Monoclonal anti-human prostatic acid phosphatase antibodies.
Hybrid cell lines producing monoclonal antibodies against human prostatic acid phosphatase (E. C. 188.8.131.52) were prepared by the fusion of mouse myeloma cells with the spleen cells of BALB/c mice and Lewis rats immunized with prostatic acid phosphatase (PAP). Approximately 14% of the hybrid cell microcultures which produced specific antibodies were cloned, and 6 eventually yielded stable cell lines. The monoclonal antibodies produced by these 6 hybridomas were characterized for their isotypes, isoelectric points, concentrations and affinities. The specificity of these monoclonal antibodies was further investigated by radioimmunoassay and immunohistochemical methods. All of the 6 monoclonal antibodies exhibited strict specificity for prostatic acid phosphatase.


Heart rate variability in elite triathletes, is variation in variability the key to effective training? A case comparison.
Measures of an athlete's heart rate variability (HRV) have shown potential to be of use in the prescription of training. However, little data exists on elite athletes who are regularly exposed to high training loads. This case study monitored daily HRV in two elite triathletes (one male: 22 year, VO2max 72.5 ml kg min(-1); one female: 20 year, VO2max 68.2 ml kg min(-1)) training 23 ± 2 h per week, over a 77-day period. During this period, one athlete performed poorly in a key triathlon event, was diagnosed as non-functionally over-reached (NFOR) and subsequently reactivated the dormant virus herpes zoster (shingles). The 7-day rolling average of the log-transformed square root of the mean sum of the squared differences between R-R intervals (Ln rMSSD), declined towards the day of triathlon event (slope = -0.17 ms/week; r2 = -0.88) in the NFOR athlete, remaining stable in the control (slope = 0.01 ms/week; r2 = 0.12). Furthermore, in the NFOR athlete, coefficient of variation of HRV (CV of Ln rMSSD 7-day rolling average) revealed large linear reductions towards NFOR (i.e., linear regression of HRV variables versus day number towards NFOR: -0.65%/week and r2 = -0.48), while these variables remained stable for the control athlete (slope = 0.04%/week). These data suggest that trends in both absolute HRV values and day-to-day variations may be useful measurements indicative of the progression towards mal-adaptation or non-functional over-reaching.


Retinal development: second sight comes first.
Mammals are functionally blind at birth because responses to rod and cone photoreceptor activation are immature. Recent studies show that the newborn retina is nevertheless sensitive to light. Indeed, intrinsically photosensitive retinal ganglion cells are present from birth and already make functional connections with the suprachiasmatic nucleus, the site of the central circadian clock.


Preferences for Alternative Care Modalities Among French Adults With Chronic Illness.
The COVID-19 pandemic led to the implementation of alternative care modalities (eg, teleconsultations and task shifting) that will continue to be implemented in parallel to traditional care after the pandemic. An ideal balance between alternative and traditional care modalities is unknown. To quantify the ideal postpandemic balance between alternative and traditional care modalities among patients with chronic illness and to qualify the circumstances in which patients consider it appropriate to replace traditional care with alternative care. This survey study invited 5999 adults with chronic illness in ComPaRe, a French nationwide e-cohort of adults with chronic conditions who volunteer their time to participate in research projects, to participate in this study, which was performed from January 27 to February 23, 2021. Participants rated the ideal proportion at which they would use 3 alternative care modalities instead of the traditional care equivalent on a 0% to 100% scale (with 0% indicating using alternative care modalities for none of one's future care and 100% indicating using alternative care modalities for all of one's future care) of their overall future care: (1) teleconsultations, (2) online symptom-checkers to react to new symptoms, and (3) remote monitoring to adapt treatment outside consultations. The median ideal proportion of alternative care use was calculated. Perceived appropriate circumstances in which each alternative modality could replace traditional care were collected with open-ended questions. Analyses were performed on a weighted data set representative of patients with chronic illness in France. Of the 5999 invited individuals, 1529 (mean [SD] age, 50.3 [14.7] years; 1072 [70.1%] female) agreed to participate (participation rate, 25.5%). Participants would choose teleconsultations for 50.0% of their future consultations (IQR, 11.0%-52.0%), online symptom-checkers over contacting their physician for 22.0% of new symptoms (IQR, 2.0%-50.0%), and remote monitoring instead of consultations for 52.3% of their treatment adaptations (IQR, 25.4%-85.4%). Participants reported 67 circumstances for which replacing traditional with alternative care modalities was considered appropriate, including 31 care activities (eg, prescription renewal and addressing acute or minor complaints), 25 patient characteristics (eg, stable chronic condition and established patient-physician relationship), and 11 required characteristics of the alternative care modalities (eg, quality assurance). Results of this survey study suggest that after the pandemic, patients would choose alternative over traditional care for 22% to 52% of the time across different care needs. Participants proposed 67 criteria to guide clinicians in replacing traditional care with alternative care. These findings provide a guide for redesigning care in collaboration with patients after the pandemic.


A method for hepatic arterial perfusion studies in the rat.
The current model for selective hepatic arterial infusion therapy was evaluated for its suitability for short-term pharmacokinetic experiments. This preparation consists of selective cannulation of the common hepatic artery via the gastroduodenal artery of the rat. Radioactive microspheres were injected to determine hepatic or extrahepatic sites of perfusion. Radioactive microsphere determination of hepatic arterial flow and cardiac output were also performed. Our data indicate that at high flow rates (2 ml/min), significant loss of drug would occur due to retrograde flow. Modification of the model to include temporary proximal hepatic artery occlusion ensures hepatic delivery of greater than 95% of drug. Furthermore, temporary hepatic artery occlusion does not alter cardiac output or hepatic arterial blood flow. Selective hepatic arterial infusion in rats with synchronous temporary hepatic artery occlusion is an adequate model for short-term pharmacokinetic studies.


[Civilian Service to Support Informal/Family Caregivers at Home: Acceptance and Need in Switzerland].
There is an unmet and increasing need for informal/family care for older adults, the sick, and those with disabilities living in private households. Alternative civilian services provided by so-called "zivis" could make an important contribution to supporting informal caregivers. However, its acceptance and the actual demand by informal caregivers and care recipients are not well understood. A total of 314 informal caregivers and 78 care recipients were surveyed about their potential demand for a zivi and their preferences regarding qualifications of zivis, kind of service expected, working time, service duration, as well as willingness to pay. We used descriptive and inferential statistical methods for the analysis. Informal caregivers (87%) and care recipients (90%) deemed zivis beneficial in private households, and acceptance increased with the general need for care. For most respondents, the qualifications of the zivis were not their first priority, but rather a "pleasant personality". Help with household chores and transportation assistance were a important for the vast majority of respondents, help with personal hygiene for 40% (caregivers) and 35% (care recipients), respectively. Zivis could serve as an important pool of carers for persons in private households with impaired ability to carry on with activities of daily life caused by ill health, especially cognitive and physical decline. They can offer help in many areas of living, but continued and reliable assistance is important.


Spontaneous pregnancy in women with a prolactin-producing pituitary adenoma.
The occurrence of spontaneous pregnancy in patients with amenorrhea-galactorrhea, hyperprolactinemia, and radiographic evidence of a pituitary tumor is unusual. We present here two patients who conceived spontaneously. One had an uneventful pregnancy. Following delivery, transsphenoidal pituitary surgery was performed, confirming the presence of a prolactin-producing adenoma. The second patient had an early pregnancy termination (at 12 weeks of gestation). These patients provide evidence that ovulation and pregnancy can occur in spite of elevated prolactin levels.


Second primary malignancy in myelofibrosis patients treated with ruxolitinib.
Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non-melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real-world context. Median follow-up from starting RUX was 2·9 years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22-4·60, P = 0·01] and thrombocytosis> 400 × 109 /l at RUX start (HR:1·98, 95%CI: 1·10-4·60, P = 0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24-7·92, P = 0·02) and duration of hydroxycarbamide and RUX therapy > 5 years (HR: 3·20, 95%CI: 1·17-8·75, P = 0·02 and HR: 2·93, 95%CI: 1·39-6·17, P = 0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11-5·25, P = 0·03), platelet > 400 × 109 /l (HR: 3·30, 95%CI: 1·67-6·50, P = 0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48-8·14, P = 0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males.


Diffuse malignant mesothelioma of the peritoneum: a clinicopathological study of 35 patients treated locoregionally at a single institution.
In the current study, the authors report the clinicopathologic features of patients with peritoneal diffuse malignant mesothelioma (DMM) who were treated in a uniform fashion at a single institution to assess prognostic factors. Thirty-five patients were treated with cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). The tumors were classified into epithelial, sarcomatoid, and biphasic types. Immunohistochemistry stains were performed for calretinin, WT-1, pCEA, Ber-EP4, epidermal growth factor receptor (EGFR), p16, matrix metalloprotease-2 (MMP-2), and MMP-9. Statistical correlation was evaluated for age, gender, completeness of cytoreduction (CC), tumor histotype, mitotic count (MC), necrosis, nuclear grade (NG), and biologic markers with regard to overall survival (OS) and progression-free survival (PFS). The patient group was comprised of 15 men and 20 women with a median age of 52 years (range, 24-73 yrs). Twenty-five patients underwent optimal cytoreduction. There were 32 epithelial tumors and 3 biphasic tumors, and 3 patients had an NG of 1, 19 had an NG of 2, and 13 had an NG of 3. The mean MC was 14.1 (range, 0-160 per 50 high-power fields). Necrosis was present in 11 cases. All the tumors were found to be positive for calretinin and WT-1 and were negative for pCEA and Ber-EP4. The NG and MC were found to be significantly associated with OS (P = 0.02 and P = 0.01, respectively) whereas CC was found to be associated with both OS (P = 0.05) and PFS (P = 0.03). No biologic markers were found to be of prognostic significance. The results of the current study indicate that NG, MC, and CC may be useful prognostic factors in patients treated with CRS and IPHP. The expression of EGFR, MMP-2, and MMP-9 and absent and/or reduced expression of p16 in DMMs confirms the results of previous studies suggesting their role in tumor pathogenesis and kinetics.


Peptic Ulcer and Exercise.
Relationships between peptic ulcer and physical activity have as yet received little attention. The prevalence of ulceration is high in racehorses and sled dogs, particularly during periods of competition. In humans, some occupational comparisons show an increased risk among manual workers, but it remains difficult to separate effects of work-related activity from social class and attendant influences of smoking, excessive alcohol consumption, shift work, and other stressors. Two studies of leisure activity point to some benefit from moderate physical activity, one finding a reduced risk of gastric ulcers and the other finding no effect on gastric ulcers but a reduced risk of duodenal ulcers in men only. Moderate physical activity could have a favorable impact on a number of risk factors for peptic ulceration. It could reduce gastric secretions and enhance immune function, with the latter reducing the risk of Helicobacter pylori infection. Moderate activity might also reduce anxiety and encourage the adoption of a healthy lifestyle, with avoidance of smoking and an excessive consumption of alcohol. However, prolonged endurance exercise seems likely to have a negative impact, suppressing immune function, reducing mucosal blood flow, and calling for frequent administration of non-steroidal anti-inflammatory drugs (NSAIDs). As with other aspects of exercise medicine, there may be a J-shaped relationship between dose and response. Limited human observations suggest a favourable response to bouts of moderate leisure activity but little benefit from heavy occupational activity and, in some animal studies, negative effects at high volumes and intensities of exercise. Further research is recommended to confirm the nature of this relationship, clarify the location of any nadir of risk for various classes of individual, and to explore mechanisms and antidotes.


A method of the rapid preparation of adenosine 5'-gamma-[32P] triphosphate by chemical synthesis.
A new chemical method for the synthesis of adenosine 5'-gamma-[32P] triphosphate has been developed based on the reaction of adenosine 5'-diphosphate with ethyl chloroformate. The resulting active mixed anhydride was able to react with [32P]-triethylammonium orthophosphate to give gamma-[32P]ATP.


Chronic ethanol self-administration in macaques shifts dopamine feedback inhibition to predominantly D2 receptors in nucleus accumbens core.
Given the high level of homology between nonhuman primates and humans in regard to anatomy, physiology and ethanol drinking patterns, nonhuman primates represent an unparalleled preclinical model for examining the neurobiological basis of ethanol abuse. Here we examined the neurochemical consequences of chronic daily ethanol use using fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens core or dorsolateral caudate taken from male cynomolgus macaques following ethanol drinking. We found that in both regions the ability of ethanol to decrease dopamine release was unchanged, indicating that ethanol self-administration does not produce tolerance or sensitization to ethanol effects on dopamine release at the dopamine terminal at this time point. We also found that in the nucleus accumbens core, autoregulation of dopamine release was shifted from equal D2 and D3 receptor involvement in control animals to primarily D2 receptor-mediated in drinkers. Specifically, the effect quinpirole, a D2/D3 receptor agonist, on dopamine release was equal across groups; however, dopamine signals were reversed to a greater extent by the selective D3 receptor antagonist SB-277,011A in control animals, indicating a greater contribution of D2 receptors in quinpirole-induced inhibition following ethanol self-administration. In the dorsolateral caudate, the effects of quinpirole and reversal with SB-277,011A was not different between ethanol and control slices. This work provides novel insight into the dopaminergic adaptations resulting from chronic ethanol use in nonhuman primates and indicates that alterations in D2/D3 dopamine autoreceptor signaling may be an important neurochemical adaptation to ethanol consumption during early use.


[Prevention in leisure time and sports].
Sport as leisure activity can make an essential contribution to fitness and quality of life. It has public health significance and its organization should not be left to chance or to individual and weak groups. Therefore a forum for casual discussion is needed which can enable the exchange of information on planned or existing projects, the cooperation in planning new programs, and thereby help to avoid unnecessary duplication.


Neurulation in the mouse: manner and timing of neural tube closure.
The manner and timing of neural fold fusion in primary neurulation were studied in 1,575 normal ICR mouse embryos by using binocular dissecting, light, and scanning electron microscopy. The initial fusion of apposing neural folds occurred at the level of the intermediate point between the third and fourth somites (i.e., in the caudal myelencephalon) and proceeded both rostrally and caudally. A second fusion occurred at what was originally the rostral end of the neural plate and proceeded rostrodorsally. A third fusion occurred in the caudal diencephalon and proceeded both rostrally and caudally. This was followed by complete closure of the telencephalic neuropore at the midpoint of the telencephalic roof and then complete closure of the metencephalic neuropore at the rostral part of the metencephalic roof. A fourth fusion occurred at what was originally the caudal end of the neural plate and proceeded rostrally. Finally, the caudal neuropore completely closed at the level of the caudal end of the future 33rd somite.


A phylogenomic approach for the analysis of colistin resistance-associated genes in Klebsiella pneumoniae, its mutational diversity and implications for phenotypic resistance.
The emergence of carbapenemase-producing Klebsiella pneumoniae strains has triggered the use of old antibiotics such as colistin. This is driving the emergence of colistin resistance in multidrug-resistant strains that underlie life-threatening infections. This study analyses the mutational diversity of 22 genes associated with colistin resistance in 140 K. pneumoniae clinical isolates integrated in a high-resolution phylogenetic scenario. Colistin susceptibility was accessed by broth microdilution. A total of 98 isolates were susceptible and 16 were resistant, 10 of which were carbapenemase producers. Across the 22 genes examined, 171 non-synonymous mutations and 9 mutations associated with promoter regions were found. Eighty-five isolates had a truncation and/or deletion in at least one of the 22 genes. However, only seven mutations, the complete deletion of mgrB or insertion sequence (IS)-mediated disruption, were exclusively observed in resistant isolates. Four of these (mgrBIle13fs, pmrBGly207Asp, phoQHis339Asp and ramAIle28Met) comprised novel mutations that are potentially involved in colistin resistance. One strain bore a ISEcp1-blaCTX-M-15::mgrB disruption, underlying co-resistance to third-generation cephalosporins and colistin. Moreover, the high-resolution phylogenetic context shows that most of the mutational diversity spans multiple phylogenetic clades, and most of the mutations previously associated with colistin resistance are clade-associated and present in susceptible isolates, showing no correlation with colistin resistance. In conclusion, the present study provides relevant data on the genetic background of genes involved with colistin resistance deeply rooted across monophyletic groups and provides a better understanding of the genes and mutations involved in colistin resistance.


Progression of myelodysplasia to acute lymphoblastic leukaemia: implications for disease biology.
Myelodysplastic syndrome (MDS) comprises a group of clonal haematopoietic disorders characterized by peripheral blood cytopenias, bone marrow hypercellularity, and abnormal blood cell differentiation. Approximately 30% of cases of MDS eventually progress to acute myelogenous leukemia (AML), while progression of MDS into acute lymphoblastic leukemia (ALL) is rare. In this report, we describe a case of MDS that progressed to ALL, and review the 21 previously reported cases of MDS to ALL transformation. We review the cancer stem cell model and its application to these disorders, and discuss the implications of the rarity of transformation of MDS to ALL for the biology of MDS and the pathogenesis of ALL.


Vagus nerve stimulation may be a sound therapeutic option in the treatment of refractory epilepsy.
Refractory epilepsy accounts for 20 to 30% of epilepsy cases and remains a challenge for neurologists. Vagus nerve stimulation (VNS) is an option for palliative treatment. It was to study the efficacy and tolerability of VNS in patients implanted with a stimulator at the Curitiba Institute of Neurology (INC). A case study of six patients with refractory epilepsy submitted to a VNS procedure at the INC in the last four years was described and discussed. Mean age at time of implantation was 29 years. Mean follow-up was 26.6 months. Seizure frequency decreased in all patients (40-50% (n=2) and ≥80% (n=4)). Three patients no longer required frequent hospitalizations. Two patients previously restricted to wheelchairs started to walk, probably because of improved mood. In this population, VNS proved to be a sound therapeutic option for treating refractory epilepsy.


Independence of normal phenotypic properties and cell surface receptor mobility in variant cell lines.
We report the use of three classes of variants from the long-established, malignantly transformed LM cell line to demonstrate that the apparent mobility of cell surface receptors need not be dependent on the expression of the transformed phenotype in vitro.


Single-cell sequencing of rotavirus-infected intestinal epithelium reveals cell-type specific epithelial repair and tuft cell infection.
Intestinal epithelial damage is associated with most digestive diseases and results in detrimental effects on nutrient absorption and production of hormones and antimicrobial defense molecules. Thus, understanding epithelial repair and regeneration following damage is essential in developing therapeutics that assist in rapid healing and restoration of normal intestinal function. Here we used a well-characterized enteric virus (rotavirus) that damages the epithelium at the villus tip but does not directly damage the intestinal stem cell, to explore the regenerative transcriptional response of the intestinal epithelium at the single-cell level. We found that there are specific Lgr5+ cell subsets that exhibit increased cycling frequency associated with significant expansion of the epithelial crypt. This was accompanied by an increase in the number of immature enterocytes. Unexpectedly, we found rotavirus infects tuft cells. Transcriptional profiling indicates tuft cells respond to viral infection through interferon-related pathways. Together these data provide insights as to how the intestinal epithelium responds to insults by providing evidence of stimulation of a repair program driven by stem cells with involvement of tuft cells that results in the production of immature enterocytes that repair the damaged epithelium.


Preparation of bio-based modified starch film and analysis of preservation mechanism for sweet cherry.
This study aimed to synthesize packaging films using bioactive ingredients. The composite film was prepared by blending octenyl succinate cassava starch ester (OSCS) with chitosan (CS) nano-ZnO and then adding ε-polylysine (ε-PL). The study also explored the effect of different concentrations of ε-PL on OSCS/CS/ZnO films. Fourier infrared spectroscopyand fluorescence microscopy revealed that the composite film was formed by both hydrogen bonding and a Schiff base reaction. The diffraction peaks of the original materials in X-ray diffraction disappeared after film formation, indicating good miscibility between the materials. Scanning electron microscope showed that the density of its structure increased with increasing the ε-PL content. The thermogravimetric analysis showed that the addition of ε-PL improved the thermal stability of the composite film to some extent. When used in cherry preservation, the bio-based modified starch film effectively reduced cherry decay, stem dryness, and weight loss, maintained surface color, and increased the soluble solid content.


Higher-order figure discrimination in fly and human vision.
Visually-guided animals rely on their ability to stabilize the panorama and simultaneously track salient objects, or figures, that are distinct from the background in order to avoid predators, pursue food resources and mates, and navigate spatially. Visual figures are distinguished by luminance signals that produce coherent motion cues as well as more enigmatic 'higher-order' statistical features. Figure discrimination is thus a complex form of motion vision requiring specialized neural processing. In this minireview, we will highlight recent advances in understanding the perceptual, behavioral, and neurophysiological basis of higher-order figure detection in flies, much of which is grounded in the historical perspective and mechanistic underpinnings of human psychophysics.


[Electron microscopic study of genome homology in 2 clones of the simian adenoviruses type 7].
Homology of the genomes of large-plaque (lp) and small-plaque (sp) clones of simian adenovirus type 7 (SV7) was studied experimentally. Guanidine chloride helped to isolate circular DNA molecules of identical length for both clones within the measurement error (1 = 11 +/- 0.2 micrometer). A heteroduplex SV7lp--SV7sp molecule was found to have two nonhomology sites 0.5 +/- 0.3 mu and 1.0 +/- 0.5 micrometer long located at a distance of 2 and 4 micrometer from one of the ends of the molecules, respectively.


Impact of Additional Chromosomal Aberrations Present at Diagnosis on Outcome of Adolescent and Young Adult Chronic Myeloid Leukemia Patients: A Single Center Experience.
Studying the influence of additional chromosomal aberrations (ACAs) present at diagnosis on the outcome of adolescent and young adult (AYA) chronic myeloid leukemia (CML) patients as it has not been addressed previously. Eighty-six AYA CML patients have been analyzed for occurrence of ACAs at diagnosis through performing bone marrow karyotyping. All patients received imatinib mesylate upon diagnosis of CML. Overall response, molecular response, survival status, progression and occurrence of events were monitored during the follow up period. There was a statistically significant difference between patients with and without ACAs regarding overall response (P = 0.049). There was insignificant difference between the two groups regarding achievement of major molecular response (MMR) (P = 0.594), MR4 (P = 0.282) and MR4.5 (P = 0.704). There was a significant difference between patients with and without ACAs regarding time to MMR (P = 0.042) and time to MR4 (P = 0.048) but not regarding time to MR4.5 (P = 0.065). There was insignificant impact of ACAs at diagnosis on overall survival (P = 0.152), progression free survival (P = 0.112), failure free survival (P = 0.114), event free survival (P = 0.194) and alternative treatment free survival (P = 0.731). The presence of ACAs at diagnosis does not signal worse prognosis in AYA CML patients but it may delay molecular response to imatinib mesylate.


Sex hormone concentrations and gonad histology in brown trout (Salmo trutta) exposed to 17beta-estradiol and bisphenol A.
The impact of 17beta-estradiol (E2) and bisphenol A (BPA) on steroid hormone levels and gonad development in brown trout (Salmo trutta) was determined. Exposure took place from 0 to 63 days post-fertilisation (dpf) and gonad development was followed till 400 dpf. The onset of xenoestrogen metabolism was examined by measurements of whole body concentrations of bisphenol A (BPA) and its conjugation product bisphenol A glucuronic acid (BPAGA). Exposure to 500 ng E2/l led to an increase in E2 levels in the embryos and fry while 10 ng E2/l did not. Metabolic conversion of BPA to BPAGA began during the first weeks of embryonic development. Few consistent effects were found on the sex differentiation of the brown trout. Only one intersex fish (4.5%) was found among male fish at 400 dpf exposed to 500 ng E2/l. Females with male germ cells among the normally developing oocytes were observed in all groups (in up to 50% of the female fish, independently of exposure regime). The fact that exposure to 500 ng E2/l only caused subtle effects in a small number of individuals indicates that exposure during early life stages results in little to no induction of endocrine disruption in brown trout.


Cholinergic and GABAergic septo-hippocampal projection neurons in mice: a retrograde tracing study combined with double immunocytochemistry for choline acetyltransferase and parvalbumin.
The present experiments were directed to determine the proportions of the cholinergic and GABAergic septo-hippocampal projection neurons in NMRI mice. For the labeling of the septal neurons we used a double immunocytochemical method combined with retrograde transport of wheatgerm agglutinin apo-horseradish peroxidase-gold (WAHG) injected unilaterally into the hippocampus. Monoclonal antibodies against choline acetyltransferase (ChAT) and parvalbumin (PARV) were used as markers for cholinergic and GABAergic neurons in the medial septum/diagonal band complex (MS/DB). Both antibodies were visualized in the same section using the ABC detection system with diaminobenzidine and 4-chloro-1-naphtol as chromogens. Cholinergic and PARV-containing neurons are coexisting in the MS/DB. About 38% of all retrogradely labeled neurons were ChAT-positive whereas only 10% of all retrogradely labeled cells were immunostained for PARV. On the other hand, 40% of all ChAT-positive neurons and about 24% of all PARV-positive neurons were retrogradely labeled. No double immunolabeled neurons were detected. The proportion of GABAergic neurons may have been underestimated because immunostaining for PARV only labels a subpopulation of GABAergic neurons. The present results were compared with those of previous studies in rats. They may serve as a basis of further comparative studies in mice.


Biorisk assessment of medical diagnostic laboratories in Nigeria.
The aim of this study was to assess public and private medical diagnostic laboratories in Nigeria for the presence of biosafety equipment, devices, and measures. A total of 80 diagnostic laboratories in biosafety level 3 were assessed for the presence of biosafety equipment, devices, and compliance rate with biosafety practices. A detailed questionnaire and checklist was used to obtain the relevant information from enlisted laboratories. The results showed the presence of an isolated unit for microbiological work, leak-proof working benches, self-closing doors, emergency exits, fire extinguisher(s), autoclaves, and hand washing sinks in 21.3%, 71.3%, 15.0%, 1.3%, 11.3%, 82.5%, and 67.5%, respectively, of all laboratories surveyed. It was observed that public diagnostic laboratories were significantly more likely to have an isolated unit for microbiological work (p = 0.001), hand washing sink (p = 0.003), and an autoclave (p ≤ 0.001) than private ones. Routine use of hand gloves, biosafety cabinet, and a first aid box was observed in 35.0%, 20.0%, and 2.5%, respectively, of all laboratories examined. Written standard operating procedures, biosafety manuals, and biohazard signs on door entrances were observed in 6.3%, 1.3%, and 3.8%, respectively, of all audited laboratories. No biosafety officer(s) or records of previous spills, or injuries and accidents, were observed in all diagnostic laboratories studied. In all laboratories (public and private) surveyed, marked deficiencies were observed in the area of administrative control responsible for implementing biosafety. Increased emphasis on provision of biosafety devices and compliance with standard codes of practices issued by relevant authorities is strongly advocated.


Diagnostic performance of whole-body MRI for the detection of persistent or relapsing disease in multiple myeloma after stem cell transplantation.
To compare the diagnostic performance of whole-body MRI (WBMRI) with haematological parameters for detecting persistent or relapsing disease in patients with multiple myeloma after stem cell transplantation. Sixty-six WBMRI acquisitions were performed in 33 patients with multiple myeloma at two time points after stem cell transplantation. Extent of disease and inter-test dynamics of intra- and extramedullary myeloma manifestations were compared (kappa statistics) with Uniform Response Criteria, comprising haematological parameters. Using data from 66 sequential WBMRI acquisitions in 33 patients, 10 patients (30.3 %) were classified as having progressive disease and 23 (69.7 %) as being in remission. Eight (80 %) of the ten patients with progressive disease revealed intramedullary lesions, and two patients (20 %) had intra- and extramedullary lesions. WBMRI and laboratory tests were concordant in 26/33 (78.8 %) patients. We found an agreement of 51.2 %, 95 % confidence interval 19.8 %-82.6 %, between results from WBMRI and haematological parameters. WBMRI had a sensitivity of 63.6 %, specificity of 86.4 %, PPV of 70.0 %, NPV of 82.6 % and accuracy of 78.8 % for detection of remission. WBMRI allows the detection and exact localisation of intra- and extramedullary myeloma manifestations after stem cell transplantation, but shows only moderate agreement with routinely performed laboratory tests for determination of remission.


Benign metastasizing leiomyoma.
Benign metastasizing leiomyoma is a rare clinical entity that has been described in several previous reports. Although the exact pathophysiology of the disease is unknown, two predominant theories exist: (1) metastasis from an existing leiomyoma (commonly seen with uterine leiomyoma) or (2) multicentric leiomyomatous growths rather than actual metastases. We present an interesting case in which several elements of the patient's history complicated the differential diagnosis.


Analysis of synonymous codon usage patterns of HPRT1 gene across twelve mammalian species.
Genetic changes in Hypoxanthine guanine phosphoribosyltransferace (HPRT1) gene can alter the expression of the dopamine neurotransmitter leads to abnormal neuron function, a disease called Lesch-Nyhan syndrome (LNS). Although different studies were conducted on LNS, information on codon usage bias (CUB) of HPRT1 gene is limited. The present study examines the genetic determinants of CUB in HPRT1 gene using twelve mammalian species. In the coding sequence of HPRT1 genes, A/T ending codons was most frequently used. A higher ENC value was observed indicating lower HPRT1 gene expression in the selected mammalian species. Correlation analysis indicates that compositional constraints under mutation pressure can involve in CUB of HPRT1 genes among the selected mammalian species. Relative synonymous codon usage (RSCU) value revealed that the codons such as ACT, AGG, ATT and AGC were over-represented in each of the mammalian species. Result from the analysis of the RSCU indicates that compositional constraint is a key driver for the variation in codon usage. Ratio of nonsynonymous (dN) and synonymous (dS) substitution further suggested that purifying selection occurs among the HPRT1 gene of studied mammals to maintain its protein function under the process of evolution. Our findings report an insight into the codon usage patterns of HPRT1 gene and will be useful for LNS management.


Integrated Analysis of miRNA and mRNA Regulation Network in Hypertension.
Hypertension is the most common chronic disease. Early diagnosis is helpful for early medical intervention. The miRNAs and the messenger RNAs (mRNAs) network may be valuable disease diagnosis markers. We aimed to explore the diagnostic value of the miRNA-mRNA network for hypertension patients. Data of miRNAs and mRNAs expression were obtained from the Gene Expression Omnibus database. The weighted gene co-expression network analysis was performed to screen hypertension-related gene modules, and these genes undergone functional enrichment analysis using "clusterProfiler" package. Differential expression analysis was applied on miRNAs expression profiles using "limma" package. TargetScanHuman and miRDB databases were used to select target mRNAs. Cytoscape software was used to visualize the miRNA-mRNA regulation network. P value < 0.05 was considered statistically significant after t test. There were 123 screened mRNAs which were enriched in 161 Gene ontology (GO) terms and 14 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Thirty-five differentially expressed miRNAs (DEMs) are found in the GSE75670. Totally 36 miRNA-mRNA pairs were obtained after the integrated analysis, and three mRNAs and the hsa-miRNA-5589-5p were identified as key joints. Hub genes, KIAA0513, ARID3A and LRPAP1, and key hsa-miRNA-5589-5p are potential diagnostic biomarkers for hypertension. Our findings are promising in the clinical application, conducive to early detection and prompt intervention of hypertension.


Duodenal ulcer healing on 2 g of sucralfate daily at bedtime compared to 1 g four times daily.
Seventy-seven patients with endoscopically verified duodenal ulcers were randomized to treatment with either 2 g sucralfate daily at bedtime or 1 g sucralfate q.d.s. in a controlled double-blind comparative study. After a 4-week treatment period, the healing rate was 68% for the former and 69% for the latter treatment.


Two new Bdellidae (Trombidiformes: Bdelloidea) from Iran and the status of Neobiscirus Gomelauri, 1963.
Two new Bdellidae, Biscirus iranensis Paktinat-Saeej & Bagheri sp. nov. and Bdella farabii Paktinat-Saeej & Bagheri sp. nov., are described from northern Iran. The monotypic genus Neobiscirus considered a junior synonym of Biscirus, and its only species therefore considered Biscirus kobachidzei (Gomelauri, 1963) comb. nov.


Trends of incidence, mortality, and disability-adjusted life years of oral cancer in Latin America.
To describe the trend in incidence, mortality and Disability Adjusted Life Years of oral cancer in Latin America according to sex between 2000 and 2020. This ecological study extracted oral cancer information from 20 Latin American countries from the GBD-2020 database. Oral cancer burden was described by age-standardized rate (ASR) of incidence, mortality, and DALYs. The data was compared according to sex and countries. Trends (Average Annual Percentage Change-AAPC) were estimated for each indicator, sex, and country between 2000 and 2020 using Joint-point software. Between 2000 and 2020, the highest incidence of oral cancer (ASR) occurred in Cuba (5.18), Brazil (4.38) and Uruguay (4.62). The countries with the highest mortality for both sexes were (ASR): Cuba (2.89), Brazil (2.71) and the Dominican Republic (2.58). The DALYs registered an average of 37.52 (Women: 22.39; Men: 52.62). The Dominican Republic reports increasing trends in incidence (AAPC: Men: 2.2; Women: 1.4), in mortality (AAPC: Men: 1.8; Women: 1.1), and in DALYs (AAPC: Men: 1.0; Women: 2.0). Costa Rica shows decreasing trends in men in incidence (AAPC: -1.3), mortality (AAPC: -1.6), and DALYs (AAPC: -1.8). Oral cancer shows increasing trends in: the incidence in both sexes in 10 countries, in mortality and DALYs in 6 countries, while the affectation between sexes does not show differences in trends.


Escalating dose-multiple binge methamphetamine treatment elicits neurotoxicity, altering gut microbiota and fecal metabolites in mice.
Methamphetamine (METH) is an addictive and illegal psychostimulant drug that can cause multiple organ dysfunction, especially in the central nervous system (CNS). Gut microbiota have been implicated in development of various CNS-related diseases, via the gut-brain axis (GBA). However, effect of METH in the alteration of gut microbiota and fecal metabolites is unclear, whereas the relationship with METH-induced neurotoxicity remains unknown. In the current study, we investigated effect of METH on neurotoxicity in striatum and colonic damage by exposing BALB/c mice to an escalating dose-multiple binge regimen, and then analyzed protein expression using Western blot analysis. We further detected and sequenced the 16 S rRNA gene in fecal samples, and performed ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics to analyze gut microbes and fecal metabolites. Exposure to METH significantly downregulated tyrosine hydroxylase (TH) proteins, but upregulated MAOA, Beclin1, Atg5, and LC3-Ⅱ. METH up-regulated inflammation-related factors, such as caspase1, TNF-α and IL-18, by activating the toll-like receptors 4 (TLR4)/myeloid differentiation factor 88 (Myd88)/nuclear factor κB (NF-κB) pathway and reduced occludin protein expression. In addition, METH exposure changed α and β diversities of gut microbiota. Specifically, METH exposure elevated relative abundances of pathogenic bacteria, but reduced those of probiotics. Metabolomics, combined with enrichment analyses revealed that METH exposure altered fecal metabolites. Our findings suggest that METH exposure induced autophagy in the CNS, elevated intestinal autophagy flora, leading to accumulation of fecal metabolites in the autophagy pathway, and causing enteritis. Moreover, METH promoted intestinal inflammation by increasing the relative abundance of the pathogenic bacteria in the intestinal tract, and reduced intestinal TJ protein expression.


Experimental and computational approaches to study the high temperature thermoelectric properties of novel topological semimetal CoSi.
Here, we study the thermoelectric properties of topological semimetal CoSi in the temperature range 300-800 K by using combined experimental and density functional theory (DFT) based methods. CoSi is synthesized using arc melting technique and the Rietveld refinement gives the lattice parameters ofa=b=c= 4.445 Å. The measured values of Seebeck coefficient (S) shows the non-monotonic behaviour in the studied temperature range with the value of ∼-81μV K-1at room temperature. The |S| first increases till 560 K (∼-93μV K-1) and then decreases up to 800 K (∼-84μV K-1) indicating the dominating n-type behaviour in the full temperature range. The electrical conductivity,σ(thermal conductivity,κ) shows the monotonic decreasing (increasing) behaviour with the values of∼5.2×105(12.1 W m-1 K-1) and∼3.6×105(14.2 W m-1 K-1) Ω-1 m-1at 300 K and 800 K, respectively. Theκexhibits the temperature dependency as,κ∝T0.16. The DFT based Boltzmann transport theory is used to understand these behaviour. The multi-band electron and hole pockets appear to be mainly responsible for deciding the temperature dependent transport behaviour. Specifically, the decrease in the |S| above 560 K and change in the slope ofσaround 450 K are due to the contribution of thermally generated charge carriers from the hole pockets. The temperature dependent relaxation time (τ) is computed by comparing the experimentalσwith calculatedσ/τand it shows temperature dependency of 1/T0.35. Further this value ofτis used to calculate the temperature dependent electronic part of thermal conductivity (κe) and it gives a fairly good match with the experiment. Present study suggests that electronic band-structure obtained from DFT provides a reasonably good estimate of the transport coefficients of CoSi in the high temperature region of 300-800 K.


Gradual transitivity in orthogonality spaces of finite rank.
An orthogonality space is a set together with a symmetric and irreflexive binary relation. Any linear space equipped with a reflexive and anisotropic inner product provides an example: the set of one-dimensional subspaces together with the usual orthogonality relation is an orthogonality space. We present simple conditions to characterise the orthogonality spaces that arise in this way from finite-dimensional Hermitian spaces. Moreover, we investigate the consequences of the hypothesis that an orthogonality space allows gradual transitions between any pair of its elements. More precisely, given elements e and f, we require a homomorphism from a divisible subgroup of the circle group to the automorphism group of the orthogonality space to exist such that one of the automorphisms maps e to f, and any of the automorphisms leaves the elements orthogonal to e and f fixed. We show that our hypothesis leads us to positive definite quadratic spaces. By adding a certain simplicity condition, we furthermore find that the field of scalars is Archimedean and hence a subfield of the reals.


Major single nucleotide polymorphisms in polypoidal choroidal vasculopathy: a comparative analysis between Thai and other Asian populations.
To investigate the association in a Thai population between the major age-related macular degeneration (AMD) susceptibility loci, Y402H and I62V in the complement factor H (CFH) and A69S in the age-related maculopathy susceptibility 2 (ARMS2) genes, and polypoidal choroidal vasculopathy (PCV). A case-control study included 97 PCV cases and 102 age- and gender-matched controls without any retinopathy. The genotypic profiles of the three polymorphisms were obtained using a real-time polymerase chain reaction assay. The allelic and genotypic association between the polymorphisms and PCV were compared with those from the compiled data of other Asian populations reported previously. Strong associations between the Y402H, I62V, and A69S polymorphisms and PCV were observed in the present study (P = 0.002, 0.003, and 0.0008 respectively) and in the compiled data (P < 0.0001 for all three polymorphisms). The risk allele frequencies of the polymorphisms in PCVs and in controls from the present study (15.0% and 5.4% for Y402H, 71.7% and 57.4% for I62V, and 54.1% and 37.3% for A69S respectively) were also comparable with the frequencies from the compiled data (10.3% and 6.4% for Y402H, 75.2% and 58.3% for I62V, and 56.8% and 36.8% for A69S respectively). The genotype distribution for each polymorphism was also comparable in both datasets. The findings of this study support a significant genetic association between the major AMD susceptibility genes and PCV across Asian populations. This suggests that AMD and PCV, despite different phenotypic manifestation, may share common genetic risk factors.


Defective DNA double-strand break repair in pediatric systemic lupus erythematosus.
Previous reports of cells from patients with systemic lupus erythematosus (SLE) note that repair of single-strand breaks is delayed, and these lesions may be converted to double-strand breaks (DSBs) at DNA replication forks. We undertook this study to assess the integrity of DSB recognition, signaling, and repair mechanisms in B lymphoblastoid cell lines derived from patients with pediatric SLE. Nine assays were used to interrogate DSB repair and recognition in lymphoblastoid cell lines from patients with pediatric SLE, including the neutral comet assay (NCA), colony survival assay (CSA), irradiation-induced foci formation for γ-H2AX and 53BP1 proteins, kinetics of phosphorylation of structural maintenance of chromosomes protein 1 (SMC1), postirradiation bromodeoxyuridine incorporation to evaluate S phase checkpoint integrity, monoubiquitination of Fanconi protein D2, ATM protein expression, and non-homologous DNA end joining protein expression and function. Three of the 9 assays revealed abnormal patterns of response to irradiation-induced DNA damage. The NCA and CSA yielded aberrant results in the majority of SLE lymphoblastoid cell lines. Abnormal prolongation of SMC1 phosphorylation was also noted in 2 of 16 SLE lymphoblastoid cell lines. Our data suggest that DSB repair is defective in some lymphoblastoid cell lines from pediatric patients with SLE, especially when assessed by both NCA and CSA. Since these studies are nonspecific, further studies of DNA repair and kinetics are indicated to further delineate the underlying pathogenesis of SLE and possibly identify therapeutic targets.


Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes.
To assess the efficacy of exenatide (EXE) once weekly + dapagliflozin once daily (DAPA) versus each drug alone in reducing biomarkers of fatty liver/steatosis and fibrosis in a post hoc analysis of DURATION-8, a 104-week study in 695 patients with type 2 diabetes uncontrolled by metformin monotherapy. We evaluated the impact of the study treatments on non-invasive markers of hepatic steatosis (fatty liver index [FLI] and non-alcoholic fatty liver disease [NAFLD] liver fat score), fibrosis (fibrosis-4 index [FIB-4]) and severe fibrosis (NAFLD fibrosis score), along with liver enzymes and insulin resistance, at weeks 28 and 52. All outcomes in this analysis were exploratory, with nominal P values reported. At week 28, biomarkers of fatty liver/steatosis and fibrosis were reduced from baseline in all treatment groups. At week 28, EXE once weekly + DAPA effects for decrease in FLI were stronger than those of EXE once weekly + placebo (PLB; -2.92, 95% confidence interval [CI] -5.11, -0.73; P = 0.0092) or DAPA+PLB (-2.77 [95% CI -4.93, -0.62]; P = 0.0119), and stronger than those of EXE once weekly + PLB at week 52 (-3.23 [95% CI -5.79, -0.68]; P = 0.0134). FIB-4 showed reduction versus baseline only in the EXE once weekly + DAPA group at both week 28 (-0.06 [95% CI -0.11, -0.01]; P = 0.0135) and week 52 (-0.05 [95% CI -0.09, -0.004]; P = 0.0308). The EXE once weekly + DAPA combination showed stronger effects than EXE once weekly + PLB or DAPA + PLB in ameliorating markers of hepatic steatosis and fibrosis in patients with type 2 diabetes. Prospective trials are needed to validate these findings.


Pharmacokinetic considerations in development of a bioartificial liver.
We consider the pharmacokinetics of bioartificial livers (BALs) prepared using a hollow fibre module with respect to two key functions, detoxification and plasma protein supply, and present the results in a simple form. We then discuss the advantages and disadvantages of BAL therapy in comparison with the non-biological therapies of haemodialysis and plasma exchange. Nitrogenous and other potentially toxic compounds, such as ammonia, mercaptans, short-chain fatty acids and gamma-aminobutyric acid, are produced in the bowels and accumulate in the systemic blood because of impaired elimination by the ailing liver. Adrenal and gonadal steroids, including corticosteroids, estrogens, progestins and androgens, are biosynthesised, and high concentrations of these hormones become harmful. All these endogenously produced toxins require effective metabolism. In haemodialysis, toxins that permeate through the hollow fibre membrane are rapidly removed by the dialysate flow, and their concentrations decrease to almost zero. In a BAL bioreactor, the toxins are slowly metabolised by hepatocytes in the hollow fibres, and decreased to concentrations that are inversely proportional to the number of hepatocytes in the BAL, even after a long-term assist. It is difficult to rationalise the clinical usage of BAL systems containing small amounts of hepatocytes (70-100g) to remove the toxins. Concentrations of plasma proteins in a patient after long-term BAL treatment are proportional to the number of hepatocytes in the device. BAL reactors prepared using porcine hepatocytes supply porcine proteins, not human proteins, to the recipient. Plasma exchange increases protein concentrations much more effectively than BAL as long as a sufficient amount of plasma is available. The blood inflow rate to the liver is about 1500 mL/min in a normal adult. On the other hand, blood draw rates to a BAL system are restricted to the range of 100-300 mL/min. Toxins that are rapidly cleared by the liver (for example, the ammonia clearance of the normal human liver is several hundred mL/min) cannot be effectively eliminated from the systemic blood by BAL systems currently under clinical evaluation. Hepatocytes are the only elements in a BAL reactor that can metabolise toxins and synthesise proteins, and thus BAL performance increases with the increasing number of hepatocytes in the bioreactor. The human liver weighs about 1500 g and contains about 80% hepatocytes, i.e. about 1200 g of hepatocytes. The blood flow through the liver is about 1500 mL/min in a normal adult. To effectively replace liver functions would require a BAL reactor containing the functional equivalent of several hundreds of grams of human hepatocytes with an extracorporeal perfusion rate of more than 1000 mL/min. At this point, only orthotopic liver transplantation can meet these criteria.


High frequency measurement of carbon emissions based on power big data: A case study of Chinese Qinghai province.
In this paper, we build the electricity‑carbon model with techniques of frequency transformation, and statistical modeling. With macro statistical data released by Statistics Bureau of Qinghai Province and high-frequency power big data provided by State Grid Qinghai Electric Power Company, based on the electricity‑carbon model we apply the inventory method to measure the monthly carbon emissions of Qinghai Province and its prefectural-level cities, as well as its industry, construction, and other five industries. Additionally, we apply the same method to measure the emission reduction contribution of green power by using the data of proportion of "green power". The results show that first there is a "double imbalanced" phenomenon for the distribution of Qinghai's carbon emissions, which means that the distribution of carbon emissions of Qinghai's prefectural-level cities is imbalanced and the distribution of carbon emissions of Qinghai's industries is also imbalanced. Second, the emission reduction effect of "green power" is significant. And the quantity of its reduction accounts for 54 % of Qinghai's total emission. Third, in comparison with the seven institutions' relative error rate which is about 7 % for measuring China's carbon emissions, our results are reliable.


Computational study of bindings of HK20 Fab and D5 Fab to HIV-1 gp41.
Antibodies HK20 and D5 have been shown to target HIV-1 gp41, thereby inhibiting membrane fusion that facilitates viral entry. The binding picture is static, based on the X-ray crystal structures of the Fab regions and gp41 mimetic five-helix bundle. In this study, we carried out molecular dynamics simulation to provide the dynamic binding picture. Calculated binding free energies are within reasonable range of and follow the trend of the experimental values: -15.28 kcal/mol for HK20 Fab (expt. -11.60 kcal/mol) and -17.90 kcal/mol for D5 Fab (expt. -11.70 kcal/mol). Alanine scanning at protein-protein interface reveals that the highest contributors to binding for HK20 Fab are F54 and I56, both of V(H) region, as well as R30' of V(L) region; whereas for D5 Fab, F54 of V(H) region, as well as W32' and Y94' of V(L) region. HK20 F54 and I56, as well as D5 I52, F54, and T56, bind to the gp41 hydrophobic binding pocket, an important region targeted by many other fusion inhibitors. Hydrogen bonding analysis also identifies high-occupancy hydrogen bonds at the periphery of gp41 hydrophobic pocket. Considering that almost all interface residues are turn residues, further work may be directed to turn mimics. Pre-orientation by the hydrogen bonds to poise this particular turn towards the binding pocket may also be a point worth pursuing.


Measuring quaternary ammonium cleaning agents with ion selective electrodes.
Data for coated-wire, ion selective electrodes (ISEs) are presented for cationic surfactant ions found in common cleaners including benzyldimethyltetradecylammonium, benzyldimethyldodecylammonium, and benzyldimethylhexadecylammonium. The ion exchangers dinonylnaphthalene sulfonic acid, tetraphenyborate, and tetrakis(4-chlorophenyl)borate are examined, showing dinonylnaphthalene sulfonic acid to be the favored species. The ISEs exhibit approximately Nernstian behavior down to the 10(-6) M limit of detection with lifetimes in excess of 50 days when used continuously, and a shelf life of over 100 days. Reaching the upper detection limit at the critical micelle concentration requires use of polymeric-membrane reference electrodes including a new membrane cocktail, which allow response measurements of an order of magnitude higher than the traditional fritted-glass reference electrode. The surfactant ISEs show excellent selectivity over the common metal ions Na+, K+, Mg2+, Ca2+, and Cu2+ with selectivity coefficients less than 10(-5.3). The ISEs are also selective over the lower molecular weight quaternary ammonium ions tetradecyltrimethylammonium, dodecyltrimethylammonium, benzyldimethyl(2-hydroxyethyl)ammonium, and tetrabutylammonium with selectivity coefficients ranging from 10(-1.7) to 10(-5.5). Use of a single electrode to determine accurately the total cationic surfactant concentration in common cleaning solutions is accomplished with information about concentration dependent interferences and a modified Nikolsky-Eisenman model. Finally, quaternary ammonium surfactants have a deleterious effect on the measurements of pH and common ions like K+, Mg2+ and Ca2+ with polymeric ISEs. This makes it critical to include surfactant electrodes in a detector array when cleaning agents are present.


A case of papillary muscle rupture caused by acute myocardial infarction.
A 63-year-old female was admitted because of cardiogenic shock due to complete rupture of the posterior papillary muscle. The diagnosis was made by echocardiography. She was treated successfully by an emergency replacement of the mitral valve. Early diagnosis and surgical treatment are mandatory and life-saving in the case of complete papillary muscle rupture.


A novel compound derived from danshensu inhibits apoptosis via upregulation of heme oxygenase-1 expression in SH-SY5Y cells.
Heme oxygenase-1 (HO-1) has potential anti-apoptotic properties. A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2- ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)] was synthesized by joining danshensu and cysteine through an appropriate linker. This study investigated if the cytoprotective properties of DSC involved the induction of HO-1. We evaluated the cytoprotective effects of DSC on H2O2-induced cell damage, apoptosis, intracellular and mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm) loss, and apoptosis-related proteins expression and its underlying mechanisms. DSC concentration-dependently attenuated cell death, lactate dehydrogenase release, intracellular and mitochondrial ROS production, and ΔΨm collapse, modulated apoptosis-related proteins (Bcl-2, Bax, caspase-3, p53, and cleaved PARP) expression, and inhibited phosphorylation of extracellular signal-regulated kinase 1/2 in SH-SY5Y cells induced by H2O2. In addition, DSC concentration-dependently induced HO-1 expression associated with nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf-2), while the effect of DSC was inhibited by a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Furthermore, the protective effect of DSC on H2O2-induced cell death was abolished by HO-1 inhibitor ZnPP, but was mimicked by carbon monoxide-releasing moiety CORM-3 or HO-1 by-product bilirubin. Finally, DSC inhibited H2O2-induced changes of Bcl-2, Bax, and caspase-3 expression, and all of these effects were reversed by HO-1 silencing. Induction of HO-1 may be, at least in part, responsible for the anti-apoptotic property of DSC, an effect that involved the activation of PI3K/Akt/Nrf-2 axis. DSC might have the potential for beneficial therapeutic interventions for neurodegenerative diseases.


Proposome for transdermal delivery of tofacitinib.
Tofacitinib citrate (TC) has recently gained interest in treating skin disorders such as psoriasis, atopic dermatitis and baldness. Unfortunately, the oral administration shows side effects, such as decreased neutrophil counts. To this end, the topical delivery of TC can be used to reduce the risk associated with systemic exposure. However, TC shows minimal absorption via skin. Hence, the objective of this study is to enhance the skin delivery of TC using a non-invasive approach. The liposomes based on propylene glycol, named as proposomes, carrying TC, were studied. The vesicle characteristics and in vitro skin permeation were assessed. The proposomes enhanced the skin permeability of TC by 4-11 folds. The composition of proposomes was found to affect the skin permeation and deposition of TC. The proposomes were stable for at least 6 months. Overall, proposomes were effective for targeted topical drug delivery.


Immediate effects and associations between interoceptive accuracy and range of motion after a HVLA thrust on the thoracolumbar junction: A randomised controlled trial.
There is paucity in the literature regarding the role of interoceptive accuracy (IAc) at predicting the effectiveness of osteopathic techniques which increase spinal mobility when directed specifically at the thoracolumbar junction (TLJ). The study aimed to explore whether a high velocity, low amplitude (HVLA) thrust of the TLJ would increase spinal mobility (measured through Range of Motion; ROM) and change IAc. Also, whether baseline IAc correlated with the post-ROM measures and change in ROM. 21 asymptomatic participants were allocated into three conditions in a randomised order. These were; (1) a high velocity low amplitude manipulation of the TLJ; (2) sham (basic touch); and (3) a control (laying supine on a plinth). Before and following each intervention, the participants' spinal ROM was measured using an Acumar digital inclinometer. In addition to this an ECG was used to measure their pre and post condition IAc. There were significant increases in ROM for all condition, however, the HVLA thrust led to a significantly greater increase in ROM (p < 0.001) when compared to the control and sham. Baseline IAc was inversely associated with post-ROM but there was no association with change in ROM. The HVLA thrust did not significantly change IAc scores from pre to post intervention. HVLA thrust over the TLJ is a useful intervention for increasing spinal ROM. IAc maybe a useful predictor for intervention effectiveness of this technique and spinal area which could in the future be utilised by osteopaths as part of their diagnostics.


Compartmentalization of cyclic nucleotide signaling: a question of when, where, and why?
Preciseness of cellular behavior depends upon how an extracellular cue mobilizes a correct orchestra of cellular messengers and effector proteins spatially and temporally. This concept, termed compartmentalization of cellular signaling, is now known to form the molecular basis of many aspects of cellular behavior in health and disease. The cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate are ubiquitous cellular messengers that can be compartmentalized in three ways: first, by their physical containment; second, by formation of multiple protein signaling complexes; and third, by their selective depletion. Compartmentalized cyclic nucleotide signaling is a very prevalent response among all cell types. In order to understand how it becomes relevant to cellular behavior, it is important to know how it is executed in cells to regulate physiological responses and, also, how its execution or dysregulation can lead to a pathophysiological condition, which forms the scope of the presented review.


Cerebrospinal fluid diversion in patients with enlarged Virchow-Robin spaces without ventriculomegaly.
Enlarged Virchow-Robin spaces (eVRS) are an MRI biomarker in several neurological diseases of inflammatory, neurodegenerative, vascular, metabolic, or genetic origin. We report on a further condition in which eVRS were observed in patients with an ongoing chronic hydrocephalus-like clinical picture without ventriculomegaly who improved after CSF diversion, and we discuss the possible mechanisms underlying this finding. A retrospective study of seven patients presenting progressive gait, cognitive, and urinary disturbances in association with eVRS was undertaken. All patients presented an Evans ratio <0.30 and >20 eVRS at the level of basal ganglia and periventricular parenchyma as assessed by T2-weighted MRI. All patients underwent prolonged external lumbar drainage (PELD) with good response. Six patients received ventriculoperitoneal shunt with improvement of their clinical status compared to that before PELD (follow-up: 8-58 months, mean 24.6). The seventh patient did not undergo ventriculoperitoneal shunt and received a second PELD with persistent improvement (follow-up: 14 months). Our results indicate that a mechanism involving CSF accumulation and stasis in the subarachnoid space was at least a concurrent factor of this clinical picture. This study should stimulate new perspectives on the role of CSF disturbances in the pathogenesis of diseases associated with VRS enlargement.


Corneal collagen crosslinking in patients treated with dextran versus isotonic hydroxypropyl methylcellulose (HPMC) riboflavin solution: a retrospective analysis.
Corneal collagen crosslinking (CXL) is a widely used treatment for halting the progression of keratoconus. Although initial studies of CXL were performed with a riboflavin solution containing dextran, recent protocols for CXL have indicated the use of a riboflavin solution containing isotonic hydroxypropyl methylcellulose (HPMC). This study was performed to investigate differences in visual outcomes and Scheimpflug (Pentacam) analysis in patients who have undergone epithelium-off CXL with riboflavin solution containing either 20% dextran versus 1.1% HPMC. All patients in this non-randomized, non-masked, retrospective cohort analysis were treated at Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY, USA. Thirty-seven eyes of 33 patients were crosslinked with a dextran solution and 19 eyes of 19 patients crosslinked with an isotonic HPMC solution, both using an epithelium-off 30-min, 3 mW/cm2 protocol. All patients had a diagnosis of keratoconus or post-refractive surgery ectasia. Best spectacle corrected visual acuity (BSCVA) and Pentacam parameters were compared at all follow up visits (1, 6, 12, and 24 months). Differences between groups treated with HPMC and dextran were compared using student's t-test. Differences between treated eye and fellow eye were calculated and compared between HPMC and dextran groups using paired t-test. Patients treated with a dextran solution had significantly greater improvement in BSCVA at 1, 6, and 24 months (p < 0.05) compared to the isotonic HPMC-treated group. Kmax increased in both groups at 1 month; however, HPMC-treated patients had a greater increase compared to dextran-treated patients (p = 0.01). Kmax decreased in both groups at 6 and 12 months, although this finding was only significant in the HPMC-treated group at 12 months. Our data suggest that crosslinking with the dextran solution may result in significantly better visual outcomes (demonstrated by visual acuity) compared to the isotonic HPMC riboflavin solution. Dextran solutions may have other potential advantages intrinsic to its biochemical properties facilitating more efficient crosslinking. Further research and long-term evidence regarding the use of dextran versus HPMC riboflavin solutions in collagen crosslinking is necessary.


Effects of blood pressure reduction on the elastic profile of the aortic tree in patients with coronary heart disease.
Decreased arterial compliance of large arteries in coronary heart disease has been reported. Using intravascular ultrasound it was demonstrated that arterial compliance decreases with increasing distance from the heart. Until now changes in the elastic profile have not been investigated after a stepwise blood pressure (BP) reduction induced by antihypertensive agents. The local viscoelastic properties of the aortic tree were analyzed before and after a mean arterial BP reduction of about 5 and 15 mm Hg below baseline by the steady-state infusion of increasing doses of nisoldipine in 15 patients with coronary artery disease. Intravascular ultrasound imaging combined with arterial pressure measurements were performed at five sites along the aortic tree to determine the viscoelastic profile before nisoldipine administration and again after the 5 and 15 mm Hg nisoldipine-induced blood pressure reductions. The elasticity parameters varied depending on the distance from the heart and on the BP level. At both BP reduction levels nisoldipine infusion led to an increase in arterial compliance at the abdominal aorta and at the aortic bifurcation. A dissociation between the 5 and the 15 mm Hg BP reduction was found at the common iliac artery and at the external iliac artery. Our results provide direct quantitative evidence that stepwise BP reductions exhibit different and, in part, contrary effects on the elastic profile, depending on the aortic tree location. The results also suggest that nisoldipine infusion can significantly ameliorate local viscoelastic properties at the abdominal aorta and at the aortic bifurcation, an effect that was associated or caused by a change in BP attributable to a decrease in peripheral resistance.


Non-recurrent laryngeal nerve: a case report and review of literature.
Right recurrent laryngeal nerve can take a "Non-Recurrent" course and can present as a Non Recurrent Laryngeal nerve which is a rare entity. Such anomalies can lead to difficulty in locating the laryngeal nerve during thyroid surgeries and there are higher chances of it being injured. Therefore, surgeons should be mindful of this entity. We report the case of a 53-year-old lady who underwent thyroid surgery and a right Non Recurrent Laryngeal Nerve was identified intra-operatively.


Factors predictive of outcomes 1 year after 3 monthly ranibizumab injections and as-needed reinjections for polypoidal choroidal vasculopathy in Japanese patients.
To determine baseline factors predictive of outcomes 1 year after 3 monthly intravitreal ranibizumab injections followed by as-needed injections for polypoidal choroidal vasculopathy. A nonrandomized prospective 1-year trial collected data from 144 Japanese patients (144 eyes) with symptomatic polypoidal choroidal vasculopathy who received one 0.5-mg intravitreal ranibizumab injection monthly for 3 months followed by as-needed retreatments. Statistical analysis evaluated baseline independent factors predictive of better visual acuity and the need for fewer injections 1 year after the first injection. After the initial 3 monthly injections, a mean ± standard deviation of 1.2 ± 1.1 as-needed injections was administered. The mean visual acuity improved significantly (P < 0.01) from 20/80 to 20/50. Better visual acuity and no history of photodynamic therapy or clusters of grape-like polypoidal lesions were significant independent baseline factors predictive of better visual acuity 1 year after the first injection. No factors were significantly associated with a need for fewer ranibizumab reinjections during follow-up. The baseline clinical characteristics predicted favorable visual acuity outcomes. These findings might be useful to explaining the prognosis of ranibizumab treatment to the patients with polypoidal choroidal vasculopathy.


Evaluation of a Patient with a Positive Family History for Long QT Syndrome.
The hereditary long QT syndrome (LQTS) is a genetic channelopathy that is associated with increased propensity for polymorphic ventricular tachyarrhythmias and sudden cardiac death in young individuals with normal cardiac morphology. The diagnosis of this genetic disorder relies on a constellation of electrocardiographic, clinical, and genetic factors. Beta-blockers are the mainstay therapy in LQTS, whereas implantation of a cardioverter defibrillator is generally reserved for secondary prevention or for those who remain symptomatic on beta-blocker therapy. Herein we present a case that demonstrates important diagnostic and management dilemmas among patients who have a positive family history of LQTS.


Improved analysis of membrane protein by PVDF-aided, matrix-assisted laser desorption/ionization mass spectrometry.
Characterization of membrane proteins remains an analytical challenge because of difficulties associated with tedious isolation and purification. This study presents the utility of the polyvinylidene difluoride (PVDF) membrane for direct sub-proteome profiling and membrane protein characterization by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The hydrophobic adsorption of protein, particularly membrane proteins, on the PVDF surface enables efficient on-PVDF washing to remove high concentrations of detergents and salts, such as up to 5% sodium dodecyl sulfate (SDS). The enhanced spectrum quality for MALDI detection is particularly notable for high molecular weight proteins. By using on-PVDF washing prior to MALDI detection, we obtained protein profiles of the detergent-containing and detergent-insoluble membrane fractions from Methylococcus capsulatus (Bath). Similar improvements of signal-to-noise ratios were shown on the MALDI spectra for proteins electroblotted from SDS-polyacrylamide gel electrophoresis (SDS-PAGE) onto the PVDF membrane. We have applied this strategy to obtain intact molecular weights of the particulate methane monooxygenase (pMMO) composed of three intrinsic membrane-bound proteins, PmoA, PmoB, and PmoC. Together with peptide sequencing by tandem mass spectrometry, post-translational modifications including N-terminal acetylation of PmoA and PmoC and alternative C-terminal truncation of PmoB were identified. The above results show that PVDF-aided MALDI-MS can be an effective approach for profiling and characterization of membrane proteins.


Learned Tensor Low-CP-Rank and Bloch Response Manifold Priors for Non-Cartesian MRF Reconstruction.
Magnetic resonance fingerprinting (MRF) can rapidly perform simultaneous imaging of multiple tissue parameters. However, the rapid acquisition schemes used in MRF inevitably introduce aliasing artifacts in the recovered tissue fingerprints, reducing the accuracy of the predicted parameter maps. Current regularized reconstruction methods are based on iterative procedures which are usually time-consuming. In addition, most of the current deep learning-based methods for MRF often lack interpretability owing to the black-box nature, and most deep learning-based methods are not applicable for non-Cartesian scenarios, which limits the practical applications. In this paper, we propose a joint reconstruction model incorporating MRF-physics prior and the data correlation constraint for non-Cartesian MRF reconstruction. To avoid time-consuming iterative procedures, we unroll the reconstruction model into a deep neural network. Specifically, we propose a learned CANDECOMP/PARAFAC (CP) decomposition module to exploit the tensor low-rank priors of high-dimensional MRF data, which avoids computationally burdensome singular value decomposition. Inspired by the MRF-physics, we also propose a Bloch response manifold module to learn the mapping between reconstructed MRF data and the multiple parameter maps. Numerical experiments show that the proposed network can reconstruct high-quality MRF data and multiple parameter maps within significantly reduced computational time.


Spontaneous coronary artery dissection: "To stent or not to stent, that is the question".
Spontaneous coronary artery dissection is a rare cause of acute coronary syndrome that typically occurs in relatively young patients without classical cardiovascular risk factors for coronary artery disease. The etiology appears to be multifactorial and optimal management is not clearly established, so the treatment strategy is often selected based on clinical presentation and coronary anatomy. We present two cases of spontaneous coronary artery dissection with different initial approaches, highlighting the importance of a case-by-case assessment.


Impacts of Rearing Enrichments on Pullets' and Free-Range Hens' Positive Behaviors across the Flock Cycle.
Enrichment during the indoor rearing of pullets destined for free-range systems may optimize pullet development including increasing motivated natural behaviors (termed 'positive behaviors') including foraging, dust bathing and chick play. Hy-Line Brown® chicks (n = 1700) were floor-reared indoors across 16 weeks with three enrichment treatments (n = 3 pens/treatment): (1) standard control, (2) weekly novel objects-'novelty', (3) perching/navigation structures-'structural'. At 16 weeks, pullets (n = 1386) were transferred to nine identical pens within rearing treatments with outdoor range access from 25 to 65 weeks. Video cameras recorded the pullet pens, adult indoor pens, and outside range. During rearing, observations of play behavior (running, frolicking, wing-flapping, sparring) in chicks at 2, 4 and 6 weeks (total of 432 thirty-second scans: 16 observations × 3 days × 9 pens) showed no overall effect of rearing treatment (p = 0.16). At 11 and 14 weeks only the 'novelty' hens were observed to increase their foraging across age (p = 0.009; dust bathing: p = 0.40) (total of 612 thirty-second scans per behavior: 17 observations × 2 days × 2 age points × 9 pens). Observations of adult hens at 26, 31, 41, 50, 60 and 64 weeks showed that the structural hens exhibited overall more dust bathing and foraging than the control hens (both p < 0.04) but both novelty and/or structural hens showed small increases depending on the behavior and location (total of 4104 scans per behavior: 17 observations × 2 days × 6 age points × 9 pens × 2 locations = 3672 + an additional 432 observations following daylight saving). Across age, adult hens differed in the degree of dust bathing performed inside or outside (both p ≤ 0.001) and foraging outside (p < 0.001) but not inside (p = 0.15). For litter-reared pullets, additional enrichments may result in some long-term increases in positive behaviors.


Dose-response involvement of constitutive androstane receptor in mouse liver hypertrophy induced by triazole fungicides.
To clarify the dose-response relationship between constitutive androstane receptor (CAR) activity and induction of cytochrome P450 2B (CYP2B) expression and hypertrophy by triazole fungicides in mouse liver, three dose levels of cyproconazole (Cypro), tebuconazole (Teb), fluconazole (Flu), and phenobarbital (PB), a typical CYP2B inducer, were administrated in diet to male wild-type (WT) and CAR-knockout (CARKO) mice for one week. In WT mice, all compounds dose-dependently induced liver weight increases and hepatocellular hypertrophy accompanied by CYP2B expression. In CARKO mice, these effects were not induced by PB, while Cypro or Flu induced these effects only at the highest dose. Dose-dependent liver hypertrophy was detected in CARKO mice treated with Teb, but at the lowest dose the intensity was weakened compared to WT mice. The present results indicate that Cypro and Flu mainly induced CAR-mediated liver hypertrophy, while Teb slightly involved CAR. The involvement of CAR in triazole-induced liver hypertrophy was dose-responsive. In addition, all three triazoles have non-CAR-mediated liver hypertrophy pathways, indicating that the hypertrophy induced by these triazoles differs from that of PB.


Construction of an Axially Chiral Fluorene Nitrile-Based Framework via Benzannulation of Indene Diene with Benzoylacetonitrile.
The methodology for the synthesis of fluorene-based atropisomers was developed via the strategy of aromatic ring formation. By this strategy, an efficient benzannulation of indene-based diene with benzoylacetonitrile divergently promoted by DABCO and a chiral organocatalyst was established, and various atropisomeric fluorene-based skeletons were generated in good yields, which not only provide a new strategy for the construction of atropisomeric biaryls but also offer a new member to the atropisomeric family.


Facial Fat Fitness: A New Paradigm to Understand Facial Aging and Aesthetics.
Traditionally, facial adipose tissue has been perceived and treated as a homogenous volume-occupying subcutaneous depot. However, recent research from across disciplines is converging to reveal a far more anatomically organized and functionally dynamic role of facial adipose tissue. In this narrative review, we will discuss new insights into adipocyte function and facial adipose anatomy that have far-reaching implications for the practice of aesthetic facial plastic surgery. These concepts are synthesized into a "facial fat fitness" model which can be used to explain clinical observations in facial aging and aesthetic surgery. Fat fitness relates to the quality of facial adipose tissue, as opposed to quantity, and describes whether adipose tissue is in a predominantly healthy hyperplastic or unhealthy hypertrophic state. Fat fitness is modulated by lifestyle factors, and may be impacted positively or negatively by facial aesthetic treatments. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


The relative roles of visuospatial and linguistic working memory systems in generating inferences during visual narrative comprehension.
This study investigated the relative roles of visuospatial versus linguistic working memory (WM) systems in the online generation of bridging inferences while viewers comprehend visual narratives. We contrasted these relative roles in the visuospatial primacy hypothesis versus the shared (visuospatial & linguistic) systems hypothesis, and tested them in 3 experiments. Participants viewed picture stories containing multiple target episodes consisting of a beginning state, a bridging event, and an end state, respectively, and the presence of the bridging event was manipulated. When absent, viewers had to infer the bridging-event action to comprehend the end-state image. A pilot study showed that after viewing the end-state image, participants' think-aloud protocols contained more inferred actions when the bridging event was absent than when it was present. Likewise, Experiment 1 found longer viewing times for the end-state image when the bridging-event image was absent, consistent with viewing times revealing online inference generation processes. Experiment 2 showed that both linguistic and visuospatial WM loads attenuated the inference viewing time effect, consistent with the shared systems hypothesis. Importantly, however, Experiment 3 found that articulatory suppression did not attenuate the inference viewing time effect, indicating that (sub)vocalization did not support online inference generation during visual narrative comprehension. Thus, the results support a shared-systems hypothesis in which both visuospatial and linguistic WM systems support inference generation in visual narratives, with the linguistic WM system operating at a deeper level than (sub)vocalization.


Carbon dots derived from peptone as "off-on" fluorescent probes for the detection of oxalic acid.
A simple and rapid microwave heating approach was reported for the preparation of water soluble carbon dots (CDs) using peptone as carbon source with the assistance of ethylenediamine. Several characterization techniques such as transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) were employed to analyze CDs. The optical properties of synthesized CDs were examined by UV-vis and fluorescence spectroscopy. The CDs exhibit strong blue emission under 365 nm UV lamp and have the excitation and pH (2.0-12.0) dependent emission behavior. The fluorescence intensity of CDs can be selectively quenched by Co2+ via dynamic mechanism, while the addition of oxalic acid (OA) results in a remarkable recovery of the fluorescence intensity due to the strong coordination binding between oxalic acid and Co2+. Hence, the prepared CDs can conveniently serve as "off-on" fluorescent probes for highly sensitive determination of oxalic acid. The wide linear range is 0.5-70 mg/L with a low detection limit of 0.288 mg/L. Furthermore, the probes were successfully applied to detect oxalic acid in tomato and cherry tomato samples with the recovery of 96.4 %-106.4 % and the relative standard deviation lower than 0.25 %.


Techniques in assessing fatigue in neuromuscular diseases.
Fatigue is common in neuromuscular disease and it may affect quality of life; however, it has not been adequately studied. We can approach fatigue in neuromuscular diseases systematically. Questionnaires are used to assess subjective or experienced fatigue, and with the wide availability of the Internet, many patients can fill out questionnaires through Web-based surveys. Researchers can use force-generation protocols to evaluate physical fatigability and attention protocols to evaluate mental fatigability. Using these techniques to further understand the mechanisms of subjective and physiologic fatigue will help physicians to develop more effective treatments for fatigue and improve patients' quality of life.


Association of serum total 25-hydroxy-vitamin D concentration and risk of all-cause, cardiovascular and malignancies-specific mortality in patients with hyperlipidemia in the United States.
Vitamin D (VD) plays an important role in decreasing the risk of adverse events for various metabolic diseases. However, for patients with hyperlipidemia, the relationship between the main VD storage within the body known as serum 25-hydroxy-VD [25(OH)VD] and the risk of all-cause, cardiovascular and malignancies-specific mortality is still unclear. A total of 6740 participants above the age of 20 years with hyperlipidemia who completed the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016 and were followed up until 2019 were included in the study. The weighted Cox proportional hazards regression model and weighted competing risk regression model were used to evaluate the risk for all-cause, cardiovascular and malignancy-related mortality in relation to the serum 25(OH)VD. The model was adjusted according to age, gender, race, body mass index, lipids status, medication usage, the Charlson comorbidity index and healthy eating index. The last restricted cubic spline (RCS) method was used to present the relationship between hazard ratios (HR) associated with diverse cause-specified modalities and the serum 25(OH)VD levels. Serum 25(OH)VD was identified as an independent factor for mortality. Lower serum 25(OH)VD under the threshold of 25.6 and 25.2 ng/ml were significantly associated with a higher risk for all-cause and cardiovascular mortalities, respectively. However, no association was found between malignancy-specific mortality and serum 25(OH)VD. Serum 25(OH)VD were identified as an independent factor associated with risks of all-cause and cardiovascular mortalities in patient with hyperlipidemia. Moreover, lower serum 25(OH)VD than 25.6 and 25.2 ng/mL were, respectively, associated with a gradual increase in a risk for all-cause and cardiovascular mortality in patients with hyperlipidemia, and therefore regular monitoring of VD levels and correction of VD deficiency is recommended in those patients.


Physiological and genomic properties of Thermus tenuipuniceus sp. nov., a novel slight reddish color member isolated from a terrestrial geothermal spring.
Two closely related, thermophilic bacteria, designated strains YIM 76954T and YIM 76947, were isolated from the Rehai Geothermal Field, Tengchong, Yunnan province, south-west China. Polyphasic approach and whole genome sequencing were used to determine the taxonomy status and genomic profiles of the novel strains. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the two isolates were closely related to Thermus scotoductus SE-1T (97.1% sequence similarity), and T. amyloliquefaciens YIM 77409T (96.6%). The strains could be differentiated from most recognized Thermus species by their whitish to slight reddish colony color, distinct DNA fingerprinting profiles and low ANI values. Cells stained Gram-negative, rod-shaped of diameter 0.2-0.5μm and length 1.5-5.0μm. Growth occurred at 50-75°C, pH 6.0-9.0 and in the presence of up to 1.0% (w/v) NaCl concentration. Thiosulfate was found to enhance cell growth, besides improving the intensity of its colony color. Oxygen, nitrate, sulfur, and Fe(III) could be used as terminal electron acceptors for growth. MK-8 was the major respiratory menaquinone. Major fatty acids were iso-C17:0, iso-C15:0, anteiso-C17:0, and anteiso-C15:0. The genome size was 2.26Mbp with 65.5% average GC content. A total of 2374 genes was predicted, comprising 2322 protein-coding and 52 RNA genes. On the basis of the polyphasic evidence presented, it is proposed that strain YIM 76954T represents a novel species of the genus Thermus, for which the name Thermus tenuipuniceus sp. nov. is proposed. The type strain is YIM 76954T (=JCM 30350T=KCTC 4677T).


Directed diastereoselectivity in the asymmetric claisen/metathesis reaction sequence.
The Claisen/metathesis sequence is a versatile synthetic tool for the synthesis of quaternary hydroxy and amino acid carbocycles. By correctly choosing both the configuration of the allylic alcohol and the double bond geometry, specific access to any one of four possible stereoisomers is possible in good yield and excellent diastereoselectivity. The enantiomerically pure allylic alcohols are easily obtained by addition of terminal alkynes to aldehydes. Controlled reduction of the triple bond then gives the desired double bond geometry.


Follicular non-Hodgkin's lymphoma in Hong Kong Chinese: a retrospective analysis.
Follicular lymphoma is relatively rare in Hong Kong Chinese. Fifty-two patients with follicular lymphoma were reviewed. The histology was nodular lymphocytic poorly differentiated (NLPD) in 75 per cent, nodular mixed (NM) in 21 per cent and nodular histiocytic (NH) in 4 per cent. Our patients appeared to have a higher proportion of NLPD and a lower proportion of NM lymphoma than the western series. Fifty patients were analysed excluding the two patients with NH lymphoma. They had a median age of 50 and a male to female ratio of 0.92. Seventy-two per cent of them presented with asymptomatic lymph node enlargement. Twenty per cent had B symptoms and 32 per cent bulky tumour. Twelve per cent had stage I disease, 2 per cent stage II, 30 per cent stage III and 56 per cent stage IV. A high incidence of bone marrow involvement (48 per cent of all patients) was found. All seven stage I-II patients responded to involved-field radiotherapy alone and none of them has relapsed. The 43 stage III-IV patients were treated with chemotherapy without deferral and a majority of them received CVP (51.1 per cent) or chlorambucil alone (34.9 per cent). The complete response rate of stage III-IV patients was 81 per cent and 26 per cent of the complete responders relapsed. The 5-years disease-free survival (DFS) and overall survival of all patients (stage III and IV) were 50 per cent and 65 per cent respectively. The DFS curve showed a pattern of continuous relapses. Stage III patients appeared to have a better complete response rate, a lower relapse rate and superior disease-free survival than stage IV patients but the differences did not reach statistical significance. However, the overall survival of stage III patients was significantly better than stage IV patients (p less than 0.02). Other factors including sex, age, presence of bulky tumour, B symptoms, histologic subtypes and the chemotherapeutic regimes did not significantly affect their prognosis.


Knowledge at what cost? An audit of the utility of panfungal PCR performed on bronchoalveolar lavage fluid specimens at a tertiary mycology laboratory.
The diagnostic utility and costs of panfungal PCR assays for invasive fungal disease (IFD) from bronchoalveolar lavage fluid (BALF) specimens are incompletely defined. In a retrospective audit, panfungal PCR results from 2014-2018 were matched with information on request forms and the registrar/microbiologist diary of clinical liaison. Identification of a single fungus other than a commensal was considered potentially clinically significant, and assessed for clinical relevance. Of 1002 specimens tested, an estimated 90% were requested in patients without clinical suspicion of IFD. There were 530 (52.9%) PCR-positive results of which 485/530 (91.5%) identified multiple fungal species or commensal fungi; 45 (8.5%) were clinically significant but only in 12 (1.2%) was panfungal PCR the sole diagnostic test leading to IFD diagnosis, all in immunocompromised patients with clinical suspicion of IFD. Costs of panfungal PCR tests averaged AUD 133 per test, or AUD 26,767/annum. However, the average cost-per-diagnosis achieved was AUD 15,978/annum. Limiting testing to patients at risk and with clinical suspicion of IFD, may save over AUD 13,383/annum (assuming 50-90% reduction in testing). The value-added utility of panfungal PCR on BALF is 1.2% (12/1002). We have since introduced pre-analytical stewardship limiting routine panfungal PCR testing of BALF to high-risk patients in our hospital.


U (VI) tolerance affects Shewanella sp. RCRI7 biological responses: growth, morphology and bioreduction ability.
Native Shewanella sp. RCRI7 is recently counted as an operative bacterium in the uranium bio-reduction. The aim of this study was to investigate the effects of uranium tolerance on the morphology and population of RCRI7, following its potential removal capacity in different time intervals. In this research, the bacterial growth and uranium removal kinetic were evaluated in aerobic TSB medium, uranium-reducing condition (URC), aerobic uranium-containing (AUC) and anaerobic uranium-free (AUF) solution, following evaluations of omcAB gene expressions. In addition, spectrophotometry analyses were performed in URC confirming the bio-reduction mechanism. It was found that the bacteria can grow efficiently in the presence of 0.5 mM uranium anaerobically, unlike AUC and AUF solutions. Since the bacterium's adsorption capacity is quickly saturated, it can be deduced that uranium reduction should be dominant as incubation times proceed up to 84 h in URC. In 92 h incubation, the adsorbed uranium containing unreduced and reduced (U (IV) monomeric), was released to the solution due to either increased pH or bacterial death. In AUC and AUF, improper conditions lead to the reduced bacterial size (coccus-shape formation) and increased bacterial aggregations; however, membrane vesicles produced by the bacteria avoid the uranium incrustation in AUC. In overall, this study implies that Shewanella sp. RCRI7 are well tolerated by uranium under anaerobic conditions and the amount of regenerated uranium increases over time in the reduced form.


Pediatric cancer-associated thrombosis: Analysis from a tertiary care cancer center in India.
Thrombotic events (TEs) have been extensively studied in adult cancer patients, but data in children are limited. We prospectively analyzed pediatric cancer-associated thrombosis (PCAT) in children with malignancies. Children below 15 years of age with confirmed malignancies, treated at a large tertiary cancer center in India from July 2015 to March 2020 developing any TE were eligible. A standardized approach for detection and management was followed. Data were collected after informed consent. Of 6132 eligible children, 150 (2.44%) had 152 TEs, with median age 8.5 years and male:female of 1.83:1. Most TEs occurred on chemotherapy: 111 (74.0%). The most common site was central nervous system (CNS) 59 (39.3%), followed by upper-limb venous system 37 (24.7%). Hemato-lymphoid (HL) malignancies were more prone to PCAT than solid tumors (ST) (incidence 3.23% vs. 1.58%; odds ratio [OR] = 2.06, 95% confidence interval [CI] [1.36-2.88]; p < .001). Malignancies associated with PCAT were acute lymphoblastic leukemia (ALL) 2.94%, acute myeloid leukemia (AML) 6.66%, and non-Hodgkin lymphomas 5.35%. Response imaging done in 106 (70.7%) children showed complete to partial resolution in almost 90% children. Death was attributable to TE in seven (4.66%) children. Age above 10 years (OR 2.33, 95% CI [1.59-3.41]; p < .001), AML (OR 4.62, 95% CI [1.98-10.74]; p = .0062), and non-Hodgkin lymphoma (OR 4.01, 95% CI [1.15-14.04]; p = .029) were significantly associated with TEs. In ALL, age more than 10 years (OR 1.86, 95% CI [1.06-3.24]; p < .03), T-ALL (OR 3.32, 95% CI [1.69-6.54]; p = .001), and intermediate-risk group (OR 4.97, 95% CI [1.12-22.02]; p = .035) were significantly associated with thrombosis. The 2-year event-free survival (EFS) for HL malignancies with PCAT was 55.3% versus 72.1% in those without PCAT (p = .05), overall survival (OS) being 84.6% versus 80.0% (p = .32). Incidence of PCAT was 2.4%, and occurred predominantly in older children with hematolymphoid malignancies early in treatment. Most resolved completely with low molecular weight heparin (LMWH) and mortality was low. In hematolymphoid malignancies, PCAT reduce EFS, highlighting the need for prevention.