The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Antiplatelet antibody-induced thrombocytopenia does not correlate with megakaryocyte abnormalities in murine immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by increased peripheral immune platelet destruction and megakaryocyte defects in the bone marrow. Although ITP was originally thought to be primarily due to antibody-mediated autoimmunity, it is now clear that T cells also play a significant role in the disease. However, the exact interplay between platelet destruction, megakaryocyte dysfunction and the elements of both humoral and cell-mediated immunity in ITP remains incompletely defined. While most studies have focused on immune platelet destruction in the spleen, an additional possibility is that the antiplatelet antibodies can also destroy bone marrow megakaryocytes. To address this, we negated the effects of T cells by utilizing an in vivo passive ITP model where BALB/c mice were administered various anti-αIIb, anti-ß3 or anti-GPIb antibodies or antisera and platelet counts and bone marrow megakaryocytes were enumerated. Our results show that after 24 hours, all the different antiplatelet antibodies/sera induced variable degrees of thrombocytopenia in recipient mice. Compared with naïve control mice, however, histological examination of the bone marrow revealed that only 2 antibody preparations (mouse-anti-mouse ß3 sera and an anti- αIIb monoclonal antibody (MWReg30) could affect bone marrow megakaryocyte counts. Our study shows that while most antiplatelet antibodies induce acute thrombocytopenia, the majority of them do not affect the number of megakaryocytes in the bone marrow. This suggests that other mechanisms may be responsible for megakaryocyte abnormalities seen during immune thrombocytopenia.

DPP4 truncated GM-CSF and IL-3 manifest distinct receptor-binding and regulatory functions compared with their full-length forms.

Dipeptidylpeptidase 4 (DPP4/CD26) enzymatically cleaves select penultimate amino acids of proteins, including colony-stimulating factors (CSFs), and has been implicated in cellular regulation. To better understand the role of DPP4 regulation of hematopoiesis, we analyzed the activity of DPP4 on the surface of immature blood cells and then comparatively assessed the interactions and functional effects of full-length (FL) and DPP4 truncated (T) factors (T-granulocyte-macrophage-CSF (T-GM-CSF)) and T-interleukin-3 (T-IL-3)) on both in vitro and in vivo models of normal and leukemic cells. T-GM-CSF and -IL-3 had enhanced receptor binding, but decreased CSF activity, compared with their FL forms. Importantly, T-GM-CSF and -IL-3 significantly, and reciprocally, blunted receptor binding and myeloid progenitor cell proliferation activity of both FL-GM-CSF and -IL-3 in vitro and in vivo. Similar effects were apparent in vitro using cluster-forming cells from patients with acute myeloid leukemia regardless of cytogenetic or molecular alterations and in vivo using animal models of leukemia. This suggests that DPP4 T-molecules have modified binding and functions compared with their FL counterparts and may serve regulatory roles in normal and malignant hematopoiesis.

Guidelines for the management of postoperative obstructive symptoms in children with Hirschsprung disease.

Although most children with Hirschsprung disease ultimately do well, many experience a variety of ongoing problems after pull-through surgery. The most common include obstructive symptoms, soiling, enterocolitis and failure to thrive. The purpose of this guideline is to present a rational approach to the management of postoperative obstructive symptoms in children with Hirschsprung disease. The American Pediatric Surgical Association Board of Governors established a Hirschsprung Disease Interest Group. Group discussions, literature review and expert consensus were then used to summarize the current state of knowledge regarding causes, methods of diagnosis, and treatment approaches to children with obstructive symptoms following pull-through for Hirschsprung disease. Causes of obstructive symptoms post-pull-through include mechanical obstruction; persistent or acquired aganglionosis, hypoganglionosis, or transition zone pull-through; internal sphincter achalasia; disordered motility in the proximal intestine that contains ganglion cells; or functional megacolon caused by stool-holding behavior. An algorithm for the diagnosis and management of obstructive symptoms after a pull-through for Hirschsprung disease is presented. A stepwise, logical approach to the diagnosis and management of patients experiencing obstructive symptoms following pull-through for Hirschsprung disease can facilitate treatment. Level of evidence V.

Rates and predictors of hypoglycaemia in 27 585 people from 24 countries with insulin-treated type 1 and type 2 diabetes: the global HAT study.

AIMS: To determine the global extent of hypoglycaemia experienced by patients with diabetes using insulin, as there is a lack of data on the prevalence of hypoglycaemia in developed and developing countries. METHODS: This non-interventional, multicentre, 6-month retrospective and 4-week prospective study using self-assessment questionnaire and patient diaries included 27 585 patients, aged ≥18 years, with type 1 diabetes (T1D; n = 8022) or type 2 diabetes (T2D; n = 19 563) treated with insulin for >12 months, at 2004 sites in 24 countries worldwide. The primary endpoint was the proportion of patients experiencing at least one hypoglycaemic event during the observational period. RESULTS: During the prospective period, 83.0% of patients with T1D and 46.5% of patients with T2D reported hypoglycaemia. Rates of any, nocturnal and severe hypoglycaemia were 73.3 [95% confidence interval (CI) 72.6-74.0], 11.3 (95% CI 11.0-11.6) and 4.9 (95% CI 4.7-5.1) events/patient-year for T1D and 19.3 (95% CI 19.1-19.6), 3.7 (95% CI 3.6-3.8) and 2.5 events/patient-year (95% CI 2.4-2.5) for T2D, respectively. The highest rates of any hypoglycaemia were observed in Latin America for T1D and Russia for T2D. Glycated haemoglobin level was not a significant predictor of hypoglycaemia. CONCLUSIONS: We report hypoglycaemia rates in a global population, including those in countries without previous data. Overall hypoglycaemia rates were high, with large variations between geographical regions. Further investigation into these differences may help to optimize therapy and reduce the risk of hypoglycaemia.

A meta-analysis of rate ratios for nocturnal confirmed hypoglycaemia with insulin degludec vs. insulin glargine using different definitions for hypoglycaemia.

AIMS: A prospective meta-analysis of phase 3 trials showed lower rates of nocturnal hypoglycaemia with insulin degludec vs. insulin glargine. We investigated the consistency of the results across different definitions of hypoglycaemia. METHODS: This post-hoc, patient-level meta-analysis included six randomized, controlled, 26- or 52-week phase 3a trials in insulin-naïve participants with Type 2 diabetes mellitus (Type 2 diabetesinsulin naïve ), participants with Type 2 diabetes mellitus using basal-bolus therapy (Type 2 diabetesBB ) and those with Type 1 diabetes mellitus. We used three definitions of hypoglycaemia and different timescales for the nocturnal period. Rates were analysed for the entire core trial period, the 'maintenance period' only, and the extension trial set population. Analyses utilized a negative binomial regression model. RESULTS: In Type 2 diabetesinsulin naïve participants, risk of nocturnal hypoglycaemia was significantly lower with insulin degludec vs. insulin glargine for all hypoglycaemia definitions and trial periods. Risk was also lower for the timescale 21.59-05.59, but not 00.01-07.59. For Type 2 diabetesBB , nocturnal hypoglycaemia rates were lower with insulin degludec vs. insulin glargine across all definitions, timescales and trial periods, with one exception. For individuals with Type 1 diabetes mellitus, nocturnal hypoglycaemia risk was significantly lower with insulin degludec during the maintenance period for the original definition (plasma glucose < 3.1 mmol/l, timescale 00.01-05.59) and in the extension trial set population for all hypoglycaemia definitions except for the nocturnal timescale 00.01-07.59. CONCLUSIONS: Compared with insulin glargine, insulin degludec is associated with lower rates of nocturnal hypoglycaemia in people with Type 2 diabetes mellitus, and similar or lower rates in Type 1 diabetes mellitus, across different definitions.

Reverse geometry shoulder replacement for proximal humeral metastases.

The management of skeletal metastases can be challenging for the orthopaedic surgeon. They represent a significant source of pain and disability for cancer patients, adding to the morbidity of their condition. Treatment is directed at the alleviation of symptoms and the restoration of function. Metastatic involvement of the proximal humerus can be especially debilitating, having the potential to cause severe pain and loss of function. We present a report of three such cases where reverse geometry proximal shoulder replacement was used to provide a pain free functional range of movement in patients with concomitant rotator cuff disease. In all cases, significant symptomatic relief was achieved postoperatively with preservation of upper limb function. No surgical complications were noted. It is our belief that this novel surgical strategy provides a valuable and effective option for the management of proximal humeral metastatic disease in the rotator cuff deficient patient.

Acute hamstring strain injury in track-and-field athletes: A 3-year observational study at the Penn Relay Carnival.

This study aimed to observe the incidence rates of hamstring strain injuries (HSIs) across different competition levels and ages during the Penn Relays Carnival. Over a 3-year period, all injuries treated by the medical staff were recorded. The type of injury, anatomic location, event in which the injury occurred, competition level, and demographic data were documented. Absolute and relative HSI (per 1000 participants) were determined, and odds ratios (ORs) were calculated between sexes, competition levels, and events. Throughout the study period 48,473 athletes registered to participate in the Penn Relays Carnival, with 118 HSIs treated by the medical team. High school girls displayed lesser risk of HSI than high school boys (OR = 0.55, P = 0.021), and masters athletes were more likely than high school- (OR = 4.26, P < 0.001) and college-level (OR = 3.55, P = 0.001) athletes to suffer HSI. The 4 × 400-m relay displayed a greater likelihood of HSI compared with the 4 × 100-m relay (OR = 1.77, P = 0.008). High school boys and masters-level athletes are most likely to suffer HSI, and there is higher risk in 400-m events compared with 100-m events.

Counting neurons is not as easy as 'one-two, three'.

An accurate determination of the number of neurons in a segment of bowel is fundamental to establish population norms and identify neurodegenerative conditions, including age-related loss of myenteric ganglion cells. Although the latter phenomenon has been observed by several laboratories in various mammals, in this issue of Neurogastroenterology and Motility, Gamage et al. present evidence that colonic myenteric ganglion cells are maintained in aged mice. These discordant findings prompt a thoughtful consideration, the range of variables affecting the accuracy of neuronal counts and the survival of neuronal populations in aging animals.

The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo.

Internal tandem duplications (ITDs) in the fms-like tyrosine kinase receptor (FLT3-ITDs) confer a poor prognosis in acute myeloid leukemia (AML). We hypothesized that increased recruitment of the protein tyrosine phosphatase, Shp2, to FLT3-ITDs contributes to FLT3 ligand (FL)-independent hyperproliferation and STAT5 activation. Co-immunoprecipitation demonstrated constitutive association of Shp2 with the FLT3-ITD, N51-FLT3, as well as with STAT5. Knockdown of Shp2 in Baf3/N51-FLT3 cells significantly reduced proliferation while having little effect on WT-FLT3-expressing cells. Consistently, mutation of N51-FLT3 tyrosine 599 to phenylalanine or genetic disruption of Shp2 in N51-FLT3-expressing bone marrow low-density mononuclear cells reduced proliferation and STAT5 activation. In transplants, genetic disruption of Shp2 in vivo yielded increased latency to and reduced severity of FLT3-ITD-induced malignancy. Mechanistically, Shp2 co-localizes with nuclear phospho-STAT5, is present at functional interferon-γ activation sites (GAS) within the BCL2L1 promoter, and positively activates the human BCL2L1 promoter, suggesting that Shp2 works with STAT5 to promote pro-leukemogenic gene expression. Further, using a small molecule Shp2 inhibitor, the proliferation of N51-FLT3-expressing bone marrow progenitors and primary AML samples was reduced in a dose-dependent manner. These findings demonstrate that Shp2 positively contributes to FLT3-ITD-induced leukemia and suggest that Shp2 inhibition may provide a novel therapeutic approach to AML.

Diffusion-weighted imaging of malignant ocular masses: initial results and directions for further study.

BACKGROUND AND PURPOSE: Ocular masses represent a spectrum of malignant tumors and benign lesions that are sometimes difficult to detect and differentiate by conventional imaging techniques. The aim of this study was to characterize a group of malignant ocular masses with DWI, with the goals of establishing reference data and identifying potential clinical applications for improved noninvasive characterization. MATERIALS AND METHODS: With institutional review board approval, 26 malignant ocular masses in 22 patients were retrospectively analyzed. Five masses were excluded from further analysis due to nonvisualization. Fifteen retinoblastomas, 5 melanomas, and 1 highly undifferentiated carcinoma were studied. Region-of-interest analysis was performed, and the ADC of each mass was measured and also compared with a normal-appearing thalamus. Lesion thickness was measured, the amount of susceptibility artifact was qualitatively assessed and graded, and the correlation between these factors and retinoblastoma ADC was determined. RESULTS: Retinoblastomas had an ADC of 0.93 ± 0.3 × 10(-3) mm(2)/s (mean). Melanoma had an ADC of 1.18 ± 0.16 × 10(-3) mm(2)/s. The ADC of retinoblastoma was strongly inversely correlated with lesion thickness, likely representing the effect of partial volume averaging. ADC was not correlated with the amount of subjectively determined susceptibility artifact. CONCLUSIONS: Malignant ocular tumors were consistently characterized with DWI, though with limitations due to artifact and partial volume averaging. Additional description of DWI of ocular masses and further technical improvements may lead to a clinical role for DWI.

Quantitation of cellular components of the enteric nervous system in the normal human gastrointestinal tract--report on behalf of the Gastro 2009 International Working Group.

BACKGROUND: Patients with gastrointestinal neuromuscular diseases may undergo operative procedures that yield tissue appropriate to diagnosis of underlying neuromuscular pathology. Critical to accurate diagnosis is the determination of limits of normality based on the study of control human tissues. Although robust diagnostic criteria exist for many qualitative alterations in the neuromuscular apparatus, these do not include quantitative values due to lack of adequate control data. PURPOSE: The aim of this report was to summarize all relevant available published quantitative data for elements of the human enteric nervous system (neuronal cell bodies, glial cells, and nerve fibers) from the perspective of the practicing pathologist. Forty studies meeting inclusion criteria were systematically reviewed with data tabulated in detail and discussed in the context of methodological variations and limitations. The results reveal a lack of concordance between observations of different investigators resulting in data insufficient to produce robust normal ranges. This diversity highlights the need to standardize the way pathologists collect, process, and quantitate neuronal and glial elements in enteric neuropathologic samples, as suggested by recent international guidelines on gastrointestinal neuromuscular pathology.

Autologous olfactory [corrected] mucosal transplant in chronic spinal cord injury: an Indian Pilot Study.

STUDY DESIGN: Prospective Pilot Study. OBJECTIVES: To determine the safety and feasibility of autologous olfactory mucosal transplantation into the spinal cord in chronic spinal cord injured using the technique developed by Carlos Lima et al. SETTING: Spinal Injury Center, New Delhi. METHODS: Five chronic, motor complete, traumatic spinal cord injury (SCI) patients with neurological level C5-T12 underwent the procedure. Participants were assessed at baseline and at 6 monthly intervals. Safety and tolerability were evaluated through monitoring for any adverse events and tests including magnetic resonance imaging (MRI) evaluation. Efficacy assessment was done through neurological, functional and psychological evaluation, electrophysiological studies and urodynamics. RESULTS: Surgery was tolerated well by all American Spinal Injury Association (ASIA) Impairment Scale (AIS) A participants. The only AIS B participant lost sensory scores significantly after surgery but is gradually regaining it. MRI evaluation revealed a syrinx in one participant and increase in length of myelomalacia in four participants. There were no other adverse findings on MRI evaluation. There was no significant improvement in any of the neurological, electrophysiological or urodynamic efficacy variables. Statistically significant improvement was seen in functional scores as evaluated by Spinal Cord Independence Measure, Beck Depression Inventory scores and life impact scores on International Spinal Cord Injury Scale. CONCLUSIONS: The procedure is relatively safe and feasible in AIS A participants with thoracic level injuries at 18 month follow-up. No efficacy could be demonstrated which could be attributed to the procedure.

MR imaging of orbital inflammatory syndrome, orbital cellulitis, and orbital lymphoid lesions: the role of diffusion-weighted imaging.

BACKGROUND AND PURPOSE: Orbital inflammatory syndrome (OIS) has clinical features that overlap with orbital lymphoid lesions and orbital cellulitis. Prompt diagnosis is needed in all 3 conditions because the management of each one differs greatly. CT and MR imaging, though useful, do not always distinguish among these conditions. The aim of this study was to identify the role of diffusion-weighted imaging (DWI) in differentiating these 3 diagnoses. MATERIALS AND METHODS: A retrospective analysis of orbital MR imaging was conducted. T1- and T2-weighted and postcontrast images were analyzed. Region-of-interest analysis was performed by using measurements in areas of abnormality seen on conventional MR imaging sequences and measurements of the ipsilateral thalamus for each patient. The DWI signal intensity of the lesion was expressed as a percentage of average thalamic intensity in each patient. Similarly, lesion apparent diffusion coefficients (ADCs) and lesion-thalamus ADC ratios were calculated. Statistical significance was determined by the Kruskal-Wallis test, and post hoc pairwise comparisons, by the Mann-Whitney U test for DWI-intensity ratio, ADC, and ADC ratio. RESULTS: A significant difference was noted in DWI intensities, ADC, and ADC ratio between OIS, orbital lymphoid lesions, and orbital cellulitis (P < .05). Lymphoid lesions were significantly brighter than OIS, and OIS lesions were significantly brighter than cellulitis. Lymphoid lesions showed lower ADC than OIS and cellulitis. A trend was seen toward lower ADC in OIS than in cellulitis (P = .17). CONCLUSIONS: DWI may help differentiate OIS from lymphoid lesions and cellulitis and may allow more rapid management.

Hemifacial microsomia: a case report.

Hemifacial microsomia is a congenital malformation in which there is a deficiency in the amount of hard and soft tissue on one side of the face. It is primarily a syndrome of the first branchial arch, involving underdevelopment of the temporomandibular joint, mandibular ramus, masticatory muscles and the ear. The affected ear may have an external soft-tissue malformation in addition to being lower set than on the contra lateral side. Hearing loss may result from underdevelopment of the osseous components of the auditory system and a diminished or absent external auditory meatus. Occasionally, second branchial arch defects involving the facial nerve and facial muscles coexist with Hemifacial microsomia. Radiographic examination in case of Hemifacial microsomia is of limited value because of superimposition of normal and abnormal bony structures. The skeletal and soft-tissue findings of a patient with Hemifacial microsomia who underwent three-dimensional computerized tomography is presented here to improve our knowledge and diagnostic skill of this uncommon entity.

A microfluidics approach for the isolation of nucleated red blood cells (NRBCs) from the peripheral blood of pregnant women.

OBJECTIVE: Nucleated red blood cells (NRBCs) have been identified in maternal circulation and potentially provide a resource for the monitoring and diagnosis of maternal, fetal, and neonatal health and disease. Past strategies used to isolate and enrich for NRBCs are limited to complex approaches that result in low recovery and less than optimal cell purity. Here we report the development of a high-throughput and highly efficient microfluidic device for isolating rare NRBCs from maternal blood. MATERIAL AND METHODS: NRBCs were isolated from the peripheral blood of 58 pregnant women using a microfluidic process that consists of a microfluidic chip for size-based cell separation and a magnetic device for hemoglobin-based cell isolation. RESULTS: The microfluidic-magnetic combination removes nontarget red blood cells and white blood cells at a very high efficiency (approximately 99.99%). The device successfully identified NRBCs from the peripheral blood of 58/58 pre-termination samples with a mean of 37.44 NRBC/mL (range 0.37-274.36 NRBC/mL). These results were compared with those from previous studies. CONCLUSION: The microfluidic device results in an approximate 10- to 20-fold enrichment of NRBCs over methods described previously. The reliability of isolation and the purity of the NRBC product have the potential to enable the subsequent application of molecular diagnostic assays.

Histological analysis of DuraGen in a human subject: case report.

OBJECT: DuraGen (Integra Neurosciences, Plainsboro, NJ, USA) is an avascular collagen matrix used for dural closure. Although, numerous animal models have been studied, histological transformation of DuraGen in humans has not been reported. MATERIAL AND METHOD: We analyzed a sample of scarred DuraGen used in a craniectomy patient at time of delayed cranioplasty. CONCLUSION: Histological analysis revealed evidence for both fibroblast infiltration and neovascularization of the DuraGen.