Journal of Internal Medicine
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Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.
El‐Salhy M, Danielsson Å, Stenling R, Grimelius L (University Hospital, Umeå; and University Hospital, Uppsala; Sweden). Colonic endocrine cells in inflammatory bowel disease.
To study colonic endocrine cell types in patients with ulcerative colitis (UC) and Crohn's disease (CD).
Departments of Medicine and Pathology, University Hospitals, Umeå and Uppsala, Sweden.
Seventeen patients with UC (seven females and 10 males) and 11 patients with CD (five females and six males). Twenty‐two patients (eight females and 14 males) operated on for colon carcinoma and without signs of inflammatory bowel disease were used as controls.
The colonic endocrine cell types were identified by immunohistochemical methods and quantified by computed image analysis.
The areas of the argyrophil cells as well as those immunoreactive to chromogranin A and serotonin were significantly increased in patients with both UC and CD, compared with those in the controls. In patients with CD, the areas of polypeptide YY(PYY)‐ and pancreatic polypeptide (PP)‐immunoreactive cells were significantly reduced, whilst the area of enteroglucagon‐immunoreactive cells was increased. There was no statistical difference in endocrine cell area between specimens with slight versus severe inflammation, except for PYY and enteroglucagon cell areas in patients with CD. Whilst the former cell area decreased, the latter increased in specimens with severe inflammation. The mean cellular area for each endocrine cell type did not differ between the controls and patients with UC or CD.
The increase in the serotonin‐immunoreactive cell area in patients with both UC and CD might be one of the factors causing reduced colonic contraction and increased intraluminal pressure observed in patients with inflammatory bowel disease. Furthermore, in patients with CD, the decreased PYY‐immunoreactive cell area may explain the decreased absorption and increased secretion found in these patients.
The main goal of our studies has been to use MRI, FDG‐PET, and CSF biomarkers to identify in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI), the earliest clinically detectable evidence for brain changes due to Alzheimer's disease (AD). A second goal has been to describe the cross‐sectional and longitudinal interrelationships amongst anatomical, CSF and cognition measures in these patient groups. It is now well known that MRI‐determined hippocampal atrophy predicts the conversion from MCI to AD. In our summarized studies, we show that the conversion of NL subjects to MCI can also be predicted by reduced entorhinal cortex (EC) glucose metabolism, and by the rate of medial temporal lobe atrophy as determined by a semi‐automated regional boundary shift analysis (BSA‐R). However, whilst atrophy rates are predictive under research conditions, they are not specific for AD and cannot be used as primary evidence for AD. Consequently, we will also review our effort to improve the diagnostic specificity by evaluating the use of CSF biomarkers and to evaluate their performance in combination with neuroimaging. Neuropathology studies of normal ageing and MCI identify the hippocampal formation as an early locus of neuronal damage, tau protein pathology, elevated isoprostane levels, and deposition of amyloid beta 1‐42 (Aβ42). Many CSF studies of MCI and AD report elevated T‐tau levels (a marker of neuronal damage) and reduced Aβ42 levels (possibly due to increased plaque sequestration). However, CSF T‐tau and Aβ42 level elevations may not be specific to AD. Elevated isoprostane levels are also reported in AD and MCI but these too are not specific for AD. Importantly, it has been recently observed that CSF levels of P‐tau, tau hyperphosphorylated at threonine 231 (P‐tau231) are uniquely elevated in AD and elevations found in MCI are useful in predicting the conversion to AD. In our current MCI studies, we are examining the hypothesis that elevations in P‐tau231 are accurate and specific indicators of AD‐related changes in brain and cognition. In cross‐section and longitudinally, our results show that evaluations of the P‐tau231 level are highly correlated with reductions in the MRI hippocampal volume and by using CSF and MRI measures together one improves the separation of NL and MCI. The data suggests that by combining MRI and CSF measures, an early (sensitive) and more specific diagnosis of AD is at hand. Numerous studies show that neither T‐tau nor P‐tauX (X refers to all hyper‐phosphorylation site assays) levels are sensitive to the longitudinal progression of AD. The explanation for the failure to observe longitudinal changes is not known. One possibility is that brain‐derived proteins are diluted in the CSF compartment. We recently used MRI to estimate ventricular CSF volume and demonstrated that an MRI‐based adjustment for CSF volume dilution enables detection of a diagnostically useful longitudinal P‐tau231 elevation. Curiously, our most recent data show that the CSF isoprostane level does show significant longitudinal elevations in MCI in the absence of dilution correction. In summary, we conclude that the combined use of MRI and CSF incrementally contributes to the early diagnosis of AD and to monitor the course of AD. The interim results also suggest that a panel of CSF biomarkers can provide measures both sensitive to longitudinal change as well as measures that lend specificity to the AD diagnosis.
The epidemics of cardiovascular disease, obesity, diabetes, HIV and cancer have all received much attention from the public, media and policymakers. By contrast, chronic kidney disease (CKD) has remained largely a ‘silent’ epidemic. This is unfortunate because early diagnosis of renal disease based on proteinuria and/or reduced estimated glomerular filtration rate could enable early intervention to reduce the high risks of cardiovascular events, end‐stage renal disease (ESRD) and death that are associated with CKD. Given the global increase in the incidence of the leading causes of CKD – hypertension, obesity and diabetes mellitus – better disease management and prevention planning are needed, as effective strategies are available to slow the progression of CKD and reduce cardiovascular risk. CKD may be regarded as a clinical model of accelerated vascular disease and premature ageing, and the risk‐factor profile changes during the progression from mild/moderate CKD to ESRD. Although many randomized controlled trials in patients with mild to moderate CKD have shown beneficial effects of interventions aimed at preventing the progression of CKD, most trials have been unable to demonstrate a beneficial effect of interventions aimed at improving outcome in ESRD. Thus, novel treatment strategies are needed in this high‐risk patient group.
Primary hyperparathyroidism (PHPT) is characterized most commonly now as an asymptomatic disorder with hypercalcaemia and elevated levels of parathyroid hormone (PTH). The elevation in PTH is detected by both the standard immunoradiometric assays (IRMA) and a more recent IRMA that detects only the 1–84 full‐length PTH molecule. The serum calcium concentration is usually <1 mg dL−1 above normal. Recently, another variant of PHPT (normocalcaemic PHPT) has been described in which the serum calcium is normal but the serum PTH is elevated, in the absence of any secondary cause for PTH elevation. Although usually sporadic, PHPT also occurs in inherited syndromes. Skeletal manifestations are appreciated by densitometry showing a typical pattern in which cancellous bone of the lumbar spine is reasonably well preserved whilst the cortical bone of the distal third of the radius is preferentially reduced. Although reduced in incidence, renal stones remain the most common overt complication of PHPT. Other organs are theoretical targets of PHPT such as the neurobehavioural axis and the cardiovascular system. Vitamin D looms as an important determinant of the activity of the PHPT state. The 2002 NIH Workshop on asymptomatic PHPT has led to revised guidelines to help doctors determine who is best advised to have parathyroid surgery and who can be safely followed without surgery. New information about the natural history of PHPT in those who did not undergo surgery has helped to define more precisely who is at‐risk for complications. At the NIH workshop, a number of items were highlighted for further investigation such as pharmacological approaches to controlling hypercalcaemia, elevated PTH levels and maintaining bone density.
The idiopathic inflammatory myopathies are characterized by muscle weakness, skin disease and internal organ involvement. Autoimmunity is known to have a role in myositis pathogenesis, and myositis‐specific autoantibodies, targeting important intracellular proteins, are regarded as key biomarkers aiding in the diagnosis of patients. In recent years, a number of novel myositis autoantibodies including anti‐
Treatment effects, especially when comparing two or more therapeutic alternatives as in comparative effectiveness research, are likely to be heterogeneous across age, gender, co‐morbidities and co‐medications. Propensity scores (
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