Carol Lin

TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice.

Abnormal accumulation of the amyloid-β peptide (Aβ) in the brain appears crucial to pathogenesis in all forms of Alzheimer disease (AD), but the underlying mechanisms in the sporadic forms of AD remain unknown. Transforming growth factor β1 (TGF-β1), a key regulator of the brains responses to injury and inflammation, has been implicated in Aβ deposition in vivo. Here we demonstrate that a modest increase in astroglial TGF-β1 production in aged transgenic mice expressing the human β-amyloid precursor protein (hAPP) results in a three-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall Aβ load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing hAPP and TGF-β1, Aβ accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human cases of AD, Aβ immunoreactivity associated with parenchymal plaques was inversely correlated with Aβ in blood vessels and cortical TGF-β1 mRNA levels. The reduction of parenchymal plaques in hAPP/TGF-β1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Recombinant TGF-β1 stimulated Aβ clearance in microglial cell cultures. These results demonstrate that TGF-β1 is an important modifier of amyloid deposition in vivo and indicate that TGF-β1 might promote microglial processes that inhibit the accumulation of Aβ in the brain parenchyma.

Amyloidogenic role of cytokine TGF-Beta-1 in transgenic mice and in Alzheimer's disease

Deposition of amyloid-β peptide in the central nervous system is a hallmark of Alzheimers disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-β peptide are not known. The transforming growth factor TGF-β1 plays a central role in the response of the brain to injury,, and increased TGF-β1 has been found in the central nervous system of patients with Alzheimers disease. Here we report that TGF-β1 induces amyloid-β deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-β1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimers like pathology, accelerated the deposition of amyloid-β peptide. More TGF-β1 messenger RNA was present in post-mortem brain tissue of Alzheimers patients than in controls, the levels correlating strongly with amyloid-β deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-β1 may initiate or promote amyloidogenesis in Alzheimers disease and in experimental models and so may be a risk factor for developing Alzheimers disease.

Chronic Overproduction of Transforming Growth Factor-β1 by Astrocytes Promotes Alzheimer's Disease-Like Microvascular Degeneration in Transgenic Mice

Cerebrovascular amyloid deposition and microvascular degeneration are frequently associated with Alzheimers disease (AD), but the etiology and pathogenetic role of these abnormalities are unknown. Recently, transforming growth factor-beta1 (TGF-beta1) was implicated in cerebrovascular amyloid formation in transgenic mice with astroglial overproduction of TGF-beta1 and in AD. We tested whether TGF-beta1 overproduction induces AD-like cerebrovascular degeneration and analyzed how cerebrovascular abnormalities develop over time in TGF-beta1-transgenic mice. In cerebral microvessels from 3- to 4-month-old TGF-beta1-transgenic mice, which display a prominent perivascular astrocytosis, levels of the basement membrane proteins perlecan and fibronectin were severalfold higher than in vessels from nontransgenic mice. Consistent with this increase, cortical capillary basement membranes of TGF-beta1 mice were significantly thickened. These changes preceded amyloid deposition, which began at around 6 months of age. In 9- and 18-month-old TGF-beta1 mice, various degenerative changes in microvascular cells of the brain were observed. Endothelial cells were thinner and displayed abnormal, microvilli-like protrusions as well as occasional condensation of chromatin, and pericytes occupied smaller areas in capillary profiles than in nontransgenic controls. Similar cerebrovascular abnormalities have been reported in AD. We conclude that chronic overproduction of TGF-beta1 triggers an accumulation of basement membrane proteins and results in AD-like cerebrovascular amyloidosis and microvascular degeneration. Closely related processes may induce cerebrovascular pathology in AD.

Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease.

Apolipoprotein E fulfills fundamental functions in lipid transport and neural tissue repair after injury.(6,8) Its three most common isoforms (E2, E3, and E4) are critical determinants of diverse human diseases, including major cardiovascular and neurodegenerative disorders.(8,14) Apolipoprotein E4 is associated with an increased risk for Alzheimers disease(3,5) and poor clinical outcome after head injury or stroke.(11,16) The precise role of apolipoprotein E4 in these conditions remains unknown. To characterize the effects of human apolipoprotein E isoforms in vivo, we analysed transgenic Apoe knockout mice that express apolipoprotein E3 or E4 or both in the brain. Hemizygous and homozygous apolipoprotein E3 mice were protected against age-related and excitotoxin-induced neurodegeneration, whereas apolipoprotein E4 mice were not. Apolipoprotein E3/E4 bigenic mice were as susceptible to neurodegeneration as apolipoprotein E4 singly-transgenic mice. At eight months of age neurodegeneration was more severe in homozygous than in hemizygous apolipoprotein E4 mice consistent with a dose effect. Thus, apolipoprotein E4 is not only less neuroprotective than apolipoprotein E3 but also acts as a dominant negative factor that interferes with the beneficial function of apolipoprotein E3. The inhibition of this apolipoprotein E4 activity may be critical for the prevention and treatment of neurodegeneration in APOE varepsilon4 carriers.

Comorbidities and Perioperative Complications in HIV-Positive Patients Undergoing Primary Total Hip and Knee Arthroplasty

BACKGROUND Highly active antiretroviral therapy has prolonged the lifespan of individuals infected with human immunodeficiency virus (HIV). We hypothesized that the number of primary total joint arthroplasties performed in this population has been increasing and that HIV infection is not an independent risk factor for postoperative complications. METHODS The Nationwide Inpatient Sample for the years 2000 through 2008 was queried to identify patients who underwent primary total joint arthroplasty. HIV, comorbidities, and complications were identified with use of ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes. Data were analyzed with use of multivariate logistic regression, the Pearson chi-square test, and the Mann-Kendall trend test. RESULTS Of the estimated 5,681,024 admissions for primary total hip and knee arthroplasty in the United States during this period, 8229 (0.14%) were in patients who had HIV. Compared with HIV-negative patients (controls), infected patients were more likely to be younger, be male, and have a history of osteonecrosis, liver disease, drug use, and coagulopathy. The number of total hip and total knee arthroplasties in HIV-positive patients increased from 2000 to 2008 (p < 0.05). Seventy-nine percent (6499) of the total joint arthroplasties in the HIV-positive patients involved the hip. Compared with HIV-negative patients undergoing total hip arthroplasty, HIV-positive patients were more likely to develop acute renal failure (1.3% compared with 0.8%, p = 0.04), develop a wound infection (0.6% compared with 0.3%, p = 0.02), and undergo postoperative irrigation and debridement (0.2% compared with 0.1%, p = 0.01). They were less likely to have a myocardial infarction (0.4% compared with 0.9%, p = 0.04). There was no difference in total complications (8.3% compared with 7.8%, p = 0.52). Similarly, there was no difference in total complications in patients undergoing total knee arthroplasty (7.8% compared with 8.0%, p = 0.76). HIV was not an independent risk factor for complications in total hip arthroplasty (odds ratio [OR], 1.18; 95% confidence interval [CI], 0.95 to 1.47) or total knee arthroplasty (OR, 0.78; 95% CI, 0.49 to 1.25). CONCLUSIONS The incidence of primary total joint arthroplasty in HIV-positive patients has been increasing. These patients were at slightly higher risk of certain immediate postoperative complications because of a higher rate of medical comorbidities. HIV infection was not an independent risk factor for the total rate of perioperative complications. LEVEL OF EVIDENCE Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Alzheimer's disease-like cerebrovascular pathology in transforming growth factor-beta 1 transgenic mice and functional metabolic correlates

Abstract: Alzheimers disease (AD) is frequently associated with cerebrovascular changes, including perivascular astrocytosis, amyloid deposition, and microvascular degeneration, but it is not known whether these pathological changes contribute to functional deficits in AD. To characterize the temporal relationship between amyloid deposition, cerebrovascular abnormalities, and potential functional changes, we studied transgenic mice that express transforming growth factor‐β1 (TGF‐β1) at low levels in astrocytes. TGF‐β1 induced a prominent perivascular astrocytosis, followed by the accumulation of basement membrane proteins in microvessels, thickening of capillary basement membranes, and later, around 6 months of age, deposition of amyloid in cerebral blood vessels. At 9 months of age, various AD‐like degenerative alterations were observed in endothelial cells and pericytes. Associated with these morphological changes were changes in regional cerebral glucose utilization. Preliminary results showed that TGF‐β1 mice had significantly decreased glucose utilization in the mammillary bodies, structures involved in mnemonic and learning processes. Glucose utilization tended to be decreased in several other brain regions as well; however, in the inferior colliculus, it was markedly higher in TGF‐β1 mice than in controls. We conclude that chronic overproduction of TGF‐β1 triggers a pathogenic cascade leading to AD‐like cerebrovascular amyloidosis, microvascular degeneration, and local alterations in brain metabolic activity. Similar mechanisms may be involved in AD pathogenesis.

Cellular Source of Apolipoprotein E4 Determines Neuronal Susceptibility to Excitotoxic Injury in Transgenic Mice

The lipid transport protein apolipoprotein E (apoE) is abundantly expressed in the brain. Its main isoforms in humans are apoE2, apoE3, and apoE4. ApoE4 is the major known genetic risk factor for Alzheimers disease and also contributes to the pathogenesis of various other neurological conditions. In the central nervous system, apoE is synthesized by glial cells and neurons, but it is unclear whether the cellular source affects its biological activities. To address this issue, we induced excitotoxic injury by systemic kainic acid injection in transgenic Apoe knockout mice expressing human apoE isoforms in astrocytes or neurons. Regardless of its cellular source, apoE3 expression protected neuronal synapses and dendrites against the excitotoxicity seen in apoE-deficient mice. Astrocyte-derived apoE4, which has previously been shown to have detrimental effects in vitro, was as excitoprotective as apoE3 in vivo. In contrast, neuronal expression of apoE4 was not protective and resulted in loss of cortical neurons after excitotoxic challenge, indicating that neuronal apoE4 promotes excitotoxic cell death. Thus, an imbalance between astrocytic (excitoprotective) and neuronal (neurotoxic) apoE4 expression may increase susceptibility to diverse neurological diseases involving excitotoxic mechanisms.

Mid-Term Outcomes in HIV-Positive Patients After Primary Total Hip or Knee Arthroplasty

We hypothesized that infection rates following total joint arthroplasty (TJA) in those with the human immunodeficiency virus (HIV) without hemophilia or drug use would be similar to rates in HIV-negative patients. Records at an urban HIV referral hospital were searched for patients who underwent primary total hip and knee arthroplasty from 2003 to 2010. The primary outcome was revision for infection. 372 HIV-negative and 22 HIV-positive TJA patients met inclusion criteria. The HIV-positive group had more deep infections than the HIV-negative group (9.1% v 2.2%, P=0.102). There were no infections in those with AIDS-defining CD4 counts. Those with HIV may have a higher risk of developing a deep infection. A low CD4 count is not an absolute contraindication to TJA in HIV positive patients.

Functional outcomes after total hip arthroplasty for the acute management of acetabular fractures: 1- to 14-year follow-up.

Objective: This study reports the complications and functional outcomes in patients treated acutely with combined open reduction internal fixation (ORIF) and immediate total hip arthroplasty (THA) for displaced comminuted acetabular fractures. Design: Single surgeon retrospective case series. Setting: Level 1 trauma center. Patients: Thirty-three consecutive patients (18 women; mean age, 66 years) from 1996 to 2011 with an average follow-up of 5.6 years (range, 1–14.3 years) were included in this study. Intervention: ORIF and immediate THA. Main Outcome Measurements: Oxford Hip Score and reoperation. Methods: All patients had at least 1 year of telephone or clinical follow-up. Postoperative complications, reoperations, and available radiographs were reviewed. Results: Six patients died of causes unrelated to their injuries or surgery; before death, these patients had well-functioning hips. There was a 15% complication rate. At last follow-up, 94% of hips remained in situ and were functioning well. The average Oxford Hip Score at final follow-up was 17 (range, 12–32), with 93% of patients reporting good to excellent function. There was no statistical association between fracture type, age, or fixation type and outcome. Conclusions: Acute ORIF and immediate THA for selected acetabular fractures is a safe viable treatment option with good to excellent functional outcomes and may reduce the need for 2 separate operations in many patients. Functional outcomes are equivalent to those after primary THA for osteoarthritis. This study does not address at which age acute THA is a cost-effective treatment option. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Increasing Use of Reverse Total Shoulder Arthroplasty for Proximal Humerus Fractures in Elderly Patients

This study described surgical treatment patterns for proximal humerus fractures among elderly patients, focusing on reverse total shoulder arthroplasty (TSA), and evaluated how the type of fixation affects inpatient factors (cost, length of stay), transfusion rates, and patient disposition (home vs skilled nursing facility). With Nationwide Inpatient Sample data from 2011 to 2013, the authors identified patients 65 years and older who had proximal humerus fractures and divided them into 3 groups: (1) open reduction and internal fixation (ORIF); (2) hemiarthroplasty; and (3) reverse TSA. From 2011 to 2013, 38,729 surgically treated proximal humerus fractures were identified. The rate of reverse TSA increased 1.8-fold during this time, from 13% of operative cases in 2011 to 24% of operative cases in 2013 (P<.001). At the same time, the rates of hemiarthroplasty and ORIF decreased (hemiarthroplasty, from 28% to 21%; ORIF, from 59% to 55%). Although reverse TSA accounted for 32.2% of arthroplasty procedures for proximal humerus fractures in 2011, this value was 53.3% in 2013 (P<.001). In 2013, mean total hospital cost for reverse TSA was