Citations

Drugs aimed at the initial stages of the Alzheimer’s disease pathology should be tested a decade before the onset of dementia.

Abstract Eosinophils play important roles in regulation of cellular responses under conditions of homeostasis or infection. Intestinal infection with the parasitic nematode, Trichinella spiralis, induces a pronounced eosinophilia that coincides with establishment of larval stages in skeletal muscle. We have shown previously that in mouse strains in which the eosinophil lineage is ablated, large numbers of T. spiralis larvae are killed by NO, implicating the eosinophil as an immune regulator. In this report, we show that parasite death in eosinophil-ablated mice correlates with reduced recruitment of IL-4+ T cells and enhanced recruitment of inducible NO synthase (iNOS)-producing neutrophils to infected muscle, as well as increased iNOS in local F4/80+CD11b+Ly6C+ macrophages. Actively growing T. spiralis larvae were susceptible to killing by NO in vitro, whereas mature larvae were highly resistant. Growth of larvae was impaired in eosinophil-ablated mice, potentially extending the period of susceptibility to the effects of NO and enhancing parasite clearance. Transfer of eosinophils into eosinophil-ablated ΔdblGATA mice restored larval growth and survival. Regulation of immunity was not dependent upon eosinophil peroxidase or major basic protein 1 and did not correlate with activity of the IDO pathway. Our results suggest that eosinophils support parasite growth and survival by promoting accumulation of Th2 cells and preventing induction of iNOS in macrophages and neutrophils. These findings begin to define the cellular interactions that occur at an extraintestinal site of nematode infection in which the eosinophil functions as a pivotal regulator of immunity.

Major depressive disorder is common in primary care. Depression Improvement Across Minnesota—Offering a New Direction (DIAMOND), using a collaborative care model, was first implemented in March 2008 starting with 5 clinics and expanding to more than 70 clinics statewide by 2010. This was intended to improve depression management and to augment the relationship between the patient, the primary care provider, and the psychiatrist. Prior retrospective studies have demonstrated the clinical effectiveness of our program. This study was designed to examine those patients who were in clinical remission (defined as a Patient Health Questionnaire–9 [PHQ-9] score <5) at 6 months (180 days) after enrollment in collaborative care management. By determining the subsequent PHQ-9 data that were obtained, a PHQ-9 response curve was developed for those patients who did improve. The pilot study demonstrated that there appeared to be rapid response to depression treatment, evident by the first month of treatment and more pronounced in severely depressed patients. Also, it demonstrated that in the patients who did respond, there was no any difference in the remission rates over the study period when evaluated by the initial severity of the depression.

Background— Right ventricular failure from increased pulmonary vascular loading is a major cause of morbidity and mortality, yet its modulation by disease remains poorly understood. We tested the hypotheses that, unlike the systemic circulation, pulmonary vascular resistance (R PA ) and compliance (C PA ) are consistently and inversely related regardless of age, pulmonary hypertension, or interstitial fibrosis and that this relation may be changed by elevated pulmonary capillary wedge pressure, augmenting right ventricular pulsatile load. Methods and Results— Several large clinical databases with right heart/pulmonary catheterization data were analyzed to determine the R PA -C PA relationship with pulmonary hypertension, pulmonary fibrosis, patient age, and varying pulmonary capillary wedge pressure. Patients with suspected or documented pulmonary hypertension (n=1009) and normal pulmonary capillary wedge pressure displayed a consistent R PA -C PA hyperbolic (inverse) dependence, C PA =0.564/(0.047+R PA ), with a near-constant resistance-compliance product (0.48±0.17 seconds). In the same patients, the systemic resistance-compliance product was highly variable. Severe pulmonary fibrosis (n=89) did not change the R PA -C PA relation. Increasing patient age led to a very small but statistically significant change in the relation. However, elevation of the pulmonary capillary wedge pressure (n=8142) had a larger impact, significantly lowering C PA for any R PA and negatively correlating with the resistance-compliance product ( P <0.0001). Conclusions— Pulmonary hypertension and pulmonary fibrosis do not significantly change the hyperbolic dependence between R PA and C PA , and patient age has only minimal effects. This fixed relationship helps explain the difficulty of reducing total right ventricular afterload by therapies that have a modest impact on mean R PA . Higher pulmonary capillary wedge pressure appears to enhance net right ventricular afterload by elevating pulsatile, relative to resistive, load and may contribute to right ventricular dysfunction.

Object The management of incidental small unruptured intracranial aneurysms (UIAs) is controversial and many factors need to be considered in the decision-making process. The authors describe a large consecutive series of patients harboring small incidental intracranial aneurysms. Treatment strategy, natural history, complications, and short-term outcomes are presented. Methods Between January 2008 and May 2011, the authors prospectively evaluated 212 patients with 272 small (< 10-mm) incidental aneurysms. Treatment recommendations (observation, endovascular treatment, or surgery), complications of treatment, and short-term outcomes were assessed. Results Recommended treatment consisted of observation in 125 patients, endovascular embolization in 64, and surgery in 18. Six patients were excluded from further analysis because they underwent treatment elsewhere. In the observation group, at a mean follow-up of 16.7 months, only 1 patient was moved to the embolization group. Seven (6%) of the 125 patients in the observation group died of causes unrelated to aneurysm. Sixty-five patients underwent 69 embolization procedures. The periprocedural permanent morbidity and mortality rates in patients undergoing endovascular treatment were 1.5% and 1.5%, respectively (overall morbidity and mortality rate 3.0%). In the surgery group no periprocedural complications were observed, although 1 patient did not return to her previous occupation. No aneurysmal rupture was documented in any of the 3 treatment groups during the follow-up period. Conclusions A cautious and individualized approach to incidental UIAs is of utmost importance for formulation of a safe and effective treatment algorithm. Invasive treatment (either endovascular or surgery) can be considered in selected younger patients, certain “higher-risk” locations, expanding aneurysms, patients with a family history of aneurysmal hemorrhage, and in those who cannot live their lives knowing that they harbor the UIA. Although the complication rate of invasive treatment is very low, it is not negligible. The study confirms that small incidental UIAs deemed to be not in need of treatment have a very benign short-term natural history, which makes observation a reasonable approach in selected patients.

Object The widespread use of imaging techniques for evaluating nonspecific symptoms (vertigo, dizziness, memory concerns, unsteadiness, and the like) and focal neurological symptoms related to cerebrovascular disease has led to increased identification of asymptomatic incidentally discovered unruptured intracranial aneurysms (UIAs). The management of these incidental aneurysms is controversial and many factors need to be considered. The authors describe reasons leading to diagnosis, demographics, and risk factors in a large consecutive series of patients with small incidentally found UIAs. Methods The authors prospectively evaluated 335 patients harboring 478 small (< 10-mm) UIAs between January 2008 and May 2011. Patients with known aneurysms, possibly symptomatic aneurysms, arteriovenous malformation–related aneurysms, patients with a history of subarachnoid hemorrhage from another aneurysm, and patients harboring extradural aneurysms were excluded from the analysis. Only truly incidental small aneurysms (272 aneurysms in 212 patients) were considered for the present analysis. Data regarding the reason for detection, demographics, location, and presence of potential risk factors for aneurysm formation were prospectively collected. Results There were 158 female (74.5%) and 54 male (25.5%) patients whose mean age was 60.6 years (median 62 years). The most common reason for undergoing the imaging study that led to a diagnosis of the aneurysms was evaluation for nonspecific spells and symptoms related to focal cerebrovascular ischemia (43.4%), known/possible intracranial or neck pathology (24%), and headache (16%). The most common location (27%) of the aneurysm was the middle cerebral artery; the second most common (22%) was the paraclinoid internal carotid artery (excluding cavernous sinus aneurysms). Sixty-nine percent of patients were current or prior smokers, 60% had a diagnosis of hypertension, and 23% had one or more relatives with a history of intracranial aneurysms with or without subarachnoid hemorrhage. Conclusions Small incidental UIAs are more commonly diagnosed in elderly individuals during imaging performed to investigate ill-defined spells or focal cerebrovascular ischemic symptoms, or during the evaluation of known or probable unrelated intracranial/neck pathology. Hypertension, smoking, and family history of aneurysms are common in this patient population, and the presence of these risk factors has important implications for treatment recommendations. Although paraclinoid aneurysms (excluding intracavernous aneurysms) are uncommon in patients with ruptured intracranial aneurysms, this location is very common in patients with small incidental UIAs.

Incidental findings pose considerable management dilemmas for the treating physician and psychological burden for the respective patient. With an aging population, more patients will be diagnosed with asymptomatic internal carotid artery stenosis. Patients will have to be counseled with regard to treatment options according to their individual risk profile and according to professionals' knowledge of evidence-based data derived from large randomized control trials. Treatment consensus has long been lacking for patients with asymptomatic carotid artery stenosis prior to any randomized controlled trials. Additionally, an individual's risk profile may be hard to assess according to knowledge gained from randomized controlled trials. Moreover, while earlier studies compared carotid endarterectomy and medical therapy, in the past years, a new therapeutic modality, carotid artery angioplasty and stenting, has emerged as a possible alternative. This has been evaluated in a recent randomized controlled trial, the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), which compared carotid endarterectomy with angioplasty and stenting in both symptomatic and asymptomatic patients. The following review summarizes current knowledge of the natural history, diagnosis, and treatment strategies to counsel patients with asymptomatic carotid artery stenosis.

The astrocytic aquaporin-4 (AQP4) water channel is the target of pathogenic antibodies in a spectrum of relapsing autoimmune inflammatory central nervous system disorders of varying severity that is unified by detection of the serum biomarker neuromyelitis optica (NMO)-IgG. Neuromyelitis optica is the most severe of these disorders. The two major AQP4 isoforms, M1 and M23, have identical extracellular residues. This report identifies two novel properties of NMO-IgG as determinants of pathogenicity. First, the binding of NMO-IgG to the ectodomain of astrocytic AQP4 has isoform-specific outcomes. M1 is completely internalized, but M23 resists internalization and is aggregated into larger-order orthogonal arrays of particles that activate complement more effectively than M1 when bound by NMO-IgG. Second, NMO-IgG binding to either isoform impairs water flux directly, independently of antigen down-regulation. We identified, in nondestructive central nervous system lesions of two NMO patients, two previously unappreciated histopathological correlates supporting the clinical relevance of our in vitro findings: ( i ) reactive astrocytes with persistent foci of surface AQP4 and ( ii ) vacuolation in adjacent myelin consistent with edema. The multiple molecular outcomes identified as a consequence of NMO-IgG interaction with AQP4 plausibly account for the diverse pathological features of NMO: edema, inflammation, demyelination, and necrosis. Differences in the nature and anatomical distribution of NMO lesions, and in the clinical and imaging manifestations of disease documented in pediatric and adult patients, may be influenced by regional and maturational differences in the ratio of M1 to M23 proteins in astrocytic membranes.

Purpose Metastatic melanoma, a highly vascularized tumor with strong expression of vascular endothelial growth factor, has an overall poor prognosis. We conducted a placebo-controlled, double-blind phase II study of carboplatin plus paclitaxel with or without bevacizumab in patients with previously untreated metastatic melanoma. Patients and Methods Patients were randomly assigned in a two-to-one ratio to carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m 2 ) and bevacizumab (15 mg/kg; CPB) or placebo (CP) administered intravenously once every 3 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS) and safety. Results Two hundred fourteen patients (73% with M1c disease) were randomly assigned. With a median follow-up of 13 months, median PFS was 4.2 months for the CP arm (n = 71) and 5.6 months for the CPB arm (n = 143; hazard ratio [HR], 0.78; P = .1414). Overall response rates were 16.4% and 25.5%, respectively (P = .1577). With 13-month follow-up, median OS was 8.6 months in the CP arm versus 12.3 months in the CPB arm (HR, 0.67; P = .0366), whereas in an evaluation 4 months later, it was 9.2 versus 12.3 months, respectively (HR, 0.79; P = .1916). In patients with elevated serum lactate dehydrogenase (n = 84), median PFS and OS were longer in the CPB arm (PFS: 4.4 v 2.7 months; HR, 0.62; OS: 8.5 v 7.5 months; HR, 0.52). No new safety signals were observed. Conclusion The study did not meet the primary objective of statistically significant improvement in PFS with the addition of bevacizumab to carboplatin plus paclitaxel. A larger phase III study will be necessary to determine whether there is benefit to the addition of bevacizumab to carboplatin plus paclitaxel in this disease setting.

Epileptic spasms, or seizures marked by flexor, extensor, or flexor-extensor spasms, are not always responsive to medical management. The purpose of our study was to evaluate the outcome of epilepsy surgery in children with medically intractable epileptic spasms. We identified 11 children with epileptic spasms who underwent lesionectomy (36%), lobectomy (27%), multi-lobectomy (9%), hemispherectomy (18%), or corpus callosotomy (9%). At the time of surgery, 6 children had developed other concurrent seizure type(s), including simple partial (9%), complex partial (27%), partial undifferentiated (9%), primary generalized tonic clonic (9%), tonic (9%), atonic (27%), and myoclonic (9%) seizures. Six children (55%) were seizure free at last follow-up from initial surgery. Predictors of favorable outcome included lack of focal slowing and the presence of less than 2 interictal epileptiform abnormalities on postoperative electroencephalogram ( P = .035 and .035, respectively). Favorable outcome was significantly associated with parent/caregiver report of improved postoperative developmental outcomes ( P = .026).