Temporal accrual of complement proteins in amyloid plaques in Down's syndrome with Alzheimer's disease

The complement system constitutes a series of enzymatic steps involved in the inflammatory response and is activated in Alzheimer's disease (AD). Using Down's syndrome (DS) brains as a temporal model for the progression of AD, we examined components of the complement cascade and their relationship to other principal events in AD pathology: Abeta42 deposition, neuritic changes, neurofibrillary tangles (NFTs), and gliosis (reactive astrocytes, activated microglia). Adjacent sections of frontal cortex from 24 DS subjects ranging in age from 12 to 73 years were immunohistochemically examined for immunoreactivity (IR) of classical complement proteins (Clq and C3), markers indicating activation of complement (C4d and C5b-9), the complement inhibitor apolipoprotein J (apo J), and markers of AD neuropathology. Abeta42-labeled diffuse plaques were first detected in a 12-year-old DS subject and were not labeled by any of the complement antibodies. Colocalization of Abeta42 with Clq, C3, C4d, and/or apo J was first detected in compacted plaques in the brain of a 15-year-old DS patient with features of mature AD pathology, such as reactive astrocytes, activated microglia, dystrophic neurites, and a few NFTs. IR for C4d and C5b-9 (membrane attack complex, MAC) was observed in small numbers of plaque-associated dystrophic neurites and in focal regions of pyramidal neurons in this 15-year-old. The only other young (相似文献   

Bone mineral density and prevalent vertebral fractures in men and women

To test the hypothesis that the association between bone mineral density (BMD) and estimated volumetric BMD and prevalent vertebral fractures differs in men and women, we studied 317 Caucasian men and 2,067 Caucasian women (average age 73 years). A total of 43 (14%) men and 386 (19%) women had a vertebral fracture identified on lateral spine radiographs using vertebral morphometry. Hip and spine areal BMD was about 1/3 standard deviation lower among men and women with a vertebral fracture. A 0.10 g/cm² decrease in areal BMD was associated with 30–40% increased odds of having a fracture in men and 60–70% increased likelihood in women. Low bone mineral apparent density (BMAD) was also associated with 40–50% increased odds of a vertebral fracture in both genders. The probability of a man having a fracture was observed at higher absolute areal BMD values than observed for women (P=values for interaction of BMD × gender: trochanter, P=0.05; femoral neck, P=0.10; total hip, P=0.09). In contrast, the probability of fracture was similar in men and women across the range of estimated volumetric BMD (BMAD). In conclusion, low BMD and low BMAD are associated with increased odds of vertebral fracture in both men and women. Measures of bone mass that partially correct for gender differences in bone size may yield universal estimates of fracture risk. Prospective studies are needed to confirm this observation.     

Cyclosporin A treatment of an induced attack in a chronic relapsing model of experimental allergic encephalomyelitis

Chronic relapsing experimental allergic encephalomyelitis (EAE) was induced in 8-week-old SJL/J mice by injecting an encephalitogenic emulsion on Day 0 and Day 7. A third injection was given on Day 70 postinoculation (PI) which precipitated an attack with high mortality (62%) after 7-9 days. Cyclosporin A (CsA) was given at doses of 5, 2, and 0.5 mg per mouse, one or three times per week starting from Day 40 PI and continuing over the next 17 days. High serum levels of CsA were measured by radioimmunoassay. However, gross and microscopic pathological examination showed no indication of hepatic or renal toxicity at these doses. In the CsA-treated mice, there was a dose-dependent shortening of the length and severity of the attack forced by challenge with the third injection. The mortality was significantly (P less than 0.05) reduced when compared with the non-CsA-treated controls. In addition, the data demonstrate a decrease of lymphocyte-derived chemotactic factor produced from phytohemagglutinin-stimulated spleen cells of mice with chronic relapsing EAE treated with CsA when compared to normal mice and mice with chronic relapsing EAE treated with vehicle alone. We conclude that it is possible to effect an induced acute attack in ongoing chronic relapsing EAE with CsA treatment.     

Increased bladder permeability in interstitial cystitis/painful bladder syndrome

The definition of interstitial cystitis (IC) has evolved over the years from being a well-defined entity characterized by diagnostic lesion (Hunner’s ulcer) in the urothelium to a clinical diagnosis by exclusion [painful bladder syndrome (PBS)]. Although the etiology is unknown, a central theme has been an association with increased permeability of the bladder. This article reviews the evidence for increased permeability being important to the symptoms of interstitial cystitis/painful bladder syndrome (IC/PBS) and in treating the disorder. Recent work showing cross-communication among visceral organs is also reviewed to provide a basis for understanding IC/PBS as a systemic disorder of a complex, interconnected system consisting of the bladder, bowel and other organs, nerves, cytokine-responding cells and the nervous system.     

Clinical and demographic factors associated with DSM-IV melancholic depression.

BACKGROUND: The purpose of this paper is to use demographic and clinical data from a large diverse group of outpatients diagnosed with non-psychotic major depression to investigate the validity of the DSM-IV concept of melancholic depression. METHODS: Baseline clinical and demographic data were collected on 1500 outpatients (1456 of whom melancholia could be determined) with non-psychotic major depressive disorder (MDD) participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Depressive symptom severity was assessed by clinical telephone interview using the 17-item Hamilton Rating Scale for Depression (HRS-D17) and the 30-item Inventory of Depressive Symptomatology (IDS-C30). The types and degrees of concurrent psychiatric symptoms were measured using a self report, the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items relevant to each diagnostic category endorsed by study participants. RESULTS: Adjusting for severity of depression (as measured by the total HRS-D17 scores), no differences were found in the rate of melancholic depression by race, marital status, education, employment status, family history of depression, primary care versus specialty care, monthly income, and degree of psychiatric and medical co-morbidity. Melancholic depression was significantly more likely in men than women. Melancholic depression after adjustment for severity was associated with a slightly younger age at study entry, as well as with greater illness severity, and slightly shorter duration of current episode. Hispanic ethnicity was associated with lower melancholic depression rates at the .06 level of significance. CONCLUSIONS: Among outpatients with MDD, melancholic features were less likely in Hispanic patients, but more likely in slightly younger patients and in men. Melancholic features were also related to a slightly shorter current episode. These findings are consistent with the notion that external socio-demographic factors do not play an important role in the pathophysiology of melancholic depression.     

Long-Term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD)

Background

Early onset of mood symptoms in bipolar disorder has been associated with poor outcome in many studies; however, the factors that might contribute to poor outcome have not been adequately investigated.

Methods

The first consecutive 1000 adult bipolar patients enrolled in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder were assessed at study entry to determine details of their age of onset of mood symptoms. Clinical course, comorbidity, and functional status and quality of life were compared for groups with very early (age < 13 years), early (age 13-18 years), and adult (age > 18 years) onset of mood symptoms.

Results

Of 983 subjects in whom age of onset could be determined, 272 (27.7%) experienced very early onset, and 370 (37.6%) experienced early onset. Earlier onset was associated with greater rates of comorbid anxiety disorders and substance abuse, more recurrences, shorter periods of euthymia, greater likelihood of suicide attempts and violence, and greater likelihood of being in a mood episode at study entry.

Conclusions

Very early or early onset of bipolar disorder might herald a more severe disease course in terms of chronicity and comorbidity. Whether early intervention might modify this risk merits further investigation.     

Digital navigators to implement smartphone and digital tools in care

While smartphone apps and other digital health tools have the clear potential to increase both quality of and access to care, actual successful implementation remains limited. Challenges often encountered in seeking to use apps in care include selecting safe/effective tools, spending clinical time troubleshooting technology instead of discussing health matters, and lack of time to check and review constant streams of data these digital tools can produce. In this ‘From Research to Clinical Practice’ piece, we focus on how a new care team member, the digital navigator, can help overcome these barriers through conducting evidence-based app evaluation to help in selecting the right apps, troubleshooting technology outside of visits to improve the therapeutic alliance during, and finally summarizing digital data to facilitate clinical care that focus on actionable data.     

Molecular targeting of Alzheimer's amyloid plaques for contrast-enhanced magnetic resonance imaging

Smart molecular probes for both diagnostic and therapeutic purposes are expected to provide significant advances in clinical medicine and biomedical research. We describe such a probe that targets beta-amyloid plaques of Alzheimer's disease and is detectable by magnetic resonance imaging (MRI) because of contrast imparted by gadolinium labeling. Three properties essential for contrast enhancement of beta-amyloid plaques on MRI exist in this smart molecular probe, putrescine-gadolinium-amyloid-beta peptide: (1) transport across the blood-brain barrier following intravenous injection conferred by the polyamine moiety, (2) binding to plaques with molecular specificity by putrescine-amyloid-beta, and (3) magnetic resonance imaging contrast by gadolinium. MRI was performed on ex vivo tissue specimens at 7 T at a spatial resolution approximating plaque size (62.5 microm(3)), in order to prove the concept that the probe, when administered intravenously, can selectively enhance plaques. The plaque-to-background tissue contrast-to-noise ratio, which was precisely correlated with histologically stained plaques, was enhanced more than nine-fold in regions of cortex and hippocampus following intravenous administration of this probe in AD transgenic mice. Continuing engineering efforts to improve spatial resolution are underway in MRI, which may enable in vivo imaging at the resolution of individual plaques with this or similar contrast probes. This could enable early diagnosis and also provide a direct measure of the efficacy of anti-amyloid therapies currently being developed.