Kevin C. Doerschug

Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting

Objectives: To (1) investigate effects of aerobic walking on motor function, cognition, and quality of life in Parkinson disease (PD), and (2) compare safety, tolerability, and fitness benefits of different forms of exercise intervention: continuous/moderate intensity vs interval/alternating between low and vigorous intensity, and individual/neighborhood vs group/facility setting. Methods: Initial design was a 6-month, 2 × 2 randomized trial of different exercise regimens in independently ambulatory patients with PD. All arms were required to exercise 3 times per week, 45 minutes per session. Results: Randomization to group/facility setting was not feasible because of logistical factors. Over the first 2 years, we randomized 43 participants to continuous or interval training. Because preliminary analyses suggested higher musculoskeletal adverse events in the interval group and lack of difference between training methods in improving fitness, the next 17 participants were allocated only to continuous training. Eighty-one percent of 60 participants completed the study with a mean attendance of 83.3% (95% confidence interval: 77.5%–89.0%), exercising at 46.8% (44.0%–49.7%) of their heart rate reserve. There were no serious adverse events. Across all completers, we observed improvements in maximum oxygen consumption, gait speed, Unified Parkinsons Disease Rating Scale sections I and III scores (particularly axial functions and rigidity), fatigue, depression, quality of life (e.g., psychological outlook), and flanker task scores (p < 0.05 to p < 0.001). Increase in maximum oxygen consumption correlated with improvements on the flanker task and quality of life (p < 0.05). Conclusions: Our preliminary study suggests that aerobic walking in a community setting is safe, well tolerated, and improves aerobic fitness, motor function, fatigue, mood, executive control, and quality of life in mild to moderate PD. Classification of evidence: This study provides Class IV evidence that in patients with PD, an aerobic exercise program improves aerobic fitness, motor function, fatigue, mood, and cognition.

Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis

IntroductionMicrovascular dysregulation characterized by hyporesponsive vessels and heterogeneous bloodflow is implicated in the pathogenesis of organ failure in sepsis. The renin-angiotensin system (RAS) affects the microvasculature, yet the relationships between RAS and organ injury in clinical sepsis remain unclear. We tested our hypothesis that systemic RAS mediators are associated with dysregulation of the microvasculature and with organ failure in clinical severe sepsis.MethodsWe studied 30 subjects with severe sepsis, and 10 healthy control subjects. Plasma was analyzed for plasma renin activity (PRA) and angiotensin II concentration (Ang II). Using near-infrared spectroscopy, we measured the rate of increase in the oxygen saturation of thenar microvascular hemoglobin after five minutes of induced forearm ischemia. In so doing, we assessed bulk microvascular hemoglobin influx to the tissue during reactive hyperemia. We studied all subjects 24 hours after the development of organ failure. We studied a subset of 12 subjects at an additional timepoint, eight hours after recognition of organ failure (early sepsis).ResultsAfter 24 hours of resuscitation to clinically-defined endpoints of preload and arterial pressure, Ang II and PRA were elevated in septic subjects and the degree of elevation correlated negatively with the rate of microvascular reoxygenation during reactive hyperemia. Early RAS mediators correlated with microvascular dysfunction. Early Ang II also correlated with the extent of organ failure realized during the first day of sepsis.ConclusionsRAS is activated in clinical severe sepsis. Systemic RAS mediators correlate with measures of microvascular dysregulation and with organ failure.

Antibiotics delay but do not prevent bacteremia and lung injury in murine sepsis.

ObjectivesTo investigate the effect of antibiotics on infection, lung injury, and mortality rate in polymicrobial sepsis and to determine whether an association exists between infection and lung injury and mortality rate. To circumvent the effect of antibiotics on cultures, we used polymerase chain reaction to detect bacteria. DesignProspective, randomized, controlled laboratory trial. SettingUniversity research laboratory. SubjectsC57/BL6 mice. InterventionsMice underwent cecal ligation and puncture without antibiotics (CLP) or with imipenem (CLP + Abx). Measurements and Main ResultsCLP resulted in 50% mortality rate at 48 hrs and 100% mortality rate at 84 hrs. Antibiotics delayed these time points to 72 and 120 hrs, respectively. Lung injury occurred before mortality in both groups. Polymerase chain reaction detected bacteria in the blood and lungs of all CLP mice by 24 hrs. Antibiotics delayed but did not prevent infection in CLP + Abx mice. Serum tumor necrosis factor-&agr; and lung endotoxin were elevated to similar concentrations in both CLP and CLP + Abx mice. ConclusionsIn this model of sepsis, antibiotics delay but do not prevent acute lung injury and mortality. Even in the presence of antibiotics, acute lung injury is strongly associated with bacteremia and bacteria within the lungs.

Insulin-like Growth Factor–1 Levels Contribute to the Development of Bacterial Translocation in Sepsis

RATIONALE Many lines of evidence point toward the gastrointestinal (GI) tract in the pathophysiology of organ dysfunction in sepsis. Splanchnic hypoperfusion during sepsis leads to enterocyte apoptosis, diminished barrier function, and release of bacterial products. Sepsis lowers levels of insulin-like growth factor (IGF)-1, a known antiapoptotic factor. We recently demonstrated that treatment with IGF-1 is protective in murine sepsis. OBJECTIVES We hypothesize that decreased IGF-1 levels in sepsis contributes to the development of bacterial translocation. METHODS Sepsis was induced in C57BL/6 mice via intratracheal instillation of Pseudomonas aeruginosa. Human subjects with sepsis were enrolled if they had a documented positive blood culture with a nonenteric organism. Bacterial translocation was measured in serum by quantitative real-time polymerase chain reaction with primers specific for enteric bacteria. Serum IGF-1 was measured by ELISA. Apoptosis of the GI epithelium was assessed via immunohistochemistry. MEASUREMENTS AND MAIN RESULTS We found that mice with severe sepsis had evidence of bacterial translocation by 24 hours. Enteric bacterial load correlated inversely with levels of serum IGF-1. If we treated mice with IGF-1, bacterial translocation was significantly decreased. In addition, we found increased GI epithelial cell apoptosis after sepsis, which was significantly decreased after IGF-1 treatment. Human subjects with nonenteric sepsis developed progressive enteric bacteremia over 3 days. The degree of enteric bacteremia correlated inversely with serum IGF-1 levels. CONCLUSIONS These data support the hypothesis that sepsis-induced reductions in IGF-1 levels contribute to the development of bacterial translocation in both a murine model and human subjects.

First-Generation Adenovirus Vectors Shorten Survival Time in a Murine Model of Sepsis

Adverse immunological reactions to adenoviral vectors have significantly impacted the utility of this virus for treating genetic and environmentally induced diseases. In this study, we evaluate the effect of adenoviral vectors on an animal model of sepsis. Systemic delivery of first-generation adenoviral vectors to septic mice (cecal ligation and puncture) resulted in a shortened survival time. This effect was not observed with second-generation or inactivated first-generation vectors. The accelerated death was accompanied by a number of important changes in the disease. These changes included increased liver cell apoptosis (including Kupffer cells) and a marked increase in liver bacterial load. In the lung, the combination induced an increase in bacterial load, as well as greater lung injury. In the serum, the combination was associated with decreased TNF-α levels and an increase in bacterial load. Finally, a profound degree of lymphocyte apoptosis was observed in these animals. These observations suggest that prior exposure to first-generation adenovirus gene therapy vectors may worsen the outcome of some forms of sepsis.

Insulin-like Growth Factor-1 Improves Survival in Sepsis via Enhanced Hepatic Bacterial Clearance

RATIONALE Both insulin-like growth factor (IGF)-1 and bacterial clearance by Kupffer cells are significantly reduced in severe sepsis. Kupffer cell apoptosis is triggered by tumor necrosis factor (TNF)-alpha and activation of the PI-3 kinase pathway prevents TNF-induced Kupffer cell death. OBJECTIVES We evaluated if the marked decline in IGF-1 is related to bacterial clearance in sepsis. METHODS Sepsis was induced in C57BL/6 mice by intratracheal inoculation with Pseudomonas aeruginosa (strain PA103). Some mice received IGF-1 24 mg/kg either before infection or 12 hours after infection. In vitro studies were performed using the clonal Kupffer cell line KC13-2. MEASUREMENTS AND MAIN RESULTS Sepsis resulted in decreased levels of IGF-1. In vitro studies with KC13-2 cells demonstrated that IGF-1 protected Kupffer cells against TNF-alpha-induced apoptosis by activating the PI-3 kinase pathway and stabilizing the inhibitor of apoptosis protein, XIAP. In the animal model, pretreatment with IGF-1 decreased hepatic TNF-alpha and IL-6, improved hepatic bacterial clearance as demonstrated by real-time polymerase chain reaction with primers specific for P. aeruginosa, and improved survival in severe sepsis. Moreover, we rescued mice from severe sepsis by IGF-1 treatment 12 hours after infection. CONCLUSIONS These studies show that the decline in IGF-1 levels in sepsis is related to bacterial clearance and that replacement of IGF-1 in a murine model of sepsis improves overall survival.

Techniques for the difficult airway.

Purpose of reviewManagement of the difficult airway is associated with significant morbidity and mortality in critically ill patients. An increasing array of advanced airway tools are available, but appropriate selection and application in the ICU remains poorly defined. Recent findingsDifficult airway incidence during emergent intubation is 10%, but complications of ICU airway management remain common. Training and equipment in many ICUs remain variable despite data that demonstrate that an ‘intubation management bundle’ and a systematic approach to teamwork and training can reduce life-threatening airway complications. A protocol employing an extraglottic airway (EGA) early in cases of inadequate ventilation has been associated with no episodes of prolonged hypoxemia in 12 225 consecutive intubations. Direct laryngoscopy with gum elastic bougie is the most commonly employed method to manage emergent difficult airways, and videolaryngoscopes also provide greater glottic visualization and a high rate of intubation success in patients with difficult airway risk factors or a failed airway. SummaryA systematic approach to intubation that emphasizes planning and teamwork can reduce intubation complications. Early use of an EGA or cricothyroidotomy may reduce complications when oxygenation is inadequate. Use of a gum elastic bougie or indirect optical device is also associated with a high rate of intubation success when oxygenation permits.

Chronic Liver Disease Impairs Bacterial Clearance in a Human Model of Induced Bacteremia

Sepsis often causes impaired hepatic function. Patients with liver disease have an increased risk of bacteremia. This is thought to be secondary to impaired reticuloendothelial system function. However, this has not been demonstrated clinically. Since transient bacteremia occurs following toothbrushing, we hypothesized that subjects with cirrhosis would have impaired bacterial clearance following toothbrushing compared with subjects with pulmonary disease and healthy controls. After baseline blood was drawn, the subjects underwent a dental examination to determine plaque index and gingival index. Following toothbrushing, blood was drawn at 30 seconds, 5 minutes, and 15 minutes. Bacteremia was measured using quantitative real‐time PCR with primers that amplify all known bacteria. We found greater than 75% incidence of bacteremia following toothbrushing. While control and pulmonary subjects were able to clear this bacteremia, subjects with cirrhosis had prolonged bacteremia. Baseline and peak bacterial load correlated with plaque index, suggesting that dental hygiene predicts the degree of bacteremia. However, only the severity of cirrhosis was predictive of bacterial clearance at 15 minutes, suggesting that liver function is important in clearing bacteremia. In this study, we demonstrate clinically that cirrhosis results in impaired bacterial clearance. This suggests that cirrhotic patients may be more susceptible to sepsis because of ineffective bacterial clearance.

Identification of a Novel Splice Variant Isoform of TREM-1 in Human Neutrophil Granules

Triggering receptor expressed on myeloid cells-1 (TREM-1) is critical for inflammatory signal amplification. Humans have two forms of TREM-1: a membrane receptor, associated with the adaptor DAP12, and a soluble receptor detected at times of infection. The membrane receptor isoform acts synergistically with the TLR pathway to promote cytokine secretion and neutrophil migration, whereas the soluble receptor functions as a counterregulatory molecule. In multiple models of sepsis, exogenous administration of soluble forms of TREM-1 attenuates inflammation and markedly improves survival. Despite intense interest in soluble TREM-1, both as a clinical predictor of survival and as a therapeutic tool, the origin of native soluble TREM-1 remains controversial. Using human neutrophils, we identified a 15-kDa TREM-1 isoform in primary (azurophilic) and secondary (specific) granules. Mass spectrometric analysis, ELISA, and immunoblot confirm that the 15-kDa protein is a novel splice variant form of TREM-1 (TREM-1sv). Neutrophil stimulation with Pseudomonas aeruginosa, LPS, or PAM(3)Cys4 resulted in degranulation and release of TREM-1sv. The addition of exogenous TREM-1sv inhibited TREM-1 receptor–mediated proinflammatory cytokine production. Thus, these data reveal that TREM-1 isoforms simultaneously activate and inhibit inflammation via the canonical membrane TREM-1 molecule and this newly discovered granular isoform, TREM-1sv.

Non-motor symptoms in Parkinson's disease

The degeneration of the dopaminergic nigrostriatal system and parkinsonism (rest tremor, rigidity, bradykinesia and postural instability/gait disorder) represent only one aspect of Parkinson’s disease (PD), a multifaceted and complex disorder. In addition to this typical motor dysfunction, non-motor symptoms (NMS) also significantly reduce of quality of life. Several non-motor features are associated with deficits in extranigral dopaminergic pathways (e.g. mesolimbic, mesocortical), while others involve non-dopaminergic systems in the nervous system (e.g. cholinergic, noradrenergic, serotoninergic). Sleep (e.g. rapid eye movement behaviour disorder), olfactory and autonomic dysfunction (e.g. constipation) may precede the onset of parkinsonism by many years, consistent with the debated notion that PD pathology starts in the lower brainstem and that midbrain (i.e. nigral) involvement represents stage three out of six pathological stages. Considering parkinsonism as just the tip of the iceberg of a multifaceted and complex disorder, PD might be better viewed as a ‘centrosympathomyenteric neuronopathy,’ as per Langston. In this article, various non-motor aspects of PD (see Table 1) are discussed.