Random amphiphilic copolymeric sub-micro particles as a carrier shielding from enzymatic attack for peptides and proteins delivery.
The development of peptide drugs and therapeutic proteins is limited by their rapid clearance in liver and other body tissues by proteolytic enzymes, and consequently peptides and proteins are difficult to administer except by injection. There is a growing effort to circumvent these problems by designing strategies to deliver these drugs to specific site of the body. Among them, this peptide carrier presents several advantages for protein therapy including stability in physiological buffer and lack of toxicity. Here, we have been developing a novel bioadhesive polymer matrix that protects entrapped proteins and peptides from degradation by serine protease. Poly(2-lactobionamidoethyl methacrylate-ran-3-acrylamidophenylboronic acid-ran-methoxypolyethylene glycol methacrylate) glycopolymers were synthesized and could self-assemble into the sub-micro particles. The loading capability of insulin, as a drug model, and the insulin release from the particles were assessed. The inhibitory effect of the particles toward trypsin, elastase, and chymotrypsin was evaluated in vitro. Insulin was effectively encapsulated, up to 10%, and could be stained release in vitro. These glycopolymers displayed a strong inhibitory effect toward these exopeptidases. Therefore, novel glycopolymers with excellent inhibitory activity against proteolytic enzymes and reasonable mucoadhesivity might be a useful tool in overcoming the enzymatic barrier to the mucosal delivery (e.g. nasal and buccal) of therapeutic peptides or proteins.


Activities of intestinal enzymes in experimental chronic renal insufficiency.
Rats with chronic uremia following five-sixths nephrectomy showed a significant fall in the sucrase and maltase activities in the small intestinal mucosa, the lactase and cellobiase activities in contrast remained uninfluenced. The activity of the L-leucyl-L-proline and L-methionyl-L-proline dipeptidases in the small intestinal mucosa was significantly increased, while the activities of seven other dipeptidases studied were unaffected. The mucosal protein and DNA content likewise remained unchanged. Occasional slight alterations of the mucosa were the only finding at histology.


Surface-Induced Dissociation of Homotetramers with D2 Symmetry Yields their Assembly Pathways and Characterizes the Effect of Ligand Binding.
Understanding of protein complex assembly and the effect of ligand binding on their native topologies is integral to discerning how alterations in their architecture can affect function. Probing the disassembly pathway may offer insight into the mechanisms through which various subunits self-assemble into complexes. Here, a gas-phase dissociation method, surface-induced dissociation (SID) coupled with ion mobility (IM), was utilized to determine whether disassembly pathways are consistent with the assembly of three homotetramers and to probe the effects of ligand binding on conformational flexibility and tetramer stability. The results indicate that the smaller interface in the complex is initially cleaved upon dissociation, conserving the larger interface, and suggest that assembly of a D2 homotetramer from its constituent monomers occurs via a C2 dimer intermediate. In addition, we demonstrate that ligand-mediated changes in tetramer SID dissociation behavior are dependent on where and how the ligand binds.


Trophic sympathetic influence weakens pro-contractile role of Cl- channels in rat arteries during postnatal maturation.
Membrane transporters and their functional contribution in vasculature change during early postnatal development. Here we tested the hypothesis that the contribution of Cl- channels to arterial contraction declines during early postnatal development and this decline is associated with the trophic sympathetic influence. Endothelium-denuded saphenous arteries from 1- to 2-week-old and 2- to 3-month-old male rats were used. Arterial contraction was assessed in the isometric myograph, in some experiments combined with measurements of membrane potential. mRNA and protein levels were determined by qPCR and Western blot. Sympathectomy was performed by treatment with guanethidine from the first postnatal day until 8-9-week age. Cl- substitution in the solution as well as Cl--channel blockers (MONNA, DIDS) had larger suppressive effect on the methoxamine-induced arterial contraction and methoxamine-induced depolarization of smooth muscle cells in 1- to 2-week-old compared to 2- to 3-month-old rats. Vasculature of younger group demonstrated elevated expression levels of TMEM16A and bestrophin 3. Chronic sympathectomy increased Cl- contribution to arterial contraction in 2-month-old rats that was associated with an increased TMEM16A expression level. Our study demonstrates that contribution of Cl- channels to agonist-induced arterial contraction and depolarization decreases during postnatal development. This postnatal decline is associated with sympathetic nerves development.


The Big Five personality traits and regularity of lifetime dental visit attendance: evidence of the Survey of Health, Ageing, and Retirement in Europe (SHARE).
Regular dental visits are essential for the prevention, early detection and treatment of worldwide highly prevalent oral diseases. Personality traits were previously associated with treatment compliance, medication adherence and regular doctor visits, however, the link between personality traits and regular dental visit attendance remains largely unexplored. Thus, the objective of this study is to clarify this link. Data (wave 7) of the Survey of Health, Ageing and Retirement in Europe (SHARE) were used, focusing on Germany (n = 2822). Personality was assessed using the 10-item Big Five Inventory (BFI-10). Regular dental visits were assessed. Multiple logistic regressions were used, adjusting for various covariates. Majority of the participants (84%) reported to attend regular dental visits during lifetime. Regularity of lifetime dental visit attendance was positively and significantly associated with increased extraversion [OR 1.13, 95% CI (1.01-1.26)], increased conscientiousness [OR 1.26, 95% CI (1.10-1.44)], and increased openness to experience [OR 1.12, 95% CI (1.01-1.26)]. However, there was a lack of association with agreeableness and neuroticism. Moreover, the outcome measure was positively associated with younger age, being female, born in Germany, being married, higher education, being retired (compared to being homemaker), whereas it was not associated with obesity or chronic diseases. Identification of personality traits that are associated with regular dental visits can support prevention, screening and clinical management of oral diseases. Further research in this field may facilitate the development and increase the incorporation of individualized concepts to enhance patient compliance and attendance, and thus the provision of oral and dental care services.


Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group.
The antitumour activity of docetaxel was investigated in patients with advanced malignant melanoma. Docetaxel, 100 mg/m2, intravenous, over 60 min, was administered every 3 weeks. Response evaluation was performed after two cycles. No prophylactic treatment with steroids or antihistamines was given. 38 patients were included, 36 were eligible and evaluable for toxicity and 30 patients were evaluable for response. The main haematological toxicity was neutropenia [17 patients with common toxicity criteria (CTC) grade 4 and 11 CTC grade 3] with nadir after 5-8 days and rapid recovery. The most frequent non-haematological toxicity was generalised alopecia (83% of the patients). Asthenia, malaise and fatigue were also seen in 58%. Skin toxicity was also frequent. Hypersensitivity reactions (erythematous rash, urticaria, blood pressure changes and tachycardia), seen in 42% of the patients, were mild to moderate. Oedema was registered in one fifth of the patients and developed after four or more treatment cycles. The overall response rate in the evaluable patients was 17% (five partial responders). We conclude that docetaxel has activity in advanced malignant melanoma.


Preisolation measures and clinical features for pediatric patients with suspicious COVID-19.
In December 2019, many cases of COVID-19 were reported in Wuhan City, Hubei Province, China. In the following 3 months, the disease out broke in China. Preisolation measures was used to screen out COVID-19 patients in the pediatric respiratory ward of our hospital. To investigate the new measures for screening COVID-19 patients and to analyze the clinical features of children with suspicious COVID-19. A total of 50 preisolated children with suspicious COVID-19 who were admitted to our hospital in Mianyang, China, between January 28 and March 5, 2020, were included. Patients presented with fever and cough or fever accompanied by vomiting and diarrhea. A detailed epidemiological history screening was performed. A real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) was used to detect SARS-COV-2 nucleic acid. Low-dose chest computed tomography (CT) was applied when pneumonia was suspicious. Routine blood tests were performed to rule out COVID-19. Patients' data were collected, and the basic clinical features, epidemiological history, clinical manifestations, auxiliary examination results, and outcomes were analyzed and summarized. No definite cases were detected, while two patients were suspected of having COVID-19. The pathogenic results of the 50 patients mainly included Mycoplasma pneumoniae, followed by Epstein-Barr virus, and rotavirus. Thirty-five patients suffered from bronchopneumonia. The preisolated patients had similar clinical and epidemiological characteristics as patients with fever, cough, vomiting, and diarrhea. Preisolation measures combined with pathogen screening can minimize the risk of hospital-acquired infections by preventing patients with suspicious COVID-19 from contacting other patients before they are explicitly excluded. Clinical analysis of the patients was helpful for clinical nursing management.


Developing Charcot-Marie-Tooth Disease Recognition System Using Bacterial Foraging Optimization Algorithm Based Spiking Neural Network.
In the developing technology Charcot-Marie-Tooth (CMT) disease is one of the teeth diseases which are occurred due to the genetic reason. The CMT disease affects the muscle tissue which reduces the progressive growth of the muscle. So, the CMT disease needs to be recognized carefully for eliminating the risk factors in the early stage. At the time of this process, the system handles the difficulties while performing feature extraction and classification part. So, the teeth images are processed by applying the normalization method which eliminates the salt and pepper noise from data. From that, modified group delay function along with Cepstral coefficient features are extracted with effective manner. After that Bacterial Foraging Optimization Algorithm based features are selected. Then the selected features are examined by applying the Bacterial Foraging Optimization Algorithm based spiking neural network which successfully recognizes the CMT disease. At that point the productivity of the framework is assessed with the assistance of exploratory outcomes.


[Comparative study of primordial germ cells in male and female mouse embryos].
To investigate the differences in the development of primordial germ cells (PGCs) between male and female mouse embryos. The morphological changes of genital ridge development were detected in C57BL/6J mouse embryos of 11-13.5 days, and the changes of PGCs quantity and proliferation were compared between the male and female embryos using immunofluorescence histochemistry. The PGCs was the most numerous at 13.5 days in male and female embryos, and the quantity of proliferating PGCs reached the maximum at 13 days. The quantity of PGCs and proliferating PGCs in male embryos at 13 days was significantly larger than that in female embryos. The development of PGCs is characterized by a gender differences in early development of mouse embryos (11-13.5 days).


Measurements in microscopic images: an inexpensive device for semi-automatic analysis of microscopic images.
Measurement of histological and cytological parameters can be performed much faster and more accurate by means of a semi-automatic device that is described in detail. The system consists mainly of a medium-sized computer and one or more peripheral terminals. Each terminal incorporates a special measurement table for data acquisition, a keyboard for manual data input, and an interface. The software program for the evaluation and storage of the digital data is simple to write and offers a high degree of flexibility to the user. The system can be operated in real time.


Cutaneous chromoblastomycosis mimicking melanoma in a renal transplant recipient.
Chromoblastomycosis is a primary implantation mycosis caused by melanized fungi. It affects mainly populations from remote and rural areas, and may cause significant morbidity and mortality. A 69-year-old kidney transplant recipient woman presented with a dark nodule on the first left toe and a satellite lesion. Dermoscopic exam showed multiple clustered black dots, blackened homogenous area and chrysalides, which led to the diagnostic hypothesis of melanoma. Histopathological examination was compatible with chromoblastomycosis.


The mechanism by which aminoglycoside antibiotics cause vasodilation of canine cerebral arteries.
The effects of aminoglycoside antibiotics were examined in canine cerebral arteries and in cultured cerebrovascular smooth muscle cells stimulated with oxyhemoglobin (OxyHb), a blood constituent which has been implicated in the pathogenesis of cerebrovascular spasm. In cerebral arterial rings precontracted with OxyHb (10 microM), the aminoglycosides caused a concentration-dependent decrease in isometric tension. The EC50s for the relaxation were 0.46+/-0.1 mM (n=6), 0.53+/-0.08 mM (n=12), 1.6+/-0.3 mM (n=7) and 3.9+/-0.5 mM (n=5) for neomycin, gentamicin, streptomycin and kanamycin, respectively. This order of potency corresponds approximately to the number of positive charges in the molecules. The aminoglycosides also inhibited the contractions to prostaglandin F2alpha (1 microM) and depolarizing concentrations of potassium chloride (60 mM). The order of potency was neomycin > gentamicin > streptomycin > kanamycin. The relaxation was maintained in vascular preparations denuded of endothelium. Neomycin (5 mM) abolished the Ca2+-independent contraction to PGF2alpha. In Fura-2-loaded cerebrovascular smooth muscle cells, OxyHb (1 microM) significantly enhanced the concentration of intracellular calcium ([Ca2+]i) by 330%. The administration of neomycin, gentamicin, kanamycin and streptomycin in concentrations corresponding to the EC50 from contractility studies, reduced the effects of OxyHb on [Ca2+]i by about 50% to 221+/-35 nM (n=7), 270+/-31 nM (n=7), 229+/-33 nM (n = 6) and 240+/-6 nM (n = 5), respectively. These results suggests that the effects of the aminoglycosides on the OxyHb-induced contraction and the long-term increase in [Ca2+]i, may arise from several effects, including inhibition of PLC, protection of calcium extrusion mechanisms, and interference with the process of [Ca2+]i accumulation.


Metagenomic surveillance uncovers diverse and novel viral taxa in febrile patients from Nigeria.
Effective infectious disease surveillance in high-risk regions is critical for clinical care and pandemic preemption; however, few clinical diagnostics are available for the wide range of potential human pathogens. Here, we conduct unbiased metagenomic sequencing of 593 samples from febrile Nigerian patients collected in three settings: i) population-level surveillance of individuals presenting with symptoms consistent with Lassa Fever (LF); ii) real-time investigations of outbreaks with suspected infectious etiologies; and iii) undiagnosed clinically challenging cases. We identify 13 distinct viruses, including the second and third documented cases of human blood-associated dicistrovirus, and a highly divergent, unclassified dicistrovirus that we name human blood-associated dicistrovirus 2. We show that pegivirus C is a common co-infection in individuals with LF and is associated with lower Lassa viral loads and favorable outcomes. We help uncover the causes of three outbreaks as yellow fever virus, monkeypox virus, and a noninfectious cause, the latter ultimately determined to be pesticide poisoning. We demonstrate that a local, Nigerian-driven metagenomics response to complex public health scenarios generates accurate, real-time differential diagnoses, yielding insights that inform policy.


Preparation of ball-milled phosphorus-loaded biochar and its highly effective remediation for Cd- and Pb-contaminated alkaline soil.
Pyrolytic biochar is a good material for remediating soils contaminated with heavy metals; however, it exhibits strong alkalinity, which easily causes soil alkalization and fertility reduction. Herein, a series of novel biochar materials (BPBCs) were prepared by combined ball milling and phosphorus (P)-loading. The optimized BPBC were fabricated in the basis of Cd and Pb adsorption capacities of the biochar, with pyrolysis at 700 °C, ball milling for 12 h and the addition of 5% red P (BPBC700). Ball milling could effectively grind pristine biochar into submicron particles and nanoscale P particles could be uniformly loaded on BPBC700. Moreover, the oxidative conversion of red P into phosphorus oxides, phosphoric acid and (hydro)phosphates was promoted due to reactions with the carbonates, alkaline minerals and O-containing functional groups of biochar. These reactions also decreased the biochar and soil pH to nearly neutral by acid-base neutralization. Pot experiments showed that BPBC700 had better effects than the pristine or ball-milled biochar in improving soil properties (e.g., cation exchange capacity and organic carbon), increasing the concentrations of soil nutrients (e.g., N and P), promoting alkaline phosphatase, catalase and urease activities, decreasing soil mobility and plant accumulation of Cd and Pb, and alleviating Cd and Pb stress on maize plants. Thus, BPBC is a promising and ecofriendly amendment to enhance its adsorption ability on Cd and Pb, soil quality and plant productivity in contaminated soil.


Cryopreservation of embryos and ova.
Development of techniques for cryopreservation of embryos of several species, principally the mouse, laid the foundation for cryopreservation of human embryos. As IVF has become more widely available and the need for the cryopreservation of human embryos has become apparent, pressure for technical development has increased. The ideal method would be simple, inexpensive, and effective. The most effective method for cryopreservation of early human embryos, such as those at the 1-cell pronuclear stage and up to the 4-cell stage, now appears to be stepwise cooling in 1,2-propanediol with sucrose in plastic ministraws. The preferred method for intermediate stage embryos uses DMSO with cooling and thawing at slow rates in a programmed biologic freezer. For the human blastocyst, slow cooling in glycerol and rapid thawing is the only method reported with survival rates comparable to those achieved for intermediate stage embryos using DMSO. The rates of survival from freezing and thawing blastocysts are not sufficiently high, however, to justify the losses associated with prolonged in vitro incubation. Even at the current level of technical achievement, cryopreservation of human embryos provides the clearest opportunity to improve the clinical results obtained with IVF. Research now underway in the modification of methods for vitrification and ultrarapid freezing holds promise for both simplification of technology and improvement of outcome. In view of legal and ethical considerations involved in embryo preservation, the desirability of ova preservation is widely accepted. Although a small number of human unfertilized mature ova have been cryopreserved using various methods, success rates are still low. Methods for the cryopreservation of eggs should be developed, but these methods probably should be proved by animal experiments to be safe, especially with regard to genetic damage, before a policy of transfer of embryos derived from frozen-thawed human ova is applied on a large scale.


Variant rs9939609 in the FTO gene is associated with body mass index among Chinese children.
Fat-mass and obesity-associated (FTO) gene is a gene located in chromosome region 16q12.2. Genetic variants in FTO are associated with the obesity phenotype in European and Hispanic populations. However, this association still remains controversial in Asian population. We aimed to test the association of FTO genetic variants with obesity and obesity-related metabolic traits among children living in Beijing, China. We genotyped FTO variants rs9939609 in 670 children (332 girls and 338 boys) aged 8-11 years living in Beijing, and analyzed its association with obesity and obesity-related metabolic traits. Overweight and obesity were defined by age- and sex-specific BMI reference for Chinese children. Obesity-related metabolic traits included fasting plasma glucose, lipid profiles, leptin, ghrelin, adiponectin and blood pressures. The frequency of rs9939609 A allele was 12.2%, which was 21.9% for the heterozygote and 1.2% for the homozygote of the A allele. The obesity prevalence among the carriers of AA/AT genotypes was significantly higher than that among those with TT genotype (36.4% vs. 22.6%, P=0.004). Compared to the carrier of TT genotype, the likelihood of obesity was 1.79 (95% confidence interval (95% CI) 1.20-2.67, P=0.004) for the carrier of AA/AT genotype, after adjustment of sex, age and puberty stages. The BMI Z-score of children with AA/AT genotype were significantly higher than that of their counterparts with the TT genotype (1.1±0.1 vs. 0.8±0.1, P=0.02). The concentration of triglyceride was 1.03±0.52 mmol/L among TT carrier and 1.13±0.68 mmol/L among AA/AT carrier (P=0.045). While, the concentrations of adiponectin were 18.0±0.4 μg/ml among carriers of TT and 16.2±0.7 μg/ml among subjects with AA/AT genotype (P=0.03). The level of glucose marginally increased in the AA/AT genotype subjects (4.67±0.40 mmol/L vs. 4.60±0.35 mmol/L, P=0.08). The evidence of association was reduced after adjustment for BMI (P=0.38 for triglyceride, P=0.20 for adiponectin and glucose). There was weak evidence of association between rs9939609 and other obesity-related metabolic traits including total cholesterol (3.92±0.03 mmol/L vs. 4.02±0.05 mmol/L, P=0.10), insulin (2.69±1.77 ng/ml vs. 3.12±2.91 ng/ml, P=0.14), and insulin resistance (HOMA-IR 0.56±0.03 vs. 0.66±0.05, P=0.10). Genetic variation in the FTO gene associates with obesity in Chinese children.


A Hybrid Mobile Phone Feasibility Study Focusing on Latino Mothers, Fathers, and Grandmothers to Prevent Obesity in Preschoolers.
To pilot the feasibility of a mobile phone childhood obesity intervention for family caregivers of Latino preschool-aged children. An evidence-based early childhood obesity intervention was adapted to have cultural relevance and a shorter-length curriculum for mothers, fathers, and grandmothers of 2- to 5-year-old Latino children. Traditional in-person group sessions (four weeks) were combined with eight weeks of mobile phone content to support parenting skills and evidence-based and age-appropriate nutritional practices in either English or Spanish. A convenience sample of Latino families were recruited from WIC and Early Education Centers in East Los Angeles. Feasibility measures were collected. Child and caregiver height and weight were measured, and caregiver surveys of child dietary intake were collected at baseline, 1- and 6-month post-baseline. Changes in child's dietary intake and BMI, as well as caregiver BMI, were examined using a mixed effects linear regression model with family random intercept and nested random slope for time period of measurement. The program was delivered to 64 low-income Latino families (46 mothers, 34 fathers, 16 grandmothers, and 48 children). Children had a reduction in raw BMI, BMI percentile, and BMI z-scores at 6-months post-baseline compared to baseline measurements. The study also demonstrated stable BMI outcomes among all caregivers. The pilot study shows promise in preventing childhood obesity, and having a multi-generational impact on weight outcomes. Leveraging the high-use of mobile phones has the potential to shorten in-person interventions, and engage fathers and grandmothers who play an important role in shaping healthy weight practices in young children.


Perinatal depression before and during the COVID-19 pandemic in New York City.
Quarantining and isolation during previous pandemics have been associated with higher levels of depression symptomatology. Studies in other countries found elevated rates of anxiety and/or depression among pregnant people during the COVID-19 pandemic compared with prepandemic rates. New York City was the initial epicenter of the pandemic in the United States, and the effects of the pandemic on perinatal depression in this population are not well known. This study aimed to evaluate the rates of perinatal depression before and during the COVID-19 pandemic. This is a single-center retrospective cohort study of patients screened for perinatal depression with the Edinburgh Postnatal Depression Scale at 2 private academic practices in New York City. This screen is done in these practices at the time of the glucose challenge test and at the postpartum visit. Patients aged ≥18 years who completed a screen at a postpartum visit and/or glucose challenge test from February 1, 2019 to July 31, 2019 and from February 1, 2020 to July 31, 2020 were identified, and the 2019 and 2020 groups were compared. The primary outcome was a positive screen, defined as ≥13 and ≥15 for postnatal and prenatal screens, respectively. Secondary outcomes included monthly changes in rates of positive screens and factors associated with perinatal depression. Data were analyzed using Mann-Whitney U test, chi-square, or Fisher exact test, and univariate and multivariate analyses with P<.05 defined as significant. A total of 1366 records met the inclusion criteria; 75% of the prepandemic (2019) records were included, as opposed to 65% of pandemic (2020) records due to a lower screen completion rate in the pandemic cohort. The 2020 cohort had a higher proportion of Hispanic patients (P=.003) and higher rates of diabetes mellitus (P=.007), preterm labor (P=.03), and current or former drug use (P<.001). The 2019 cohort had higher rates of hypertension (P=.002) and breastfeeding (P=.03); 4.6% of the 2020 cohort had a suspected or confirmed COVID-19 infection. There was no difference in perinatal depression between the 2019 and 2020 cohorts (2.8% vs 2.6%; P>.99). This finding persisted after adjusting for baseline differences (adjusted odds ratio, 0.89; 95% confidence interval, 0.38-1.86; P=.76). There were no differences in rates of positive Edinburgh Postnatal Depression Scale by month. Several risk factors were associated with a positive screen, including being unmarried (P<.001), pulmonary disease (P=.02), depression (P<.001), anxiety (P=.01), bipolar disorder (P=.009), and use of anxiolytics (P=.04). There were no differences in the rates of perinatal depression between the periods before and during the COVID-19 pandemic. The rate of perinatal depression in this cohort was below the reported averages in the literature. Fewer women were screened for perinatal depression in 2020, which likely underestimated the prevalence of depression in our cohort. These findings highlight potential gaps in care in a pandemic setting.


Tracking oocyte development and the timing of skipped spawning for north-east Arctic haddock (Melanogrammus aeglefinus).
The present study tracked oocyte development over 9 months and noted incidences of 'skipping', i.e., adults terminating their upcoming reproductive cycle, in field-caught north-east Arctic (NEA) haddock (Melanogrammus aeglefinus), currently the largest stock of this species. Applications of advanced image and histological techniques revealed the presence of cortical alveoli oocytes (CAO), which prevailed as the most advanced oocyte phase for 4-5 months. This new finding of an extended and early appearance of CAOs in this gadoid was supported by that vitellogenesis first started to appear 3 months later. The subsequent oocyte growth trajectories indicated that larger individuals [total length (TL) = 70 cm] typically spawn in the order of 3 weeks earlier than the smaller ones (TL = 40 cm). The spawning season appeared stretched over about 3 months. The majority of skipping females arrested oocyte growth at the CAO phase followed by atretic reabsorption. Compared to those individuals maturing for the spawning season, 'skippers' generally exhibited lower body condition, characterized also by relatively lower liver sizes at the time of the main spawning season. This study demonstrated well-developed skipping dynamics, but also that the CAO period, i.e., when skipping takes place, may be exceedingly long in this commercially valuable gadoid and that its reproductive cycle in many ways deviates from that of the data-rich, sympatric NEA cod (Gadus morhua).


Therapeutic drug monitoring of lamotrigine.
To evaluate the usefulness of routine monitoring of serum lamotrigine concentration. Literature was accessed through MEDLINE (1990-January 2001). Key search terms included lamotrigine, pharmacokinetics, and epilepsy. A decision-making algorithm was used to evaluate the clinical evidence to support or refute the routine use of serum lamotrigine concentrations to adjust doses. The value of serum lamotrigine concentration monitoring remains controversial, primarily because clear relationships between concentration and pharmacologic response (either efficacy or toxicity) have not been demonstrated. Serum concentration monitoring of lamotrigine is not recommended as a tool for routine dose adjustment.


Real-life effectiveness of anti-malarial treatment regimens: what are we aiming for?
Three-day artemisinin-based combination therapy (ACT) is the current standard of care for the treatment of malaria. However, specific drug resistance associated with reduced efficacy of ACT has been observed, therefore necessitating the clinical development of new anti-malarial drugs and drug combinations. Previously, Single Encounter Radical Cure and Prophylaxis (SERCAP) has been proposed as ideal target-product-profile for any new anti-malarial drug regimen as this would improve treatment adherence besides ensuring complete cure and prevention of early reinfection. Arguably, this concept may not be ideal as it (1) necessitates administration of an excessively high dose of drug to achieve plasmodicidal plasma levels for a sufficient time span, (2) increases the risk for drug related adverse drug reactions, and (3) leaves the patient with a one-time opportunity to achieve-or not-cure by a single drug intake. Over the past years, SERCAP has led to the halt of promising drug development programmes, leading to potentially unnecessary attrition in the anti-malarial development pipeline. One proposition could be the concept of single-day multi-dose regimens as a potentially better alternative, as this allows to (1) administer a lower dose of the drug at each time-point leading to better tolerability and safety, (2) increase treatment adherence based on the intake of the anti-malarial drug within 24 h when malaria-related symptoms are still present, and (3) have more than one opportunity for adequate intake of the drug in case of early vomiting or other factors causing reduced bioavailability. In line with a recently published critical viewpoint on the concept of SERCAP, an alternative proposition is-in contrast to the current World Health Organization (WHO) treatment guidelines-to aim for less than three days, but still multiple-dose anti-malarial treatment regimens. This may help to strike the optimal balance between improving treatment adherence, maximizing treatment effectiveness, while keeping attrition of new drugs and drug regimens as low as possible.


The effect of contraceptives containing nonoxynol-9 on the genital transmission of simian immunodeficiency virus in rhesus macaques.
The ability of two nonoxynol-9 spermicide preparations to prevent the genital transmission of SIV in rhesus macaques was compared. Administration of one mL of contraceptive foam before the intravaginal inoculation of cell-free SIV prevented the genital transmission of SIV to three of six animals, and using one mL of contraceptive gel prevented the genital transmission of SIV to two of six animals. Thus, both contraceptive foams and gels containing nonoxynol-9 provided protection against the genital transmission of SIV.


Frequency and patterns of psychiatric comorbidity in a sample of primary care patients with anxiety disorders.
The current report examines the rates of psychiatric comorbidity in a sample of 539 primary care patients diagnosed with anxiety disorders using the Structured Clinical Interview for DSM-IV (SCID-IV). Though not a typical psychiatric sample, rates of comorbidity were found to be as high or higher than those reported in studies conducted in traditional mental health settings. Multiple anxiety disorders were diagnosed in over 60% of participants and over 70% of participants had more than one current axis I diagnosis. Rates of current and lifetime comorbid major depression were also very high. Patterns of diagnostic comorbidity were also examined, with significantly elevated risks for the co-occurrence of several specific pairings of disorders being found. The study results are discussed in context of a recently published, large-scale study of anxiety disorder comorbidity in psychiatric patients (Brown et al., 2001). Implications of these results for both the mental health and primary care fields are also discussed.


General Anesthesia Imposes Negative Effects on Heart Rate and Blood Pressure Regulation in Patients With a History of Head and Neck Radiation Therapy.
Head and neck radiation therapy (HNRT) impairs baroreflex sensitivity, and it may potentiate the effects of anesthetics on heart rate (HR) and blood pressure (BP) regulation. Currently, the impacts of HNRT on HR and BP under anesthesia remain unclear. In this study, 472 patients with primary oral cavity or oropharyngeal cancer at all stages were examined. Half of the patients underwent HNRT plus surgery. The other half underwent surgery only and was matched with the treatment patients according to age, sex, and body mass index at a 1:1 ratio. The HRs and BPs in the 2 groups during anesthetic induction, skin incision, and emergence were compared retrospectively. A multivariable model of repeated measures with unstructured covariance structure was used to examine the associations of HNRT with intraoperative HRs and BPs after adjusting for baseline HR and BP, time, use of β-blockers, history of chemotherapy, and American Society of Anesthesiologists physical status score. BPs and HRs were collected every 5 minutes. The baseline HR and BP measurements were not included in the outcome vector and were only used as adjustment for baselines. Compared with corresponding baseline values in controls, the baseline HR was significantly higher (P = .0012) and the baseline systolic BP was lower (P < .0001) in the treatment group. The baseline diastolic BP levels did not differ significantly (P = .6411). Fewer patients receiving HNRT than controls took β-blockers daily (17% vs 28%; P = .0041). Comparing the corresponding values in control and treatment groups, multivariable analysis revealed significant associations of HNRT with decreases in HR during anesthesia induction (-2.21 [95% confidence interval {CI}, -4.42 to -0.01]; P = .0492) and skin incision (-2.66 [95% CI, -5.16 to -0.16]; P = .0373) and of HNRT with decreases in systolic BP during anesthesia induction (-6.88 [95% CI, -10.99 to -2.78]; P = .0011) and skin incision (-15.87 [95% CI, -20.45 to -11.29]; P < .001). However, we observed a significant association of HNRT with decrease in diastolic BP only during skin incision (-6.50 [95% CI, -9.47 to -3.53]; P < .0001). The significant finding in the study was that general anesthesia imposed a negative chronotropic effect on HR in the group given HNRT. Therefore, one should be watchful for bradycardia in these patients; particularly those with low BPs. Their hemodynamics may rapidly progress into an unstable status when bradycardia and hypotension develop altogether.


Regulation of the dystrophin-associated glycoprotein complex composition by the metabolic properties of muscle fibres.
The dystrophin-glycoprotein complex (DGC) links the muscle cytoskeleton to the extracellular matrix and is responsible for force transduction and protects the muscle fibres from contraction induced damage. Mutations in components of the DGC are responsible for muscular dystrophies and congenital myopathies. Expression of DGC components have been shown to be altered in many myopathies. In contrast we have very little evidence of whether adaptive changes in muscle impact on DGC expression. In this study we investigated connection between muscle fibre phenotype and the DGC. Our study reveals that the levels of DGC proteins at the sarcolemma differ in highly glycolytic muscle compared to wild-type and that these changes can be normalised by the super-imposition of an oxidative metabolic programme. Importantly we show that the metabolic properties of the muscle do not impact on the total amount of DGC components at the protein level. Our work shows that the metabolic property of a muscle fibre is a key factor in regulating the expression of DGC proteins at the sarcolemma.


[Effects of the organophosphorus insecticide Ofunack on the metabolism of cells cultured in vitro].
The effects of "ofunack (0,0-diethyl-0-(3-oxo-2-phenyl-2H-pyridazine-6-y1) phosphorothionate on the metabolism of IB-RS-2 cell line were studied. "Ofunack" stimulates cell growth and protein synthesis till 24 hours after its addition to the maintenance medium. Otherwise after this time "ofunack" induces an inhibition both on cell growth and on protein synthesis. This insecticide also inhibits the synthesis of RNA and DNA.


Phakic retinal detachment associated with atrophic hole of lattice degeneration of the retina.
Forty patients with phakic nontraumatic retinal detachment caused by atrophic retinal hole of lattice degeneration were reviewed. The condition was characterized by insidious, slowly developing shallow detachment, with frequent formation of demarcation lines. Often, the patients did not recognize their visual problems until the detachment had extended to the macular region. Young patients under 40 years of age were more common than older patients. Myopic refractive errors were frequently associated. The results of surgical repair were favorable. The risk of retinal detachment in lattice degeneration with atrophic holes was estimated to be about 1 in 90 patients, and prophylactic treatment for this common anomaly is not readily recommended.


[The immune system and Alzheimer's disease].
It has still not been established unequivocally whether vascular risk factors and inflammatory reactions, determined by heredity, are a cause or a result of Alzheimer's disease If the offspring of parents with AD have more risk factors and more frequent and severe inflammatory reactions than the offspring of parents without AD , this argues strongly in favor of a causal relationship between vascular risk factors, a pro-inflammatory cytokine response and AD. To determine whether the offspring of parents with ad have more risk factors and more frequent and severe inflammatory reactions than the offspring of parents without ad. method Vascular risk-factors, pro-inflammatory cytokines and the apoe genotype were determined in 206 offspring of parents with ad and in 200 offspring of parents without AD. Offspring of parents with ad carried more apoe epsilon4 than offspring of parents without ad (47% vs 21%). Middle-aged offspring of parents with a history of ad also had higher blood pressure and a greater atherosclerotic burden than the offspring of parents without AD. Also their response to the pro-inflammatory cytokine was significantly higher. Hypertension and an inherited pro-inflammatory cytokine profile in middle age are early risk factors that contribute to the development of ad in old age. Offspring with a parental history of AD should therefore be offered screening and treatment for hypertension and have their blood pressure checked so that the development of AD in old age can be prevented.


Time-lapse microscopy and fluorescence resonance energy transfer to analyze the dynamics and interactions of nucleolar proteins in living cells.
The dynamics of proteins play a key role in the organization and control of nuclear functions. Techniques were developed recently to observe the movement and interactions of proteins in living cells; time-lapse microscopy using fluorescent-tagged proteins gives access to observations of nuclear protein trafficking over time, and fluorescence resonance energy transfer (FRET) is used to investigate protein interactions in the time-lapse mode. In this chapter, we describe the application of these two approaches to follow the recruitment of nucleolar processing proteins at the time of nucleolar assembly. We question the role of prenucleolar bodies (PNB) during migration of the processing proteins from the chromosome periphery to sites of ribosomal genes (rDNA) transcription. The order of recruitment of different processing proteins into nucleoli is the consequence of differential sorting from the same PNBs. The dynamics of the interactions between processing proteins in PNBs suggest that PNBs are preassembly platforms for ribosomal RNA (rRNA) processing complexes.


Methodological issues in adherence to cancer control regimens.
A six-factor model provides a heuristic framework for understanding adherence behavior: (1) effective provider communication; (2) rapport with provider; (3) client's beliefs and attitudes; (4) client's social climate and norms; (5) behavioral intentions; and (6) supports for and barriers to adherence. Four classes of methodological issues are discussed. Recruitment may be affected by the sociodemographics of the target population, biomedical variables, population size and location, and patient sources utilized. Interventions can be structured to maximize enrollment, participation and long-term retention, and adherence to the regimen promoted with behavioral methodology. Measurement of adherence optimally includes multiple measures at multiple time points, a well-defined focus and unit of adherence, well-constructed response options, and multiple sources of information. Sample size calculations and interpretation of clinical trial results are affected by adherence rates. Multivariate analytic techniques, such as structural equation modeling, make it possible to specify models depicting hypothesized structural relationships between different theoretical constructs and to evaluate the plausibility of these models.


Advancing Pharmacogenomics Education in the Core PharmD Curriculum through Student Personal Genomic Testing.
To develop, implement, and evaluate "Test2Learn" a program to enhance pharmacogenomics education through the use of personal genomic testing (PGT) and real genetic data. One hundred twenty-two second-year doctor of pharmacy (PharmD) students in a required course were offered PGT as part of a larger program approach to teach pharmacogenomics within a robust ethical framework. The program added novel learning objectives, lecture materials, analysis tools, and exercises using individual-level and population-level genetic data. Outcomes were assessed with objective measures and pre/post survey instruments. One hundred students (82%) underwent PGT. Knowledge significantly improved on multiple assessments. Genotyped students reported a greater increase in confidence in understanding test results by the end of the course. Similarly, undergoing PGT improved student's self-perceived ability to empathize with patients compared to those not genotyped. Most students (71%) reported feeling PGT was an important part of the course, and 60% reported they had a better understanding of pharmacogenomics specifically because of the opportunity. Implementation of PGT in the core pharmacy curriculum was feasible, well-received, and enhanced student learning of pharmacogenomics.


Development of immunoassay based on a specific antibody for sensitive detection of nicosulfuron in environment.
Nicosulfuron, one of the most widely used selective herbicides in corn field, can effectively control annual and perennial grass weeds, sedges, and some broadleaf weeds. The residual phytotoxicity of nicosulfuron in soil and water has become increasingly prominent. Therefore, an efficient method for detection of nicosulfuron was critical to ensure the sustainable and healthy development of agriculture and the ecological environment. In this paper, five nicosulfuron haptens which contained carboxyl group or aldehyde groups were designed and synthesized, and an indirect competitive immunoassay was developed for the first time. The assay showed an IC50 of 8.42 ng/mL and had negligible cross reactivities toward other sulfonylurea herbicides. In the spike and recovery studies, the recovery rate from soil samples was 95 %-104 %, and that of wheat roots was 92 %-98 %, which showed a good correlation with LC-MS analysis for nicosulfuron. The immunoassay was then used to quantify nicosulfuron concentration which could cause the obvious phytotoxic symptoms to wheat. Obvious symptoms of nicosulfuron phytotoxicity in wheat root was observed at the concentration of 0.068 ± 0.006 mg/kg (ELISA result) which was consistent with 0.072 ± 0.007 mg/kg obtained by LC-MS. The developed immunoassay method is an effective tool for environment contamination monitoring.


Cerebral blood volume analysis in glioblastomas using dynamic susceptibility contrast-enhanced perfusion MRI: a comparison of manual and semiautomatic segmentation methods.
To compare the reproducibilities of manual and semiautomatic segmentation method for the measurement of normalized cerebral blood volume (nCBV) using dynamic susceptibility contrast-enhanced (DSC) perfusion MR imaging in glioblastomas. Twenty-two patients (11 male, 11 female; 27 tumors) with histologically confirmed glioblastoma (WHO grade IV) were examined with conventional MR imaging and DSC imaging at 3T before surgery or biopsy. Then nCBV (means and standard deviations) in each mass was measured using two DSC MR perfusion analysis methods including manual and semiautomatic segmentation method, in which contrast-enhanced (CE)-T1WI and T2WI were used as structural imaging. Intraobserver and interobserver reproducibility were assessed according to each perfusion analysis method or each structural imaging. Interclass correlation coefficient (ICC), Bland-Altman plot, and coefficient of variation (CV) were used to evaluate reproducibility. Intraobserver reproducibilities on CE-T1WI and T2WI were ICC of 0.74-0.89 and CV of 20.39-36.83% in manual segmentation method, and ICC of 0.95-0.99 and CV of 8.53-16.19% in semiautomatic segmentation method, repectively. Interobserver reproducibilites on CE-T1WI and T2WI were ICC of 0.86-0.94 and CV of 19.67-35.15% in manual segmentation method, and ICC of 0.74-1.0 and CV of 5.48-49.38% in semiautomatic segmentation method, respectively. Bland-Altman plots showed a good correlation with ICC or CV in each method. The semiautomatic segmentation method showed higher intraobserver and interobserver reproducibilities at CE-T1WI-based study than other methods. The best reproducibility was found using the semiautomatic segmentation method based on CE-T1WI for structural imaging in the measurement of the nCBV of glioblastomas.


Endoscopic management of intralingual thyroglossal duct cysts: Case series and systematic review.
To discuss our institutional experience with endoscopic management of intralingual thyroglossal duct cyst (TGDC) and review cases in the published literature in a systematic review. Pediatric patients with intralingual TGDC treated with endoscopic surgery at our institution from 2009-2019 were identified. Metrics from our case series were then compared to those in the literature in a systematic review to assess pooled outcomes of endoscopic or transoral management. Patient demographics, age of presentation, presenting symptomatology, size of cyst on imaging, type of surgery, and post-operative outcomes were assessed. We identified 5 institutional cases of intralingual TGDC and 48 cases of intralingual TGDC described in the literature. The average age of presentation was 20.36 months. 69.8% (N=37) of patients presented with at least one respiratory symptom, 22.6% (N=12) presented with dysphagia, 9.4% (N=5) presented with an identified mass in the oropharynx, and 15.1% (N=8) had the cyst discovered as an incidental finding. Three patients required revision surgeries due to prior incomplete TGDC excisions and one patient experienced a recurrence >6 months after primary excision requiring a second procedure. Our data pooled with published case series in systematic review confirms that endoscopic or transoral management are excellent options for definitive management of intralingual TGDC. Intralingual TDGC is a potentially life-threatening variant of TGDC. Our results pooled with published series in a systematic review suggest that endoscopic or transoral management of intralingual TGDC are excellent minimally invasive treatments with a low risk of recurrence. Postoperative surveillance up to one year is recommended.


Isolation and screening of rare Actinobacteria, a new insight for finding natural products with antivascular calcification activity.
Vascular calcification (VC) is a significant pathological process in some life-threatening diseases. Several pathological mechanisms, including transdifferentiation of vascular smooth muscle cells to osteoblast-like cells and apoptosis are involved in VC. Compounds with an inhibitory effect on these processes are potentially efficient medications. In consideration of the multiple biological activities of Actinobacteria, this research was aimed at finding anti-VC metabolite-producing Actinobacteria. After the isolation and identification of Actinobacteria, the effect of their fermentation broth extracts on the apoptosis rate was measured using various methods, for example, ethidium bromide/acridine orange staining, DNA laddering and diphenylamine assays. The effect of the most effective fermentation broth extract of Actinobacteria (FBEA) on the mRNA expression of runt-related transcription factor 2 (Runx2) and osteopontin (OPN) was examined. Finally, the most effective FBEA was fractionated and the chemical composition of anti-VC fractions was analysed using GC-MS. Various VC inhibition rates were observed in the tested FBEA (20 μg ml-1 ; 17·9-60·15%). The inhibition of DNA fragmentation was 7-48%. The FBE with the greatest anticalcification activity belonged to Kribbella sp. UTMC 267 and, according to 16S rRNA analysis, Kribbella sancticallisti with a similarity of 98·53% is its nearest neighbour. The FBE of Kribbella sp. UTMC 267 reduced Runx2 mRNA expression by 2·95-fold and OPN mRNA expression by 28·57-fold, both of which are considered significant (P < 0·05). Finally, GC-MS analysis showed the existence of potent anti-oxidative and anti-inflammation agents in FBE of Kribbella sp. UTMC 267. Actinobacterial metabolites can provide a new strategy for treating VC diseases by reducing the expression of osteogenic genes, the apoptosis rate and oxidative stress. This study highlights the therapeutic potential of Kribbella sp. metabolites and Actinobacteria as a new natural source for drug discovery programs in the nonantibiotic bioactivity field.


Mechanism behind the deterioration in gel properties of collagen gel induced by high-temperature treatments: A molecular perspective.
This study aims to elucidate the mechanism behind the deterioration in the gel properties of collagen gel resulting from high-temperature treatment. The results show that the high level of triple-helix junction zones and related lateral stacking contribute to the dense and orderly collagen gel network with high gel strength and storage modulus. The analysis of the molecular properties of heated collagen shows that high-temperature treatment leads to serious denaturation and degradation of collagen, resulting in the formation of gel precursor solutions composed of low-molecular-weight peptides. The short chains in the precursor solution are not easy to nucleation and can limit the growth of triple-helix cores. To conclude, the decrease in triple-helix renaturation and crystallization abilities of peptide components is the reason for the deterioration in the gel properties of collagen gel induced by high temperature. The findings presented in this study add the understanding of texture deterioration in high-temperature processed collagen-based meat products and related products, and provide a theoretical basis for establishing methods to overcome the production dilemma faced by these products.


A Case with Micromegakaryocytes.
A boy with no previous history of bleeding presented with ecchymoses and splenomegaly. He was followed up for thrombocytopenia and micromegakaryocytes for 20 months till clinically malignancy was diagnosed. Micromegakaryocytes must always be treated with suspicion, as they may provide an important clue for dyshematopoesis. Micromegakaryocytes, Leukemia, Dismegakaryopoesis.


Pathophysiological regulation of lung function by the free fatty acid receptor FFA4.
Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein-coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to Gq/11 signaling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated at least in part by the release of the prostaglandin E2 (PGE2) that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. In acute and chronic ozone models of pollution-mediated inflammation and house dust mite and cigarette smoke-induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, a response that was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was similar to that observed in mice, and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation ex vivo. Our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy and might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.


Neural Mechanisms That Make Perceptual Decisions Flexible.
Neural mechanisms of perceptual decision making have been extensively studied in experimental settings that mimic stable environments with repeating stimuli, fixed rules, and payoffs. In contrast, we live in an ever-changing environment and have varying goals and behavioral demands. To accommodate variability, our brain flexibly adjusts decision-making processes depending on context. Here, we review a growing body of research that explores the neural mechanisms underlying this flexibility. We highlight diverse forms of context dependency in decision making implemented through a variety of neural computations. Context-dependent neural activity is observed in a distributed network of brain structures, including posterior parietal, sensory, motor, and subcortical regions, as well as the prefrontal areas classically implicated in cognitive control. We propose that investigating the distributed network underlying flexible decisions is key to advancing our understanding and discuss a path forward for experimental and theoretical investigations.


Hepatic carcinosarcoma: clinicopathologic features and a review of the literature.
Hepatic carcinosarcoma (HCS) is defined as a malignant tumor containing an intimate mixture of carcinomatous and sarcomatous elements. Here, we report the case of a 72-year-old man who developed HCS from an otherwise normal liver. The patient had no history of alcohol abuse or hepatitis B or C infection. An enhanced abdominal CT scan revealed a 9-cm heterogeneous tumor, with enhancement during the arterial phase and delayed wash-out in the latter phases. Also, a marked elevation in alpha-fetoprotein level (15,164 ng/mL; normal range, < 10 ng/mL) was noted. He underwent resection of liver segments V and VI under a pre-operative diagnosis of atypical hepatocellular carcinoma (HCC). The diagnosis of HCS was made based on thorough pathologic examination with a panel of immunohistochemical staining. Following surgery, the patient made an uneventful recovery, and at present, 16 months post-surgery, he remains well with no evidence of tumor recurrence. In conclusion, pre-operative diagnosis of HCS is difficult and radical resection in the early stage is encouraged to improve the prognosis of these patients.


Improving comparability between qPCR-based telomere studies.
Comparability of findings from qPCR-based telomere studies is hampered by such measurement results being assay-specific, precluding a direct quantitative comparisons of observed differences and/or slopes of associations between studies. It is proposed that this can be partially alleviated by expressing qPCR-based telomere data as Z-scores.


Patients' experiences of psychiatric care in emergency departments: A secondary analysis.
The number of psychiatric emergencies presenting to EDs in the United States continues to rise. Evidence suggests that psychiatric ED care encounters can have less than optimal outcomes, and result in stress for providers. The primary aim of this study is to describe the perceptions of ED visits by persons experiencing emotional distress, identifying themes among these that may guide nursing interventions that minimize stress and optimize outcomes in the treatment of psychiatric emergency. This secondary analysis used a qualitative, phenomenological method to analyze a de-identified data set originally collected in a study of experiences of psychiatric emergency in a community based crisis management setting. Findings consist of three major themes: "Emergency rooms are cold and clinical", "They talk to you like you're a crazy person", and "You get put away against your will". An overarching theme through all three is the influence of RN communication, both positive and negative, on patient perceptions of their ED encounters. While nurse-patient communication is basic to all areas of practice, it may be a low priority in the urgent and chaotic context of the ED. However, our findings suggest that increased attention to timely, empathic and validating communication and openness to the patient's reality may decrease severity of symptoms, optimize outcomes, and decrease provider stress.


Long-term culture of cells from bone affected by Paget's disease.
Cells obtained from surgical bone specimens of eight patients with Paget's disease of bone were maintained in culture for up to 8 months and seven passages. The doubling time during the period of maximal cell growth ranged from 4 to 12 days. Evidence consistent with the hypothesis that many of the cells were bone cells included the following: (a) histochemical techniques demonstrated staining of some cells for alkaline phosphatase or acid phosphatase and succinic dehydrogenase; (b) parathyroid extract stimulated increased uptake of 3H-thymidine and 3H-uridine; (c) parathyroid extract suppressed and salmon calcitonin stimulated uptake of 3H-proline; and (d) crystalline calcium deposits were found within cells and extracellularly. Ultrastructural analysis revealed that three of the eight cultures contained cells whose nuclei had inclusions which were almost identical to those found in the osteoclast nuclei of all patients with Paget's disease. The maintenance of cells derived from pagetic bone in long-term culture should aid in testing the hypothesis that Paget's disease represents a slow virus infection of bone.


Treatment of liver metastases, an update on the possibilities and results.
Long-term results after liver resection for colorectal liver metastases show 5-year survival rates between 35 and 40%. However, only a limited number of patients appear to be candidates for resection, far more patients prove to have unresectable disease. Present challenges in liver surgery for colorectal metastases are to improve patient selection, to increase the resectability rate and to improve survival by multimodality treatment approaches. The variables most consistently associated with a poor prognosis and tumour recurrence are tumour-positive resection margins and the presence of extra-hepatic disease. Hence, patient selection and preoperative staging should concentrate on accurate imaging of the liver lesions and the detection of extrahepatic disease. For liver imaging, spiral computed tomography (CT) scan or magnetic resonance imaging (MRI), supplemented by intra-operative ultrasound, are currently regarded as the best methods for evaluating the anatomy and resectability of colorectal liver metastases. Extrahepatic disease should be investigated by spiral CT of the chest and abdomen and when possible by 2-fluouro-2-deoxy-D-glucose-positron emission tomography (FDG-PET). Resection remains the gold standard for the surgical treatment of colorectal liver metastases. In experienced centres, resection is a safe procedure and mortality rates are below 5%. The aim of resection should be to obtain tumour-negative resection margins. Edge cryosurgery should be considered in cases where very close resection margins are anticipated. The role of adjuvant chemotherapy after resection is still controversial, although two recent studies show a clear benefit. For the moment, local tumour ablative therapies such as cryotherapy and radiofrequency therapy should be considered as an adjunct to hepatic resection in those cases in which resection can not deal with all of the tumour lesions. In these cases, there seems a beneficial effect of a combined treatment consisting of resection and local tumour ablation. At this stage, there are no randomised data that local tumour ablation is as effective as resection. For a selected group of patients with unresectable liver metastases, there may be a chance to turn unresectable disease to resectable disease by aggressive neo-adjuvant chemotherapy or portal vein embolisation. For patients with unresectable disease, many different chemotherapy schedules may be used based on systemic drug administration. Regional chemotherapy and isolated liver perfusion should only be used within a study design.


Clinical negligence in ophthalmology: fifteen years of national health service litigation authority data.
To categorize and understand the reasons behind ophthalmic clinical negligence claims in the National Health Service and how such claims can be avoided. Retrospective analyses of all ophthalmic clinical negligence claims between 1995 and 2009 were carried out. Data were obtained from the National Health Service Litigation Authority through the Freedom of Information Act. Claims were classified according to ophthalmic subspecialty, mean payment per subspecialty, severity, paid-to-closed ratio, and cost. One thousand two hundred fifty-three ophthalmology-related claims occurring from 1995 through 2009. Of these, 963 claims were closed over the 15-year period. Eighty-four were excluded because of insufficient case data. Retrospective analysis of all public sector ophthalmology litigation claims over a 15-year period in England. Subspecialty pertaining to claim, mean payment per claim, and severity of outcome of clinical incident. Nine hundred sixty-three claims were closed over a 15-year period, of which 67% resulted in payment. The total cost of claims was £32.1 million ($50.3 million), with a mean payment per claim of £33 300 ($52 300). The specialties with the highest mean payment per claim were neuro-ophthalmology and pediatric ophthalmology. Cataract subspecialty had the highest number of claims, accounting for 34% of all claims. Overall, the number of litigation claims in ophthalmology is low, relative to the high volume of outpatient and surgical workload.


Comparison of olanzapine and risperidone in 367 first-episode patients with non-affective or affective psychosis: results of an open retrospective medical record study.
Previous studies comparing olanzapine (OLZ) and risperidone (RIS) have tended to focus on multiple-episode patients, with no studies examining their comparative efficacy in a non-selective sample of first-episode psychosis. The Early Psychosis Prevention and Intervention Centre in Australia had admitted 786 first-episode psychosis (FEP) patients between 1998-2000. Data were collected from the medical records (MR) of 367 patients, which met inclusion criteria. The primary objective was to evaluate the efficacy of OLZ vs. RIS as measured by CGI-S, CGI-BP (symptomatic level), GAF and SOFAS (functioning level). 367 FEP patients were entered into the study, 278 in the RIS- (2.7 mg/day) and 89 in the OLZ group (10.2 mg/day). No between-group differences were found in non-affective FEP (n = 273). In affective FEP patients (n = 94), mainly treated for acute mania (86.7 %), OLZ treatment was related to better response on the symptomatic (CGI-S; p = .002), but not on the functioning level (GAF and SOFAS; ns). There were trends in the OLZ group towards a higher rate of remission of positive symptoms ( p = .054) and a shorter treatment duration to reach this remission in affective FEP patients ( p = .077). More extrapyramidal side effects ( p <.001) were related to RIS and more weight gain to OLZ-treatment ( p <.001). Despite the limitations of a retrospective MR design, study results suggest equal therapeutic efficacy of OLZ and RIS in non-affective FEP and some therapeutic advantages of OLZ compared to RIS in affective FEP patients, especially in those with acute mania. Results may serve as hypotheses for future randomised controlled trials.


Herpesvirus latency and therapy--from a veterinary perspective.
This short review considers how the human herpesviruses were among the first viruses to be effectively treated by means of antiviral therapy although the ability of alphaherpsviruses to establish neuronal latency with reactivation remains the major obstacle to achieving a cure. Laboratory animals played an essential role in the development of herpes antivirals including our understanding of the complexity of the neurological infection in relation to chemotherapy. The existence of natural herpesvirus infections in domestic species also contributes to our understanding of latency and reactivation relevant to antiviral therapy although the use of antivirals to treat or prevent virus infections in veterinary species has been minimal, to date. The review briefly focuses on herpes infections in the horse and cat where some progress has already been achieved in the veterinary antiviral field.


The morphologic spectrum of lobular carcinoma in situ (LCIS) observations on clinical significance, management implications and diagnostic pitfalls of classic, florid and pleomorphic LCIS.
Lobular carcinoma in situ (LCIS) is a non-invasive proliferation of atypical dyscohesive epithelial cells characterized by loss or functional alteration of E-cadherin-mediated cell adhesion. The morphologic spectrum of LCIS encompasses classic (C-LCIS), florid (F-LCIS) and pleomorphic LCIS (P-LCIS), as recently defined by the World Health Organization (WHO) Expert Consensus Group. Atypical lobular hyperplasia (ALH) is also part of this spectrum.This article highlights the morphologic and immunohistochemical features of the three forms of LCIS and summarizes their management implications and prognosis, with emphasis on F-LCIS and P-LCIS.


A DOC2 protein identified by mutational profiling is essential for apicomplexan parasite exocytosis.
Exocytosis is essential to the lytic cycle of apicomplexan parasites and required for the pathogenesis of toxoplasmosis and malaria. DOC2 proteins recruit the membrane fusion machinery required for exocytosis in a Ca(2+)-dependent fashion. Here, the phenotype of a Toxoplasma gondii conditional mutant impaired in host cell invasion and egress was pinpointed to a defect in secretion of the micronemes, an apicomplexan-specific organelle that contains adhesion proteins. Whole-genome sequencing identified the etiological point mutation in TgDOC2.1. A conditional allele of the orthologous gene engineered into Plasmodium falciparum was also defective in microneme secretion. However, the major effect was on invasion, suggesting that microneme secretion is dispensable for Plasmodium egress.


Reorganization of the functional connectome from rest to a visual perception task in schizophrenia and bipolar disorder.
Functional connectome organization is altered in schizophrenia (SZ) and bipolar disorder (BD). However, it remains unclear whether network reorganization during a task relative to rest is also altered in these disorders. This study examined connectome organization in patients with SZ (N = 43) and BD (N = 42) versus healthy controls (HC; N = 39) using fMRI data during a visual object-perception task and at rest. Graph analyses were conducted for the whole-brain network using indices selected a priori: three reflecting network segregation (clustering coefficient, local efficiency, modularity), two reflecting integration (characteristic path length, global efficiency). Group differences were limited to network segregation and were more evident in SZ (clustering coefficient, modularity) than in BD (clustering coefficient) compared to HC. State differences were found across groups for segregation (local efficiency) and integration (characteristic path length). There was no group-by-state interaction for any graph index. In summary, aberrant network organization compared to HC was confirmed, and was more evident in SZ than in BD. Yet, reorganization was largely intact in both disorders. These findings help to constrain models of dysconnection in SZ and BD, suggesting that the extent of functional dysconnectivity in these disorders tends to persist across changes in mental state.


Oxygen-glucose deprivation (OGD) and interleukin-1 (IL-1) differentially modulate cathepsin B/L mediated generation of neuroprotective perlecan LG3 by neurons.
Brain extracellular matrix (ECM) is highly degraded after cerebral ischemia. The perlecan c-terminal fragment LG3 is generated at increased levels by proteolytic processing as long as 3 days after ischemia. It has previously been shown that oxygen-glucose deprivation (OGD), reperfusion and interleukin-1 α (IL-1α) stimulate brain cells to yield increased levels of LG3. This LG3, in turn, is neuroprotective against OGD, and may therefore represent one of the brain's defenses against ischemic injury. Here, we investigate whether, in neurons, this increased LG3 is the result of increased perlecan generation and cellular release, increased protease release (to generate LG3 from previous extracellularly deposited perlecan) or both. We found that pre-synthesized perlecan may be exocytosed by neurons during OGD and de novo synthesis of perlecan is increased during reperfusion, even 24 h after OGD. Furthermore, while cathepsin L activity was seen to be marginally important to generate LG3 during normoxic conditions, cathepsin B activity was found to be important to generate increased levels of LG3 following OGD and reperfusion. On the other hand, IL-1α treatment raised levels of cathepsin L in neuronal media, and both cathepsin L and cathepsin B were demonstrated to be important for increasing LG3 levels after IL-1α treatment.


Intracerebral temperature monitoring in severely head injured patients.
In a series of 6 severely head injured patients, intraventricular as well as rectal, bladder and jugular vein temperature is recorded. The relationship between these temperatures in different conditions is evaluated. Intracerebral temperature is 0.5 +/- 0.2 degrees C (mean +/- SD) higher than bladder temperature except in conditions such as brain death. It is concluded that rectal temperature is not representative and therefore not a good alternative to the measurement of brain temperature. More data on human intracerebral temperature are mandatory as well as prospective studies correlating intracerebral temperature with final outcome in head injury.


The effects of CO2 pneumoperitoneum on the survival of women with persistent metastatic ovarian cancer.
The effects of CO(2) pneumoperitoneum on the survival of women with metastatic ovarian cancer have not been documented. We sought to describe the survival of women with persistent stage III-IV ovarian cancer as documented by positive second-look laparoscopy or laparotomy and to see whether the laparoscopic approach with CO(2) pneumoperitoneum has a negative effect on overall survival. We conducted a retrospective review of all patients with FIGO stage III-IV invasive epithelial ovarian cancer who were found to have persistent disease at second-look surgery. All patients underwent primary surgery followed by intravenous chemotherapy and were clinically without evidence of disease prior to second-look surgery. Second-look laparoscopy began to be utilized regularly in 1994. The selection of the second-look surgical approach depended on the surgeon's discretion. CO(2) pneumoperitoneum was utilized for all laparoscopic cases with the maximum intra-abdominal pressure maintained at 15 mm Hg. Patients received a variety of additional intravenous, intraperitoneal, or oral chemotherapy following positive second-look surgery. Between 6/1/91 and 6/30/02, 289 patients were found to have persistent ovarian/peritoneal cancer at second look. Second-look operations included 131 (45%) transperitoneal laparoscopies and 139 (48%) laparotomies. Nineteen (7%) patients underwent laparoscopy followed immediately by laparotomy. The mean age, stage distribution, histology, grade, and size of residual disease at second look did not differ between the two groups. The median overall survival for patients who underwent laparoscopy, 41.1 months (95% CI, 33.2-58.1), did not significantly differ from that of the laparotomy group, 38.8 months (95% CI, 31.9-44.2) (P = 0.742). Transperitoneal laparoscopy with CO(2) pneumoperitoneum does not appear to reduce the overall survival of women with persistent metastatic intra-abdominal carcinoma of ovarian/peritoneal origin. The overall survival appears to be independent of the second-look surgical approach.


Relationship of body mass index and arm anthropometry to outcomes after pediatric allogeneic hematopoietic cell transplantation for hematologic malignancies.
Although nutritional status may adversely affect various health outcomes, the relationship between anthropometry and outcomes after hematopoietic cell transplantation (HCT) has not been fully studied in children. We analyzed the impact of pre-HCT body mass index (BMI), arm muscle area, and arm fat area on outcomes in 733 patients age 2-18 years who underwent allogeneic HCT for a hematologic malignancy between 1985 and 2009. We evaluated these 3 variables according to patient group based on age- and sex-adjusted percentiles for BMI, arm muscle area (<5th, 5th-24th, 25th-94th, and ≥95th), and arm fat area (<25th, 25th-94th, and ≥95th). Cox proportional hazards regression models for event-free survival (EFS), relapse, and nonrelapse mortality (NRM) at 100 days and 3 years after HCT, as well as grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD, were performed using the 3 major variables and adjusted for covariates. BMI was <5th percentile in only 3% of patients and ≥95th percentile in 15% of patients, but outcomes for both groups were similar to those for the BMI 25th-94th percentile group. The BMI 5th-24th percentile group had lower EFS (P = .01) and higher relapse (P = .003) at day +100 post-HCT, but these associations did not hold at 3 years post-HCT. Arm muscle area was <5th percentile in 8% of patients, and arm fat area was <25th percentile in 10%. Analysis of arm muscle area showed that the <5th percentile group had lower EFS and higher NRM and relapse rate at day +100 (P = .002, .04, and .01, respectively) and 3 years (P = .0004, .008, and .01, respectively) post-HCT. Arm fat area <25th percentile was associated with lower EFS at day +100 (hazard ratio, 1.5; P = .05), but not at 3 years post-HCT. Anthropometry variables were not associated with acute or chronic GVHD. In conclusion, arm muscle area <5th percentile appears to be a stronger predictor than BMI of poor outcomes after HCT in children with hematologic malignancies.


Updated cost-effectiveness analysis of lung cancer screening for Australia, capturing differences in the health economic impact of NELSON and NLST outcomes.
A national, lung cancer screening programme is under consideration in Australia, and we assessed cost-effectiveness using updated data and assumptions. We estimated the cost-effectiveness of lung screening by applying screening parameters and outcomes from either the National Lung Screening Trial (NLST) or the NEderlands-Leuvens Longkanker Screenings ONderzoek (NELSON) to Australian data on lung cancer risk, mortality, health-system costs, and smoking trends using a deterministic, multi-cohort model. Incremental cost-effectiveness ratios (ICERs) were calculated for a lifetime horizon. The ICER for lung screening compared to usual care in the NELSON-based scenario was AU$39,250 (95% CI $18,150-108,300) per quality-adjusted life year (QALY); lower than the NLST-based estimate (ICER = $76,300, 95% CI $41,750-236,500). In probabilistic sensitivity analyses, lung screening was cost-effective in 15%/60% of NELSON-like simulations, assuming a willingness-to-pay threshold of $30,000/$50,000 per QALY, respectively, compared to 0.5%/6.7% for the NLST. ICERs were most sensitive to assumptions regarding the screening-related lung cancer mortality benefit and duration of benefit over time. The cost of screening had a larger impact on ICERs than the cost of treatment, even after quadrupling the 2006-2016 healthcare costs of stage IV lung cancer. Lung screening could be cost-effective in Australia, contingent on translating trial-like lung cancer mortality benefits to the clinic.


Decompression of the heart with siphon drainage.
A simple technique for inducing intracavitary hypothermic cardioplegia and decompressing the left heart through the ascending aorta is presented. The technique is based on siphon drainage, which eliminates the dangers of air embolism.


RNA Sequencing and Bioinformatics Analysis Reveals the Downregulation of DNA Replication Genes by Morindone in Colorectal Cancer Cells.
Morindone, a natural anthraquinone compound, has been reported to have significant pharmacological properties in different cancers. However, its anticancer effects in colorectal cancer (CRC) and the underlying molecular mechanisms remain obscure. In this study, RNA sequencing was used to assess the differentially expressed genes (DEGs) following morindone treatment in two CRC cell lines, HCT116 and HT29 cells. Functional enrichment analysis of overlapping DEGs revealed that negative regulation of cell development from biological processes and the MAPK signalling pathway were the most significant Gene Ontology terms and Kyoto Encyclopaedia of Genes and Genome pathway, respectively. Seven hub genes were identified among the overlapping genes, including MCM5, MCM6, MCM10, GINS2, POLE2, PRIM1, and WDHD1. All hub genes were found downregulated and involved in DNA replication fork. Among these, GINS2 was identified as the most cancer-dependent gene in both cells with better survival outcomes. Validation was performed on seven hub genes with rt-qPCR, and the results were consistent with the RNA sequencing findings. Collectively, this study provides corroboration of the potential therapeutic benefits and suitable pharmacological targets of morindone in the treatment of CRC.


Notch activity modulates the responsiveness of neural progenitors to sonic hedgehog signaling.
Throughout the developing nervous system, neural stem and progenitor cells give rise to diverse classes of neurons and glia in a spatially and temporally coordinated manner. In the ventral spinal cord, much of this diversity emerges through the morphogen actions of Sonic hedgehog (Shh). Interpretation of the Shh gradient depends on both the amount of ligand and duration of exposure, but the mechanisms permitting prolonged responses to Shh are not well understood. We demonstrate that Notch signaling plays an essential role in this process, enabling neural progenitors to attain sufficiently high levels of Shh pathway activity needed to direct the ventral-most cell fates. Notch activity regulates subcellular localization of the Shh receptor Patched1, gating the translocation of the key effector Smoothened to primary cilia and its downstream signaling activities. These data reveal an unexpected role for Notch shaping the interpretation of the Shh morphogen gradient and influencing cell fate determination.


Asymmetrical flow field-flow fractionation coupled with multi-angle light scattering and refractive index detections for characterization of ultra-high molar mass poly(acrylamide) flocculants.
The molar mass distributions of ultra-high molar mass polyacrylamide-based flocculants were measured using asymmetrical flow field-flow fractionation (AFFFF) coupled with multi-angle light scattering and refractive index detectors. The mass load onto the separation channel was found to be critical in obtaining a good size separation. The detailed investigation with ultra-high molar mass polyacrylamides found that the injected amount should be </=1microg to ensure separation according to AFFFF mechanism. As a consequence of the limited sample mass load, the signal-to-noise ratio (S/N) of the detector responses was low. To overcome this limitation and thereby to obtain more accurate and precise molar mass and radius information, each sample was injected 10 times and the resulting signals were averaged before calculating the molar mass and radius. In addition, the channel was equipped with a slotted outlet to increase the concentration of sample passing through the detectors. After implementing the above strategies, it was possible to perform separation of polymers having molar mass and size as high as 10(8)gmol(-1) and root-mean-square radius of approximately 250nm, respectively. The resulting weight-average molar mass of the highest MW sample was in excess of 18x10(6)gmol(-1).


Repression of CRNDE enhances the anti-tumour activity of CD8 + T cells against oral squamous cell carcinoma through regulating miR-545-5p and TIM-3.
Immunotherapy has been identified a promising treatment of cancers, including Oral squamous cell carcinoma (OSCC). CRNDE is highly overexpressed in various cancers. Many lncRNAs have been reported in CD8 T lymphocytes. Little is investigated about their effects in the functions of CD8 + T cells in OSCC. Currently, the influence of lncRNA CRNDE on the function of CD8 + T cells in OSCC progression was investigated. Here, CRNDE was obviously elevated and negatively correlated with IFN-γ production in tumour-infiltrating CD8 + T cells isolated from OSCC patients. CRNDE can exhibit a crucial role in activating CD8 + T-cell exhaustion. Mechanistically, CRNDE specifically sponged miR-545-5p to induce T-cell immunoglobulin and mucin domain-3 (TIM-3), thus contributing to CD8 + T-cell exhaustion. The function of miR-545-5p on T-cell function remains poorly known. TIM-3 is a significant immune checkpoint, and it inhibits cancer immunity. TIM-3 can demonstrate an important role in CD8 + T-cell exhaustion. In summary, loss of CRNDE could induce miR-545-5p and inhibit TIM3 expression, thus significantly activated the anti-tumour effect of CD8 + T cells.


Bone Mineral Density and Renal Function in Chronic Hepatitis B Patients Receiving Nucleotide versus Nucleoside Analogs: A Pilot Prospective Study.
The use of nucleotide analogs (NTAs) can be associated with negative effects on renal function and bone mineral density (BMD) due to proximal tubular dysfunction and hypophosphatemia; however, prospective data assessing the bone and renal safety of these agents are limited. This study aimed to evaluate the prevalence of bone diseases among chronic hepatitis B (CHB) patients without cirrhosis and the changes in BMD and glomerular filtration rate (GFR) between patients receiving NTAs versus nucleoside analogs (NSAs). We prospectively collected data from non-cirrhotic CHB patients who had been treated for < 1 year in Rajavithi Hospital (Bangkok, Thailand) between 2012 and 2014. Patients with significant comorbidities or those being treated for bone diseases were excluded. BMD assessment was performed at the lumbar spine (LS) and femoral neck (FN). BMD T-scores were used to define osteopenia (-2.5 to -1) and osteoporosis (< -2.5), and the GFR was estimated using the Cockcroft-Gault method. Twenty patients were included: 65% were men; 40% were HBeAg positive; and the median age was 42.7 (25.6-64.2) years. Ten patients had been treated with NTAs (7 with tenofovir 3 with adefovir) and 10 patients had been treated with NSAs (8 with lamivudine, 2 with entecavir), with a median follow-up period of 1.5 years (1.2-1.6). At baseline, the overall prevalence of osteopenia was 45% and the median GFR was 94 (51-144) mL/min. BMD in CHB patients was slightly lower than in an age-matched population based on Z-scores. Changes in LS-BMD and FN-BMD were not significantly different between groups. The annual reduction in GFR was more pronounced in the NTA group (-7.4% vs. -1.39%, p = 0.018). Osteopenia is common in CHB patients without cirrhosis. Changes in BMD were not significantly different between groups. The annual reduction in GFR was more pronounced in the NTA group.


The view of Hong Kong parents on secondary use of dried blood spots in newborn screening program.
Residual dried blood spots (rDBS) from newborn screening programmes represent a valuable resource for medical research, from basic sciences, through clinical to public health. In Hong Kong, there is no legislation for biobanking. Parents' view on the retention and use of residual newborn blood samples could be cultural-specific and is important to consider for biobanking of rDBS. To study the views and concerns on long-term storage and secondary use of rDBS from newborn screening programmes among Hong Kong Chinese parents. A mixed-method approach was used to study the views and concerns on long-term storage and secondary use of rDBS from newborn screening programmes among Hong Kong Chinese parents of children 0-3 years or expecting parents through focus groups (8 groups; 33 participants) and a survey (n = 1012, 85% mothers) designed with insights obtained from the focus groups. We used framework analysis to summarise the themes as supportive factors, concerns and critical arguments for retention and secondary use of rDBS from focus group discussion. We used multiple logistic regression to assess factors associated with support for retention and secondary use of rDBS in the survey. Both in focus groups and survey, majority of parents were not aware of the potential secondary use of rDBS. Overall secondary use of rDBS in medical research was well accepted by a large proportion of Hong Kong parents, even if all potential future research could not be specified in a broad consent. However parents were concerned about potential risks of biobanking rDBS including leaking of data and mis-use of genetic information. Parents wanted to be asked for permission before rDBS are stored and mainly did not accept an "opt-out" approach. The survey showed that parents born in mainland China, compared to Hong Kong born parents, had lower awareness of newborn screening but higher support in biobanking rDBS. Higher education was associated with support in rDBS biobanking only among fathers. Long-term storage and secondary use of rDBS from newborn screening for biomedical research and a broad consent for biobanking of rDBS are generally acceptable to Hong Kong parents given their autonomy is respected and their privacy is protected, highlighting the importance of an accountable governance and a transparent access policy for rDBS biobanks.


In Vitro and In Vivo Sequestration of Phencyclidine by Me4 Cucurbit[8]uril*.
We report investigations of the use of cucurbit[8]uril (CB[8]) macrocycles as an antidote to counteract the in vivo biological effects of phencyclidine. We investigate the binding of CB[8] and its derivative Me4 CB[8] toward ten drugs of abuse (3-9, 12-14) by a combination of 1 H NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me4 CB[8] are able to encapsulate the 1-amino-1-aryl-cyclohexane ring system of phencyclidine (PCP) and ketamine as well as the morphinan skeleton of morphine and hydromorphone with Kd values ≤50 nm. In vitro cytotoxicity (MTS metabolic and adenylate kinase cell death assays in HEK293 and HEPG2 cells) and in vivo maximum tolerated dose studies (Swiss Webster mice) which were performed for Me4 CB[8] indicated good tolerability. The tightest host⋅guest pair (Me4 CB[8]⋅PCP; Kd =2 nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me4 CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me4 CB[8] significantly reduces the locomotion levels.


Genomic landscape of single-stranded DNA gapped intermediates in Escherichia coli.
Single-stranded (ss) gapped regions in bacterial genomes (gDNA) are formed on W- and C-strands during replication, repair, and recombination. Using non-denaturing bisulfite treatment to convert C to U on ssDNA, combined with deep sequencing, we have mapped gDNA gap locations, sizes, and distributions in Escherichia coli for cells grown in mid-log phase in the presence and absence of UV irradiation, and in stationary phase cells. The fraction of ssDNA on gDNA is similar for W- and C-strands, ∼1.3% for log phase cells, ∼4.8% for irradiated log phase cells, and ∼8.5% for stationary phase cells. After UV irradiation, gaps increased in numbers and average lengths. A monotonic reduction in ssDNA occurred symmetrically between the DNA replication origin of (OriC) and terminus (Ter) for log phase cells with and without UV, a hallmark feature of DNA replication. Stationary phase cells showed no OriC → Ter ssDNA gradient. We have identified a spatially diverse gapped DNA landscape containing thousands of highly enriched 'hot' ssDNA regions along with smaller numbers of 'cold' regions. This analysis can be used for a wide variety of conditions to map ssDNA gaps generated when DNA metabolic pathways have been altered, and to identify proteins bound in the gaps.


Phosphine control of the oxidative addition chemistry of tetrathiocins to palladium(0): characterization of mono-, di-, and hexanuclear palladium(II) dithiolate complexes.
The outcome of the oxidative addition reactions of bis(4',5'-dimethoxybenzo)-1,2,5,6-tetrathiocin to Pd2dba3 under microwave conditions is sensitive to the nature of the phosphine coreagent; the bidentate phosphines dppm, dppe, and dppf afford the mononuclear dithiolates (dmobdt)Pd(dppm) (4), (dmobdt)Pd(dppe) (2), and (dmobdt)Pd(dppf) (5), whereas more labile monodentate phosphines lead to aggregation; Ph3P afforded the dinuclear dithiolate (dmobdt)2Pd2(PPh3)2 (6), whereas (t)Bu3P generated the phosphine-free hexanuclear edge-capped octahedral complex Pd6(dmobdt)6 (7) [dmobdt = 4,5-dimethoxybenzenedithiolate, (MeO)2C6H2S2(2-)].


Squamous cell carcinoma of the pinna: which histological features could be used to predict prognosis?
Squamous cell carcinoma (SCC) that originates in the pinna is thought to have a high risk of metastases (up to 16%) compared with under 5% for cutaneous SCC at any other site, and histological features of the primary tumour may provide evidence for further surveillance or treatment. To identify any association between histological features and the risk of metastases we made an electronic search of the histopathological records at the University Hospital Southampton NHS Foundation Trust for all patients who presented with auricular SCC from 2007-2012. Inclusion criteria included origin in the pinna, complete two-year follow up, and no history of immunosuppressive treatment. We looked for histopathological features that were thought to be relevant to metastases. We studied specimens from 192 patients, four of whom developed metastases (2%), each with involved lymph nodes. Perineural invasion and local recurrence were significantly associated with increased risk of metastases (p<0.001 and p=0.006). The overall metastatic rate was much lower than those reported in other studies, and factors other than histological features alone may explain the results. We suggest that although some histological features were significantly associated, they do not predict a high enough risk of metastatic disease to provide evidence for further surveillance or elective lymphadenopathy.


Corpectomy and spinal stabilization using a 3D-printed spine model and custom jigs to address severe spinal deformities from T9-11 and L2-4 in a 6-month-old German shepherd puppy.
This report describes surgical decompression and stabilization of 2 hemivertebrae in a German shepherd dog. Long-term clinical and imaging outcomes are documented. Spinal cord decompression via corpectomy improved neurological function and intrinsic spinal cord changes on MRI. The dog improved to have minimal paraparesis and an active lifestyle.


Silent slipped capital femoral epiphysis in overweight and obese children and adolescents.
Abnormal loading of the hip in obese children may lead to anatomic alterations and an increased prevalence of slipped capital femoral epiphysis (SCFE). The aims of this study were to examine the hip motion in obese children and adolescents and to estimate the prevalence of SCFE in a subgroup of patients characterized by pathological clinical examination and/or pain in the knee or hip joint. A total of 411 individuals (196 males), mean age 14.5 ± 2.5 years (7.8-20.4), mean BMI of 32.9 ± 5.6 kg/m(2) (20.3-51.5, z score +2.65) who were consecutively admitted for an inpatient weight loss program were included in the study. Twenty-six percent of the patients had load-dependent and 11.7 % had load-independent pain in the knee joint. A total of 9.3 % had load-dependent and 4.7 % had load-independent pain in the hip joint. Two patients (0.5 %) underwent surgical treatment of SCFE prior to entry. A total of 18.2 % of the patients showed a reduced range of motion for hip flexion (<90°) and 18.5 % a pathological decreased internal rotation (<10°). Radiological evaluation of the hips in the clinically conspicuous subgroup (n = 54) revealed an abnormal head-neck ratio as a sign of prior silent slipped capital femoral epiphysis in 11 patients (20.4 % of the 54 patients, 2.7 % of total cohort). In conclusion, these data show a high prevalence of SCFE-like tilt deformities in a selected group of severely obese children. Mild deformation of the epiphysis at young age might be a major predisposing factor for the development of hip osteoarthritis in obese adults.


A rare late complication of breast cancer treatment.
In 1948 Stewart and Treeves recognised and described six cases of lymphangiosarcoma arising in the oedematous upper limb of patients who had previously undergone radical mastectomy and radiotherapy for breast carcinoma. The incidence of lymphangiosarcoma in such patients is 0.45% and is uniformly aggressive and fatal, with a 5-year survival of less than 5% regardless of the treatment modality. We present a case report to increase the clinical awareness of this rare and fatal iatrogenic complication occurring subsequent to breast cancer treatment, and speculate on ways of improving survival.


Silica nanoparticles based label-free aptamer hybridization for ATP detection using hoechst33258 as the signal reporter.
In this work, we have developed a simple and sensitive method for ATP detection using silica nanoparticles (NPs) as the platform and hoechst33258 as the signal reporter. The ATP-binding aptamers hybridize with the probe DNA (DNA(p)) immobilized NPs to form the aptamer/DNA(p) duplex on the NPs surface. The conformational change of the aptamer leads to the decrease of the aptamer/DNA(p) duplex on the NPs due to the ATP-binding aptamer switches its structure from the aptamer/DNA(p) duplex to the aptamer/target complex in the presence of ATP. ATP detection can be easily realized by separating the silica nanoparticles and adding the hoechst33258 of intercalating to aptamer/DNA(p) (dsDNA). Good selectivity between ATP and CTP, GTP or UTP has been demonstrated, which is due to the specific recognition between ATP aptamer and ATP. The K(d) was estimated to be ∼1mM from 0 to 4mM and a liner response was observed from 0 to 0.2mM with a detection limit of ∼20μM. Compared with other methods, the carboxyl-modified silica nanoparticles (∼60nm) prepared by the reverse microemulsion method can serve as a stable and sensitive sensor platform because of their smaller size and facile conjugation with amine-containing molecules. In addition, the high sensitivity and selectivity of hoechst33258 was employed for the ssDNA and dsDNA determination, which takes advantage of the label-free aptamer and lower cost.