Hyperphosphatemia,Phosphoprotein Phosphatases,and Microparticle Release in Vascular Endothelial Cells

Hyperphosphatemia in patients with advanced CKD is thought to be an important contributor to cardiovascular risk, in part because of endothelial cell (EC) dysfunction induced by inorganic phosphate (Pi). Such patients also have an elevated circulating concentration of procoagulant endothelial microparticles (MPs), leading to a prothrombotic state, which may contribute to acute occlusive events. We hypothesized that hyperphosphatemia leads to MP formation from ECs through an elevation of intracellular Pi concentration, which directly inhibits phosphoprotein phosphatases, triggering a global increase in phosphorylation and cytoskeletal changes. In cultured human ECs (EAhy926), incubation with elevated extracellular Pi (2.5 mM) led to a rise in intracellular Pi concentration within 90 minutes. This was mediated by PiT1/slc20a1 Pi transporters and led to global accumulation of tyrosine- and serine/threonine-phosphorylated proteins, a marked increase in cellular Tropomyosin-3, plasma membrane blebbing, and release of 0.1- to 1-μm-diameter MPs. The effect of Pi was independent of oxidative stress or apoptosis. Similarly, global inhibition of phosphoprotein phosphatases with orthovanadate or fluoride yielded a global protein phosphorylation response and rapid release of MPs. The Pi-induced MPs expressed VE-cadherin and superficial phosphatidylserine, and in a thrombin generation assay, they displayed significantly more procoagulant activity than particles derived from cells incubated in medium with a physiologic level of Pi (1 mM). These data show a mechanism of Pi-induced cellular stress and signaling, which may be widely applicable in mammalian cells, and in ECs, it provides a novel pathologic link between hyperphosphatemia, generation of MPs, and thrombotic risk.     

A simple nutrition screening tool for hemodialysis nurses.

OBJECTIVE: To assess the reliability of a nurse-performed nutrition screening tool (NST) for hemodialysis (HD) patients to identify nutritionally at-risk patients. DESIGN: Tool reliability assessment. SETTING AND PARTICIPANTS: The setting was nine non-hospital private (n = 3) and public (n = 6) HD units in Australia (two rural and seven metropolitan). Participants were 112 HD patients. RESULTS: A total of 112 HD patients (male = 65, female = 47) from 9 non-hospital HD units in Australia (seven metropolitan and two rural) were screened with the NST and the outcome of dietitian referral compared with Standard Dietitians Assessment. The mean age of patients was 57.6 years. Overall, the NST showed a sensitivity of 0.84 (range, 0.71 to 0.94; P < .05) and a specificity of 0.9 (range, 0.82 to 0.98; P < .05). The NST was more sensitive (sensitivity, 0.93 [range, 0.87 to 0.99; P < .05]) and was more specific for men (specificity, 0.92 [range, 0.85 to 0.99; P < .05]). Specificity was very strong in metropolitan patients (specificity, 0.94 [range, 0.87 to 1.01; P < .05]). CONCLUSIONS: The tool was more sensitive and specific than the NST previously reported by the same investigators. The tool is particularly specific in that it screens those patients not requiring dietitian intervention. The use of this tool may benefit HD units that do not have on-site or regular dietetic support to prioritize patients needing dietitian intervention.     

A dyadic genotype–phenotype approach to diagnostic criteria for Proteus syndrome

Phenotype‐based diagnostic criteria were developed for Proteus syndrome in 1999 and updated in 2006. Subsequently, the causative mosaic gene alteration was discovered, the c.49G>A p.E17K variant in AKT1. As well, a number of overlapping overgrowth disorders attributable to mosaic PIK3CA variants have now been characterized, leading to the designation of PIK3CA‐related overgrowth spectrum (PROS). Finally, ongoing work to better characterize Proteus syndrome has led to identification of additional features of that disorder that could be useful in diagnostic criteria. We have taken the opportunity of these discoveries to re‐evaluate the Proteus syndrome diagnostic criteria. Here we propose a new set of diagnostic criteria that establishes a weighted, point‐based system for the phenotypic attributes and then integrates that with the potential molecular test results to result in one of two designations: AKT1‐related Proteus syndrome or AKT1‐related overgrowth spectrum. A patient whose only manifestation is an AKT1 c.49G>A‐positive tumor would receive neither of these designations. Here we review the rational basis of diagnostic criteria and argue that a unitary diagnostic entity is a distinct gene‐phenotype dyad and that this should be the model for all mendelian disorders. The gene‐alone or phenotype‐alone approach is inadequate to rigorously delineate a unitary diagnostic entity.     

Placental efficiency and adaptation: endocrine regulation

Size at birth is critical in determining life expectancy and is dependent primarily on the placental supply of nutrients. However, the fetus is not just a passive recipient of nutrients from the placenta. It exerts a significant acquisitive drive for nutrients, which acts through morphological and functional adaptations in the placenta, particularly when the genetically determined drive for fetal growth is compromised by adverse intrauterine conditions. These adaptations alter the efficiency with which the placenta supports fetal growth, which results in optimal growth for prevailing conditions in utero . This review examines placental efficiency as a means of altering fetal growth, the morphological and functional adaptations that influence placental efficiency and the endocrine regulation of these processes.     

Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: analysis of histopathology and outcome

To examine the histopathologic effect of neoadjuvant therapy and its impact on survival in patients with carcinoma of the pancreas, we retrospectively reviewed the records of 116 patients who underwent resections for pancreatic cancer from 1987 to 2000. Median follow-up of surviving patients was 19 mo(range 4-150 mo). Preoperative chemotherapy was administered in 61 patients (53%) and consisted of 5-fluorouracil/mitomycin C in 35 patients and gemcitabine in 26 patients, given concurrently with external beam radiation (5040 cGy). All resections were performed with curative intent (98 Whipples, 11 total, 6 distal, and 1 central pancreatectomy). Histopathologic examination included an estimation of the amount of fibrosis present in the tumor specimen (expressed as the percentage of fibrosis identified relative to the amount of neoplastic cells present). The mean fibrosis level for the series was 56% (range 5% to 100%). The administration of neoadjuvant therapy resulted in greater fibrosis (73%) than no preoperative treatment (38%) (p = 0.0001). Higher mean fibrosis levels were observed in patients with negative lymph nodes (p = 0.0006) and negative margins (p = 0.05). Factors associated with improved survival(log rank test) included: negative margins (p = 0.001), negative lymph nodes (p = 0.03), and use of neoadjuvant therapy (p = 0.03). Median survival in the neoadjuvant group was 23 mo vs 16 mo without preoperative therapy (p = 0.03). In conclusion, the use of neoadjuvant therapy resulted in a greater degree of fibrosis in the specimen. Patients with negative margins and negative lymph nodes had a greater amount of fibrosis present, and these were significant predictors of improved outcome. Although retrospective,this series suggests an improvement in survival in patients treated with neoadjuvant therapy.     

Challenges and remediation for Patient Safety Indicators in the transition to ICD-10-CM

Reporting of hospital adverse events relies on Patient Safety Indicators (PSIs) using International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes. The US transition to ICD-10-CM in 2015 could result in erroneous comparisons of PSIs. Using the General Equivalent Mappings (GEMs), we compared the accuracy of ICD-9-CM coded PSIs against recommended ICD-10-CM codes from the Centers for Medicaid/Medicare Services (CMS). We further predict their impact in a cohort of 38 644 patients (1 446 581 visits and 399 hospitals). We compared the predicted results to the published PSI related ICD-10-CM diagnosis codes. We provide the first report of substantial hospital safety reporting errors with five direct comparisons from the 23 types of PSIs (transfusion and anesthesia related PSIs). One PSI was excluded from the comparison between code sets due to reorganization, while 15 additional PSIs were inaccurate to a lesser degree due to the complexity of the coding translation. The ICD-10-CM translations proposed by CMS pose impending risks for (1) comparing safety incidents, (2) inflating the number of PSIs, and (3) increasing the variability of calculations attributable to the abundance of coding system translations. Ethical organizations addressing ‘data-, process-, and system-focused’ improvements could be penalized using the new ICD-10-CM Agency for Healthcare Research and Quality PSIs because of apparent increases in PSIs bearing the same PSI identifier and label, yet calculated differently. Here we investigate which PSIs would reliably transition between ICD-9-CM and ICD-10-CM, and those at risk of under-reporting and over-reporting adverse events while the frequency of these adverse events remain unchanged.     

Concepts of rehabilitation for the management of low back pain

This chapter develops rehabilitation principles for the clinical and occupational management of non-specific low back pain (LBP). Rehabilitation has traditionally been a secondary intervention, which focused on permanent impairment, but this is inappropriate for LBP. Most patients with LBP do not have any irremediable impairment and long-term incapacity is not inevitable: given the right care, support and opportunity, most should be able to return to work. Rehabilitation should then address obstacles to recovery and barriers to (return to) work. Rehabilitation should not be a separate, second stage after 'treatment' is complete: rehabilitation principles should be integral to clinical and occupational management. It should be possible to reduce sickness absence and long-term incapacity due to LBP by at least 30-50%, but this will require a fundamental shift in management culture.