Structural features are as important as sequence homologies inDrosophila heat shock gene upstream regions

Summary Pelham has shown that theDrosophila hsp 70 gene is not transcribed under heat shock conditions unless a given upstream region is present. Davidson et al. have recently compiled a list of sequences homologous to this region in otherDrosophila heat shock genes. They proposed that a set of unlinked genes, such as the heat shock genes, could be coordinately induced through an interaction in cis with a common regulatory molecule. That this interaction involves structural elements is suggested by the fact that these upstream regions share inverted repeats as well as areas of Z-DNA potential. Furthermore, using the Calladine-Dickerson rules for local helical parameters, we show that these regions share structural homology. This is significant because the presence of regions homologous to a derived consensus sequence does not necessarily imply structural similarity. Therefore, we suggest that these structural features are at least as important as the sequence homologies in enabling the heat shock response.     

Toxic shock syndrome following breast and nasal surgery

Toxic shock syndrome is a rapidly developing disease which may be lethal if not recognized and treated early. While this disease is usually associated with menstruating females, it is being seen in both male and female patients following clean, elective surgery. Toxic shock syndrome has been reported following surgical procedures which normally have a very low incidence of postoperative wound infections. Toxic shock syndrome is associated with Staphylococcus aureus bacteria which produce the toxic shock syndrome toxin 1. Three patients with postoperative toxic shock syndrome, of varying degrees of severity, are presented. Prompt institution of resuscitative and therapeutic measures can prevent the potentially fatal outcome of this postoperative complication.     

TREATMENT OF ENDOTOXIC SHOCK—The Dilemma of Vasopressor and Vasodilator Therapy

Hemodynamic studies have demonstrated that the fall of blood pressure in shock caused by endotoxin in dogs does not result primarily from dilatation or “vasomotor collapse.” Indeed, vasoconstriction is increased and may be excessive. Progression of shock has recently been blamed on such excessive vasoconstriction. For this reason the use of sympathomimetic drugs as vasopressor agents has been challenged and sympatholytic or adrenolytic agents have been recommended.In the present study, vasopressor and vasodilator drugs were used for the treatment of shock in dogs caused by endotoxin. Vasodilator drugs, when used after the onset of shock, hastened a fatal outcome but vasopressor agents were not detrimental when used in moderate doses.The effectiveness of the vasopressor agent is not necessarily due to a primary vasoconstrictor action on arteries and arterioles, as previously assumed.     

Selective transport of staphylococcal enterotoxin A through in vitro generated human M cells

Staphylococcal enterotoxins are responsible for food poisoning and toxic shock syndrome due to their superantigen activity on T cells. Although their activity necessarily involves passage through the intestinal epithelium, little is known about this critical step. In the present study, we compared the in vitro transport of staphylococcal enterotoxin A through human intestinal absorptive and M cells. We found that the transport of the toxin through M cells was polarized and temperature-sensitive, in contrast with the less efficient transport of the toxin by absorptive cells. These data suggest the involvement of M cells in the intestinal absorption of staphylococcal enterotoxins.     

Gene expression pattern in human monocytes as a surrogate marker for systemic inflammatory response syndrome (SIRS).

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is a mild inflammatory episode which, in a minority of patients, may deteriorate into septic shock. In the mouse, injection of bacteria or bacterial endotoxin induces systemic inflammation through the activation of blood monocytes, which leads to lethal shock. A number of intervention strategies have been shown to prevent progression to shock in mouse model systems. However, recent clinical trials of a number of these therapeutic strategies in patients have been uniformly disappointing. In contrast to the situation in the mouse models, there may be many different ways to initiate systemic inflammation in patients and not all of them need necessarily involve activation of blood monocytes. If there is no unifying mechanism behind the induction of systemic inflammation in patients and no common rules governing its development, then it is unlikely that generally applicable therapeutic strategies will be found that can prevent progression into shock. MATERIALS AND METHODS: We used differential display to compare gene expression patterns in monocytes of recent-admission multi-trauma patients with clinically diagnosed SIRS to the patterns in monocytes of healthy controls. RESULTS: Of seven differentially displayed bands that were recovered and sequenced, five were associated with SIRS and two were preferentially expressed in the monocytes of healthy controls. CONCLUSION: The data show that monocytes of SIRS patients are in an activation state that is different from that of monocytes from the healthy controls, that monocytes from many individual patients share similar patterns of differentially expressed sequences, and that by this criterion, the multi-trauma SIRS patients are a remarkably coherent group.     

Heat shock proteins in health and disease: therapeutic targets or therapeutic agents?

For many years, heat shock or stress proteins have been regarded as intracellular molecules that have a range of housekeeping and cytoprotective functions, only being released into the extracellular environment in pathological situations such as necrotic cell death. However, evidence is now accumulating to indicate that, under certain circumstances, these proteins can be released from cells in the absence of cellular necrosis, and that extracellular heat shock proteins have a range of immunoregulatory activities. The capacity of heat shock proteins to induce pro-inflammatory responses, together with the phylogenetic similarity between prokaryotic and eukaryotic heat shock proteins, has led to the proposition that these proteins provide a link between infection and autoimmune disease. Indeed, both elevated levels of antibodies to heat shock proteins and an enhanced immune reactivity to heat shock proteins have been noted in a variety of pathogenic disease states. However, further evaluation of heat shock protein reactivity in autoimmune disease and after transplantation has shown that, rather than promoting disease, reactivity to self-heat shock proteins can downregulate the disease process. It might be that self-reactivity to heat shock proteins is a physiological response that regulates the development and progression of pro-inflammatory immunity to these ubiquitously expressed molecules. The evolving evidence that heat shock proteins are present in the extracellular environment, that reactivity to heat shock proteins does not necessarily reflect adverse, pro-inflammatory responses and that the promotion of reactivity to self-heat shock proteins can downregulate pathogenic processes all suggest a potential role for heat shock proteins as therapeutic agents, rather than as therapeutic targets.     

Shock: the essentials of recognition and management

The main types of shock seen in clinical practice are discussed with emphasis on practical management considerations. The clinical features of the shock syndrome are described and the underlying cause is explained for each of the three types commonly encountered, namely hypovolemic, cardiac and septic shock. The essential information required for diagnosis and monitoring of therapy is detailed and appropriate therapy for each of the principal types of shock is discussed. The possible etiological factors, manifestations and therapy of the enigmatic respiratory distress syndrome are discussed. Some of the controversies on the drug therapy of shock are outlined and the suggestion is made that commonsense measures should prevail until reliable evidence to settle the disputes becomes available.     

Plasma levels of F-actin and F:G-actin ratio as potential new biomarkers in patients with septic shock

Objective: To compare plasma levels of F-actin, G-actin and thymosin beta 4 (TB4) in humans with septic shock, noninfectious systemic inflammatory response syndrome (SIRS) and healthy controls.

Results: F-actin was significantly elevated in septic shock as compared with noninfectious SIRS and healthy controls. G-actin levels were greatest in the noninfectious SIRS group but significantly elevated in septic shock as compared with healthy controls. TB4 was not detectable in the septic shock or noninfectious SIRS group above the assay’s lowest detection range (78?ng/ml).

Conclusions: F-actin is significantly elevated in patients with septic shock as compared with noninfectious SIRS. F-actin and the F:G-actin ratio are potential biomarkers for the diagnosis of septic shock.     

TREATMENT OF THE NEPHROTIC SYNDROME

The nephrotic syndrome may be due to varied cause. It may end fatally or in complete healing. No specific cure exists as yet, and basic treatment is dietary. The degree of edema does not necessarily hold a direct relationship to the status of the kidneys or to the eventual outcome.     

Inflammatory peptides derived from adipose tissue

The low-grade inflammation seen with aging is noted particularly in subjects with the metabolic syndrome of aging. Insulin resistance, obesity/abdominal obesity, and risks for many age-related diseases characterize this common syndrome. It is becoming clear that this increased adipose tissue is not simply a reservoir for excess nutrients, but rather an active and dynamic organ capable of expressing several cytokines and other fat-derived peptides (FDP). Some, but not all, FDP may have a role in development of the metabolic syndrome but there is no evidence that these FDP are causing inflammation directly. We suggest that high levels of inflammatory peptides are markers for obesity/abdominal obesity seen with aging, but some may not necessarily have a causative role in the development of inflammation.     

Toxic shock syndrome in a patient with systemic lupus erythematosus.

A case is presented of toxic shock syndrome in a patient with systemic lupus erythematosus. Toxic shock syndrome is rarely reported in patients who are immunosuppressed, perhaps because such patients are often treated vigorously with antibiotics at the earliest sign of infection. The association in this case may have been coincidental.     

Construction of Saccharomyces cerevisiae strains that accumulate relatively low concentrations of trehalose, and their application in testing the contribution of the disaccharide to stress tolerance

Genetically related diploid strains of Saccharomyces cerevisiae that accumulate varied amounts of trehalose during starvation for nitrogen have been constructed. Strains that produced greater than 5% trehalose (dry cell weight) were more tolerant of thermal, or freeze-thaw stresses than strains that produced less than 4% trehalose. Thus trehalose appears to play a role in stress tolerance of yeast. The significance of these results is that, for the first time, a series of related, unmutated strains have been used to test the effect of trehalose on thermotolerance. Previous studies employed either heat shock treatment, or mutated strains to provide trehalose variations, and as such the contribution of the disaccharide to stress tolerance could not necessarily be separated from other factors such as heat shock proteins.     

Heat shock-induced, caspase-3-independent rapid breakdown of Akt and consequent alteration of its total phosphorylation/activity level

The immediate effect of a 15-min heat shock was examined on the level and the activity of Akt. Following heat shock, the Akt level decreased by 15-70% in a temperature-dependent and phosphorylation status-independent manner. This decrease of Akt level was not prevented by caspase inhibitors. At 48 degrees C, the extent of the breakdown was so immense that the total phosphorylation/activity level of Akt was not increased over the control level, implying that the total cellular activity of Akt governed by the level and the molar activity does not necessarily undergo the ensuing change.     

Acute respiratory distress in diabetic ketoacidosis: possible contribution of low colloid osmotic pressure.

The "shock lung" syndrome may occur in diabetic ketoacidosis in association with disseminated intravascular coagulation; occasionally it occurs alone after treatment of the ketoacidosis. Two patients developed pulmonary opacities with clinical features of acute respiratory distress such as are seen in the shock lung syndrome; in both, however, the findings suggested a different mechanism from that occurring in the syndrome. Hypoalbuminaemia was prominent, and it is postulated that a low plasma osmotic pressure caused by high volume crystalloid infusions may have precipitated the acute respiratory complications. Plasma osmotic pressure may be an important variable in patients given large volumes of crystalloid infusions; further studies are required to elucidate mechanisms of pulmonary oedema in such patients.     

Translational inhibition of heat-shock induced gene expression in picornavirus-infected Drosophila melanogaster cells

Picornavirus infection of Drosophila melanogaster cells inhibited the appearance of heat-shock induced proteins. Examination of intracellular mRNAs revealed that those coding for heat shock proteins were present in a translationally competent form in infected cells. Inhibition of induced gene expression in infected Drosophila cells therefore involves, but is not necessarily solely mediated by, effects at the level of translation.     

The critical segment for the Langer-Giedion syndrome: 8q24.11----q24.12

An 18-year-old intellectually normal male with characteristic features of the Langer-Giedion syndrome is reported. High resolution chromosome analysis showed a small deletion in the region of bands 8q24.11 and 8q24.12 in addition to an apparently balanced de novo translocation (2;9)(q21;q13). This finding provides additional information on the minimum deleted segment required to produce the Langer-Giedion syndrome and may indicate that deletions of this size or smaller are not necessarily associated with mental retardation.     

Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects

Pharmacological up-regulation of heat shock proteins (hsps) rescues motoneurons from cell death in a mouse model of amyotrophic lateral sclerosis. However, the relationship between increased hsp expression and neuronal survival is not straightforward. Here we examined the effects of two pharmacological agents that induce the heat shock response via activation of HSF-1, on stressed primary motoneurons in culture. Although both arimoclomol and celastrol induced the expression of Hsp70, their effects on primary motoneurons in culture were significantly different. Whereas arimoclomol had survival-promoting effects, rescuing motoneurons from staurosporin and H₂O₂ induced apoptosis, celastrol not only failed to protect stressed motoneurons from apoptosis under same experimental conditions, but was neurotoxic and induced neuronal death. Immunostaining of celastrol-treated cultures for hsp70 and activated caspase-3 revealed that celastrol treatment activates both the heat shock response and the apoptotic cell death cascade. These results indicate that not all agents that activate the heat shock response will necessarily be neuroprotective.