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J C Marshall

Publications and source records attributed to J C Marshall.

At least 55 records · Page 3Linked to original sources
PubMed2000

Kicking over the traces: A note in response to Zurif and Piñango (1999).

Zurif and Piñango (1999) claimed that they excluded the four agrammatic patients reported by Druks and Marshall (1991) from their review article because two of the patients were nonnative speakers of Hebrew and because the Hebrew sentences we used in our investigations were ungrammatical. In Druks and Marshall (1991) we have shown that the presence or the absence of a trace in two types of Hebrew passives had no effect on the patients' performance. Two patients, without comprehension deficits, performed equally well on both types of passives and two patients, with comprehension deficits, were equally impaired on both types. We remind Zurif and Piñango of our previous response to the claims of ungrammaticality of our materials (Druks & Marshall, 1992) and argue that there were no justifiable reasons for excluding these cases from the review. We also comment on Zurif and Piñango's (1999) and Grodzinsky's (2000) new proposal that the association of agrammatic comprehension should be with Broca's aphasia and not with agrammatism.

Aphasia, Broca↗
PubMed2000

Clinical trials of mediator-directed therapy in sepsis: what have we learned?

Almost 60 randomized controlled clinical trials have been undertaken, testing the hypothesis that modulation of the endogenous host inflammatory response can improve survival for patients with a clinical diagnosis of sepsis. The results have been tantalizing, but frustrating, and no new agent has been introduced into clinical practice. Analysis of pooled data from studies of the use of an neutralizing antibody to tumor necrosis factor, or recombinant interleukin 1 receptor antagonist, show that these two approaches yield a statistically significant, but small improvement in 28 day all-cause mortality. However variability in results from one study to the next, the small absolute mortality reduction, the emerging evidence of a substantial potential for harm, and the predicted costs of recombinant biologic agents has engendered a climate of caution and pessimism. The challenge is to find methods of refining investigative approaches to maximize benefit and minimize harm. This paper reviews the recent history of sepsis clinical trials, focussing on emerging insights into the limitations of study entry criteria and measures of biologic activity and clinical benefit that may inform and direct future investigations. The biologic complexity of systemic inflammation, and the multiple interactions between clinical biology and the process of care suggest that future success in clinical research in sepsis will occur through the conduct of highly focussed investigations in a small number of dedicated centres of excellence.

Antibodies, Monoclonal↗
PubMed2000

'Where' depends on 'what': a differential functional anatomy for position discrimination in one- versus two-dimensions.

Line bisection is widely used as a clinical test of spatial cognition in patients with left visuospatial neglect after right hemisphere lesion. Surprisingly, many neglect patients who show severe impairment on marking the center of horizontal lines can accurately mark the center of squares. That these patients with left neglect are also typically poor at judging whether lines are correctly prebisected implies that the deficit can be perceptual rather than motoric. These findings suggest a differential neural basis for one- and two-dimensional visual position discrimination that we investigated with functional neuroimaging (fMRI). Normal subjects judged whether, in premarked lines or squares, the mark was placed centrally. Line center judgements differentially activated right parietal cortex, while square center judgements differentially activated the lingual gyrus bilaterally. These distinct neural bases for one- and two-dimensional visuospatial judgements help explain the observed clinical dissociations by showing that as a stimulus becomes a better, more 'object-like' gestalt, the ventral visuoperceptive route assumes more responsibility for assessing position within the object.

Adult↗
PubMed2000

Neural consequences of acting in near versus far space: a physiological basis for clinical dissociations.

We used PET to determine which brain regions are implicated when normal volunteers bisect horizontal lines and point to dots in near (peripersonal) or far (extrapersonal) space. Studies of line bisection in patients with right hemisphere lesions have shown that bisection performance can be severely impaired in either near or far space while remaining within normal limits in the other spatial domain. Likewise, clinical dissociations between pointing to objects in near and far space have been reported. The normal functional anatomy of these dissociations has not been demonstrated convincingly. Regional cerebral blood flow measurements using PET were carried out in 12 healthy right-handed male volunteers who bisected lines or pointed to dots in near or far space, using a laser pen. Subjects performing either task in near space showed neural activity in the left dorsal occipital cortex, left intraparietal cortex, left ventral premotor cortex and left thalamus. In far space, subjects performing either task showed activation of the ventral occipital cortex bilaterally and the right medial temporal cortex. These data provide physiological support for the clinically observed dissociations demonstrating that attending to and acting in near space differentially employs dorsal visuomotor processing areas, whereas attending to and acting in far space differentially draws on ventral visuoperceptual processing areas, even when the motor components of the tasks are identical when performed in the two spaces.

Adult↗
PubMed2000

Phagocytosis of Candida albicans induces apoptosis of human neutrophils.

Neutrophil-mediated inflammation is terminated through the programmed cell death or apoptosis of the neutrophil, a process that can be inhibited by soluble mediators released during an inflammatory response. It has been reported, however, that the phagocytosis of intact bacteria can accelerate apoptosis. We evaluated the effects of the phagocytosis of a common nosocomial pathogen, Candida albicans, on the expression of apoptosis. Phagocytosis of killed Candida induced a dose-dependent increase in the apoptosis of normal neutrophils after 18 h of in vitro culture, from 40.7+/-9.1% to 81.7+/-4.5%, while supernatants from neutrophil:Candida co-cultures actually inhibited apoptosis. Induction of apoptosis was not dependent on phagocytosis, since opsonization of yeast with serum failed to increase apoptosis, while inhibition of phagocytosis with latrunculin B resulted in a slightly increased apoptotic rate. Increased apoptosis induced by Candida was associated with increased activity of the membrane-associated apoptotic enzyme, caspase 8, and with increased expression of the active form of the key executioner caspase, caspase 3. Increased apoptosis was associated with depletion of intracellular glutathione (GSH), and could be inhibited by the addition of exogenous GSH. These data demonstrate an important physiologic role for host-pathogen interactions in the resolution of inflammation and suggest that the response to an invading pathogen is an important stimulus to the restoration of normal immunologic homeostasis.

Apoptosis↗
PubMed2000

In vivo and in vitro modulation of intercellular adhesion molecule (ICAM)-1 expression by hypertonicity.

Hepatic ischemia-reperfusion (I/R) is an important cause of organ dysfunction in the critically ill. With reperfusion, Kupffer cells release pro-inflammatory cytokines that promote endothelial cell (EC) expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1, facilitating neutrophil (PMN) infiltration. Studies suggest hypertonic saline (HTS) might exert beneficial effects on development of organ injury following shock on the basis of reduced PMN-EC interactions. We hypothesized that HTS alters expression of EC ICAM-1 and thus minimizes PMN-mediated injury. To test our hypothesis, we used an in vivo model of hepatic I/R and an in vitro model of activated EC. Rats underwent 30 min of hepatic ischemia after pretreatment with HTS (7.5% NaCl, 4cc/kg ia) or normal saline (NS). At 4 h reperfusion, plasma was taken for aspartate aminotransferase (AST) and liver tissue was harvested for assessment of hepatic ICAM-1 mRNA by Northern blot analysis. Human umbilical vein endothelial cells (HUVECs) were activated by lipopolysaccharide (LPS) and exposed to hypertonic medium (350-500 mOsM). HUVEC ICAM-1 protein was measured by cell ELISA and ICAM-1 mRNA by Northern blot analysis. HTS prevented hepatic I/R injury as measured by AST. AST of shams was 282.6+/-38.1 IU/L. I/R following NS pretreatment caused significant injury (AST 973.8+/-110.9 IU/L) compared to sham (SM) (P < 0.001). Pretreatment with HTS exerted significant protection following I/R with an AST of 450.9+/-56.3 IU/L (P < 0.05). There was no significant difference in AST levels between SM and HTS groups. Reduced hepatic injury after HTS and I/R was accompanied by inhibition of I/R-induced hepatic ICAM-1 mRNA expression compared to NS treated animals (P < 0.01). Similarly, hypertonicity inhibited HUVEC LPS-induced ICAM-1 protein (LPS: 1.86+/-0.19 absorbance units; 400 mOsM +/- LPS: 1.45+/-0.14 absorbance units; 450 mOsM + LPS: 1.02+/-0.19 absorbance units, P < 0.001) and mRNA expression. Thus, hypertonicity modulates endothelial ICAM-1 expression as one possible protective mechanism against I/R injury.

Animals↗
PubMed2000

Priming for enhanced alveolar fibrin deposition after hemorrhagic shock: role of tumor necrosis factor.

Hemorrhagic shock due to major trauma predisposes to the development of acute respiratory distress syndrome. Because lung fibrin deposition is one of the hallmarks of this syndrome, we hypothesized that resuscitated shock might predispose to the development of a net procoagulant state in the lung. A rodent model of shock/resuscitation followed by low-dose intratracheal lipopolysaccharide (LPS), a clinically relevant "two-hit" model, was used to test this hypothesis. Resuscitated shock primed the lungs for an increased tissue factor and plasminogen activator (PA) inhibitor-1 gene expression in response to LPS, while the fibrinolytic PA was reduced. These alterations were recapitulated in isolated alveolar macrophages, suggesting their role in the process. LPS-induced tumor necrosis factor (TNF) was also augmented in animals after antecedent shock/resuscitation, and studies using anti-TNF antibodies revealed that TNF expression was critical to the induction of the procoagulant molecules and the reduction in PA. By contrast, TNF did not appear to play an important role in neutrophil sequestration in this model, inasmuch as anti-TNF had no effect on lung neutrophil accumulation or chemokine expression. However, treatment prevented albumin leak by preventing alveolar neutrophil activation. The inclusion of the antioxidant N-acetyl-cysteine in the resuscitation fluid resulted in prevention of both the development of the net procoagulant state and lung neutrophil sequestration, suggesting a role for upstream oxidant effects in the priming process. These studies provide a cellular and molecular basis for lung fibrin deposition after resuscitated shock and demonstrate a divergence of pathways responsible for fibrin generation and neutrophil accumulation.

Acetylcysteine↗
PubMed2000

Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone.

Polycystic ovarian syndrome (PCOS) is a complex disorder with multiple abnormalities, including hyperandrogenism, ovulatory dysfunction, and altered gonadotropin secretion. The majority of patients have elevated LH levels in plasma and a persistent rapid frequency of LH (GnRH) pulse secretion, the mechanisms of which are unclear. Earlier work has suggested that the sensitivity of the GnRH pulse generator to inhibition by ovarian steroids is impaired. We performed a study to determine whether antiandrogen therapy with flutamide could enhance feedback inhibition by estradiol (E2) and progesterone (P) in women with PCOS. Ten anovulatory women with PCOS and nine normal controls (days 8-10 of the cycle) were studied on three occasions. During each admission, LH and FSH were determined every 10 min and E2, P, and testosterone (T) every 2 h for 13 h. After 12 h, GnRH (25 ng/kg) was given iv. After the first admission, patients were started on flutamide (250 mg twice daily), which was continued for the entire study. The second admission occurred on days 8-10 of the next menstrual cycle for normal controls and on study day 28 for PCOS patients. Subjects were then given E2 transdermally (mean plasma E2, 106+/-18 pg/mL) and P by vaginal suppository to obtain varied plasma concentrations of P (mean P, 4.4+/-0.5 ng/mL; range, 0.6-9.0 ng/mL), and a third study was performed 7 days later. At baseline women with PCOS had higher LH pulse amplitude, response to GnRH, T, androstenedione, and insulin and lower sex hormone-binding globulin concentrations (P < 0.05). Most hormonal parameters were not altered by 4 weeks of flutamide, except T in controls and E2 and FSH in PCOS patients, which were lower. Of note, flutamide alone had no effect on LH pulse frequency or amplitude, mean plasma LH, or LH responsiveness to exogenous GnRH. After the addition of E2 and P for 7 days, both PCOS patients and normal controls had similar reductions in LH pulse frequency (4.0+/-0.7 and 5.8+/-0.7 pulses/12 h, respectively). This contrasts with our earlier results in the absence of flutamide, where a plasma P level of less than 10 ng/mL had minimal effects on LH pulse frequency in women with PCOS, but was effective in controls. These results suggest that although the elevated LH pulse frequency in PCOS may in part reflect impaired sensitivity to E2 and P, continuing actions of hyperandrogenemia are important for sustaining the abnormal hypothalamic sensitivity to feedback inhibition by ovarian steroids.

17-alpha-Hydroxyprogesterone↗
PubMed2000

SIRS and MODS: what is their relevance to the science and practice of intensive care?

SIRS (the Systemic Inflammatory Response Syndrome) and MODS (the Multiple Organ Dysfunction Syndrome) are not diseases or syndromes, but concepts. Common to both is the notion that the morbidity of critical illness arises indirectly, from the response of the host to an acute, life-threatening challenge to systemic homeostasis. The biology of that response is complex and variable, yet implicit in our evolving understanding of systemic inflammation is the possibility that shared biologic mechanisms may permit the development of effective therapy for a wide variety of disorders that appear superficially heterogeneous. The challenge lies in characterizing common pathologic processes or diseases. The four criteria that define SIRS are non-specific measures of physiologic severity, rather than distinctive manifestations of a disease process. Perhaps the use of the systemic correlates of the cardinal manifestations of inflammation developed by Galen and Celsus would provide a more satisfactory clinical characterization of the clinical disorder. However, the complexity of the biologic processes involved suggest that a clinical syndrome of systemic inflammation is of no more use to the clinician than a clinical syndrome of cancer. As the functio laesa of systemic inflammation, organ dysfunction is more appropriately viewed as an undesireable outcome of systemic inflammation, a complication to be prevented, rather than a disease to be treated. As concepts, SIRS and MODS provide a useful intellectual framework for investigation, but the clinician must treat diseases, no acronyms. The challenge will be to characterize these disease.

Animals↗
PubMed1999

Regulation of Fas antibody induced neutrophil apoptosis is both caspase and mitochondrial dependent.

Resolution of neutrophil mediated inflammation is achieved, in part, through induction of neutrophil apoptosis. This constitutively expressed programme can be delayed by inflammatory mediators and induced by ligation of the Fas receptor. However, functional activation of the neutrophil results in resistance to Fas signalled death. We evaluated the effects of Fas antibody engagement on caspase activation and mitochondrial permeability, and the impact of co-stimulation by lipopolysaccharide (LPS) or granulocyte macrophage-colony stimulating factor (GM-CSF) on these events. Fas engagement by an agonistic anti-Fas antibody resulted in enhanced caspase 3 and 8 activity and increased mitochondrial permeability. Studies with pharmacological inhibitors of caspase activity showed that activation of caspase 8 occurred before, and activation of caspase 3 occurred after mitochondrial disruption. The mitochondrial stabilising agent bongkrekic acid also inhibited caspase activation and apoptosis. LPS, GM-CSF and increased glutathione stabilised the mitochondria and inhibited caspase 3. Caspase 8 activity was also inhibited by co-stimulation through a mechanism independent of mitochondrial stabilisation. Glutathione directly inhibited caspase 3 and 8 activity. We conclude inhibition of Fas antibody induced apoptosis by inflammatory proteins is associated with augmented mitochondrial stability and reduced caspase 3 activity that may be glutathione mediated.

Acetylcysteine↗
PubMed1999

Selective decontamination of the digestive tract in surgical patients: a systematic review of the evidence.

OBJECTIVE: To determine the comparative efficacy of selective decontamination of the digestive tract in critically ill surgical and medical patients, and in selected subgroups of surgical patients with pancreatitis, major burn injury, and those undergoing major elective surgery and transplantation. DATA SOURCES: The MEDLINE database was searched from January 1966 to December 1996 using the terms "decontamination or prophylaxis," "intensive care units," and "antibiotics." The search was limited to English-language studies evaluating the efficacy of selective decontamination of the digestive tract in human subjects. STUDY SELECTION: The primary review was restricted to prospective randomized trials. DATA EXTRACTION: End points of interest included rates of nosocomial pneumonia, bacteremia, urinary tract infection, wound infection, mortality, and length of intensive care unit stay. Methodologic quality of individual studies was assessed using a previously described model. DATA SYNTHESIS: Odds ratios (ORs) together with their (95% confidence interval [Cls]) were reported and determined using the Mantel-Haenszel method. Mortality was significantly reduced with the use of selective decontamination of the digestive tract in critically ill surgical patients (OR, 0.7, 95% CI, 0.52-0.93), while no such effect was demonstrated in critically ill medical patients (OR, 0.91; 95% CI, 0.71-1.18). The greatest effect was demonstrated in studies where both the topical and systemic components of the regimen were used. Rates of pneumonia were reduced in both subsets of patients, while those of bacteremia were significantly reduced only in surgical patients. CONCLUSIONS: Selective decontamination of the digestive tract notably reduces mortality in critically ill surgical patients, while critically ill medical patients derive no such benefit. These data suggest that the use of selective decontamination of the digestive tract should be limited to those populations in whom rates of nosocomial infection are high and in whom infection contributes notably to adverse outcome.

Antibiotic Prophylaxis↗
PubMed1999

Redox manipulation using the thiol-oxidizing agent diethyl maleate prevents hepatocellular necrosis and apoptosis in a rodent endotoxemia model.

Manipulation of the intracellular redox state has been shown to alter cell activation pathways with resultant changes in cellular function. Previous studies have suggested that thiol oxidation, using the glutathione-depleting agent diethyl maleate (DEM), was able to inhibit endothelial cell activation. We hypothesized that this agent might exert beneficial effects following endotoxemia in the rat, a model in which transendothelial migration of neutrophils is central to the development of hepatocellular injury. Sprague-Dawley rats treated intraperitoneally with lipopolysaccharide (LPS) (200 microg/kg) plus D-galactosamine (GalN) (600 mg/kg) developed hepatocellular necrosis, as evidenced by liver enzyme release and morphological changes. Pretreatment with DEM abrogated this injury in a dose-dependent fashion. Histology revealed reduced neutrophil accumulation in both the parenchyma and sinusoids, consistent with reduced neutrophil sequestration and transendothelial migration. This effect appeared to be related to the ability of DEM to prevent LPS-induced up-regulation of both vascular cell adhesion molecule-1 (VCAM-1) mRNA and intercellular adhesion molecule-1 (ICAM-1) mRNA in the liver, as well as reducing tumor necrosis factor (TNF) mRNA expression. In addition, DEM prevented hepatocyte apoptosis following LPS treatment. The effect was reproduced when TNF was used as an inflammatory stimulus, suggesting a direct protective effect on the hepatocyte. Taken together, these studies show that redox manipulation through thiol oxidation may represent a novel approach to preventing liver necrosis and apoptosis in inflammatory conditions.

Alanine Transaminase↗
PubMed1999

Maternal neutrophil apoptosis in normal pregnancy, preeclampsia, and normotensive intrauterine growth restriction.

OBJECTIVE: In normal pregnancy there is both a neutrophilia and a mild neutrophil activation. In preeclampsia both direct and indirect evidence supports further marked neutrophil activation. In the pathogenesis of preeclampsia peripheral blood neutrophils may play a vital role in communicating between the preeclamptic placenta and the maternal vascular endothelium and contribute to the endothelial cell dysfunction that characterizes the maternal syndrome of preeclampsia. Preeclampsia shares many elements with the systemic inflammatory response syndrome. Neutrophils, key effectors of the systemic inflammatory response syndrome, are associated with hepatic necrosis and adult respiratory distress syndrome, both of which most commonly kill women with preeclampsia. We hypothesized that delayed neutrophil apoptosis could explain (1) the neutrophilia of normal pregnancy and (2) the differential maternal responses to the shared placental abnormality of preeclampsia and normotensive intrauterine growth restriction. STUDY DESIGN: Neutrophils were isolated (dextran 500, Ficoll [Amersham Pharmacia Biotech AB, Uppsala, Sweden], and erythrocyte lysis) from (1) case patients with preeclampsia at </=34 weeks' gestation, (2) healthy pregnant control subjects, (3) case patients with normotensive intrauterine growth restriction at </=34 weeks' gestation, and (4) nonpregnant female control subjects. Apoptosis was determined after 18 hours of incubation (with or without endotoxin or anti-Fas monoclonal antibody) by deoxyribonucleic acid profile (propidium iodide study), annexin V binding, and CD16 expression. RESULTS: Compared with propidium iodide profile values in nonpregnant women (median, 25%; range, 14%-40%) neutrophil apoptosis was significantly delayed in normal pregnancy (median, 9.5%; range, 7.6%-15%) and normotensive pregnancy with intrauterine growth restriction (median, 11%; range. 9.3%-19%) and was further delayed in preeclampsia (median, 6.9%; range, 4.1%-8. 2%; P </=.005 vs normal pregnancy and normotensive intrauterine growth restriction). All neutrophils remained sensitive to endotoxin inhibition but were resistant to anti-Fas induction of apoptosis. Spontaneous neutrophil apoptosis decreased as gestational age increased (r (2) = 0.48). CONCLUSIONS: Impaired neutrophil apoptosis may explain the neutrophilia associated with normal pregnancy. In women with preeclampsia activated neutrophils remain in the circulation, perhaps contributing to the persistence of preeclampsia after delivery. Neutrophils appear to modulate the variation in maternal response between preeclampsia and normotensive intrauterine growth restriction.

Adult↗
PubMed1999

Hemispheric asymmetries in global/local processing are modulated by perceptual salience.

It has been claimed that a left hemisphere bias toward local and right hemisphere bias toward global visual processing can be explained in terms of specialization for relatively high and low spatial frequencies, respectively. Using non-representational figures, we tested this hypothesis in experiment 1 using positron emission tomography (PET) measures of cerebral activity in 10 normal volunteers. In each block of trials subjects viewed either a relatively high or a relatively low spatial frequency grating. The orientation (vertical or horizontal) of the grating changed from trial to trial. In a directed attention task, subjects reported the orientation of either the whole stimulus (globally directed attention) or the orientation of the component parts thereof (locally directed attention). A significant interaction between hierarchical processing level (global or local) and stimulus level (relatively high or relatively low spatial frequency within the absolute low spatial frequency range) was found. Globally directed attention led to significantly increased cerebral activity in the right hemisphere when relatively high spatial frequency stimuli were used but not when relatively low spatial frequency stimuli were used. Likewise, locally directed attention increased cerebral activity when low but not high spatial frequency stimuli were used. On the basis of these results we suggest that perceptual salience of the global or local form modulates hemispheric processing asymmetries in early visual cortex. In experiment 2, the perceptual salience of global form in relatively high spatial frequency stimuli and of local form in relatively low spatial frequency stimuli was confirmed in a reaction time (RT) study. In combination, the results of the two experiments suggest that perceptual salience takes precedence over spatial frequency (within the range studied here) in determining the cerebral organization of global/local processing.

Adult↗