, depression, and hostility are defined as feelings common to nurses in working with dying patients. Anxiety and depression were significantly lowered in nurses who attended at least three of the five inservice sessions. Hostility levels did not significantly change. This paper also examines the role of the psychiatric nruse consultant in assisting staff nurses to improve the quality of care provided by examining their own emotional system. The consultant can act as faciltator of the group process so that nurses can continue to function independent of the consultant after the consulting process has ended. The psychiatric nurse consultant can utilize inservice curricula such as the one described above to produce affective change in nurses who work with dying patients, which has the potential to improve the quality of care given to the dying.


Genome Editing in Human Neural Stem and Progenitor Cells.
Experimental tools for precise manipulation of mammalian genomes enable reverse genetic approaches to explore biology and disease. Powerful genome editing technologies built upon designer nucleases, such as CRISPR/Cas9, have recently emerged. Parallel progress has been made in methodologies for the expansion and differentiation of human pluripotent and tissue stem cells. Together these innovations provide a remarkable new toolbox for human cellular genetics and are opening up vast opportunities for discoveries and applications across the breadth of life sciences research. In this chapter, we review the emergence of genome editing technologies and how these are being deployed in studies of human neurobiology, neurological disease, and neuro-oncology. We focus our discussion on CRISPR/Cas9 and its application in studies of human neural stem and progenitor cells.


Pulmonary valve neocuspidisation with glutaraldehyde-treated autologous pericardium-A novel technique in pulmonary valve endocarditis.
Infective endocarditis (IE) is a serious condition leading to heart failure, persistent sepsis. The management of IE involving valve is mainly excision of the infected valve and replacement with a heart valve; which are also at the risk of prosthetic valve endocarditis. Hence repair of the valve with autologous pericardium is much more physiological. We had a 20-year-old male presented with features of heart failure and high-grade fever not responding to optimum medical management. Two-dimensional echocardiogram revealed vegetation on pulmonary valve cusps with the erosion of the left and right cusps. Neo cusps with autologous pericardium offered good hemodynamics with trivial regurgitation. The patient is doing well with normal pulmonary valve function 3 months after surgery. This technique is reliable, economic, and easily reproducible.


Green synthesis of κ-carrageenan@Ag submicron-particles with high aqueous stability, robust antibacterial activity and low cytotoxicity.
Silver nanoparticles (AgNPs) are effective antimicrobial reagent, especially for the treatment of multidrug-resistant microorganisms. However, it is difficult to remove the residual harmful reducing agents in AgNPs synthesized by the traditional chemical reduction method. In addition, AgNPs exhibit cytotoxicity when exposed directly to cells for biomedical applications and will rapidly aggregate in aqueous environment. Herein, we develop a new route to synthesize submicron-particles containing AgNPs (κC@Ag MPs) with high aqueous stability, robust antibacterial activity and low cytotoxicity. AgNPs were firstly greenly synthesized using κ-carrageenan as environmental friendly reducing and stabilizing agent under heating in aqueous solution. Then the AgNPs were immobilized in the net of κ-carrageenan by adding KCl to obtain κC@Ag MPs. The results indicated that κC@Ag MPs were quite stable without any agglomeration and precipitation in aqueous solution for more than three months. κC@Ag MPs exhibited robust antibacterial activity against Gram-positive and Gram-negative bacteria, even better than that of pure AgNPs. Notably, κC@Ag MPs maintained the long-lasting retention of antibacterial activity. In addition, κC@Ag MPs possessed well cytocompatibility towards the L02 and L929 cells. Overall, κC@Ag MPs may have prospective application as effective and sustainable antibacterial agent in biomedical fields.


ω-3 Fatty acids for major depressive disorder in adults: an abridged Cochrane review.
To assess the effects of n-3 polyunsaturated fatty acids (n-3PUFAs; also known as ω-3 fatty acids) compared with comparator for major depressive disorder (MDD) in adults. Systematic review and meta-analyses. The Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Registers (CCDANCTR) and International Trial Registries searched to May 2015. CINAHL searched to September 2013. a randomised controlled trial (RCT); that provided n-3PUFAs as an intervention; used a comparator; measured depressive symptomology as an outcome; and was conducted in adults with MDD. Primary outcomes were depressive symptomology and adverse events. 20 trials encompassing 26 relevant studies were found. For n-3PUFAs versus placebo, n-3PUFA supplementation resulted in a small-to-modest benefit for depressive symptomology: SMD=-0.32 (95% CI -0.52 to -0.12; 25 studies, 1373 participants, very low-quality evidence), but this effect is unlikely to be clinically meaningful, is very imprecise and, based on funnel plot inspection, sensitivity analyses and comparison with large well-conducted trials, is likely to be biased. Considerable evidence of heterogeneity between studies was also found, and was not explained by subgroup or sensitivity analyses. Numbers of individuals experiencing adverse events were similar in intervention and placebo groups (OR=1.24, 95% CI 0.95 to 1.62; 19 studies, 1207 participants; very low-quality evidence). For n-3PUFAs versus antidepressants, no differences were found between treatments in depressive symptomology (MD=-0.70 (95% CI -5.88 to 4.48); 1 study, 40 participants, very low-quality evidence). At present, we do not have sufficient evidence to determine the effects of n-3PUFAs as a treatment for MDD. Further research in the form of adequately powered RCTs is needed.


Echinococcus granulosus of camel origin: development in dogs and parasite morphology.
The developmental characteristics of Echinococcus granulosus of camel origin were studied in four dogs artificially infected with protoscolices originating from hydatid cysts isolated from the lung of a camel (Camelus dromedarius). Two dogs each were necropsied 34/35 and 41 days post-infection (p.i.); one dog had a low worm burden and the others were heavily infected (27,625-41,150 worms). At day 35 p.i., 20% of the parasites had developed three segments and the uterus of the vast majority of the total population was full of developing eggs in the terminal segment. At day 41, up to 58% of the parasites contained mature eggs (embryonated eggs with fully developed, "thick-shelled" embryophores). Morphological studies revealed the following major characteristics for 35 day-old worms: the mean length of the terminal segment accounted for 54% of the total worm length; the position of the sexually mature segment was always terminal; the female reproductive system possessed an elongated ovary with compact lobules; the female ducts were also compact; the Mehlis' gland was covered by the vitelline gland and the testes were distributed throughout the segment, with 1 row posterior to the vitelline gland. The camel isolate can readily be distinguished from the horse and sheep strains, but it is similar to the cattle strain in some respects, particularly in its precocious development. However, the camel isolate differs from the cattle strain in the position of the sexually mature segment, arrangement of the testes and structure of the female reproductive system. As in the cattle strain, the metacestodes in the principal intermediate host are mostly localised in the lung and have a high fertility rate.(ABSTRACT TRUNCATED AT 250 WORDS)


3-Nitrotyrosine immunoreactivity in olfactory receptor neurons of patients with Alzheimer's disease: implications for impaired odor sensitivity.
Olfactory sensory function is impaired in patients with the diagnosis of probable Alzheimer's disease (AD) compared to elderly controls, and the olfactory epithelium (OE) of AD patients exhibits several pathological changes characteristic of the AD brain. To confirm that the populations from whom our postmortem tissues are obtained exhibit similar decrements in sensory function, threshold testing was performed; probable AD patients had significantly higher olfactory thresholds than controls. To determine if oxidative stress contributes to decreased olfactory function in AD, we localized 3-nitrotyrosine (3-NT) immunoreactivity in OE obtained postmortem from patients with neuropathologically confirmed AD and age-matched controls with brains free of significant neurodegenerative pathology. In AD patients, immunoreactivity was localized in olfactory receptor neurons (ORNs), including dendritic knobs where ion channels that participate in sensory transduction are located, suggesting a direct mechanism for olfactory impairment. In controls, immunoreactivity occurred in blood vessel endothelium, suggesting age-related vascular dysfunction. Immunohistochemistry for CD68, a macrophage scavenger receptor, demonstrated activated macrophages, a source of free radicals contributing to 3-NT formation, in the OE of AD patients but not controls. These results demonstrate increased oxidative stress and modification of ORN proteins that may contribute directly to olfactory impairment in AD patients.


Monoclonal Antibodies in the Treatment of Relapsing Multiple Sclerosis: an Overview with Emphasis on Pregnancy, Vaccination, and Risk Management.
Monoclonal antibodies have become a mainstay in the treatment of patients with relapsing multiple sclerosis (RMS) and provide some benefit to patients with primary progressive MS. They are highly precise by specifically targeting molecules displayed on cells involved in distinct immune mechanisms of MS pathophysiology. They not only differ in the target antigen they recognize but also by the mode of action that generates their therapeutic effect. Natalizumab, an [Formula: see text]4[Formula: see text]1 integrin antagonist, works via binding to cell surface receptors, blocking the interaction with their ligands and, in that way, preventing the migration of leukocytes across the blood-brain barrier. On the other hand, the anti-CD52 monoclonal antibody alemtuzumab and the anti-CD20 monoclonal antibodies rituximab, ocrelizumab, ofatumumab, and ublituximab work via eliminating selected pathogenic cell populations. However, potential adverse effects may be serious and can necessitate treatment discontinuation. Most importantly, those are the risk for (opportunistic) infections, but also secondary autoimmune diseases or malignancies. Monoclonal antibodies also carry the risk of infusion/injection-related reactions, primarily in early phases of treatment. By careful patient selection and monitoring during therapy, the occurrence of these potentially serious adverse effects can be minimized. Monoclonal antibodies are characterized by a relatively long pharmacologic half-life and pharmacodynamic effects, which provides advantages such as permitting infrequent dosing, but also creates disadvantages regarding vaccination and family planning. This review presents an overview of currently available monoclonal antibodies for the treatment of RMS, including their mechanism of action, efficacy and safety profile. Furthermore, we provide practical recommendations for risk management, vaccination, and family planning.


Overexpression of native Saccharomyces cerevisiae ER-to-Golgi SNARE genes increased heterologous cellulase secretion.
Soluble N-ethylmaleimide-sensitive factor attachment receptor proteins (SNAREs) are essential components of the yeast protein-trafficking machinery and are required at the majority of membrane fusion events in the cell, where they facilitate SNARE-mediated fusion between the protein transport vesicles, the various membrane-enclosed organelles and, ultimately, the plasma membrane. We have demonstrated an increase in secretory titers for the Talaromyces emersonii Cel7A (Te-Cel7A, a cellobiohydrolase) and the Saccharomycopsis fibuligera Cel3A (Sf-Cel3A, a β-glucosidase) expressed in Saccharomyces cerevisiae through single and co-overexpression of some of the endoplasmic reticulum (ER)-to-Golgi SNAREs (BOS1, BET1, SEC22 and SED5). Overexpression of SED5 yielded the biggest improvements for both of the cellulolytic reporter proteins tested, with maximum increases in extracellular enzyme activity of 22 % for the Sf-Cel3A and 68 % for the Te-Cel7A. Co-overexpression of the ER-to-Golgi SNAREs yielded proportionately smaller increases for the Te-Cel7A (46 %), with the Sf-Cel3A yielding no improvement. Co-overexpression of the most promising exocytic SNARE components identified in literature for secretory enhancement of the cellulolytic proteins tested (SSO1 for Sf-Cel3A and SNC1 for Te-Cel7A) with the most effective ER-to-Golgi SNARE components identified in this study (SED5 for both Sf-Cel3A and Te-Cel7A) yielded variable results, with Sf-Cel3A improved by 131 % and Te-Cel7A yielding no improvement. Improvements were largely independent of gene dosage as all strains only integrated single additional SNARE gene copies, with episomal variance between the most improved strains shown to be insignificant. This study has added further credence to the notion that SNARE proteins fulfil an essential role within a larger cascade of secretory machinery components that could contribute significantly to future improvements to S. cerevisiae as protein production host.


Trypanosoma cruzi: quantification in tissues of experimentally infected mice by limiting dilution analysis.
A limiting dilution assay (LDA) was developed for the quantification of Trypanosoma cruzi in the heart and blood of infected mice. Three groups of swiss mice were injected ip with "CL", "Colombiana," and "Y" strains. At 1-day intervals after infection, blood and the heart were removed. Serial blood dilutions in LIT medium were performed and distributed in four groups of 24 microplate wells. The growth of parasite was visually checked in an inverted microscope. It was found that curves of parasitemia obtained by parasite counting in a hemocytometer or estimated by LDA were similar. A similar method was used to quantify parasites in the heart of mice. The heart was cut, washed, dried, and its weight was determined. The heart pieces were disrupted by passage through a mesh stainless-steel screen into LIT. Serial dilutions of the heart homogenate were made in LIT and added to at least 24 replicate microplate wells. Parasites were detectable earlier in the heart of mouse infected with Y strain when compared to CL and Colombiana strains. Parasites were detected in the heart of mice of all strains by 6 days after infection. This LDA for quantification of T. cruzi permits a more precise evaluation of the number of living parasites in infected tissues.


Perioperative outcomes of 6042 nephrectomies in 2012: surgeon-reported results in the UK from the British Association of Urological Surgeons (BAUS) nephrectomy database.
To present the perioperative outcomes from the British Association of Urological Surgeons (BAUS) nephrectomy dataset for 2012, the first year of public reporting of individual surgeon outcomes in the UK. All nephrectomies performed in the year 2012 and recorded in the database were analysed. These were divided into simple nephrectomy (SN), partial nephrectomy (PN), radical nephrectomy (RN), and nephroureterectomy (NU). The estimated capture rate for nephrectomy was 80%. The outcomes measured were 30-day mortality (30-DM), Clavien-Dindo complications grade ≥III, blood transfusion, conversion to open, and length of stay. The overall 30-DM was 0.55% (SN 0.53%; PN 0.10%; RN 0.52%; NU 1.27%). Clavien-Dindo complications grade ≥III were recorded in 3.9% of nephrectomies (SN 4.3%; PN 5.4%; RN 3.1%; NU 4.5%). Blood transfusion was required during surgical admission for 8.4% of nephrectomies (SN 5.2%; PN 3.4%; RN 11.1%; NU 8.3%). Conversion to open was carried out in 5.5% of minimally invasive nephrectomies (SN 6.1%; PN 4.0%; RN 5.5%; NU 5.6%). Open nephrectomy patients remained in hospital for a median of 6 days (SN 7; PN 5; RN 7; NU 8 days), which was higher than the median 4-day stay (SN 3; PN 4; RN 4; NU 5 days) for minimally invasive surgery. Nephrectomy in 2012 was a safe procedure with morbidity and mortality rates comparable with or less than published series. The collection of surgeon-specific data should be iterative with further refinement of data categories, support for the collection process and independent validation of results.


Automated morphometric magnetic resonance imaging analysis for the detection of periventricular nodular heterotopia.
To describe a novel magnetic resonance imaging (MRI) postprocessing technique for the detection of periventricular nodular heterotopia (PNH) and to evaluate its diagnostic value. The method is a further development of voxel-based morphometric analysis with focus on a region of interest around the lateral ventricles to increase the sensitivity and specificity for automated detection of abnormally located gray matter in this area. T(1) -weighted MRI volume data sets were normalized and segmented in statistical parametric mapping (SPM 5 software), and the distribution of gray matter was compared to a normal database. As a new approach, individual masks derived from segmentation of the lateral ventricles were used to restrict the search for ectopic gray matter to the periventricular area. PNH were automatically detected by localizing the maximum deviation from the normal database in this area, provided that the z-score exceeded a certain threshold. The optimal z-score threshold for maximum sensitivity and specificity was determined by a receiver operating characteristic (ROC) curve analysis. The method was applied in 40 patients with PNH and 400 controls. PNH were detected in 37 of 40 patients, and false positives were found in 34 of 400 controls, amounting to 92.5% sensitivity and 91.5% specificity. In 17 of the patients in whom PNH could be identified, these lesions had been overlooked in the past, and in 8 patients even in the high-resolution MRI subsequently used for postprocessing. The results suggest that automated morphometric MRI analysis with focus on ectopic gray matter in the periventricular areas facilitates the evaluation of MRI data and increases the sensitivity for the detection of PNH.


Neonatal bacterial endocarditis of the pulmonary valve: report of two cases.
Bacterial endocarditis in the neonate is rare and fatal in the majority of reported cases. This article reports two neonates who survived bacterial endocarditis. One patient was infected with group B beta-hemolytic streptococcus (GBBS) while the second grew Streptococcus saluvarius from the blood.


Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors.
Introduction This phase 1, open-label, multicenter, single-arm, dose-escalation study aimed to evaluate safety, pharmacokinetics (PK), and pharmacodynamics of erdafitinib (JNJ-42756493), an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, and to determine the recommended phase 2 dose in Japanese patients with advanced or refractory solid tumors. Methods Three to 6 patients were enrolled into sequentially escalating dose cohorts (erdafitinib 2, 4, or 6 mg) with a daily dosing schedule of 21-day cycles or a 7 days-on/7 days-off intermittent schedule (erdafitinib 10 mg or 12 mg) of 28-day cycles. Results Nineteen patients received escalating doses of erdafitinib with a daily or intermittent schedule. The most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (73.7%), nausea (36.8%), stomatitis (26.3%), dysgeusia (26.3%) and dry mouth (21.1%). The maximum tolerated dose was not reached in this study. No Grade 3 or higher TEAEs, or serious TEAEs were noted and no clinically significant changes in vital signs, laboratory parameters, and electrocardiogram readings were observed. However, one case of dose-limiting toxicity in the 12 mg intermittent dosing group was observed: Grade 2 detachment of retinal pigment epithelium (bilateral) with treatment discontinuation. The maximum plasma concentrations of erdafitinib exhibited a dose-dependent increase. The median tmax ranged from 2 to 3 h after the initial dose to 2-6 h following multiple daily dosing. Based on the safety and PK data, the 10 mg 7 days-on/7 days-off regimen was determined as the recommended phase 2 dose in this study. Conclusions Erdafitinib was well tolerated in Japanese patients with advanced or refractory solid tumors. NCT01962532.


Chiral amines derived from 2-arylpropionic acids: novel reagents for the liquid chromatographic (LC) fluorescence assay of optically active carboxylic acid xenobiotics.
For the enantiospecific analysis of optically active carboxylic acids, the availability of readily detectable coupling components is desirable, but highly fluorescent chiral amines are rare. From activated enantiomers of fluorescent 2-arylpropionic acids fluorescent chiral amines were synthesized via Curtius degradation, i.e., under formation of the acyl azide, the isocyanate, and finally, the amine. The formation of isocyanates and of amine hydrochlorides led to an inversion of the direction of rotation of polarized light. Amines derived from R- and S-flunoxaprofen, R- and S-naproxen, and R/S-benoxaprofen were characterized. The amines were found to be applicable for the chiral separation of carboxylic acids (such as 2-arylpropionic acids) as diastereomeric derivatives via high-performance liquid-chromatographic (normal and reversed-phase) and thin-layer chromatographic techniques.


Antimicrobial activity effects of electrolytically generated hypochlorous acid-treated pathogenic microorganisms by isothermal kinetic simulation.
This study involves isothermal kinetic simulation to evaluate the parameters of inhibition conditions for Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) of high-risk pathogens. This is because the new type of the 2019 novel coronavirus (2019-nCoV) is continuously spreading and the importance of public health issues. Environmental disinfection and personal wearing of masks have become important epidemic prevention measures. Selection of concentration kinetics could be estimated best for E. coli and S. aureus of pathogens, 2.74 × 104 and 105 and 2.44 × 104 and 105 colony-forming units (CFU mL-1), by isothermal micro-calorimeter (TAM Air) tests, respectively. Comparisons were made of different doses of 0-70 ppm (in 20 mL test ampoule) hypochlorous acid treatment for conducting nth-order and autocatalytic reaction simulation to evaluate the inhibition reaction parameters, which determined the autocatalytic kinetic model that was beneficially applied on the E. coli and S. aureus. We developed the inhibition reaction parameters of the pathogens, which included the activation energy (E a), the natural logarithm of pre-exponential factor (lnk 0), the enthalpy of inhibition microbial growth reaction (∆H), inhibition microbial growth, and the inhibition growth analysis. Overall, we conducted isothermal kinetic simulation to understand the antimicrobial activity effects of electrolytically generated hypochlorous acid-treated pathogenic microorganisms, which will provide reference for public health and medical-related fields for SDG3, and can contribute to ensuring human health and hygiene.


Heat-shock protein 70 (HSP70) polymorphisms affect the risk of coke-oven emission-induced neurobehavioral damage.
Epidemiology studies indicated that coke-oven workers with long-term exposure to polycyclic aromatic hydrocarbons (PAHs) often have some neurobehavioral abnormalities especially impairment for cognitive function, while the underlying mechanisms are not fully understood. Numerous studies have indicated the antioxidant and anti-apoptosis roles of heat shock protein 70 (Hsp70). The genetic polymorphisms in HSP70 genes are associated with multiple diseases including neurotoxicity. However, it is unclear whether HSP70 polymorphisms are related to the neurotoxicity of PAH. We, therefore, investigate the possible association between HSP70 polymorphisms and neurobehavioral abnormalities. 188 coke-oven workers and 137 control workers were recruited in this study. Emotional and cognitive function was assessed using the WHO/NCTB. HSP70 polymorphisms (HSP70-1 G190C, HSP70-2 G1267 A and HSP70-hom T2437C) were checked by PCR-RFLP. The results indicated that HSP70-1 CC genotypes in coke-oven workers were associated with poor neurobehavioral performance such as the attention /response speed and visual perception/memory, while the HSP70-2 AA genotypes were associated with lower short-term auditory memory. HSP70-1 CC and HSP70-2 AA genotypes in coke-oven workers may increase the risk for neurobehavioral damage, especially attention, learning and memory.


Experimental model of thrombus adherence to the vessel wall.
Clot adherence to peritoneal cavity mesothelium was studied in rats in an attempt to contribute to the problem of thrombus embolization. The adherence was decreased by platelets and the active constituent was identified as adenosine diphosphate which decreased the sticking of fibrin to cellular linings as well as to artificial surfaces.


Violence and home care. A focus group study.
This study describes home caregivers' and managers' beliefs and experiences related to violence in their workplace. Suggested strategies are recommended that can help home care organizations recognize, prevent, and manage violence in their workplace.


Ethosuximide induced macroglossia and oropharyngeal edema.
Acute macroglossia and laryngeal edema are rare adverse side effects that can cause life-threatening airway obstruction. We report a case of acute macroglossia that began after initiation of ethosuximide in a 15-year-old female with severe medically refractory epilepsy. Macroglossia worsened over the next two weeks of ethosuximide administration, preventing extubation. Macroglossia and laryngeal edema improved upon ethosuximide wean, and completely resolved after discontinuation. The patient was extubated successfully, with precautionary nasal trumpet placement and dexamethasone administration prior to extubation. In medically complex patients on multiple pharmacologic agents, anti-epileptic drugs should be suspected as a possible cause of acute macroglossia.


Psychological stress in IBD: new insights into pathogenic and therapeutic implications.
Psychological stress has long been reported anecdotally to increase disease activity in inflammatory bowel disease (IBD), and recent well designed studies have confirmed that adverse life events, chronic stress, and depression increase the likelihood of relapse in patients with quiescent IBD. This evidence is increasingly supported by studies of experimental stress in animal models of colitis. With the evolving concept of psychoneuroimmunology, the mechanisms by which the nervous system can affect immune function at both systemic and gut mucosal levels are gradually becoming apparent. Recent data suggest that stress induced alterations in gastrointestinal inflammation may be mediated through changes in hypothalamic-pituitary-adrenal (HPA) axis function and alterations in bacterial-mucosal interactions, and via mucosal mast cells and mediators such as corticotrophin releasing factor (CRF). To date, the therapeutic opportunities offered by stress reduction therapy remain largely unexplored, in part because of methodological difficulties of such studies. This paper reviews recent advances in our understanding of the pathogenic role of psychological stress in IBD and emphasises the need for controlled studies of the therapeutic potential of stress reduction.


Prevalence of cancer in Italian obese patients referred for bariatric surgery.
An association between obesity and cancer has been shown in large epidemiological studies. The aim of this study was to evaluate the prevalence and types of malignancies in an Italian cohort of obese patients referred to a bariatric center. A retrospective, observational study was conducted. Between Jan 1996 and Dec 2004, 1,333 obese patients (M=369, F=964) were seen in the center for minimally invasive treatment of morbid obesity. Morbid obesity were considered as BMI >40 kg/m(2) or BMI >35 kg/m(2) with at least one co-morbidity. Obese and morbidly obese patients who suffered any form of cancer were reviewed. 43 patients (3.2%) presented various malignancies, with 88.3% in females. The prevalence of cancer in the younger group (21-46 years) was higher than in the older group (47-70 years), 2.1% vs 1.1%. 26 obese patients out of the 43 (60.5%) (age 41+/-7.9 years, BMI 38.2+/-9.9) presented hormone-related tumors. The most frequent site of cancer was breast (20.9%), followed closely by thyroid. This is the first Italian report on prevalence of cancer in a homogeneous obese population attending an academic bariatric center. The morbidly obese patients appear to have a higher risk of developing cancer, with a higher prevalence of hormone-related tumors. The predominant gender affected by both obesity and cancer was female. Thus, a preoperative work-up for cancer screening is indicated in this group of patients.


Olaparib monotherapy as primary treatment in unselected triple negative breast cancer.
The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure. In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples. The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response. Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations. ClinicalTrials.gov identifier: NCT02624973.


YY1-induced long non-coding RNA small nucleolar RNA host gene 8 promotes the tumorigenesis of melanoma via the microRNA-656-3p/SERPINE1 mRNA binding protein 1 axis.
Long non-coding (lnc) RNA serves a vital role in the cellular processes of carcinoma. This study aimed to explore the accurate mechanism underlying lncRNA small nucleolar RNA host gene 8 (SNHG8) in melanoma. In this study, lncRNA SNHG8 expression were upregulated in melanoma tissues and cells, and lncRNA SNHG8 knockdown reduced melanoma cell viability, migration and invasion. Moreover, lncRNA SNHG8 expression could be induced by transcription factor YY1. In addition, we found that miR-656 could directly bind to lncRNA SNHG8 and SERPINE1 mRNA binding protein 1 (SERBP1). Rescue assays indicated that miR-656 overexpression inhibited the aforementioned cellular activities in melanoma cells, which were reversed by SERBP1 overexpression. In conclusion, this work elucidated that YY1-induced upregulation of lncRNA SNHG8 boosted the development of melanoma via the miR-656-3p/SERBP1 axis, providing a novel therapeutic strategy for melanoma treatment.


Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease: evaluation of the protective role of the metabolic modulator trimetazidine.
We sought to assess the effects of heparin and the potential protective effects of trimetazidine (TMZ) on exercise performance, plasma nitric oxide (NO), endothelin-1 (ET-1) and free fatty acid (FFA) release in patients with stable coronary artery disease (CAD). Heparin has been shown to reduce the ischemic threshold in patients with CAD. Trimetazidine may affect myocardial substrate utilization by shifting energy production from FFA to glucose oxidation. In four consecutive days, nine patients with CAD each received one of the following four regimens: 1) one tablet of placebo the evening before and at 8 AM and 4 PM on the day of the study, 10 ml of saline in a bolus 10 min before exercise, followed by an infusion of the same preparation; 2) placebo at the same times as in the first regimen, 5,000 IU of heparin 10 min before exercise, followed by 1,000 IU/h; 3) 20 mg TMZ at the same times as in the first regimen, 5,000 IU of heparin 10 min before exercise, followed by 1,000 IU/h; or 4) TMZ at the same times as in the first regimen, 10 ml of saline 10 min before exercise, followed by an infusion of the same preparation. During placebo (test 2), heparin reduced the time to 1-mm ST-segment depression and prolonged the recovery time, as compared with the results of test 1. When heparin was administered after TMZ (test 3), the time to 1-mm ST-segment depression and the recovery time were similar to those recorded during saline (test 1). Finally, compared with all study phases, TMZ during saline (test 4) prolonged the time to 1 mm. No changes in NO release were found, whereas ET-1 was decreased at peak exercise and during recovery, when the patients were receiving TMZ (tests 3 and 4). Free fatty acids increased after heparin, both with placebo and TMZ. In patients with CAD, heparin reduces the ischemic threshold. Trimetazidine reduces the effects of heparin, probably by inhibiting FFA oxidation and enhancing glucose metabolism. The concomitant novel observation of reduced ET-1 release is likely to be also dependent on TMZ-induced improvement of endothelial metabolism or reduction of myocardial ischemia.


Neuroinflammation and neuroprogression in depression: Effects of alternative drug treatments.
Given that available antidepressant pharmacotherapies are not optimally effective, there is a need for alternative treatment options that are rooted in a comprehensive understanding of the illness's pathophysiology. Major depressive disorder (MDD) has been historically attributed to monoamine, i.e., serotonin (5-hydroxytryptamine, 5-HT) imbalance and some brain morphological pathologies that have directed treatment towards particular medications that are only minimally effective. MDD pathophysiologies have now been regarded as linked to chronic inflammation and MDD can be treated with compounds that have anti-inflammatory properties. Individuals vulnerable to MDD have increased baseline neuroinflammatory response that is exacerbated by psychogenic stress. When pro-inflammatory mechanisms are chronically hyperactive, dysfunction of brain-related processes occur. We propose that inflammation is one of the primary mechanisms that trigger biological changes leading to MDD. Inflammatory resolution occurs when homeostasis is achieved after an inflammatory response. However, cascading biological events are likely to prevent resolution from occurring and worsen both inflammation and MDD. Novel and alternative pharmacotherapies-e.g., ketamine, cannabinoids, and psychedelics-provide a richer mechanistic perspective on the role of neuroinflammation and neuroprogression by means of rapid, short-term, and long-term symptom relief potentially based on their anti-inflammatory properties. These drugs ultimately decrease proinflammatory cytokine levels that correspond with improved symptoms. However, it is unclear what differentiates these compounds from others in their mechanistic efficacy. Thus, a closer investigation into their anti-inflammatory effects is imperative in order to better elucidate the link between MDD and inflammation, as well as uncover the mechanisms involved in long-term symptom reduction of MDD.


High-throughput virtual screening approach involving pharmacophore mapping, ADME filtering, molecular docking and MM-GBSA to identify new dual target inhibitors of PfDHODH and PfCytbc1 complex to combat drug resistant malaria.
Emerging cases of drug resistance against Artemisinin combination therapies which are the current and the last line of defense against malaria makes the situation very alarming. Due to the liability of single-target drugs to be more prone to drug resistance, the trend of development of dual or multi-target inhibitors is emerging. Recently, a malaria box molecule, MMV007571 which is a well known new permeability pathways inhibitor was investigated to be also multi-targeting Plasmodium falciparum dihydroorotate dehydrogenase and cytochrome bc1 complex. The aspiration behind this study was to use the information of its pharmacophoric features essential for binding as two of its new targets. In this regard, high throughput virtual screening involving pharmacophore mapping, ADME filtering, molecular docking, and MM-GBSA calculations were carried out. This approach has lead to the identification of two new hits namely DT00V1902 and DT00V1922 which binds with -37.85 and -24.65 kcal/mol of more stable ΔG Bind energy at two targets than the lead molecule, MMV007571. The screened compounds are indicated to be carry improvement in binding potential and pharmacokinetic characters as per in silico studies. The authors propose that DT00V1902 and DT00V1922 can be forwarded for experimental validation and clinical studies for antimalarial chemotherapy. Communicated by Ramaswamy H. Sarma.


Can mental practice increase ankle dorsiflexor torque?
Mental practice has been shown to be effective in increasing the force production of the abductor digiti minimi muscle in the hand. The aim of this study was to determine whether mental practice could produce strength gains in the larger ankle dorsiflexor muscles, which are important during walking. Twenty-four subjects were randomly assigned to a physical practice group, a mental practice group, or a control group (8 subjects per group). In the practice groups, subjects either physically or mentally practiced producing maximal isometric contractions for 3 sets of 10 repetitions, 3 times per week for 4 weeks. Changes in mean peak isometric torque normalized to body weight and the resulting percentage of improvement were analyzed across the 3 groups. Differences in raw torque production after training in the 2 practice groups resulted in significant percentages of improvement for the physical practice group (25.28%) and the mental practice group (17.13%), but not for the control group (-1.77%). The 2 practice groups were not statistically different in their maximal torque-generating capacity after training. These findings show that mental practice in people without impairments can lead to an increase in torque production similar to that produced by physical practice. Such a technique may prove to be a useful adjunct to traditional treatment options aimed at increasing muscle strength.


Effects of vestibular stimulation on gait stability when walking at different step widths.
Vestibular information modulates muscle activity during gait, presumably to contribute to stability. If this is the case, stronger effects of perturbing vestibular information on local dynamic stability of gait, a measure of the locomotor system's response to small, naturally occurring perturbations, can be expected for narrow-base walking (which needs more control) than for normal walking and smaller effects for wide-base walking (which needs less control). An important mechanism to stabilize gait is to coordinate foot placement to center of mass (CoM) state. Vestibular information most likely contributes to sensing this CoM state. We, therefore, expected that stochastic electrical vestibular stimulation (EVS) would decrease the correlation between foot placement and CoM state during the preceding swing phase. In 14 healthy participants, we measured the kinematics of the trunk (as a proxy of the CoM), and feet, while they walked on a treadmill in six conditions: control (usual step width), narrow-base, and wide-base, each with and without stochastic EVS (peak amplitude of 5 mA; RMS of ~ 1.2 mA; frequency band from 0 to 25 Hz). Stochastic EVS decreased local dynamic stability irrespective of step width. Foot placement correlated stronger with trunk motion during walking with EVS than without in the control condition. However, residual variance in foot placement was increased when walking with EVS, indicating less precise foot placement. Thus, a vestibular error signal leads to a decrease in gait stability and precision of foot placement, but these effects are not consistently modulated by step width.


Comparison of tunnel ligament release instrument assisted minimally open surgery and conventional open surgery in the treatment of tarsal tunnel syndrome.
This study compared the results of tarsal tunnel syndrome release surgeries using mini-open incisions and standard incisions. From January 2012 until April 2018, 31 feet of 29 patients diagnosed with tarsal tunnel syndrome were treated surgically. 15 feet of 15 patients underwent surgeries utilizing minimally open technique and 16 feet of 14 patients underwent surgeries utilizing standard incisions. The following preoperative and postoperative data was obtained: foot and ankle muscle testing results, posture analyses, anthropometric measurements, joint movement ranges, pain complaints, endurance evaluation results, and functional test results. The mean follow-up period was 38 months (13-88 months). The mean operation times were 26.8 min (23-30 min) using the standard incision and 13.3 min (9-17 min) using the mini-open incision (p < 0.05). In the preoperative and postoperative comparisons of the total muscle strength and total joint limit values of the healthy and affected feet, statistically significant improvements were observed in both the mini-open incision and standard incision groups (p < 0.05). Moreover, statistically significant improvements were seen in both groups in the postoperative repeated toe raises for 1 minute assessments of the affected foot (p < 0.05). In the foot function index and functional foot score values, statistically significant improvements were seen between the preoperative and postoperative values in both groups (p < 0.05). Based on the results of this study, using a tunnel ligament release instrument assisted minimally open surgery to loosen the laciniate ligament may present an alternative to the standard incision, with its significantly decreased morbidity rate and cosmetic success.


Immunological correlates between multiple isolated subunits of Androctonus australis and Limulus polyphemus hemocyanins: an evolutionary approach.
Immunological cross-reactivities between isolated subunits of the scorpion Androctonus australis (Aa) and of the horseshoe crab Limulus polyphemus (Lp) hemocyanins were studied using subunit-specific antibodies prepared through immunoadsorption to pure immobilized subunits. Rocket immunoelectrophoreses of the various subunits of both hemocyanins were carried out at constant antigen concentration against the various subunit-specific antibody preparations. Then the data were analyzed through factorial correspondence analysis and compared to the respective intramolecular locations of the subunits in both hemocyanins. The results show that the dimeric subunits located in the central part of each (4 X 6)meric structure (Aa whole molecule and Lp half molecule) were strongly preserved. In addition, the (8 X 6)mer-forming subunit of Lp hemocyanin (LpIV) and the subunit occupying the same intramolecular position in Aa hemocyanin (Aa5A) were also strongly preserved. Besides the strong antigenic relatedness, less pronounced crossed immunoprecipitations or no precipitation at all were observed between subunits with homologous positions suggesting a minor structural and/or functional roles for these subunits. All the antigen-antibody combinations leading to an absence of immunoprecipitation were screened for the presence of soluble immunocomplexes by radioimmunological tests. In all cases, soluble immunocomplexes were observed. These results suggest the following evolution scenario. First, the central dimeric subunits, responsible of the dodecamer aggregation (Aa3C and 5B and LpV and VI) were already differentiated when Merostomata diverged from Arachnida. Second, the differentiation of the (8 X 6)mer-forming subunit occurred in the Merostomata ramification in a preserved subunit already possessing a functional advantage. Third, the differentiation of subunits Aa3A and Aa3B recently occurred in the scorpion ramification.


Implantation of pericardial substitutes.
Pericardial substitutes have been shown to decrease the formation of pericardial adhesions. For a pericardial substitute to be properly implanted, it must lie over the heart smoothly without buckling and prevent the accumulation of blood under its surface. The technique we describe prevents buckling of the pericardial substitute and consequently reduces the formation of pericardial adhesions.


Analysis of furan and its major furan derivatives in coffee products on the Chinese market using HS-GC-MS and the estimated exposure of the Chinese population.
The current study analysed concentrations of furan and its derivatives in coffee products commercially available in China based on an improved headspace gas chromatography-mass spectrometry (HS-GC-MS) method and estimated health risks. A total of 101 samples of coffee products on the Chinese market was analysed. Furan (98%, ND-6569 μg/kg) and 2-methylfuran (100%, 2-29639 μg/kg) were the compounds with the highest concentrations and detection rates in coffee products. The mean dietary exposure of Chinese consumers to furan and the sum of furan, 2-methylfuran and 3-methylfuran in coffee products was 0.09 and 0.46 μg/kg bw/day, respectively. For the neoplastic effects of furan, the margin of exposure (MOE) was 14,556 for the mean dietary exposure of consumers. For the non-neoplastic effects of furan, MOEs were 711 and 139 for furan and the sum of furan, 2-methylfuran and 3-methylfuran, respectively. Overall, a health concern is indicated for coffee consumers with MOEs below 10000.


Planetary Health and the Role of Nursing: A Call to Action.
To discuss the drivers of planetary health, responses, and the role of nursing in making health systems more resilient in an era of increasing stresses. As health providers, scientists, educators, and leaders, nurses have an obligation to prepare for climate change and other impacts of ecosystem strain on human health. Review of literature relevant to a planetary health framework. Population displacement, new disease patterns and health needs, stresses on air quality, food production and water systems, and equity concerns, as well as the generation of sustainable energy, are all intimately related to health. Nurses are key to achieving the sustainable development goals that, like the planetary health framework, focus on environmental sustainability and human well-being. Nurses contribute to resilient health systems, as trusted leaders and providers of health care, and as advocates and change makers impacting the world. It is critical that nurses and other health professionals consider the multiple effects of ecosystem strain on human health, and anticipate population health and health system planning and response.


Passive and dynamic shoulder rotation range in uninjured and previously injured overhead throwing athletes and the effect of shoulder taping.
To investigate: (1) the passive and dynamic shoulder internal (IR) and external (ER) rotation range of motion (ROM) of 2 groups of asymptomatic overhead throwing athletes: one group who had never experienced shoulder symptoms and another who had shoulder symptoms >12 months ago, (2) the effect of taping on the passive and dynamic IR-ER ROM in both these groups. A within-subject repeated measures analysis of variance design to determine the differences in passive and dynamic shoulder rotation range and the effect of shoulder taping on the rotation range in a group of uninjured and previously injured overhead throwing athletes. Academic institution sports medicine setting. Twenty-six overhead throwing collegiate athletes: 17 with no history of shoulder injury and 9 with previous shoulder injury. Passive shoulder ROM was measured with a goniometer with the subject in the supine position. To measure dynamic ROM, the subjects sat on a chair and threw a handball into a net. An 8-camera Vicon Motion Capture system recorded markers placed on the upper limb and trunk. Dynamic ROM was calculated with inverse kinematics by using OpenSim. Shoulder IR-ER ROM. Dynamic IR-ER ROM was significantly greater than passive IR-ER ROM (P < .0001). There was no difference in passive IR-ER ROM between the uninjured and previously injured overhead throwing athletes. However, there was a significant difference in the total dynamic IR-ER ROM, whereby the overhead throwing athletes who had never experienced shoulder symptoms had less IR-ER ROM than the previously injured group (173.9° versus 196.9°, respectively; P = .049). Taping the shoulder increased the passive ROM in both groups of subjects (P < .001), increased the dynamic IR-ER ROM in the uninjured subjects, but decreased the dynamic IR-ER ROM in the previously injured subjects, although this was not statistically significant (P = .07). Passive IR-ER ROM is a poor indication of dynamic shoulder function. Athletes who have had a previous shoulder injury demonstrate a greater dynamic IR-ER ROM than athletes who have never had a shoulder injury. Shoulder taping decreased the dynamic range of the previously injured athlete, so that it was nearer the dynamic range of the uninjured athlete. Shoulder taping might provide increased protection for the injured athlete by decreasing the dynamic IR-ER ROM and by facilitating better shoulder and scapular muscle control. Further studies are necessary to demonstrate whether this finding is clinically significant.


Incidental Findings in CT Scans on Screening for COVID-19.
Incidentalomas on computed tomography (CT) scans are incidental or unsuspected findings that are detected when obtaining a CT examination for an unrelated reason. Incidentalomas on CT scans are common. This study was conducted to examine the rates of incidental findings on CT chest in patients who were screened for COVID-19. Three thousand one hundred ninety-one CT scans were assessed for incidental findings. These CT scans were taken from an urban diagnostics laboratory in Hyderabad (IN) over a period of 2 months (April to May 2021) when the COVID-19 s wave peaked. Data from these reports were tabulated with demographic information and findings. Out of 3191 scans, 277 (8.68%) showed incidental findings, the most common of which was lung nodules and other individual findings. There were 6 total malignancies detected and a further 92 cases that required follow-up. CT scans are important for the detection of incidental findings. Care should be taken to follow up on patients with incidental findings that are undetermined to catch a lesion in the early stage.


Is there a role for drain use in elective laparoscopic cholecystectomy? A controlled randomized trial.
Although the issue of drain use in open cholecystectomy has been adequately addressed by prospective randomized trials, there is lack of evidence on the usefulness of drains in elective laparoscopic cholecystectomy, and the surgeons follow their beliefs and bias on this debate. Therefore, a controlled randomized trial was designed to assess the value of drains in elective laparoscopic cholecystectomy. During a 5-year period (January 2002 to December 2006), 284 patients were randomized to have a drain placed (group A), whereas 281 patients were randomized not to have a drain (group B) placed in the subhepatic space. End points of this trial were to detect any differences in morbidity, postoperative pain, and hospital stay between the 2 groups. There was no mortality in either group and no statistically significant difference in morbidity or hospital stay between the 2 groups. However, postoperative pain was significantly increased in patients who had a drain placed; median visual analog scale (VAS) score was 5 (range 1 to 8) versus 3 (range 1 to 8), in the non-drained group (P < .0001). Interestingly, in 2 of 3 patients in whom a drain was placed against randomization because of bile leak suspicion, a bile leak occurred. The routine use of a drain in elective laparoscopic cholecystectomy has nothing to offer; in contrast, it is associated with increased pain. It would be reasonable, however, to leave a drain if there is a worry about an unsolved or potential bile leak, bearing in mind that drain placement, although sometimes providing a false sense of security, does not guarantee either prevention or treatment of postoperative bile collections, bleeding, or bile peritonitis.


Status of ghrelin as an islet hormone and paracrine/autocrine regulator of insulin secretion.
Ghrelin is expressed in the pancreatic islet cells as well as the stomach. In the perfused pancreas and isolated islets, GHS-R antagonism, ghrelin immunoneutralization and ghrelin-knockout (Ghr-KO) all increase glucose-induced insulin release. Thus, pharmacological, immunological and genetic blockades of ghrelin in the pancreatic islets all markedly augment glucose-induced insulin release, showing that islet-derived ghrelin physiologically restricts insulin release in rodents. In this review, we focus on the current understanding of the following key questions: 1) from which islet cells ghrelin is released, 2) on which islet cells ghrelin acts, and 3) mechanisms by which the islet-derived ghrelin inhibits insulin secretion.


Long-term risk of venous thromboembolism recurrence after isolated superficial vein thrombosis.
Essentials Long-term risk of recurrence of isolated superficial vein thrombosis (SVT) is under-studied. We analyzed data from a cohort of first SVT and proximal deep vein thrombosis (DVT) without cancer. The risk of recurrence as DVT or pulmonary embolism is twice lower in SVT patients. However, overall risk of recurrence is similar between SVT and proximal DVT patients. Click to hear Dr Decousus' perspective on superficial vein thrombosis SUMMARY: Background Isolated superficial vein thrombosis (iSVT) (without concomitant deep vein thrombosis [DVT] or pulmonary embolism [PE]) is a frequent event, but available data on long-term outcomes are scarce and retrospective. Therefore, we aimed to determine prospectively the risk and type of venous thromboembolism (VTE) recurrence after iSVT and compare them with those of proximal DVT. Methods Using data from the prospective, multicenter, observational, OPTIMEV study, we assessed, at 3 years and after anticoagulants were stopped, the incidence and the type of VTE recurrence (iSVT/DVT/PE) of patients with a first objectively confirmed iSVT without cancer (n = 285), and compared these with those of patients with a first proximal DVT without cancer (n = 262). Results As compared with proximal DVT patients, iSVT patients had a similar overall incidence of VTE recurrence (5.4% per patient-year [PY] versus 6.5% per PY, adjusted hazard ratio [aHR] 0.9, 95% confidence interval [CI] 0.5-1.6), but iSVT recurred six times more often as iSVT (2.7% versus 0.6%, aHR 5.9, 95% CI 1.3-27.1) and 2.5 times less often as deep-VTE events (2.5% versus 5.9%, aHR 0.4, 95% CI 0.2-0.9). Varicose vein status did not influence the risk or the type of VTE recurrence. Saphenian junction involvement by iSVT was not associated with a higher risk of recurrence (5.2% per PY versus 5.4% per PY), but was associated with recurrence exclusively as deep-VTE events. Conclusion In patients with a first iSVT without cancer, after stopping anticoagulants, the incidence of deep-VTE recurrence is half that of DVT patients, but the overall risk of recurrence is similar. Ssaphenian junction involvement seems to influence the risk of deep-VTE recurrence, whereas varicose vein status has no impact or a low impact on VTE recurrence.


Are we taught how to use a radiology department as medical students?
Thirty-six final year medical students and 28 senior house officers answered a questionnaire designed to evaluate their efficacy in requesting common radiological procedures and their knowledge of what the patient experiences during the investigation. Both groups revealed a significant degree of ignorance, though the house officers were better informed than the students. The need for undergraduate teaching in radiology, particularly in the role of diagnostic radiology in clinical management is discussed.


Pharyngoplasty for obstructive sleep apnea: The influence of surgical technique.
Obstructive sleep apnea is the most frequent sleep disorder worldwide, with rising incidence. Pharyngoplasty is an alternative treatment in patients not suitable to continuous positive airway pressure devices (CPAP). The aim of this study is to compare different surgical techniques of pharyngoplasty for treatment of obstructive sleep apnea and evaluate its influence in surgical success. Retrospective study of 92 patients that underwent pharyngoplasty for treatment of obstructive sleep apnea from 2001 to 2020. Included patients performed classic uvulopalatopharyngoplasty (UPPP), radiofrequency assisted uvulopalatopharyngoplasty (RF-UPPP) or barbed reposition pharyngoplasty (BRP). Surgical success was defined and outcomes and complications assessed for each procedure. Most patients were male, with a mean age of 49.36±9.6 years and a mean apnea hypopnea index (AHI) of 29.14±2.94events/h. Thirty-six patients performed classic UPPP, thirty-one underwent RF-UPPP and the remaining twenty-five performed BRP. BRP achieved the highest success rate (66%) in comparison with UPPP (57%) and RF-UPPP (54%) (p=0.032). Mean relative AHI reduction after surgery was not statistically different between three procedures (p=0.098), although there was a tendency for greater reduction with BRP. Most symptoms improved after surgery and snoring was the most recurrent symptom. BRP had less foreign body sensation after surgery, however, it was the procedure with highest rate of post-operative tonsillar bleeding. In our department, the introduction of recent techniques of velopharyngeal surgery, focused in functional and lateral muscular collapse, has translated into an increase in success rate after surgery. The relative ease of the procedure and reduction of long term complications make BRP an attractive alternative option for CPAP in OSA, in carefully selected patients.


Regional repositories, reintermediation and the new GMS contract: cardiovascular disease in Tayside.
The new contract for general medical practitioners will make increasing demands on the primary care informatics community. There are a number of potential ways to provide reports which meet the requirements for data on the quality of care being provided by practices. In Scotland there are four components of the national information technology strategy which make meaningful comparisons of data possible. Using cardiovascular data as an example, to describe how the community health index number, managed clinical networks (MCNs), increasing consistency of Read codes, and regional repositories of data make the acquisition, processing and use of data more straightforward. The cardiovascular MCN collects the majority of its data electronically and four properties are crucial to its success: automatic collection of electronic data from many sources, prioritisation of data derived from multiple sources, record linkage processes, and manual validation of electronic data. Clinicians in primary and secondary care enter data during consultations and see the results of consultations recorded elsewhere. Because all data from the region are able to be Read coded according to prespecified templates, we are able to indicate to practices where they are in relation to the new contract targets and indicate which patients need to be seen, or excluded from, calculations. Effectively integrated management is facilitated by provision of regular prompted recall and review of people with chronic disease by multidisciplinary teams collaborating across the health service and into the community. In Scotland, use of newer informatics tools are proving to be useful contributions from primary care computing to equitable, evidence-based care.


Insights into the molecular architecture of a peptide nanotube using FTIR and solid-state NMR spectroscopic measurements on an aligned sample.
Queuing up: Molecular orientation within macroscopically aligned nanotubes of the peptide AAAAAAK can be studied by solid-state NMR and IR spectroscopy. Line shape analysis of the NMR spectra indicates that the peptide N-H bonds are tilted 65-70° relative to the nanotube long axis. Re-evaluation of earlier X-ray fiber diffraction data suggests that the peptide molecules are hydrogen-bonded in a helical arrangement along the nanotube axis.


Pulsed dose-rate perioperative interstitial brachytherapy for soft tissue sarcomas of the extremities and skeletal muscles of the trunk.
This study evaluated the role of pulsed dose-rate (PDR) brachytherapy (BRT), delivered alone or as a boost to external beam radiotherapy, as adjuvant therapy for the local control of soft tissue sarcomas of the extremities and skeletal muscles of the trunk that have undergone surgical treatment. Between July 1998 and January 2002, 42 patients were treated with a combination of surgery and BRT alone (18 patients) or BRT/external beam radiotherapy (24 patients) for the treatment of primary (n = 32) and recurrent (n = 10) soft tissue sarcomas located in the proximal extremity (n = 17), distal extremity (n = 17), and trunk (n = 8). Tumor size was <5 cm in 20 cases and >5 cm in 22 cases, with histological grading of 1 (n = 7), 2 (n = 18), or 3 (n = 17). The median BRT dose delivered was 15 Gy, and the median external beam irradiation dose was 50 Gy. With a median follow-up of 34 months, the 36-month survival was 83.9% (SE, 6.1%), and the local control was 89%. PDR interstitial BRT for soft tissue sarcoma is an effective, well-tolerated adjuvant radiation treatment that offers several practical advantages, among which are low acute and late toxicity with maximum normal tissue and critical structure sparing and overall shorter radiotherapy and hospital stay.


Quantification of fatty acid oxidation products using online high-performance liquid chromatography tandem mass spectrometry.
Oxidized fatty acids formed via lipid peroxidation are implicated in pathological processes such as inflammation and atherosclerosis. A number of methods may be used to detect specific oxidized fatty acids containing a single or multiple combinations of epoxide, hydroxyl, ketone, and hydroperoxide moieties on varying carbon chain lengths from C8 up to C30. Some of these methods are nonspecific and their use in biological systems is fraught with difficulty. Measures of specific oxidized fatty acid derivatives help in identifying oxidation pathways in pathological processes. We used liquid chromatography coupled with electrospray ionization tandem mass spectrometry as an efficient, selective, and sensitive method for identifying and analyzing multiple specific fatty acid peroxidation products in human plasma and other biological matrices. We then distilled the essential components of a number of these analyses to provide an efficient protocol by which fatty acid oxidation products and their parent compounds can be determined. In this protocol, addition of a synthetic internal standard to the sample, followed by base hydrolysis at elevated temperature and liquid-liquid phase sample extraction with lighter-than-water solvents, facilitates isolation of the oxidized fatty acid species. These species can be identified and accurately quantified using stable-isotope dilution and multiple-reaction monitoring. Use of a coupled multiplexed gradient HPLC system on the front end enables high-throughput chromatography and more efficient use of mass spectrometer time.


Laparoscopic management of the perforated viscus.
Perforation of a hollow viscus is an emergency which should prompt a rapid and effective treatment. Open surgery has been considered the standard approach, but the use of laparoscopy for diagnostic purposes and treatment in favorable circumstances and locations appears to be a safe alternative with a number of advantages. Indications and contraindications, which depend on the nature of the disease, the duration of the perforation and the location, are discussed in detail.


Chronic daily headache: transformational migraine, chronic migraine, and related disorders.
Chronic daily headache is an important category of headache illness that affects 4% of the general population. Within this classification are four chronic headache entities: chronic migraine/transformational migraine, chronic tension-type headache, hemicrania continua, and new daily persistent headache. Chronic migraine/transformational migraine is the most common of these entities and is frequently accompanied by medication overuse, neurobehavioral comorbidity, and disability. The terminology and classification of this entity continue to be confounding. Current research is directed at identifying factors that might promote the progression of this disorder from episodic migraine to daily or almost daily headache, and at identifying the best approaches to treatment, which include both pharmacotherapeutic and non-medicinal interventions. Patients with intractable cases are often hospitalized as a consequence of the convergence of several factors that make outpatient management unlikely to succeed.