Indicators of choking risk in adults with learning disabilities: a questionnaire survey and interview study

Purpose. Feeding and swallowing impairments are key predictors of increased morbidity and mortality in adults with learning disabilities. This postal survey and interview study sought to identify risk factors in adults with learning disabilities who have histories of choking. Method. A total of 2000 questionnaires were sent to carers of all adults with learning disabilities registered as service users by three local health authorities. (A 'service user' may be using any specialist learning disability health or social care facility with day, residential or therapeutic services). Of the 674 service users for whom surveys were returned, 47 were living in hospital, 396 were living in residential or group homes and 208 were living with relatives, or in their own homes. Eighteen subjects who had reported serious or repeated episodes of choking were interviewed in depth in their residences or workplaces. Responses were subjected to frequency analyses. Personal characteristics were analysed. Choking patterns were differentiated by food texture. Results. A total of 34% of questionnaires on 674 service users were returned; 42% of respondents reported one or more choking episodes. There was a significantly greater occurrence of choking among people with more severe learning disability, with Down syndrome, people who had an incomplete dentition or were taking a greater number of psychotropic drugs. Antisocial eating habits learnt in institutional settings presented an additional choking hazard for some individuals. Conclusion. Choking is a serious hazard for many adults with learning disabilities. This study establishes many of the characteristics associated with swallowing problems in this population. Clinicians and carers should benefit from awareness of these predictors, leading to better management of eating behaviours and habits. A choking and swallowing risk assessment should be included in routine health assessments of adults with learning disability, paying especial attention to the condition of a person's teeth; possible side effects from prescribed medication, and abnormal eating behaviour.     

Do current therapeutic anti-Aβ antibodies for Alzheimer’s disease engage the target?

Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer’s disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.     

Childhood central nervous system tumors at MAHAK’s Pediatric Cancer Treatment and Research Center (MPCTRC), Tehran,Iran

Purpose

As central nervous system (CNS) tumors account for second most common childhood malignancies and the first cause of mortality in children with cancer, improving treatment modalities can lead to increase the health care of patients. In this study, we examined the prevalence of childhood brain tumors in patients who referred to MAHAK’s Pediatric Cancer Treatment and Research Center (MPCTRC) for treatment.

Methods

A retrospective review of all children less than 15 years old with a CNS histologically proven tumor, who presented to MPCTRC from April 2007 to April 2010, was performed. Data was analyzed by SPSS version 19 with Kolmogorov–Smirnov and Chi-square tests.

Results

There were 198 (124 boys) children eligible for the study. The majority of the tumors were infratentorial (n?=?134), and the rest were supratentorial (n?=?60) and spinal (n?=?4) cases. The median age was 6.11?±?3.65 years old. Medulloblastoma (n?=?66), low-grade glioma (n?=?52), and high-grade glioma (n?=?40) were the most common tumors. The mean duration of follow-up was 21 months. At the time of this analysis, there were 105 (53 %) children alive, 82 (41.4 %) deaths, and 11 (5.6 %) lost for follow-up. The survival rate was 51.68?±?5.22 %.

Conclusions

In contrast of high rate of death in this study, other general characteristics can serve as benchmark for improving our care for children with brain tumors in Iran.     

Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer

ObjectivesIn patients with a rising prostate-specific antigen (PSA) level during treatment with androgen deprivation therapy, identification of men who progress to bone metastasis and death remains problematic. Accurate risk stratification models are needed to better predict risk for bone metastasis and death among patients with castration-resistant prostate cancer (CRPC). This study evaluates whether alkaline phosphatase (AP) kinetics predicts bone metastasis and death in patients with CRPC.Methods and materialsA retrospective cohort study of 9,547 patients who underwent treatment for prostate cancer was conducted using the Center for Prostate Disease Research Multi-center National Database. From the entire cohort, 347 were found to have CRPC and, of those, 165 had 2 or more AP measurements during follow-up. To determine the AP velocity (APV), the slope of the linear regression line of all AP values was plotted over time. Rapid APV was defined as the uppermost quartile of APV values, which was found to be ≥6.3 IU/l/y. CRPC was defined as 2 consecutive rising PSA values after achieving a PSA nadir<4 ng/ml and documented testosterone values less than 50 ng/dl. The primary study outcomes included bone metastasis–free survival (BMFS) and overall survival (OS).ResultsRapid APV and PSA doubling time (PSADT) less than 10 months were strong predictors of both BMFS and OS in a multivariable analysis. Faster PSADT was a stronger predictor for BMFS (odds ratio [OR] = 12.1, P<0.0001 vs. OR = 2.7, P = 0.011), whereas rapid APV was a stronger predictor of poorer OS (OR = 5.11, P = 0.0001 vs. OR = 3.98, P = 0.0034). In those with both a rapid APV and a faster PSADT, the odds of developing bone metastasis and death exceeded 50%.ConclusionAPV is an independent predictor of OS and BMFS in patients with CRPC. APV, in conjunction with PSA-based clinical parameters, may be used to better identify patients with CRPC who are at the highest risk of metastasis and death. These findings need validation in prospective studies.     

Breast Cancer Risk and Aging—Misquoted Data and Public Information

The “risk of breast cancer in women increases with age” is a longtime misstatement that does not conform to statistical data. Contrary to the common perception and widely publicized statements, the overall risk of developing breast cancer decreases in women as they grow old.     

Global Analysis Reveals the Complexity of the Human Glomerular Extracellular Matrix

The glomerulus contains unique cellular and extracellular matrix (ECM) components, which are required for intact barrier function. Studies of the cellular components have helped to build understanding of glomerular disease; however, the full composition and regulation of glomerular ECM remains poorly understood. We used mass spectrometry-based proteomics of enriched ECM extracts for a global analysis of human glomerular ECM in vivo and identified a tissue-specific proteome of 144 structural and regulatory ECM proteins. This catalog includes all previously identified glomerular components plus many new and abundant components. Relative protein quantification showed a dominance of collagen IV, collagen I, and laminin isoforms in the glomerular ECM together with abundant collagen VI and TINAGL1. Protein network analysis enabled the creation of a glomerular ECM interactome, which revealed a core of highly connected structural components. More than one half of the glomerular ECM proteome was validated using colocalization studies and data from the Human Protein Atlas. This study yields the greatest number of ECM proteins relative to previous investigations of whole glomerular extracts, highlighting the importance of sample enrichment. It also shows that the composition of glomerular ECM is far more complex than previously appreciated and suggests that many more ECM components may contribute to glomerular development and disease processes. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD000456.The glomerulus is a sophisticated organelle comprising unique cellular and extracellular matrix (ECM) components. Fenestrated capillary endothelial cells and overlying podocytes are separated by a specialized glomerular basement membrane (GBM), and these three components together form the filtration barrier. Mesangial cells and their associated ECM, the mesangial matrix, exist between adjacent capillary loops and maintain the three-dimensional organization of the capillary bundle. In turn, the parietal epithelial cells and ECM of Bowman’s capsule enclose this network of capillaries. Cells adhere to ECM proteins by adhesion receptors, and these interactions are required to maintain intact barrier function of the glomerulus.^1,2In addition to operating as a signaling platform, ECM provides a structural scaffold for adjacent cells and has a tissue-specific molecular composition.^3,4 Candidate-based investigations of glomerular ECM have focused on the GBM and shown that it resembles the typical basal lamina found in multicellular organisms, containing a core of glycoproteins (collagen IV, laminins, and nidogens) and heparan sulfate proteoglycans (agrin, perlecan, and collagen XVIII).⁵ Mesangial and parietal cell ECMs have been less well investigated; nonetheless, they are also thought to contain similar core components in addition to other glycoproteins, including fibronectin.^6,7 Thus, the glomerulus consists of a combination of condensed ECM within the GBM and Bowman’s capsule and loose ECM supporting the mesangial cells.The ECM compartments in the glomerulus are thought to be distinct and exhibit different functional roles. The GBM is integral to the capillary wall and therefore, functionally linked to glomerular filtration.⁵ Mutations of tissue-restricted isoforms of collagen IV (COL4A3, COL4A4, and COL4A5) and laminin (LAMB2), which are found in the GBM, cause significant barrier dysfunction and ultimately, renal failure.^8,9 Less is understood about the functions of mesangial and parietal cell ECMs, although expansion of the mesangial compartment is a histologic pattern seen across the spectrum of glomerular disease.¹⁰Compositional investigation of the distinct glomerular ECM compartments is limited by the technical difficulties of separation. Early investigations of GBM constituents used the relative insolubility of ECM proteins to facilitate separation from cellular proteins in the glomerulus but did not separate the GBM from mesangial and parietal cells ECMs.^11,12 Recently, studies incorporating laser microdissection of glomerular sections have been coupled with proteomic analyses.^13,14 These studies report both cellular and ECM components and typically require pooled material from glomerular sections to improve protein identification. The ability of laser microdissection to separate glomerular ECM compartments has not yet been tested; however, this approach will be limited by the amount of protein that is possible to retrieve. To achieve good coverage of ECM proteins within a tissue, proteomic studies need to combine a reduction in sample complexity with maximal protein quantity. Currently, the inability to separate glomerular ECM compartments in sufficient quantity is a limitation that prohibits proteomic studies of these structures; however, for other tissues, proteomic analysis of ECM has been achieved by enrichment of ECM combined with sample fractionation.¹⁵Although the composition of the ECM in other tissues has been addressed using proteomic approaches,¹⁵ studies of glomerular ECM to date have used candidate-based technologies. These studies have identified key molecular changes during development and disease and highlighted the compositional and organizational dynamics of glomerular ECM. Nonetheless, the extracellular environment within the glomerulus is the setting for a complex series of interactions between both structural ECM proteins and ECM-associated proteins, such as growth factors^16–18 and proteases,¹⁹ which together provide a specialized niche to support glomerular cell function. Therefore, to interrogate this complexity effectively, a systems-level understanding of glomerular ECM is required. To address the need for a global analysis of the extracellular environment within the glomerulus, we used mass spectrometry (MS)-based proteomics of glomerular ECM fractions to define the human glomerular ECM proteome.     

Biomechanical analysis of the upper thoracic spine after decompressive procedures

Background contextDecompressive procedures such as laminectomy, facetectomy, and costotransversectomy are routinely performed for various pathologies in the thoracic spine. The thoracic spine is unique, in part, because of the sternocostovertebral articulations that provide additional strength to the region relative to the cervical and lumbar spines. During decompressive surgeries, stability is compromised at a presently unknown point.PurposeTo evaluate thoracic spinal stability after common surgical decompressive procedures in thoracic spines with intact sternocostovertebral articulations.Study designBiomechanical cadaveric study.MethodsFresh-frozen human cadaveric spine specimens with intact rib cages, C7–L1 (n=9), were used. An industrial robot tested all spines in axial rotation (AR), lateral bending (LB), and flexion-extension (FE) by applying pure moments (±5 Nm). The specimens were first tested in their intact state and then tested after each of the following sequential surgical decompressive procedures at T4–T5 consisting of laminectomy; unilateral facetectomy; unilateral costotransversectomy, and subsequently instrumented fusion from T3–T7.ResultsWe found that in all three planes of motion, the sequential decompressive procedures caused no statistically significant change in motion between T3–T7 or T1–T12 when compared with intact. In comparing between intact and instrumented specimens, our study found that instrumentation reduced global range of motion (ROM) between T1–T12 by 16.3% (p=.001), 12% (p=.002), and 18.4% (p=.0004) for AR, FE, and LB, respectively. Age showed a negative correlation with motion in FE (r=?0.78, p=.01) and AR (r=?0.7, p=.04).ConclusionsThoracic spine stability was not significantly affected by sequential decompressive procedures in thoracic segments at the level of the true ribs in all three planes of motion in intact thoracic specimens. Age appeared to negatively correlate with ROM of the specimen. Our study suggests that thoracic spinal stability is maintained immediately after unilateral decompression at the level of the true ribs. These preliminary observations, however, do not depict the long-term sequelae of such procedures and warrant further investigation.