Assessment of finger dexterity through the DIGITS joint tracking web application-An evaluation study with comparison to the nine-hole pegboard test.

BACKGROUND: Hand dexterity is an important clinical marker after hand surgery as it can greatly impact one's ability to perform their day-to-day activities. With the increased focus on remote patient monitoring after hand surgery, new technologies are required to remotely monitor hand dexterity. PURPOSE: The purpose of this study is to identify dexterity outcomes using the web application "DIGITS" and compare these outcomes to the nine-hole-pegboard test (NHPT). STUDY DESIGN: Cross-sectional observational study. METHODS: This was a two-part study with a pilot of our remote dexterity design using DIGITS followed by a validation study comparing DIGITS to a gold-standard metric of dexterity, NHPT. The pilot study recruited 42 healthy subjects between the ages of 18-65 to perform a remote finger tapping exercise using DIGITS. The second part of the study included 50 subjects between the ages of 18-65. Participants completed a demographic questionnaire and then completed three finger tapping sequences for 20 seconds using DIGITS and three trials of the NHPT with each hand. Correlational analyses were done to compare the DIGITS dexterity test with the NHPT. RESULTS: Four outcome measures to assess dexterity were identified, which included (1) total sequences completed in 20 seconds, (2) time to complete 10 sequences, (3) average frequency per sequence, and (3) sequence accuracy. Significant negative correlations were found with the NHPT and total sequences completed in 20 seconds in both dominant and non-dominant hand trials. Additionally, significant negative correlations were found between the NHPT and the time to complete 10 sequences and average frequency in the non-dominant hand trials. CONCLUSIONS: This study shows promising results for the use of DIGITS as a remote measure of hand dexterity. The total number of sequences completed significantly correlates with the NHPT and should be further explored in representative patient populations.

Applying Machine Learning in Liver Disease and Transplantation: A Comprehensive Review.

Machine learning (ML) utilizes artificial intelligence to generate predictive models efficiently and more effectively than conventional methods through detection of hidden patterns within large data sets. With this in mind, there are several areas within hepatology where these methods can be applied. In this review, we examine the literature pertaining to machine learning in hepatology and liver transplant medicine. We provide an overview of the strengths and limitations of ML tools and their potential applications to both clinical and molecular data in hepatology. ML has been applied to various types of data in liver disease research, including clinical, demographic, molecular, radiological, and pathological data. We anticipate that use of ML tools to generate predictive algorithms will change the face of clinical practice in hepatology and transplantation. This review will provide readers with the opportunity to learn about the ML tools available and potential applications to questions of interest in hepatology.

α-galactosidase A deficiency promotes von Willebrand factor secretion in models of Fabry disease.

Fabry disease results from loss of activity of the lysosomal enzyme α-galactosidase A (GLA), leading to the accumulation of globoseries glycosphingolipids in vascular endothelial cells. Thrombosis and stroke are life-threatening complications of Fabry disease; however, the mechanism of the vasculopathy remains unclear. We explored the relationship between GLA deficiency and endothelial cell von Willebrand factor (VWF) secretion in in vivo and in vitro models of Fabry disease. Plasma VWF was significantly higher at two months and increased with age in Gla-null compared to wild-type mice. Disruption of GLA in a human endothelial cell line by siRNA and CRISPR/Cas9 resulted in a 3-fold and 5-fold increase in VWF secretion, respectively. The increase in VWF levels was associated with decreased endothelial nitric oxide synthase (eNOS) activity in both in vitro models. Pharmacological approaches that increase nitric oxide bioavailability or decrease reactive oxygen species completely normalized the elevated VWF secretion in GLA deficient cells. In contrast, the abnormality was not readily reversed by recombinant human GLA or by inhibition of glycosphingolipid synthesis with eliglustat. These results suggest that GLA deficiency promotes VWF secretion through eNOS dysregulation, which may contribute to the vasculopathy of Fabry disease.

Dissociation of globotriaosylceramide and impaired endothelial function in α-galactosidase-A deficient EA.hy926 cells.

Fabry disease, a rare, X-linked lysosomal storage disease, arises from deficiency of the lysosomal hydrolase, α-galactosidase A (GLA) which disrupts the catabolism of globo- series glycosphingolipids (GSLs). One potential link between GLA deficiency and vascular dysfunction may be changes in endothelial nitric oxide synthase (eNOS) function. GLA-deficient EA.hy926 cells were obtained by siRNA knockdown of GLA expression and by mutation of GLA with CRISPR/Cas9 gene editing to investigate the effects of GLA deficiency on eNOS. As previously observed with siRNA knockdown of GLA, globotriaosylceramide (Gb3) accumulated in EA.hy926 cells. In contrast, Gb3 did not accumulate in CRISPR/Cas9 gene edited GLA-deficient cells, but instead, globotetraosylceramide (Gb4). However, in both the siRNA and CRISPR/Cas9 models globotriaosylsphingosine (lyso-Gb3) was elevated. As was previously observed with siRNA knockdown of GLA expression, CRISPR/Cas9 GLA-deficient cells had lower eNOS activity. Restoring GLA activity in GLA-deficient cells with exogenous GLA treatment improved eNOS activity. In contrast, treating cells with the glucosylceramide synthase inhibitor, eliglustat, decreased NOS activity. These results suggest that eNOS uncoupling is due to GLA deficiency, and not necessarily due to elevated Gb3 per se. It was observed that lyso-Gb3 inhibits eNOS activity.

Effect of aromatic ring fluorination on CHπ interactions: microwave spectrum and structure of the 1,2-difluorobenzeneacetylene dimer.

Rotational spectra for the normal isotopic species and for six additional isotopologues of the 1,2-difluorobenzeneacetylene (C6H4F2HCCH) weakly bound dimer have been assigned in the 6-18 GHz region using chirped-pulse Fourier-transform microwave spectroscopy. This is the third complex in a series of fluorinated benzeneacetylene dimers. In 1,2-difluorobenzeneHCCH, the Hπ distance (2.725(28) Å) is longer by about 0.23 Å, and the estimated binding energy (EB = 2.3(6) kJ mol(-1)) is weaker by about 1.8 kJ mol(-1), than in the previously studied fluorobenzeneHCCH complex. In addition, in 1,2-difluorobenzeneacetylene, HCCH tips ∼46(3)° away from perpendicular to the aromatic ring, with the H nearest the ring moving away from the fluorine atoms along the C2 axis of the monomer, while in the fluorobenzene and benzene complexes HCCH is perpendicular (benzeneHCCH) or nearly perpendicular (fluorobenzeneHCCH, ∼7° tilt) to the ring plane. Results from ab initio and DFT calculations will be compared to an experimental structure determined from rotational constants for the DCCD and five unique (13)C substituted isotopologues.

Endothelial nitric oxide synthase uncoupling and microvascular dysfunction in the mesentery of mice deficient in α-galactosidase A.

A defect in the gene for the lysosomal enzyme α-galactosidase A (Gla) results in globotriaosylceramide (Gb3) accumulation in Fabry disease and leads to premature death from cardiac and cerebrovascular events. However, gastrointestinal symptoms are often first observed during childhood in these patients and are not well understood. In this study, we demonstrate an age-dependent microvasculopathy of the mesenteric artery (MA) in a murine model of Fabry disease (Gla-knockout mice) resulting from dysregulation of the vascular homeostatic enzyme endothelial nitric oxide synthase (eNOS). The progressive accumulation of Gb3 in the MA was confirmed by thin-layer chromatographic analysis. A total absence of endothelium-dependent dilation was observed in MAs from mice at 8 mo of age, while suppression of ACh-mediated vasodilation was evident from 2 mo of age. Endothelium-independent dilation with sodium nitroprusside was normal compared with age-matched wild-type mice. The microvascular defect in MAs from Fabry mice was endothelium-dependent and associated with suppression of the active homodimer of eNOS. Phosphorylation of eNOS at the major activation site (Ser(1179)) was significantly downregulated, while phosphorylation at the major inhibitory site (Thr(495)) was remarkably enhanced in MAs from aged Fabry mice. These profound alterations in eNOS bioavailability at 8 mo of age were observed in parallel with high levels of 3-nitrotyrosine, suggesting increased reactive oxygen species along with eNOS uncoupling in this vascular bed. Overall, the mesenteric microvessels in the setting of Fabry disease were observed to have an early and profound endothelial dysfunction associated with elevated reactive nitrogen species and decreased nitric oxide bioavailability.

Rotational spectroscopy and molecular structure of the 1,1,2-trifluoroethylene-hydrogen chloride complex.

Fourier transform microwave spectra in the 6-20 GHz region are obtained for the complex formed between 1,1,2-trifluoroethylene and hydrogen chloride, including both (35)Cl and (37)Cl isotopomers. Analysis of the spectra provides rotational constants and additionally, the complete quadrupole hyperfine coupling tensor in both the inertial and principal electric field gradient axis systems. The inertial information contained in the rotational constants combined with the results of the hyperfine analysis provides the structure for CF(2)CHF-HCl. A primary, hydrogen bonding interaction exists between the HCl donor and the F atom geminal to the H atom on the substituted ethylene. The hydrogen bond is bent from linearity to allow a secondary interaction to form between this H atom and the Cl atom. Comparisons made to similar complexes involving both other protic acids (HF and HCCH) and fluoroethylenes (vinyl fluoride and 1,1-difluoroethylene) reveal the effects of varying gas phase hydrogen bond donor strength, of increasing fluorine substitution on fluorine atom nucleophilicity, and on the relative importance of steric versus electrostatic effects in determining the structures of these species.

Voluntary wheel running activates Akt/AMPK/eNOS signaling cascades without improving profound endothelial dysfunction in mice deficient in α-galactosidase A.

Fabry disease is caused by loss of activity of the lysosomal hydrolase α-galactosidase A (GLA). Premature life-threatening complications in Fabry patients arise from cardiovascular disease, including stroke and myocardial infarction. Exercise training has been shown to improve endothelial dysfunction in various settings including coronary artery disease. However, the effects of exercise training on endothelial dysfunction in Fabry disease have not been investigated. Gla knockout mice were single-housed in a cage equipped with a voluntary wheel (EX) or no wheel (SED) for 12 weeks. Exercised mice ran 10 km/day on average during the voluntary running intervention (VR) period. Despite significantly higher food intake in EX than SED, body weights of EX and SED remained stable during the VR period. After the completion of VR, citrate synthase activity in gastrocnemius muscle was significantly higher in EX than SED. VR resulted in greater phosphorylation of Akt (S473) and AMPK (T172) in the aorta of EX compared to SED measured by western blot. Furthermore, VR significantly enhanced eNOS protein expression and phosphorylation at S1177 by 20% and 50% in the aorta of EX when compared with SED. Similarly, plasma nitrate and nitrite levels were 77% higher in EX than SED. In contrast, measures of anti- and pro-oxidative enzymes (superoxide dismutase and p67phox subunit of NADPH oxidase) and overall oxidative stress (plasma oxidized glutathione) were not different between groups. Although the aortic endothelial relaxation to acetylcholine was slightly increased in EX, it did not reach statistical significance. This study provides the first evidence that VR improves Akt/AMPK/eNOS signaling cascades, but not endothelial function in the aorta of aged Gla deficient mice.

Assaying endogenous matrix metalloproteinases (MMPs) in acid-etched dentinal cavity walls.

Endogenous dentinal matrix metalloproteinases (MMPs) have been implicated in the auto-degradation of collagen fibrils within resin infiltrated layers of dentinal attachment. In order to target these proteinases, we must know which MMPs are produced and activated at the resin/dentin interface. In this study, we have optimized an extraction procedure and quantitated levels of endogenous MMPs in samples of dentin removed from the cavity walls of a single, extracted tooth. In our tooth-cavity model, an occlusal cavity (2×4×2 mm) was prepared and removed from the tooth crown, leaving surrounding dentinal walls of 1-mm-thick. The samples were pulverized with an analytic mill. Using enzyme-linked immunosorbent assay (ELISA), an average of 34.7 picograms of MMP-9 was detected in less than 300 mg of dentinal powder. This is the first study of its kind to quantitate endogenous levels of MMP in dentinal protein isolated from the cavity walls of a single, extracted tooth.

Acute cholecystitis with a hemocholecyst as an unusual presentation of gallbladder cancer: report of a case.

Several atypical presentations of gallbladder carcinoma have been reported, but one of the rarest is intraluminal hemorrhage. We report a case of carcinoma of the gallbladder disclosed by an emergency cholecystectomy, performed for acute cholecystitis caused by a hemocholecyst. The diagnostic approaches and characteristics of a hemocholecyst associated with carcinoma of the gallbladder are discussed.