Microvascular changes in Down syndrome with Alzheimer's-type pathology: Insights into a potential vascular mechanism for Down syndrome and Alzheimer's disease.

INTRODUCTION: The mechanism triggering degeneration in Alzheimer's disease (AD) remains uncertain. Therapeutic failure following amyloid ß (Aß) removal casts doubt on amyloid neurotoxicity per se as the primary cause of AD. Impaired microvascular function has been suggested as an alternative etiology. People with Down syndrome (DS) develop Alzheimer's pathology, but whether microvascular impairment also occurs in DS (as in AD) is unknown. METHODS: We examined brain microvasculature in five DS subjects with AD-type histopathology, seven AD cases, and seven controls without AD-type pathology. We counted microvessels in five anatomic regions and assessed endothelial integrity by CD31 immunohistochemistry. RESULTS: Microvascular numbers and endothelial integrity were significantly diminished in DS brains compared with controls and were similar to AD brains. DISCUSSION: People with DS and trisomy 21 produce a large amount of Aß. If Alzheimer's pathology occurred in DS without microvascular loss or endothelial impairment, a direct neurotoxic Aß mechanism would be supported and microvascular impairment rejected. The observation of microvascular impairment in DS with Alzheimer's disease changes fails to reject the microvascular hypothesis and provides some support for this potential mechanism of injury.

The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease.

The "amyloid hypothesis" has dominated Alzheimer research for more than 20 years, and proposes that amyloid is the toxic cause of neural/synaptic damage and dementia. If correct, decreasing the formation or removing amyloid should be therapeutic. Despite discrepancies in the proposed mechanism, and failed clinical trials, amyloid continues to be considered the cause of a degenerative cascade. Alternative hypotheses must explain three features: (i) why amyloid toxicity is not the etiology of Alzheimer's disease (AD), (ii) what alternative mechanisms cause the degeneration and dementia of AD, and (iii) why increased amyloid accumulates in the brain in AD. We propose that AD, which occurs in elderly, already vulnerable brains, with multiple age-related changes, is precipitated by impaired microvascular function, resulting primarily from decreased Notch-related angiogenesis. With impaired microvasculature, a lack of vascular endothelial-derived trophic factors and decreased cerebral blood flow cause the atrophy of neural structures. Therapeutic strategies should focus on supporting normal angiogenesis.

The relationship of plasma glucose and glycosylated hemoglobin A1C levels among nondiabetic trauma patients.

OBJECTIVE: : Hyperglycemia (blood glucose >/=110 mg/dL) in trauma patients without a known history of diabetes mellitus (DM) is often attributed to the metabolic stress response of injury. We studied whether this hyperglycemia may actually indicate the presence of occult DM (ODM) as demonstrated by elevated glycosylated hemoglobin A1C (gHbA1C). METHODS: : After obtaining approval from the Institutional Review Board, a prospective, sequential case series study of nondiabetic adult patients presenting to an urban Level I trauma center from September 2006 to February 2007 was performed. In addition to basic demographics, all hyperglycemic patients had a measured gHbA1C. ODM was diagnosed when gHbA1C was >/=6%. RESULTS: : A total of 1,039 trauma patients were screened with 192 (18%) noted to be hyperglycemic. Of these 192 patients, 22% (n = 42) were found to have an elevated gHbA1C. Using logistic regression, being older (Odds ratio [OR] = 1.04; p < 0.004), having a higher body mass index (BMI) (OR = 1.12; p < 0.003), and being Native American (OR = 5.08; p < 0.017) were each identified as significant risk factors for elevated gHbA1C levels and the diagnosis of ODM. In contrast, the magnitude of observed hyperglycemia, gender, or other races were not shown to be significant risk factors for the presence of ODM. CONCLUSION: : Almost a quarter of nondiabetic trauma patients presenting with hyperglycemia were found to have elevated gHbA1C levels and ODM. Risk factors for ODM included advancing age and body mass index as well as being Native American. The hyperglycemia seen in trauma patients should not solely be attributed to the hormonal and metabolic response to injury; wider ODM screening for both acute management strategies and long-term health benefits is warranted.

Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations.

Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.

Empiric, broad-spectrum antibiotic therapy with an aggressive de-escalation strategy does not induce gram-negative pathogen resistance in ventilator-associated pneumonia.

BACKGROUND: Early, empiric, broad-spectrum antibiotics followed by de-escalation to pathogen-specific therapy is the standard of care for ventilator-associated pneumonia (VAP). In our surgical intensive care unit (SICU), imipenem-cilastatin (I-C) in combination with tobramycin (TOB) or levofloxacin (LEV) has been used until quantitative bronchoalveolar lavage results are finalized, at which time de-escalation occurs to pathogen-specific agents. With this practice, however, alterations in antimicrobial resistance remain a concern. Our hypothesis was that this strict regimen does not alter antimicrobial susceptibility of common gram-negative VAP pathogens in our SICU. METHODS: After Institutional Review Board approval, a retrospective review of SICU-specific antibiograms was performed for the sensitivities of common gram-negative VAP pathogens. Time periods were defined as early (January-June 2005) and late (July-December 2006). Chart review of empiric and de-escalation antibiotic usage was obtained. Data were collated, and statistical significance was assessed with the chi-square test using the on-line Simple Interactive Statistical Analysis tool. RESULTS: Imipenem-cilastatin was used 198 times for empiric VAP coverage (811 patient-days), whereas TOB and LEV were given a total of 149 (564 patient-days) and 61 (320 patient-days) times, respectively. Collectively, the susceptibility of gram-negative organisms to I-C did not change (early 91.4%; late 97%; p = 0.33). Individually, non-significant trends to greater sensitivity to I-C were noted for both Pseudomonas aeruginosa (early 85.7%; late 90.9%; p = 0.73) and Acinetobacter baumannii (early 80%; late 100%; p = 0.13). Further, both TOB (early 77.1%; late 70.0%; p = 0.49) and LEV (early 74.3%; late 70.0%; p = 0.67) were found to maintain their susceptibility profiles. The frequency of resistant gram-positive VAPs was unchanged during the study period. Our de-escalation compliance (by 96 h) was 78% for I-C, 77.2% for TOB, and 59% for LEV. When infections requiring I-C were removed from the analysis, de-escalation compliance was improved to 92%. CONCLUSIONS: In our SICU, early, empiric broad-spectrum VAP therapy followed by de-escalation to pathogen-specific agents did not alter antimicrobial resistance and is a valid practice. Further, our compliance with de-escalation practices was higher than published rates.

The utility of diagnostic laparoscopy in the evaluation of anterior abdominal stab wounds.

BACKGROUND: To assess if diagnostic laparoscopy (DL) is superior to nonoperative modes (serial abdominal examination with/without computed axial tomography [CAT] and diagnostic peritoneal lavage) in determining the need for therapeutic laparotomy (TL) after anterior abdominal stab wound (ASW). METHODS: Retrospective review of ASW patients. Patients were divided into group A (DL/exploratory laparotomy) to identify peritoneal violation (PV) and group B (initial nonoperative modes). RESULTS: Seventy-three patients met inclusion criteria. In group A (n = 38), 29 patients (76%) had PV by DL and underwent exploratory laparotomy. Only 10 (35%) underwent TL (sensitivity for PV = 100%; specificity and positive predictive value of PV in determining need for TL = 29% and 33%, respectively). In group B (n = 35), 7 patients (20%) underwent TL, yielding an improved specificity (96%) and positive predictive value (88%). CONCLUSIONS: We find no role for DL in the evaluation of ASW patients solely to determine PV.

Aging of the brain, entropy, and Alzheimer disease.

Sporadic Alzheimer disease (AD) is related to advancing age far more than to any other risk factor and ultimately affects almost half of the population over age 85. Despite its remarkable prevalence among the elderly, it has been regarded as a specific disease, distinct from "normal aging." This view is supported in large part by clinical and pathologic similarities to early-onset, dominantly inherited familial AD, where genetic mutations related to beta-amyloid have been identified. There is much evidence that sporadic AD overlaps with normal aging in many clinical and pathologic features. Some of the many molecular age-related changes (ARCs) affecting the brain, both intrinsic (programmed) and extrinsic (stochastic), are reviewed, with discussion of the effects they have singly and collectively on neuronal viability and vulnerability. The effect of ARCs on the brain is seen as the biologic manifestation of increasing entropy, an approach that helps to explain the progressive decline of neural and cognitive function over time; the ability of multiple, varied ARCs to summate as individuals age; the transitional relationship between normal aging, mild cognitive impairment, and AD; and the apparent differences between normal aging and AD. Increasing entropy, manifest through a complex network of interacting ARCs, is seen as the fundamental driving cause of neural and cognitive decline in the elderly, as well as the overriding etiologic principle in further transition to sporadic AD. Research on sporadic AD has largely focused on finding a single causal metabolic disorder or genetic mutation. Multiple ARCs contribute to declining function and increased frailty in the aging brain, however, and to the catastrophic disintegration of sporadic AD. Effective prevention or treatment will depend on recognizing the contributions of a multiplicity of ARCs to AD and reducing the burden of as many as possible. The role of amyloid is seen as one element in the larger network of senescent changes involving the aging brain.

Screening for dementia in "real world" settings: the cognitive assessment screening test: CAST.

Among elderly people who do not present with complaints of memory impairment, dementia is often missed by physicians, and time-consuming screening tests requiring expertise to administer and interpret are rarely done. Easily administered, reliable and cost effective dementia screening tests are needed for elderly individuals. The "pencil and paper" Cognitive Assessment Screening Test (CAST) takes minimal examiner time/training, and is both sensitive and specific in discriminating demented patients from healthy controls. The objectives of this study were to: (1) confirm the validity of the CAST in identifying individuals with dementia in a real-world setting (nonassisted living retirement community); (2) compare the sensitivity and specificity with other screening tests and extensive psychometric tests; and (3) assess the reliability of the CAST in test-retest conditions over time. The CAST was both sensitive and specific and showed reliability on retesting. The CAST is both simpler to administer and more accurate than other screening tests for elderly subjects.