Terminating nutrition and hydration from patients in persistent vegetative states

It can no longer reasonably be denied that potentiated remedies such as those used by homoeopaths can have profound effects on the health of human beings. A possible mechanism for the way in which these remedies influence a live biological mammalian system is presented.     

Patients in the persistent vegetative state: problems in their long term management

Physicians responsible for the long term management of patients in the persistent vegetative state face several problems. These include deciding whether tube feeding is treatment or nutritional care, whether withdrawal of tube feeding is an appropriate form of management, what clinical advantage there is in active treatment; at what level of awareness can a patient be said to have a quality of life; and who should determine a patient's right to die. These problems are determined more by social, legal, emotional, cultural, religious, and economic forces than by clinical facts.     

Detection of pro- and anti-inflammatory cytokines in stools of patients with inflammatory bowel disease

Astroglial cells protect neurons against oxidative damage. The antioxidant glutathione plays a pivotal role in the neuroprotective action of astroglial cells which is impaired following loss of glutathione. Anethole dithiolethione (ADT), a sulfur-containing compound which is used in humans as a secretagogue, increases glutathione levels in cultured astroglial cells under "physiological" conditions and is thought thereby to protect against oxidative damage. Presently, we report the effect of ADT (3-100 microM) on glutathione content of and efflux from rat primary astroglia-rich cultures under "pathological" conditions, i.e., extended deprivation of glucose and amino acids. Although cellular viability was not affected significantly, starvation of these cultures for 24 h in a bicarbonate buffer lacking glucose and amino acids led to a decrease in glutathione and protein content of approximately 43% and 40%, respectively. Although no effect on the protein loss occurred, the presence of ADT during starvation counteracted the starvation-induced loss of intracellular glutathione in a concentration-dependent way. At a concentration of 100 microM ADT even a significant increase in astroglial glutathione content was noted after 24 h of starvation. Alike intracellular glutathione levels, the amount of glutathione found in the buffer was elevated substantially if ADT was present during starvation. This ADT-mediated, apparent increase in glutathione efflux was additive to the stimulatory effect on extracellular glutathione levels of acivicin (100 microM), an inhibitor of extracellular enzymatic glutathione breakdown. However, the ADT-induced elevation of both intra- and extracellular glutathione content during starvation was prevented completely by coincubation with buthionine sulfoximine (10 microM), an inhibitor of glutathione synthesis. These results demonstrate that, most likely through stimulation of glutathione synthesis, ADT enables astroglial cells to maintain higher intra- and extracellular levels of glutathione under adverse conditions. Considering the lowered glutathione levels in neurodegenerative syndromes, we conclude that further evaluation of the therapeutic potential of the compound is warranted.     

Correlation of inflammatory cytokines with arthroscopic findings in patients with temporomandibular joint internal derangements

PURPOSE: The goal of this study was to evaluate the presence of the inflammatory cytokines interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) within the superior temporomandibular joint (TMJ) space in patients with internal derangements and to compare these values with the pathologic findings seen arthroscopically. PATIENTS AND METHODS: Thirty patients with symptomatic TMJ dysfunction and clinical and imaging evidence of internal derangements of the TMJ were evaluated. Before entering the superior joint space with the arthroscope, 2 mL sterile saline was injected and, after 30 seconds of equilibration, was aspirated for analysis. The surgeon then performed diagnostic arthroscopy. The degree of synovitis, degeneration, percent condylar roofing, and any pathologic changes, such as perforations, were recorded. The level of total protein in each sample was ascertained, as well as the levels of IL-1 beta, IL-6, and TNF-alpha. RESULTS: Of 30 samples tested, three were discarded because of failure to gain access into the superior joint space. Of the 27 remaining samples, IL-6 showed the closest correlation with the level of acute synovitis demonstrated arthroscopically. Two of the higher IL-6 levels (167 and 324 pg/microg protein) were seen with patients with a significant disc perforation. In patients with a high degree of vascularity, IL-6 was found to be between 0 to 581 pg/microg protein with an average of 80 pg/microg protein and a median value of 43 pg/mg. These values significantly correlated with the degree of vascularity (P < or = .02). This is in comparison with the 10 remaining patients, who showed significantly fewer vascular changes arthroscopically. In these patients, the range of IL-6 was 0 to 35 pg/microg protein, with an average of 19 pg/microg protein and a median value of 14.5 pg/microg. These values significantly correlated with the smaller degree of vascularity (P < or = .02). In seven patients, the role of nonsteroidal antiinflammatory drug (NSAID) use resulted in decreased levels of IL-6, which has been noted in previous studies. In patients with higher rated redundancy of the synovial tissue, the average IL-6 level was 92 pg/microg protein, whereas the median value was 44 pg/microg protein. In patients with little or no redundant synovial tissue, an average IL-6 level of 22 pg/microg protein was present. The median value in these same joints was 15 pg/microg protein. These IL-6 values significantly correlated with the degree of redundancy (P < or = .03). The degree of degenerative change (chondromalacia, fibrillation), disc displacement (roofing), and the presence or absence of adhesions did not significantly affect the levels of IL-6 within the patients studied. The presence of IL-1 beta and TNF-alpha was not found to correlate with the arthroscopic findings in the superior joint space. CONCLUSIONS: The presence of IL-6 correlated with the degree of acute synovitis. IL-1 beta and TNF-alpha were not found in significant levels within the superior joint space. These findings correlated with those reported by other investigators. The production of IL-6 by synovial cells and its role in TMJ disease warrants further investigation.     

Hematolymphopoietic and inflammatory cytokines in neural development

It is now clear that cytokines traditionally viewed as immune modulators participate in inflammatory responses within the adult nervous system. However, in the developing nervous system hematolymphopoietic cytokines also play a role unrelated to neural-immune interactions. Instead, many of these factors subserve primary regulatory functions related both to the morphogenesis and to the cellular maturation of the central and peripheral nervous systems. This article focuses specifically on cytokine actions in neural development.     

Network of inflammatory cytokines and correlation with disease activity in ulcerative colitis

OBJECTIVE: The inflammatory component of most human inflammatory chronic diseases implicates the production of proinflammatory cytokines. Tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL1beta) seem to play an important role in ulcerative colitis (UC) in relevant experimental models. Moreover, antiTNF therapy seems promising experimentally and clinically. However, these cytokines, and TNFalpha more particularly, are hardly seen in vivo in such patients. The mediators of choice, correlated with disease activities or drug efficacy, remain unclear. To characterize in vivo the network of colonic cytokines in patients with UC, and the contribution of the various cytokines to disease activity we performed this study, using the colonic perfusion method. METHODS: A 20-cm colon length was perfused. Perfusate samples were collected for cytokine determination by enzyme-linked immnoassays. Nineteen perfusions were performed in mild to moderate UC, including two successive perfusions in four patients. Six healthy control patients and four having Crohn's disease (CD) with rectal involvement were studied. Endoscopic score, leukocyte scintigraphy, and systemic markers of inflammation were simultaneously quantified. RESULTS: Large amounts of IL1beta, TNFalpha, IL6, and IL8 were produced in UC patients with a highly significant correlation between TNFalpha, IL1beta and IL8 two by two. Multivariate factorial analysis indicated that IL1beta showed the best correlation with disease activity. Locally produced IL6 was strongly associated with circulating platelet counts. Moreover, production of inflammatory cytokines was associated with similar variations of disease activity in the four patients with two successive perfusions performed. The level of inflammatory cytokines in CD was lower than in UC; TNFalpha, IL1beta, and IL6 were not found in any control patients. CONCLUSION: UC appears to be a chronic inflammatory disease characterized by high production of all four proinflammatory cytokines (IL1beta, TNFalpha, IL6, and IL8). These results suggest that colonic perfusion may be a suitable method to evaluate the local anticytokine properties of new drugs, in correlation with disease activity and systemic markers of inflammation.     

Synergistic effect of immunoregulatory cytokines on peripheral blood monocytes from patients with inflammatory bowel disease

Active inflammatory bowel disease (IBD) is characterized by increased monocyte secretion of proinflammatory cytokines. Immunoregulatory cytokines such as Interleukin (IL)-4, IL-10, and IL-13 are capable of inhibiting the proinflammatory cytokine response of activated monocytes. The aim of our study was to determine the effect of different antiinflammatory cytokines under various culture conditions and to evaluate combinations of antiinflammatory cytokines in down-regulating monocyte response in IBD. Peripheral monocytes from patients with active IBD were isolated and stimulated with pokeweed mitogen (PWM). IL-4, IL-10, IL-13 and a combination of IL-4/IL-10 and IL-10/IL-13 were added at different concentrations and different times. Secretion of IL-1beta and TNF-alpha was assessed using sandwich ELISA systems. There was a diminished down-regulation of TNF-alpha by IL-4 and IL-13 in IBD when the cytokines were added at the time of stimulation, while there was a significantly higher down-regulation when monocytes were primed with these Th-2 cytokines 24 hr before activation. IL-10 plus IL-4 and IL-10 plus IL-13, respectively, inhibited the proinflammatory cytokine response of monocytes as well as matured macrophages much more than IL-4, IL-10, or IL-13 alone. Even at suboptimal concentrations for each cytokine alone, a combination of cytokines showed synergistic inhibitory effects. In summary, a combination of antiinflammatory cytokines is more effective in down-regulating the response of activated monocytes than using the cytokines alone and thus may have a potential therapeutic benefit for patients with IBD.     

Medical, juridical and ethical problems in permanent vegetative state

Except in the United Kingdom, there are no epidemiological data on permanent vegetative state in Europe over the last 12 years. Transposing the British (and Japanese) data to Switzerland with a population of 7 million, an annual incidence of some 70 cases can be expected and a prevalence of about 200-350 cases. The ethics committees of a number of Anglo-American societies specialized in the field postulate the ending of life-sustaining measures if the diagnosis of permanent vegetative state is definitely established. The medical, legal and ethical grounds for such a postulate are summarized.     

Circulating intercellular adhesion molecule-1 in the sera of patients with systemic sclerosis: enhancement by inflammatory cytokines

We measured serum levels of circulating intercellular adhesion molecule-1 (cICAM-1) in patients with systemic sclerosis (SSc) and normal controls. The levels of cICAM-1 were determined by sandwich enzyme-linked immunosorbent assay in sera from 88 patients with SSc and in 20 healthy controls. In addition, these levels were examined in the supernatants of cultured peripheral blood mononuclear cells (PBMC) and dermal fibroblasts from 10 patients with SSc and 10 healthy control subjects. Serum levels of cICAM-1 were significantly higher in patients with SSc than in healthy controls. Serum cICAM-1 levels were significantly higher in patients with diffuse cutaneous SSc (dcSSc) than in patients with limited cutaneous SSc (lcSSc). These serum levels were correlated with the presence of contracture of phalanges, pulmonary fibrosis, joint involvement and increased erythrocyte sedimentation rate. The release of cICAM-1 was significantly increased in the supernatants of cultured PBMC from patients with SSc. Moreover, inflammatory cytokines (interferon-gamma, interleukin-1 and tumor necrosis factor-alpha) enhanced the release of cICAM-1 in vitro in SSc cells. These findings suggest that cICAM-1 may be involved in immune reactions in this disease.     

Increased intracellular Th1 cytokines in scid mice with inflammatory bowel disease

Severe combined immunodeficient (scid) mice engrafted with small pieces of full thickness gut wall from immunocompetent syngenic donors develop a chronic and lethal colitis. Lymphocytes from the lamina propria of engrafted mice were analyzed for phorbol ester/ionomycin-induced cytokine production by intracellular staining. A 4-5-fold increase in the fraction of IFN-gamma-producing CD4+ lamina propria T cells was found in moderately and severely diseased mice when compared to healthy congenic C.B-17 control mice. The number of IL-2-producing T cells was increased by approximately 2-fold when comparing mice suffering from severe disease to healthy control mice. The fraction of TNF-alpha positive CD4+ T cells was increased by a factor of two in both moderately and severely diseased mice. When analyzing Th2 cytokines, it was found that the levels of IL-4-producing CD4+ T cells was not altered in diseased animals, whereas the fraction IL-10-producing CD4+ T cells was reduced by a factor of 20. The combined data showed a 15-25-fold increase in the Th1/Th2 ratio of diseased mice when compared to healthy control mice. No intracellular cytokines could be detected in lymphocytes not treated with phorbol ester/ionomycin. The present data identify a prominent role for Th1-type T helper cells in the immunopathogenesis of gut wall graft-induced inflammatory bowel disease in scid mice.     

Elevation of platelet activating factor, inflammatory cytokines, and coagulation factors in the internal jugular vein of patients with subarachnoid hemorrhage

The hemodynamic responses to acute (45 min) partial aortic constriction were studied in conscious intact (N = 7) or sinoaortic denervated (SAD) adult male Wistar rats (280-350 g, N = 7) implanted with carotid and femoral arterial catheters, a pneumatic cuff around the abdominal aorta and a pulsed Doppler flow probe to measure changes in aortic resistance. In addition, the hypertensive response and the reflex bradycardia elicited by total (N = 8) vs partial (N = 7) aortic constriction (monitored by maintenance of the pressure distal to the cuff at 50 mmHg) were compared in two other groups of intact rats. Intact rats presented a smaller hypertensive response (26 to 40% above basal level) to partial aortic constriction than SAD rats (38 to 58%). The calculated change in aortic resistance imposed by constriction of the aorta increased progressively only in intact rats, but was significantly smaller (193 to 306%) than that observed (501 to 591%) in SAD rats. Intact rats showed a significant bradycardia (23 to 26% change in basal heart rate) throughout coarctation, whereas the SAD rats did not (1 to 3%). Partial or total occlusion of the aorta induced similar hypertensive responses (37-38% vs 24-30% for total constriction) as well as reflex bradycardia (-15 to -17% vs -22 to -33%) despite a greater gradient in pressure (97-98 vs 129-140 mmHg) caused by total constriction. The present data indicate that the integrity of the baroreflex in intact rats can cause the hypertensive response to level off at a lower value than in SAD rats despite a progressive increase in aortic resistance. In addition, they also indicate that the degree of partial aortic constriction by maintenance of the pressure distal to the cuff at 50 mmHg already elicits a maximal stimulation of the arterial baroreflex.     

New developments in the role of cytokines and chemokines in inflammatory myopathies

Humans are readily able to distinguish expected and unexpected sensory events. Whether a single mechanism underlies this ability is unknown. The most common type of expected sensory events are those generated as a consequence of self-generated actions. Using H2 15O PET, we studied brain responses to such predictable sensory events (tones) and to similar unpredictable events and especially how the processing of predictable sensory events is modified by the context of a causative self-generated action. Increases in activity when the tones were unpredictable were seen in the inferior and superior temporal lobe bilaterally, the right parahippocampal gyrus and right parietal cortex. Self-generated actions produced activity in a number of motor and premotor areas, including dorsolateral prefrontal cortex. We observed an interaction between the predictability of stimuli and self-generated actions in several areas, including the medial posterior cingulate cortex, left insula, dorsomedial thalamus, superior colliculus and right inferior temporal cortex. This modulation of activity associated with stimulus predictability in the context of self-generated actions implies that these areas may be involved in self-monitoring processes. Detection of expected stimuli and the detection of the sensory consequences of self-generated actions appear to be functionally distinct processes, and are carried out in different cortical areas. These observations support theoretical approaches to cognition that postulate the existence of a self-monitoring system.