Type 2 diabetes mellitus is a heterogeneous inherited disorder characterized by chronic hyperglycemia resulting from pancreatic β-cell dysfunction and insulin resistance. Although the pathogenic ...mechanisms are not fully understood, manifestation of the disease most likely requires interaction between both environmental and genetic factors. In the search for such susceptibility genes, we have performed a genomewide scan in 58 multiplex families (comprising 440 individuals, 229 of whom were affected) from the Botnia region in Finland. Initially, linkage between chromosome 12q24 and impaired insulin secretion had been reported, by Mahtani et al., in a subsample of 26 families. In the present study, we extend the initial genomewide scan to include 32 additional families, update the affectation status, and fine map regions of interest, and we try to replicate the initial stratification analysis. In our analysis of all 58 families, we identified suggestive linkage to one region, chromosome 9p13-q21 (nonparametric linkage NPL score 3.9;
P<.0002). Regions with nominal
P values <.05 include chromosomes 2p11 (NPL score 2.0
P<.03), 3p24-p22 (NPL score 2.2
P<.02), 4q32-q33 (NPL score 2.5
P<.01), 12q24 (NPL score 2.1
P<.03), 16p12-11 (NPL score 1.7
P<.05), and 17p12-p11 (NPL score 1.9
P<.03). When chromosome 12q24 was analyzed in only the 32 additional families, a nominal
P value <.04 was observed. Together with data from other published genomewide scans, these findings lend support to the hypothesis that regions on chromosome 9p13-q21 and 12q24 may harbor susceptibility genes for type 2 diabetes.
The Laser Interferometer Gravitational Wave Observatory (LIGO) consists of two widely separated 4 km laser interferometers designed to detect gravitational waves from distant astrophysical sources in ...the frequency range from 10 Hz to 10 kHz. The first observation run of the Advanced LIGO detectors started in September 2015 and ended in January 2016. A strain sensitivity of better than 10 super(-23)/radicalHz was achieved around 100 Hz. Understanding both the fundamental and the technical noise sources was critical for increasing the astrophysical strain sensitivity. The average distance at which coalescing binary black hole systems with individual masses of 30Mmiddot could be detected above a signal-to-noise ratio (SNR) of 8 was 1.3 Gpc, and the range for binary neutron star inspirals was about 75 Mpc. With respect to the initial detectors, the observable volume of the Universe increased by a factor 69 and 43, respectively. These improvements helped Advanced LIGO to detect the gravitational wave signal from the binary black hole coalescence, known as GW150914.
Low serum ferritin concentrations at birth, which reflect neonatal iron stores, track through to early childhood and have been associated with poorer neurodevelopmental outcomes. We aimed to identify ...maternal, antenatal and birth-associated factors that influence iron stores at birth in a prospective maternal-infant birth cohort.
In a population-based, longitudinal, birth cohort in Ireland, 413 maternal-infant dyads with prospectively collected lifestyle and clinical data from 15 weeks' gestation had umbilical cord serum ferritin concentrations measured. Regression models were developed to identify independent factors associated with cord ferritin concentrations.
Median (IQR) cord ferritin concentrations were 185.7 (131.7, 385.5) μg/l, and 8% (n=33) of infants had low iron stores (ferritin <76 μg/l) at birth. Maternal obesity (BMI ⩾30 kg/m
) at 15 weeks' gestation (adj. estimate (95% confidence interval (CI)): -66.4 (-106.9, -25.9) μg/l, P<0.0001) and delivery by caesarean section (-38.8 (-70.2, -7.4) μg/l, P=0.016) were inversely associated with cord ferritin concentrations. In addition, maternal smoking at 15 weeks' gestation (adj. odds ratio (95% CI): 2.9 (1.2, 7), P=0.020) and being born small-for-gestational age (3.4 (1.3, 8.9), P=0.012) were associated with an increased risk of low iron stores (ferritin <76 μg/l) at birth.
We have identified a number of potentially modifiable lifestyle factors that influence iron stores at birth, with the important role of overall maternal health and lifestyle during pregnancy highlighted. Public health policies targeting women of child-bearing age to improve nutrition and health outcomes should be prioritised for the health of the next generation.
The mechanisms that regulate functional adaptation of the articular ends of long bones are poorly understood. However, endochondral ossification of articular cartilage and modeling/remodeling of the ...subchondral plate and epiphyseal trabeculae are important components of the adaptive response. We performed a histologic study of the distal end of the third metacarpal/metatarsal bone of Thoroughbreds after bones were bulk-stained in basic fuchsin and calcified sections were prepared. The Thoroughbred racehorse is a model of an extreme athlete which experiences particularly high cyclic strains in distal limb bones. The following variables were quantified: microcrack boundary density in calcified cartilage (N.Cr/B.Bd); blood vessel boundary density in calcified cartilage (N.Ve/B.Bd); calcified cartilage width (Cl.Cg.Wi); duplication of the tidemark; and bone volume fraction of the subchondral plate (B.Ar/T.Ar). Measurements were made in five joint regions (lateral condyle and condylar groove; sagittal ridge; medial condylar and condylar groove). N.Cr/B.Bd was site-specific and was increased in the condylar groove region; this is the joint region from which parasagittal articular fatigue (condylar) fractures are typically propagated. Formation of resorption spaces in the subchondral plate was co-localized with microcracking. N.Ve/B.Bd was also site-specific. In the sagittal ridge region, N.Ve/B.Bd was increased, Cl.Cg.Wi was decreased, and B.Ar/T.Ar was decreased, when compared with the other joint regions. Multiple tidemarks were seen in all joint regions. Cumulative athletic activity was associated with a significant decrease in B.Ar/T.Ar in the condylar groove regions. N.Cr/B.Bd was positively correlated with B.Ar/T.Ar (
P < 0.05,
r
s = 0.29) and N.Ve/B.Bd was negatively correlated with B.Ar/T.Ar (
P < 0.005,
r
2 = 0.14) and Cl.Cg.Wi (
P < 0.05,
r
2 = 0.07). We conclude that endochondral ossification of articular cartilage and modeling/remodeling of the subchondral plate promote initiation and propagation of site-specific fatigue microcracking of the joint surface, respectively, in this model. Microcracking of articular calcified cartilage likely represents mechanical failure of the joint surface. Propagation of microcracks into the subchondral plate is a critical factor in the pathogenesis of articular condylar fatigue (stress) fracture. Functional adaptation of the joint likely protects hyaline cartilage from injury in the short-term but may promote joint degeneration and osteoarthritis with ongoing athleticism.
Background
Pre-eclampsia (PE) is associated with vascular endothelial dysfunction and oxidative stress initiated by impaired trophoblast invasion. Oxidative stress modifies circulating low-density ...lipoprotein (LDL) to oxidized LDL (oxLDL). Lectin-like oxLDL receptor-1 (LOX-1) is a scavenger receptor for oxLDL. We hypothesized that plasma from patients with PE alters LOX-1 in normal human vessels during pregancy, causing oxLDL-induced impairment of vascular function.
Methods
Control-matched plasma was obtained from women with PE (n = 6). Oxidized LDL and soluble LOX-1 levels were determined by enzyme-linked immunoassay (ELISA). Remaining plasma was pooled and stored at -80ºC. Human omental arteries were incubated in 3% plasma from normal pregnant (NP) women or plasma from women with PE. Expression of LOX-1 in these vessels was determined by immunohistochemistry with antibodies against LOX-1. The omental vessels were exposed to oxLDL and the LOX-1 inhibitor TS20. Vascular function was assessed in response to the vasoconstrictor U46619 and the vasodilators bradykinin (BK) and sodium nitroprusside (SNP).
Results
No significant differences in the concentrations of oxLDL or soluble LOX-1 (sLOX-1) were found in plasma from women with PE as compared with NP women. The expression of LOX-1 was not significantly different in either the NP or PE incubated omental vessels. Incubation of vessels from NP women in plasma from women with PE impaired their relaxation in response to BK as compared with that of NP vessels incubated in plasma from NP women. Exposure to oxLDL further impaired relaxation in NP vessels incubated with plasma from women with PE. Inhibition of LOX-1 protected against the impairment of vascular relaxation induced by plasma from women with PE.
Conclusion
Inhibition of LOX-1 prevents endothelial dysfunction in an in vitro model of PE and may prove useful as a therapeutic target in the treatment of PE.
Purpose:
Pubertal suppression is standard of care for early pubertal transgender youth to prevent the development of undesired and distressing secondary sex characteristics incongruent with gender ...identity. Preliminary evidence suggests pubertal suppression improves mental health functioning. Given the widespread changes in brain and cognition that occur during puberty, a critical question is whether this treatment impacts neurodevelopment.
Methods:
A Delphi consensus procedure engaged 24 international experts in neurodevelopment, gender development, puberty/adolescence, neuroendocrinology, and statistics/psychometrics to identify priority research methodologies to address the empirical question: is pubertal suppression treatment associated with real-world neurocognitive sequelae? Recommended study approaches reaching 80% consensus were included in the consensus parameter.
Results:
The Delphi procedure identified 160 initial expert recommendations, 44 of which ultimately achieved consensus. Consensus study design elements include the following: a minimum of three measurement time points, pubertal staging at baseline, statistical modeling of sex in analyses, use of analytic approaches that account for heterogeneity, and use of multiple comparison groups to minimize the limitations of any one group. Consensus study comparison groups include untreated transgender youth matched on pubertal stage, cisgender (i.e., gender congruent) youth matched on pubertal stage, and an independent sample from a large-scale youth development database. The consensus domains for assessment includes: mental health, executive function/cognitive control, and social awareness/functioning.
Conclusion:
An international interdisciplinary team of experts achieved consensus around primary methods and domains for assessing neurodevelopmental effects (i.e., benefits and/or difficulties) of pubertal suppression treatment in transgender youth.
BackgroundHypertensive disorders of pregnancy (HDP) have been linked to adverse neurodevelopmental outcomes, including attention deficit hyperactivity disorder (ADHD). However, limitations of the ...literature such as residual confounding, and confounding due to shared genetics need to be addressed before more definitive conclusions can be reached. Therefore, the objective of this study was to examine the association between HDP and ADHD, using large Swedish-based registry data, allowing us to control for a wide range of confounding factors including confounding due to shared genetics.MethodsAll singleton live births in Sweden from 1990 to 2010 were included in the study. Data on HDP were obtained from the Medical Birth Register, and included three exposures of interest: 1. Preeclampsia 2. Chronic hypertension (both of which were classified according to ICD-9 and ICD-10 coding) 3. Preeclampsia and small for gestational age (SGA) combined, used as a proxy for the recent inclusion of uteroplacental dysfunction in the definition of preeclampsia. Data on ADHD was obtained from the National Patient Register and Prescribed Drug Register. A diagnosis of ADHD was determined in one of two ways: 1. If a diagnosis of ADHD was present in the National Patient Register, using ICD-10 coding. 2. If an individual was in receipt of ADHD medication, classified according to Anatomical Therapeutic Chemical classification system. Multivariate Cox proportional hazards regression analysis was conducted, adjusting for several perinatal and sociodemographic factors, selected a priori from previous literature. Sibling-matched analysis further controlled for shared genetic and familial confounding when an association was present in the adjusted Cox model.ResultsThe cohort consisted of 2,047,619 children, with 114,934 (5.6%) cases of ADHD. In the adjusted Cox model, preeclampsia was associated with a 15% increase in the likelihood of ADHD (Hazard Ratio (HR): 1.15, 95% CI: 1.12, 1.19) compared to those unexposed to preeclampsia. Result of the sibling-matched analysis did not change materially (HR: 1.13, 95% CI: 1.05, 1.22). The HR for preeclampsia and those born SGA was 1.43 (95% CI: 1.31, 1.55) in the adjusted model, and 1.55 (95% CI: 1.28, 1.88) in the sibling-matched analysis. The HR for chronic hypertension-ADHD was 1.07 (95% CI: 0.97, 1.18) in the adjusted Cox model.ConclusionExposure to preeclampsia or preeclampsia/SGA (i.e. SGA baby exposed to preeclampsia) was associated with ADHD, while chronic hypertension was not associated with ADHD. Placental pathology may be a common factor increasing the likelihood of ADHD given the stronger association with preeclampsia/SGA than preeclampsia alone.
Surfaces containing 4 × 8 × 40 μm staggered rhombus posts were hydrophobized using two methods. One, using a dimethyldichlorosilane reaction in the vapor phase, introduces a smooth modified layer, ...and the other, a solution reaction using methyltrichlorosilane, imparts a second (nanoscopic) length scale of topography. The smooth modified surface exhibits contact angles of θA/θR = 176°/156°. Arguments are made that the pinning of the receding contact line by the post tops (with θA/θR = 104°/103°) is responsible for the hysteresis. The second level of topography raises the contact angles of the post tops and the macroscopic sample to θA/θR = >176°/>176° and eliminates hysteresis. The increase in Laplace pressure due to the increase in the advancing contact angle of the post tops is a second reason that two length scales of topography are important.
The Far Ultraviolet Spectroscopic Explorer satellite observes light in the far-ultraviolet spectral region, 905-1187 Å, with a high spectral resolution. The instrument consists of four co-aligned ...prime-focus telescopes and Rowland spectrographs with microchannel plate detectors. Two of the telescope channels use Al:LiF coatings for optimum reflectivity between approximately 1000 and 1187 Å, and the other two channels use SiC coatings for optimized throughput between 905 and 1105 Å. The gratings are holographically ruled to correct largely for astigmatism and to minimize scattered light. The microchannel plate detectors have KBr photocathodes and use photon counting to achieve good quantum efficiency with low background signal. The sensitivity is sufficient to examine reddened lines of sight within the Milky Way and also sufficient to use as active galactic nuclei and QSOs for absorption-line studies of both Milky Way and extragalactic gas clouds. This spectral region contains a number of key scientific diagnostics, including O VI, H I, D I, and the strong electronic transitions of H2 and HD.
Objective
The objective was to evaluate the findings and diagnostic accuracy of ultrasound in antero-lateral ankle impingement (ALI) with clinical and arthroscopic correlation.
Design and patients
...Seventeen elite footballers with chronic ankle pain were referred for ultrasound with a clinical diagnosis of ALI (
n
= 8) or a control condition (
n
= 9; lateral mechanical instability, osteochondral defect, intra-articular bodies and osteoarthritis). Ultrasound examination included the antero-lateral gutter for abnormal synovial tissue (synovitic lesion), lateral ligament integrity, tibiotalar joint and osseous spurs of the distal tibia and talus. Ultrasound findings were correlated with subsequent arthroscopic appearance.
Results
Ultrasound examination detected a synovitic mass in the antero-lateral gutter in all 8 footballers with clinical ALI (100%) and in 2 patients with a control diagnosis (22%). Arthroscopic correlation of antero-lateral synovitis and fibrosis was present in all 10 cases (100%). The synovitic lesion was seen at ultrasound as a nodular soft tissue mass of mixed echogenicity within the antero-lateral gutter, which extruded anteriorly with manual compression of the distal fibula against the tibia. Increased blood supply was detected using power Doppler imaging in only 1 patient. The synovitic lesion measured >10 mm in its maximum dimension in 7 footballers with clinical ALI and <10 mm in the control group. Additional ultrasound findings in patients with abnormal antero-lateral synovial tissue included an anterior talofibular ligament injury in all patients (
n
= 10), a tibiotalar joint effusion (
n
= 6) and osseous spurs (
n
= 4). Antero-lateral synovitic tissue was accurately identified at ultrasound in the absence of an effusion (
n
= 4). No synovitic lesion was detected at ultrasound or arthroscopy in the remaining 7 patients with a control diagnosis.
Conclusion
Ultrasound is accurate in detecting synovitic lesions within the antero-lateral gutter, demonstrating associated ligamentous injuries and in differentiating soft tissue from osseous impingement. Synovitic lesions in two control patients suggest that abnormal antero-lateral soft tissue does not necessarily imply the presence of symptomatic ALI. Synovitic lesions in excess of 10 mm were associated with symptoms. Ultrasound will not demonstrate osteocartilaginous lesions or stress fractures and may overlook some loose bodies. Ultrasound findings together with clinical correlation can be used to direct arthroscopic examination and surgical debridement.
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