The pattern of neuronal loss and survival may reflect differential expression of proteasome activators in Parkinson's disease

The basis of neuronal vulnerability, degeneration, and sparing in PD are unknown, but there is increasing evidence to suggest that the ubiquitin‐proteasome system (UPS) plays an important role in the pathogenesis of the disorder. In this study, we employed an immunocytochemical approach to determine if the differential expression of key UPS components in various brain regions and cells might underlie the pattern of neuronal degeneration and survival seen in PD. We showed that the ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and 26/20S proteasome α‐ and β‐subunits, are abundantly expressed in the substantia nigra pars compacta (SNc) and in cultured dopaminergic neurons. Although the proteasome activator PA700 is expressed in the medial SNc, levels are low in the lateral region, and expression of the other proteasome activator, PA28, is near absent in the entire SNc. PA28 (but not PA700) was found to be poorly expressed in noradrenergic neurons in the locus coeruleus (LC) compared with adjacent cells in the mesencephalic nucleus. PA700 and PA28 are also poorly expressed in dopaminergic neurons compared with other cell types in culture. Inhibition of proteasomal function, generation of misfolded proteins, induction of oxidative stress or impairment of mitochondrial complex I activity, caused a compensatory upregulation in PA700 and PA28 in a variety of cells but not in dopaminergic neurons in culture. These findings are consistent with the demonstration that, in sporadic PD, proteasomal activity and levels of PA700/PA28 are reduced in the SNc butare markedly upregulated in regions/cells that are spared from the neurodegenerative process. Thus, the differential distribution and activity of proteasome activations could play a significant role in the pathogenesis of PD. Synapse 64:241–250, 2010. © 2009 Wiley‐Liss, Inc.     

Distinct patterns of neuronal inputs and outputs of the juxtaparaventricular and suprafornical regions of the lateral hypothalamic area in the male rat

We have analyzed at high resolution the neuroanatomical connections of the juxtaparaventricular region of the lateral hypothalamic area (LHAjp); as a control and in comparison to this, we also performed a preliminary analysis of a nearby LHA region that is dorsal to the fornix, namely the LHA suprafornical region (LHAs). The connections of these LHA regions were revealed with a coinjection tract-tracing technique involving a retrograde (cholera toxin B subunit) and anterograde (Phaseolus vulgaris leucoagglutinin) tracer. The LHAjp and LHAs together connect with almost every major division of the cerebrum and cerebrospinal trunk, but their connection profiles are markedly different and distinct. In simple terms, the connections of the LHAjp indicate a possible primary role in the modulation of defensive behavior; for the LHAs, a role in the modulation of ingestive behavior is suggested. However, the relation of the LHAjp and LHAs to potential modulation of these behaviors, as indicated by their neuroanatomical connections, appears to be highly integrative as it includes each of the major functional divisions of the nervous system that together determine behavior, i.e., cognitive, state, sensory, and motor. Furthermore, although a primary role is indicated for each region with respect to a particular mode of behavior, intermode modulation of behavior is also indicated. In summary, the extrinsic connections of the LHAjp and LHAs (so far as we have described them) suggest that these regions have a profoundly integrative role in which they may participate in the orchestrated modulation of elaborate behavioral repertoires.     

Mapping mesoscale cortical connectivity in monkey sensorimotor cortex with optical imaging and microstimulation

To map in vivo cortical circuitry at the mesoscale, we applied a novel approach to map interareal functional connectivity. Electrical intracortical microstimulation (ICMS) in conjunction with optical imaging of intrinsic signals (OIS) was used map functional connections in somatosensory cortical areas in anesthetized squirrel monkeys. ICMS produced activations that were focal and that displayed responses which were stimulation intensity dependent. ICMS in supragranular layers of Brodmann Areas 3b, 1, 2, 3a, and M1 evoked interareal activation patterns that were topographically appropriate and appeared consistent with known anatomical connectivity. Specifically, ICMS revealed Area 3b connections with Area 1; Area 1 connections with Areas 2 and 3a; Area 2 connections with Areas 1, 3a, and M1; Area 3a connections with Areas M1, 1, and 2; and M1 connections with Areas 3a, 1, and 2. These somatosensory connectivity patterns were reminiscent of feedforward patterns observed anatomically, although feedback contributions are also likely present. Further consistent with anatomical connectivity, intra-areal and intra-areal patterns of activation were patchy with patch sizes of 200–300 μm. In summary, ICMS with OIS is a novel approach for mapping interareal and intra-areal connections in vivo. Comparisons with feedforward and feedback anatomical connectivity are discussed.     

Lower dosage of recombinant tissue-type plasminogen activator (rt-PA) in the treatment of acute pulmonary embolism: A systematic review and meta-analysis

Background and Objective

According to US Food and Drugs Administration (FDA), 2 hour recombinant tissue plasminogen activator (rt-PA) 100 mg infusion is recommended for eligible patients with acute pulmonary embolism (PE). However,there exists evidence implying that a lower dosage of rt-PA can be equally effective but potentially safer compared with rt-PA 100 mg regimen. The aim of this systematic review and meta-analysis is to assess the efficacy and safety of low dose rt-PA in the treatment of acute PE.

Material and Method

We searched Pubmed, EMBASE, the Cochrane library and CBM Literature Database for randomized controlled trials (RCT) focusing on low dose rt-PA for acute PE. Outcomes were described in terms of changes of image tests and echocardiography, major bleeding events, all-cause death, and recurrence of PE.

Results

Five studies (440 patients) were included, three of which compared low dose rt-PA (0.6 mg/kg, maximum 50 mg or 50 mg infusion 2 h) with standard dose (100 mg infusion 2 h). There were more major bleeding events in standard dose rt-PA group than in low dose group (OR 0.33, 95%CI 0.12-0.91;P = 0.94,I² = 0%), while there were no statistical differences in recurrent PE or all cause mortality between these two groups. Two studies compared low dose (0.6 mg/kg, maximum 50 mg/2 min bolus or 10 mg bolus, ≤ 40 mg/2 h) with heparin. There was no significant difference in major bleeding events (OR 0.73, 95% CI 0.14-3.98;P = 0.72), recurrent PE or all cause mortality. No dose-related heterogeneity was found for all the included studies.

Conclusions

The results of this meta-analysis were hypothesis-generating. Based on the limited data, our systematic review suggested that low dose rt-PA had similar efficacy but was safer than standard dose of rt-PA. In addition, compared with heparin, low dose rt-PA didn’t increase the risk of major bleeding for eligible PE patients.     

Adipocytes derived from PA6 cells reliably promote the differentiation of dopaminergic neurons from human embryonic stem cells

The PA6 stromal cell line comprises a heterogeneous population of cells that can induce both mouse and human embryonic stem cells to differentiate into dopaminergic neurons. This ability of PA6 cells has been termed stromal cell‐derived inducing activity (SDIA). The level of SDIA has been found to vary considerably between and within batches of PA6 cells. Not only are the molecular mechanisms that underlie SDIA unknown but also the cell type(s) within the heterogeneous PA6 cultures that underlie SDIA remain poorly defined. In this study, we reveal that adipocytes, which are present within the heterogeneous PA6 cell population, robustly release the factors mediating SDIA. Furthermore, we report that the coculture of human embryonic stem cells with PA6‐derived adipocytes reliably induces their differentiation into midbrain dopaminergic neurons. © 2014 Wiley Periodicals, Inc.     

Predictors and outcomes of jejunostomy tube placement at the time of pancreatoduodenectomy

BackgroundClinically relevant postoperative pancreatic fistula and delayed gastric emptying cause substantial morbidity after pancreatoduodenectomy. Per international guidelines, the placement of jejunostomy tubes may be considered for patients at risk for malnutrition, such as those with a high risk for clinically relevant postoperative pancreatic fistula and related complications. This study determined predictors and postoperative outcomes of jejunostomy tube placement.MethodsPatients undergoing pancreatoduodenectomy in 2014 to 2015 were identified using the American College of Surgeons National Surgical Quality Improvement Program and Procedure-Targeted Pancreatectomy Participant Use Files. Multivariable logistic regressions were used to identify factors associated with concurrent jejunostomy tube placement and postoperative outcomes.ResultsOf 3,600 patients, 8.9% underwent jejunostomy tube placement. Patients given a jejunostomy tube were more likely white (odds ratio 1.46, P = .016), to have low preoperative serum albumin levels (odds ratio 2.13, P < .001), to have received neoadjuvant radiotherapy (odds ratio 2.14, P < .001), and to have received an intraoperative transfusion (odds ratio 1.50, P = .004). We observed no association between jejunostomy tube placement and an increasing number of risk factors for clinically relevant postoperative pancreatic fistula (P = .96) or delayed gastric emptying (P = .54). Overall, jejunostomy tube placement was associated with increased morbidity (odds ratio 1.34, P = .020) and duration of stay (P < .001), but not mortality (P = .12). Among patients with low serum albumin or those who developed clinically relevant postoperative pancreatic fistula or delayed gastric emptying, jejunostomy tube utilization was not associated with morbidity or mortality.ConclusionJejunostomy tube placement during pancreatoduodenectomy was not driven by risk factors for clinically relevant postoperative pancreatic fistula or delayed gastric emptying, suggesting that practice patterns play a role. Among patients with at-risk preoperative albumin or who developed these complications, jejunostomy tube placement was not associated with worse outcomes, supporting selective utilization per guideline recommendations.     

Bariatric surgery is safe and effective in Medicare patients regardless of age: an analysis of primary gastric bypass and sleeve gastrectomy outcomes

BackgroundNumerous studies have shown that bariatric surgery in older patients is safe and effective. However, both the Agency for Healthcare Research and Quality (AHRQ) and a Medicare Evidence Advisory Committee (MEDCAC) have cited gaps in the evidence for outcomes in Medicare patients undergoing bariatric surgery. These gaps are predominantly in the safety and outcomes evidence in Medicare patients younger than 65 years old (Centers for Medicare and Medicaid Services [CMS] < 65).ObjectivesThe aim of our study was to review both the safety and efficacy of gastric bypass (RYGB) and sleeve gastrectomy (SG) in Medicare patients compared with other payers.SettingA single academic medical center.MethodsA prospectively maintained database of 3300 patients who underwent bariatric surgery between January 2007 and December 2017 was utilized. The outcomes of Medicare patients undergoing RYGB and SG were analyzed and compared to those of similar patients covered by Medicaid or Commercial insurers.ResultsThere were too few patients with commercial insurance older than 65 to compare to those with Medicare (CMS ≥ 65). Mortality at 90 days for CMS ≥ 65 was 1.3% and the overall complication rate was 20.1% (minor 15.6%; major 7.1%). Total weight loss (TWL) at 6 months and 1, 2, and 3 years was 25.3%, 30.0%, 29.9%, and 29.4% respectively. For any time after surgery, 23% of CMS ≥ 65 had complete remission of diabetes and 45% had partial remission.Demographic analysis of CMS < 65 found Medicare patients were significantly older with more diabetes, hypertension and hyperlipidemia than those with commercial payers. Mortality at 90 days for CMS < 65 was 0.6% and the overall complication rate was 18.3% (minor 14.3%; major 4.7%). Mortality was not significantly different between payers. After adjustment for baseline differences and comparing to the Medicare group, the commercial group was less likely to have minor complications (P = .019), any complications (P = .007), and extended length of stay (P < .001). The TWL for the entire cohort age <65 at 6 months and 1, 2, and 3 years was 28.1%, 34.1%, 34.1%, and 31.8% respectively. After adjusting for differences, there was no significant difference in TWL between payers. For any time after surgery, complete remission of diabetes was 45% in CMS < 65 patients and partial remission was 59%. The comparison of remission between groups was then adjusted for DiaRem score and surgery type. CMS < 65 patients had significantly less partial remission of diabetes than commercial patients (P = .034) but no difference in complete remission.ConclusionsRYGB and SG are both safe and effective in Medicare patients of all ages. CMS ≥ 65 have acceptable mortality and complication rates with TWL and diabetes remission similar to younger patients. CMS < 65 patients are older than those with commercial insurance with more comorbid disease. While they have longer hospital stays after bariatric surgery, their weight loss and complete remission of diabetes are no different than patients with Medicaid or commercial insurance. This study helps fill an important evidence gap in bariatric surgical patients raised by both Agency for Healthcare Research and Quality, and a Medicare Evidence Advisory Committee.     

Pathology of valved venous homografts used as right ventricle-to-pulmonary artery conduits in congenital heart disease surgery

Objectives

Although valved venous homografts (VVHs) are used for establishing right ventricle-to-pulmonary artery continuity in some complex heart defects, the tissue changes that occur in situ have not been described. We review the gross and microscopic changes observed in explanted VVH conduits and their effects on functionality.