Light to moderate coffee consumption is associated with lower risk of death: a UK Biobank study.
To study the association of daily coffee consumption with all-cause and cardiovascular (CV) mortality and major CV outcomes. In a subgroup of participants who underwent cardiovascular magnetic resonance (CMR) imaging, we evaluated the association between regular coffee intake and cardiac structure and function. UK Biobank participants without clinically manifested heart disease at the time of recruitment were included. Regular coffee intake was categorized into three groups: zero, light-to-moderate (0.5-3 cups/day), and high (>3 cups/day). In the multivariate analysis, we adjusted for the main CV risk factors. We included 468 629 individuals (56.2 ± 8.1 years, 44.2% male), of whom 22.1% did not consume coffee regularly, 58.4% had 0.5-3 cups per day, and 19.5% had >3 cups per day. Compared to non-coffee drinkers, light-to-moderate (0.5-3 cups per day) coffee drinking was associated with lower risk of all-cause mortality [multivariate hazard ratio (HR) = 0.88, 95% confidence interval (CI): 0.83-0.92; P < 0.001] and CV mortality (multivariate HR = 0.83, 95% CI: 0.74-0.94; P = 0.006), and incident stroke (multivariate HR = 0.79, 95% CI: 0.63-0.99 P = 0.037) after a median follow-up of 11 years. CMR data were available in 30 650 participants. Both light-to-moderate and high coffee consuming categories were associated with dose-dependent increased left and right ventricular end-diastolic, end-systolic and stroke volumes, and greater left ventricular mass. Coffee consumption of up to three cups per day was associated with favourable CV outcomes. Regular coffee consumption was also associated with a likely healthy pattern of CMR metrics in keeping with the reverse of age-related cardiac alterations.


Mutagenicity of Nagara river sediment.
The sediments of Nagara river and its bystreams were extracted with ether. The mutagenicities of the extracts were determined by the Ames test with Salmonella typhimurium TA100 with S9 mix. The extracts were fractionated on an activated silica-gel column with four kinds of organic solvent, namely iso-octane, iso-octane:benzene (1:1), benzene:ethyl acetate (1:1) and benzene:methanol (1:1). The highest mutagenicity was observed in the iso-octane-benzene fraction of Arata river by using TA100 with S9 mix. Chemical substances in this fraction were identified by GC-MS and GC, and several kinds of polycyclic aromatic hydrocarbons (PAH) were found. Several peaks were unidentified, but these PAH, especially benzo [b] fluoranthene and benzo [a] pyrene, may contribute substantially to the mutagenicity of this fraction.


Pharmacology of CS-866, a novel nonpeptide angiotensin II receptor antagonist.
CS-866, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxy-4-(1-hydroxy-1- methylethyl)-2-propyl-1-(4-[2-(tetrazol-5-yl)-phenyl]phenyl)met hylimidazol- 5-carboxylate, a prodrug type angiotensin receptor antagonist, is deesterified to the active acid, RNH-6270. RNH-6270 inhibited [125I]angiotensin II binding to bovine adrenal cortical membranes (angiotensin AT1 receptors) with an IC50 value of 7.7 nM, but not [125I]angiotensin II binding to bovine cerebellar membranes (angiotensin AT2 receptors), indicating the selectivity of the compound for angiotensin AT1 receptors. In guinea pig aortas, RNH-6270 reduced the maximal response of the concentration-contractile curve for angiotensin II (pD'2 = 9.9), but had no effect on the contractile response induced by phenylephrine or KCl. In conscious rats, intravenously injected RNH-6270 inhibited angiotensin II-induced pressor responses in a dose-dependent manner, and orally administered CS-866 produced a long-lasting inhibition of angiotensin II pressor responses. SK&F-525A, a P-450 inhibitor, suppressed the angiotensin II inhibitory effect of losartan, but not that of CS-866. These results demonstrate that RNH-6270 is a potent and AT1-selective angiotensin receptor antagonist and that, after oral administration, CS-866 has a long-lasting angiotensin II inhibitory action which is not affected by drug metabolizing enzymes in the liver.


Spontaneous automaticity arising from a successfully ablated Mahaim fiber.
The authors describe a 22-year-old woman with regular and irregular arrhythmias exhibiting left bundle branch block (LBBB) morphology at various heart rates. An atriofascicular fiber was diagnosed as the underlying mechanism for the antidromic reciprocating tachycardia. In addition, spontaneous automaticity of the Mahaim fiber was present during electrophysiologic study. The accessory pathway was ablated successfully, targeting a Mahaim potential at the supero-anterior tricuspid valve annulus. Relatively slow automatic rhythms with identical LBBB morphology were recorded immediately after ablation, as well as during long-term follow-up in a more sporadic and subclinical form. Abnormal automaticity arising from the distal portions of the remnant pathway was considered to be the origin of the slow ventricular rhythms in this peculiar case.


Multiple species and deep genomic divergences despite little phenotypic differentiation in an ancient Neotropical songbird, Tunchiornis ochraceiceps (Sclater, 1860) (Aves: Vireonidae).
Several bird taxa have been recently described or elevated to full species and almost twice as many bird species than are currently recognized may exist. Defining species is one of the most basic and important issues in biological science because unknown or poorly defined species hamper subsequent studies. Here, we evaluate the species limits and evolutionary history of Tunchiornis ochraceiceps-a widespread forest songbird that occurs in the lowlands of Central America, Chocó and Amazonia-using an integrative approach that includes plumage coloration, morphometrics, vocalization and genomic data. The species has a relatively old crown age (~9 Ma) and comprises several lineages with little, if any, evidence of gene flow among them. We propose a taxonomic arrangement composed of four species, three with a plumage coloration diagnosis and one deeply divergent cryptic species. Most of the remaining lineages have variable but unfixed phenotypic characters despite their relatively old origin. This decoupling of genomic and phenotypic differentiation reveals a remarkable case of phenotypic conservatism, possibly due to strict habitat association. Lineages are geographically delimited by the main Amazonian rivers and the Andes, a pattern observed in studies of other understory upland forest Neotropical birds, although phylogenetic relationships and divergence times among populations are idiosyncratic.


Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma.
Treatment of eyes with retinoblastoma failing systemic chemoreduction and external beam radiotherapy is seldom efficacious. This study compares the efficacy and toxicity of intra-arterial ophthalmic artery chemotherapy (IAO) to our historical cohort of sequential periocular and systemic chemotherapy in such patients. Eighteen eyes (15 consecutive patients) were retrospectively evaluated. Eight eyes received IAO for a median of four cycles (range: 2-9) including melphalan alone (n = 3) or after topotecan and carboplatin (n = 4) or topotecan and carboplatin without melphalan (n = 1). Ten eyes received a median of two cycles (range: 1-3) of periocular topotecan (n = 9) or carboplatin (n = 1) followed by intravenous topotecan and cyclophosphamide in three patients if at least stable disease was achieved. Both groups were comparable for disease extension and prior therapy. No extraocular dissemination or second malignancy occurred and all patients are alive. The probability of enucleation-free eye survival at 12 months was 0.87 (95% CI: 0.42-0.97) for the IAO group, compared to 0.1 (95% CI: 0.06-0.35) for the periocular group (P < 0.01). Ocular toxicity was mild and similar in both groups (mostly mild orbital edema). Systemic toxicity was low for IAO and periocular injection, but children who received sequentially intravenous chemotherapy (n = 12 cycles) had five episodes of grade 4 neutropenia, three of which resulted in hospitalizations. No case in the IAO group presented these complications. IAO is significantly superior to sequential periocular-intravenous topotecan-containing regimens in eyes with relapsed intraocular retinoblastoma with a more favorable toxicity profile.


An analysis of behavioral plasticity in male Caenorhabditis elegans.
Caenorhabditis elegans is a simple soil-dwelling nematode which has two sexes, hermaphrodite and male. The male C. elegans is differentiated from the hermaphrodite by the presence of 14 sensory structures in the tail. In this study, we compared the behavioral responses of males and hermaphrodites to head-touch and to tap. We hypothesized that the anatomical difference in sensory structures might result in behavioral differences in the reversal response to vibratory stimulation (a tap to the side of the holding dish). In the response to increasing intensities of tap, both sexes showed an increase in response magnitude, with the males showing larger responses than hermaphrodites. In addition, the male was shown to be capable of simple nonassociative learning: it demonstrated habituation and recovery from habituation in a similar manner as the hermaphrodite. Tail-touch-induced inhibition of the reversal response appeared to be similar in males and hermaphrodites. The evidence suggests that the touch withdrawal circuit in hermaphrodites is also present in the male C. elegans, and that the subtle differences in response to tap seen in males may result from the additional sensory receptors of the copulatory bursa of the tail. It seems clear from these studies that these structures do not play a key role in the male worm's response to tap.


[Pneumopericardium after hyperemesis. Possible result of the Macklin effect].
Pneumopericardium is a rare but serious finding. It may indicate severe chest trauma and be associated with tracheobronchial and oesophageal injuries. On the other hand, oesophageal rupture such as Boerhaave's syndrome may also be accompanied by pneumopericardium. A case of spontaneous pneumopericardium and pneumomediastinum after alcohol-induced emesis is reported. Tracheal, bronchial, and oesophageal injury were excluded by radiology and endoscopy. Interstitial lung emphysema is discussed as the pathogenesis.


Understanding the literature: Complexity of statistical methods used in high-impact cardiothoracic surgery research.
Biostatistics are frequently used in research published in the domain of cardiothoracic surgery. The objective of this study was to describe the scope of statistical techniques reported in the literature and to highlight implications for editorial review and critical appraisal. Original research articles published between January and April 2017 in the Journal of Thoracic and Cardiovascular Surgery, Annals of Thoracic Surgery, and the European Journal of Cardio-Thoracic Surgery were examined. For each article, the statistical method(s) reported were recorded and categorized by complexity. We reviewed 293 articles that reported 1068 statistical methods. The mean number of different statistical methods reported per article was 3.6 ± 1.9, with variation by subspecialty and journal. The most common statistical methods were contingency tables (in 59% of articles), t tests (49%), and survival methods (49%). Only 4% of articles used descriptive statistics alone. An introductory level of statistical knowledge was deemed sufficient for understanding 16% of articles, whereas for the remainder a higher level of knowledge would be needed. Contemporary cardiothoracic surgery research frequently requires the use of complex statistical methods. This was evident across articles for all cardiothoracic surgical subspecialties as reported in 3 high-impact journals. Routine review of manuscript submissions by biostatisticians is needed to ensure the appropriate use and reporting of advanced statistical methods in cardiothoracic surgery research.


Are treatment effects consistent with hypothesized mechanisms of action proposed for postoperative delirium interventions? Reanalysis of systematic reviews.
Aim: Postoperative delirium (POD) is associated with increased morbidity and is poorly understood. The aim of this review was to identify putative mechanisms through re-analysis of randomized trials on treatment or prevention of POD. Materials & methods: A systematic review was performed to identify systematic reviews of treatments for POD. Constituent randomized controlled trials were identified, and interventions were grouped according to hypothesized mechanisms of action. Effects were meta-analyzed by hypothesized mechanism and timing of intervention. Results: A total of 116 randomized controlled trials described 47 individual interventions for POD, with nine mechanisms identified. The largest effects were observed for postoperative inflammation reduction, and preoperative reinforcement of sleep-wake cycle. Conclusion: This approach identifies treatments focused on mechanisms of action that may be front runners for future trials and interventions.


Localization of substance P-like immunoreactivity in Hydra.
Substance P-like immunoreactivity was found in Hydra attenuata mainly but not exclusively in the nerve and interstitial cells, localized in the cytoplasm and on the cell surface membranes.


Host resistance in liver disease--its evaluation and therapeutic modification.
We have attempted to review some of the factors involved in host resistance and the variations in the individual responses to the infectious and noxious agents to which we are increasingly exposed. Few treatment modalities are available to favorably influence host resistance, but clearly, this approach to the treatment of liver disease represents an opportunity for the future.


Central regulation of gastric acid secretion by platelet-activating factor in anesthesized rats.
PAF has been implicated in the pathogenesis of acute gastric injury. When given peripherally, PAF induces severe gastric mucosal damage. PAF metabolizing enzymes are present in the brain but the central effects of PAF on the stomach are unknown. We have investigated in the rat the gastric secretion and gross mucosal integrity in response to intracerebroventricular (icv) PAF and compared it with that to icv TRH, a known central gastric secretagogue. Gastric acid output was markedly increased by TRH (171.6 +/- 26.3 mumol/h mean +/- SE) and by 20 micrograms/kg/h iv pentagastrin (107.6 +/- 23.6) when compared to controls receiving icv vehicle (20.2 +/- 7.5; p less than 0.01 for both). In contrast, acid output decreased after icv PAF (13.5 +/- 7.5). Furthermore, icv PAF markedly inhibited acid output stimulated by iv pentagastrin (45.1 +/- 7.03; p less than 0.05). Morphological studies showed acute gastric mucosal erosions after icv TRH and no damage was observed after icv PAF or vehicle. Thus, icv PAF reduces pentagastrin stimulated acid output and does not alter gastric mucosal integrity, whereas icv TRH stimulates acid secretion and induces gastric injury. The opposite effects of PAF and TRH suggests the existence of a gastric modulatory system at the central level.


Neuroimaging of Infectious Vasculopathy.
Vasculitis is a complication of several infectious diseases affecting the central nervous system, which may result in ischemic and/or hemorrhagic stroke, transient ischemic attack, and aneurysm formation. Infectious agents may directly infect the endothelium causing vasculitis or indirectly affect the vessel wall through an immunological cascade. Clinical manifestations usually overlap with those of noninfectious vascular diseases, making diagnosis challenging. Neuroimaging enables the identification of inflammatory changes in intracranial vasculitis. In this article, we review the imaging features of infectious vasculitis of bacterial, viral, fungal and parasitic causes.


Statistical finite elements for misspecified models.
We present a statistical finite element method for nonlinear, time-dependent phenomena, illustrated in the context of nonlinear internal waves (solitons). We take a Bayesian approach and leverage the finite element method to cast the statistical problem as a nonlinear Gaussian state-space model, updating the solution, in receipt of data, in a filtering framework. The method is applicable to problems across science and engineering for which finite element methods are appropriate. The Korteweg-de Vries equation for solitons is presented because it reflects the necessary complexity while being suitably familiar and succinct for pedagogical purposes. We present two algorithms to implement this method, based on the extended and ensemble Kalman filters, and demonstrate effectiveness with a simulation study and a case study with experimental data. The generality of our approach is demonstrated in SI Appendix, where we present examples from additional nonlinear, time-dependent partial differential equations (Burgers equation, Kuramoto-Sivashinsky equation).


Metabolic activation of aflatoxin B1 to aflatoxin B1-8,9-epoxide in woodchucks undergoing chronic active hepatitis.
Chronic hepatitis B virus infection as well as consumption of food contaminated with the mycotoxin aflatoxin B1 are considered to be 2 major risk factors for the development of primary liver cancer in humans. Furthermore, epidemiological surveys indicate that hepatitis B virus and aflatoxin B1 might act synergistically to induce primary liver cancer. In the present study, we have tested the hypothesis that the metabolic activation of aflatoxin B1 to aflatoxin B1-8,9-epoxide, the ultimate mutagenic and carcinogenic mycotoxin metabolite, is enhanced in an experimental model of chronic hepatitis using woodchucks, chronically infected with the woodchuck hepatitis virus. Woodchuck liver microsomes were incubated with radiolabeled aflatoxin B1, the resulting aflatoxin B1-8,9-epoxide was trapped as a glutathione conjugate and its formation rate was determined by a reversed-phase HPLC analysis. In woodchuck hepatitis virus-positive woodchucks, activation of aflatoxin B1 to aflatoxin B1-8,9-epoxide was reduced when compared to woodchuck hepatitis virus-free animals, and the extent of the reduction was dependent on the severity of the hepatitis. Hence, at least in woodchucks, a chronic hepadnaviral infection does not lead to an enhanced activation of aflatoxin B1.


Obesity in early onset breast cancer in African American patients.
Obesity is a modifiable risk factor in breast cancer patients and is predictive of disease outcomes in early-onset breast cancer survivors. The purpose of this review is to summarize the current evidence in the association between early-onset breast cancer and obesity, specifically in African-American women. Reviewing the molecular mechanisms and social determinants of disease in this population can provide a foundation for future interventions in prevention, detection, and treatment aiming at improving outcomes for young breast cancer patients.


Radiographic findings of spontaneous subluxation of the sternoclavicular joint.
Eight middle-aged women with spontaneous atraumatic subluxation of the sternoclavicular joint were evaluated with radiography and computed tomography. All patients were employed in occupations involving moderate to heavy physical labour, and no patients could recall a specific traumatic incident associated with onset of symptoms. In seven of the eight patients, the displacement of the medial clavicle was in a cranial direction; in four of the eight patients, there was an associated anterior subluxation, and in one patient, the subluxation was purely anterior. All five patients with an anterior component to the sternoclavicular subluxation had associated condensing osteitis of the clavicle. The sclerosis of the medial clavicle is possibly the result of chronic abrasion on the sternum and first costal cartilage in association with normal respiration and with upper extremity motion.


Further observations on the activation of lysosomal acid alpha-glucosidase by cortisone derivatives.
1. Cortisone acetate activates the acid alpha-glucosidase in rat liver slices and in isolated liver lysosomes. 2. The reaction is steroid specific and moreover does not occur with lysosomal acid phosphatase or beta-galactosidase. 3. After pretreatment of the lysosomes with cortisone, substrate (maltose) binding to the soluble lysosomal acid alpha-glucosidase is not affected, but the steroid does increase the V(max.) value. Membrane-bound enzyme is not activated by cortisone. 4. 4-[(14)C]Cortisone is preferentially bound to the lysosomal membrane and the possible involvement of this structure in the activation phenomenon is discussed.


In vivo approach of simply constructed pyrazinamide conjugated chitosan-g-polycaprolactone micelles for methicillin resistance Staphylococcus aureus.
Methicillin-resistant Staphylococcus aureus (MRSA) is an extensive origin of nosocomial infections that are very much challenging as well as complicated to eradicate mostly due to their strong resistance against all existing antibiotic therapies. Here the chitosan-grafted-polycaprolactone/maleic anhydride-pyrazinamide (CS-g-PCL/MA-PZA) polymeric drug carrier constructed via dialysis for anti-MRSA drugs like rifampicin (RF) and pyrazinamide (PZA) delivery. Nearly 200 nm size of the spherical particle with -20.04 mV of zeta potential observed. The cumulative PZA and RF releases from the carrier were observed 83.25% and 76.54% respectively in pH 5.5, and the in vitro drug release profile demonstrates that the fabricated micelle was pH-responsive. For the intestinal colonization, an in vivo assay performed using C. elegans, and the CS-g-PCL/MA-PZA/RF micelles treated worms generally belong to the weakly colonized category. Therefore, the study revealed that CS-g-PCL/MA-PZA/RF micelle could be a promising approach for therapeutic applications to achieve efficient anti-MRSA drug delivery.


COVID-19 Infection and Circulating Microparticles-Reviewing Evidence as Microthrombogenic Risk Factor for Cerebral Small Vessel Disease.
Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) due to novel coronavirus disease 2019 (COVID-19) has affected the global society in numerous unprecedented ways, with considerable morbidity and mortality. Both direct and indirect consequences from COVID-19 infection are recognized to give rise to cardio- and cerebrovascular complications. Despite current limited knowledge on COVID-19 pathogenesis, inflammation, endothelial dysfunction, and coagulopathy appear to play critical roles in COVID-19-associated cerebrovascular disease (CVD). One of the major subtypes of CVD is cerebral small vessel disease (CSVD) which represents a spectrum of pathological processes of various etiologies affecting the brain microcirculation that can trigger subsequent neuroinflammation and neurodegeneration. Prevalent with aging, CSVD is a recognized risk factor for stroke, vascular dementia, and Alzheimer's disease. In the background of COVID-19 infection, the heightened cellular activations from inflammations and oxidative stress may result in elevated levels of microthrombogenic extracellular-derived circulating microparticles (MPs). Consequently, MPs could act as pro-coagulant risk factor that may serve as microthrombi for the vulnerable microcirculation in the brain leading to CSVD manifestations. This review aims to appraise the accumulating body of evidence on the plausible impact of COVID-19 infection on the formation of microthrombogenic MPs that could lead to microthrombosis in CSVD manifestations, including occult CSVD which may last well beyond the pandemic era.


Pneumococcal meningitis in adults in 2014-2018 after introduction of pediatric 13-valent pneumococcal conjugate vaccine in Japan.
We assessed the impact of the pediatric 13-valent pneumococcal conjugate vaccine (PCV13) on pneumococcal meningitis in adults in Japan in 2014-2018 by comparing epidemiological characteristics of adults with invasive pneumococcal disease with (n = 222) and without (n = 1258) meningitis. The annual incidence of pneumococcal meningitis in 2016-2018 was 0.20-0.26 cases/100,000 population. Age (p < 0.001) and case fatality rate (p = 0.003) were significantly lower in patients with meningitis than in those without meningitis. The odds of developing meningitis were higher in asplenic/hyposplenic or splenectomized patients (adjusted odds ratio [aOR] 2.29, 95% CI 1.27-4.14), for serotypes 10A (aOR 3.26, 95% CI 2.10-5.06) or 23A (aOR 3.91, 95% CI 2.47-6.19), but lower for those aged ≥ 65 years (aOR 0.59, 95% CI 0.44-0.81). PCV13 had an indirect effect on nonmeningitis, but its impact on meningitis was limited because of an increase in non-PCV13 serotypes. Of meningitis isolates, 78 (35.1%) and 3 (1.4%) were penicillin G- or ceftriaxone-resistant, respectively. We also confirmed an association of the pbp1bA641C mutation with meningitis (aOR 2.92, 95% CI 1.51-5.65).


TALEs for the masses.
An optimized transcription activator–like effector (TALE) and an improved assembly method promise efficient genome editing and transcriptome modulation.


Urethral hemangioma.
Urethral hemangiomas are uncommon lesions that can cause significant hemorrhagic morbidity. Since the lesions tend to recur complete urethral excision and subsequent urethral reconstruction have been advocated in the past as the preferred method of treatment. We present an alternative method of management of urethral hemangioma.


On the mechanisms involved in antinociception induced by diphenyl diselenide.
In this study, we described the local peripheral antinociceptive activity produced by diphenyl diselenide in the formalin test as compared to ebselen, an amply studied organoselenium compound. A second objective was to evaluate, the possible mechanisms underlying the antinociceptive effect caused by diphenyl diselenide. Administration of diphenyl diselenide or ebselen produced a significant antinociceptive local effect on the late phase (15-30min) of the formalin test. As well, diphenyl diselenide and ebselen injected in the contra lateral paw produced a significant decrease in licking time on the late phase (15-30min). The mechanisms underlying the analgesic action of diphenyl diselenide seem to be unlike the activation of opioid, dopaminergic D2, muscarinic cholinergic receptors or the interaction with α(1) and α(2) adrenoceptors. Furthermore, the effect of a 5-HT(3) receptor antagonist in abolishing the antinociception induced by diphenyl diselenide suggests the involvement of serotonergic pathways.


[Rheumatoid arthritis and myocardiopathy. A patient awaiting a heart transplant].
Cardiovascular pathology is common in rheumatoid arthritis. However, myocardial affection is unusual and clinical disease is rare. We report a case of dilated cardiomyopathy in a patient with rheumatoid arthritis and progressive heart failure that required inclusion into a heart transplantation list.


Four-component radical-dual-difunctionalization (RDD) and decarbonylative alkylative peroxidation of two different alkenes with aliphatic aldehydes and TBHP.
From difunctionalization of a single alkene to radical-dual-difunctionalization of two different alkenes! Abundant aliphatic aldehydes were readily decarbonylated into alkyl radicals for the cascade construction of C(sp3)-C(sp3), C(sp3)-C(sp3) and C(sp3)-O bonds via double radical addition and radical-radical coupling, following the intrinsic nucleophilic/electrophilic reactivity of both the radicals and alkenes.


Assignment of mouse beta-spectrin gene to chromosome 12.
The structural gene for the beta-subunit of the mouse erythrocyte spectrin, hereinafter designated as Sp-b, was assigned to the mouse chromosome 12. This assignment was made by Southern analysis of genomic DNA from mouse X Chinese hamster hybrid cells using cloned mouse erythrocyte beta-spectrin cDNA as a probe. In the PstI-digested genomic hamster cell DNA a single band of 2.0 kb was detected, whereas PstI-digested mouse DNA gave a band of 4.2 kb, when probed with the mouse erythroid beta-spectrin cDNA clone. This allowed us to analyze a panel of mouse X Chinese hamster somatic cell hybrids to map this gene to chromosome 12. Interestingly, this assignment is different from that observed for the alpha-subunit of spectrin, which has been mapped to chromosome 1 in mouse. These results serve as a basis for further genetic characterization of the mouse hemolytic anemias.


[Comparison of right ventricular function between prevention and enlargement of pulmonary valve annulus after repair of tetralogy of Fallot; mid-term results].
Total of 41 patients with tetralogy of Fallot (TOF) who underwent intracardiac repair from 1993 to 1998 were divided into 2 groups: preservation (n = 14) or enlargement (n = 27) of the pulmonary valve annulus. The procedure was decided on the Z value of the annular size: above or under -2 SD of the standard value. Although postoperative right ventricular (RV) diastolic volume (RVEDV) and cardiothoracic ratio (CTR) were larger than the preservation group and pulmonary regurgitation (PR) existed in the enlargement group, RV pressure was decreased and central venous pressure (CVP) was low and RV contraction was preserved. The exercise capacity was also good and no significant arrhythmia was recognized. Our mid-term results showed that appropriate enlargement of the pulmonary valve annulus preserved good RV function in patients with TOF.


Combination effects of antifungal nagilactones against Candida albicans and two other fungi with phenylpropanoids.
Antifungal activity of three nagilactones isolated from the root bark of Podocarpus nagi (Podocarpaceae), alone and in combination with a variety of phenylpropanoids, was investigated against three fungi, Candida albicans, Saccharomyces cerevisiae, and Pityrosporum ovale. Nagilactone E [2], the most abundant norditerpene dilactone, showed moderate to weak activity against these fungi. This activity was dramatically enhanced by several naturally occurring phenylpropanoids such as anethole [5] and isosafrole. For example, anethole enhanced the activity of nagilactone E as much as 128-fold for C. albicans, decreasing the MIC of this nagilactone from 800 to 6.25 micrograms/ml.


Discolored Red Seaweed Pyropia yezoensis with Low Commercial Value Is a Novel Resource for Production of Agar Polysaccharides.
The red seaweed Pyropia yezoensis has been demonstrated to be a novel resource for the production of high-quality agar. P. yezoensis is grown for the food industry in large-scale Japanese mariculture operations. However, discolored P. yezoensis is mostly discarded as an industrial waste, although it has some kind of utility values. Here, we evaluated the utility of discolored P. yezoensis as a resource for agar production. The quality of agar from the discolored seaweed was comparable to that from normal seaweed. In addition, as a distinguishing characteristic, agar yield was higher from discolored seaweeds than from normal types. Moreover, we successfully used agar from discolored P. yezoensis for bacterial plate media and DNA electrophoresis gels without agarose purification. Thus, our results demonstrate that discolored P. yezoensis is suitable for agar production and use in life science research. Diverting discolored P. yezoensis from disposal to agar production provides a solution to the current industrial waste problem in mariculture, as well as a secure source of agar for research purposes.


Waist to height ratio is associated with an increased risk of mortality in Chinese patients with heart failure with preserved ejection fraction.
Abdominal obesity as a predominant comorbidity has played a key role in the incidence and worsening of heart failure with preserved ejection fraction (HFpEF), and waist-to-height ratio (WHtR) behaves better than waist circumference or body mass index in evaluating abdominal obesity. While the association between WHtR and all-cause death in Chinese patients with HFpEF remains unclear. Patients with stable HFpEF (N = 2041) who presented to our hospital from January 2008 to July 2019 were divided into low-WHtR (< 0.5, N = 378) and high-WHtR (≥ 0.5, N = 1663). Multivariable Cox proportional-hazard models were used to examine the association of WHtR with all-cause death. The average age was 76.63 ± 11.44 years, and the mean follow-up was 4.53 years. During follow-up, 185 patients (9.06%) reached the primary outcome of all-cause death. As for the secondary outcome, 79 patients (3.87%) experienced cardiovascular death, 106 (5.19%) had non-cardiovascular death, and 94 (4.61%) had heart failure rehospitalization. After multivariable adjustment, a higher WHtR was significantly associated with the increased risks of all-cause death [adjusted hazard ratios (HR) 1.91, 95% confidence interval (CI) 1.06-3.45, p = 0.032], cardiovascular death (adjusted HR 2.58; 95% CI 1.01-6.67, p = 0.048), and HF rehospitalization (adjusted HR 3.04; 95% CI 1.26-7.31, p = 0.013). Higher WHtR is an independent risk factor for all-cause death in Chinese patients with HFpEF.


Effect of student-directed solicitation of evaluation forms on the timeliness of completion by preceptors in the United States.
Summative evaluation forms assessing a student's clinical performance are often completed at the end of a clinical experience from a faculty preceptor. In our institution, despite the use of an electronic system, completion timeliness has been suboptimal potentially limiting our ability to monitor student progress. The aim of the present study was to determine if a student-centered approach to summative evaluation form collection at the end of a pediatrics clinical experience will enhance timeliness of completion for third year medical students at Pennsylvania State College of Medicine. This was a pre- and post-intervention educational quality improvement project focused on 156 (82 pre-intervention, 74 post-intervention) third year medical students at Pennsylvania State College of Medicinecompleting their four-week pediatric clerkship. Utilizing Research Electronic Data Capture (REDCap) informatics support, student-directed evaluation form solicitation was encouraged. Wilcoxon rank sum test was applied to compare pre-intervention (May 1, 2017 to March 2, 2018) and post-intervention (April 2, 2018 to December 21, 2018) percentages of forms completed before rotation midpoint. Seven hundred and forty evaluation forms were submitted during the pre-intervention phase and five-hundred and seventeen were submitted during the post-intervention phase. Form completion percentage before rotation midpoint increased after implementation of student-directed solicitation (9.6% versus 39.7%, P<0.05). Our clerkship relies on subjective summative evaluations to track student progress, employ improvement strategies, and determine criteria for advancement; however, our preceptors struggled with timely submission. Allowing students to direct the solicitation of evaluation forms enhanced the timeliness of completion at our institution and should be considered in clerkships with similar difficulties.


Hataedock treatment has preventive therapeutic effects for atopic dermatitis through skin barrier protection in Dermatophagoides farinae-induced NC/Nga mice.
Hataedock treatment is traditionally used for the purpose of preventing the future skin disease by feeding herbal extracts to the newborn in traditional Chinese and Korean medicine. This study investigated the preventive therapeutic effects of Hataedock (HTD) treatment for atopic dermatitis (AD) through skin barrier protection in Dermatophagoides farinae-induced NC/Nga mice. To the HTD treatment group, the extract of Coptis japonica Makino and Glycyrrhiza uralensis Fischer, which analyzed with High Performance Liquid Chromatography (HPLC)-fingerprint for quality consistency, was administered orally to the 3-week-old mice before inducing AD. After that, Dermatophagoides farinae was applied except the control group to induce AD-like skin lesions. We confirmed the effects of HTD on morphological changes, protection of skin barrier, regulation of Th2 differentiation, inflammation regulation and induction of apoptosis through histochemistry, immunohistochemistry, and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. HTD effectively reduced edema, angiogenesis and skin lesion. HTD also increased the levels of liver X receptor (LXR) and filaggrin but decreased the level of protein kinase C (PKC) (p<0.01). The levels of interleukin-4 (IL-4), IL-13, signal transducer and activator of transcription-6 (STAT-6) and Cluster of differentiation 40 (CD40) were significantly reduced in the HTD treated group (p<0.01). HTD also suppressed the mast cell degranulation and the level of the high-affinity IgE receptor (FcɛRI), substance P, Matrix metalloproteinases-9 (MMP-9) and 5-hydroxytryptamine (5-HT) (p<0.01). The levels of inflammatory factors such as nuclear factor-kappaB (NF-κB) p65, phosphorylated IκB (p-IκB) and inducible nitric oxide synthase (iNOS) were also decreased (p<0.01). Apoptosis of inflammatory cells was also found to increase (p<0.01). Our results indicate that HTD effectively regulate the Th2 differentiation, mast cell activation and various inflammatory responses on AD-induced mice through protection of skin barrier. Therefore, HTD may have potential applications for alternative and preventive treatment in the management of AD.


Co-encapsulation of amyloglucosidase with starch and Saccharomyces cerevisiae as basis for a long-lasting CO2 release.
CO2 is known as a major attractant for many arthropod pests which can be exploited for pest control within novel attract-and-kill strategies. This study reports on the development of a slow-release system for CO2 based on calcium alginate beads containing granular corn starch, amyloglucosidase and Saccharomyces cerevisiae. Our aim was to evaluate the conditions which influence the CO2 release and to clarify the biochemical reactions taking place within the beads. The amyloglucosidase was immobilized with a high encapsulation efficiency of 87% in Ca-alginate beads supplemented with corn starch and S. cerevisiae biomass. The CO2 release from the beads was shown to be significantly affected by the concentration of amyloglucosidase and corn starch within the beads as well as by the incubation temperature. Beads prepared with 0.1 amyloglucosidase units/g matrix solution led to a long-lasting CO2 emission at temperatures between 6 and 25 °C. Starch degradation data correlated well with the CO2 release from beads during incubation and scanning electron microscopy micrographs visualized the degradation of corn starch granules by the co-encapsulated amyloglucosidase. By implementing MALDI-ToF mass spectrometry imaging for the analysis of Ca-alginate beads, we verified that the encapsulated amyloglucosidase converts starch into glucose which is immediately consumed by S. cerevisiae cells. When applied into the soil, the beads increased the CO2 concentration in soil significantly. Finally, we demonstrated that dried beads showed a CO2 production in soil comparable to the moist beads. The long-lasting CO2-releasing beads will pave the way towards novel attract-and-kill strategies in pest control.


Evaluation of metals and trace elements in sediments of Kanyakumari beach (southernmost India) and their possible impact on coastal aquifers.
Beach sediments of Kanyakumari at the southernmost India were evaluated for metals and trace elements and to assess their possible impact on coastal ecosystems. Positive correlations (except for Cd and Sr) between them indicated metamorphic lithologies and heavy mineral deposits as possible sources. Significant-extremely high enrichment and very high contamination of Th, Zr, Mo, Ti and U reflected the presence of different heavy minerals. The geo-accumulation index, however, mirrored their variable abundances at different sites. Association of Cd with P suggested the influence of anthropogenic solid waste from fishing industry. It might have caused >41-fold enrichment of Cd and the Fe- Mn-oxides possibly acted as scavengers for 13-fold enrichment of As compared to UCC. Concentrations of Zn and Cr between ERL and ERM in 13% and 93% of the samples, and Ni > ERM in 87% of sediments suggest their bioavailability to seawater with a potential risk for coastal aquifers.


The risk factors of heart failure in elderly patients with hip fracture: what should we care.
Heart failure is a common adverse postoperative complication in elderly patients. It is necessary to explore the risk factors of heart after the operation of elderly patients with hip fracture during hospitalization. Patients with hip fractures admitted to our hospital from January 1, 2019 to December 31 2020 were included, all the patients received internal fixation surgery. The characteristics of patients with and without postoperative heart failure were compared. Multivariate logistic regression analyses were applied to analyze the risk factors of heart failure in elderly patients with hip fracture. A total of 283 patients with hip fractures were included, the incidence of heart failure was 12.37 %. There were significant differences in the age, hypertension, anemia hypoalbuminemia and duration of surgery between heart failure and no heart failure group(all p < 0.05). There were no significant differences in the gender, BMI, diabetes mellitus, hyperlipidemia, history of heart failure, cognitive dysfunction, type of fracture, preoperative oxygen saturation, white blood cell count, platelet count, red blood cell count, creatinine, alanine aminotransferase, aspartate aminotransferase and estimated blood loss during surgery between heart failure and no heart failure group(all p > 0.05). Logistic regression analyses indicated that age ≥ 70y(OR2.446, 95% CI1.044 ~ 4.149), hypertension(OR2.152, 95% CI1.125 ~ 4.023), anemia(OR3.094, 95% CI1.294 ~ 5.907), hypoalbuminemia(OR2.377, 95% CI1.205 ~ 4.537), duration of surgery ≥ 120 min(OR1.683, 95% CI1.094 ~ 2.782) were the risk factors of heart failure in elderly patients with hip fracture(all p < 0.05). The incidence of postoperative heart failure in elderly patients with hip fracture is relatively high, which is the result of a combination of high-risk factors. Peri-period risk assessment and prevention of related risks are the keys to a good prognosis for patients.


Lymphatic spread of nodal metastases in high-risk prostate cancer: The ascending pathway from the pelvis to the retroperitoneum.
The aim of this study was to map the nodal metastases distribution in patients with high-risk prostate cancer (PCa) treated with extended pelvic lymph node dissection (ePLND) and retroperitoneal lymph node dissection (rLND) at the time of radical prostatectomy (RP). This prospective mapping study included 19 patients with high-risk PCa (sharing at least two out of the three following parameters: PSA >20 ng/ml, cT3, biopsy Gleason score ≥8). All patients were treated with RP, ePLND (removal of the obturator, hypogastric, external iliac, presacral, and common iliac lymph nodes) and rLND (removal of para-aortal/para-caval and inter-aorto-caval lymph nodes) by a single surgeon. All patients signed an informed consent highlighting the absence of clinical data supporting the benefit of this surgical approach. Overall, 18 out of 19 patients (94.7%) had pelvic lymph node invasion. The most commonly affected pelvic nodal landing site was obturator (88.8%), followed by external iliac (83.3%), common iliac (77%), hypogastric (44.4%), and presacral (33.3%). Moreover, 14 (77.8%) patients also had involvement of retroperitoneal lymph nodes. Only patients with positive common iliac lymph nodes having at least five positive lower pelvic lymph nodes (n = 14), also had invariably positive retroperitoneal lymph nodes. No patients with negative common iliac lymph nodes had positive retroperitoneal lymph nodes. PCa lymphatic spread ascends from the pelvis up to the retroperitoneum invariably through common iliac lymph nodes. PCa lymphatic spread can be divided in two main levels: pelvic and common iliac plus retroperitoneal lymph nodes.


Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer.
The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC). We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes. In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS. TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.


Antibody assay for measles virus: comparisons of immune-adherence haemagglutination, single radial haemolysis, enzyme immunoassay and haemagglutination inhibition.
Immune-adherence haemagglutination (IAHA); single radial haemolysis and enzyme immunoassay (ELISA) versus haemagglutination inhibition (HAI) for detecting antibodies to measles virus were evaluated. The rank correlation computed according to Spearman for the sera of healthy individuals gave values of 0.66, 0.73, 0.72, respectively, for HAI-IAHA, HAI-single radial haemolysis (SRH) and HAI-ELISA. High percentages of accordance were observed as regards sera from both healthy and vaccinated individuals. In the case of vaccinated individuals the discordance analysis showed significant differences between HAI and IAHA, HAI and SRH, SRH and ELISA. The discordances indicate higher sensitivity of HAI and ELISA for the detection of seroconversion.


Investigating reactions of squirrel monkeys (Saimiri sciureus) towards unequal food distributions in a tray-pulling paradigm.
The fact that squirrel monkeys do not routinely cooperate in the wild has been proposed to explain their failure to show disadvantageous inequity aversion (i.e., negative reactions when receiving less than a partner) in an experimental exchange. Here we assessed whether the use of a tray-pulling paradigm, allowing for a larger variety of unequal testing situations, would bring additional insights into inequity aversion in this species. Squirrel monkeys were tested in pairs in which only the donor could pull a tray baited with food to within reach of itself and a recipient. Using pairs with different social relationships, we examined donors' frequencies of pulling both in the presence and absence of a recipient, as well as across three different food distributions: equal, qualitative inequity (higher-value reward for the recipient), and quantitative inequity (no food reward for the donor). Results showed that female donors pulled the tray less often in the quantitative inequity condition with an out-group female recipient than when alone. However, such discrimination was not observed when females were with female in-group and male out-group recipients. By contrast, male donors did not adjust their pull frequencies according to the recipient's presence or identity (female and male out-group recipients). These results point towards possible disadvantageous inequity aversion in female squirrel monkeys. However, alternative hypotheses such as increased arousal caused by out-group female recipients cannot be ruled out. We discuss the data in line with major theories of inequity aversion and cooperation in primates.


Whole brain in vivo neuropathology: Imaging site-specific changes in brain structure over time following trimethyltin exposure in rats.
Presented is a diffusion weighted imaging protocol with measures of apparent diffusion coefficient which when registered to a 3D MRI rat brain atlas provides site-specific information on 173 different brain areas. This protocol coined "in vivo neuropathology" was used to follow the progressive neurotoxic effects of trimethyltin on global gray matter microarchitecture. Four rats were given an IP injection of 7 mg/kg of the neurotoxin trimethyltin and imaged for changes in water diffusivity at 3- and 7-days post injections. At 3 days, there was a significant decrease in apparent diffusion coefficient, a proxy for cytotoxic edema, in several cortical areas and cerebellum. At 7 days the level of injury expanded to include most of the cerebral cortex, hippocampus, olfactory system, and cerebellum/brainstem corroborating much of the work done with traditional histopathology. Analysis is achieved with a minimum number of rats adhering to the laws and regulations around the humane care and use of laboratory animals, providing an alternative to the traditional tests for assessing drug neurotoxicity. "In vivo neuropathology" can minimize the cost, expedite the process, and identify subtle changes in site-specific brain microarchitecture across the entire brain.


Random distribution of the glucose transporter of human erythrocytes in reconstituted liposomes.
The glucose transporter of human erythrocytes was reconstituted with soybean phospholipids by the freeze-thaw/sonication method and the distribution of the transporter molecules in liposomes was studied. The steady state level of glucose transport in reconstituted liposomes showed saturation when increased amounts of the transporter were used for reconstitution. The saturation curve fitted well to a theoretical curve which was derived assuming a Poisson distribution of the transporter. Freeze-fracture electron micrographs showed random distribution of intramembraneous particles on liposomes, irrespective of liposome size or amount of the transporter added. A detailed study showed a parameter of the distribution (the ratio of transporter to liposome) obtained from the transport measurement can be used for the analysis of the distribution of intramembraneous particles, indicating that most of the molecules seen as particles were active in transport.


FTIR-ATR studies of the effect of shear rate upon albumin adsorption onto polyurethaneurea.
The effect of wall shear rate upon albumin adsorption onto a polyurethaneurea, Biomer, was studied using FTIR-ATR spectroscopy. In these experiments, nondiffusion controlled adsorption was observed from 10 mg/ml solutions at known wall shear rates. Results show that increasing wall shear rate during adsorption does not significantly affect the adsorption kinetics, but does decrease the rate of protein desorption. These results suggest that albumin adsorbed at higher shear rates is more tightly bound to the surface. Comparison of the data to simple mathematical models suggests that more than one layer of protein adsorbs in 2 h.


UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development.
UTX (KDM6A) and UTY are homologous X and Y chromosome members of the Histone H3 Lysine 27 (H3K27) demethylase gene family. UTX can demethylate H3K27; however, in vitro assays suggest that human UTY has lost enzymatic activity due to sequence divergence. We produced mouse mutations in both Utx and Uty. Homozygous Utx mutant female embryos are mid-gestational lethal with defects in neural tube, yolk sac, and cardiac development. We demonstrate that mouse UTY is devoid of in vivo demethylase activity, so hemizygous X(Utx-) Y(+) mutant male embryos should phenocopy homozygous X(Utx-) X(Utx-) females. However, X(Utx-) Y(+) mutant male embryos develop to term; although runted, approximately 25% survive postnatally reaching adulthood. Hemizygous X(+) Y(Uty-) mutant males are viable. In contrast, compound hemizygous X(Utx-) Y(Uty-) males phenocopy homozygous X(Utx-) X(Utx-) females. Therefore, despite divergence of UTX and UTY in catalyzing H3K27 demethylation, they maintain functional redundancy during embryonic development. Our data suggest that UTX and UTY are able to regulate gene activity through demethylase independent mechanisms. We conclude that UTX H3K27 demethylation is non-essential for embryonic viability.


A simple method for the determination of section thickness with high accuracy.
Using the partial carbon-coating of histological sections their thickness was determined by a relatively simple and accurate method. Calculations were based on the instrumental recording of the distance of focus change between the upper and lower section-surfaces. Determination of tissue refractive index was not required. Results compared favourably with those of more complicated techniques.


Effect of serine protease KEX2 on Candida albicans virulence under halogenated methyl sulfones.
The effect of KEX2 mutations on C. albicans virulence and resistance to halogenated methyl sulfones was assessed. The mechanism of action of sulfones was studied using flow cytometry and microscopy. Expression of KEX2 and SAP5 was assessed using quantitative Real-Time-PCR. 2,3-Bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide and lactate dehydrogenase assays were elaborated to study, respectively, metabolism of Candida treated with sulfones and their cytotoxicity against tissues. Inflammatory response was detected by ELISA. Lysosome permeabilization and dose-dependent programmed cell death under sulfones were noted. KEX2 induction depended on halogenomethylsulfonyl groups, which affected cell wall biosynthesis and adhesion. Sulfones treatment reduced Candida pathogenicity in Galleria mellonella. Sulfones are an alternative for antifungal therapies due to their safety profile and antibiofilm activity.


[Five-year follow up in patients after surgery for clear cell renal carcinoma].
Evaluation of the five-year follow-up of patients treated for clear-cell renal carcinoma in dependency on its characteristic and extension. PATIENTS' COHORT AND METHODS: Retrospective analysis of five-year follow-up of 269 patients treated for clear-cell renal carcinoma in dependency on T, N, M and clinical tumor stage; presence of lymphatic and distant metastases, cellular grade and tumor necrosis. Tumor-specific surviving is presented on Kaplan-Meier curves. Five-year patients surviving with tumor T1, T2 and T3 were 91.8%, 70.7% and 34.6% respectively. Surviving patients without lymphatic metastases was 85%; with metastases was 6.9%. Surviving patients without distant metastases was 84.1%; with metastases was 0%. Surviving of patients with clinical tumor stage I, II, III and IV were 94.6%, 83.8%, 48.7% and 0% respectively. Surviving of patients with tumor cellular grade G1, G2, G3 and G4 were 87.5%, 95.5%, 64.2% and 27.6% respectively. Surviving patients without tumor necrosis was 92.4%; with metastases was 31.9%. Tumor size and the presence of metastases are very significant factors to patient survival. Histological characteristics as a nuclear grade and a tumor necrosis have been important prognostic factors for the future of the patient. Early diagnosis and aggressive surgical treatment are the most important for the positive course of the disease.


Nursing staff member experiences with household model implementation in a nursing home setting.
This qualitative study used conventional content analysis of interview data to examine nursing staff members' experiences with Household Model implementation in a nursing home setting. Staff members were recruited from the skilled nursing center post implementation and completed individual interviews (N=16). Participants described the impact of implementation in relation to three categories: antecedents, explicit reactions and change consequences. Participants described barriers and facilitators to implementation as well as outcomes such as role strain, feelings of isolation and harder working conditions. This study provides opportunities for further examination of nursing staff members' experiences with person centered care models in nursing homes, how those experiences may relate to effectiveness of implementation and the need for support of nursing home staff.


Method for Developing Optical Sensors Using a Synthetic Dye-Fluorescent Protein FRET Pair and Computational Modeling and Assessment.
Biosensors that exploit Förster resonance energy transfer (FRET) can be used to visualize biological and physiological processes and are capable of providing detailed information in both spatial and temporal dimensions. In a FRET-based biosensor, substrate binding is associated with a change in the relative positions of two fluorophores, leading to a change in FRET efficiency that may be observed in the fluorescence spectrum. As a result, their design requires a ligand-binding protein that exhibits a conformational change upon binding. However, not all ligand-binding proteins produce responsive sensors upon conjugation to fluorescent proteins or dyes, and identifying the optimum locations for the fluorophores often involves labor-intensive iterative design or high-throughput screening. Combining the genetic fusion of a fluorescent protein to the ligand-binding protein with site-specific covalent attachment of a fluorescent dye can allow fine control over the positions of the two fluorophores, allowing the construction of very sensitive sensors. This relies upon the accurate prediction of the locations of the two fluorophores in bound and unbound states. In this chapter, we describe a method for computational identification of dye-attachment sites that allows the use of cysteine modification to attach synthetic dyes that can be paired with a fluorescent protein for the purposes of creating FRET sensors.


Automated high-performance liquid chromatographic determination of plasma free fatty acids using on-line derivatization with 9-bromomethylacridine based on micellar phase-transfer catalysis.
The on-line use of micellar phase-transfer catalysis is described for the automated reversed-phase high-performance liquid chromatographic (RP-HPLC) determination of free fatty acids in plasma; minimum manual sample handling is involved. After diluting plasma ten-fold with the aqueous micellar system, which contains 25 mM of the non-ionic surfactant, Arkopal N-130 and 6 mM of the ion-pair agent tetrakis(decyl)ammonium bromide, the reaction of the fatty acids with the fluorophore 9-bromomethylacridine is complete within 5 min at 60 degrees C. Prior to RP-HPLC separation, interfering proteins are removed using an on-line filter and a column-switching unit. More than 100 samples can be injected onto a single pre-column. The detection limit is ca. 300 nM; the precision is better than 3% using an internal standard.


Histologic, ultrastructural, and immunocytochemical features of the granulomas seen in a child with the syndrome of familial granulomatous arthritis, uveitis, and rash.
A family with a syndrome consisting of granulomatous arthritis, uveitis, and rash was first described in 1985. Another family with the same syndrome was described subsequently in 1990. The condition, in both families, is clinically different from sarcoidosis. To verify whether the granulomas in such patients also could be distinctive, we performed histologic, ultrastructural, and immunocytochemical studies on skin and synovial biopsy specimens from a child under our care who suffered from the same syndrome. The results indicated that the granulomas could not be distinguished from those seen in sarcoidosis either by light microscopy or by immunocytochemical studies. However, by electron microscopy, "wormlike" or "comma-shaped" bodies were noted within the cytoplasm of epithelioid cells. The significance of this observation is discussed.


Size-exclusion high-performance liquid chromatography of Sendai virus membrane proteins in different detergents. A comparison of different columns.
Four column packings for size-exclusion high-performance liquid chromatography (HPLC) of proteins with particle sizes from 3 to 13 micron were compared, using 0.1% sodium dodecyl sulphate in the solvent. Their suitability for the purification of hydrophobic membrane proteins was studied with Sendai virus proteins as a model. The calibration curves of the two 13-micron column packings were linear up to high molecular weights. In contrast to this, large proteins (greater than 100-150 kD) were eluted later than expected from the 3- and 6-micron packings. Peak capacities for proteins larger than 20 kD ranged from 4.7 to 5.5. Therefore, purification of complex mixtures of membrane proteins will often require rechromatography by a different mode of HPLC. Non-ionic detergents are suitable for further ion-exchange chromatography. The effect of addition of 0.1% of five non-ionic detergents (three gluco-methylalkanamide detergents, octylglucoside, and decyl-polyethyleneglycol-300) to the solvent was investigated and decyl-polyethyleneglycol-300 was found to be most suitable. Size-exclusion HPLC with this detergent resulted in the separation of micelles of three different sizes, of which the larger two contained exclusively the Sendai virus F protein.


5-(Hydroxyimino)-4-methoxy-2-(pivaloylimino)thiazolidine-3 -acetamide, a reduced nitroheterocyclic derivative with potent schistosomicidal properties.
The synthesis and antischistosome properties of 5-(hydroxyimino)-4-methoxy-2-(pivaloylimino)thiazolidine-3- acetamide (1) are described. The compound was prepared by reduction of the nitrothiazoline (2) with stannous chloride in methanol, and represents the first example of a reduced nitroheterocyclic compound showing potent schistosomicidal properties. The possible relationship of compounds such as 1 to the as yet unidentified reduced active but toxic entities formed in vivo from nitroheterocyclics like metronidazole is discussed.


Validation of the TOPAS Monte Carlo toolkit for HDR brachytherapy simulations.
The goal of this work is to validate the user-friendly Geant4-based Monte Carlo toolkit TOol for PArticle Simulation (TOPAS) for brachytherapy applications. Brachytherapy simulations performed with TOPAS were systematically compared with published TG-186 reference data. The photon emission energy spectrum, the air-kerma strength, and the dose-rate constant of the model-based dose calculation algorithm (MBDCA)-WG generic Ir-192 source were extracted. For dose calculations, a track-length estimator was implemented. The four Joint AAPM/ESTRO/ABG MBDCA-WG test cases were evaluated through histograms of the local and global dose difference volumes. A prostate, a palliative lung, and a breast case were simulated. For each case, the dose ratio map, the histogram of the global dose difference volume, and cumulative dose-volume histograms were calculated. The air-kerma strength was (9.772 ± 0.001) × 10-8 U Bq-1 (within 0.3% of the reference value). The dose-rate constant was 1.1107 ± 0.0005 cGy h-1 U-1 (within 0.01% of the reference value). For all cases, at least 96.9% of voxels had a local dose difference within [-1%, 1%] and at least 99.9% of voxels had a global dose difference within [-0.1%, 0.1%]. The implemented track-length estimator scorer was more efficient than the default analog dose scorer by a factor of 237. For all clinical cases, at least 97.5% of voxels had a global dose difference within [-1%, 1%]. Dose-volume histograms were consistent with the reference data. TOPAS was validated for high-dose-rate brachytherapy simulations following the TG-186 recommended approach for MBDCAs. Built on top of Geant4, TOPAS provides broad access to a state-of-the-art Monte Carlo code for brachytherapy simulations.


Elevated serum ceruloplasmin levels are associated with albuminuria in Korean men with type 2 diabetes mellitus.
The aim of this study was to examine the possible association between serum ceruloplasmin, a copper carrying protein, and albuminuria in 456 males with type 2 diabetes. Multivariate regression analysis demonstrated that elevated serum ceruloplasmin was a determinant of albuminuria independently of conventional risk factors.


Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia.
To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26-80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (<10-3) as measured by flow cytometry. After a median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate 64%. In multivariate analysis, complex karyotype predicted lower response (p = 0.0001), while pretreatment with hypomethylating agents (p = 0.02) and adverse European LeukemiaNet 2017 genetic risk (p < 0.0001) were associated with lower OS. Allogeneic hematopoietic cell transplantation (allo-HCT) was performed in 116 patients (62%) resulting in promising outcome (median survival not reached, 1-year OS 73%), especially in MRD-negative patients (p = 0.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. These real-world data confirm CPX-351 as efficient treatment for these high-risk AML patients facilitating allo-HCT in many patients with promising outcome after transplantation.


Effects of melatonin and hypothyroidism on somatomedin levels of female Syrian hamsters.
Female Syrian hamsters maintained on a 14 h light, 10 h dark photoperiod were injected once daily (1-2 h before lights out) with melatonin (25 micrograms), alone or in combination with thiourea, or with thiourea plus thyroxine. Serum levels of the somatomedin, Insulin-like growth factor-I (IGF-I), were significantly reduced by thiourea as well as by melatonin administration. These data suggest that in the female hamster melatonin-induced reduction of circulating IGF-I depends largely on a reduction in circulating levels of thyroid hormones. However, melatonin-induced changes in secretion of thyroid hormones, gonadal hormones, and hypothalamic hormones could contribute to decreased growth hormone (GH)-stimulated somatomedin secretion.


An E. coli expression system optimized for DELLA proteins.
The DELLA proteins are involved in regulation of plant growth in response to phytohormonal signals such as GA, ethylene, and auxin. They have become one of most challenging and active area of research due to their fundamental roles in plant biology. Here, we describe the first successful expression of the N-terminal domains of DELLA proteins of Arabidopsis thaliana and Malus domestica in Escherichia coli system which will be used to produce monoclonal antibodies for profiling protein micro-arrays. Optimizations of the cloning, expression, and purification using specific tags have been discussed.


Rapid prototyping in tissue engineering: challenges and potential.
Tissue engineering aims to produce patient-specific biological substitutes in an attempt to circumvent the limitations of existing clinical treatments for damaged tissue or organs. The main regenerative tissue engineering approach involves transplantation of cells onto scaffolds. The scaffold attempts to mimic the function of the natural extracellular matrix, providing a temporary template for the growth of target tissues. Scaffolds should have suitable architecture and strength to serve their intended function. This paper presents a comprehensive review of the fabrication methods, including conventional, mainly manual, techniques and advanced processing methods such as rapid prototyping (RP) techniques. The potential and challenges of scaffold-based technology are discussed from the perspective of RP technology.


Potential causes of cognitive alterations in temporal lobe epilepsy.
Spatial and non-spatial memories are key processes whereby we process our environment on a daily basis, coding space, time and items to form unique memories. Both types of memory involve distributed and complex temporal lobe (TL) networks. In this review, we will discuss potential causes of spatial and non-spatial memory deficits, taking the example of temporal lobe epilepsy (TLE), a widespread neurological disorder characterized by cognitive comorbidities, in both animal models and TLE patients. We will start by briefly introducing TLE, then highlight by which underlying mechanisms TLE impairs TL-dependent cognitive functions.


The contribution of peroxynitrite generation in HIV replication in human primary macrophages.
Monocytes/Macrophages (M/M) play a pivotal role as a source of virus during the whole course of HIV-1 infection. Enhanced oxidative stress is involved in the pathogenesis of HIV-1 infection. HIV-1 regulatory proteins induce a reduction of the expression and the activity of MnSOD, the mitochondrial isoform leading to a sustained generation of superoxide anions and peroxynitrite that represent important mediators of HIV-1 replication in M/M. MnTBAP (Mn(III)tetrakis(4-benzoic acid)porphrin chloride), a synthetic peroxynitrite decomposition catalyst, reduced oxidative stress subsequent to peroxynitrite generation. Virus production was assessed by p24 ELISA, western blot, and electron microscopy during treatment with MnTBAP. MnTBAP treatment showed a reduction of HIV-1 replication in both acutely and chronically infected M/M: 99% and 90% inhibition of p24 released in supernatants compared to controls, respectively. Maturation of p55 and p24 was strongly inhibited by MnTBAP in both acutely and chronically infected M/M. EC50 and EC90 are 3.7 (+/- 0.05) microM and 19.5 (+/- 0.5) microM, in acutely infected M/M; 6.3 (+/- 0.003) microM and 30 (+/- 0.6) microM, in chronically infected M/M. In acutely infected peripheral blood limphocytes (PBL), EC50 and EC90 are 7.4 (+/- 0.06) microM and of 21.3 (+/- 0.6) microM, respectively. Treatment of acutely-infected M/M with MnTBAP inhibited the elevated levels of malonildialdehyde (MDA) together with the nitrotyrosine staining observed during HIV-1 replication. MnTBAP strongly reduced HIV-1 particles in infected M/M, as shown by electron microscopy. Moreover, in presence of MnTBAP, HIV-1 infectivity was reduced of about 1 log compared to control. Results support the role of superoxide anions in HIV-1 replication in M/M and suggest that MnTBAP may counteract HIV-1 replication in combination with other antiretroviral treatments.


Association of Medicaid Expansion in Arkansas With Postpartum Coverage, Outpatient Care, and Racial Disparities.
Non-Hispanic Black individuals are disproportionally covered by Medicaid during pregnancy and, compared with non-Hispanic White individuals, have higher rates of postpartum coverage loss and mortality. Expanded Medicaid coverage under the Affordable Care Act may have increased continuity of coverage and access to care in the critical postpartum period in expansion states. To examine the association of Medicaid expansion in Arkansas with continuous postpartum coverage, postpartum health care use, and change in racial disparities in the study outcomes. This cohort study with a difference-in-differences analysis compared persons with Medicaid and commercially financed childbirth, stratified by race, using Arkansas' All-Payer Claims Database for persons with a childbirth between 2013 and 2015. Race and ethnicity from birth certificate data were classified as Hispanic, non-Hispanic Black (hereafter Black), non-Hispanic White (hereafter White), and other (including Asian, Native American or Alaska Native, and Pacific Islander) or unknown race. Data were analyzed between June 2020 and August 2021. Medicaid-paid childbirth after January 1, 2014. Continuous health insurance coverage and the number of outpatient visits during the first 6 months postpartum. A total of 60 990 childbirths (mean [SD] age of birthing person, 27 [5.3] years; 67% White, 22% Black, and 7% Hispanic) were included, among which 72.3% were paid for by Medicaid and 27.7% were paid for by a commercial payer. Medicaid expansion in Arkansas was associated with a 27.8 (95% CI, 26.1-29.5) percentage point increase in continuous insurance coverage and an increase in outpatient visits of 0.9 (95% CI, 0.7-1.1) during the first 6 months postpartum, representing relative increases of 54.9% and 75.0%, respectively. Racial disparities in postpartum coverage decreased from 6.3 (95% CI, 3.9-8.7) percentage points before expansion to -2.0 (95% CI, -2.8 to -1.2) percentage points after expansion. However, disparities in outpatient care between Black and White individuals persisted after Medicaid expansion (preexpansion difference, 0.4 [95% CI, 0.2-0.6] visits; postexpansion difference, 0.5 [95% CI, 0.4-0.6] visits). In this cohort study with a difference-in-differences analysis of 60 990 childbirths, Medicaid expansion was associated with higher rates of postpartum coverage and outpatient visits and lower racial and ethnic disparities in postpartum coverage. However, disparities in outpatient visits between Black and White individuals were unchanged. Additional policy approaches are needed to reduce racial and ethnic disparities in postpartum care.


Farmer's lung disease: Analysis of 75 cases.
Farmer's lung disease (FLD) is a common form of hypersensitivity pneumonitis possibly underdiagnosed in our midst. The aim of this study was to describe clinical characteristics, evolution and factors that influence the prognosis of patients with FLD. A retrospective study that included all patients diagnosed with FLD presenting an environmental exposure risk, a clinic, lung function and a compatible radiology, in which antigen sensitisation was demonstrated and/or a concordant pathology. We selected 75 patients with FLD, 50 with acute or subacute form (ASF) and 25 with chronic form (CF). Forty-four percent of patients (n=33) were diagnosed during the months of March and April, especially those with ASF compared to CF (52 vs. 28%; P=.0018). In the ASF group, DLco showed an improvement during follow-up (P=.047). The determination of specific IgG antibodies was positive in 39 patients (78%) with ASF (44% of them against Aspergillus) and CF 12 (48%). The realisation of antigenic avoidance (OR 9.26, 95% CI 1.3-66.7, P=.026) and the administration of immunosuppressive therapy (OR 16.13, 95% CI 1.26-200, P=.033) were predictors of better disease progression. FLD is predominantly seasonal in our environment. CF usually has a negative specific IgG antibodies unlike ASF, where antibodies against Aspergillus are the most common. The realisation of antigenic avoidance and immunosuppressive treatment are possible predictors of better disease progression.


Superoxide generation by neonatal and adult rabbit alveolar macrophages.
We compared the abilities of alveolar macrophages (AM) from neonatal and adult rabbits to generate and release superoxide (O2-) after exposure to soluble and particulate stimuli. Basal rates of O2- release, 0.1-0.2 nmol/10(6)AM/10 min, were modestly increased by exposing AM to phorbol myristate acetate, (dihydro)cytochalasin B, or cytochalasin C. Opsonized zymosan was a more effective stimulus, and maximal rates of O2- release were observed when AM were stimulated by a combination of opsonized zymosan and one of the aforementioned cytochalasins. Cytochalasins D and E were each potent activators of O2- production by AM in the absence of additional stimuli. Adult AM released 24.8 +/- 6.0, 20.4 +/- 4.4, and 33.5 +/- 6.4 nmol O2-/10(6)AM/10 min after stimulation by cytochalasin D, cytochalasin E, and dihydrocytochalasin B plus opsonized zymosan, respectively. Following exposure to the same stimuli, AM from 1, 3- and 7-day-old rabbits released O2- at rates that ranged from 45 to 75% of corresponding adult values. The discrepancy between O2- production by neonatal and adult AM was accentuated when comparisons were restricted to AM recovered from bacteriologically sterile respiratory tracts. Our data show the O2- generating capacity of neonatal AM to be substantially less than that of the adult AM. Immaturity of this response could predispose neonates to pulmonary infection.


Temporal modulation of pyrrolizidine alkaloid intake and genetic variation in performance of Utetheisa ornatrix caterpillars.
Foraging on a variety of different food items allows individuals to balance nutrient intake, but it also may dilute toxins present in single items of the diet. The distinction between nutrient balancing and toxin dilution becomes less clear, however, for organisms that sequester potentially toxic compounds for their own benefit. Additionally, specific dietary components chosen may or may not affect metabolic rate, growth, and other measures of fitness. Using the arctiid moth Utetheisa ornatrix, we (1) evaluated the temporal pattem of larval feeding behavior when presented with diet enriched with the pyrrolizidine alkaloid (PA), monocrotaline, (2) estimated the cost of ingesting PAs by measuring larval nutritional performance on diets containing different amounts of usaramine, and (3) investigated the magnitude of genetic effects on the performance of families raised on diets of different usaramine concentrations. We demonstrate that an herbivorous insect can temporally vary its intake of sequestered allelochemical. Individuals combined a preference for intermediate amounts of monocrotaline with temporal modulation of the specific amount of PA ingested on a given day. Using usaramine, we found little evidence for a cost of ingesting PAs, except among some family groups. Measures of digestive and metabolic efficiency showed no consistent reduction in performance on higher alkaloid diets. Only when larvae in family groups were fed a single concentration of PA over more than one instar was there any evidence for a cost of ingestion. Additionally, there were large genetic components to both growth and an individual's growth response to dietary alkaloid. These results suggest that while genetic variation in performance on alkaloid-rich diets exists, modulation of intake rate by caterpillars may be an important mechanism to reduce effects on the growth and fitness of individuals.


Vinorelbine, cyclophosphamide and 5-FU effects on the circulating and intratumoural landscape of immune cells improve anti-PD-L1 efficacy in preclinical models of breast cancer and lymphoma.
Anti-PD-1 and anti-PD-L1 checkpoint inhibitors (CIs) are clinically active in many types of cancer. However, only a minority of patients achieve a complete and/or long-lasting clinical response. We studied the effects of different doses of three widely used, orally active chemotherapeutics (vinorelbine, cyclophosphamide and 5-FU) over local and metastatic tumour growth, and the landscape of circulating and tumour-infiltrating immune cells involved in CI activity. Immunocompetent Balb/c mice were used to generate models of breast cancer (BC) and B-cell lymphoma. Vinorelbine, cyclophosphamide and 5-FU (alone or in combination with CIs), were given at low-dose metronomic, medium, or maximum tolerable dosages. Cyclophosphamide increased circulating myeloid derived suppressor cells (MDSC). Vinorelbine, cyclophosphamide and 5-FU reduced circulating APCs. Vinorelbine and cyclophosphamide (at medium/high doses) reduced circulating Tregs. Cyclophosphamide (at low doses) and 5-FU (at medium doses) slightly increased circulating Tregs. Cyclophosphamide was the most potent drug in reducing circulating CD3+CD8+ and CD3+CD4+ T cells. Vinorelbine, cyclophosphamide and 5-FU reduced the number of circulating B cells, with cyclophosphamide showing the most potent effect. Vinorelbine reduced circulating NKs, whereas cyclophosphamide and 5-FU, at low doses, increased circulating NKs. In spite of reduced circulating T, B and NK effector cells, preclinical synergy was observed between chemotherapeutics and anti-PD-L1. Most-effective combinatorial regimens where associated with neoplastic lesions enriched in B cells, and, in BC-bearing mice (but not in mice with lymphoma) also in NK cells. Vinorelbine, cyclophosphamide and 5-FU have significant preclinical effects on circulating and tumour-infiltrating immune cells and can be used to obtain synergy with anti-PD-L1.


Twenty-four-week treatment with extended release methylphenidate improves emotional symptoms in adult ADHD.
Treatment investigations with methylphenidate in adults with ADHD focus preferentially on the classical psychopathology: inattention, hyperactivity and impulsivity. ADHD-associated emotional symptoms, which are frequently present at least in ADHD subpopulations, were studied rarely. The vast majority of the placebo-controlled trials had observation periods between 4 and 8 weeks. To assess the medium- to long-term effects of extended release methylphenidate (MPH-ER) on emotional symptoms and other psychopathology frequently seen in ADHD patients, we conducted a large-scale, multicenter treatment study. We performed a randomised, 24-week, double-blind, placebo-controlled study in adults with ADHD. The diagnosis was made on the basis of the DSM-IV criteria, which were confirmed by clinical history and a structured psychopathological interview and the use of rating instruments. 363 patients were randomized to MPH-ER or placebo at a ratio of 2:1. The duration of the titration period was 5 weeks followed by a maintainance phase of 19 weeks. The efficacy measures were the observer rated 10-item Emotional Dysregulation Scale (EDS) derived from the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) and a self-report, six-item Emotional Lability Scale (ELS) extracted from the long version of the Conners Adult ADHD Self Report Scale (CAARS:S:L). In addition we used the SCL-90-R for the assessment of ADHD associated and comorbid psychopathology. MPH-ER was statistically superior to placebo in reducing emotional symptoms as assessed by the EDS and the ELS. Obsessive-compulsive symptoms and those of problems with self-concept declined until the end of the observation period. The decline was more pronounced in MPH-ER treated individuals. The effects remained robust during the entire maintenance period until week 24. Symptoms of anxiety, depression, anger and hostility, phobia, paranoid ideations and psychoticism were not improved. MPH-ER appears to be an efficacious treatment for emotional symptoms with ADHD. Also obsessive-compulsive symptoms and problems with self-concept were affected positively.


The olive flounder (Paralichthys olivaceus) Pax3 homologues are highly conserved, encode multiple isoforms and show unique expression patterns.
Pax genes encode a highly conserved family of transcription factors that play crucial roles in the formation of tissues and organs during development. Pax3 plays crucial roles in patterning of the dorsal central nervous system (CNS), neural crest and skeletal muscle. Here, we identified two spliced isoforms of Pax3a and three spliced isoforms of Pax3b and characterized their expression patterns. Both of flounder Pax3a-1 and Pax3b-1 contain the conserved paired domain (PD), an octapeptide motif (OP), and a paired type homeodomain (HD). But the PD domain in Pax3a-2 and Pax3b-3 is not intact and there is no HD in Pax3b-2 and Pax3b-3. Pax3a and Pax3b show distinct temporal expression patterns during embryogenesis. Whole-mount in situ hybridization demonstrates that Pax3a and Pax3b are expressed in overlapping patterns in the dorsal central nervous system, with some subtle regional differences between the two genes. In addition, Pax3a is scattered in the somites while Pax3b is specifically expressed in the newly forming somites. RT-PCR results have shown that there were different expression patterns between the different isoforms. These results indicate subfunction partitioning of the duplicated Pax3 genes. The duplicated Pax3 may provide additional flexibility in fine-tuning neurogenesis and somitogenesis.


Survival of adrenal gland implants in the neocortex of the rat: a morphological study.
The survival of adrenal gland implantation in the cerebral cortex of the rat was studied. In the present study, mature adrenal gland had survived after six months of implantation. No scar tissue was observed between the adrenal gland cortex and the host cerebral cortex. The implanted tissue showed some reorganization in its cortex and medulla. In the adrenal cortex there was an observable increase in connective tissue fibers and some degeneration of cells. In the medulla, again, both surviving and degenerating cells were observed. This study shows that mature adrenal gland has the capacity to survive after implantation in the cerebral cortex of the rats. Further studies are being carried out on fetal and mature tissue implantation and the ability of the adrenal medulla to secrete catecholamines.


Optical coherence tomography for the monitoring of neovascular age-related macular degeneration: a systematic review.
To compare the accuracy of optical coherence tomography (OCT) with alternative tests for monitoring neovascular age-related macular degeneration (nAMD) and detecting disease activity among eyes previously treated for this condition. Traditionally, fundus fluorescein angiography (FFA) has been considered the reference standard to detect nAMD activity, but FFA is costly and invasive. Replacement of FFA by OCT can be justified if there is a substantial agreement between tests. Systematic review and meta-analysis. The index test was OCT. The comparator tests were visual acuity, clinical evaluation (slit lamp), Amsler chart, color fundus photographs, infrared reflectance, red-free images and blue reflectance, fundus autofluorescence imaging, indocyanine green angiography (ICGA), preferential hyperacuity perimetry, and microperimetry. We searched the following databases: MEDLINE, MEDLINE In-Process, EMBASE, Biosis, Science Citation Index, the Cochrane Library, Database of Abstracts of Reviews of Effects, MEDION, and the Health Technology Assessment database. The last literature search was conducted in March 2013. We used the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) to assess risk of bias. We included 8 studies involving more than 400 participants. Seven reported the performance of OCT (3 time-domain [TD] OCT, 3 spectral-domain [SD] OCT, 1 both types) and 1 reported the performance of ICGA in the detection of nAMD activity. We did not find studies directly comparing tests in the same population. The pooled sensitivity and specificity of TD OCT and SD OCT for detecting active nAMD was 85% (95% confidence interval [CI], 72%-93%) and 48% (95% CI, 30%-67%), respectively. One study reported ICGA with sensitivity of 75.9% and specificity of 88.0% for the detection of active nAMD. Half of the studies were considered to have a high risk of bias. There is substantial disagreement between OCT and FFA findings in detecting active disease in patients with nAMD who are being monitored. Both methods may be needed to monitor patients comprehensively with nAMD.


Review of clinical, cytogenetic, and molecular aspects of Ph-negative CML.
Between 1985 and 1989, many cases of Philadelphia (Ph) chromosome negative chronic myelogenous leukemia (CML) were reported. For this review, the following selection criteria were used: the original articles on Ph-negative cases should provide clinical, hematologic, cytogenetic as well as molecular data. In addition, eight unpublished cases of Ph-negative CML are included that were studied in our institute during the last two years. Our purpose was to correlate presence or absence of the Ph rearrangement with the clinical features in an attempt to test whether the entity "Ph-negative CML" really exists and to identify the pathologic characteristics, frequency of occurrence, prognosis for survival, and underlying molecular mechanisms. Data on Ph-negative CML patients were compared with data on Ph-positive CML, atypical CML (aCML), and chronic myelomonocytic leukemia (CMMoL), reported in the same papers as the Ph negative patients. Essential for comparison of data from the different investigators appeared to be a clear description of criteria they used to establish the diagnosis CML, or alternatively a complete presentation of data for all patients reported in the articles. In most cases, Ph-negative CML was distinguishable from CMMoL and aCML, using simple criteria, e.g., differential count of peripheral blood and absence of dysplasia in the bone marrow. Cytogenetic analysis showed normal karyotype in most cases of Ph-negative CML. Interestingly, in cases with abnormal karyotype, chromosome 9 band q34 was relatively frequently involved in translocations with other chromosomes than chromosome 22, suggesting a variant Ph translocation not visible by cytogenetic techniques. This assumption was confirmed by molecular analysis, demonstrating bcr-abl rearrangement in 9 out of 10 of the latter cases. Results of cytogenetic and molecular investigations in 136 cases of Ph-negative CML reviewed in this article clearly indicated that molecular techniques are valuable tools for identification of bcr-abl rearrangements, indicative for the Ph translocation. The different mechanisms responsible for bcr-abl rearrangement in Ph-negative CML patients are discussed. The question remains whether all Ph-negative CML patients will have bcr-abl rearrangements, or whether alternative mechanisms will be identified that are responsible for this disease.


Properties of the Interphase Formed between Argyrodite-Type Li6PS5Cl and Polymer-Based PEO10:LiTFSI.
All-solid-state lithium metal batteries using thiophosphate solid electrolytes (SE) present a promising alternative to state-of-the-art lithium-ion batteries due to their potentially superior energy and power. However, reactions occurring at the lithium metal | SE interface result in an increasing internal resistance and limited cycle life. A stable solid polymer electrolyte (SPE) may be used as protective interlayer to prevent the SE from direct contact and reaction with lithium metal. This creates a new and rarely studied heteroionic interface between the inorganic SE and the SPE, which we investigate here. The interface resistance between argyrodite-type Li6PS5Cl and a poly(ethylene oxide)/LiTFSI-based SPE is quantified by four-point electrochemical impedance measurements using two wire-shaped reference electrodes (2.4 Ω cm2 at 80 °C). Two distinct processes are observed and attributed to lithium-ion conduction through a formed solid-polymer electrolyte interphase (SPEI) and an ionic charge-transfer (CT) process. The SPEI predominantly consists of polysulfides and lithium fluoride (LiF), as identified by X-ray photoelectron spectroscopy (XPS) analysis. A temperature-enhanced SPEI growth is observed using electrochemical impedance spectroscopy (EIS) and depth profiling combined with time-of-flight secondary ion mass spectrometry (ToF-SIMS). The results highlight the importance of four-point measurements to determine electrolyte-electrolyte interface properties. Overall, the low resistance and low activation energy of the SPEI makes the SPE interlayer an attractive candidate to protect Li6PS5Cl from decomposition at the lithium metal anode.


Use of synthetic luteinizing hormone-releasing hormone in induction of ovulation in amenorrheic patients.
Luteinizing hormone-releasing hormone (LH-RH), administered to normal women in divided intrramuscular doses or by intravenous infusion, resulted in a prolonged release of luteinizing hormone and follicle-stimulating hormone from the pituitary gland, reliably resulting in ovulation during the late follicular phase. LH-RH was administered 6 days after clomiphene to 18 amenorrheic, anovulatory, infertile women in whom clomiphene therapy had failed previously. When LH-RH was administered intramuscularly in two divided doses, ovulation occurred in six of eight women and in 11 of 22 woman-months of stimulation (50%). One pregnancy occurred. When LH-RH was administered by intravenous infusion, ovulation occurred in nine of ten women and in 16 of 26 woman-months of stimulation (61.5%); three of the ten women became pregnant. Pregnancy also followed treatment withLH-RH in one patient with irregular menses and functional sterility.


Super U Technique for Ingrown Nails.
Ingrown nails are a common problem, seen mostly in young adults. Also known as onychcrypotisis, this condition typically affects the great toenail. Four stages have been defined according to the severity and duration of the condition, and treatment varies from conservative to surgical techniques depending on the stage. We present our experience with this condition, describing the characteristics of our population and surgical treatment, in particular the super U technique. This was a retrospective, descriptive study of patients with ingrown great toenail treated surgically using the super U technique. We also describe postoperative management. Ten patients with a mean age of 35.7 years underwent operation, 9 for unilateral ingrown great toenail and 1 for bilateral disease. Stage II ingrown nail was the most common. Half of the patients had been treated previously using other surgical techniques. The mean time to healing was 6 weeks. The only postoperative complication was infection in 1 patient. Mild to moderate postoperative pain persisted for a week. The majority of patients were satisfied with the cosmetic result. We believe the super U technique is very useful in stage II ingrown nail and in disease that has recurred after previous surgery, and is the treatment of choice in stage III or IV disease in which excessive hypertrophic tissue is found.


The Role of Compassionate Care in Medicine: Toward Improving Patients' Quality of Care and Satisfaction.
Despite its description as a cornerstone of a healthcare provider's professional identity, the impact of compassionate care on various aspects of medicine has been poorly defined. In this review, we aimed to elucidate the role of compassionate care in various aspects of medicine and healthcare delivery. Four databases were searched using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol for a literature review regarding compassionate care and its intersection with medical education, patient-provider communication, patient care, and clinical outcomes, patient and provider characteristics, telemedicine and artificial intelligence, caregiver compassion fatigue, and cost of care. Twenty-two articles met the inclusion criteria. Analysis revealed that clinical outcomes are correlated with the degree of patients' perception of empathy and compassion from their providers. Along with enhanced patient outcomes, compassionate care was shown to reduce the costs of care, compassion fatigue and burnout, and the number of malpractice claims. However, compassion can be perceived differently among patients of various cultural and ethnic backgrounds. Compassion training sessions can be implemented among residents in surgical and nonsurgical medical specialties to improve perceived compassion. Furthermore, the use of telehealth modalities may positively or negatively impact compassionate care, requiring further exploration. Compassionate care plays a crucial role in improving patient care and clinical outcomes while reducing caregiver burnout and the risk of malpractice litigation. However, a lack of compassion training and caregiver compassion fatigue may detract from the delivery of effective compassionate care.


Neo-CheckRay: radiation therapy and adenosine pathway blockade to increase benefit of immuno-chemotherapy in early stage luminal B breast cancer, a randomized phase II trial.
Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. Novel strategies are needed to stimulate the immune response and increase the response rate to ICB in luminal B BC. The Neo-CheckRay trial is a randomized phase II trial investigating the impact of stereotactic body radiation therapy (SBRT) to the primary breast tumor in combination with an anti-CD73 (oleclumab) to increase response to anti PD-L1 (durvalumab) and NACT. The trial is designed as a three-arm study: NACT + SBRT +/- durvalumab +/- oleclumab. The result at surgery will be evaluated using the residual cancer burden (RCB) index as the primary endpoint. Six patients will be included in a safety run-in, followed by a randomized phase II trial that will include 136 evaluable patients in 3 arms. Inclusion is limited to luminal B breast cancers that are MammaPrint genomic high risk. combination of ICB with chemotherapy in luminal B BC might benefit from immune priming agents to increase the response rate. As none have been identified so far, this phase II trial will evaluate SBRT and oleclumab as potential immune priming candidates. trial registered on ClinicalTrials.gov ( NCT03875573 ) on March 14th, 2019.


Arteriograms of the palatine arteries in normal and cleft palate dogs.
Arteriography was used to study the arterial distribution of the hard and soft palate in dogs with and without cleft palate. Selective catheterization of the maxillary arteries produced arteriograms of the palatine arteries. Surgical exposure of the left common carotid artery or the right femoral artery was used for entry into the arterial system. The control dogs demonstrated a normal number of foramina (one on each side) with cross communication of the terminal arteries. The presence of additional foramina on the left side of the cleft as compared with the right side indicates the possibility of greater vascularity unilaterally. These findings may be of clinical significance.