By adapting OPT to include the capability of imaging in the near infrared (NIR) spectrum, we here illustrate the possibility to image larger bodies of pancreatic tissue, such as the rat pancreas, and to increase the number of channels (cell types) that may be studied in a single specimen. We further describe the implementation of a number of computational tools that provide: 1/ accurate positioning of a specimen's (in our case the pancreas) centre of mass (COM) at the axis of rotation (AR)2; 2/ improved algorithms for post-alignment tuning which prevents geometric distortions during the tomographic reconstruction2 and 3/ a protocol for intensity equalization to increase signal to noise ratios in OPT-based BCM determinations3. In addition, we describe a sample holder that minimizes the risk for unintentional movements of the specimen during image acquisition. Together, these protocols enable assessments of BCM distribution and other features, to be performed throughout the volume of intact pancreata or other organs (e.g. in studies of islet transplantation), with a resolution down to the level of individual islets of Langerhans.
Medicine; Issue 71; Biomedical Engineering; Cellular Biology; Molecular Biology; Biophysics; Pancreas; Islets of Langerhans; Diabetes Mellitus; Imaging; Three-Dimensional; Optical Projection Tomography; Beta-cell Mass; Near Infrared; Computational Processing
Neisseria meningitidis is a major cause of sepsis and bacterial meningitis worldwide. This bacterium expresses type IV pili (Tfp), which mediate important virulence traits such as the formation of bacterial aggregates, host cell adhesion, twitching motility, and DNA uptake. The meningococcal PilT protein is a hexameric ATPase that mediates pilus retraction. The PilU protein is produced from the pilT-pilU operon and shares a high degree of homology with PilT. The function of PilT in Tfp biology has been studied extensively, whereas the role of PilU remains poorly understood. Here we show that pilU mutants have delayed microcolony formation on host epithelial cells compared to the wild type, indicating that bacterium-bacterium interactions are affected. In normal human serum, the pilU mutant survived at a higher rate than that for wild-type bacteria. However, in a murine model of disease, mice infected with the pilT mutant demonstrated significantly reduced bacterial blood counts and survived at a higher rate than that for mice infected with the wild type. Infection of mice with the pilU mutant resulted in a trend of lower bacteremia, and still a significant increase in survival, than that of the wild type. In conclusion, these data suggest that PilU promotes timely microcolony formation and that both PilU and PilT are required for full bacterial virulence.
Long-term sickness absence is one of the main risk factors for permanent exit out of the labour market. Early identification of the condition is essential to facilitate return to work. The aim of this study was to analyse possible determinants of return to work and their relative impact.
All 943 subjects aged 18 to 63 years, sickness certified at a Primary Health Care Centre in Sweden from 1 January until 31 August 2004, were followed up for three years. Baseline information on sex, age, sick leave diagnosis, employment status, extent of sick leave, and sickness absence during the year before baseline was obtained, as was information on all compensated days of sick leave, disability pension and death during follow-up.
Slightly more than half the subjects were women, mean age was 39 years. Half of the study population returned to work within 14 days after baseline, and after three years only 15 subjects were still on sick leave. In multivariate proportional hazards regression analysis the extent of previous sick leave, age, being on part-time sick leave, and having a psychiatric, musculoskeletal, cardiovascular, nervous disease, digestive system, or injury or poisoning diagnosis decreased the return to work rate, while being employed increased it. Marital status, sex, being born in Sweden, citizenship, and annual salary had no influence. In logistic regression analyses across follow-up time these variables altogether explained 88-90% of return to work variation.
Return to work was positively or negatively associated by a number of variables easily accessible in the GP’s office. Track record data in the form of previous sick leave was the most influential variable.
The anticancer prodrug 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) selectively releases a short-lived cytotoxin following enzymatic reduction in hypoxic environments found in solid tumors. KS119, in addition to two enantiomers, has two stable atropisomers (conformers differing in structure owing to hindered bond rotation) that interconvert at 37 °C in aqueous solution by first order kinetics with t1/2 values of ~50 and ~64 hours. The atropisomers differ in physical properties such as partition coefficients that allow their chromatographic separation on non-chiral columns. A striking difference in the rate of metabolism of the two atropisomers occurs in intact EMT6 murine mammary carcinoma cells under oxygen deficient conditions. A structurally related molecule, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(3-hydroxy-4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119WOH), was also found to exist in similar stable atropisomers. The ratio of the atropisomers of KS119 and structurally related agents has the potential to impact the bioavailability, activation and therapeutic activity. Thus, thermally stable atropisomers/conformers in small molecules can result in chemically and enantiomerically pure compounds having differences in biological activities.
KS119; prodrug; atropisomers; conformers; hypoxia; targeting; cytotoxicity; chemotherapy
Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.
RESEARCH DESIGN AND METHODS
We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.
Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.
We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
An understanding of the occurrence and comparative timing of influenza infections in different age groups is important for developing community response and disease control measures. This study uses data from a Scandinavian county (population 427.000) to investigate whether age was a determinant for being diagnosed with influenza 2005–2010 and to examine if age was associated with case timing during outbreaks. Aggregated demographic data were collected from Statistics Sweden, while influenza case data were collected from a county-wide electronic health record system. A logistic regression analysis was used to explore whether case risk was associated with age and outbreak. An analysis of variance was used to explore whether day for diagnosis was also associated to age and outbreak. The clinical case data were validated against case data from microbiological laboratories during one control year. The proportion of cases from the age groups 10–19 (p<0.001) and 20–29 years old (p<0.01) were found to be larger during the A pH1N1 outbreak in 2009 than during the seasonal outbreaks. An interaction between age and outbreak was observed (p<0.001) indicating a difference in age effects between circulating virus types; this interaction persisted for seasonal outbreaks only (p<0.001). The outbreaks also differed regarding when the age groups received their diagnosis (p<0.001). A post-hoc analysis showed a tendency for the young age groups, in particular the group 10–19 year olds, led outbreaks with influenza type A H1 circulating, while A H3N2 outbreaks displayed little variations in timing. The validation analysis showed a strong correlation (r = 0.625;p<0.001) between the recorded numbers of clinically and microbiologically defined influenza cases. Our findings demonstrate the complexity of age effects underlying the emergence of local influenza outbreaks. Disentangling these effects on the causal pathways will require an integrated information infrastructure for data collection and repeated studies of well-defined communities.
Thoracic aortic aneurysm (TAA) is a common complication in patients with a bicuspid aortic valve (BAV), the most frequent congenital heart disorder. For unknown reasons TAA occurs at a younger age, with a higher frequency in BAV patients than in patients with a tricuspid aortic valve (TAV), resulting in an increased risk for aortic dissection and rupture. To investigate the increased TAA incidence in BAV patients, we obtained tissue biopsy samples from nondilated and dilated aortas of 131 BAV and TAV patients. Global gene expression profiles were analyzed from controls and from aortic intima-media and adventitia of patients (in total 345 samples). Of the genes found to be differentially expressed with dilation, only a few (<4%) were differentially expressed in both BAV and TAV patients. With the use of gene set enrichment analysis, the cell adhesion and extracellular region gene ontology sets were identified as common features of TAA in both BAV and TAV patients. Immune response genes were observed to be particularly overexpressed in the aortic media of dilated TAV samples. The divergent gene expression profiles indicate that there are fundamental differences in TAA etiology in BAV and TAV patients. Immune response activation solely in the aortic media of TAV patients suggests that inflammation is involved in TAA formation in TAV but not in BAV patients. Conversely, genes were identified that were only differentially expressed with dilation in BAV patients. The result has bearing on future clinical studies in which separate analysis of BAV and TAV patients is recommended.
Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10−41 and rs6258, p = 2.3×10−22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10−16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.
Testosterone is the most important testicular androgen in men. Low serum testosterone concentrations are associated with cardiovascular morbidity, metabolic syndrome, type 2 diabetes mellitus, atherosclerosis, osteoporosis, sarcopenia, and increased mortality risk. Thus, there is growing evidence that serum testosterone is a valuable biomarker of men's overall health status. Studies in male twins indicate that there is a strong heritability of serum testosterone. Here we perform a large-scale genome-wide association study to examine the effects of common genetic variants on serum testosterone concentrations. By examining 14,429 men, we show that genetic variants in the sex hormone-binding globulin (SHBG) locus and on the X chromosome are associated with a substantial variation in serum testosterone concentrations and increased risk of low testosterone. The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone. Importantly, we identified the first known genetic variant, which affects SHBG's affinity for binding testosterone and the free testosterone fraction and could therefore influence the calculation of free testosterone. This finding suggests that individual-based SHBG-testosterone affinity constants are required depending on the genotype of this single-nucleotide polymorphism.
Bacterial auto-aggregation is a critical step during adhesion of N. meningitidis to host cells. The precise mechanisms and functions of bacterial auto-aggregation still remain to be fully elucidated. In this work, we characterize the role of a meningococcal hypothetical protein, NMB0995/NMC0982, and show that this protein, here denoted NafA, acts as an anti-aggregation factor. NafA was confirmed to be surface exposed and was found to be induced at a late stage of bacterial adherence to epithelial cells. A NafA deficient mutant was hyperpiliated and formed bundles of pili. Further, the mutant displayed increased adherence to epithelial cells when compared to the wild-type strain. In the absence of host cells, the NafA deficient mutant was more aggregative than the wild-type strain. The in vivo role of NafA in sepsis was studied in a murine model of meningococcal disease. Challenge with the NafA deficient mutant resulted in lower bacteremia levels and mortality when compared to the wild-type strain. The present study reveals that meningococcal NafA is an anti-aggregation factor with strong impact on the disease outcome. These data also suggest that appropriate bacterial auto-aggregation is controlled by both aggregation and anti-aggregation factors during Neisseria infection in vivo.
Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10−36), SULT2A1 (rs2637125; p = 2.61×10−19), ARPC1A (rs740160; p = 1.56×10−16), TRIM4 (rs17277546; p = 4.50×10−11), BMF (rs7181230; p = 5.44×10−11), HHEX (rs2497306; p = 4.64×10−9), BCL2L11 (rs6738028; p = 1.72×10−8), and CYP2C9 (rs2185570; p = 2.29×10−8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
Dehydroepiandrosterone sulphate (DHEAS), mainly secreted by the adrenal gland, is the most abundant circulating steroid in humans. It shows a significant physiological decline after the age of 25 and diminishes about 95% by the age of 85 years, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. Twin- and family-based studies have shown that there is a substantial genetic effect with heritability estimate of 60%, but no specific genes regulating serum DHEAS concentration have been identified to date. Here we take advantage of recent technical and methodological advances to examine the effects of common genetic variants on serum DHEAS concentrations. By examining 14,846 Caucasian individuals, we show that eight common genetic variants are associated with serum DHEAS concentrations. Genes at or near these genetic variants include BCL2L11, ARPC1A, ZKSCAN5, TRIM4, HHEX, CYP2C9, BMF, and SULT2A1. These genes have various associations with steroid hormone metabolism—co-morbidities of ageing including type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins—suggesting a wider functional role for DHEAS than previously thought.
Advanced technical systems and analytic methods promise to provide policy
makers with information to help them recognize the consequences of
alternative courses of action during pandemics. Evaluations still show that
response programs are insufficiently supported by information systems. This
paper sets out to derive a protocol for implementation of integrated
information infrastructures supporting regional and local pandemic response
programs at the stage(s) when the outbreak no longer can be contained at its
Nominal group methods for reaching consensus on complex problems were used to
transform requirements data obtained from international experts into an
implementation protocol. The analysis was performed in a cyclical process in
which the experts first individually provided input to working documents and
then discussed them in conferences calls. Argument-based representation in
design patterns was used to define the protocol at technical, system, and
pandemic evidence levels.
The Protocol for a Standardized information infrastructure for Pandemic and
Emerging infectious disease Response (PROSPER) outlines the implementation
of information infrastructure aligned with pandemic response programs. The
protocol covers analyses of the community at risk, the response processes,
and response impacts. For each of these, the protocol outlines the
implementation of a supporting information infrastructure in hierarchical
patterns ranging from technical components and system functions to pandemic
The PROSPER protocol provides guidelines for implementation of an information
infrastructure for pandemic response programs both in settings where
sophisticated health information systems already are used and in developing
communities where there is limited access to financial and technical
resources. The protocol is based on a generic health service model and its
functions are adjusted for community-level analyses of outbreak detection
and progress, and response program effectiveness. Scientifically grounded
reporting principles need to be established for interpretation of
information derived from outbreak detection algorithms and predictive
The global spread of a novel A (H1N1) influenza virus in 2009 has highlighted the possibility of a devastating pandemic similar to the ‘Spanish flu’ of 1917–1918. Responding to such pandemics requires careful planning for the early phases where there is no availability of pandemic vaccine. We set out to compute a Neighborhood Influenza Susceptibility Index (NISI) describing the vulnerability of local communities of different geo-socio-physical structure to a pandemic influenza outbreak. We used a spatially explicit geo-physical model of Linköping municipality (pop. 136,240) in Sweden, and employed an ontology-modeling tool to define simulation models and transmission settings. We found considerable differences in NISI between neighborhoods corresponding to primary care areas with regard to early progress of the outbreak, as well as in terms of the total accumulated share of infected residents counted after the outbreak. The NISI can be used in local preparations of physical response measures during pandemics.
Prenatal life exposures, potentially manifested as altered birth size, may influence the later risk of major chronic diseases through direct biologic effects on disease processes, but also by modifying adult behaviors such as physical activity that may influence later disease risk.
We investigated the association between birth weight and leisure time physical activity (LTPA) in 43,482 adolescents and adults from 13 Nordic cohorts. Random effects meta-analyses were performed on categorical estimates from cohort-, age-, sex- and birth weight specific analyses. Birth weight showed a reverse U-shaped association with later LTPA; within the range of normal weight the association was negligible but weights below and above this range were associated with a lower probability of undertaking LTPA. Compared with the reference category (3.26–3.75 kg), the birth weight categories of 1.26–1.75, 1.76–2.25, 2.26–2.75, and 4.76–5.25 kg, had odds ratios of 0.67 (95% confidence interval: 0.47, 0.94), 0.72 (0.59, 0.88), 0.89 (0.79, 0.99), and 0.65 (0.50, 0.86), respectively. The shape and strength of the birth weight-LTPA association was virtually independent of sex, age, gestational age, educational level, concurrent body mass index, and smoking.
The association between birth weight and undertaking LTPA is very weak within the normal birth weight range, but both low and high birth weights are associated with a lower probability of undertaking LTPA, which hence may be a mediator between prenatal influences and later disease risk.
Poor mental health has large social and economic consequences both for the individual and society. In Sweden, the prevalence of mental health symptoms has increased since the beginning of the 1990s. There is a need for a better understanding of the area for planning preventive activities and health care.
The study is based on a postal survey questionnaire sent to a random sample of men and women aged 18–84 years in 2004. The overall response rate was 64%. The area investigated covers 55 municipalities with about one million inhabitants in central part of Sweden. The study population includes 42,448 respondents. Mental health was measured with self-reported symptoms of anxiety/depression (EQ-5D, 5th question). The association between socio-economic conditions, lifestyle factors and mental health symptoms was investigated using multivariate multinomial logistic regression models.
About 40% of women and 30% of men reported that they were moderately or extremely anxious or depressed. Younger subjects reported poorer mental health than older subjects, the best mental health was found at ages 65–74 years.
Factors that were strongly and independently related to mental health symptoms were poor social support, experiences of being belittled, employment status (receiving a disability pension and unemployment), economic hardship, critical life events, and functional disability. A strong association was also found between how burdensome domestic work was experienced and anxiety/depression. This was true for both men and women. Educational level was not associated with mental health symptoms.
Of lifestyle factors, physical inactivity, underweight and risk consumption of alcohol were independently associated with mental health symptoms.
Our results support the notion that a ground for good mental health includes balance in social relations, in domestic work and in employment as well as in personal economy both among men and women. In addition, physical inactivity, underweight and risk consumption of alcohol are associated with mental health symptoms independent of socio-economic factors.
AIM: To elucidate the differences in somatic, psycho-logical and biochemical pattern between the subtypes of irritable bowel syndrome (IBS).
METHODS: Eighty IBS patients, 30 diarrhoea predominant (D-IBS), 16 constipation predominant (C-IBS) and 34 alternating IBS (A-IBS) underwent physiotherapeutic examinations for dysfunctions in body movements and awareness and were compared to an apparently healthy control group (AHC). All groups answered questionnaires for gastrointestinal and psychological symptoms. Biochemical variables were analysed in blood.
RESULTS: The D-IBS group showed less body awareness, less psychological symptoms, a more normal sense of coherence and psychosocial rating as well as higher C-peptide values. C-IBS had a higher degree of body dysfunction and psychological symptoms, as well as the lowest sense of coherence compared to controls and D-IBS. They also demonstrated the most elevated prolactin levels. A-IBS had the lowest degree of body disturbance, deteriorated quality of life and affected biochemical pattern. All subtypes had higher pain scores compared to controls. In addition they all had significantly increased triglycerides and elevated morning cortisol levels, however, without statistical significance compared with the controls.
CONCLUSION: IBS subtypes showed different profiles in body awareness, somatic and psychological symptoms and in biochemical variables. D-IBS differed compared to the other groups by lowered body awareness, less psychological symptoms and a higher sense of coherence and elevated C-peptide values. C-IBS and A-IBS subtypes suffered more from depression and anxiety, associated with a lower quality of life. These differences may be important and will be taken into account in our treatment of these patients.
Irritable bowel syndrome subtypes; Physiotherapy; Body awareness; Stress; Biochemistry
The immune response against the infecting group A streptococcus (GAS) extracellular products (EP) was determined in acute- and convalescent-phase sera from 75 patients with different clinical manifestations of GAS infection. All EP elicited a high proliferative response in human peripheral blood mononuclear cells. In patients with bacteremia, low neutralization in acute-phase sera was associated with development of streptococcal toxic shock syndrome. Lack of neutralization in acute-phase sera was more common in patients infected with the T1emm1 serotype. The majority of patients did not develop the ability to neutralize the mitogenic activity of their infecting isolate despite a significant increase in enzyme-linked immunosorbent assay titer in early convalescent-phase sera. In patients with the ability to neutralize GAS EP, the immune response remained high over at least 3 years. In contrast, the neutralization capacity conferred by intravenous immunoglobulin and/or plasma treatment disappeared within 3 months.
Selective estrogen receptor modulators (SERMs) have been developed in order to create means to control estrogenic effects on different tissues. A major drawback in treatment of estrogen receptor (ER) positive breast cancer with the antagonist tamoxifen (TAM) is its agonistic effect in the endometrium. Raloxifene (RAL) is the next generation of SERMs where the agonistic effect on the endometrium has been reduced.
The aim of the present study was to determine the effect of SERM treatment on the uterus, as assessed by proliferation markers and several factors involved in uterine growth. Ovariectomized (ovx) rats were treated with estradiol (E2), tamoxifen (TAM), RAL, ICI182780 (ICI) or vehicle (OVX-controls). We studied the effects on mRNA levels of the growth hormone (GH) receptor, insulin-like growth factor-I (IGF-I), ERα and ERβ. In addition, by immunohistochemistry the proliferation markers PCNA and Ki-67, as well as ERα and ERβ, were detected.
The uterine weight of the rats treated with E2 or TAM was increased as compared to OVX-controls. The uterine GH-receptor mRNA level was highest in the E2 treated animals. In ICI treated rats no GH-receptor mRNA could be detected. The IGF-I mRNA level increased 16-fold in uteri of the TAM treated group and 9-fold in the E2 treated rats as compared to OVX-controls. The ERα mRNA level was increased in the E2 treated rats, while the ERβ mRNA level was increased after TAM treatment. The proliferation, as assessed by PCNA, was lowest in ICI treated animals.
The uterine wet weight, the LE height and the GH-receptor mRNA levels showed similar patterns, indicating that GH is involved in the regulation of uterine weight. Tamoxifen, which has been related to increased incidence of endometrial carcinoma in women, dramatically increased IGF-I mRNA levels in rat uterus. Since proliferation was not higher in TAM and E2 treated rats than in OVX controls, this assay of simple, early proliferation does not give the full explanation of why TAM should enhance the risk of developing endometrial cancer.
The previous suggestion that streptococcal superantigen SpeF might be identical to DNase B was confirmed in this study. Polyclonal SpeF-specific antisera were able to inhibit depolymerization of methyl-green DNA by DNase B. However, T-cell mitogenicity and nuclease activity appear to involve separate immune epitopes on SpeF, since sera with the capacity to neutralize the mitogenic activity of SpeF did not always inhibit the DNase activity.
Twelve patients with familial amyloidosis with polyneuropathy were examined both by cross sectional echocardiography and by technetium-99m pyrophosphate scintigraphy to assess involvement of the heart non-invasively. All 12 patients had echocardiographic abnormalities. The most prominent findings were highly refractile myocardial echoes, thickened heart valves, and increased thickness of the heart walls. Four patients had abnormal myocardial uptake of technetium-99m pyrophosphate. The remaining eight had equivocal or no myocardial uptake and were considered to have normal scintigrams. A certain amount of amyloid is probably required to produce an abnormal scintigram, although lesions with less amyloid can evidently be identified by echocardiography. Neither the duration of polyneuropathy nor its severity showed any relation to the echocardiographic or scintigraphic findings. It is concluded that cross sectional echocardiography is superior to technetium-99m pyrophosphate scintigraphy in detecting cardiac involvement in familial amyloidosis with polyneuropathy and that these results may also be applicable to other forms of amyloidosis.
Aortic valve calcification (AVC), even without haemodynamic significance, may be prognostically import as an expression of generalized atherosclerosis, but techniques for echocardiographic assessment are essentially unexplored.
Two-dimensional (2D) echocardiographic recordings (Philips IE33) of the aortic valve in short-axis and long-axis views were performed in 185 consecutive patients within 1 week before surgery for aortic stenosis (n = 109, AS), aortic regurgitation (n = 61, AR), their combination (n = 8) or dilation of the ascending aorta (n = 7). The grey scale mean (GSMn) of the aortic valve in an end-diastolic short-axis still frame was measured. The same frame was scored visually 1–5 as indicating that the aortic valve was normal, thick, or had mild, moderate or severe calcification. The visual echodensity of each leaflet was determined real time applying the same 5-grade scoring system for each leaflet, and the average for the whole valve was calculated. Finally, a similar calcification score for the whole valve based on inspection and palpation by the surgeon was noted.
Visual assessment of real-time images using the proposed scoring system showed better correlation with the surgical evaluation of the degree of valve calcification (r = 0·83, P<0·001) compared to evaluation of stop frames by visual assessment (r = 0·66, P<0·001) or the GSMn score (r = 0·64, P<0·001). High inter- and intra-observer correlations were observed for real-time visual score (both intraclass correlation coefficient = 0·93).
Real-time evaluation of the level of AVC is superior to using stop frames assessed either visually or by dedicated computer grey scale measurement software.
aortic regurgitation; aortic stenosis; grey scale; sclerosis; ultrasound
Medicine & Public Health; Orthopedics
To map health outcome related variables from a national register, not part of any validated instrument, with EQ-5D weights among stroke patients.
We used two cross-sectional data sets including patient characteristics, outcome variables and EQ-5D weights from the national Swedish stroke register. Three regression techniques were used on the estimation set (n = 272): ordinary least squares (OLS), Tobit, and censored least absolute deviation (CLAD). The regression coefficients for “dressing“, “toileting“, “mobility”, “mood”, “general health” and “proxy-responders” were applied to the validation set (n = 272), and the performance was analysed with mean absolute error (MAE) and mean square error (MSE).
The number of statistically significant coefficients varied by model, but all models generated consistent coefficients in terms of sign. Mean utility was underestimated in all models (least in OLS) and with lower variation (least in OLS) compared to the observed. The maximum attainable EQ-5D weight ranged from 0.90 (OLS) to 1.00 (Tobit and CLAD). Health states with utility weights <0.5 had greater errors than those with weights ≥0.5 (P < 0.01).
This study indicates that it is possible to map non-validated health outcome measures from a stroke register into preference-based utilities to study the development of stroke care over time, and to compare with other conditions in terms of utility.
Mapping; Quality of life; Stroke; Sweden; Transfer to utility; Utility
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
The decline in sea cucumber fisheries that serve the Asian dried seafood market has prompted an increase in global sea cucumber aquaculture. The tropical sandfish (Holothuria scabra) has, in this context, been reared and produced with mixed success. In the Western Indian Ocean, villagers often participate in the export fishery for sea cucumbers as a source of income. However, with a growing concern of depleted stocks introduction of hatcheries to farm sandfish as a community livelihood and to replenish wild stocks is being promoted. This review identifies and discusses a number of aspects that constitute constraints or implications with regard to development of sandfish farming in the region. The conclusion is that for sandfish farming to live up to its expectations the possible impacts need to be further studied, and that improved evaluation of ongoing projects is required. In the interim, a precautionary approach toward new enterprise activities is suggested.
Sandfish; Holothuria scabra; Farming; Re-stocking; Environmental impacts; Governance
STAT4 is an important transcription factor that contributes to the incidence and severity of different autoimmune diseases and is implicated in the antiviral immune responses in mice. In this study, we evaluated the role of STAT4 in human and murine herpes simplex virus 2 (HSV-2) infections. We show that STAT4 regulates antiviral gamma interferon (IFN-γ) responses and disease severity during chronic HSV-2 infections in humans and vaccine-induced IFN-γ-mediated protection against HSV-2 infection in mice. In a cohort of 228 HSV-2-infected individuals, representing both patients with recurrent disease and asymptomatic HSV-2 carriers, we found that genetic variations in the STAT4 gene were associated with asymptomatic HSV-2 infection, as well as with increased in vitro secretion of IFN-γ in response to the virus. Mice that lacked STAT4 had impaired HSV-2-specific IFN-γ production and delayed-type hypersensitivity responses following vaccination, which led to impaired viral clearance in the genital tract of vaccinated animals after a genital HSV-2 challenge. We conclude that STAT4 plays an important role in IFN-γ-mediated HSV-2-specific immunity, affecting the severity of genital HSV-2 infection.