Nephrogenic systemic fibrosis is a clinical syndrome occurring in a small subset of patients with end-stage renal disease (ESRD). Exposure to certain of the gadolinium-based contrast agents during ...magnetic resonance imaging appears to be a trigger. The pathogenesis of the disease is largely unknown. The present study addresses potential pathophysiologic mechanisms.
We have compared responses in organ-cultured skin and skin fibroblasts from individuals with ESRD to responses of healthy control subjects to Omniscan treatment.
Treatment of skin from ESRD patients with Omniscan stimulated production of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1, but not type I procollagen. The same treatment also stimulated an increase in hyaluronan production. Similar results were seen with skin from normal controls but basal levels were higher in ESRD patients. Fibroblasts in monolayer culture gave the same responses, but there were no differences based on whether the cells were isolated from the skin of healthy subjects or those with ESRD.
These data indicate that Omniscan exposure alters an enzyme/inhibitor system responsible for regulating collagen turnover in the skin and directly stimulates hyaluronan production. The higher basal levels of type I procollagen, matrix metalloproteinase-1, tissue inhibitor of metalloproteinases-1, and hyaluronan in the skin from ESRD patients could contribute to the sensitivity of this patient population to fibrotic changes, which might be induced by exposure to some of the gadolinium-based contrast agents.
Atheroembolism, caused by peripheral embolization of small cholesterol crystals that fracture off of ruptured atherosclerotic plaques in the major vessels, leads to multifocal ischemic lesions and ...progressive tissue loss. The end result is often ischemic injury in the skin, kidney, brain, myocardium, and intestine, but any organ distal to the culprit lesion may be affected. The precise incidence of this serious clinical syndrome has been difficult to ascertain from the available literature, but it appears to be much more common than has been assumed. The objective of the present study is to clarify the incidence of atheroembolism among inpatients in an acute hospital setting.
We surveyed inpatient nephrology consultations during a 7-month period from January through July 1994. From a pool of 402 consultation charts, 99 were identified with two or more substantive risk factors for atheroembolism. The records of 85 of these patients were available for careful review. More than 300 additional patients were found to have ICD-9 discharge codes for other vascular conditions, but we were unable to confirm that any of these were in fact cases of atheroembolism, since there is no specific ICD-9 discharge code for this entity. In the 85 cases reviewed, a diagnosis of atheroembolism was made only if the patient had identifiable substantive risk factors, suggestive physical findings, and supporting laboratory results.
Eleven of the 85 surveyed records documented strong evidence supporting a “probable” diagnosis of atheroembolism. Tissue was examined in 4 of these 11, resulting in definitive histologic confirmation in 3. Another 5 of the 85 surveyed records were “suggestive” of atheroembolism. Altogether, atheroembolism was a likely diagnosis in a total of 16 cases during this 7-month period, or 1 case every 2 weeks. These cases comprised 19% of nephrology consultations in which 2 or more risk factors were present, or 4% of all nephrology consultations. The patients' records confirmed the serious implications of clinically detectable atheroembolism. Several patients underwent lower extremity amputation, nearly half required acute or chronic dialysis, and more than half died within several months of diagnosis.
The present study suggests that at least 4% of all inpatient nephrology consultations, representing approximately 5% to 10% of the acute renal failure encountered, involve clinically significant atheroembolism. Patients with atheroembolism appear at a rate of at least 1 case every 2 weeks. They often have identifiable substantive risk factors at initial consultation, and probably represent only the most severe cases of atheroembolism. In view of the serious implications of this basically untreatable syndrome, heightened awareness and preventive maneuvers in the population at risk are essential.
Human skin produces increased amounts of matrix metalloproteinase-1 (MMP-1) when exposed in organ culture to Omniscan, one of the gadolinium-based MRI contrast agents (GBCA). MMP-1, by virtue of its ...ability to degrade structural collagen, contributes to collagen turnover in the skin. The objective of the present study was to determine whether collagenolytic activity was concomitantly up-regulated with increased enzyme.
Skin biopsies from normal volunteers were exposed in organ culture to Omniscan. Organ culture fluids obtained from control and treated skin were examined for ability to degrade type I collagen. The same culture fluids were examined for levels of MMP-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and complexes of MMP-1 and TIMP-1.
Although MMP-1 was increased in culture fluid from Omniscan-treated skin, there was no increase in collagenolytic activity. In fact, collagenolytic activity declined. Increased production of TIMP-1 was also observed in Omniscan-treated skin, and the absolute amount of TIMP-1 was greater than the amount of MMP-1. Virtually all of the MMP-1 was present in MMP-1-TIMP-1 complexes, but the majority of TIMP-1 was not associated with MMP-1. When human dermal fibroblasts were exposed to TIMP-1 (up to 250 ng/mL), no increase in proliferation was observed, but an increase in collagen deposition into the cell layer was seen.
Gadolinium-based MRI contrast agent exposure has recently been linked to a fibrotic skin condition in patients with impaired kidney function. The mechanism is unknown. The increase in TIMP-1 production and concomitant reduction in collagenolytic activity demonstrated here could result in decreased collagen turnover and increased deposition of collagen in lesional skin.
Chronic dialysis imposes ongoing stress on patients and staff and engenders recurring contact and long-term relationships. Thus, chronic dialysis units are opportune settings in which to investigate ...the impact of patients' relationships with staff on patient well-being. The authors designed the present study to examine the degree to which perceptions of open communication between patients and staff affect patient mental health. A one-year, two-wave longitudinal survey assessed patient (N = 109) perceptions of the interpersonal environment and mental health. Assessments included sharing personal information (open disclosure), assisting one another (helping), staff respect for patients (respect), and hierarchical patient—staff relations (formal staff authority). Cross-sectional and longitudinal regression analyses examined how these characteristics of the interpersonal environment relate to depression and subjective well-being among patients. Multivariate analysis showed that open disclosure correlated independently with lower levels of depression at baseline (N = 109) and a predicted significant decrease in depression over time (N = 64). Other interpersonal characteristics did not correlate with depression or subjective well-being at baseline or longitudinally. The interpersonal climate in chronic dialysis units influences patient well-being. Contrary to traditional views, open disclosure in patients' relationships with staff is not detrimental and contributes to well-being.
Diarrhoea is a leading cause of death and illness globally among children younger than 5 years. Mortality and short-term morbidity cause substantial burden of disease but probably underestimate the ...true effect of diarrhoea on population health. This underestimation is because diarrhoeal diseases can negatively affect early childhood growth, probably through enteric dysfunction and impaired uptake of macronutrients and micronutrients. We attempt to quantify the long-term sequelae associated with childhood growth impairment due to diarrhoea.
We used the Global Burden of Diseases, Injuries, and Risk Factors Study framework and leveraged existing estimates of diarrhoea incidence, childhood undernutrition, and infectious disease burden to estimate the effect of diarrhoeal diseases on physical growth, including weight and height, and subsequent disease among children younger than 5 years. The burden of diarrhoea was measured in disability-adjusted life-years (DALYs), a composite metric of mortality and morbidity. We hypothesised that diarrhoea is negatively associated with three common markers of growth: weight-for-age, weight-for-height, and height-for-age Z-scores. On the basis of these undernutrition exposures, we applied a counterfactual approach to quantify the relative risk of infectious disease (subsequent diarrhoea, lower respiratory infection, and measles) and protein energy malnutrition morbidity and mortality per day of diarrhoea and quantified the burden of diarrhoeal disease due to these outcomes caused by undernutrition.
Diarrhoea episodes are significantly associated with childhood growth faltering. We found that each day of diarrhoea was associated with height-for-age Z-score (–0·0033 95% CI −0·0024 to −0·0041; p=4·43 × 10−14), weight-for-age Z-score (–0·0077 –0·0058 to −0·0097; p=3·19 × 10−15), and weight-for-height Z-score (–0·0096 –0·0067 to −0·0125; p=7·78 × 10−11). After addition of the DALYs due to the long-term sequelae as a consequence of undernutrition, the burden of diarrhoeal diseases increased by 39·0% (95% uncertainty interval UI 33·0–46·6) and was responsible for 55 778 000 DALYs (95% UI 49 125 400–62 396 200) among children younger than 5 years in 2016. Among the 15 652 300 DALYs (95% UI 12 951 300–18 806 100) associated with undernutrition due to diarrhoeal episodes, more than 84·7% are due to increased risk of infectious disease, whereas the remaining 15·3% of long-term DALYs are due to increased prevalence of protein energy malnutrition. The burden of diarrhoea has decreased substantially since 1990, but progress has been greater in long-term (78·7% reduction 95% UI 69·3–85·5) than in acute (70·4% reduction 95% UI 61·7–76·5) DALYs.
Diarrhoea represents an even larger burden of disease than was estimated in the Global Burden of Disease Study. In order to adequately address the burden of its long-term sequelae, a renewed emphasis on controlling the risk of diarrhoea incidence may be required. This renewed effort can help further prevent the potential lifelong cost on child health, growth, and overall potential.
Bill & Melinda Gates Foundation.
Highlights • Obstructive sleep apnea (OSA) remains under-appreciated after stroke and TIA • We examined whether paper-based screening tools could rule out OSA after stroke/TIA • We evaluated 69 ...patients (53 with stroke, 16 with TIA); 32 patients (46.4%) had OSA • The 4V and STOP-BAG were the best tools for ruling out OSA • Future work should refine these tools to enhance their utility after stroke/TIA
Background Advances in acute management and secondary prevention have reduced mortality and early recurrent risk after stroke and transient ischemic attack (TIA). However, whether improved outcomes ...are sustained long term among those without early adverse complications is not clear. We describe trends in long-term mortality and morbidity in patients with ischemic stroke or TIA who are clinically stable at 90 days. Methods This is a longitudinal cohort registry study (2003-2013) of patients presenting to stroke centers in Ontario, Canada, with a stroke or TIA, with no hospitalization, stroke, myocardial infarction (MI), institutionalization, or death within 90 days (N = 26,698). Primary outcomes were 1-, 3-, and 5-year age-adjusted composite rates of death, stroke or MI, and institutionalization, and secondary analyses evaluated outcomes individually. Trend tests were used to evaluate change over time. Results One-year adjusted composite rates decreased from 9.3% in 2003 to 7.4% in 2012 (trend test P = .02). Significant decreases in 3-year ( P < .001) and 5-year ( P = .002) composite rates were also observed. Rates of recurrent stroke decreased at 1 and 3 years ( P < .01), but not 5 years ( P = .21), whereas death rates declined across follow-up times. Conversely, rates of institutionalization increased at 3 and 5 years ( P < .01). Conclusions Long-term mortality and morbidity post stroke and TIA have declined, confirming trends for improved long-term outcomes for patients clinically stable during the initial high-risk period. However, increased long-term rates of institutionalization also suggest that stroke and TIA patients are at risk of long-term functional decline, despite improved clinical outcomes. Further studies evaluating challenges for sustaining functional gains after stroke and TIA are required.
Summary Pancreatic adenosquamous carcinoma is a rare morphological variant of pancreatic adenocarcinoma with an especially poor prognosis. The purpose of this study is to identify clinicopathologic ...features associated with prognosis, assess whether the percentage of squamous differentiation in pancreatic adenosquamous carcinoma is associated with an inferior prognosis, and examine the impact of adjuvant chemoradiation therapy on overall survival. Forty-five (1.2%) of 3651 patients who underwent pancreatic resection at the Johns Hopkins Hospital, Baltimore, MD, between 1986 and 2007 were identified with adenocarcinoma of the pancreas with any squamous differentiation. All pathologic specimens were re-reviewed. Statistical analyses were performed on the 38 patients amenable to adjuvant chemoradiation therapy for whom clinical outcome data could be obtained. Median age was 68 years (61% male). Sixty-one percent underwent pancreaticoduodenectomy. Median tumor size was 5.0 cm. Seventy-six percent of carcinomas were node positive, 37% were margin-positive resections, and 68% had 30% or more squamous differentiation. Median overall survival of the pancreatic adenosquamous carcinoma cohort was 10.9 months (range, 2.1-140.6 months; 95% confidence interval, 8.2-12.5 months). Adjuvant chemoradiation therapy was associated with superior overall survival in patients with pancreatic adenosquamous carcinoma ( P = .005). Adjuvant chemoradiation therapy was associated with improved survival in patients with tumors 3 cm or larger and vascular or perineural invasion ( P = .02, .03, .02, respectively). The proportion of squamous differentiation was not associated with median overall survival (<30% versus ≥30%, P = .82). Survival after pancreatic resection of pancreatic adenosquamous carcinoma is poor. Treatment with adjuvant chemoradiation therapy is associated with improved survival. The proportion of squamous differentiation in resected pancreatic adenosquamous carcinoma specimens does not appear to impact overall survival.
Background Home sleep apnea testing (HSAT) is an alternative to polysomnography for the detection of obstructive sleep apnea (OSA). We assessed the feasibility of HSAT as an unattended screening tool ...for patients with a stroke or transient ischemic attack (TIA). Aims The primary outcome was the feasibility of unattended HSAT, as defined by analyzability of the data. Secondary outcomes included determining (1) predictors of obtaining nonanalyzable sleep data and (2) time to OSA detection and continuous positive airway pressure (CPAP) initiation. Methods In this single-center prospective observational study, inpatients or outpatients who had sustained a stroke or TIA were screened for OSA using the ApneaLink Plus ambulatory sleep monitor in their home or hospital room. Results There were 102 patients who completed unattended sleep monitoring. Mean age was 68.7 ± 13.7 years, 55.9% were male, 57.8% were outpatients, and 77.5% had a stroke (22.5% with TIA). Eighty-two (80.4%) patients obtained four or more hours of analyzable sleep data. Functional dependence (defined as a modified Rankin Scale of >2) and elevated body mass index were independently associated with obtaining nonanalyzable data. OSA was detected in 63.4% (52 of 82) of patients and, of those, 34 of 52 (65.4%) initiated CPAP therapy. The mean time from study recruitment to HSAT was 1.7 days (median: 1, interquartile range IQR: 2) and CPAP was initiated on average within 62.7 days of recruitment (median: 53, IQR: 30). Conclusions Unattended HSAT can be feasibly implemented after stroke or TIA. This method facilitates rapid diagnosis and management of OSA in both the outpatient and inpatient settings.
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