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John C Marshall

Publications and source records attributed to John C Marshall.

At least 19 recordsLinked to original sources
PubMed2006

The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism.

CONTEXT: Adolescent hyperandrogenemia is considered a forerunner of adult polycystic ovary syndrome, but its etiology remains uncertain. OBJECTIVE: Our objective was to explore the hypothesis that peripubertal obesity is associated with hyperandrogenemia. DESIGN AND SETTING: We performed a cross-sectional analysis of data obtained at General Clinical Research Centers. SUBJECTS: Subjects were 41 obese [body mass index (BMI) for age, >or=95%] and 35 normal-weight (BMI for age, <95%) peripubertal girls. INTERVENTION: We used pooled blood samples (approximately 0500-0700 h; n = 64) while fasting or single morning (fasting) samples (n = 12). MAIN OUTCOME MEASURES: We assessed adiposity and androgen concentrations. RESULTS: BMI correlated with total testosterone (T) (r(s) = 0.59), SHBG (r(s) = -0.69), and free T (r(s) = 0.69); free T was three times as great in obese girls compared with normal-weight girls (P < 0.0001 for all). BMI correlated with insulin (r(s) = 0.52); both insulin and LH correlated with free T (r(s) = 0.45 and 0.44, respectively; P < 0.001 for all). When analyzing early pubertal girls (pubertal stages 1-3; n = 36) alone, BMI correlated with total T (r(s) = 0.65), SHBG (r(s) = -0.74), and free T (r(s) = 0.75); free T was five times as great in obese early-pubertal girls (P < 0.001 for all). BMI correlated with insulin (r(s) = 0.65), and insulin correlated with free T (r(s) = 0.63, P < 0.01 for both). BMI correlated with free T while simultaneously adjusting for age, pubertal stage, insulin, LH, and dehydroepiandrosterone sulfate. CONCLUSION: Peripubertal obesity is associated with marked hyperandrogenemia, which is especially pronounced in early puberty.

Adolescent↗
PubMed2006

Using fMRI to decompose the neural processes underlying the Wisconsin Card Sorting Test.

The specific role of particular cerebral regions with regard to executive functions remains elusive. We conducted a functional magnetic resonance imaging (fMRI) study to segregate different network components underlying the Wisconsin Card Sorting Test (WCST), a test widely applied clinically to assess executive abilities. Three different test variants of the WCST, differing in task complexity (A > B > C), were contrasted with a high-level baseline condition (HLB). Cognitive subcomponents were extracted in a serial subtraction approach (A-C, A-B, B-C). Imaging data were further subjected to a correlational analysis with individual behavioral parameters. Contrasting A with the HLB revealed the entire neural network underlying WCST performance, including frontoparietal regions and the striatum. Further analysis showed that, within this network, right ventrolateral prefrontal cortex related to simple working memory operations, while right dorsolateral prefrontal cortex related to more complex/manipulative working memory operations. The rostral anterior cingulate cortex (ACC) and the temporoparietal junction bilaterally represented an attentional network for error detection. In contrast, activation of the caudal ACC and the right dorsolateral prefrontal cortex was associated with increased attentional control in the context of increasing demands of working memory and cognitive control. Non-frontal activations were found to be related to (uninstructed relative to instructed) set-shifting (cerebellum) and working memory representations (superior parietal cortex, retrosplenium). The data provide neural correlates for the different cognitive components involved in the WCST. They support a central role of the right dorsolateral prefrontal cortex in executive working memory operations and cognitive control functions but also suggest a functional dissociation of the rostral and caudal ACC in the implementation of attentional control.

Brain↗
PubMed2006

Surgical decision-making: integrating evidence, inference, and experience.

Evidence-based medicine provides a well-developed framework for evaluation of clinical research. Well-designed and adequately powered randomized controlled trials provide the best information on therapeutic efficacy; however, extrapolation of the trials' conclusions to individual patients may be difficult, and for many important surgical problems, trial data are unavailable. A complementary approach of inferential decision-making helps address these limitations, and increases the clinician's confidence in the safety of an approach of unknown efficacy. Experience establishes norms and expectations, and emphasizes events that are uncommon but clinically important. Although it cannot eliminate uncertainty or controversy, the integration of analytic techniques of evidence, inference, and experience provides the surgeon with the best means of adapting treatment to the unique circumstances of the individual patient.

Clinical Competence↗
PubMed2005

The staging of sepsis: understanding heterogeneity in treatment efficacy.

Human sepsis is an intrinsically complex disease. Populations of patients enrolled into clinical trials of novel sepsis therapies are notoriously heterogeneous with respect to the inciting cause of their disease, the co-morbid conditions that define its course, and the acute severity of their initial presentation. This heterogeneity is reflected in strikingly variable mortality risks across studies, and probably, though less clearly-established, in variable response rates to a given intervention. In an accompanying article in this issue of Critical Care, Macias and colleagues argue that the effectiveness of adjuvant sepsis therapies is not dependent on the baseline mortality risk, since the few "positive" trials that have been published show widely divergent placebo mortality rates. But this analysis assumes that biologically distinct interventions will be equally efficacious in clinically diverse populations, and confuses severity as a population descriptor with severity as a surrogate measure of a biologic state in an individual patient. In a pivotal trial of recombinant human activated protein C (rhAPC) in patients with severe sepsis, an aggregate 6% mortality decrement appeared to be the result of negligible efficacy in the least severely ill patients, and considerably greater efficacy in those who were at greatest risk of dying. A larger follow-up study recruiting low risk patients confirmed this impression, showing a convincing absence of benefit in patients who clinicians judged to be less severely ill. If we accept Macias' argument, we are led to the conclusion that rhAPC is of limited use in the management of severe sepsis. On the other hand, if we view severity as a crude surrogate for a particular pathologic state, we would shift our focus to better defining those populations most likely to benefit from intervention, including patients who may not have met criteria for entry in the original PROWESS trial--those with disseminated intravascular coagulation or acute organ dysfunction from causes other than sepsis. Staging systems that stratify heterogeneous patient populations by risk and by potential to benefit from intervention have proven to be essential to the development of multimodal adjuvant treatment for cancer. They will be no less important in the optimal management of sepsis.

APACHE↗
PubMed2005

Lipopolysaccharide: an endotoxin or an exogenous hormone?

Conventional models of the pathogenesis of sepsis assume that microorganisms or their products are necessarily injurious to the host. In contrast, an evolutionary perspective suggests that host-microbial interactions are a symbiotic model and that disease results from the disruption of a mutually beneficial homeostatic state. Lipopolysaccharide (LPS) from gram-negative bacteria is a prototypical trigger of sepsis and a target for the development of novel therapeutics. The biological mechanisms underlying the recognition of, and response to, LPS are more characteristic of a hormone than of a toxin. All mammals carry endogenous stores of LPS and express dedicated carrier proteins, a cellular receptor complex, and mechanisms that specifically antagonize the response to LPS. Disruption of any component of this complex recognition system jeopardizes host defenses against infection with exogenous microorganisms. Thus, LPS is not less an endotoxin than an exohormone, and its neutralization may potentially result in either benefit or harm.

Animals↗
PubMed2005

Directed and divided attention during hierarchical processing in patients with visuo-spatial neglect and matched healthy volunteers.

Hierarchically organized figures (for example, a large E made up of smaller N's) are frequently used to investigate directed and divided attention. Investigations of neurological and psychiatric patients, and also tachistoscopic and functional neuroimaging studies on healthy subjects, typically find the right hemisphere to be specialized for the processing of global stimuli and the left hemisphere to be specialized for the processing of local stimuli. In the current study, a group of 12 patients with visuo-spatial neglect (NP) after right hemisphere lesions and 12 age and sex-matched control subjects (CO) performed a directed and a divided attention task with hierarchically organized letters. As expected, faster reaction times were found for control subjects than for neglect patients, especially for the directed global attention task. Lower error rates were found for CO and NP for local than for global targets during the divided attention condition. Local on global interference was found for both groups in reaction times. These local processing advantages for older healthy adults have been reported previously. Additionally, an impairment in the divided attention task was found in both groups, but especially for global targets in NP. This impairment is consistent with other evidence of difficulty in disengaging attention shown by patients with visuo-spatial neglect.

Adult↗
PubMed2005

Progesterone inhibition of the hypothalamic gonadotropin-releasing hormone pulse generator: evidence for varied effects in hyperandrogenemic adolescent girls.

Compared with normal women, adults with polycystic ovarian syndrome (PCOS) require higher progesterone (P) concentrations to inhibit GnRH (LH) pulse frequency, which contributes to persistently rapid GnRH pulses and elevated LH levels in PCOS. To explore the origin of this abnormality, we assessed hypothalamic sensitivity to P feedback in nine normal controls and 11 hyperandrogenemic (HA) adolescents. Subjects first underwent frequent blood sampling for 11 h to assess baseline LH pulse frequency. Thereafter, oral estradiol and micronized P were given for 7 d to achieve mean estradiol and P levels of 143 +/- 16 pg/ml (524 +/- 60 pmol/liter) and 7.8 +/- 0.7 ng/ml (24.9 +/- 2.3 nmol/liter), respectively. LH pulse frequency was then reassessed. On d 7, the slope of the percent reduction of LH pulses per 11 h as a function of the d 7 P concentration was less in the HA group compared with controls (P = 0.02) despite similar P levels. LH pulse frequency was suppressed in all NC (mean, 7.0 to 3.4 pulses/11 h), but was unchanged in six of the HA girls (mean, 8.3 to 7.5 pulses/11 h). In contrast, in the other five HA adolescents, P induced similar slowing of LH pulses to that seen in NC (mean, 10.0 to 5.0 pulses/11 h). Baseline free testosterone levels were similar in both HA groups; the only observed difference between these HA groups is that the P-suppressible subjects were all of Hispanic descent. These data suggest that hyperandrogenemia during adolescence is variably associated with decreased sensitivity to P, which may have a partially genetic basis.

Adolescent↗
PubMed2005

Burden of illness in venous thromboembolism in critical care: a multicenter observational study.

PURPOSE: The frequency of clinically diagnosed venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE) in medical-surgical critically ill patients is unclear. The objectives of this study were to estimate the prevalence and incidence of radiologically confirmed DVT and PE in medical-surgical intensive care unit (ICU) patients and to determine the impact of prophylaxis on the frequency of these events. MATERIALS AND METHODS: In a retrospective observational cohort study in 12 adult ICUs, we identified prevalent cases (diagnosed in the 24 hours preceding ICU admission up to 48 hours post-ICU admission) and incident cases (diagnosed 48 hours or more after ICU admission and up to 8 weeks after ICU discharge) of upper or lower limb DVT or PE. Deep venous thrombosis was diagnosed by compression ultrasound or venogram. Each DVT was classified as clinically suspected or not clinically suspected in that the latter was diagnosed by scheduled screening ultrasonography. Pulmonary embolism was diagnosed by ventilation-perfusion lung scan, computed tomography pulmonary angiography, echocardiography, electrocardiography, or autopsy. RESULTS: Among 12,338 patients, 252 (2.0%) patients had radiologically confirmed DVT or PE and another 47 (0.4%) had possible DVT or PE. Prevalent DVTs were diagnosed in 0.4% (95% confidence interval [CI], 0.3%-0.5%) of patients and prevalent PEs were diagnosed in 0.4% (95% CI, 0.3%-0.6%). Incident DVTs were diagnosed in 1.0% (95% CI, 0.8%-1.2%) of patients, and incident PEs were diagnosed in 0.5% (95% CI, 0.4%-0.6%). Of patients with incident VTE, 65.8% of cases occurred despite receipt of thromboprophylaxis for at least 80% of their days in ICU. The median (interquartile range) ICU length of stay was similar for patients with DVT (7 [3-17]) and PE (5 [2-8]). For all patients with VTE, ICU mortality was 16.7% (95% CI, 12.0%-21.3%) and hospital mortality was 28.5% (95% CI, 22.8%-34.1%). CONCLUSIONS: Venous thromboembolism appears to be an apparently infrequent, but likely underdiagnosed problem, occurring among patients receiving prophylaxis. Findings suggest the need for increased suspicion among clinicians, renewed efforts at thromboprophylaxis, and evaluation of superior prevention strategies.

Anticoagulants↗
PubMed2005

Outcome measures for clinical research in sepsis: a report of the 2nd Cambridge Colloquium of the International Sepsis Forum.

BACKGROUND AND OBJECTIVES: Sepsis is the leading cause of morbidity and mortality for patients admitted to an intensive care unit. The evaluation of new therapies has been hampered by the underdevelopment of outcome measures used to detect biological activity and patient-centered benefit in a complex and highly heterogeneous patient population. We sought to evaluate existing approaches and to draw on insights from other disciplines to propose a comprehensive approach to outcome evaluation in sepsis clinical trials. METHODS: An expert colloquium organized by the International Sepsis Forum brought together sepsis researchers, clinical epidemiologists, and experts in the development and implementation of outcome measures in rheumatology, neurology, and oncology. RESULTS: The translation of an evolving understanding of the biology of sepsis into effective new therapies for critically ill patients requires a reevaluation of the end points used to determine response to intervention. These represent a continuum that measures biological activity against the target at one end and sustained improvement in survival or quality of life at the other. Early phase research should determine whether an intervention works in vivo, using measures that are responsive and informative to provide proof of principle, to aid in selecting optimal patient populations for study, and to gain insights into optimal dose and duration of therapy. After in vivo biology has been demonstrated and the possibility of efficacy inferred by plausible improvements in surrogate physiologic measures, definitive studies should seek robust evidence of benefit using end points that measure important, patient-centered benefit, including intermediate and longer term survival and health-related quality of life. Nonmortal measures of benefit assume particular importance for populations, such as children, whose mortality risk is low, or who have significant rates of comorbidities that independently limit survival. Composite measures that integrate morbidity and mortality effects may provide the most meaningful information about therapeutic efficacy. CONCLUSIONS: The development of explicit, hypothesis-driven, and iterative approaches to outcome measure development, patterned on approaches used in the fields of rheumatology and oncology, may improve the conduct of clinical studies in the critically ill.

Clinical Trials as Topic↗
PubMed2005

Intraabdominal infections in infants and children: descriptions and definitions.

OBJECTIVE: To define intraabdominal infections in infants and children. DESIGN: Summary of the literature with review and consensus by experts in the field. RESULTS: Intraabdominal infections are common in infants and children and comprise a broad range of disorders of greatly variable severity. In addition to microbiologically mediated processes, other inflammatory disorders frequently present similar clinical syndromes. More aggressive and effective therapy for prematurity, chronic diseases of childhood, malignancies, immunodeficiencies, and organ failure, including transplantation, is likely to increase the frequency with which some of these infections are encountered. Only a limited number of processes have been clearly defined in the pediatric literature. CONCLUSIONS: Criteria defining intraabdominal infection are proposed based on reports in the pediatric literature and expert opinion. Additional study of individual disorders, diagnostic criteria, and approach to management is warranted.

Abdominal Abscess↗
PubMed2005

Neutralization of tumor necrosis factor in preclinical models of sepsis.

Tumor necrosis factor (TNFalpha), a cardinal early mediator of the innate host inflammatory response, has been an attractive target for therapeutic intervention in human sepsis. However, pooled data from 12 completed randomized controlled trials show only a very modest impact on mortality in a highly heterogeneous population of patients. To gain insight into the preclinical in vivo biology of TNFalpha that might aid in better identifying appropriate patient populations for therapeutic intervention, we undertook a systematic review of published reports of preclinical studies assessing the consequences of neutralization of TNFalpha in models of acute infection or inflammation. We identified 143 reports incorporating 484 unique experimental comparisons in seven different animal species. The effects of neutralization of TNFalpha in these were quite variable. Neutralization of TNFalpha was beneficial in endotoxemia, or after systemic challenge with gram-negative organisms, Staphylococcus aureus, or Group B streptococci. On the other hand, neutralization was detrimental in infections caused by Streptococcus pneumoniae, Candida spp., or intracellular pathogens such as Listeria and Mycobacterium tuberculosis, and in models of pneumonia. Treatment was more efficacious when delivered before infectious challenge, and the therapeutic signal increased as the baseline mortality in the placebo group increased. Evidence of neutralization of TNFalpha bioactivity, and of attenuation of inflammation, was typically accompanied by evidence of impairment of antimicrobial defenses. Multiple specific and nonspecific therapeutic strategies were identified. We conclude that the beneficial effects of TNF in systemic inflammation occur at the cost of impaired antimicrobial defenses, and that a better understanding of the consequences of neutralization of TNFalpha in vivo could aid in better defining optimal patient populations for therapeutic intervention.

Animals↗
PubMed2005

The effects of granulocyte colony-stimulating factor in preclinical models of infection and acute inflammation.

The cytokine granulocyte colony-stimulating factor (G-CSF) is a potent endogenous trigger for the release of neutrophils from bone marrow stores and for their activation for enhanced antimicrobial activity. G-CSF has been widely evaluated in preclinical models of acute illness, with generally promising though divergent results. A recombinant G-CSF molecule has recently undergone clinical trials to assess its efficacy as an adjuvant therapy in community-acquired and nosocomial pneumonia, however, these studies failed to provide convincing evidence of benefit. We undertook a systematic review of the published literature reporting the effects of modulation of G-CSF in preclinical in vivo models to determine whether evidence of differential efficacy might explain the disappointing results of human studies and point to disease states that might be more likely to benefit from G-CSF therapy. G-CSF has been evaluated in 86 such studies involving a variety of different models. The strongest evidence of benefit was seen in studies involving intraperitoneal challenge with live organisms; benefit was evident whether the agent was given before or after challenge. G-CSF demonstrates anti-inflammatory activity in models of systemic challenge with viable organisms or endotoxin, but only when the agent is given before challenge; evidence of benefit after challenge was minimal. Preclinical models of intrapulmonary challenge only show efficacy when the cytokine is administered before the infectious challenge, and suggested harm in gram-negative pneumonia resulting from challenge with Escherichia coli or Klebsiella. There is little evidence for therapeutic efficacy in noninfectious models of acute illness. We conclude that the most promising populations for evaluation of G-CSF are neutropenic patients with invasive infection and patients with intra-abdominal infection, particularly those with the syndrome of tertiary, or recurrent, peritonitis. Significant variability in the design and reporting of studies of preclinical models of acute illness precludes more sophisticated data synthesis.

Animals↗