Coprescription of Chinese herbal medicine and Western medication among female patients with breast cancer in Taiwan: analysis of national insurance claims.
Many female breast cancer (FBC) patients take Chinese herbal medicine (CHM) and Western medication (WM) concurrently in Taiwan. Despite the possibility of interactions between the CHM and WM mentioned in previous studies, the pattern of these coprescriptions in FBC patients remains unclear. Hence, the aim of the present study is to investigate the utilization of coprescriptions of CHM and WM among the FBC patients in Taiwan. The study was a cross-sectional survey using the sampled cohort in 2009 obtained from the National Health Insurance Research Database in Taiwan. There were 3,507 FBC patients identified from the registry for catastrophic illness patients. Ambulatory visit records, corresponding prescriptions, and the data of beneficiaries belonging to the FBC patients were further extracted. A total of 1,086 FBC patients used CHM at least once. CHM and WM prescribed within any overlapping duration were defined as coprescriptions. There were 868 (80.0%) patients simultaneously receiving CHM and WM. A total of 4,927 CHM prescriptions and 6,358 WM prescriptions were prescribed concurrently. Among these coprescriptions, the most frequently used CHM was jia-wei-xiao-yao-san (21.2%), and the most frequently coprescribed WM was acetaminophen (38.9%), followed by tamoxifen (25.5%). There were 346 patients using systemic adjuvant therapy and CHM concurrently. The most commonly coprescribed CHM with chemotherapy, endocrine therapy, and trastuzumab was xiang-sha-liu-jun-zi-tang, jia-wei-xiao-yao-san, and zhi-gan-cao-tang, respectively. The combined use of CHM with WM is prevalent. The main purpose of combining CHM with systemic cancer treatment is to alleviate the treatment-related adverse effects. However, the combination may result in the potential risk of drug-herb interactions. Further clinical studies are needed to evaluate the efficacy and safety of the CHM and WM coprescriptions for FBC patients.


Post-operative capsular opacification.
Post-operative capsular opacification (PCO) is a multifactorial physiological consequence of cataract surgery. Opacification involving the central posterior capsule has a significant impact on high and low contrast acuity and low contrast sensitivity. The assessment of PCO on cadaver eyes, experimental studies and culture models and in clinical studies has provided an understanding of its pathogenesis. The proliferation, migration and abnormal differentiation of residual lens epithelial cells and fibers in the capsular bag have been implicated in the pathogenesis of PCO. The incidence and severity of PCO correlates to the use of surgical techniques, intraocular lens (IOL) optic edge designs and IOL materials. This article summarizes the clinical studies with recommendations for retarding the development of central PCO. It discusses experiments with pharmacological agents broadly categorized as anti-inflammatory, immuno-modulating, antiproliferative, antiadhering and antitransdifferentiating agents for the prevention of PCO. These studies will remain critical for future endeavors undertaken for the eradication of PCO.


[Prohepsidin in diagnostic of iron deficiency in patients with chronic cardiac failure and anemia].
The sample for examination included 52 patients with chronic cardiac failure and 26 patients with anemia amongst. The expected increase of production of prohepsidin against the background of increased serum concentrations of anti-inflammatory cytokines was not detected. The tendency to decrease level of prohepsidin alongside with decrease of content of serum iron and ferritin in blood serum testified depletion of iron resources in organism.


Synthesis and crystal structure of double-three ring (D3R)-type cage siloxanes modified with dimethylsilanol groups.
The controlled assembly of molecular building blocks enables the rational design of nanomaterials. In this study, two types of cage-type oligosiloxanes with double-three ring (D3R) structures are modified with dimethylsilanol groups to form supramolecular assemblies. One is the siloxane cage derived from Si(OEt)4 (denoted as the Q6 cage), and the other is the organosiloxane cage derived from (EtO)3Si-CH2-Si(OEt)3 (denoted as the T6 cage). The syntheses of the silanol-modified cages are performed in two steps: (i) dimethylsilylation of the corner Si-O- groups on the Q6 and T6 cages to introduce Si-H groups and (ii) subsequent oxidation of the Si-H groups to Si-OH groups. Dimethylsilylation of the cages is conducted at much lower temperatures (-94 and -78 °C for Q6 and T6 cages, respectively) than those used for conventional silylation, which is the key to suppressing the deterioration of the unstable D3R structure. The subsequent oxidation of the Si-H groups proceeds successfully, and the crystallization of these molecules is induced by the hydrogen bonds of the silanol groups. The crystal structure of the Q6 cage modified with dimethylsilanol groups can be regarded as a layered structure with tetrahydrofuran between the layers. In contrast, the T6 cage modified with dimethylsilanol groups assembled to form a more densely packed structure with no included solvent molecules. The differences between the crystal structures are discussed in terms of the shape of the cages. The insight into the effect of the shape of the cage on its assembly behavior will lead to the designable synthesis of crystalline siloxane-based materials.


Communal peeing: a new mode of flood control in ants.
The behavioral response of the obligate bamboo-nesting ant Cataulacus muticus to nest flooding was studied in a perhumid tropical rainforest in Malaysia and in the laboratory. The hollow internodes of giant bamboo, in which C. muticus exclusively nests, are prone to flooding by heavy rains. The ants showed a two-graded response to flooding. During heavy rain workers block the nest entrances with their heads to reduce water influx. However, rainwater may still intrude into the nest chamber. The ants respond by drinking the water, leaving the nest and excreting water droplets on the outer stem surface. This cooperative 'peeing' behavior is a new survival mechanism adaptive to the ants' nesting ecology. Laboratory experiments conducted with two other Cataulacus species, C. catuvolcus colonizing small dead twigs and C. horridus inhabiting rotten wood, did not reveal any form of water-bailing behavior.


Physical inactivity, TV-watching hours and body composition in children and adolescents.
Physical inactivity is a predisposing factor to the onset/worsening of other cardiovascular risk factors, particularly obesity. To determine physical activity level (PAL) and daily number of hours of TV (HTV) and the association and/or correlation of these variables with age, gender, economic class, public/private school, overweight and obesity in children and adolescents. Cross sectional study, school-based population, public and private education, primary and secondary education. The sample was calculated based on the minimum expected prevalence of several variables, including physical inactivity. Cluster sampling. structured questionnaire, including Physical Activity for Older Children Questionnaire (PAQ-C) measurements of weight, height, body mass index (BMI) and triceps skinfold (TSF). Chi-square, linear correlation. Among the 1,253 students, averaging 12.4 ± 2.9 years old, of which 549 were male, there was a prevalence of inactivity in 93.5%, more commonly found in female adolescents and there was no association between PAL and excess weight or body fat, soccer and dance were the most frequent activities in boys and girls, respectively; 60% of students did not have physical education classes. Average and median HTV were respectively 3.6 and 3 hours; there was a significant association between HTV and obesity and significant correlation between PAL and age (negative) and between BMI and TSF (positive). Physical inactivity is present in 93.5% of children and adolescents from Maceió. It is more commonly found among teenagers and females, with no association or correlation of this variable with excess weight or body fat; obesity was associated with ≥ 3 HTV.


The transition to parenthood: what does it mean for fathers?
This paper is a report of a study to explore the needs of first-time fathers in relation to the care, support and education provided by healthcare professionals during the antenatal period, particularly in relation to preparing them for the transition to fatherhood. Pregnancy and transition to parenthood are major developmental periods within families throughout the world. Previous research suggests that fathers in many different countries feel unprepared for parenthood. Purposive sampling was used to recruit 20 partners of primiparous women from two healthcare provider organizations in South-West England between December 2005 and July 2006. Recruitment took place at about 28 weeks gestation. Semi-structured interviews were undertaken at home in the last trimester of pregnancy and 3-4 months postpartum. Content analysis of the interview data was undertaken. Several common themes emerged from both the ante- and postnatal data, including lack of support mechanisms, involvement in antenatal provision and the need for more information given in the antenatal period on parenting, baby care and relationships. Adequately preparing new fathers for parenthood in advance of the birth of their baby is important, and healthcare professionals can contribute to this by involving and supporting new fathers. Further study is needed to explore the role of fathers in antenatal education and the types of interventions that are effective in improving their early experiences of parenthood. The study needs to be repeated with fathers from black and ethnic minority groups.


Is the Human Activity Profile a useful measure in people with knee osteoarthritis?
This study evaluated the usefulness of the Human Activity Profile (HAP) in people with knee osteoarthritis (OA). People with OA (N = 226) completed the HAP and a battery of pain and physical function measures. Healthy elderly controls (N = 33) also completed the HAP, and 20 OA participants underwent repeat testing 2 to 7 days later. Test-retest reliability was excellent (intraclass correlation coefficients 0.96 and 0.95). The HAP was sensitive enough to detect differences in physical activity between people with (N = 33) and without OA (N = 33) (p < 0.01). When OA individuals were classified as impaired, moderately active, or active based on HAP score, differences in pain and physical function were detected (p < 0.05). Correlations between HAP and commonly used pain and physical function measures were weak to moderate (r = 0.18-0.63, all p < 0.01), indicating that the HAP measures additional information not gained by other assessment tools. The HAP is a reliable measure, and it is sensitive enough to discriminate between people with and without knee OA, and within an OA cohort. The HAP appears to have greater applicability in osteoarthritic women than men.


The Economic Burden of Bipolar Disorder in the United States: A Systematic Literature Review.
Bipolar disorder (BD) is a mood disorder with subtypes characterized by episodes of mania, hypomania, and/or depression. BD is associated with substantial economic burden, and the bipolar I disorder (BD-I) subtype is associated with high medical costs. This review further evaluated the economic burden of BD and BD-I in the United States (US), describing health-care resource utilization (HCRU) and sources of direct medical and indirect costs. Data were obtained from systematic searches of MEDLINE®, EMBASE®, and National Health Service Economic Evaluation Database. Citations were screened to identify primary research studies (published 2008-2018) on the economic burden of BD/BD-I or its treatment in real-world settings. Reported costs were converted to 2018 US dollars. Of identified abstracts (N=4111), 56 studies were included. The estimated total annual national economic burden of BD/BD-I was more than $195 billion, with approximately 25% attributed to direct medical costs. Individuals with BD/BD-I used health-care services more frequently and had higher direct medical costs than matched individuals without the disease. Drivers of higher direct costs included frequent psychiatric interventions, presence of comorbid medical/psychiatric conditions, and both suboptimal medication adherence and clinical management. Indirect costs (eg, unemployment, lost work productivity for patients/caregivers) accounted for 72-80% of the national economic burden of BD/BD-I. Different definitions for study populations and cost categories limited comparisons of economic outcomes. This review builds on existing literature describing the economic burden of BD and confirmed cost drivers of BD/BD-I. Improved clinical management of BD/BD-I and associated comorbidities, together with better medication adherence, may reduce health-care costs and improve patient outcomes.


The relationship between cortisol, C-reactive protein and hypertension in African and Causcasian women: the POWIRS study.
Research on the roles that C-reactive protein (CRP) and other risk factors such as cortisol and obesity play in the diagnosis of cardiovascular disease (CVD) in African and Caucasian women has become increasingly imperative when one considers the prevalence of hypertension in these groups. CRP and cortisol have been associated with an increased prevalence of hypertension and obesity. Cortisol has also been linked with both hypertension and the hypothalamic-pituitary-adrenal (HPA) response. African women have previously presented with an increased vascular reactivity. Conversely, Caucasian women have displayed an increased central cardiac reactivity. We included African (n = 102) and Caucasian (n = 115) women in the study, matched for age and body mass index. Elevated CRP levels were observed in African women compared to Caucasian women. A trend of hypocortisolism was exhibited in both hypertensive ethnic groups. Systolic blood pressure (SBP) and a vascular marker, arterial compliance (Cw), predicted hypertension in African women. Conversely, in Caucasian women, only SBP predicted hypertension. These results suggest the apparently diverse roles that dysregulation by the HPA axis, in conjunction with the respective cardiac and vascular responses in both Caucasian and African women, can play in future cardiovascular risk for these groups.


Non-parametric statistical formulas for factors of safety of plant stems
A previously proposed statistical approach for computing factors of safety (i.e. numerical measures of mechanical reliability) for any load bearing structure, like a vertical plant stem, is here extended to cope with organic structures whose morphological or mechanical properties have Weibull frequency distributions. This approach is illustrated using the actual length L and critical buckling length Lerof flower stalks (peduncles) collected from isogenic garlic (Allium sativum) populations grown under windy field and protected glasshouse conditions. Our analyses of the data indicate that L and Lerof peduncles harvested from both populations have Weibull frequency distributions, that the factor of safety for glasshouse grown peduncles is very near unity (i.e. S=1.03), and that the factor of safety of field grown peduncles is 73% higher than that of glasshouse grown plants (i.e. S=1.73). Comparisons between the S -values computed on the basis of our formulas and on the basis of the quotient of the mean values of Lerand L for each of the two populations indicate that the statistical method gives biologically realistic S -values and that the difference in the S -values for stems grown under protected and unprotected environmental conditions likely reflects the effects of chronic mechanical perturbation (due to wind-induced drag) on normal stem growth and development. Copyright 1999 Academic Press.


The Diabetes Prevention Program: recruitment methods and results.
The Diabetes Prevention Program (DPP) is a multicenter randomized controlled trial designed to test whether diet and exercise or medication can prevent or delay the onset of type 2 diabetes in persons with impaired glucose tolerance, who are at increased risk of the disease. This paper describes DPP recruitment methods, strategies, performance, and costs. The DPP developed an organizational structure for comprehensive management and continuous monitoring of recruitment efforts. The DPP utilized a variety of recruitment strategies, alone or in combination, and a stepped informed consent procedure leading to randomization. Studywide and clinic-specific recruitment data were monitored, analyzed, and used to modify recruitment approaches. DPP recruitment was completed slightly ahead of schedule, meeting goals for the proportion of women enrolled and nearly meeting goals for the proportion of racial/ethnic minorities. Clinics varied widely in the recruitment strategies they used, and these strategies also varied by participant age, gender, and race/ethnicity. Staff time devoted to recruitment averaged 86.8 hours per week per clinic, with the majority of effort by staff specifically assigned to recruitment. The number of staff hours required to recruit a participant varied by recruitment strategy. Recruitment cost (excluding staff cost) was about 1075 US dollars per randomized participant. The DPP experience offers lessons for those planning similar efforts: (1) a method for ongoing assessment and revision of recruitment strategies is valuable; (2) a range of recruitment strategies may be useful; (3) the most effective methods for recruiting potential subjects may vary according to the gender, age, and race/ethnicity of those individuals; (4) recruitment strategies vary in the amount of staff time required to randomize a participant; and (5) a stepped screening may make it easier to identify and recruit volunteers who understand the requirements of the study.


Does the Arcto-Tertiary biogeographic hypothesis explain the disjunct distribution of Northern Hemisphere herbaceous plants? The case of Meehania (Lamiaceae).
Despite considerable progress, many details regarding the evolution of the Arcto-Tertiary flora, including the timing, direction, and relative importance of migration routes in the evolution of woody and herbaceous taxa of the Northern Hemisphere, remain poorly understood. Meehania (Lamiaceae) comprises seven species and five subspecies of annual or perennial herbs, and is one of the few Lamiaceae genera known to have an exclusively disjunct distribution between eastern Asia and eastern North America. We analyzed the phylogeny and biogeographical history of Meehania to explore how the Arcto-Tertiary biogeographic hypothesis and two possible migration routes explain the disjunct distribution of Northern Hemisphere herbaceous plants. Parsimony and Bayesian inference were used for phylogenetic analyses based on five plastid sequences (rbcL, rps16, rpl32-trnH, psbA-trnH, and trnL-F) and two nuclear (ITS and ETS) gene regions. Divergence times and biogeographic inferences were performed using Bayesian methods as implemented in BEAST and S-DIVA, respectively. Analyses including 11 of the 12 known Meehania taxa revealed incongruence between the chloroplast and nuclear trees, particularly in the positions of Glechoma and Meehania cordata, possibly indicating allopolyploidy with chloroplast capture in the late Miocene. Based on nrDNA, Meehania is monophyletic, and the North American species M. cordata is sister to a clade containing the eastern Asian species. The divergence time between the North American M. cordata and the eastern Asian species occurred about 9.81 Mya according to the Bayesian relaxed clock methods applied to the combined nuclear data. Biogeographic analyses suggest a primary role of the Arcto-Tertiary flora in the study taxa distribution, with a northeast Asian origin of Meehania. Our results suggest an Arcto-Tertiary origin of Meehania, with its present distribution most probably being a result of vicariance and southward migrations of populations during climatic oscillations in the middle Miocene with subsequent migration into eastern North America via the Bering land bridge in the late Miocene.


Identification of influential users on Twitter: A novel weighted correlated influence measure for Covid-19.
In the era of advanced mobile technology, freedom of expression over social media has become prevalent among online users. This generates a huge amount of communication that eventually forms a ground for extensive research and analysis. The social network analysis allows identifying the influential people in society over microblogging platforms. Twitter, being an evolving social media platform, has become increasingly vital for online dialogues, trends, and content virality. Applications of discovering influential users over Twitter are manifold. It includes viral marketing, brand analysis, news dissemination, health awareness spreading, propagating political movement, and opinion leaders for empowering governance. In our research, we have proposed a sustainable approach, namely Weighted Correlated Influence (WCI), which incorporates the relative impact of timeline-based and trend-specific features of online users. Our methodology considers merging the profile activity and underlying network topology to designate online users with an influence score, which represents the combined effect. To quantify the performance of our proposed method, the Twitter trend #CoronavirusPandemic is used. Also, the results are validated for another social media trend. The experimental outcomes depict enhanced performance of proposed WCI over existing methods that are based on precision, recall, and F1-measure for validation.


Use of Antifungals and Outcomes Among Inpatients at Risk of Invasive Aspergillosis or Mucormycosis in the USA: A Retrospective Cohort Study.
Prophylaxis and treatment of invasive aspergillosis (IA) and mucormycosis (IM) within a real-world US inpatient setting is undocumented since the introduction of isavuconazole. This retrospective medical record review aimed to describe characteristics, triazole use, and outcomes among inpatients across the USA who initiated antifungal monotherapy (AFMT) as prophylaxis or treatment of IA/IM. A convenience sample of US physicians abstracted data from randomly selected records of hospitalized patients aged ≥ 18 years initiating AFMT (amphotericin B, isavuconazole, voriconazole, or posaconazole) as prophylaxis or treatment of IA/IM between 2013 and 2017. Retrieved data included background characteristics, dosage and duration of AFMT, healthcare resource use, and survival. Characteristics and outcomes were compared (prophylaxis vs treatment) using Fisher's exact and one-way analysis of variance tests where applicable. Exploratory Kaplan-Meier analyses described overall and inpatient survival. Physicians (n = 23) retrieved 124 patient records (43 prophylaxis; 81 treatment). Median duration of first-line AFMT was 14 days (range 1-603 days) and 19 days (range 3-351 days) in the prophylaxis and treatment groups, respectively. One patient received second-line therapy. Median duration of hospitalization was 29 days (range 4-259 days) and 31 days (range 6-980 days) in the prophylaxis and treatment groups, respectively. Admission to intensive care occurred in 14% and 52% of patients in the prophylaxis and treatment groups, respectively. At the time of data retrieval, overall and inpatient survival rates in the prophylaxis group were 88% and 87%, respectively, and in the treatment group were 66% and 76%, respectively. This study documented real-world prophylactic and therapeutic AFMT use for IA/IM and associated outcomes among hospitalized patients in the USA since approval of isavuconazole. IA/IM were associated with lengthy hospital stays commonly requiring intensive care. Prophylactic and therapeutic AFMT dosages and duration generally followed recommendations and switching between agents was rare. Astellas Pharma Global Development, Inc., Northbrook, IL, USA.


Nitrogen availability increases in a tundra ecosystem during five years of experimental permafrost thaw.
Perennially frozen soil in high latitude ecosystems (permafrost) currently stores 1330-1580 Pg of carbon (C). As these ecosystems warm, the thaw and decomposition of permafrost is expected to release large amounts of C to the atmosphere. Fortunately, losses from the permafrost C pool will be partially offset by increased plant productivity. The degree to which plants are able to sequester C, however, will be determined by changing nitrogen (N) availability in these thawing soil profiles. N availability currently limits plant productivity in tundra ecosystems but plant access to N is expected improve as decomposition increases in speed and extends to deeper soil horizons. To evaluate the relationship between permafrost thaw and N availability, we monitored N cycling during 5 years of experimentally induced permafrost thaw at the Carbon in Permafrost Experimental Heating Research (CiPEHR) project. Inorganic N availability increased significantly in response to deeper thaw and greater soil moisture induced by Soil warming. This treatment also prompted a 23% increase in aboveground biomass and a 49% increase in foliar N pools. The sedge Eriophorum vaginatum responded most strongly to warming: this species explained 91% of the change in aboveground biomass during the 5 year period. Air warming had little impact when applied alone, but when applied in combination with Soil warming, growing season soil inorganic N availability was significantly reduced. These results demonstrate that there is a strong positive relationship between the depth of permafrost thaw and N availability in tundra ecosystems but that this relationship can be diminished by interactions between increased thaw, warmer air temperatures, and higher levels of soil moisture. Within 5 years of permafrost thaw, plants actively incorporate newly available N into biomass but C storage in live vascular plant biomass is unlikely to be greater than losses from deep soil C pools.


Balance between cardiac output and sympathetic nerve activity in resting humans: role in arterial pressure regulation.
Large, reproducible interindividual differences exist in resting sympathetic nerve activity among normotensive humans with similar arterial pressures, resulting in a lack of correlation between muscle sympathetic nerve activity (MSNA) and arterial pressure among individuals. Although it is known that the arterial pressure is the main short-term determinant of MSNA in humans via the arterial baroreflex, the lack of correlation among individuals suggests that the level of arterial pressure is not the only important input in regulation of MSNA in humans. We studied the relationship between cardiac output (CO) and baroreflex control of sympathetic activity by measuring MSNA (peroneal microneurography), arterial pressure (arterial catheter), CO (acetylene uptake technique) and heart rate (HR; electrocardiogram) in 17 healthy young men during 20 min of supine rest. Across individuals, MSNA did not correlate with mean or diastolic blood pressure (r<0.01 for both), but displayed a significant negative correlation with CO (r=-0.71, P=0.001). To assess whether CO is related to arterial baroreflex control of MSNA, we constructed a baroreflex threshold diagram for each individual by plotting the percentage occurrence of a sympathetic burst against diastolic pressure. The mid-point of the diagram (T50) at which 50% of cardiac cycles are associated with bursts, was inversely related to CO (r=-0.75, P<0.001) and stroke volume (SV) (r=-0.57, P=0.015). We conclude that dynamic inputs from CO and SV are important in regulation of baroreflex control of MSNA in healthy, normotensive humans. This results in a balance between CO and sympathetically mediated vasoconstriction that may contribute importantly to normal regulation of arterial pressure in humans.


Elevated expression of cancer/testis antigen FSIP1 in ER-positive breast tumors.
The study aimed to identify and characterize highly specific breast tumor biomarkers. A microarray data set comprised of 513 diverse normal and tumor mRNA samples was analyzed to identify breast tumor biomarkers with minimal expression in normal tissues. FSIP1 was identified as a breast tumor biomarker with elevated mRNA expression in breast tumors and minimal expression in most normal tissues except the testis. Quantitative real-time PCR confirmed the elevated expression of FSIP1 mRNA in breast tumors and revealed a significant correlation with ER-positive status. Immunofluorescence staining of breast tumor sections showed that the majority of breast tumors examined in this study (20 out of 22) expressed detectable FSIP1 protein, with significantly higher than average expression in ER-positive versus ER-negative breast tumors. The prevalence and uniformity of FSIP1 expression in breast tumors, taken together with the highly restricted expression in normal tissues, suggests that FSIP1 may be an attractive target for breast cancer immunotherapy.


The effects of a resistance-training program on strength, body composition and baseline hormones in male athletes training concurrently for rugby union 7's.
To examine the effects of a resistance-training program on strength, body composition and baseline hormones in male athletes training concurrently for rugby union 7's. Participants (N.=12) completed a six-week resistance-training program focusing on general strength development while still performing additional rugby union 7's training involving agility, speed and cardiovascular fitness. One repetition maximum (1RM) strength was assessed pre and post training across 5 exercises (bench press, back squats, deadlifts, military press and chins), along with body composition and baseline salivary testosterone (T) and cortisol (C) concentrations. Significant improvements in bench press (11%), back squat (13%), deadlift (13%), military press (10%) and chin-up (6%) 1RM strength were observed after training (P < 0.05). These changes were accompanied by a significant reduction (-1%) in body fat and an increase (1.3%) in fat-free mass. Baseline T and C concentrations and the T/C ratio did not change significantly with training (P>0.05). Correlational analyses indicated that most of the individual changes in strength, body composition and hormones were not significantly related. The implementation of a resistance-training program in male athletes already training for rugby union 7's led to all-round improvements in maximal dynamic strength even while they continued to perform other forms of rugby-specific training. These findings support the use of resistance exercise as a supplement to sport-specific training for improving the performance capacity of 7's rugby players.


Treatment of glomus jugulare tumors with gamma knife radiosurgery.
Surgical resection, preoperative embolization, radiation therapy, and stereotactic radiosurgery have been used to treat glomus jugulare tumors (GJT). However, the optimal treatment of these tumors remains unclear. The authors report their data on treatment of GJTs with gamma knife radiosurgery (GKS). Retrospective review and pooled analysis. Fifteen patients (nine female, six male) were treated with GKS at a single tertiary care institution for GJTs over a 14-year period. Criteria for selection included GKS followed by at least one posttreatment radiographic image, and volumetric analysis was performed. A required 15% change in tumor volume was considered real. Pooled analysis was performed to compare outcomes with other series. The mean total radiologic follow-up was 43.2 months. The mean dose-to-the tumor margin was 14.6 Gy. The mean tumor size at treatment was 7.3 cc and 6.3 cc at last follow-up. After treatment, seven tumors decreased (46.7%), five remained unchanged (33.3%), and three (20%) grew on imaging. Treatment failures received a mean marginal dose of 13.2 Gy compared with 15.1 Gy for treatment successes (P =.08). Overall tumor control rate after GKS in the existing literature with inclusion of the present study is 90.5%. GKS is an effective treatment option for patients with GJTs, including those with prior surgical resection. Marginal radiation doses greater than 13 Gy may be optimal for tumor control. Longer follow-up will better define the benefits and risks of stereotactic radiosurgery in treating patients with GJT.


Human blood basophils synthesize interleukin-2 binding sites.
Recent data suggest that basophils express receptors for a variety of lymphokines. In this study we present the biochemical characterization of the interleukin-2 (IL-2) receptor on the basophil surface membrane. Highly enriched populations (purity: 92% to 99%) of blood basophils were obtained from chronic granulocytic leukemia (CGL) patients (n = 3) by negative selection using monoclonal antibodies (MoAbs) and complement. CGL basophils were found to bind CD25 MoAbs (n = 4) directed against different epitopes of the 55- to 60-Kd subunit of the IL-2 receptor (= Tac peptide). Immunoprecipitation experiments with lysates of purified CGL basophils and CD25 MoAbs showed a protein with a molecular weight of 60 Kd, equivalent to the Tac peptide on human T blasts. Quantitative binding studies and Scatchard plot analysis using radiolabeled recombinant human (rh) IL-2 indicated the presence of 12,000 +/- 4,700 low affinity IL-2 binding sites (kd = 66 nmol/L) per purified CGL basophil. Northern blot analysis with enriched CGL basophils showed two messenger RNA bands of 3.5 and 1.5 kilobases hybridizing to radiolabeled Tac cDNA. Immunoprecipitation of the Tac peptide from enriched basophils metabolically labeled with 35S-methionine showed active synthesis of the IL-2 receptor. Our results show that human blood basophils synthesize and express receptors for IL-2.


Rapid quantitative determination of cyanide in biological fluids from coyotes killed with a coyote getter.
A number of methods for the determination of cyanide in biological fluids have been published. Many are not really rapid or else rely on elaborate specialized equipment. The method reported here is rapid, uses only inexpensive disposable, and produces a quantitative result within 1 minute on as little as a few drops of blood. Cyanide concentrations found by this method in the blood of coyotes killed by sodium cyanide blasted into the mouth with a snub-nosed gun concealed in bait are given and discussed. Cyanide levels in blood from the left ventricle of the heart were always much higher than those from the right ventricle, and concentrations in the right ventricle were always very close to 700 micrograms/L.


Anticancer Effects of Mesothelin-Targeted Immunotoxin Therapy Are Regulated by Tyrosine Kinase DDR1.
Recombinant immunotoxins (RIT) have been highly successful in cancer therapy due, in part, to the high cancer-specific expression of cell surface antigens such as mesothelin, which is overexpressed in mesothelioma, ovarian, lung, breast, and pancreatic cancers, but is limited in normal cells. RG7787 is a clinically optimized RIT consisting of a humanized anti-mesothelin Fab fused to domain III of Pseudomonas exotoxin A, in which immunogenic B-cell epitopes are silenced. To enhance the therapeutic efficacy of RITs, we conducted a kinome RNAi sensitization screen, which identified discoidin domain receptor 1 (DDR1), a collagen-activated tyrosine kinase, as a potential target. The collagen/DDR1 axis is implicated in tumor-stromal interactions and potentially affects tumor response to therapy. Therefore, we investigated the effects of DDR1 on RIT. Knockdown of DDR1 by siRNA or treatment with inhibitor, 7rh, greatly enhanced the cytotoxic activity of RG7787 in several cancer cell lines. Investigation into the mechanism of action showed DDR1 silencing was associated with decreased expression of several ribosomal proteins and enhanced inhibition of protein synthesis. Conversely, induction of DDR1 expression or collagen-stimulated DDR1 activity protected cancer cells from RG7787 killing. Moreover, the combination of RG7787 and DDR1 inhibitor caused greater shrinkage of tumor xenografts than either agent alone. These data demonstrate that DDR1 is a key modulator of RIT activity and represents a novel therapeutic strategy to improve targeting of mesothelin-expressing cancers.


Antimicrobial activity of South African medicinal plants.
This paper reviews the antimicrobial research undertaken on South African medicinal plants during the period 1997-2008. Antimicrobial methods (disc diffusion, minimum inhibitory concentration (MIC), bio-autography) are briefly discussed and an analysis of the publications reviewed indicates that the majority of papers use MIC assays for antimicrobial determination. Antimicrobial investigations on extracts are presented where the most active plants are identified from screening publications. A summary of some bioactive compounds are given with data restricted to papers reporting quantitative antimicrobial activity equivalent to or below 200 microg/ml. Antimicrobial activities on the essential oils of indigenous medicinal aromatic plants are also reviewed. An overview is given on what activities (extracts, compounds and oils) should be considered noteworthy for publication. Studies focusing on geographical ethnobotany, specific pathogenesis, formulation aspects and in vivo investigations are examined. Future recommendations to consider include pathogen selection, interactive studies and dosage administrations.


Bipolar multi-electrode balloon catheter radiofrequency renal denervation with the Vessix system: preclinical safety evaluation.
A bipolar multi-electrode 7 Fr-compatible balloon-catheter radiofrequency (RF) renal denervation system (Vessix™ Renal Denervation System; Boston Scientific, Marlborough, MA, USA) was evaluated for safety in domestic swine. Renal arteries of 27 swine received overlapping treatments proximally/single treatments distally to mimic balloon overlap clinically. Each histopathology cohort (30, 90, 180 days) had four RF-treated and three sham-treated (no RF energy delivered) animals, with the response of artery/surrounding nerves to bilateral treatment examined (42 arteries). Scanning electron microscopy of the renal artery flow surface for endothelialisation was performed in six additional pigs (three at each of 30 and 90 days: 12 arteries) following unilateral whole artery treatment with proximal overlap: RF one side, sham the other side. Power was ~1 watt, treatment duration 30 seconds, target temperature 68°C. Renal histology and assessment for off-target injury was performed in all 27 swine. Renal artery thermal injury was transmural and segmental involving <10% to >90% of the circumference (typically 30-60%) with segmental neointimal hyperplasia exceeding shams but haemodynamically trivial (maximum stenosis 17.7%). Healing of necrotic arterial media was by replacement fibrosis. Overlying nerves also became fibrotic. Endothelialisation was focally incomplete at 30 days but confluent at 90 days. No off-target injury occurred outside the renal arteries. Safety was demonstrated.


A versatile and highly sensitive homogeneous electrochemical strategy based on the split aptamer binding-induced DNA three-way junction and exonuclease III-assisted target recycling.
Herein, a highly sensitive and versatile homogeneous electrochemical biosensing strategy is proposed, based on the split aptamer-incorporated DNA three-way junction and the exonuclease (Exo) III-assisted target recycling. The aptamer of adenosine triphosphate (ATP, chosen as the model analyte) is split into two fragments and embedded in single-stranded DNA1 and DNA2, respectively. ATP specifically binds with the split aptamers, bringing DNA1 and DNA2 close to each other, thus inducing the DNA three-way junction formation through the partial hybridization among DNA1, DNA2 and the methylene blue-labelled MB-DNA. Subsequently, MB-DNA is specifically digested by Exo III, releasing a MB-labelled mononucleotide, as well as a DNA1-ATP-DNA2 complex, which acts as the recycled target and hybridizes with another intact MB-DNA to initiate the subsequent cycling cleavage process. As a result, large amounts of MB-labelled mononucleotides are released, generating a significantly amplified electrochemical signal toward the ATP assay. To the best of our knowledge, it is the first example to successfully incorporate split aptamers into DNA three-way junctions and to be adopted in a homogeneous electrochemical assay. In addition to high sensitivity, this strategy also exhibits the advantages of simplicity and convenience, because it is carried out in a homogeneous solution, and sophisticated electrode modification processes are avoided. By simply changing the sequences of the split aptamer fragments, this versatile strategy can be easily adopted to assay a large spectrum of targets. Due to its advantages of high sensitivity, excellent selectivity, versatility and simple operation, the as-proposed approach has great potential to be applied in biochemical research and clinical practices.


Replication Timing of Human Telomeres is Conserved during Immortalization and Influenced by Respective Subtelomeres.
Telomeres are specific structures that protect chromosome ends and act as a biological clock, preventing normal cells from replicating indefinitely. Mammalian telomeres are replicated throughout S-phase in a predetermined order. However, the mechanism of this regulation is still unknown. We wished to investigate this phenomenon under physiological conditions in a changing environment, such as the immortalization process to better understand the mechanism for its control. We thus examined the timing of human telomere replication in normal and SV40 immortalized cells, which are cytogenetically very similar to cancer cells. We found that the timing of telomere replication was globally conserved under different conditions during the immortalization process. The timing of telomere replication was conserved despite changes in telomere length due to endogenous telomerase reactivation, in duplicated homologous chromosomes, and in rearranged chromosomes. Importantly, translocated telomeres, possessing their initial subtelomere, retained the replication timing of their homolog, independently of the proportion of the translocated arm, even when the remaining flanking DNA is restricted to its subtelomere, the closest chromosome-specific sequences (inferior to 500 kb). Our observations support the notion that subtelomere regions strongly influence the replication timing of the associated telomere.


System calibration and statistical image reconstruction for ultra-high resolution stationary pinhole SPECT.
For multipinhole single-photon emission computed tomography (SPECT), iterative reconstruction algorithms are preferred over analytical methods, because of the often complex multipinhole geometries and the ability of iterative algorithms to compensate for effects like spatially variant sensitivity and resolution. Ideally, such compensation methods are based on accurate knowledge of the position-dependent point spread functions (PSFs) specifying the response of the detectors to a point source at every position in the instrument. This paper describes a method for model-based generation of complete PSF lookup tables from a limited number of point-source measurements for stationary SPECT systems and its application to a submillimeter resolution stationary small-animal SPECT system containing 75 pinholes (U-SPECT-I). The method is based on the generalization over the entire object to be reconstructed, of a small number of properties of point-source responses which are obtained at a limited number of measurement positions. The full shape of measured point-source responses can almost be preserved in newly created PSF tables. We show that these PSFs can be used to obtain high-resolution SPECT reconstructions: the reconstructed resolutions judged by rod visibility in a micro-Derenzo phantom are 0.45 mm with 0.6-mm pinholes and below 0.35 mm with 0.3-mm pinholes. In addition, we show that different approximations, such as truncating the PSF kernel, with significant reduction of reconstruction time, can still lead to acceptable reconstructions.


The kinematics of far-near re-fixation saccades.
We have analyzed the three-dimensional spatiotemporal characteristics of saccadic refixations between far and near targets in three behaviorally trained rhesus monkeys. The kinematics underlying these rapid eye movements can be accurately described by rotations of the eyes in four different planes, namely, first disconjugate rotations in the horizontal plane of regard converging the eyes toward the near target, followed by rotations in each eye's vertical direction plane, and finally, disconjugate rotations in a common frontoparallel plane. This compounded rotation of the eye was underlying an initially fast-rising variable torsion that typically overshot the final torsion, which the eyes attained at the time of target acquisition. The torsion consisted of a coarse, widely varying component of opposite polarity in the two eyes, which contained a more robust, much smaller modulation that sharply increased toward the end of saccades. The reorientation of the eyes in torsion depended on each eye's azimuth, elevation, and target distance. We conclude that refixation saccades are generated by motor commands that control ocular torsion in concert with the saccade generator, which operates in Donders-Listing kinematics underlying Listing's law.


The effects of therapeutic ultrasound on heart rate variability: a placebo controlled trial.
The effect of therapeutic ultrasound (US) on nervous system is controversial and the effect on autonomic nervous system is not clear. Therefore, the present placebo-controlled trial was planned to investigate the effects of therapeutic US application on right-side stellate ganglion, by using analysis of heart rate variability (HRV). A total 12 healthy volunteers were included in the study. RR intervals were recorded for 5 min before and after the US application, in supine and sitting positions. All procedures were repeated in all participants with sham US one week later. The heart rate (HR) was obtained by time-domain analysis and low frequency (LF) power (%), high frequency (HF) power (%) and LF/HF ratio values were obtained by frequency-domain (power spectral density) analysis. After the US application, there was a decrease in the HR (p = 0.002) and the HF power (%) component (p = 0.015) in supine position and a decrease in HR (p = 0.002) and LF/HF ratio (p = 0.028) in sitting position. There was no significant difference after the sham US application. In conclusion, we observed that therapeutic US application on stellate ganglion causes alterations on HRV parameters.


[Arterial hypertension and its control in therapeutic districts of various polyclinics of the Lithuanian S.S.R].
Within the framework of integrated chronic noncommunicable disease prevention program, a study of the prevalence and control of hypertension was carried out in five randomly selected therapeutic districts of the Lithuanian SSR using the rapid diagnosis method of the Institute of Preventive Cardiology at the National Cardiology Center. In all, 2271 persons aged 15 years and more, were examined simultaneously in all therapeutic districts within five days by specially trained teams of investigators. Our findings showed high prevalence of hypertension among the population of the therapeutic districts (21.6%) and failure to attain its effective control. The comparison of the data obtained by this method with those of screening tests provided a convincing proof of the feasibility of rapid identification of risk factors as whole, and those relating to hypertension in particular, in large populations, thus making it useful for following the effectiveness of intervention trials.


MicroRNA-599-Regulated Susceptibility to Acute Kidney Injury in Patients with Cirrhosis is Mediated by the Sirtuin 1 (SIRT1) rs4746720 Single Nucleotide Polymorphism.
The aim of this case-control study was to analyze the association between sirtuin 1 (SIRT1) single nucleotide polymorphism (SNP) and the risk of acute kidney injury (AKI) in Han Chinese patients with cirrhosis and to explore its potential mechanism. Twenty-nine AKI patients with cirrhosis (AKI group) and 87 non-AKI patients with cirrhosis (control group) were recruited from a Han Chinese population. SNaPshot sequencing technology was used for the detection of SNPs. Dual luciferase reporter vectors were constructed and co-transfected into HK-2 human proximal tubular epithelial cells. SIRT1-overexpressing recombinant plasmids were constructed and co-transfected into HK-2 cells. The expression of microRNA-599 (miR-599) and SIRT1/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)/nuclear respiratory factor 1 (NRF1)/mitochondrial transcription factor A (TFAM) was detected by the quantitative polymerase chain reaction, and the expression of the corresponding proteins was detected by Western blotting. There were no statistically significant between-group differences in the genotype and allele frequencies of SIRT1 rs4746720. In the subgroup of patients with hepatic encephalopathy, the SIRT1 rs4746720 SNP was significantly associated with the development of AKI, and the risk of AKI in patients with the T allele was six times higher than in those with the C allele. The results of the in vitro experiments demonstrated that the T allele of SIRT1 rs4746720 increased the binding of miR-599 to the rs4746720 locus within the 3'-UTR of SIRT1 (p < 0.001). The results of the SIRT1-overexpressing recombinant plasmid experiments confirmed that the T allele of SIRT1 rs4746720 mediated the binding of miR-599, leading to decreased SIRT1 and PGC-1α, NRF1, and TFAM (p < 0.05). The SIRT1 rs4746720 SNP might be linked with AKI in cirrhotic patients, and the T allele increased the risk of AKI in those with hepatic encephalopathy. The rs4746720 SNP in the SIRT1 3'-UTR is linked to the development of AKI in cirrhotic patients with hepatic encephalopathy, potentially by mediating the binding of miR-599.


Utility of targeted sonography in the evaluation of focal breast pain.
To determine the utility of targeted sonography in the evaluation of patients with focal breast pain. From January 1995 through December 1999, 110 targeted sonographic examinations were performed in 99 patients for evaluation of focal breast pain in the absence of an associated palpable mass. The sonographic, mammographic, and clinical findings were reviewed. The hospital pathology database was searched to identify any interval cancers and false-negative interpretations. No cancer was identified in any of the 110 examinations. Eighty-five (77.3%) of the examinations had negative findings. Cysts were identified in 15 cases (13.6%), and 3 solid masses (2.7%) were identified. Two of these 3 solid masses had biopsies and were shown to be benign, whereas the third mass was followed for 29 months without change. Most patients were premenopausal, had no family or personal history of breast cancer, and were not taking exogenous hormones. Eighty-five patients (77%) were referred by primary care physicians. In patients with focal breast pain without an associated palpable mass, sonography may be more useful for patient reassurance than for cancer detection.


A randomized trial comparing digital and live lecture formats [ISRCTN40455708.
Medical education is increasingly being conducted in community-based teaching sites at diverse locations, making it difficult to provide a consistent curriculum. We conducted a randomized trial to assess whether students who viewed digital lectures would perform as well on a measure of cognitive knowledge as students who viewed live lectures. Students' perceptions of the digital lecture format and their opinion as whether a digital lecture format could serve as an adequate replacement for live lectures was also assessed. Students were randomized to either attend a lecture series at our main campus or view digital versions of the same lectures at community-based teaching sites. Both groups completed the same examination based on the lectures, and the group viewing the digital lectures completed a feedback form on the digital format. There were no differences in performance as measured by means or average rank. Despite technical problems, the students who viewed the digital lectures overwhelmingly felt the digital lectures could replace live lectures. This study provides preliminary evidence digital lectures can be a viable alternative to live lectures as a means of delivering didactic presentations in a community-based setting.


Antimicrobial therapy in periodontitis: the use of systemic antimicrobials against the subgingival biofilm.
The aim was to answer three relevant questions: can systemic antimicrobials be efficacious if the biofilm is not disrupted? Can the type of debridement of the subgingival biofilm impact upon the clinical outcomes of the adjunctive antimicrobial therapy? Is the efficacy of the adjunctive systemic antimicrobial therapy dependent on the quality of the debridement of the subgingival biofilm and the sequence debridement-antibiotic usage? Relevant papers were searched, critically analysed and their data were extracted. For the first question, studies assessing susceptibility of bacteria in biofilms, and clinical studies evaluating systemic antimicrobials as monotherapy, were reviewed. For the second question, clinical studies comparing systemic antimicrobials as adjuncts to non-surgical debridement or to periodontal surgery and clinical trials using systemic antibiotics with periodontal surgery were evaluated. For the third question, a previous systematic review was updated. If systemic antimicrobials are indicated in periodontal therapy, they should be adjunctive to mechanical debridement. There is not enough evidence to support their use with periodontal surgery. Indirect evidence suggests that antibiotic intake should start on the day of debridement completion, debridement should be completed within a short time (preferably <1 week) and with an adequate quality, to optimize the results.


Optical, magnetic, and electronic properties of peripherally fused macrocycles: molybdocene porphyrazines.
Metal-free and copper porphyrazines, [H(2)pz] and [Cu pz], have been fused at the periphery with molybdocene dithiolene, [Cp(2)Mo]. The optical, magnetic, and electronic properties of the resulting neutral and cationic complexes are studied, using first-principles density functional theory implemented by the discrete variational method. Analysis of the charge and spin distribution shows that the porphyrazine core is strongly coupled with the peripheral complex. The calculated optical absorption is found to be in reasonable agreement with experimental spectra, lending support to our theoretical model. Under appropriate circumstances one observes interaction of unpaired spins localized in the vicinity of both metal sites. The calculated spin distribution shows that [Cp(2)Mo][Cu pz] and [Cp(2)Mo][H(2)pz](+) have a magnetic moment of 1 micro(B) while [Cp(2)Mo][Cu pz](+) and [Cp(2)Mo][H(2)pz] have no moment, in good agreement with the results of X-band EPR spectra. The Cu-Mo magnetic interaction is antiferromagnetic, being mediated by pyrrol nitrogens, meso nitrogens, carbons, and sulfurs.


Ventricular atriopeptin. Unmasking of messenger RNA and peptide synthesis by hypertrophy or dexamethasone.
Left ventricular hypertrophy or treatment with dexamethasone caused a 2.5-fold to threefold increase in both immunoreactive atriopeptin (AP) and AP messenger RNA (mRNA), primarily in left ventricular tissue. The combined treatments increased immunoreactive AP and AP mRNA more than either treatment alone. In the animals in which cardiac hypertrophy had been produced by abdominal aortic constriction, there was a decrease in atrial levels of AP and an increase in plasma levels of immunoreactive AP. The increase in left ventricular immunoreactive AP was confirmed by immunohistochemical staining of tissue from hypertrophied and/or dexamethasone-treated rats. The mRNA accumulated in the left ventricle was identical to atrial AP mRNA, as judged by transcriptional start site and by size on Northern blots. Because the mass of ventricular tissue is substantially greater than that of atrial tissue, the induced mRNA levels may represent a total abundance approaching one third of the total AP mRNA in the atria. High performance liquid chromatographic purification of ventricular extracts primarily demonstrated the presence of the high molecular precursor and small amounts of C-terminal peptide AP. Induction of ventricular AP (mRNA and peptide) may represent regression of the tissue to an earlier developmental form. These data provide a unique example of regulation of AP biosynthesis in nonatrial tissue.


Genetic regulation of the antibody response to H-2Db alloantigens in mice. II. Tolerance to non-H-2 determinants abolishes the antibody response to H-2Db in B10.A(5R) mice.
B10.A(5R) mice (H-2i5), immunized with spleen cells from congenic B10 mice (H-2b), responded to alloantigens of the H-2Db region by producing antibodies of only IgM type. In contrast, they produced both IgM and IgG antibodies when immunized with noncongenic H-2b cells that carry other foreign cell surface antigens (non-H-2) in addition to H-2Db. A hypothesis was proposed comparing the H-2Db antigen on a congenic cell to a hapten on a nonimmunogenic carrier which fails to induce T-cell helper function responsible for the switch from IgM to IgG secretion in B cells. Data presented here confirmed this hypothesis. 5R mice rendered tolerant to the relevant non-H-2 antigens were unable to mount the anti-H-2Db IgG response in a noncongenic immunization. Tolerance induction did not lead to abrogation of the T-cell mediated cytotoxicity.


Design Parameters for a Small-Gauge Fragmatome.
Manufacturers of surgical instrumentation have increasingly sought to decrease the size of ophthalmic surgical instruments. We have used finite element modeling to model the stress and strain present in a fragmatome as a function of driving frequency and fragmatome dimensions. Finite element calculations using the COMSOL Multiphysics system v3.5 were used to elucidate the influence of wall thickness, length, and excitation frequency on a titanium fragmatome tube with outer diameters of 20, 23, 25, and 27 gauge. By coupling structural mechanics, fluid mechanics, and acoustical physics, we were able to determine the eigenfrequencies (resonant frequencies) as well as parameters in which the von Mises stress in a fragmatome tube exceeds the yield strength, leading to destruction of the instrument. Solid fragmatomes have far fewer possible failure modes than fragmatomes with a standard wall thickness. Eigenfrequency analysis and finite element calculations can be critical in predicting potentially catastrophic designs in modern surgical instruments. Instruments developed for microsurgical applications cannot always simply be scaled down versions of conventional instruments. Such an approach can lead to potentially dangerous intraoperative failures, such as a fragmatome shattering inside the eye. Modern engineering techniques are increasingly necessary to investigate potential instrument failure mechanisms and to optimize device performance in a design in silico before in vivo testing.


Perspectives on the Genomics of HSP Beyond Mendelian Inheritance.
Hereditary Spastic Paraplegia is an extraordinarily heterogeneous disease caused by over 50 Mendelian genes. Recent applications of next-generation sequencing, large scale data analysis, and data sharing/matchmaking, have discovered a quickly expanding set of additional HSP genes. Since most recently discovered HSP genes are rare causes of the disease, there is a growing concern of a persisting diagnostic gap, estimated at 30-40%, and even higher for sporadic cases. This missing heritability may not be fully closed by classic Mendelian mutations in protein coding genes. Here we show strategies and published examples of broadening areas of attention for Mendelian and non-Mendelian causes of HSP. We suggest a more inclusive perspective on the potential final architecture of HSP genomics. Efforts to narrow the heritability gap will ultimately lead to more precise and comprehensive genetic diagnoses, which is the starting point for emerging, highly specific gene therapies.


Fate of heterotrophic bacteria in Lake Tanganyika (East Africa).
Bacterial mortality was studied using two complementary methods between 2002 and 2004 in the two main basins (north and south) of Lake Tanganyika. The disappearance of radioactivity from the DNA of natural assemblages of bacteria previously labeled with tritiated thymidine was used to estimate the mortality due to grazing by predators (72%) and due to the cell lysis (28%). Measurements of ingestion rate of bacteria by protozoa using fluorescent micro-particles yielded protozoan grazing rates similar to those provided by the thymidine method, and showed that heterotrophic nano-flagellates were responsible for most of the grazing pressure on the bacterial community of the pelagic zone (92-99%). Bacterial cell lysis was the second process involved in bacterial mortality, ranking before ciliate grazing. Overall, bacterial mortality was balanced with bacterial production. With regard to the assessment of the trophic role of bacteria, it was estimated that c. 5-8% of the organic carbon taken up by bacteria was converted into protozoan biomass and was thus available for metazoans.


Poly r(C) binding protein (PCBP) 1 expression is regulated by the E3 ligase UBE4A in thyroid carcinoma.
Thyroid cancer patients with high miR-490-3p inhibit translation of PCBP1 mRNA, whereas in patients with low miR-490-3p PCBP1 mRNA expression is high; however, the resultant protein is targeted for degradation through the proteasome. The objective of the present study was to evaluate the molecular mechanism that regulates post-translation degradation of poly r(C) binding protein (PCBP) 1 expression in thyroid cancer cells. Mass spectrometric analysis of PCBP1 immunoprecipitates from MG-132 treated TPC1 cells revealed a list of ubiquitin ligases associated with PCBP1. RNAi-mediated silencing of the candidate ubiquitin ligases revealed that knockdown of the ubiquitin ligase UBE4A stabilized PCBP1 in TPC1 cells. Concurrent overexpression of the candidate ubiquitin ligases in the normal thyroid epithelial cell line Nthy-ori 3-1 confirmed that ubiquitin conjugation factor E4 A (UBE4A) is the ubiquitin ligase that is degrading PCBP1. Coimmunoprecipitation of HA-tagged PCBP1 in TPC1 cells cotransfected with FLAG-UBE4A revealed robust polyubiquitinated smear of PCBP1, thus confirming UBE4A as the ubiquitin ligase of PCBP1. UBE4A expression mimicked PCBP1 mRNA expression in thyroid cancer patients and was inversely correlated to PCBP1 protein expression. Low UBE4A expression level was associated with a better prognosis in thyroid cancer patients. Our data reveal a post-translational regulatory mechanism of regulating PCBP1 expression in thyroid cancer cells.


Dental abnormalities and preventive oral care in Schimke immuno-osseous dysplasia.
Schimke immuno-osseous dysplasia (SIOD) is a rare, severe, autosomal recessive disorder that results in spondyloepiphyseal dysplasia, renal dysfunction, immunodeficiency, facial dysmorphism and growth failure. Little is known about oral features associated with SIOD. Some of the dental anomalies encountered are specific to SIOD and have only been reported in individuals with SIOD. This paper describes the clinical and radiographic dental manifestations of SIOD in two Caucasian brothers. Both lived to be about 10 years old. After a variety of symptoms were reported, a diagnosis of SIOD was finally made when the brothers were, respectively, 5 and 8 years old. At that time, dental anomalies, such as dyschromia, bulbous crowns, short and thin roots, had not been taken into account to establish the diagnosis. However, knowledge of the dental features characteristic of this disease could have helped make the diagnosis. Although both were caries- and periodontal disease-free, special attention was focused on prevention, including dietary counselling, plaque control, oral hygiene instructions and the use of fluoridated toothpaste. The two patients were followed every 6 months, for over 2 years (until their death), by both a private dentist and a university hospital dentist, which helped them maintain good oral health. Oral hygiene was assessed at each appointment and fissure sealants were placed by the private practitioner on their first permanent molars. This report describes dental anomalies specific to SIOD that could facilitate diagnosis. Clinicians and dentists should work in collaboration to diagnose and treat children with SIOD. These patients require regular and specific dental management because of their fragile health and their characteristic dental anomalies. Ideally, preventive visits should be scheduled every 6 months in addition to curative visits as needed.


Trait-based analysis of decline in plant species ranges during the 20th century: a regional comparison between the UK and Estonia.
Although the distribution ranges and abundance of many plant species have declined dramatically in recent decades, detailed analysis of these changes and their cause have only become possible following the publication of second- and third-generation national distribution atlases. Decline can now be compared both between species and in different parts of species' ranges. We extracted data from distribution atlases to compare range persistence of 736 plant species common to both the UK and Estonia between survey periods encompassing almost the same years (1969 and 1999 in the UK and 1970 and 2004 in Estonia). We determined which traits were most closely associated with variation in species persistence, whether these were the same in each country, and the extent to which they explained differences in persistence between the countries. Mean range size declined less in Estonia than in the UK (24.3% vs. 30.3%). One-third of species in Estonia (239) maintained >90% of their distribution range compared with one-fifth (141) in the UK. In Estonia, 99 species lost >50% of their range compared with 127 species in the UK. Persistence was very positively related to original range in both countries. Major differences in species persistence between the studied countries were primarily determined by biogeographic (affiliation to floristic element) and ecoevolutionary (plant strategy) factors. In contrast, within-country persistence was most strongly determined by tolerance of anthropogenic activities. Decline of species in the families Orchidaceae and Potamogetonaceae was significantly greater in the UK than in Estonia. Almost all of the 736 common and native European plant species in our study are currently declining in their range due to pressure from anthropogenic activities. Those species with low tolerance of human activity, with biotic pollination vectors and in the families referred to above are the most vulnerable, especially where human population density is high.


Lack of Bdnf and TrkB signalling in the postnatal cochlea leads to a spatial reshaping of innervation along the tonotopic axis and hearing loss.
Members of the neurotrophin gene family and their high-affinity Trk receptors control innervation of the cochlea during embryonic development. Lack of neurotrophin signalling in the cochlea has been well documented for early postnatal animals, resulting in a loss of cochlear sensory neurones and a region-specific reduction of target innervation along the tonotopic axis. However, how reduced neurotrophin signalling affects the innervation of the mature cochlea is currently unknown. Here, we have analysed the consequences of a lack of the TrkB receptor and its ligand, the neurotrophin brain-derived neurotrophic factor (Bdnf), in the late postnatal or adult cochlea using mouse mutants. During early postnatal development, mutant animals show a lack of afferent innervation of outer hair cells in the apical part of the cochlea, whereas nerve fibres in the basal part are maintained. Strikingly, this phenotype is reversed during subsequent maturation of the cochlea, which results in a normal pattern of outer hair cell innervation in the apex and loss of nerve fibres at the base in adult mutants. Measurements of auditory brain stem responses of these mice revealed a significant hearing loss. The observed innervation patterns correlate with opposing gradients of Bdnf and Nt3 expression in cochlear neurones along the tonotopic axis. Thus, the reshaping of innervation may be controlled by autocrine signalling between neurotrophins and their receptors in cochlear neurones. Our results indicate a substantial potential for re-innervation processes in the mature cochlea, which may also be of relevance for treatment of hearing loss in humans.


Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data.
Osteoarthritis (OA) is a major debilitating disease affecting approximately 27 million persons in the US. Yet, the financial costs to patients and insurers remain poorly understood. The purpose of this study was to quantify by multivariate analyses the relationships between OA and annual health care expenditures borne by patients and insurers. Data from the Medical Expenditure Panel Survey (MEPS) for the years 1996-2005 were used. MEPS is a large, nationally representative US database that includes information on health care expenditures, medical conditions, health insurance status, and sociodemographic characteristics. Individual and nationally aggregated cost estimates are provided. OA was found to contribute substantially to health care expenditures. Among women, OA increased out-of-pocket (OOP) expenditures by $1,379 per annum (2007 dollars) and insurer expenditures by $4,833. Among men, OA increased OOP expenditures by $694 per annum and insurer expenditures by $4,036. Given the high prevalence of OA, the aggregate effects on health care expenditures were very large. OA raised aggregate annual medical care expenditures by $185.5 billion. Of that amount, insurer expenditures were $149.4 billion and OOP expenditures were $36.1 billion. Because of the greater prevalence of OA in women and their more intensive use of health care, total expenditures for this group accounted for $118 billion, or almost two-thirds of the total increase in health care expenditures resulting from OA. The health care cost burden associated with OA is quite large for all groups examined and is disproportionately higher for women. Although insurers bear the brunt of treatment costs for OA, the OOP costs are also substantial.


Predictors of Persistent Infant Car Seat Challenge Failure.
Premature and other at-risk infants can experience cardiorespiratory problems when positioned in their car seats. The American Academy of Pediatrics recommends that all premature and at-risk infants undergo a period of observation in their car seat to monitor for apnea, bradycardia, and oxygen desaturation before hospital discharge. This Infant Car Seat Challenge (ICSC) is used to determine readiness for infant travel in a car seat. Infants failing the ICSC are discharged home in car beds and referred for a follow-up screen in the outpatient clinic. The purpose of this study was to identify predictors for infants failing the follow-up ICSC after hospital discharge. A retrospective, cross-sectional study design was used to examine charts of 436 infants referred from across New England, to Boston Children's Hospital's, Center for Healthy Infant Lung Development clinic between August 2008 and May 2015 for a follow-up ICSC. Infants who failed the follow-up ICSC had statistically significant lower weights (0.27 ± 0.14 kg, difference ± standard error, P = .03) and younger postmenstrual ages (0.9 ± 0.4 weeks, P = .03). History of a cardiac condition (odds ratio, 3.6; 95% confidence interval, 1.5-8.5; P = .005) and respiratory illness (odds ratio, 2.1; confidence interval, 1.1 to 4.2; P = .03) were significant predictors of ICSC failure. A follow-up ICSC is recommended for the safe transition of infants from a car bed to a car seat. Further research is needed to investigate the causes of ICSC failure among high-risk infant populations.


The little elongation complex regulates small nuclear RNA transcription.
Eleven-nineteen lysine-rich leukemia (ELL) participates in the super elongation complex (SEC) with the RNA polymerase II (Pol II) CTD kinase P-TEFb. SEC is a key regulator in the expression of HOX genes in mixed lineage leukemia (MLL)-based hematological malignancies, in the control of induced gene expression early in development, and in immediate early gene transcription. Here, we identify an SEC-like complex in Drosophila, as well as a distinct ELL-containing complex that lacks P-TEFb and other components of SEC named the "little elongation complex" (LEC). LEC subunits are highly enriched at RNA Pol II-transcribed small nuclear RNA (snRNA) genes, and the loss of LEC results in decreased snRNA expression in both flies and mammals. The specialization of the SEC and LEC complexes for mRNA and snRNA-containing genes, respectively, suggests the presence of specific classes of elongation factors for each class of genes transcribed by RNA polymerase II.


Effects of family-centered empowerment intervention on stress, anxiety, and depression among family caregivers of patients with epilepsy.
Family caregivers face numerous challenges in taking care of their family members with epilepsy. The empowerment of this group of people, who can be described as forgotten patients, should always be considered through supportive interventions; therefore, this study investigated the effect of a family-centered intervention program on stress, anxiety, and depression among family caregivers of patients with epilepsy. In 2017, a trial was conducted in Iran among subjects selected by the convenience sampling method and randomly assigned to two groups: intervention and control. After five sessions per week over a four-week period, the intervention- and control-group data were collected using the Depression Anxiety Stress Scale (DASS) in three stages: before, immediately after, and two months after the intervention. Data were analyzed with Statistical Package for the Social Sciences (SPSS) software using descriptive and analytical statistics, an independent t-test, and repeated measures Analysis of variance (ANOVA). In this study, the family caregivers included 61.3% women and 38.7% men, with a mean age of 37.5 years. The findings showed no significant differences in the mean scores of stress (p = 0.93), anxiety (p = 0.91), and depression (p = 0.56) before the interventional program between the intervention and control groups, but these differences were statistically significant in the mean score of stress (p = 0.003) in the immediately after the interventional program, whereas the mean scores of depression were not decreased significantly (p = 0.3). Two months after the interventional program the mean scores of stress (p = 0.001) and anxiety (p = 0.001) were significantly decreased in the intervention group, but the mean score of depression was not decreased significantly (p = 0.09). The results suggested that a family-centered intervention program reduced the stress, anxiety, and depression of caregivers because of feasibility, simplicity, and utility of intervention. This program was focused on psychological issues of caregivers, and an emphasis on their empowerment helped them in managing their problems in the caregiving situation and achieved greater psychological potency in the caring process.


A phase II study of spirogermanium in patients with metastatic malignant melanoma. An NCI Canada Clinical Trials Group Study.
The National Cancer Institute of Canada Clinical Trials Group conducted a phase II study of spirogermanium given daily for 5 days every 3 weeks to previously untreated patients with malignant melanoma. In 21 evaluable patients one complete response was seen (response rate 5%). Disease progression occurred in the other 20 patients. Toxicity was primarily neurologic and mild or moderate in most patients, though there was one treatment related death. In this schedule spirogermanium has extremely limited activity against malignant melanoma and will not contribute significantly to the systemic therapy of this disease.


Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial.
X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated. Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed. Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants. Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study. Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).


Advances in computed radiography systems and their physical imaging characteristics.
Radiological imaging is progressing towards an all-digital future, across the spectrum of medical imaging techniques. Computed radiography (CR) has provided a ready pathway from screen film to digital radiography and a convenient entry point to PACS. This review briefly revisits the principles of modern CR systems and their physical imaging characteristics. Wide dynamic range and digital image enhancement are well-established benefits of CR, which lend themselves to improved image presentation and reduced rates of repeat exposures. However, in its original form CR offered limited scope for reducing the radiation dose per radiographic exposure, compared with screen film. Recent innovations in CR, including the use of dual-sided image readout and channelled storage phosphor have eased these concerns. For example, introduction of these technologies has improved detective quantum efficiency (DQE) by approximately 50 and 100%, respectively, compared with standard CR. As a result CR currently affords greater scope for reducing patient dose, and provides a more substantive challenge to the new solid-state, flat-panel, digital radiography detectors.


Pneumatically Actuated Soft Gripper with Bistable Structures.
This study presents the design and test of a novel self-adaptive soft gripper, integrating pneumatic actuators and bistable carbon-fiber reinforced polymer laminates. The morphology was designed using the distinct structural characteristics of bistable structures; and the stable gripping configuration of the gripper was maintained through the bistability without continuous pressure application. The sufficient compliance of bistable structures makes the gripper versatile and adaptable to gripping deformable objects. First, a pneumatic-actuated method was introduced to achieve the reversible shape transition of the bistable structure. Next, three arrangement methods for actuators were analyzed with respect to the bistable transition and curvature, where it was found that the cross-arrangement is optimal. The effects of pneumatic actuators with different geometrical parameters on the response times are discussed, and the results show that the bistable structure can achieve shape transition within milliseconds under low pressure. Furthermore, the numerical and experimental results show good agreement between critical pressures and out-of-plane deformation. Furthermore, the shape retention function of the soft gripper was studied by using it to grasp objects of various sizes even when the pressure was reduced to the initial state. The bistable laminates exhibit sufficient compliance, and the deformed laminates can automatically accommodate the deformation of objects. The relationship between the weight and size of available gripping objects was studied; functional tests confirmed that the proposed soft gripper is versatile and adaptable for gripping objects of various shapes, sizes, and weights. This gripper has immense potential to reduce energy consumption in vacuum environments such as underwater and space.


Genotypic characterization of Echinococcus granulosus isolates based on the mitochondrial cytochrome c oxidase 1 (cox1) gene in Northwest Iran.
Hydatidosis is one of the most important zoonotic parasitic diseases caused by the larval stage of Echinococcus granulosus which causes great health and economic losses. The aim of this study was to use the sequencing method to evaluate genotypes of E. granulosus isolated from humans and bovines using mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. The samples were taken in the East Azerbaijan Province, Northwest Iran. Overall, 26 hydatid cyst samples (10 human and 16 cattle isolates) were collected. DNA extraction was taken from the protoscoleces of human and germinal layer of bovine samples. PCR was performed using the mitochondrial cytochrome c oxidase subunit 1(cox1) gene, and then it was sequenced. Sequences were analyzed for identification of their genotypes. All 16 bovine isolates were recognized as G1 genotypes (sheep strain) and G1B subtypes. Out of ten human host samples, seven isolates were G1B subtypes, and three samples were identified as G3 genotypes. The results of this study showed that G1 and especially G1B are the predominant genotype and subtype in humans and cattle in Northwest Iran.


[Search for antibiotic antimetabolites].
Special media have been developed during the past years, which provided detection of new antibiotics with the properties of antimetabolites produced by microorganisms. Antimetabolites of amino acids, vitamins and nucleic acids were found among the antimetabolite antibiotics. The antimetabolites of nucleic acids with an antitumor activity were most interesting. This group of the compounds included 5-asacytidin and antibiotic 1719 identical to azotomycin.


A genetically unique Chinese cattle population shows evidence of common ancestry with wild species when analysed with a reduced ascertainment bias SNP panel.
In Hong Kong, there is a cattle population of ~1,200 individuals of uncertain origin and genetic diversity. This population shows heterogeneous morphology, both in body type and pigmentation. Once used as draught animals by the local farmers, they were abandoned around the 1970s due to changes in the economy, and since then have lived as feral populations. To explore the origins of these cattle, we analysed ~50k genotype data of 21 Hong Kong feral cattle, along with data from 703 individuals of 36 cattle populations of European, African taurine, and Asian origin, the wild x domestic hybrid gayal, plus two wild bovine species, gaur and banteng. To reduce the effect of ascertainment bias ~4k loci that are polymorphic in the two wild species were selected for further analysis. The stringent SNP selection we applied resulted in increased heterozygosity across all populations studies, compared with the full panel of SNP, thus reducing the impact of ascertainment bias and facilitating the comparison of divergent breeds of cattle. Our results showed that Hong Kong feral cattle have relatively high levels of genetic distinctiveness, possibly due to the low level of artificial selection, and a likely common ancestry with wild species. We found signs of a putative taurine introgression, probably dating to the import of north European breeds during the British colonialism of Hong Kong. We showed that Hong Kong feral cattle, are distinct from Bos taurus and Bos indicus breeds. Our results highlight the distinctiveness of Hong Kong feral cattle and stress the conservation value of this indigenous breed that is likely to harbour adaptive genetic variation, which is a fundamental livestock resource in the face of climate change and diversifying market demands.


Preperitoneal insufflation pressure of the abdominal wall in a porcine model.
Most complications and adverse events during laparoscopic surgery occur during initial entry into the peritoneal cavity. Among them, preperitoneal insufflation occurs when the insufflation needle is incorrectly placed, and the abdominal wall is insufflated. The objective of this study was to find a range for static pressure which is low enough to allow placement of a Veress needle into the peritoneal space without causing preperitoneal insufflation, yet high enough to separate abdominal viscera from the parietal peritoneum. A pressure test was performed on twelve fresh porcine carcasses to determine the minimum preperitoneal insufflation pressure and the minimum initial peritoneal cavity insufflation pressure. Each porcine model had five needle placement categories. One category tested the initial peritoneal cavity insufflation pressure beneath the umbilicus. The four remaining categories tested the preperitoneal insufflation pressure at four different anatomical locations on the abdomen that can be used for initial entry. The minimum initial insufflation pressures from each carcass were then compared to the preperitoneal insufflation pressures to obtain an optimal range for initial insufflation. Increasing the insufflation pressure increased the probability of preperitoneal insufflation. Also, there was a statistically significant difference (p < 0.05) between the initial peritoneal cavity insufflation pressures (8.83 ± 4.19 mmHg) and the lowest preperitoneal pressures (32.54 ± 7.84 mmHg) (mean ± SD). Pressures greater than 10 mmHg resulted in initial cavity insufflation and pressures greater than 20 mmHg resulted in preperitoneal insufflation in porcine models. By knowing the minimum pressure required to separate the layers of the abdominal wall, the risk of preperitoneal insufflation can be mitigated while obtaining safe and efficient entry into the peritoneal cavity. The findings in this research are not a guideline for trocar or Veress needle placement, but instead reveal preliminary data which may lead to more studies, technology, etc.


Monkeypox Presenting as a Hand Consult in the Emergency Department: Two Case Reports.
The ongoing outbreak of the monkeypox virus (now referred to as "mpox") was deemed a public health emergency by the World Health Organization in 2022. The United States now reports the highest number of mpox cases, with 29 980 cases and 21 deaths as of January 11, 2023. The most common presenting symptom is a pruritic, vesicular rash that commonly involves the hands. While covering hand call, our division has encountered 2 cases of mpox in the emergency department for which the chief complaint was a hand lesion. Because hand surgeons will be called upon to make an initial diagnosis, the purpose of these case reports is to describe the presentation, disease course, treatment, and outcomes of these mpox patients. These patients had both uncontrolled HIV as well as other sexually transmitted disease. Symptoms included painful vesicular hand lesions with ulceration and eventual central necrosis, followed by similar lesions on the face, trunk, and genital area. Diagnosis was made using nucleic acid amplification testing through polymerase chain reaction. The patients were treated with restoration of immunity through control of HIV as well as treatment of all secondary bacterial infections. One patient died in the hospital, and the other survived without any long-term defects.


Nanoparticulate assembly of mannuronic acid- and guluronic acid-rich alginate: oral insulin carrier and glucose binder.
The relationship of high and low molecular weight mannuronic acid (M)- and guluronic acid (G)-rich alginate nanoparticles as oral insulin carrier was elucidated. Nanoparticles were prepared through ionotropic gelation using Ca(2+) , and then in vitro physicochemical attributes and in vivo antidiabetic characteristics were examined. The alginate nanoparticles had insulin release retarded when the matrices had high alginate-to-insulin ratio or strong alginate-insulin interaction via OH moiety. High molecular weight M-rich alginate nanoparticles were characterized by assemblies of long polymer chains that enabled insulin encapsulation with weaker polymer-drug interaction than nanoparticles prepared from other alginate grades. They were able to encapsulate and yet release and have insulin absorbed into systemic circulation, thereby lowering rat blood glucose. High molecular weight G- and low molecular weight M-rich alginate nanoparticles showed remarkable polymer-insulin interaction. This retarded the drug release and negated its absorption. Blood glucose lowering was, however, demonstrated in vivo with insulin-free matrices of these nanoparticles because of the strong alginate-glucose binding that led to intestinal glucose retention. Alginate nanoparticles can be used as oral insulin carrier or glucose binder in the treatment of diabetes as a function of its chemical composition. High molecular weight M-rich alginate nanoparticles are a suitable vehicle for future development into oral insulin carrier.


Phenotypic characterization of lymphocytes in HCV/HIV co-infected patients.
While hepatitis C virus (HCV)-specific immune responses are attenuated in HCV/HIV co-infected patients compared to those infected with HCV alone, the reasons for this remain unclear. In this study, the proportions of regulatory, naïve, and memory T cells, along with chemokine receptor expression, were measured in co-infected and mono-infected patients to determine if there is an alteration in the phenotypic profile of lymphocytes in these patients. HCV/HIV co-infected patients had increased proportions of CD4(+) naïve cells and decreased proportions of CD4(+) effector cells when compared to HCV mono-infected patients. The proportions of CD4(+) Tregs and CD4(+) CXCR3(+) T cells were also significantly lower in co-infected patients. A decrease in CD4(+) Tregs and subsequent loss of immunosuppressive function may contribute to the accelerated progression to liver disease in co-infected individuals. Dysregulation of immune responses following reduction in the proportions of CD4(+) CXCR3(+) Th-1 cells may contribute to the reduced functional capacity of HCV-specific immune responses in co-infected patients. The findings of this study provide new information on the T-cell immunophenotype in HCV/HIV co-infected patients when compared to those infected with HCV alone, and may provide insight into why cell-mediated immune responses are diminished during HCV infection.


Responses in mice to Sj26, a glutathione S-transferase of Schistosoma japonicum worms.
The genetic variation in antibody responses of mice to glutathione S-transferase (GST) enzymes of Schistosoma japonicum worms, and in particular to a Mr 26,000 species termed Sj26, was analysed. Sera from infected mice, or mice immunized with adjuvant and an Sj26 beta-galactosidase fusion protein produced in Escherichia coli (Sj26FP), or purified near-native recombinant Sj26 produced in E. coli (rSj26), were assayed by enzyme-linked immunosorbent assay (ELISA) for antibody titres to GST purified from adult worms. Anti-GST antibody levels are high in a mouse strain, WEHI 129/J, that is genetically resistant to infection with S. japonicum. Antibody responses to GST are low in BALB/c mice and intermediate in most other mouse strains analysed such as CBA/H and C57B1/6. Responsiveness to Sj26 in adjuvant is dominant in (BALB/c x WEHI 129/J)F1 hybrids. BALB/c.H-2b and BALB/c.H-2k mice are higher responders than BALB/c. One feature of antibody responses to Sj26 is the variability within a group of mice. When rSj26 conjugated to the hapten azobenzenearsonate was used as immunogen, BALB/c mice produced substantial amounts of anti-Sj26 antibodies. In an attempt to correlate antibody levels with resistance in infected mice, a new functional assay was devised to measure the ability of sera to inhibit the binding of rSj26 to glutathione. However, there was no correlation between inhibitory titre in this assay and the numbers of worms recovered. In regard to the candidacy of GST as a vaccinating antigen in schistosomiasis japonica, the data raise the problem of variable responsiveness to the antigen that will need to be overcome by antigen modification and/or powerful adjuvants.


Genetic test reporting enhances understanding of risk information and acceptance of prevention recommendations compared to family history-based counseling alone.
It is unknown whether or why genetic test reporting confers benefits in the understanding and management of cancer risk beyond what patients learn from counseling based on family history. A prospective nonexperimental control group study compared participants from melanoma-prone families who underwent CDKN2A/p16 (p16) genetic testing (27 carriers, 38 noncarriers) to participants from equivalently melanoma-prone families known not to carry a deleterious p16 mutation (31 no-test controls). All participants received equivalent counseling concerning elevated lifetime melanoma risk and corresponding recommendations for prevention and screening. Both immediately and 1 month after counseling, participants receiving a genetic test result reported greater understanding of their risk, decreased derogation of the risk information, and greater personal applicability of prevention recommendations than no-test controls. Decreased derogation of risk information after test reporting predicted further increases in understanding of melanoma risk and applicability of prevention recommendations 1 month later. Results suggest unique benefits of genetic test reporting in promoting understanding and acceptance of information about hereditary cancer risk and its management.


Markov chain Monte Carlo for mapping a quantitative trait locus in outbred populations.
A Bayesian approach is presented for mapping a quantitative trait locus (QTL) using the 'Fernando and Grossman' multivariate Normal approximation to QTL inheritance. For this model, a Bayesian implementation that includes QTL position is problematic because standard Markov chain Monte Carlo (MCMC) algorithms do not mix, i.e. the QTL position gets stuck in one marker interval. This is because of the dependence of the covariance structure for the QTL effects on the adjacent markers and may be typical of the 'Fernando and Grossman' model. A relatively new MCMC technique, simulated tempering, allows mixing and so makes possible inferences about QTL position based on marginal posterior probabilities. The model was implemented for estimating variance ratios and QTL position using a continuous grid of allowed positions and was applied to simulated data of a standard granddaughter design. The results showed a smooth mixing of QTL position after implementation of the simulated tempering sampler. In this implementation, map distance between QTL and its flanking markers was artificially stretched to reduce the dependence of markers and covariance. The method generalizes easily to more complicated applications and can ultimately contribute to QTL mapping in complex, heterogeneous, human, animal or plant populations.