Fabry disease Enzyme Enhancement on migalastat Study: FEES.

BACKGROUND: There is limited information on the α-galactosidase A (α-Gal-A) in vivo response in Fabry patients receiving migalastat. In this single centre study, we evaluated changes from baseline in α-Gal A activity, lyso-Gb3 and other assessments in patients on migalastat. RESULTS: 79 patients were recruited (48 M:31F; median duration receiving migalastat 3.8 years [range = 0.4-14.9 years]). N215S was the commonest genotype in males (67 %) and females (29 %). Leukocyte α-Gal-A showed a positive change from baseline in males (n = 4; median = 20.05); females (n = 8; median = 26). Of these, 3 males and 1 female had N215S (median = 16.7), while 7 females and 1 male had other genotypes (median = 26). No significant changes observed in plasma α-Gal-A. Cross-sectional analysis of post-baseline data confirmed leukocyte α-Gal-A enhancement in males (n = 47; median = 20); females (n = 30; median = 72); N215S (n = 41; median = 29) and other genotypes (n = 36; median = 36.5). Plasma and dried blood spot (DBS) lyso-Gb3 correlated at baseline and post-baseline (r = 0.77 and r = 0.96; p=<0.0001). CONCLUSIONS: In the 12 patients with paired data, there was a median enzyme enhancement of 17.4 (relative change = 2.54) and 33 (relative change = 0.87) in males and in females, respectively. The cross-sectional post-baseline data in 47 patients corroborated leukocyte α-Gal-A enhancement on migalastat. Plasma and DBS lyso-Gb3 correlated well supporting DBS utility for disease monitoring.

Back Pain According to Roland-Morris Low Back Pain Scale After Abdominoplasty With Plication: A Prospective Case Series.

INTRODUCTION: Chronic back pain is a physically debilitating condition that affects more than 80% of adults in the United States. A recent case series highlighted how abdominoplasty with plication can offer an alternative surgical approach for treating chronic back pain. These results have been corroborated by a large prospective series. However, this study excluded male and nulliparous subjects, who may also benefit from this surgery. Our group aims to investigate the effect of abdominoplasty on back pain in a more diverse patient population. METHODS: Subjects older than 18 years undergoing abdominoplasty with plication were recruited. An initial survey called the Roland-Morris Disability Questionnaire (RMQ) was administered at the preoperative visit. This questionnaire inquiries about and grades the patient's history of back pain and surgery. Demographic, medical, and social history was also obtained. A follow-up survey and RMQ was then given 6 months after surgery. RESULTS: Thirty subjects were enrolled. Subjects had a mean age of 43.4 ± 14.3 years. Twenty-eight subjects were female and 26 were postpartum. Twenty-one subjects reported initial back pain on the RMQ scale. Of these, 19 reported a decrease in RMQ score after surgery, including male and nulliparous subjects. A significant decrease in mean RMQ score was demonstrated 6 months after surgery (2.94-0.44, P < 0.001). Further subgroup analysis of female subjects demonstrated significantly decreased final RMQ score in parous women, vaginal or cesarean section delivery, and absence of twin gestation. CONCLUSIONS: Abdominoplasty with plication significantly decreases self-reported back pain 6 months after surgery. These results support that abdominoplasty is not purely a cosmetic procedure but can also be applied therapeutically to improve functional symptoms of back pain.

Examining impact forces during posterior spinal fusion to implement in a novel physics-driven virtual reality surgical simulator.

This study aims to understand the impact forces that surgeons apply to the human spine during a posterior spinal fusion procedure towards the development of a novel spine surgical simulator for training medical residents. The foci of this study are impact forces during graft placement and spinal interbody cage insertion. This study examined the lumbar intervertebral discs of two male cadaveric specimens. Impact forces were collected during graft and spinal cage insertion over multiple levels. An impulse hammer and a camera were used to collect impact forces and displacements, respectively. The results demonstrated a logarithmic relationship between impact forces and cumulative displacement during graft placement. This was also observed between cumulative displacement and number of impacts during spinal cage insertion. A linear relationship was observed for the impact forces and number of impacts during graft placement. Results suggest that surgeons rely on the feedback experienced from impact forces during graft insertion to gauge the amount of graft that was placed in a specific area of the disc. Impact forces during cage insertion provide information about any encountered obstacles. When developing surgical simulators, designing the force feedback system should require modelling these behaviors to effectively impart corresponding skills on a trainee.

Psoriatic Arthritis: The Influence of Co-morbidities on Drug Choice.

Psoriatic arthritis (PsA) is associated with a higher burden of co-morbidities such as obesity, cardiovascular disease, non-alcoholic fatty liver disease, inflammatory eye disease, inflammatory bowel disease, skin cancer and depression compared to the general population. In the last 20 years, the therapeutic options for PsA have increased exponentially with the availability of tumor necrosis factor-alpha (TNF) inhibitors, interleukin (IL)-17 inhibitors, IL-12/23 inhibitors and Janus kinases/signal transducer and activator of transcription proteins (JAK/STAT) inhibitors. The articular and extra-articular manifestations of PsA usually dictate the treatment choice but important consideration must be given to the corresponding co-morbidities while deciding the drug therapy due to associated safety profile, effect on disease activity, etc. This review provides a comprehensive review of common co-morbidities in PsA and how they can influence treatment choices.

The Role of Early Subspeciality Consultation in the Timing of Hemophagocytic Lymphohistiocytosis Diagnosis and Management.

OBJECTIVE: The aim of this study was to investigate the relation between timing of subspeciality consult and hemophagocytic lymphohistiocytosis (HLH) consideration, immunosuppression initiation, and in-hospital mortality in patients with HLH. METHODS: We conducted a medical records review study of patients 18 years or older with definite or probable HLH at Montefiore Medical Center between 2006 and 2019. Earlier subspeciality consultation (rheumatology, hematology, and infectious disease) was defined as consultation in less than or equal to 18 hours from time of admission. Demographic, clinical characteristics, and outcomes were compared between patients with early and later subspecialty consultation. RESULTS: A total of 28 patients were included. The median age was 40 years, and 61% of patients were male. Infection was identified as a cause of HLH in 13 patients (46%). Fifteen patients (54%) were classified as having an earlier subspeciality consultation with a median time (interquartile range) to HLH consideration of 1.0 day (0.3-4.2 days) compared with 7.9 days (3.1-9.9 days) for the later consultation group (p = 0.002). The median time (interquartile range) to immunosuppression initiation was 4.6 days (1.7-7.8 days) versus 10.9 days (5.1-13.4 days) (p = 0.01), respectively. Five patients (33%) had in-hospital deaths in the early consultation group compared with 7 patients (54%) in later consultation group (p = 0.27). Among the subset of patients who survived to discharge, the 90-day readmission rate was higher in the later consultation group (83% vs 30%, p = 0.12). CONCLUSIONS: In patients with HLH, earlier subspeciality consultation may play a role in earlier HLH consideration and treatment initiation.

Midfacial Degloving Technique for Free Flap Reconstruction of Nasal and Anterior Skull Base Defects.

SUMMARY: Traditionally, surgical access for extirpation and reconstruction of midfacial tumors requires external incisions that can cause a myriad of complications, especially in irradiated patients. The modern midfacial degloving approach involves hidden, sublabial and intranasal incisions that provide reliable access for free flap reconstruction of nasal and maxillofacial tumors. Seven patients with a history of radiation therapy underwent free flap reconstruction of the midface. Five patients underwent the technique in a delayed manner, and the remaining two underwent reconstruction immediately at the time of resection. Five patients underwent free radial forearm fasciocutaneous free flaps and two underwent reconstruction with anterolateral thigh perforator flaps. Bone and/or rib cartilage grafting was used in all patients. All patients underwent successful free flap reconstruction of the midface without external incisions. The most common complication was postoperative infection requiring oral or intravenous antibiotics. No patients sustained loss of their grafts or hardware in the postoperative period. The midfacial degloving technique provides satisfactory exposure to the nasal cavity, midface, orbits, and skull base for free flap reconstruction, without disrupting the external soft tissue. The authors describe a novel use of the midfacial degloving technique to provide safe and reliable results with improved cosmetic outcome.

Development and Validation of a Mixed Reality Configuration of a Simulator for a Minimally Invasive Spine Surgery Using the Workspace of a Haptic Device and Simulator Users.

Most surgical simulators leverage virtual or bench models to simulate reality. This study proposes and validates a method for workspace configuration of a surgical simulator which utilizes a haptic device for interaction with a virtual model and a bench model to provide additional tactile feedback based on planned surgical manoeuvers. Numerical analyses were completed to determine the workspace and position of a haptic device, relative to the bench model, used in the surgical simulator, and the determined configuration was validated using device limitations and user data from surgical and nonsurgical users. For the validation, surgeons performed an identical surgery on a cadaver prior to using the simulator, and their trajectories were then compared to the determined workspace for the haptic device. The configuration of the simulator was determined appropriate through workspace analysis and the collected user trajectories. Statistical analyses suggest differences in trajectories between the participating surgeons which were not affected by the imposed haptic workspace. This study, therefore, demonstrates a method to optimally position a haptic device with respect to a bench model while meeting the manoeuverability needs of a surgical procedure. The validation method identified workspace position and user trajectory towards ideal configuration of a mixed reality simulator.

Deep brain optogenetics without intracranial surgery.

Achieving temporally precise, noninvasive control over specific neural cell types in the deep brain would advance the study of nervous system function. Here we use the potent channelrhodopsin ChRmine to achieve transcranial photoactivation of defined neural circuits, including midbrain and brainstem structures, at unprecedented depths of up to 7 mm with millisecond precision. Using systemic viral delivery of ChRmine, we demonstrate behavioral modulation without surgery, enabling implant-free deep brain optogenetics.

Severe hand pain as an extracardiac manifestation of transthyretin amyloidosis.

Transthyretin amyloidosis is a multisystemic disease caused by the aggregation of amyloid fibrils, resulting in high morbidity and mortality in the presence of cardiac involvement. Patients often experience vague symptoms that make amyloidosis difficult to diagnose. Differential diagnosis for hand pain in a patient with systemic amyloidosis is broad. We present a patient with severe hand cramping and inability to perform activities of daily living. This preceded a new diagnosis of familial amyloid cardiomyopathy. The patient was a poor responder to systemic corticosteroids, anti-inflammatories and anticonvulsant therapy. Her unique presentation gives insight into a rare but debilitating disorder and the potential link between amyloidosis and other disease processes.

Conformationally constrained peptides target the allosteric kinase dimer interface and inhibit EGFR activation.

Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, we sought to explore whether allosteric activation mechanisms could effectively be disrupted. The kinase domain of EGFR forms an atypical asymmetric dimer via head-to-tail interactions and serves as a requisite for kinase activation. The kinase dimer interface is primarily formed by the H-helix derived from one kinase monomer and the small lobe of the second monomer. We hypothesized that a peptide designed to resemble the binding surface of the H-helix may serve as an effective disruptor of EGFR dimerization and activation. A library of constrained peptides was designed to mimic the H-helix of the kinase domain and interface side chains were optimized using molecular modeling. Peptides were constrained using peptide "stapling" to structurally reinforce an alpha-helical conformation. Peptide stapling was demonstrated to notably enhance cell permeation of an H-helix derived peptide termed EHBI2. Using cell-based assays, EHBI2 was further shown to significantly reduce EGFR activity as measured by EGFR phosphorylation and phosphorylation of the downstream signaling substrate Akt. To our knowledge, this is the first H-helix-based compound targeting the asymmetric interface of the kinase domain that can successfully inhibit EGFR activation and signaling. This study presents a novel, alternative targeting site for allosteric inhibition of EGFR.

Imidazo[1,2-a]pyridines linked with thiazoles/thiophene motif through keto spacer as potential cytotoxic agents and NF-κB inhibitors.

A series of new imidazo[1,2-a]pyridine linked with thiazole/thiophene motif through a keto spacer were synthesized and tested for their cytotoxic potential against three human cancer cell lines including A549, HeLa and U87-MG using MTT assay. Compounds A2, A3, A4, C1 and C2 showed cytotoxicity against all the three cell lines. The selectivity index for compound A4 for A549 and HeLa cells was comparable to that of doxorubicin. Among the synthesized compounds, B5 showed the maximum inhibition of NF-κB activity as ascertained by NF-κB reporter assay (IC50 = 6.5 ±â€¯0.6 µM). Treatment of NCI-H23 cells (EGFR overexpressed, KRAS G12V mutant) with erlotinib and gefitinib along with compounds A4 and B5 indicated synergistic and additive potential of combination therapy.

Diffuse reduction of cerebral grey matter volumes in Erdheim-Chester disease.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis characterized by systemic inflammation and granulomatous infiltration of multiple organs including the central nervous system (CNS), bones, and retroperitoneum. CNS infiltration occurs in one third of patients, but cognitive changes are common in patients without CNS disease. Here we investigate whether there is a neuroanatomic basis to observed cognitive deficits, even in absence of CNS disease. METHODS: We present a volumetric analysis of eleven ECD patients without CNS tumors or prior neurotoxic treatments. RESULTS: Compared to age-matched controls, ECD patients have diffuse, bihemispheric reduction in cortical thickness and subcortical gray matter. CONCLUSIONS: These findings provide the first corroborating evidence for neurologic disease in ECD patients without direct CNS infiltration.

Bone marrow necrosis and fat embolism syndrome in sickle cell disease: increased susceptibility of patients with non-SS genotypes and a possible association with human parvovirus B19 infection.

Fat embolism syndrome (FES) due to extensive bone marrow necrosis (BMN) in sickle cell disease (SCD) is a potentially under-diagnosed complication associated with severe morbidity and mortality. We identified 58 cases reported in the world literature to date. Typically, patients presented with a seemingly uncomplicated vaso-occlusive crisis (VOC) and subsequently deteriorated rapidly with a drop in their haemoglobin and platelets, development of respiratory failure, encephalopathy and varying degrees of involvement of other systems. Overall mortality in the reported cases was 64% but differed according to the use of transfusion and was 29%, 61% and 91% for patients receiving exchange, top-up or no transfusion respectively. Patients most at risk appear to be those with a "milder" form of SCD as 81% of patients had a genotype other than HbSS and the majority had no history of significant sickle-related complications. Human parvovirus B19 (HPV B19) infection was documented in 24% of cases.

Angiocidin inhibits breast cancer proliferation through activation of epidermal growth factor receptor and nuclear factor kappa (NF-ĸB).

Angiocidin, a tumor-associated peptide, has been previously shown to inhibit tumor progression by blocking angiogenesis. We now show that angiocidin has a direct inhibitory effect on tumor cell proliferation. MDA-MB-231 breast cancer cells were inhibited from proliferating in the presence of epidermal growth factor (EGF) and angiocidin. Angiocidin transfected breast cancer cells also displayed growth inhibition in vitro and failed to develop significant tumors in mice as compared to vector controls. The anti-proliferative effect of angiocidin was reversed by treating the cells with the epidermal growth factor receptor (EGFR) inhibitor 4557W, a potent tyrosine kinase inhibitor. Consistent with these results, we found that treatment of breast cancer cells with angiocidin induced a 2.3 fold increase in EGFR tyrosine 845 phosphorylation while no change in phosphorylation was observed in the remaining 16 phosphorylation sites of EGFR and those of its family members as measured by a human EGFR phosphorylation array. Treatment of breast cancer cells with angiocidin also resulted in the activation of nuclear factor ĸB (Nf-ĸB) and the de novo up-regulation of many down-stream genes transcribed by Nf-ĸB, including cytokines, inflammatory mediators and the cell cycle inhibitor p21(waf1). Therefore, angiocidin is a peptide that not only inhibits tumor angiogenesis but also directly induces inhibition of tumor growth progression through the activation of EGFR and down-stream genes transcribed by Nf-ĸB.

Comparing enhancement and washout patterns of hepatic lesions between sonazoid-enhanced ultrasound and contrast-enhanced computed tomography.

PURPOSE: To compare sonazoid-enhanced ultrasound (SEUS) and contrast-enhanced computed tomography (CECT) enhancement and washout patterns in hepatic lesions. METHODS: Enhancement and washout patterns on SEUS were compared with those on CECT for 61 lesions. There were 36 hepatocellular carcinomas, three intrahepatic cholangiocarcinomas, three metastatic lesions, eight focal nodular hyperplasias, two angiomyolipomas, and nine undetermined benign lesions. Diagnosis was based on histopathology, or CECT and tumor markers, or findings on 2-year follow-up. RESULTS: All 61 lesions (100%) showed arterial enhancement on both SEUS and CECT. The "washout/no washout" agreement between SEUS and CECT for the 61 lesions was 93.4% (κ coefficient: 0.816). Of the 42 malignant lesions, 38 lesions (90.5%) showed washout on both SEUS and CECT. The remaining four malignant lesions, of which three lesions contained fibrosis (two intrahepatic cholangiocarcinomas and one scirrhous hepatocellular carcinoma), showed washout on SEUS but not on CECT. For the 19 benign lesions, agreement between SEUS and CECT was 100% (κ coefficient: 1), with seven lesions showing washout with both methods and 12 lesions showing no washout with both methods. CONCLUSION: The overall concordance rate between SEUS and CECT was good, but some differences were seen in the washout patterns of malignant lesions.

Brain lesions with elevated lactic acid peaks on magnetic resonance spectroscopy.

Magnetic resonance (MR) spectroscopy is a noninvasive imaging tool that provides information on various metabolite concentrations within brain lesions. The biochemical information obtained with MR spectroscopy, along with the morphologic appearance of a lesion on MR imaging, allows for better characterization and improved diagnostic ability. Lactic acid is an end product of anaerobic metabolism. Under conditions of anaerobic metabolism or inflammation, lactate levels become elevated and a characteristic peak at 1.3 ppm is detected on MR spectroscopy. This review will discuss the significance of lactate as a metabolite and will describe various brain lesions and disease conditions in which elevated lactate levels are detected.