Precise Intraoperative 60° Skin Z-plasty

The primary objective of this tip is to assist foot and ankle surgeons in performing a precise 60° lengthening Z-plasty in the operating room without the use of a template or protractor. A ruler and basic trigonometric principles are applied to the line of contracture to obtain consistent and reliable results.     

Unaltered negative selection and Treg development of self‐reactive thymocytes in TCR transgenic Fyn‐deficient mice

The tyrosine kinase Fyn has been implicated as playing an important role in the generation of both stimulatory and inhibitory signaling events induced by TCR engagement. To assess the role of Fyn for antigen‐driven negative selection and Treg development, which are both dependent on the strength and nature of TCR signaling, we generated mice that co‐express the transgenes for OVA and the OT‐II TCR, which recognizes a peptide from OVA. In mice expressing both transgenes, negative selection, Treg development in the thymus, and the number of Treg in the periphery were each unaffected by ablation of Fyn. Moreover, fyn^?/? Treg were functional, as assessed in vitro. We further tested the role of Fyn for the adaptor function of c‐Cbl, using mice containing a point mutation in c‐Cbl that abolishes its E3 ubiquitin ligase function but maintains its adaptor function. The functional and signaling properties of this mutant c‐Cbl were unaltered in fyn^?/? thymocytes. Combined, these data indicate that Fyn was not required for the induction of central tolerance by negative selection, the adaptor protein role of c‐Cbl, or the normal development and function of Treg.     

Shorter telomeres may indicate dementia status in older individuals with Down syndrome

We have recently reported reduced telomere length in T lymphocytes of individuals with Down syndrome (DS) and dementia due to Alzheimer's disease (AD). We have now replicated and extended that study by finding that people with DS and mild cognitive impairment (MCI-DS) also have shorter telomeres than people with DS without MCI-DS. Additional new findings demonstrated that light intensity measurements from chromosome 21 alone, or in concert with chromosomes 1, 2, and 16, exhibited shorter telomeres in adults with DS and with either dementia or MCI-DS compared to aging per se. Chromosome 21 measurements appeared to be especially promising for use as a biomarker because there was no overlap in the distribution of light intensity measurement scores between demented or MCI-DS and non-demented participants. Given that early clinical symptoms of AD can be very difficult to recognize in this population of adults due to their pre-existing cognitive impairments, a valid biomarker would be of great value. Early detection is especially important because it would allow treatments to begin before significant damage to the central nervous system has occurred. Our findings suggest that it may be feasible to use telomere shortening as a biomarker for accurately inferring dementia status.     

Bacteroides fragilis RecA protein overexpression causes resistance to metronidazole

Bacteroides fragilis is a human gut commensal and an opportunistic pathogen causing anaerobic abscesses and bacteraemias which are treated with metronidazole (Mtz), a DNA damaging agent. This study examined the role of the DNA repair protein, RecA, in maintaining endogenous DNA stability and its contribution to resistance to Mtz and other DNA damaging agents. RT-PCR of B. fragilis genomic DNA showed that the recA gene was co-transcribed as an operon together with two upstream genes, putatively involved in repairing oxygen damage. A B. fragilis recA mutant was generated using targeted gene inactivation. Fluorescence microscopy using DAPI staining revealed increased numbers of mutant cells with reduced intact double-stranded DNA. Alkaline gel electrophoresis of the recA mutant DNA showed increased amounts of strand breaks under normal growth conditions, and the recA mutant also showed less spontaneous mutagenesis relative to the wild type strain. The recA mutant was sensitive to Mtz, ultraviolet light and hydrogen peroxide. A B. fragilis strain overexpressing the RecA protein exhibited increased resistance to Mtz compared to the wild type. This is the first study to show that overexpression of a DNA repair protein in B. fragilis increases Mtz resistance. This represents a novel drug resistance mechanism in this bacterium.     

Trophoblast- and Vascular Smooth Muscle Cell-Derived MMP-12 Mediates Elastolysis during Uterine Spiral Artery Remodeling

During the first trimester of pregnancy, the uterine spiral arteries are remodeled, creating heavily dilated conduits that lack maternal vasomotor control but allow the placenta to meet an increasing requirement for nutrients and oxygen. To effect permanent vasodilatation, the internal elastic lamina and medial elastin fibers must be degraded. In this study, we sought to identify the elastolytic proteases involved in this process. Primary first-trimester cytotrophoblasts (CTBs) derived from the placenta exhibited intracellular and membrane-associated elastase activity; membrane-associated activity was primarily attributable to matrix metalloproteinases (MMP). Indeed, Affymetrix microarray analysis and immunocytochemistry implicated MMP-12 (macrophage metalloelastase) as a key mediator of elastolysis. Cultured human aortic smooth muscle cells (HASMCs) exhibited constitutive membrane-associated elastase activity and inducible intracellular elastase activity; these cells also expressed MMP-12 protein. Moreover, a specific inhibitor of MMP-12 significantly reduced CTB- and HASMC-mediated elastolysis in vitro, to 31.7 ± 10.9% and 23.3 ± 8.7% of control levels, respectively. MMP-12 is expressed by both interstitial and endovascular trophoblasts in the first-trimester placental bed and by vascular SMCs (VSMCs) in remodeling spiral arteries. Perfusion of isolated spiral artery segments with CTB-conditioned medium stimulated MMP-12 expression in medial VSMCs. Our data support a model in which trophoblasts and VSMCs use MMP-12 cooperatively to degrade elastin during vascular remodeling in pregnancy, with the localized release of elastin peptides and CTB-derived factors amplifying elastin catabolism.Transformation of the uterine spiral arteries during the first 20 weeks of gestation ensures that a constant supply of blood is delivered to the developing placenta, at an optimal rate of flow.^1–3 This allows the placenta to meet an increasing requirement for nutrients and oxygen and enables the developing fetus to attain its growth potential. The remodeling process leads to vessel dilatation, loss of spirality, and decreased vasoactivity, allowing a nonpulsatile low-pressure supply of blood to be delivered to placental villi at the maternofetal interface. Early alterations in arterial structure include endothelial vacuolation, hypertrophy of vascular smooth muscle cells (VSMCs), and disruption of medial smooth muscle layers, which occur in the absence of fetal-derived trophoblast and correlate with perivascular accumulation of macrophages and uterine natural killer (uNK) cells.^4,5 After colonization of the uterine decidua and myometrium by extravillous cytotrophoblast (EVT), endothelial cells and VSMCs are lost from the arterial wall and replaced by trophoblast embedded in a fibrinoid matrix. Remodeling is regulated in a spatial and temporal manner, such that the successive steps of trophoblast adherence, intravasation, fibrinoid deposition, and mural incorporation are effected without any loss in vessel integrity. A complex and highly orchestrated combination of vascular cell apoptosis, dedifferentiation, and matrix breakdown is probably required to achieve this alteration in vessel wall structure.^5–9Two distinct populations of EVT originate from anchoring placental villi and contribute to vessel transformation.^10,11 Interstitial EVT invade the uterine wall, migrating through the decidua and myometrium to adopt a perivascular position. Endovascular EVT enter the lumen of the spiral arteries and migrate as far as the first third of the myometrium, colonizing the arterial wall from within. Impaired arterial remodeling is distinguished by shallow EVT invasion, decreased numbers of EVT, and the persistence of muscular, narrow-bore arteries, and is associated with second trimester miscarriage,¹² preterm labor,¹³ pre-eclampsia,¹⁴ and fetal growth restriction.¹⁵To effect a permanent increase in vessel diameter it is crucial that elastin fibers within each artery are catabolized, eliminating their capacity for stretch and recoil. Myometrial segments of the spiral arteries possess an internal elastic lamina (IEL), and the musculo-elastic media of both decidual and myometrial arteries is rich in elastic fibers.^16,17 During pregnancy, EVT traverse the IEL during mural incorporation,¹⁸ thus it is highly likely that they possess elastase activity: indeed, first-trimester EVT synthesize and secrete the elastolytic proteases matrix metalloproteinase-2 (MMP-2), MMP-7, MMP-9, cathepsin B, and cathepsin L.^19,20 Although both uNK cells and macrophages produce enzymes capable of elastolysis,⁵ uNK cells are not abundant in myometrium,²¹ and elastin breakdown is associated with the presence of endovascular EVT¹⁷ rather than macrophages.²² Previous studies have demonstrated that the availability of nitric oxide (NO) can influence protease expression and activity,^23–26 and we have shown NO to be an important regulator of trophoblast function.^27–29 As dysregulation of NO production has been implicated in the pathogenesis of pre-eclampsia and intrauterine growth restriction (IUGR),^30–32 NO availability may regulate the process of arterial remodeling by controlling trophoblast elastolysis.Rodent models of atherosclerosis have highlighted a role for VSMC-derived cathepsins as mediators of IEL breakdown during lesion formation,³³ demonstrating that the arterial wall may be a potential source of elastases. Similarly, caspase-2, −3, and −7 derived from apoptotic VSMCs have been implicated as mediators of elastin breakdown.³⁴ Thus, during the process of spiral artery transformation, resident VSMCs may also be stimulated to produce elastase(s) in response to pregnancy hormones, trophoblast invasion, or soluble factors released by cells within the placental bed. In this study we have investigated the origin and identity of the proteases involved in mediating elastin breakdown during spiral artery remodeling.     

Anxiety, depression and saliva cortisol in women with a medical disorder during pregnancy

Anxiety and depression during pregnancy increase the risk for an adverse pregnancy outcome and neurodevelopmental problems in the child. The aim of this study was to investigate anxiety and depression in women with a medical disorder of pregnancy compared with control antenatal women, and any association with saliva cortisol. One hundred and twenty pregnant women (60 with a known medical disorder and 60 without, mean gestation 32 weeks) completed five self-rating questionnaires (Spielberger State and Trait Anxiety, Edinburgh Postnatal Depression Scale (EPDS), the Adult Wellbeing Scale and a Life Events Questionnaire). Diurnal saliva samples were obtained from 39 women with a medical disorder and 50 controls for cortisol analysis. The medical disorders group were significantly more anxious and depressed than the controls (mean (SD)) state anxiety 40.0 (11.5) vs. 31.6 (8.8), p = 0.00; trait anxiety 39.4 (9.5) vs. 35.2 (9.2), p = 0.02; adult wellbeing 15.9 (7.5) vs. 12.3 (7.5) p = 0.01; and EPDS 9.6 (5.4) vs. 5.9 (4.8), p = 0.00). There was no difference in the life events scores between the groups. The subgroup of women suffering from hyperemesis gravidarum had particularly high EPDS scores, (16.2 (3), n = 5, p = 0.00) compared with controls. There were no significant differences in the cortisol levels between the groups. Some women with a medical disorder during pregnancy showed considerably elevated levels of anxiety and depression. Health professionals need to be aware that these women need extra psychological support.     

Symmetrical enchondromatosis is associated with duplication of 12p11.23 to 12p11.22 including PTHLH

We describe a patient with striking generalized symmetrical enchondromatosis of the tubular bones and a de novo duplication of chromosome 12p11.23 to 12p11.22. The PTHLH gene within this region encodes a ligand for PTHR1: mutations in the gene encoding this receptor are associated with some cases of Ollier disease, several skeletal dysplasias including Blomstrand, Eiken, and Jansen and down-regulation of PTHLH expression in brachydactyly type E. Our findings suggest that abnormal PTHLH-PTHR1 signaling may underly this unusual form of enchondromatosis and indicate that unlike most cases of Ollier disease it is dominantly inherited.     

Prospective follow-up of girls with attention-deficit/hyperactivity disorder into adolescence: Evidence for continuing cross-domain impairment

The authors performed 5-year prospective follow-up (retention rate = 92%) with an ethnically diverse sample of girls, aged 11-18 years, who had been diagnosed in childhood with attention-deficit/ hyperactivity disorder (ADHD; N = 140) and a matched comparison group (N = 88). Hyperactive-impulsive symptoms were more likely to abate than inattentive symptoms. Across multiple domains of symptoms and functional impairment, girls with ADHD continued to display deficits of moderate to large effect size in relation to the comparison girls, but few differences emerged between the inattentive versus combined types. Follow-up effects withstood statistical control of crucial covariates for most outcomes, meaning that there were specific effects of childhood ADHD on follow-up status; in other instances, baseline disruptive disorders accounted for adolescent effects. For outcomes identical at baseline and follow-up, girls with ADHD showed more improvement across time than comparison girls (except for math achievement). Overall, ADHD in girls portends continuing impairment 5 years after childhood ascertainment.