Novel mutation in COL1A1 associated with Osteogenesis imperfecta not compatible with life

Osteogenesis imperfecta (OI) is a skeletal dyscrasia characterized by decreased bone strength and associated fractures. Over 95% of autosomal dominant forms of this disease are associated with defects in the genes for collagen COL1A1 and COL1A2.1 The lethal type II disease has been identified antenatally by symmetrically shortened long bones and micromelia. Many reports have indicated that a femur length to abdominal circumference ratio (FL:AC) of less than 0.16 is predictive of lethality associated with OI.2,3 We report a case that presented at 20 weeks’ gestation with shortening of the lower limbs, specifically a lagging femur length and FL:AC of < 0.16. On subsequent ultrasound examinations, progressive shortening of the femur as well as shortening of the long bones of the upper extremities was documented. The thorax appeared normal until 31 weeks. The FL:AC remained below 0.16 throughout pregnancy. Workup in the neonatal period identified a novel mutation in COL1A1. The neonate was able to breathe spontaneously at birth requiring minimal respiratory support for the initial 2 weeks and lived for 26 days

Elevated Chemokine C-C motif ligand 2 (CCL2) early in pregnancy is associated with increased risk of preeclampsia in obese parturients

The objective of this study is to measure plasma CCl2 and leptin early in control and obese women and associate pregnancy outcomes with these levels. We hypothesize that early elevations of plasma CCL2 will be predictive of the development of poor pregnancy outcomes

Calpain 4 Is Not Necessary for LFA-1-Mediated Function in CD4+ T Cells

T cell activation and immune synapse formation require the appropriate activation and clustering of the integrin, LFA-1. Previous work has reported that the calpain family of calcium-dependent proteases are important regulators of integrin activation and modulate T cell adhesion and migration. However, these studies have been limited by the use of calpain inhibitors, which have known off-target effects.Here, we used a LoxP/CRE system to specifically deplete calpain 4, a small regulatory calpain subunit required for expression and activity of ubiquitously expressed calpains 1 and 2, in CD4+ T cells. CD4+ and CD8+ T cells developed normally in Capn4(F/F):CD4-CRE mice and had severely diminished expression of Calpain 1 and 2, diminished talin proteolysis and impaired casein degradation. Calpain 4-deficient T cells showed no difference in adhesion or migration on the LFA-1 ligand ICAM-1 compared to control T cells. Moreover, there was no impairment in conjugation between Capn4(F/F):CD4-CRE T cells and antigen presenting cells, and the conjugates were still capable of polarizing LFA-1, PKC-theta and actin to the immune synapse. Furthermore, T cells from Capn4(F/F):CD4-CRE mice showed normal proliferation in response to either anti-CD3/CD28 coated beads or cognate antigen-loaded splenocytes. Finally, there were no differences in the rates of apoptosis following extrinsic and intrinsic apoptotic stimuli.Our findings demonstrate that calpain 4 is not necessary for LFA-1-mediated adhesion, conjugation or migration. These results challenge previous reports that implicate a central role for calpains in the regulation of T cell LFA-1 function

L-Plastin nanobodies perturb matrix degradation, podosome formation, stability and lifetime in THP-1 macrophages

Podosomes are cellular structures acting as degradation ‘hot-spots’ in monocytic cells. They appear as dot-like structures at the ventral cell surface, enriched in F-actin and actin regulators, including gelsolin and L-plastin. Gelsolin is an ubiquitous severing and capping protein, whereas L-plastin is a leukocyte-specific actin bundling protein. The presence of the capping protein CapG in podosomes has not yet been investigated. We used an innovative approach to investigate the role of these proteins in macrophage podosomes by means of nanobodies or Camelid single domain antibodies. Nanobodies directed against distinct domains of gelsolin, L-plastin or CapG were stably expressed in macrophage-like THP-1 cells. CapG was not enriched in podosomes. Gelsolin nanobodies had no effect on podosome formation or function but proved very effective in tracing distinct gelsolin populations. One gelsolin nanobody specifically targets actin-bound gelsolin and was effectively enriched in podosomes. A gelsolin nanobody that blocks gelsolin-G-actin interaction was not enriched in podosomes demonstrating that the calcium-activated and actin-bound conformation of gelsolin is a constituent of podosomes. THP-1 cells expressing inhibitory L-plastin nanobodies were hampered in their ability to form stable podosomes. Nanobodies did not perturb Ser5 phosphorylation of L-plastin although phosphorylated L-plastin was highly enriched in podosomes. Furthermore, nanobody-induced inhibition of L-plastin function gave rise to an irregular and unstable actin turnover of podosomes, resulting in diminished degradation of the underlying matrix. Altogether these results indicate that L-plastin is indispensable for podosome formation and function in macrophages

Novel mutation in COL1A1 associated with Osteogenesis imperfecta not compatible with life

Osteogenesis imperfecta (OI) is a skeletal dyscrasia characterized by decreased bone strength and associated fractures. Over 95% of autosomal dominant forms of this disease are associated with defects in the genes for collagen COL1A1 and COL1A2.1 The lethal type II disease has been identified antenatally by symmetrically shortened long bones and micromelia. Many reports have indicated that a femur length to abdominal circumference ratio (FL:AC) of less than 0.16 is predictive of lethality associated with OI.2,3 We report a case that presented at 20 weeks’ gestation with shortening of the lower limbs, specifically a lagging femur length and FL:AC of < 0.16. On subsequent ultrasound examinations, progressive shortening of the femur as well as shortening of the long bones of the upper extremities was documented. The thorax appeared normal until 31 weeks. The FL:AC remained below 0.16 throughout pregnancy. Workup in the neonatal period identified a novel mutation in COL1A1. The neonate was able to breathe spontaneously at birth requiring minimal respiratory support for the initial 2 weeks and lived for 26 days

More than grit: growing and sustaining physician-scientists in obstetrics and gynecology

Obstetricians know the statistics-1 out of every 10 babies is born premature; preeclampsia affects 1 in 25 pregnant people; the United States has the highest rate of maternal mortality in the developed world. Yet, physicians and scientists still do not fully understand the biology of normal pregnancy, let&nbsp;alone what causes these complications. Obstetrics and gynecology-trained physician-scientists are uniquely positioned to fill critical knowledge gaps by addressing clinically-relevant problems through fundamental research and interpreting insights from basic and translational studies in the clinical context. Within our specialty, however, physician-scientists are relatively uncommon. Inadequate guidance, lack of support and community, and structural barriers deter fellows and early stage faculty from pursuing the physician-scientist track. One approach to help cultivate the next generation of physician-scientists in obstetrics and gynecology is to demystify the process and address the common barriers that contribute to the attrition of early stage investigators. Here, we review major challenges and propose potential pathways forward in the areas of mentorship, obtaining protected research time and resources, and ensuring diversity, equity, and inclusion, from our perspective as early stage investigators in maternal-fetal medicine. We discuss the roles of early stage investigators and leaders at the institutional and national level in the collective effort to retain and grow our physician-scientist workforce. We aim to provide a framework for early stage investigators initiating their research careers and a starting point for discussion with academic stakeholders. We cannot afford to lose the valuable contributions of talented individuals due to modifiable factors or forfeit our voices as advocates for the issues that impact pregnant populations

Diplopic versus nondiplopic strabismus: effects on functional vision and eye-related quality of life in adolescents

Twenty adolescents (12-17 years old) with diplopic strabismus and 20 with nondiplopic strabismus (matched to diplopic subjects for direction and magnitude of ocular deviation) completed the Pediatric Eye Questionnaire (PedEyeQ). Children completed the Child PedEyeQ, and one parent for each child completed the Proxy PedEyeQ and Parent PedEyeQ. PedEyeQ Rasch domain scores were calculated and converted to a scale of 0 (worst) to 100 (best). Distributions of domain scores were compared between diplopic and nondiplopic cohorts using Wilcoxon tests. Diplopic adolescents had significantly lower Child PedEyeQ scores on Functional Vision (72 vs 90; P = 0.008), Bothered by Eyes/Vision (65 vs 90; P = 0.009), and Frustration/Worry (53 vs 75; P 0.06 for each comparison). These findings highlight the importance of addressing diplopia when managing childhood strabismus.12 month embargo; published: 20 August 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]