Faculty Bibliography

Trichorhinophalangeal syndrome type 1 (TRPS1; Online Mendelian Inheritance in Man #190350) is an autosomal dominant disorder caused by mutations in TRPS1. We report a Thai male with TRPS1 who carried a c.1842C>T (p.Arg615Ter) mutation. He had 15 supernumerary teeth, double mental foramina, hypoplastic mandibular condyles with slender condylar necks and unique ultrastructural hair findings. Body hair was absent. The hair in the area of a congenital melanocytic nevus had a greater number of hair cuticles than normal. Occipital hair had abnormal hair follicles and cuticles. The scale edges of the hair cuticles were detached and rolled up. Hypoplastic mandibular condyles with slender condylar necks, double mental foramina and the rolled up edges of hair cuticles have not been reported in patients with TRPS1.

Objective: The anatomical calcaneal external fixator was designed by measuring and calculating the morphological data of the heel.
Method(s): A total of 100 normal people were randomly selected to obtain 200 hind foot data, including 45 males and 55 females, with an average age of 43.9 years (range, 19-67 years). According to the principles of human engineering and local anatomy, the morphological data of the heel in the weight-bearing standing position and supine position were measured with the direct measurement mode. The heel length, heel width, heel height, medial ankle height, lateral ankle height, and calcaneal pitch angle (CPA) were measured by vernier calipers and ulnar markers in weight-bearing standing position, and the gender groups and left and right foot groups were compared; the shape of the hind foot in the supine position was measured by three-dimensional (3D) dot matrix inverse model method. According to the stereoscopic data of the comprehensive anatomical morphology of the heel, the anatomical calcaneal external fixator was designed with AutoCAD 2019 and other 3D industrial design softwares.
Result(s): The measurements of shoe size, heel length, heel width, heel height, medial ankle height, lateral ankle height, and CPA in male were significantly higher than those in female ( P<0.05). There was no significant difference between the left and right feet in the other indexes except that the height of the medial malleolus of the left foot was significantly lower than that of the right foot ( t=-2.827, P=0.005). The measurement of 3D dot matrix inverse model in supine position showed that the heel part was non-circular arc edge, and many groups of arc edges fluctuate in a limited range. Based on the above data, an anatomical calcaneal external fixator was designed, which could fit the anatomic radian in theory, so as to be flexible in configuration. On this basis, the ordinary configuration, compression configuration, and orthodontic configuration were designed to meet the treatment needs of calcaneal fractures in different degrees. The ordinary configuration was suitable for patients with Sanders I, IIA, and IIB calcaneal fractures with no or slight displacement of intra-articular fractures; the ordinary configuration was mainly used for simple fixing. The compression configuration was suitable for patients with Sanders IIC, IIIA, and IIIB, tongue fractures, and avulsion fractures with severe displacement of intra-articular fractures; the compression configuration used obliquely drawn console wires to fix the displaced bones. The orthodontic configuration was suitable for patients with Sanders IIIC and IV calcaneal fractures with severe displacement of intra-articular fractures or severe calcaneal bone defects; the orthodontic configuration was a multi-module design, which took into account the stable fixation of the fracture and the arbitrary adjustment of the joint fixation angle.
Conclusion(s): The hind foot is special for morphology, so the external fixator designed based on the vernier caliper measurement method and 3D dot matrix measuring plate measurement method is an anatomical type and its configuration can theoretically meet stable and flexible clinical needs

Human and murine skin wounding commonly results in fibrotic scarring, but the murine wounding model wound-induced hair neogenesis (WIHN) can frequently result in a regenerative repair response. Here, we show in single-cell RNA sequencing comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.

Lysosomal dysfunction is considered pathogenic in Alzheimer disease (AD). Loss of presenilin-1 (PSEN1) function causing AD impedes acidification via defective vacuolar ATPase (vATPase) V0a1 subunit delivery to lysosomes. We report that isoproterenol (ISO) and related β2-adrenergic agonists reacidify lysosomes in PSEN1 Knock out (KO) cells and fibroblasts from PSEN1 familial AD patients, which restores lysosomal proteolysis, calcium homeostasis, and normal autophagy flux. We identify a novel rescue mechanism involving Portein Kinase A (PKA)-mediated facilitation of chloride channel-7 (ClC-7) delivery to lysosomes which reverses markedly lowered chloride (Cl^-) content in PSEN1 KO lysosomes. Notably, PSEN1 loss of function impedes Endoplasmic Reticulum (ER)-to-lysosome delivery of ClC-7. Transcriptomics of PSEN1-deficient cells reveals strongly downregulated ER-to-lysosome transport pathways and reversibility by ISO, thus accounting for lysosomal Cl^- deficits that compound pH elevation due to deficient vATPase and its rescue by β2-adrenergic agonists. Our findings uncover a broadened PSEN1 role in lysosomal ion homeostasis and novel pH modulation of lysosomes through β2-adrenergic regulation of ClC-7, which can potentially be modulated therapeutically.

Mammalian cells have evolved multiple pathways to repair DNA double strand breaks (DSBs) and ensure genome stability. In addition to non-homologous end-joining (NHEJ) and homologous recombination (HR), cells evolved an error-prone repair pathway termed microhomology-mediated end joining (MMEJ). The mutagenic outcome of MMEJ derives from the activity of DNA polymerase theta (Polθ) - a multidomain enzyme that is minimally expressed in normal tissue but overexpressed in tumors. Polθ expression is particularly crucial for the proliferation of HR deficient cancer cells. As a result, this mutagenic repair emerged as an attractive target for cancer therapy, and inhibitors are currently in pre-clinical development. Here, we review the multifunctionality of this enigmatic polymerase, focusing on its role during DSB repair in mammalian cells and its impact on cancer genomes.

PURPOSE OF REVIEW/OBJECTIVE:Since the first discovery of Angiopoetin-like 4 (ANGPTL4) in 2000, the involvement of ANGPTL4 in different aspects of lipid metabolism and vascular biology has emerged as an important research field. In this review, we summarize the fundamental roles of ANGPTL4 in regulating metabolic and nonmetabolic functions and their implication in lipid metabolism and with several aspects of vascular function and dysfunction. RECENT FINDINGS/RESULTS:ANGPTL4 is a secreted glycoprotein with a physiological role in lipid metabolism and a predominant expression in adipose tissue and liver. ANGPTL4 inhibits the activity of lipoprotein lipase and thereby promotes an increase in circulating triglyceride levels. Therefore, ANGPTL4 has been highly scrutinized as a potential therapeutic target. Further involvement of ANGPTL4 has been shown to occur in tumorigenesis, angiogenesis, vascular permeability and stem cell regulation, which opens new opportunities of using ANGPTL4 as potential therapeutic targets for other pathophysiological conditions. SUMMARY/CONCLUSIONS:Further determination of ANGPTL4 regulatory circuits and defining specific molecular events that mediate its biological effects remain key to future ANGPTL4-based therapeutic applications in different disease settings. Many new and unanticipated roles of ANGPTL4 in the control of cell-specific functions will assist clinicians and researchers in developing potential therapeutic applications.

In sweep rowers, the lower extremities muscle strength translates into the driving force of the boat. Therefore, isokinetic assessment of muscle torque is used by coaches as an indicator of the level of athletes' preparation for competitions. A total of 22 elite sweep rowers performed an isokinetic test of knee joint flexors and extensors, and a test on an asymmetric ergometer with the electromyography measures. Significantly higher quadriceps peak torque was shown during the beginning than the end of the preparatory period (p < 0.05). However, there was no significant knee peak torque difference between the lower extremities (p = 0.398). In the case of the electromyography test of quadriceps, hamstrings and lumbar erector spinae, analysis demonstrated significant bioelectrical activity differences between the sides (p < 0.05). Lower values of quadriceps peak torque at the end of the preparatory period may result from a decrease in the number of power training units during the entire preparatory period. A similar muscle strength between both lower extremities seems to be the correct result in the context of injury prevention. In turn, significant bioelectrical activity differences between the sides possibly are associated with the asymmetric movement pattern in sweep rowers.

Background Transesophageal echocardiography (TEE) is the gold standard for determining mitral regurgitant (MR) leaflet morphology and suitability for edge-to-edge (E2E) repair. Computed tomography (CT) has become essential for evaluation for transcatheter mitral valve replacement (TMVR) and has the temporal and spatial resolution to show leaflet abnormalities with great clarity (figure) but the correlation of findings with TEE has not been well studied. Methods A consecutive series of patients attending clinic for moderate-severe or greater mitral regurgitation underwent CT and TEE. Data was analyzed for leaflet morphology with blinded independent analyses by CT and TEE expert readers. Results A study flow diagram is shown (figure). Mean age was 79.6 (SD 10.9) and mean STS score (repair) was 4.8% (SD3.7). Analyses were independently performed (figure). There was a strong correlation between mitral valve orifice area (MVOA) by CT and TEE (r=0.86, p<0.001), however MVOA was on average 0.45 cm² larger (p=0.003) on CT (5.24cm², SD 1.84) than TEE (4.79cm², SD 1.91). For those cases where CT could make an interpretation on suitability for E2E repair there was 100% concordance between CT and TEE (figure). Conclusion In this preliminary retrospective analysis, a comparison of CT and TEE suggested that CT may be a useful non-invasive modality for the assessment of mitral leaflet morphology and suitability for E2E repair. A prospective comparison is ongoing and will be completed at the time of presentation. [Figure presented]
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Background Computed tomography (CT) has become the standard of care for assessment for the suitability for transcatheter mitral valve replacement (TMVR); however, variation in mitral annular measurements across the cardiac cycle has thus far been poorly studied. Because of this, currently TMVR assessment is cumbersome and involves the assessment of multiple phases. We sought to further understand variation in mitral annular dimensions with the cardiac cycle and assess its potential implications for Methods A total of 118 patients presented to the heart valve clinic and underwent CT for possible TMVR assessment and were consecutively studied with multiphase CT. The mitral annulus was measured in 10 phases using 3mensio mitral planning software and several parameters collected including perimeter, area, anterior-posterior (AP) dimension and commissure-commissure (CC) dimension. Results Of the 118 patients screened, 83.9% had predominant MR, 10.2% mixed MS/MR and 5.9% predominant MS. Changes in perimeter, Area, AP and CC dimensions are shown (figure). Comparison of largest and smallest mean measurements for each phase for perimeter, Area, AP and CC dimensions showed a 2.02%, 4.36%, 8.09% and 2.86% variation respectively. Conclusion In contrast to the dynamism of the aortic annulus and neo-LVOT, the mitral annulus does not vary significantly. This may allow limitation of radiation restricting CT acquisitions to mid-systole where the neo-LVOT is smallest. [Figure presented]
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