Electron paramagnetic resonance evidence of hydroxyl radical generation and oxidative damage induced by tetrabromobisphenol A in Carassius auratus.
Tetrabromobisphenol A (TBBPA) is one of the most widely used brominated flame retardants (BFRs). To confirm its putative oxidative stress-inducing activity, freshwater fish Carassius auratus were injected intraperitoneally with TBBPA. One experiment lasted 3h to 28 days after a single injection of 100mg/kg TBBPA, and the other lasted 24h after a single injection of 0-300 mg/kg TBBPA. Reactive oxygen species (ROS) were trapped by phenyl-tert-butyl nitrone (PBN) and detected by electron paramagnetic resonance (EPR). Protein carbonyl (PCO) and lipid peroxidation product (LPO) content were also determined. A six-line EPR spectrum was detected in the sample prepared in air, and a multiple one was obtained in nitrogen. The observed spectrum in nitrogen fits the simulation one with PBN/OCH(3) and PBN/CH(3) quite well. As compared to the control group, TBBPA significantly induced ROS production marked by the intensity of the prominent spectra in liver and bile. TBBPA (100mg/kg) also significantly increased PCO content in liver starting 24h and LPO content 3 days after injection. Either PCO or LPO content showed significant relation with ROS production. Based on the hyperfine constants and shape of the spectrum, ROS induced by TBBPA was determined as OH. The results clearly indicated that TBBPA could induce OH generation and result in oxidative damage in liver of C. auratus.


Pathologic complete response and survival in HER2-low and HER2-zero early breast cancer treated with neoadjuvant chemotherapy.
Breast cancers without HER2 amplification but still expressing this membrane protein constitute a new entity called HER2-low tumors. It is important to characterize them in terms of sensitivity to treatment and prognosis. To investigate chemosensitivity and long-term prognosis of HER2-low early breast cancer (eBC), compared to HER2-0 tumors, we retrospectively retrieved clinicopathological characteristics, response to treatment, and survival data from 511 patients treated for eBC with neoadjuvant chemotherapy (NAC) in a French cancer center between 2007 and 2018. Factors associated with the achievement of pathologic complete response (pCR) and survival were studied among hormone receptor positive (HR+) and negative (HR-) eBC. A total of 280 HR+ (61% HER2-low), and 231 HR- (28% HER2-low) eBC were included. We found classical clinicopathological factors usually associated with chemosensitivity and prognosis, in both HR+ and HR- eBC. By uni- and multivariable analysis, HER2 status (low vs 0) was not independently associated with pCR, either in HR+ or HR- eBC. Relapse free (RFS) and overall survival (OS) were not significantly different between HER2-low and HER2-0 among HR+ tumors. In contrast, among HR- negative tumors, RFS and OS were slightly better in HER2-0 eBC by univariable but not by multivariable analysis. In eBC patients treated with NAC, taking into account HR expression subtype and other current clinicopathological features, HER2-low tumors did not appear to have different chemosensitivity or prognosis, compared to their HER2-0 counterparts.


Traditional Chinese medicine in the Chinese health care system.
This study examines the role and value of traditional Chinese medicine (TCM) in the current health care system in China. Based on literature review and publicly available data in China. The study shows that TCM is well integrated in the Chinese health care system as one of the two mainstream medical practices. Also, the Chinese government is supportive of TCM development by increasing investment in TCM research and administration. However, there is downsizing of TCM utilization, a lack of TCM professionals with genuine TCM knowledge and skills, and limitations of and increasing public opinions on modernization and westernization. TCM is still facing many challenges in playing critical roles in improving public health in China. These challenges can be explained from different perspectives. In addition to the unique characteristics of TCM, economic, cultural, and historical evolution in China may also be major determinants.


A minimally invasive surgical approach for the treatment of piriformis syndrome: a case series.
Piriformis syndrome accounts for approximately 6% of patients who present with sciatic pain. There are many treatment options ranging from physical therapy, to trigger point injections, to surgical intervention. We discuss a surgical method that represents a minimally invasive technique for the treatment of piriformis syndrome. We describe a novel operative approach and technique for release of the piriformis muscle in the treatment of piriformis syndrome. Described are the preoperative planning, incision and approach, and technique for identifying and releasing the piriformis muscle. Three patients were treated for piriformis syndrome using the described technique. Each patient displayed successful relief of their symptoms immediately following the surgical procedure and at delayed follow-up. Early experience with our method of piriformis release suggests that it is well suited for the treatment of piriformis syndrome. The novel integration of pre-operative trigger point localization coupled with intraoperative neuromonitoring allows effective pain relief with minimal morbidity.


Relationships between area-specific measures of self-concept, self-esteem and academic achievement for junior high school students.
Physical maturity, peer relations, academic success and school adaptiveness self-concept and self-esteem measures were correlated with reading, language, mathematics, and composite achievement scores for 26 male and 48 female junior high school students. Academic success self-concept was significantly correlated with each of the achievement measures. Peer relations self-concept and self-esteem correlated with language, math, and composite achievement. Academic success self-esteem measures did not correlate with any of the measures of achievement.


Unusual drainage of the inferior caval vein in left atrial isomerism.
Two of the 26 cases of left atrial isomerism in our clinical material had an unusual drainage of the inferior caval vein. In one, the inferior caval vein crossed from left to right infradiophragmatically and then drained into the right-sided morphologically left atrium. In the second case, there was azygos continuation to both right and left superior caval veins. These variations have major surgical significance.


Monoclonal IgG affinity and treatment time alters antagonism of (+)-methamphetamine effects in rats.
The roles of monoclonal antibody affinity and treatment time of (+)-methamphetamine-induced pharmacological effects in rats were studied using two anti-(+)-methamphetamine monoclonal antibodies. These studies tested the preclinical protective effects of monoclonal antibody antagonists in (+)-methamphetamine overdose and pretreatment scenarios. The higher affinity antibody (mAb6H4; KD=11 nM for (+)-methamphetamine) more effectively antagonized (+)-methamphetamine-induced behavioral effects (distance and rearing) than the low affinity antibody (designated mAb6H8; KD=250 nM) and had a longer duration of action. Both antibodies more effectively reduced (+)-methamphetamine effects in the overdose model than in the pretreatment model. (+)-Methamphetamine pharmacokinetic studies showed the mAb6H4 significantly reduced brain concentrations over time in both models. However, while mAb6H4 immediately reduced brain concentrations in the overdose model, it did not prevent the initial distribution of (+)-methamphetamine into the brain in the pretreatment model. Thus, anti-(+)-methamphetamine monoclonal antibody affinity and administration time (relative to (+)-methamphetamine dosing) are critical determinants of therapeutic success.


Sleep Deficiency in Pregnancy.
Sleep is a critical aspect of one's daily life for overall health, with a recommended 7 to 9 hours in adulthood (ages 26-64). Up to a third of women do not sleep sufficiently, and pregnant women are at an increased risk for sleep deficiency. Throughout pregnancy, sleep is affected in differing ways. For example, in the first trimester, hormones affect sleep cycles, but by the third trimester, physical complaints such as increasing frequent urination and fetal movement create frequent awakenings. Associations between sleep deficiency and gestational diabetes, hypertensive disorders, depression, and some evidence regarding preterm birth exist. A woman's labor course and perception of delivery are also negatively affected by short sleep duration.


Assessing the feasibility of intranasal radiotracer administration for in brain PET imaging.
The development of clinically useful tracers for PET imaging is enormously challenging and expensive. The intranasal (IN) route of administration is purported to be a viable route for delivering drugs to the brain but has, as yet, not been investigated for the delivery of PET tracers. If the intranasal (IN) pathway presents a viable option, it extends the PET imaging field by increasing the number of tracers available for human use. Here we report the results of a rodent study testing the feasibility of the IN route to administer radiotracers for brain PET imaging. We used two different, well characterised, brain penetrant radiotracers, [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fallypride, and aimed to evaluate the pharmacokinetics after administration of the tracers via the intranasal route, and contrast this to intravenous administration. Image acquisition was carried out after tracer administration and arterial blood samples were collected at different time intervals, centrifuged to extract plasma and gamma counted. We hypothesised that [brain region]:[plasma] ratios would be higher via the intranasal route as there are two inputs, one directly from the nose to the brain, and another from the peripheral circulation. To assess the feasibility of using this approach clinically, we used these data to estimate radiation dosimetry in humans. Contrary to our hypothesis, in case of both radiotracers, we did not see a higher ratio in the expected brain regions, except in the olfactory bulb, that is closest to the nose. It appears that the radiotracers move into the olfactory bulb region, but then do not progress further into other brain regions. Moreover, as the nasal cavity has a small surface area, the extrapolated dosimetry estimations for intranasal human imaging showed an unacceptably high level (15 mSv/MBq) of cumulative skin radiation exposure. Therefore, although an attractive route for brain permeation, we conclude that the intranasal route would present difficulties due to non-specific signal and radiation dosimetry considerations for brain PET imaging.


No phylogeny without ontogeny: a comparative and developmental search for the sources of sleep-like neural and behavioral rhythms.
A comprehensive review is presented of reported aspects and putative mechanisms of sleep-like motility rhythms throughout the animal kingdom. It is proposed that 'rapid eye movement (REM) sleep' be regarded as a special case of a distinct but much broader category of behavior, 'rapid body movement (RBM) sleep', defined by intrinsically-generated and apparently non-purposive movements. Such a classification completes a 2 × 2 matrix defined by the axes sleep versus waking and active versus quiet. Although 'paradoxical' arousal of forebrain electrical activity is restricted to warm-blooded vertebrates, we urge that juvenile or even infantile stages of development be investigated in cold-blooded animals, in view of the many reports of REM-like spontaneous motility (RBMs) in a wide range of species during sleep. The neurophysiological bases for motorically active sleep at the brainstem level and for slow-wave sleep in the forebrain appear to be remarkably similar, and to be subserved in both cases by a primitive diffuse mode of neuronal organization. Thus, the spontaneous synchronous burst discharges which are characteristics of the sleeping brain can be readily simulated even by highly unstructured neural network models. Neuromotor discharges during active sleep appear to reflect a hierarchy of simple relaxation oscillation mechanisms, spanning a wide range of spike-dependent relaxation times, whereas the periodic alternation of active and quiet sleep states more likely results from the entrainment of intrinsic cellular rhythms and/or from activity-dependent homeostatic changes in network excitability.


Hypertrophic cardiomyopathy complicated by severe bradycardias: a pedigree report.
We describe four patients with nonobstructive hypertrophic cardiomyopathy (HCM) from an extended Chinese family. The patients had remarkably similar physical and echocardiographic findings including a harsh localized systolic murmur and apical left ventricular hypertrophy. All four had severe sinus bradycardia and atrial-ventricular conduction block (AVB) manifest by recurrent syncope. Two died suddenly due to bradycardia. Holter monitoring showed no tachycardias. Late potentials were not present. We conclude that this unusual form of HCM may be caused by a new and as yet unknown gene mutation.


Mobilisation in the EveNing to prevent and TreAt deLirium (MENTAL): a mixed-methods, randomised controlled feasibility trial.
Delirium is common in critically ill patients and associated with longer hospital stays, increased morbidity and higher healthcare costs. Non-pharmacological interventions have been advocated for delirium management, however there is little evidence evaluating feasibility and acceptability of physical interventions administered in the evening. The aim of this study was to conduct a feasibility trial of evening mobilisation to prevent and treat delirium in patients admitted to intensive care. In this mixed-methods, randomised controlled feasibility trial we recruited participants from intensive care units at two university hospitals in the United Kingdom. Eligible participants who were able to respond to verbal stimulus (Richmond agitation and sedation scale ≥3) and expected to stay in intensive care for at least 24 h were randomly assigned (1:1) to receive usual care or usual care plus evening mobilisation. The evening mobilisation was delivered between 19:00 and 21:00, for up to seven consecutive evenings or ICU discharge, whichever was sooner. All outcome assessments were completed by a team member blinded to randomisation and group allocation. Primary objective was to assess feasibility and acceptability of evening mobilisation. Primary feasibility outcomes were recruitment, consent and retention rates, and intervention fidelity. Intervention acceptability was evaluated through semi-structured interviews of participants and staff. Secondary outcomes included prevalence in incidence and duration of delirium, measured using the Confusion Assessment Method for ICU. This trial is registered at ClinicalTrials.gov, NCT05401461. Between July 16th, 2022, and October 31st, 2022, 58 eligible patients (29 usual care; 29 usual care plus evening mobilisation) were enrolled. We demonstrated the feasibility and acceptability of both the trial design and evening mobilisation intervention. Consent and retention rates over three months were 88% (58/66) and 90% (52/58) respectively, with qualitative analysis demonstrating good acceptability reported by both participants and staff. Secondary outcomes for the evening intervention group compared with the control group were: delirium incidence 5/26 (19%; 95% CI: 6-39%) vs 8/28 (29%; 95% CI: 13-49%) and mean delirium duration 2 days (SD 0.7) vs 4.25 days (SD 2.0). Results of this trial will inform the development of a definitive full-scale randomised controlled trial investigating the effects of evening mobilisation to treat delirium and improve health-related outcomes. None.


Apps and intensive care medicine.
Technological advances have played a key role over the last century in the development of humankind. Critical Care Medicine is one of the greatest examples of this revolution. Smartphones with multiple sensors constitute another step forward, and have led to the development of apps for use by both professionals and patients. We discuss their main medical applications in the field of Critical Care Medicine.


Variability and symmetry of gait kinematics under dual-task performance of older patients with depression.
Depression in old age is associated with an increased fall risk. Especially in cognitively challenging situations, fall-promoting gait deviations could appear due to depression- and age-related cognitive deficits. This study investigates (i) whether there are differences in gait performance between depressed older patients and healthy controls and (ii) if gait patterns aggravate when performing a cognitive task whilst walking. 16 depressed older patients (mean age: 73.1 ± 5.8 years) and 19 healthy controls (mean age: 73.3 ± 6.1 years) were included in the study. Spatiotemporal gait parameters (speed, stride length, swing time) and minimum toe clearance were recorded using a three-dimensional motion-capture system under a single- and a dual-task condition (counting backwards). After Bonferroni correction, depressed older patients showed significantly slower walking speed, shorter strides and smaller minimum toe clearance, as well as greater variability in stride length than healthy controls. Under the dual-task, gait performance deteriorated compared with single-task, with slower gait speed, shorter strides, and longer swing time. Slower walking speed and shorter steps of depressed patients may be a strategy to counteract their fall risk. Increased variability suggests a less stable gait pattern in patients, which could be a reason for their increased fall risk. Depression in old age has a strong effect on gait performance. Possible interventions that might prevent falls in this vulnerable group are discussed. The study was registered at Open Science Framework on May 18, 2021 (publicly accessible May 30, 2023).


Interruption of agitation of platelet concentrates: a multicenter in vitro study by the BEST Collaborative on the effects of shipping platelets.
Transported platelets (PLTs) are not under continuous agitation. The aim of this study was to determine whether PLTs shipped between 24 and 48 hours would be able to maintain a pH(22 degrees C) value of 6.5 at the end of 7 days of storage. Six laboratories prepared leukoreduced PLTs. PLT pools were divided into low and high PLT concentration with paired shipped (20-43 hr) and unshipped controls. Units were under continuous agitation at 22 +/- 2 degrees C when not being transported. In vitro measures including pH, pO(2), and pCO(2) were determined over 7 days. Ninety-two PLT components from 24 pools were eligible for analysis. One unshipped control and three shipped products failed to maintain a pH(22 degrees C) value of 6.5 through 7 days. In vitro characteristics were maintained slightly better over 7 days of storage in the unshipped control arms. PLT concentration, shipping time, and their interaction were significant determinants of the final pH at the end of storage (p < 0.05). Lactate generation rate increased by 35 +/- 2 (mean +/- SE) micromol per 10(12) PLTs per hour over baseline during shipping (p < 0.0001). After restoration of standard blood banking conditions with agitation, this rate dropped 24 +/- 2 micromol per 10(12) PLTs per hour (p < 0.0001). PLTs in plasma shipped for at least 20 to 24 hours maintain a pH(22 degrees C) value of 6.5 for 7 days. A longer shipping time may result in a pH(22 degrees C) value of 6.5. During shipping, glycolysis was up regulated in these PLTs resulting in increased lactic acid production. After restoration of agitation, shipped products down regulated glycolysis. These effects should be accounted for in the development of PLT storage and transportation systems.


Changes in gloss after simulated generalized wear of composite resins.
Generalized wear of composite resins in the noncontact area may result in changes of gloss, which can influence esthetics of restorations. The purpose of this study was to determine the changes in gloss of composite resins after generalized wear simulation. Surface roughness and amount of wear were measured for comparison. Generalized wear simulation was performed with a wear tester for 400,000 cycles with 6 composite resins (Estelite Sigma, Esthet X improved, Filtek Supreme, Heliomolar, Renamel Microfill, and Tetric-Ceram). Composite resin was placed into a mold (8 mm in diameter, 3 mm in depth) in an acrylic resin block, and 8 specimens were prepared per group. A flat-planed stylus made with polyacetal was loaded perpendicularly. Gloss was measured after every 100,000 cycles with a glossmeter in gloss units (GU). Average surface roughness (R(a)) of each specimen before and after 400,000 cycles of wear was determined. The amount of wear was measured with a 3-dimensional profilometer. Changes in gloss were analyzed by repeated-measures analysis of variance, and mean values were compared by Fisher's PLSD interval (alpha=.05). Gloss was influenced by the number of wear cycles and the composite resin, and there was a significant interaction (P=.000) between the number of wear cycles and the brand of composite resin. There were no significant correlations between the wear depth and the gloss or changes in gloss after 400,000 cycles. Generalized wear simulation for approximately 3 years of clinical use resulted in gloss changes of 36 to 64 GU, and maximum wear depth was in the range of 35 to 75 mum. Change in gloss varied among the composite resins, but average surface roughness was not influenced by the various composite resins.


Mass gathering medicine (Hajj Pilgrimage in Saudi Arabia): The clinical pattern of pneumonia among pilgrims during Hajj.
The planned annual Hajj to the holy shrines in Makkah, Saudi Arabia, is recognized as one of the largest recurring religious mass gatherings globally, and the outbreak of infectious diseases is of major concern. We aim to study the incidence, etiology, risk factors, length of hospital stay, and mortality rate of pneumonia amongst pilgrims admitted to Al-Ansar general hospital, Madinah, Saudi Arabia during the Hajj period of December 2004-November 2013. A retrospective analysis of all patients diagnosed and admitted as pneumonia was done. Patients were assessed according to the CURB-65 scoring system and admitted to the ward or intensive care unit accordingly. Throat and nasopharyngeal swabs, sputum, and blood culture were collected prior to antibiotic treatment. 1059 patients were included in the study (23% of total hospital admissions and 20% of ICU admissions). The mean age of participants was 56.8 years, the Male:Female ratio was 3:1, and the lengths of stay in the ward and intensive care units were 5 and 14.5 days, respectively. The main organisms cultured from sputum were Klebsiella Pneumoniae, Streptococcus Pneumoniae, Haemophilus Influenzae, Staphylococcus Aureus, Pseudomonas aeruginosa, and community-acquired MRSA. The mortality rate in the ward was 2.4%, while the rate in the ICU was 21.45%. The organisms which caused pneumonia were found to be different during Hajj. The usual standard guideline for the treatment of pneumonia was ineffective for the causative organisms. Therefore, specific adjustments in the guidelines are needed. All efforts should be made to determine the infectious agent. Healthcare workers and pilgrims should adhere to preventive measures.


Left Atrial Localized Low-Voltage Areas Indicate Whole Left Atrial Electrophysiological Degeneration in Atrial Fibrillation Patients.
The efficacy of ablation targeting low-voltage areas (LVAs) is controversial, although LVA presence is well known to be associated with atrial fibrillation (AF) recurrence after ablation. AF substrate may not localize within LVAs.Methods and Results:This observational study enrolled 405 consecutive patients who underwent an initial AF ablation procedure. The left atrial (LA) voltage map was obtained after pulmonary vein isolation. LVAs were defined as areas with voltage <0.5 mV. To estimate whole LA electrophysiological degeneration, mean regional voltage at each of the 6 regions and LA total conduction velocity were measured. LVAs existed in 143 of 405 (35.3%) patients. Patients with LVAs demonstrated lower mean regional voltages throughout all 6 regions compared to those without LVAs (1.3 [1.8, 0.8] vs. 0.6 [1.0, 0.2] mV for the anterior wall, P<0.001). In contrast, LA conduction velocity was lower in patients with LVAs than in those without (0.89 [1.01, 0.74] vs. 0.93 [1.03, 0.87] m/s, P<0.001). Multivariate analysis revealed that low LA total conduction velocity and a higher number of regions with mean voltage reduction were independently associated with AF recurrence, although LVA presence was not. Patients with localized LA LVAs were characterized by whole LA electrophysiological degeneration as assessed by mean regional voltage and conduction velocity. In addition, whole LA electrophysiological degeneration parameters were well associated with AF recurrence.


[Debating the "Unresolved Potential Dangers of Genetic Engineering". Public Science, Strategies of Enactment and Performance of Science in the Context of the West German Debate of Genetic Engineering].
In March 1986, a public symposium took place in Heidelberg about the "unresolved potential dangers of genetic engineering". The event was organized by institutions affiliated with the environmental movement. Choosing this symposium as an example, the article shows how the public appearance of scientists can be understood as a form of political activism. The article shows how specialists from fields as diverse as biology, chemistry, physics, law and political sciences tried to place political messages by putting themselves in the limelight as independent scientists. I argue that the symposium was both: a place of science communication intertwined with political agitation that, as should be noted, happened in a time when the West German government was working on the legislation of genetic engineering, legitimated by relying on independent expertise. It can be concluded that the discourse of scientific independence became a strategic tool in the controversial debate about the uses and dangers of genetic engineering. Thus, it draws attention to a dimension of political-scientific activity which cannot be fully grasped by the concept of 'the expert' that is established in the history of science.


Does fludrocortisone influence autobiographical memory retrieval? A study in patients with major depression, patients with borderline personality disorder and healthy controls.
There is evidence that stimulation of mineralocorticoid receptors (MR) enhances memory in healthy subjects and in patients with major depression (MDD). In contrast, in patients with borderline personality disorder (BPD), this effect seems to be task dependent. The aim of this study was to investigate the effect of MR stimulation on autobiographical memory retrieval in healthy individuals, patients with MDD, and patients with BPD. We conducted a placebo-controlled study in an intra-individual cross-over design. Twenty-four patients with MDD, 37 patients with BPD, and 67 healthy participants completed an autobiographical memory test after receiving 0.4 mg fludrocortisone, a mineralocorticoid receptor preferring agonist, or placebo in a randomized order. Healthy subjects, patients with MDD, and patients with BPD did not differ in their autobiographical memory retrieval. Furthermore, the administration of fludrocortisone had no effect on autobiographical memory. In conclusion, the stimulation of MR does not influence autobiographical memory retrieval in healthy subjects, patients with MDD, and patients with BPD. Our results do not support a role of MR in autobiographical memory.


The mechanics of setting up a COVID-19 response: Experiences of the COVID-19 epidemic from Groote Schuur Hospital, Cape Town, South Africa.
The SARS-CoV-2 pandemic has challenged the provision of healthcare in ways that are unprecedented in our lifetime. Planning for the sheer numbers expected during the surge has required public hospitals to de-escalate all non-essential clinical services to focus on COVID-19. Western Cape Province was the initial epicentre of the COVID-19 epidemic in South Africa (SA), and the Cape Town metro was its hardest-hit geographical region. We describe how we constructed our COVID-19 hospital-wide clinical service at Groote Schuur Hospital, the University of Cape Town's tertiary-level teaching hospital. By describing the barriers and enablers, we hope to provide guidance rather than a blueprint for hospitals elsewhere in SA and in low-resource countries that face similar challenges now or during subsequent waves.


Allosteric modulation of ligand-gated ion channels.
Ligand-gated ion channels (LGICs) are cell surface proteins that play an important role in fast synaptic transmission and in the modulation of cellular activity. Due to their intrinsic properties, LGICs respond to neurotransmitters and other effectors (e.g. pH) and transduce the binding of a ligand into an electrical current on a microsecond timescale. Following activation, LGICs open allowing an ion flux across the cell membrane. Depending upon the charge and concentration of ions, the flux can cause a depolarization or hyperpolarization, thus modulating excitability of the cell. While our understanding of LGICs has significantly progressed during the past decade, many properties of these proteins are still poorly understood, in particular their modulation by allosteric effectors. LGICs are often thought as a simple on-off switches. However, a closer look at these receptors reveals a complex behavior and a wide repertoire of subtle modulation by intrinsic and extrinsic factors. From a physiological point of view, this modulation can be seen as an additional level of complexity in the cell signaling process. Here we review the allosteric modulation of LGICs in light of the latest findings and discuss the suitability of this approach to the design of new therapeutic molecules.


Reparative dentin formation in rat molars after direct pulp capping with growth factors.
Growth factors involved in normal wound healing may promote tissue repair when applied as a direct pulp capping medication. A minimal pulp exposure was made in rat molars, a pulp capping medication was placed, and the cavity was sealed. Epidermal growth factor, basic fibroblast growth factor, insulin-like growth factor II, platelet-derived growth factor-BB, and transforming growth factor-beta 1 (TGF-beta 1)--each absorbed onto a sterile collagen membrane (BioMend; Calcitek, Carlsbad, CA)--were used separately as pulpal medicaments. Dycal, unimpregnated collagen membrane, and no medication were used as controls. Eight samples from each treatment regimen were collected 2 and 3 weeks after surgery. Pulpal soft and hard tissue responses were graded. Data were analyzed by one-way ANOVA and Tukey-Kramer tests. No significant differences were detected after 2 wk. Pulp treated with TGF-beta 1 showed significantly improved soft and hard tissue healing at week 3, compared with the procedure control. We conclude that TGF-beta 1 as a pulp-capping medication enhances reparative dentin formation in rat molars.


Impact of Cold Ischemia Time on Outcomes of Liver Transplantation: A Single Center Experience.
Significant geographic disparities exist in access to liver transplantation and consequently the current liver allocation system is being challenged. We sought to describe our unique experience with using organs with long cold ischemia times from the largest donation service area. From 2009-2014 we performed 350 liver transplants. 167 (48%) had a cold ischemia time <8 hours, 134 (38%) between 8 and 12 hours, and 49 (14%) greater than 12 hours. Early allograft dysfunction was observed more commonly with increasing cold ischemia times. 53% of the recipients in the >12 h group had early allograft dysfunction compared to 28% in the 8-12 h group, and 18% in the <8 h group (P<0.001). We found no correlation between early allograft dysfunction and allograft or patient survival. One-year liver allograft survival was 92%, 94%, 87%, three-year graft survival was 82%, 89%, and 87%, and five-year graft survival was 82%, 89%, and 79% in the <8 h, 8-12 h, and >12 h cold ischemia time groups, respectively. One-year patient survival was 95%, 94%, and 92% and five-year patient survival was 90%, 89%, and 83% in the <8 h, 8-12 h, and >12 h cold ischemia time groups, respectively. Both unadjusted and multivariate Cox regression analyses indicated no statistically significant associations between cold ischemia time and graft or patient survival. In conclusion, the prolonged cold ischemia time led to early allograft dysfunction but did not have a deleterious association with graft or patient survival.


The Rise of AI: How Artificial Intelligence is Revolutionizing Infectious Disease Control.
Artificial Intelligence (AI) has proven to be an effective tool in predicting, detecting, and mitigating the spread of infectious diseases, especially during the COVID-19 pandemic. The technology is increasingly playing a role in preventing future health crises by predicting outbreaks, identifying high-risk areas, and aiding in vaccine development. AI can track and trace infected individuals and identify potential hotspots, help reduce the spread of infectious diseases, and monitor patient symptoms, enabling healthcare professionals to provide effective treatment.


Mycobacterium kansasii and Pneumocystis carinii pneumonia in a patient with the acquired immunodeficiency syndrome.
The case of a Swiss AIDS patient suffering from Mycobacterium kansasii lung disease is described. The course of the illness was complicated by Pneumocystis carinii pneumonia. Therapy with isoniazid, ethambutol, clofazimine, ciprofloxacin and, after the onset of P. carinii pneumonia, trimethoprim-sulfamethoxazole led to a rapid and sustained clinical recovery of the patient.


Rapid preparation of lecture slides using the computer.
Information displayed on a computer monitor can be easily photographed to produce attractive color slides for lectures. The authors describe a simple technique which emphasizes flexibility, convenience and expediency.


Geriatric syndromes in the population older than 90 years: The prevalence and association with chronic diseases.
The aim of this study was to explore the prevalence of geriatric syndromes and comorbid conditions, as well as their interrelationships, in individuals aged 90 years and over. This study included participants aged 90 years and older who underwent a comprehensive geriatric assessment in a tertiary geriatric outpatient clinic. Demographic and clinical characteristics were obtained using the electronic medical records. The geriatric syndrome burden was calculated by adding each syndrome, which was then stratified into one of two groups based on the median value: no or low burden (<4) and high burden (≥4). The modified Charlson comorbidity index was used to determine chronic disease burden. A total of 235 participants (93.2 ± 2.7 years) were recruited in this study. The mean index score was 7.3, and 46% (n = 107) of participants had a high geriatric syndrome burden. The most common geriatric syndrome was incontinence (69%), followed by polypharmacy (60%) and depression (43%). When compared to patients without such a diagnosis, the prevalence of polypharmacy was significantly higher in patients diagnosed with hypertension, chronic kidney disease, cardiovascular disease, diabetes mellitus and chronic obstructive pulmonary disease (p = 0.02, p = 0.02, p < 0.001, p = 0.008, p = 0.007, respectively). However, no chronic disease was associated with geriatric syndrome burden. We found that the burden of medical conditions in the older population over 90 years of age could influence general health status significantly, with a high prevalence of chronic diseases and geriatric syndromes.


Treat the "Untreatable" by a Photothermal Agent: Triggering Heat and Immunological Responses for Rabies Virus Inactivation.
Rabies is a fatal neurological zoonotic disease caused by the rabies virus (RABV), and the approved post-exposure prophylaxis (PEP) procedure remains unavailable in areas with inadequate medical systems. Although strategies have been proposed for PEP and postinfection treatment (PIT), because of the complexity of the treatment procedures and the limited curative outcome, developing an effective treatment strategy remains a holy grail in rabies research. Herein, a facile approach is proposed involving photothermal therapy (PTT) and photothermally triggered immunological effects to realize effective PEP and PIT simultaneously. The designed photothermal agent (N+ TT-mCB nanoparticles) featured positively charged functional groups and high photo-to-heat efficiency, which are favorable for virus targeting and inactivation. The level of the virus at the site of infection in mice is significantly decreased upon treatment with orthotopic PTT, and the transfer of the virus to the brain is significantly inhibited. Furthermore, the survival ratio of the mice three days postinfection is increased by intracranial injection of N+ TT-mCB and laser irradiation. Overall, this work provides a platform for the effective treatment of RABV and opens a new avenue for future antiviral studies.


Brivaracetam: a new drug in development for epilepsy and neuropathic pain.
Epilepsy is a neurological disorder with a worldwide prevalence estimated to be 0.5-1.0% of the population. Many potent antiepileptic drugs (AED) have been used for treatment but still about 30% of patients are resistant to current AEDs. Some AEDs are also used for the treatment of neuropathic pain. The aim of this report is to present preclinical and clinical studies of brivaracetam (UCB-34714), a new drug developed by UCB Pharma. Published results of preclinical studies in several animal models of epilepsy, neuropathic pain, essential tremor and results of Phase I and II evaluations of brivaracetam have been analysed. Brivaracetam represents a new mechanism of action being a ligand of synaptic vesicle protein 2A. It is undergoing Phase III evaluation after a successful Phase II programme in which was effective as an adjunctive treatment in partial-onset epilepsy (50 mg/day). It is well tolerated, without serious adverse side effects.


The emerging roles of circular RNAs in regulating the fate of stem cells.
Circular RNAs(circRNAs) are a large family of RNAs shaping covalently closed ring-like molecules and have become a hotspot with thousands of newly published studies. Stem cells are undifferentiated cells and have great potential in medical treatment due to their self-renewal ability and differentiation capacity. Abundant researches have unveiled that circRNAs have unique expression profile during the differentiation of stem cells and could serve as promising biomarkers of these cells. There are key circRNAs relevant to the differentiation, proliferation, and apoptosis of stem cells with certain mechanisms such as sponging miRNAs, interacting with proteins, and interfering mRNA translation. Moreover, several circRNAs have joined in the interplay between stem cells and lymphocytes. Our review will shed lights on the emerging roles of circRNAs in regulating the fate of diverse stem cells.


Multimodal imaging of a micro-anatomical structure in the vitreous base.
To describe an ultrastructure in the vitreous base (VB) and its micro-anatomical characteristics by multimodal imaging. Light and transmission electron microscopy of the VB were performed on specimens from post-trauma eyes and one healthy donor eye. Intra-operative fundus images associated with VB abnormalities were captured from 4 cases, including 2 retinal detachment (RD) with PVR eyes and 2 post-trauma eyes. Images during micro-anatomical observation of the three specimens were analyzed along with the fundus images obtained during vitrectomy. Densely packed collagen fibers were observed by light microscopy between the pigment epithelium layer and uveal tissue within the ora serrata region in specimen 1 and the post-mortem healthy eye, respectively. A similar structure was also observed by transmission electron microscopy interior to the pigment epithelium layer and exposed to the vitreous cavity in specimen 2. The collagen fibers, which were termed ciliary body-choroid-retina (CB-C-R) connector, connects to the vitreous fibers interiorly, ciliary epithelium anteriorly, peripheral retina posteriorly, and uveal tissue exteriorly. The three different RD boundaries related to the posterior edge of the VB, ora serrata, and ciliary epithelium are demonstrated with the micro-anatomical characteristics of the CB-C-R connector. The CB-C-R connector exists deep in the VB.


Fabrication of Eu(III) complex doped nanofibrous membranes and their oxygen-sensing properties.
In this paper, we report the synthesis, characterization, and photophysical properties of Eu(TTA)₃ECIP, where TTA=2-thenoyltrifluoroacetonate, and ECIP=1-ethyl-2-(N-ethyl-carbazole-yl-4-)imidazo[4,5-f]1,10-phenanthroline. Its elementary application for oxygen-sensing application is also investigated by doping it into a polymer matrix of polystyrene (PS). Experimental data suggest that the 2.5 wt% doped Eu(TTA)₃ECIP/PS nanofibrous membrane exhibits a high sensitivity of 3.4 towards oxygen with a good linear relationship of R² = 0.9962. In addition, the 2.5 wt% doped Eu(TTA)₃ECIP/PS nanofibrous membrane owns a quick response of 8s towards oxygen, along with its excellent atmosphere insensitivity and photobleaching resistance. All these results suggest that both Eu(TTA)₃ECIP and Eu(TTA)₃CIP/PS system are promising candidates for oxygen-sensing optical sensors.


β-tricalcium phosphate for bone substitution: Synthesis and properties.
β-tricalcium phosphate (β-TCP) is one the most used and potent synthetic bone graft substitute. It is not only osteoconductive, but also osteoinductive. These properties, combined with its cell-mediated resorption, allow full bone defects regeneration. Its clinical outcome is sometimes considered to be "unpredictable", possibly due to a poor understanding of β-TCP physico-chemical properties: β-TCP crystallographic structure is not fully uncovered; recent results suggest that sintered β-TCP is coated with a Ca-rich alkaline phase; β-TCP apatite-forming ability and osteoinductivity may be enhanced by a hydrothermal treatment; β-TCP grain size and porosity are strongly modified by the presence of minute amounts of β-calcium pyrophosphate or hydroxyapatite impurities. The aim of the present article is to provide a critical, but still rather comprehensive review of the current state of knowledge on β-TCP, with a strong focus on its synthesis and physico-chemical properties, and their link to the in vivo response. STATEMENT OF SIGNIFICANCE: The present review documents the richness, breadth, and interest of the research devoted to β-tricalcium phosphate (β-TCP). β-TCP is synthetic, osteoconductive, osteoinductive, and its resorption is cell-mediated, thus making it one of the most potent bone graft substitutes. This comprehensive review reveals that there are a number of aspects, such as surface chemistry, crystallography, or stoichiometry deviations, that are still poorly understood. As such, β-TCP is still an exciting scientific playground despite a 50 year long history and > 200 yearly publications.


The conformation of purified Toxoplasma gondii SAG1 antigen, secreted from engineered Pichia pastoris, is adequate for serorecognition and cell proliferation.
A truncated form of SAG1, the immunodominant surface antigen of Toxoplasma gondii, has been produced in the methylotrophic yeast, Pichia pastoris. By construction, the recombinant protein lacks C-terminal residues 308-336 which, in native SAG1, encompass the glycosylphosphatidylinositol anchorage site. Secretion of anchor-less SAG1 proceeded via the yeast prepro alpha-mating factor signal peptide and yielded two immunoreactive protein species having apparent molecular masses of 31.5 and 34.5 kDa, respectively, and differing only by N-glycosylation of the single Asn-X-Ser site present in the molecule. Purification of the anchor-less SAG1 was achieved by a combination of ion-exchange and size-exclusion chromatographies. N-terminal amino acid sequencing of the products indicated the presence of additional residues glutamic acid--alanine at the N-terminal end of the products. Despite incomplete processing and unnatural glycosylation, anchor-less SAG1 proteins apparently adopted a suitable conformation recognized by monoclonal and human serum-derived antibodies, specific for the native SAG1. In addition, the recombinant anchor-less SAG1 proved competent for inducing proliferation, in vitro, of mononuclear cells from seropositive individuals. Finally, properly adjuvanted anchor-less SAG1 was able to induce protection of mice against a lethal challenge with T. gondii tachyzoites.


Use of enzyme-linked immunosorbent assay to measure bovine milk and serum antibodies to alpha toxin, beta toxin, and capsular antigens of Staphylococcus aureus.
An enzyme-linked immunosorbent assay (ELISA) procedure was used to quantitate milk and serum antibodies (IgG) to Staphylococcus aureus alpha and beta toxins, and S. aureus 2-8 and Smith diffuse strain capsular antigens. Milk samples were collected on two occasions. A comparison was made between levels of milk antibodies specific for the two toxins and capsular antigens for 41 cows that were infected with S. aureus on both sampling dates, and 18 cows not S. aureus-infected on either date. Staphylococcus aureus-infected cows were grouped according to somatic cell counts. All groups of infected cows, regardless of somatic cell counts, had significantly higher milk antibody levels to alpha and beta toxins than did the non-infected cows (P less than .002). Serum samples taken for 13 infected and 4 non-infected cows also indicated that significant elevations in anti-alpha toxin and anti-beta toxin IgG were present in S. aureus-infected cows, compared to non-infected cows. A similar immune response was not seen to capsular antigens, however. No significant differences were present between the two groups of cows for either milk or serum antibodies to Smith diffuse strain capsular antigens. Milk antibodies to 2-8 capsule were significantly elevated only in infected cows with somatic cell counts greater than 10(6)/ml, compared to non-infected cows; no differences were present for serum antibodies to 2-8 capsule between infected and non-infected cows. These results indicate that significant increases in milk (and possibly serum) antibodies to alpha and beta toxins are present in cows with chronic staphylococcal mastitis, apparently resulting from a systemic immune response to these toxins. There does not appear to be a similar immune response to capsular antigens.


[The action of extracellular calcium and the temperature of the isolation of lymphocytes on their viability].
The effect of extracellular calcium binding and temperature of isolation and storage of thymus lymphocytes on their viability was studied. The last was evaluated by the fluorescence intensity of fluoresceindiacetate stained cells and by the intracellular ATP content. The rise of temperature of isolation and storage of lymphocytes from 1 degree to 22 degrees C significantly lowered the intracellular ATP concentration in cells storing in dense suspension [(3-4) x 10(9) lymphocytes/ml]. However, the ATP content in lymphocytes increased as a result of short-term incubation by diluted suspension (3 x 10(7) lymphocytes/ml) at 22 degrees C. The fluorescence of fluorescein introduced into lymphocytes decrease in the presence of 1-5 mM EGTA (EDTA).


Healing the sole.
The benefits of reflexology are explored in the fourth article in our series on complementary and alternative therapies.


Characterization of TiO2 and ZnO nanoparticles and their applications in photocatalytic degradation of azodyes.
TiO2 nanoparticles have been synthesized from the inorganic precursor Ti [OC3H7]4via sol-gel technique. Similarly, ZnO nanoparticles have also been synthesized from zinc sulfate precursor using precipitation method. The prepared nanoparticles was characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) techniques to study the morphology, structural configuration and its functionality. The average particle size for TiO2 and ZnO nanoparticles was 15.4nm and 17.9nm, respectively. The synthesized TiO2 and ZnO nanoparticles have been used for degradation of acid red 27 and coralene red F3BS dyes under the UV light. The regeneration of TiO2 photocatalyst was also tested.


Characterization of ClpS2, an essential adaptor protein for the cyanobacterium Synechococcus elongatus.
The adaptor protein ClpS associates to the Clp protease and promotes degradation of N-end rule substrates in eubacteria and in algal/plant chloroplasts. Cyanobacteria are unusual in having two distinct ClpS paralogs. Although ClpSl is typical of bacterial ClpS, ClpS2 differs in crucial ways. ClpS2 in Synechococcus elongatus is a relatively low-abundant, soluble protein essential for phototrophic growth. Like ClpSl, ClpS2 binds to the ClpCP3/R protease to block α-casein degradation and promote that of N-end rule substrates in vitro. However, their substrate specificity differs, with ClpSl recognizing destabilizing Phe and Tyr residues at the substrate N-terminus whereas ClpS2 recognizes Leu. Overall, ClpS2 appears to have independently evolved in cyanobacteria to degrade a particular group of proteins, whose turnover is vital for cell viability.


Polymorphism rs1057147 located in mesothelin gene predicts lymph node metastasis in patients with gastric cancer.
Lymph node metastasis, a crucial factor in the spread of gastric cancer (GC), is strongly associated with a negative prognosis for patients. This study aimed to investigate the association of the mesothelin (MSLN) gene polymorphisms (rs3764247, rs3764246, rs12597489, rs1057147, and rs3765319) with the risk of lymph node metastasis of GC patients in a Chinese Han population. The PCR-LDR genotyping was used to detect the genotypes of MSLN polymorphisms in GC patients with lymph node metastasis (n = 610) or without (n = 356). Our research indicates that certain genetic markers, specifically rs3764247, rs3764246, rs12597489, and rs3765319, do not appear to be linked with an increased risk of lymph node metastasis in GC. However, we did observe that patients with the rs1057147 GA genotype exhibited a higher likelihood of lymph node metastasis in GC when compared to those with the GG genotype (OR = 1.33, 95% CI = 1.01 - 1.76, P = 0.045). Patients with rs1057147 GA + AA genotype were found to have a higher likelihood of lymph node involvement (OR = 1.35, 95% CI = 1.03 - 1.77, P = 0.029) when compared to those with GG genotype in the dominant model. The allelic model revealed that the A allele of rs1057147 exhibited a stronger correlation with lymph node metastasis compared to the G allele (OR = 1.28, 95% CI = 1.02 - 1.60, P = 0.031). In addition, we found that rs1057147 polymorphism revealed a poor prognosis for GC patients with lymph node metastasis. Further stratified analysis revealed that the prognostic effect of rs1057147 was more pronounced in patients with GC who had lymph node metastasis and had a tumor size of 4 cm or greater, as well as more than 2 lymph node metastases. Bioinformatics studies showed that the binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147. Our study confirmed the important role of MSLN rs1057147 polymorphism locus in GC lymph node metastases and suggested a potential prognostic factor during GC progression. KEY POINTS: • Rs1057147 GA genotype had an increased risk of lymph node metastasis in gastric cancer. • The A allele of rs1057147 had a stronger association with lymph node metastasis than the G allele. • The binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147.


Enhancing contraception: a comprehensive review.
This review covers familiar and emerging contraceptive methods, comparing the risks and benefits of each. These basics will help you connect patients with the most acceptable form of contraception for them.


Petasis three-component coupling reactions of hydrazides for the synthesis of oxadiazolones and oxazolidinones.
An application of readily available hydrazides in the Petasis 3-component coupling reaction is presented. An investigation of the substrate scope was performed to establish a general, synthetically useful protocol for the formation of hydrazido alcohols, which were selectively converted to oxazolidinone and oxadiazolone ring systems through triphosgene-mediated cyclization reactions.


Purification and quantification of recombinant Epstein-Barr viral glycoproteins gp350/220 from Chinese hamster ovary cells.
Truncated Epstein-Barr virus (EBV) membrane antigen gp350/220 (EBV-MA) lacking the membrane anchor was expressed and secreted into the medium of recombinant Chinese hamster ovary cells that had been cultured in Plasmapur hollow-fibre modules using defined serum-free medium. The EBV-MA in the medium was concentrated by 70% (w/v) ammonium sulphate precipitation and subsequently purified by immunoaffinity chromatography using an anti-EBV-MA (EBV.0T6) monoclonal antibody (mAb) column. Adsorbed antigen was eluted with 3 M MgCl2 in phosphate-buffered saline, concentrated by Mono Q anion-exchange chromatography and analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis, silver staining and Western blotting using EBV-positive serum and anti-EBV-MA specific mAbs. Monospecific polyclonal rabbit antibodies against the purified EBV-MA were raised and purified by protein G affinity chromatography. For the measurement of EBV-MA antigen levels a sandwich enzyme-linked immunosorbent assay using rabbit polyclonal antibodies and a horseradish peroxidase-conjugated anti-MA mAb was developed having a detection level of 10 ng/ml.


Comparison between the analgesic efficacy of transversus abdominis plane (TAP) block and placebo in open retropubic radical prostatectomy: a prospective, randomized, double-blinded study.
To compare the efficacy of ultrasound-guided tansversus abdominis plane (TAP) block with placebo for postoperative analgesia after retropubic radical prostatectomy (RRP). Prospective, randomized, double-blinded study. Tertiary-care Veterans Affairs (VA) hospital. ASA physical status 1, 2, and 3 patients scheduled for RRP. Patients were randomized to two groups: the TAP group and the control group. All patients underwent an ultrasound-guided TAP block procedure after induction of general anesthesia and received either local anesthetic (TAP group) or normal saline (control group). Opioid use and verbal analog pain scores at 1, 6, 12, and 24 hours after surgery were recorded, as was the frequency of side effects. Times to ambulation and first oral intake also were recorded. The TAP block group had lower pain scores and required less total opioid in the first 24 hours after surgery. Time to first oral intake and time to ambulation were similar between the two groups. The TAP block has early benefits in postoperative analgesia after RRP.


Introducing new group leaders: Devin Schweppe.
We talk to Devin Schweppe about setting up his group at the University of Washington, studying quantitative-mass-spectrometry-based proteomics (a field that is constantly evolving), overcoming self-doubt, going with your gut when hiring, and how he hopes to build an environment of excellence, inclusion, and trust and always encourage his lab members to keep asking "why?"


A Pilot Study of Dynamic 18F-DCFPyL PET/CT Imaging of Prostate Adenocarcinoma in High-Risk Primary Prostate Cancer Patients.
The primary aim of this study was to investigate the pharmacokinetics of 18F-DCFPyL, an 18F-labeled PSMA-based ligand, and to explore the utility of early time point positron emission tomography (PET) imaging extracted from PET data to distinguish malignant primary prostate from benign prostate tissue. Ten consecutive patients with biopsy-proven high-risk prostate cancer underwent a dynamic 18F-DCFPyL PET/CT scan of the pelvis for the first 45 min post-injection (p.i.) followed by a static PET/CT at 2 h p.i. 18F-DCFPyL uptake values and kinetics were compared between benign prostate tissue and prostate cancer, including quantitative pharmacokinetic PET parameters extracted from 18F-DCFPyL time activity curves generated from dynamic data using a two-tissue compartment model and Patlak plots. 18F-DCFPyL uptake values were significantly higher in primary prostate tumors than those in benign prostatic hyperplasia (BPH) and normal prostate tissue at 5 min, 30 min, and 120 min p.i. (P = 0.0002), when examining both SUVmax and SUVmean values. The two-tissue compartment model found an overall influx value (Ki) of 0.063 in primary prostate cancer, demonstrating a Ki over 15-fold higher in malignant prostate tissue compared with BPH (Ki = 0.004) and normal prostate tissue (Ki = 0.005) (P = 0.0001). High-risk primary prostate cancer is readily identified on dynamic and static, delayed, 18F-DCFPyL PET images. The tumor-to-background ratio increases over time, with optimal 18F-DCFPyL PET/CT imaging at 120 min p.i. for evaluation of prostate cancer, but not necessarily ideal for clinical application. Primary prostate cancer demonstrates different uptake kinetics in comparison to BPH and normal prostate tissue. The 15-fold difference in Ki between prostate cancer and non-cancer (BPH and normal) tissues translates to an ability to distinguish prostate cancer from normal tissue at time points as early as 5 to 10 min p.i.


Multidimensional significance of crystallin protein-protein interactions and their implications in various human diseases.
Crystallins are the important structural and functional proteins in the eye lens responsible for refractive index. Post-translational modifications (PTMs) and mutations are major causative factors that affect crystallin structural conformation and functional characteristics thus playing a vital role in the etiology of cataractogenesis. The significance of crystallin protein-protein interactions (PPIs) in the lens and non-lenticular tissues is summarized. Aberrancy of PPIs between crystallin, its associated protein and metal ions has been accomplished in various human diseases including cataract. A detailed account on multidimensional structural and functional significance of crystallin PPI in humans must be brought into limelight, in order to understand the biochemical and molecular basis augmenting the aberrancies of such interaction. In this scenario, the present review is focused to shed light on studies which will aid to expand our present understanding on disease pathogenesis related to loss of PPI thereby paving the way for putative future therapeutic targets to curb such diseases. The interactions with α-crystallins always aid to protect their structural and functional characteristics. The up-regulation of αB-crystallin in the non-lenticular tissues always decodes as biomarker for various stress related disorders. For better understanding and treatment of various diseases, PPI studies provide overall outline about the structural and functional characteristics of the proteins. This information not only helps to find out the route of cataractogenesis but also aid to identify potential molecules to inhibit/prevent the further development of such complicated phenomenon. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.


Impact of colostomy on intestinal microflora and bacterial translocation in young rats fed with heat-killed Lactobacillus acidophilus strain LB.
A rat animal model of left colostomy was found to significantly impair the growth curve of rats. Assessment of the intestinal flora showed that colostomy mostly affects the cecal but not colonic microflora. Generally, the number of enterococci was increased in both ileum and cecum; cecal lactobacilli also rose, accounting for a promotion of lactic acid bacteria in colostomised rats. No significant differences between colostomised, laparotomised and control rats could be observed for the translocation of intestinal bacteria to internal organs of rats (i.e. spleen, kidneys, lungs or liver), whatever their diet. Heat-killed Lactobacillus acidophilus strain LB administration (dead probiotic bacteria) tended to exhibit a stimulatory effect on bifidobacteria, probably affecting the culture-medium fermentation substances included in the pharmaceutical product. This effect was abolished by laparotomy and colostomy. A trend towards a probiotic-like effect, not susceptible to colostomy, was also witnessed as counts of lactobacilli tended to increase in both cecum and colon of all animals fed with L. acidophilus LB.


TLR4-IN-C34 Inhibits Lipopolysaccharide-Stimulated Inflammatory Responses via Downregulating TLR4/MyD88/NF-κB/NLRP3 Signaling Pathway and Reducing ROS Generation in BV2 Cells.
TLR4 signal activated by lipopolysaccharide (LPS) is involved in the pathological process of the central nervous system (CNS) diseases and the suppression of TLR4 signal may become an effective treatment. TLR4-IN-C34, a TLR4 inhibitor, is expected to become a candidate compound with anti-neuroinflammatory response. In the present study, the anti-neuroinflammatory effects and possible mechanism of TLR4-IN-C34 were investigated in BV2 microglia cells stimulated by LPS. The results showed that TLR4-IN-C34 decreased the levels of pro-inflammatory factors and chemokines including NO, TNF-α, IL-1β, IL-6, and MCP-1 in the supernatant of LPS-stimulated BV2 cells. Further research indicated that TLR4-IN-C34 suppressed the expression or phosphorylation levels of inflammatory proteins regarding TLR4/MyD88/NF-κB/NLRP3 signaling pathway. In addition, TLR4-IN-C34 reduced ROS production in BV2 cells after LPS treatment. In conclusion, our findings suggest that anti-neuroinflammatory activity of TLR4-IN-C34 may be interrelated to the inhibition of TLR4/MyD88/NF-κB/NLRP3 signaling pathway and reduction of ROS generation.


Management of iron overload in the pediatric patient.
Iron overload is a major complication of long-term transfusion therapy. In the absence of treatment, the excessive iron causes diffuse organ damage, usually culminating in death from heart disease. Deferoxamine, an iron-chelating drug, removes tissue iron, prevents iron-induced organ dysfunction, and prolongs life. Proper administration of deferoxamine requires careful attention to dose, route and duration of administration, and compliance. Better chelators are needed but are unlikely to be available soon. Other methods for preventing or reducing iron accumulation involve alterations in the transfusion program or the blood product. Prevention of iron overload should improve the lives of patients with transfusion-dependent anemias and extend the usefulness of transfusion in chronic hematologic disorders.


Which feature influences on-eye power change of soft toric contact lenses: Design or corneal shape?
This study investigates how both the peripheral zone design and corneal shape affect the behaviour of soft contact lenses on-eye. In this study, soft contact lenses of varying nominal cylindrical powers and peripheral zone designs-a single-prism gravity-based stabilised lens (G1P), two-prism blink-based stabilised lens (B2P) and four-prism blink-based stabilised lens (B4P)-were generated as finite element models. The on-eye simulation results were analysed to identify the impact of each peripheral zone design (Each with different volume ratios) on the effective power change (EPC) when worn by a subject. Topographies of three eyes of varying average simulated anterior corneal curvature (flat, average & steep) were used in this study. The volume of the lens's peripheral zone as a ratio of the total lens volume (Vp) recorded very weak correlations with the effective power change (EPC) among the three investigated designs when they were fitted to the flat eye (R = -0.19, -0.15 & -0.22 respectively), moderate correlations with the average eye (R = 0.42, 0.43 & 0.43 respectively) and strong correlations with the steep eye (R = 0.91, 0.9 & 0.9 respectively). No significant differences were noticed among the three investigated designs and none of the cylindrical lenses designed with axis 90° recorded EPC values outside the acceptance criteria range (ACR) of ±0.25 D. No significant differences in EPC were recorded among the three designs G1P, B2P and B4P (p>0.6) when they were designed with three axes at 90°, 45° and 0°. Moving the toric lens axis away from 90° dragged the EPC to the negative side and most of the investigated lenses with axes at 45° and 0° recorded EPCs outside the ±0.25D range. In all cases, the shape of the cornea had a more dominant effect on EPC when compared to the peripheral zone design. Corneal shape influences the soft toric contact lens's on-eye power change more than the lens design.


Independent co-delivery of model actives with different degrees of hydrophilicity from oil-in-water and water-in-oil emulsions stabilised by solid lipid particles via a Pickering mechanism: a-proof-of-principle study.
The development of vehicles for the co-encapsulation of actives with diverse characteristics and their subsequent controllable co-delivery is gaining increasing research interest. Predominantly centred around pharmaceutical applications, the majority of such co-delivery approaches have been focusing on solid formulations and less so on liquid-based systems. Simple emulsions can be designed to offer a liquid-based microstructural platform for the compartmentalised multi-delivery of actives. In this work, solid lipid nanoparticle stabilised Pickering emulsions were used for the co-encapsulation/co-delivery of two model actives with different degrees of hydrophilicity. Lipid particles containing a model hydrophobic active were prepared in the presence of either Tween 20 or whey protein isolate, and were then used to stabilise water-in-oil or oil-in-water emulsions, containing a secondary model active within their dispersed phase. Solid lipid nanoparticles prepared with either type of emulsifier were able to provide stable emulsions. Release kinetic data fitting revealed that different co-delivery profiles can be achieved by controlling the surface properties of the lipid nanoparticles. The current proof-of-principle study presents preliminary data that confirm the potential of this approach to be utilised as a flexible liquid-based platform for the segregated co-encapsulation and independent co-release of different combinations of actives, either hydrophobic/hydrophilic or hydrophobic/hydrophobic, with diverse release profiles.


Vibrational Stark Effects on Carbonyl, Nitrile, and Nitrosyl Compounds Including Heme Ligands, CO, CN, and NO, Studied with Density Functional Theory.
Changes in the matrix electric field in a protein, due for example to mutations or structural fluctuations, can be correlated with changes in the vibrational transition frequencies of suitable chromophores measured by IR spectroscopy through the Stark tuning rate. To make this correlation, the Stark tuning rate must be known from experiment or theory. In this paper, density functional theory at the B3LYP/TZV level of theory is used to compute the Stark tuning rate of adducts of heme porphyrin, namely, -CO, -CN, and -NO+ compounds. The results are compared with the corresponding vibrational frequencies-field dependencies from vibrational Stark spectroscopy of heme-proteins. The zero-field computed Stark tuning rate of 1.3 cm-1/MV/cm for heme-CO is in agreement with experiment, where typically the rate is 2.4/f cm-1/MV/cm for myoglobin, where f is a local field correction between 1.1 and 1.4. Several small nitrile, carbonyl, and dinitrile molecules were studied to rationalize the findings for the heme-adducted models. Here, the higher B3LYP/6-311++G(2d,2p) level of theory could be used so the agreement with recent experimental results is even better than for heme-adducted groups.


Association of Estrogen Receptor Gene Polymorphisms and Primary Biliary Cirrhosis in a Chinese Population: A Case-Control Study.
Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease characterized by destruction of the interlobular bile ducts and a striking female predominance. The aim of this study was to identify associations between estrogen receptor (ESR) gene polymorphisms with the risk of developing PBC and abnormal serum liver tests in a Chinese population. Thirty-six patients with PBC (case group) and 35 healthy individuals (control group) from the First Hospital of Jilin University were studied. Whole genomic DNA was extracted from all the participants. Three single-nucleotide polymorphisms (rs2234693, rs2228480, and rs3798577) from ESR1 and two (rs1256030 and rs1048315) from ESR2 were analyzed by a pyrosequencing method. Demographic data and liver biochemical data were collected. Subjects with the T allele at ESR2 rs1256030 had 1.5 times higher risk of developing PBC than those with the C allele (odds ratio [OR] = 2.1277, 95% confidence interval [CI] = 1.1872-4.5517). Haplotypes TGC of ESR1 rs2234693, rs2228480, and rs3798577 were risk factors for having PBC. The C allele at ESR1 rs2234693 was associated with abnormal alkaline phosphatase (OR = 5.2469, 95% CI = 1.3704-20.0895) and gamma-glutamyl transferase (OR = 3.4286, 95% CI = 1.0083-13.6578) levels in PBC patients. ESR2 rs1256030 T allele may be a significant risk factor for the development of PBC. Screening for patients with gene polymorphisms may help to make early diagnoses in patients with PBC.


Prognostic value of Mini Nutritional Assessment-Short Form with aortic valve stenosis following transcatheter aortic valve implantation.
Older adults at risk for malnutrition are known to have a high mortality rate. This study aimed to investigate whether the Mini Nutritional Assessment-Short Form (MNA-SF) could predict midterm mortality in patients undergoing transcatheter aortic valve implantation (TAVI). We applied the MNA-SF in 288 patients who had undergone TAVI from January 2016 to June 2019 at the St. Marianna University School of Medicine hospital. Using the MNA-SF cut-off value to indicate the risk of malnutrition, patients were divided into two groups, namely, those with an MNA-SF score ≤11 (impaired MNA-SF group) and those with an MNA-SF score ≥12 (maintained MNA-SF group). We used this value to investigate the association between the MNA-SF and all-cause mortality. Overall, 188 (65%) and 100 (35%) patients comprised the impaired MNA-SF and maintained MNA-SF groups, respectively, and 41 patients died after TAVI (mean follow-up duration, 458 ± 315 days). Kaplan-Meier analyses showed that patients in the impaired MNA-SF group had a significantly higher incidence of all-cause mortality (hazard ratio 2.67; 95% confidence interval 1.29-6.21; P = 0.01). Multivariate Cox regression analyses showed that the MNA-SF score was an independent predictor of all-cause mortality after adjusting for the Society of Thoracic Surgeons risk score, Katz Index, and brain natriuretic peptide test results (hazard ratio 1.14; 95% confidence interval 1.01-1.28; P = 0.04). The MNA-SF was useful to screen for the risk of malnutrition in patients with TAVI and in predicting midterm prognoses in patients undergoing TAVI and could predict patient mortality after the procedure.


A predictive structural model for bulk metallic glasses.
Great progress has been made in understanding the atomic structure of metallic glasses, but there is still no clear connection between atomic structure and glass-forming ability. Here we give new insights into perhaps the most important question in the field of amorphous metals: how can glass-forming ability be predicted from atomic structure? We give a new approach to modelling metallic glass atomic structures by solving three long-standing problems: we discover a new family of structural defects that discourage glass formation; we impose efficient local packing around all atoms simultaneously; and we enforce structural self-consistency. Fewer than a dozen binary structures satisfy these constraints, but extra degrees of freedom in structures with three or more different atom sizes significantly expand the number of relatively stable, 'bulk' metallic glasses. The present work gives a new approach towards achieving the long-sought goal of a predictive capability for bulk metallic glasses.


Hückel- and Baird-Type Global Aromaticity in a 3D Fully Conjugated Molecular Cage.
Global aromaticity in 3D π-conjugated molecular cages remains largely unexplored. Herein, we report the facile synthesis of a fully conjugated molecular cage (1) containing two bridged triphenylamine units and three quinoidal bithiophene arms. X-ray crystallographic analysis, NMR/ESR measurements and theoretical calculations reveal that: 1) its dication (12+ ) has an open-shell singlet ground state and is 3D globally aromatic, with individual macrocycles being 2D Hückel aromatic; 2) its tetracation (14+ ) has a triplet ground state and is also 3D globally aromatic, with individual macrocycles being 2D Baird aromatic; and 3) its hexacation (16+ ) has a closed-shell nature and shows local aromaticity. The study demonstrated a close relationship between 2D Hückel/Baird aromaticity and 3D global π-aromaticity.


Complete neuroendoscopic versus microscopical trigeminal neuralgia microvascular decompression (MVD) in primary trigeminal neuralgia (PTN).
To compare complete neuroendoscopic and microscopic microvascular decompression (MVD) in primary trigeminal neuralgia (PTN) and their impacts on the microstructure of the trigeminal nerve. Eighty-seven PTN patients admitted in our hospital from July 2017 to December 2019 were selected for this prospective study and divided into the endoscopic group (n=45) (complete neuroendoscopic MVD) and the microscope group (n=42) (microscopic MVD) according to the treatment method each patient underwent. All the patients underwent MRI scanning, and the fractional anisotropy (FA) scores and the apparent diffusion coefficient (ADC) values of the neurovascular compression (NVC) sites were measured. The operation times, the treatment efficacy, the microstructural changes in the trigeminal nerve, the complications, and the recurrence and mortality rates at one year after the operations were compared. The endoscopic group observed a superior therapeutic effect compared with the microscope group one year after the surgeries (P=0.046). After the surgeries, the endoscopic group observed a greater increase in their FA values and a larger decline in their ADC values than the microscope group did (P=0.014, 0.015, 0.011, 0.002). The complication rate in the endoscopic group was 11.11%, and the complication rate in the microscopic group was 30.95% (P=0.022). One year after the surgeries, we found a lower recurrence rate in the endoscopic group (P=0.001). The perforator vessels from the offending vessel to the outlet area of the durmedulla, the distances between the front edge of the bone window and the inner surfaces of the petrous part of the temporal bone ≥ the distance between the duration ≥ the duration of conventional MVD were independent risk factors for complications after MVD in the hemifacial spasm patients (P=0.001, 0.037, 0.023, 0.005). Complete neuroendoscopic MV yields better long-term treatment outcomes than microscopic MVD, and it is more effective at improving the microstructure of the trigeminal nerve and has fewer postoperative complications.


Diagnosing the culprit behind a subtle case of concomitant right atrial myxoma and atrial fibrillation: A case report.
Myxomas are rare tumors arising from the uncontrolled proliferation of mesenchymal cells. Among cardiac conditions, cardiac myxomas account for less than 0.1% of cases, with the majority found in the left atrium and only 8% in the right atrium. Atrial myxomas present with various clinical manifestations, including constitutional symptoms, symptoms caused by blood flow obstruction, and tumor embolism. This case report describes a 50-year-old male patient presenting with syncope, fatigue, and dyspnea, who had a history of well-controlled hypertension and atrial fibrillation. Physical examination, further diagnostic workup, and echocardiography led to a provisional diagnosis of right atrial myxoma. The patient underwent a median sternotomy, and the tumor was surgically excised, resulting in both diagnostic and curative outcomes. Histological analysis confirmed the diagnosis of myxoma. This case report contributes valuable insights into the presentation, diagnostic challenges, and treatment of atrial myxoma.


Exploration of ligand binding modes towards the identification of compounds targeting HuR: a combined STD-NMR and Molecular Modelling approach.
Post-transcriptional processes have been recognised as pivotal in the control of gene expression, and impairments in RNA processing are reported in several pathologies (i.e., cancer and neurodegeneration). Focusing on RNA-binding proteins (RBPs), the involvement of Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs in the aetiology of various dysfunctions, has suggested the great potential of compounds able to interfere with the complex stability as an innovative pharmacological strategy for the treatment of numerous diseases. Here, we present a rational follow-up investigation of the interaction between ELAV isoform HuR and structurally-related compounds (i.e., flavonoids and coumarins), naturally decorated with different functional groups, by means of STD-NMR and Molecular Modelling. Our results represent the foundation for the development of potent and selective ligands able to interfere with ELAV-RNA complexes.


Treatment of female stress urinary incontinence using suburethral slings: comparative, retrospective, observational study of two surgical techniques.
The treatment of female stress urinary incontinence has undergone a revolution in recent years due the emergence on the market of suburethral slings. The aim of this study is to compare two surgical techniques for treating stress urinary incontinence: Monarc™ (transobturator suburethral sling) and MiniArc(®) (single-incision suburethral mini-sling). Comparative, retrospective, observational study from January 2005 to December 2011 on 317 women diagnosed with stress urinary incontinence. Of these, 214 were treated with the Monarc™ transobturator suburethral sling, and 103 were treated with the MiniArc(®) mini-sling. The results were treated with SPSS v.15 software, and the statistical significance was P≤.005. The two patients groups were homogeneous in terms of age, number of births, presence of urgency urinary incontinence and prior hysterectomy. There were significant differences in hospital stay, surgical time and early complications in favour of the MiniArc(®), technique, but overall there were no significant differences in the late complications. Some 84% of the patients treated with the Monarc™ transobturator sling were cured compared with the 72% of patients in whom we implanted a MiniArc(®), a difference that was statistically significant. We need to perform more high-quality, prospective and randomised studies with larger numbers of patients and longer follow-up times to confirm or disprove the difference that we found in the success rate for the Monarc™ transobturator suburethral sling.


Ameloblastin expression and putative autoregulation in mesenchymal cells suggest a role in early bone formation and repair.
Ameloblastin is mainly known as a dental enamel protein, synthesized and secreted into developing enamel matrix by the enamel-forming ameloblasts. The function of ameloblastin in tooth development remains unclear, but it has been suggested to be involved in processes varying from regulating crystal growth to activity as a growth factor or partaking in cell signaling. Recent studies suggest that some enamel matrix proteins also might have important functions outside enamel formation. In this context ameloblastin has recently been reported to induce dentin and bone repair, as well as being present in the early bone and cartilage extracellular matrices during embryogenesis. However, what cells express ameloblastin in these tissues still remains unclear. Thus, the expression of ameloblastin was examined in cultured primary mesenchymal cells and in vivo during healing of bone defects in a "proof of concept" animal study. Real time RT-PCR analysis revealed human ameloblastin (AMBN) mRNA expression in human mesenchymal stem cells and primary osteoblasts and chondrocytes. Expression of AMBN mRNA was also confirmed in human CD34 positive cells and osteoclasts. Western and dot blot analysis of cell lysates and medium confirmed the expression and secretion of ameloblastin from mesenchymal stem cells, primary human osteoblasts and chondrocytes. Expression of ameloblastin was also detected in newly formed bone in experimental bone defects in adult rats. Together these findings suggest a role for this protein in early bone formation and repair.


Hemodynamic effects of alpha1-adrenoceptor antagonist, doxazosin, in patients with chronic congestive heart failure.
Non-selective alpha-adrenoceptor antagonists have not demonstrated significant beneficial effects in chronic heart failure. Previous studies with the selective alpha1-adrenoceptor antagonist, doxazosin, led to conflicting results. We assessed the hypothesis that treatment with doxazosin adjuvant to standard oral therapy results in significant increase in cardiac index in patients with chronic heart failure. A double-blind, randomized study was conducted on 30 patients with chronic congestive heart failure (NYHA III-IV), with cardiac index<2.5 l/minxm, and/or with pulmonary capillary wedge pressure>16 mm Hg. Of the 30 patients, 15 were treated with doxazosin and 15 with placebo, both adjuvant to stable oral therapy, which included a minimum of an ACE inhibitor and a diuretic. Hemodynamic measurements were performed on days 1 and 2, and after 12 weeks on study medication. On day 1, patients were treated with 4 mg doxazosin or placebo. On day 2 and throughout the following 12 weeks, the patients were treated with 4 mg or 8 mg doxazosin/d (the latter, if 4 mg/d did not induce an increase >0.75 l/minxm in cardiac index), or with placebo. Six patients were treated with 4 mg doxazosin/d (group A), 9 patients with 8 mg doxazosin/d (group B), and 15 with placebo. Baseline values for the cardiac index on day 1, day 2, and after 12 weeks failed to disclose significant differences between patient groups and between the days of study. On day 1, the increase in cardiac index compared with baseline was significantly higher in group A than in the placebo group (P=0.004) and group B (P=0.001). On day 2, the increase in cardiac index compared with baseline on day 1 was significantly higher in group A than in group B (P=0.003) (with reference to alpha/3=0.0167 according to Bonferroni). This was no longer observed after 12 weeks. In the placebo group, following significant changes occurred in baseline values, heart rate was lower (P=0.023) and stroke volume index was higher after 12 weeks in comparison to day 1 (P=0.032). In conclusion, oral application of doxazosin supplementary to standard oral medication did not induce sustained hemodynamic benefit. Significant acute increase in cardiac index was observed in a minority (40%) of patients, whereas favorable changes in baseline hemodynamic parameters after 12 weeks occurred in the placebo group.


Is severe obesity a cardiovascular health concern in the Inuit population?
Obesity is rising globally and severe obesity (SO) [body mass index (BMI) = 40 kg/m(2) or = 35 kg/m(2) with co-morbidity] is growing at a much faster rate. Amongst the Inuit, evolution of SO remains unknown. We investigated whether the level of SO changed and whether the cardio-metabolic profile improved or deteriorated in Nunavik Inuit between 1992 and 2004. SO subjects were selected from two comparable population-based studies. These studies were undertaken in Nunavik (Quebec, Canada), and were performed in two different time frames, separated by 12 years. Physiological (lipid profile, fasting insulin, fasting glucose, and blood pressure) as well as anthropometric data (BMI, waist circumference, and waist to hip ratio) were collected in both studies. There was approximately a fourfold increase in the prevalence of SO in comparable age groups. This increase affected both genders between 1992 and 2004. Smoking rates in SO populations have significantly decreased during this period, from 85% to 41% (P < 0.0001). Overall, there were no statistically significant differences in the cardio-metabolic profile (insulin, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, systolic and diastolic blood pressures, BMI, and waist to hip ratio). There was, however, a significant increase in waist circumference (P < 0.001), especially in women (P < 0.01). Type 2 diabetes remained stable, at around 40% in this population. Although the prevalence of SO increased, the cardio-metabolic profile remained stable. Nevertheless, regular monitoring of chronic disease in this population remains crucial.


Establishment of an ELISA system for the determination of Japanese monkey calreticulin and its application to plasma samples in macaques.
Calreticulin (Crt) is a molecular chaperone in endoplasmic reticulum, assisting a correct folding of glycoproteins. Establishment of its assay method might be advantageous to determine the Crt level in cell or other biosystems. An enzyme-linked immunosorbent assay (ELISA) system for the determination of Crt of Japanese monkey, Macaca fuscata, was developed in this study. Japanese monkey Crt protein expressed in Escherichia coli was used as a standard protein. The assay was sensitive even to <10 ng/ml of Crt. Since the amino acid sequence of Crt is quite similar (99%, similarity) between the Japanese and rhesus monkeys, the ELISA was applied to the determination of plasma Crt in these two species in association with various diseases. The Crt level increased significantly in monkeys suffering from pneumonia and diarrhea, suggesting that the ELISA might be applicable for preliminary diagnosis of inflammatory disease.


Magnetic susceptibility measurements of deoxygenated hemoglobins and isolated chains.
Static magnetic susceptibility measurements have been performed in a wide temperature range (4.5-300 degrees K) on ligquid/frozen solutions of deoxygenated human hemoglobin and its isolated chains. The effects of buffer, pH, dielectric constant and phosphate have been investigated. Measurements have been done also on human fetal chains, on des-Arg and SucNEt-des-Arg hemoglobins. In all the proteins under study of the Fe2+ is the high spin state (S=2). At room temperature the magnetic moments lie in range 4.90 (theoretical spin-only value) to 5.45 Bohr magnetons. Local differences between the iron sites are revealed by the low temperature measurements. A mechanism is proposed to explain the effect of phosphate binding on the magnetic susceptibility.


Implementing a genomic data management system using iRODS in the Wellcome Trust Sanger Institute.
Increasingly large amounts of DNA sequencing data are being generated within the Wellcome Trust Sanger Institute (WTSI). The traditional file system struggles to handle these increasing amounts of sequence data. A good data management system therefore needs to be implemented and integrated into the current WTSI infrastructure. Such a system enables good management of the IT infrastructure of the sequencing pipeline and allows biologists to track their data. We have chosen a data grid system, iRODS (Rule-Oriented Data management systems), to act as the data management system for the WTSI. iRODS provides a rule-based system management approach which makes data replication much easier and provides extra data protection. Unlike the metadata provided by traditional file systems, the metadata system of iRODS is comprehensive and allows users to customize their own application level metadata. Users and IT experts in the WTSI can then query the metadata to find and track data.The aim of this paper is to describe how we designed and used (from both system and user viewpoints) iRODS as a data management system. Details are given about the problems faced and the solutions found when iRODS was implemented. A simple use case describing how users within the WTSI use iRODS is also introduced. iRODS has been implemented and works as the production system for the sequencing pipeline of the WTSI. Both biologists and IT experts can now track and manage data, which could not previously be achieved. This novel approach allows biologists to define their own metadata and query the genomic data using those metadata.


A three generations nation-wide population study of family load estimates in bipolar disorder with different age at onset.
This nation-wide register-based study investigates how often bipolar disorder (BD) occurs in affected families compared to control families by estimating the family load as a random effect; this effect measures the degree of dependence among family members in relation to BD. Furthermore, the study addresses the impact of certain risk factors, namely, sex, age at onset of BD, degree of urbanization, year of birth, month of birth, and maternal and paternal age at birth. A total of N=1204 children and adolescent psychiatric cases born between 1950 and 1997 and registered in the Danish Central Psychiatric Register (DPCR) developed BD before the age of 58 years. N=3553 controls without any psychiatric diagnosis were matched for age, gender, and region of residence. Psychiatric diagnoses were also obtained on the relatives, e.g. parents, siblings, and offspring as a part of the Danish Three Generation Study (3GS). A family component was obtained by using different regression models. Familial factors accounted for 20% of the variation in disease outcome when controlling for year and month of birth, sex, and degree of urbanization. Only female sex was associated with an increased hazard ratio of BD. Also having a mother, father or a sibling with the disorder was proven to be a significant risk factor. Furthermore, case relatives did not develop BD earlier than control relatives. These findings based on a very large and representative dataset provide further and very solid evidence for the high family aggregation of BD.


Use of mixed anhydrides for the determination of terfenadine in dosage forms and spiked human plasma.
Terfenadine reacts with mixed anhydrides (malonic and acetic anhydrides) producing a yellow-coloured product with intense fluorescence. Based on this fact, a spectrophotometric method was developed for the determination of terfenadine in dosage forms. The relation between the absorbance at 395 nm and the concentration is rectilinear over the range 0.5-5 microg ml(-1) (molar absorptivity is 1.405 x 10(5) l mol(-1) cm (-1)). The reaction product was also measured spectrofluorimetrically at 435 nm after excitation at 395 nm. The fluorescence intensity was directly proportional to the concentration over the range 0.5-4 ng ml(-1) with minimum detectability (S/N = 2) of 0.07 microg ml(-1) (approximately 1.5 x 10(-10) M). The different parameters affecting the development and stability of the reaction product were carefully studied and incorporated into the procedure. The proposed spectrophotometric method was successfully applied to the determination of terfenadine in tablets and suspensions; the percentage recoveries were 99.83 +/- 0.75 and 99.65 +/- 0.83, respectively. The proposed spectrofluorimetric method was applied to the determination of terfenadine in spiked human plasma. The percentage recovery was 99.35 +/- 2.19. The method is highly sensitive and specific. No interference was noticed from co-formulated drugs, such as pseudoephedrine and ibuprofen.


Evaluation of the changes of immune cells during lipopolysaccharide-induced mastitis in rats.
The aim of this study was to evaluate in rats, changes in peripheral blood immune cells and mammary tissue after an intramammary infusion of lipopolysaccharide (LPS). The results of the study showed that infusion of LPS induced a rapid migration of neutrophils (PMNs) from the blood to mammary alveoli, increased the activity of myeloperoxidase (MPO) and the concentration of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in mammary tissues, decreased the activity of myeloperoxidase in serum and reduced the CD4+/CD8+ ratio. This is the first report of changes in peripheral blood immune cells and mammary tissue in rat mastitis.


Pyrrhic victory? Long-term results of biliopancreatic diversion on patients with type 2 diabetes and severe obesity.
The long-term results after biliopancreatic diversion (BPD) in patients with type 2 diabetes (T2D) and severe obesity is still being debated. Retrospective evaluation of the long-term metabolic and clinical conditions of patients with T2D following BPD. University hospital. A total of 173 patients with T2D and severe obesity were investigated prior to and at 3-5 and 10-20 years after BPD. Anthropometric, biochemical, and clinical findings preoperatively and throughout follow-up were considered. The long-term data were compared with those of a cohort of 173 T2D patients with obesity treated with conventional therapy. T2D resolved within the first postoperative phases in most patients, and in the long and very long term, the fasting blood glucose level remained above the normal range in only 8% of patients. Likewise, a stable improvement of blood lipid pattern was observed (follow-up rate 63%). In contrast, in nonsurgical patients in the long term, the glucose and lipid metabolic parameters remained in the pathologic range in all cases. In the BPD group, a very high number of severe BPD-related complications was recorded, and 27% of the BPD patients died, whereas in the control group, 87% of patients were still alive at the end of the follow-up period (P < .02). Despite the high T2D stable resolution rate and the normalization of most metabolic data at 10-20 years following surgery, these results indicate that BPD should be indicated with caution in the surgical treatment of T2D in patients with severe obesity.


Trans-4-methyl-3-imidazoyl pyrrolidine as a potent, highly selective histamine H3 receptor agonist in vivo.
Extensive structural modification of immepyr (+)-2 led to the discovery of trans-4-methyl-3-imidazoyl pyrrolidine (+/-)-3a as a potent and highly selective H3 agonist. The pyrroline (+/-)-3a was resolved, and its (+) enantiomer, Sch 50971 [(+)-3a], showed a greater separation of H3 and H1 activities in vivo (H3/H1 ratio >> 330) than (R)-alpha-methylhistamine (+)-1 (H3/H1 ratio = 17), the standard H3 agonist.


Factors affecting COVID-19 vaccine hesitancy in parents of children with cancer.
Little research exists on coronavirus (COVID-19) vaccine hesitancy among caregivers of children with cancer. We aimed to (a) describe vaccine hesitancy in parents of children with cancer for both their child and self, and (b) examine the mediating role of parent-reported COVID impact on the association between COVID exposure and vaccine hesitancy. We conducted a national survey of parents of children with cancer via Facebook and Momcology, a pediatric cancer community-based organization recruited February-May 2021. Parents completed standardized measures online. A series of mediation models assessed the role of COVID-19 impact (e.g., effects on parenting and well-being) on associations between COVID-19 exposure (e.g., direct/indirect exposure) and vaccine hesitancy. Moderation models examined the role of treatment status, COVID-19 exposure, impact, and vaccine hesitancy. Parents (n = 491; 90% mothers; 93% White) reported moderate vaccine hesitancy (M = 2.08, SD = 0.76). Specifically, 18.5% (n = 90) reported they would not vaccinate their child, and 24.4% (n = 119) would only consider vaccination. Parents expressed higher concerns about vaccine side effects for their children (M = 3.01, SD = 0.95) than for themselves (M = 2.61, SD = 1.03; t[479] = 9.07, p < .01). Mediation analysis revealed a significant indirect effect of impact (95% CI [-0.013, -0.001]) on the association between higher exposure and higher vaccine hesitancy (b = .02, p = .06). There was no moderating effect of treatment status. Income remained a significant covariate (b = -.11, p < .01). Lower parent-reported COVID exposure, higher COVID impact, concern for side effects, and lower income may be important factors related to vaccine hesitancy among parents of children with cancer. Providers of childhood cancer survivors should address vaccine hesitancy and potential health risks.


Ligand Binding-Induced Structural Changes in the M2 Muscarinic Acetylcholine Receptor Revealed by Vibrational Spectroscopy.
M2 muscarinic acetylcholine receptor (M2R) is a prototypical G protein-coupled receptor (GPCR) that responds to acetylcholine and mediates various cellular responses in the nervous system. Here, we used attenuated total reflection-Fourier transform infrared spectroscopy analyses on M2R reconstituted in a lipid membrane to understand the molecular mechanism behind the ligand binding-induced conformational changes. Upon agonist binding, M2R shows large spectral change of the amide-I band corresponding to backbone C═O stretch, which likely connects with the receptor activation in the lipid environment. These results pave the way to probe effects of different ligand binding on GPCRs using vibrational spectroscopy.