A vaccine against Asian schistosomiasis: the story unfolds

The development of an effective vaccine against the Asian schistosome is at a critical stage. Despite the fact that progress has been relatively slow, the successful use in animals of attenuated vaccines combined with recent encouraging results using defined native and recombinantly derived Schistosoma japonicum antigens, suggests that development of a safe and effective vaccine is feasible. This review examines current progress aimed at achieving this objective, and a summary is provided of recent results obtained with the most encouraging vaccine antigens. When available for wide-scale use, it is envisaged that the vaccine would be applied in the first instance, at least in China, in the veterinary context (to impact on human transmission) and then, perhaps, if required, clinically (to prevent or reduce disease). The search for the final product is likely to be demanding, and funding issues pertaining to Good Manufacturing Practice-scale-up of the vaccine for the required extensive veterinary coverage, and to support any future human trials, will need to be resolved. As such, we may still have to wait some time before the ultimate vaccine, possibly comprising a cocktail of several molecules, is available. Even then, the vaccine would probably be used optimally as one component of an integrated programme of schistosomiasis control that would include effective and well-tested approaches, such as health education and targeted chemotherapy.     

The cardiokine story unfolds: ischemic stress-induced protein secretion in the heart

Intercellular communication depends on many factors, including proteins released via the classical or non-classical secretory pathways, many of which must be properly folded to be functional. Owing to their adverse effects on the secretion machinery, stresses such as ischemia can impair the folding of secreted proteins. Paradoxically, cells rely on secreted proteins to mount a response designed to resist stress-induced damage. This review examines this paradox using proteins secreted from the heart, cardiokines, as examples, and focuses on how the ischemic heart maintains or even increases the release of select cardiokines that regulate important cellular processes in the heart, including excitation-contraction coupling, hypertrophic growth, myocardial remodeling and stem cell function, in ways that moderate ischemic damage and enhance cardiac repair.     

Craniosynostosis genetics: The mystery unfolds

Craniosynsostosis syndromes exhibit considerable phenotypic and genetic heterogeneity. Sagittal synostosis is common form of isolated craniosynostosis. The sutures involved, the shape of the skull and associated malformations give a clue to the specific diagnosis. Crouzon syndrome is one of the most common of the craniosynostosis syndromes. Apert syndrome accounts for 4.5% of all craniosynostoses and is one of the most serious of these syndromes. Most syndromic craniosynostosis require multidisciplinary management. The following review provides a brief appraisal of the various genes involved in craniosynostosis syndromes, and an approach to diagnosis and genetic counseling.     

The effective duration of the delay phenomenon in the rat.

In standard skin flaps in the rat, the effect of a delay was undetectable for the first 3 weeks and the maximum benefit was not apparent until the sixth week. At all time intervals the delay phenomenon was not as pronounced in the rat as in other species. The delay phenomenon in the rat lasts at least 30 weeks. The rat does not appear to be an ideal model for the study of skin flaps.     

Denervation supersensitivity and the delay phenomenon.

We have reviewed the denervation supersensitivity-AV shunt hypothesis (explaining the delay phenomenon) and assessed the contribution of each of the two components of denervation supersensitivy to delay. We concluded that adrenergic denervation supersensitivity contributes little to the delay phenomenon. We propose a new hypothesis, based on the effects of prolonged vascular smooth muscle relaxation in the precapillary arterioles, to explain the delay phenomenon.     

An anatomic review of the delay phenomenon: II. Clinical applications.

This paper applies the anatomic concepts and data obtained from our animal experimental studies of the delay phenomenon to a series of clinical cases. Similar clinical results were obtained to those seen in Part I of our study when skin flaps were raised with and without a delay, when a tissue expander was used, and when the delay technique was extended to musculocutaneous flaps. In each instance, the cutaneous perforators were identified with the Doppler probe to facilitate the delay of specific vessels rather than dividing those at random. Intraoperative arteriograms and venograms reveal that the choke arteries dilate and the anatomically unfavorable valved vein segments become regurgitant. The end result is the observation that at least one additional anatomic vascular territory can be added to the length of a flap with safety following a surgical delay.     

Mitochondrial stress signaling: a pathway unfolds

Disruption of protein homeostasis in mitochondria elicits a cellular response, which upregulates mitochondrial chaperones and other factors that serve to remodel the mitochondrial-folding environment. In a recent study, Haynes and colleagues uncovered a novel signal transduction pathway underlying this process. The upstream mitochondrial component of this pathway is an orthologue of Escherichia coli ClpP, which functions in the bacterial heat-shock response. These findings suggest that molecular aspects of stress sensing might be conserved between bacteria and mitochondria.     

Mechanism of the delay phenomenon: tissue protection is mediated by heme oxygenase-1

Induction of the "delay phenomenon" by chronic ischemia is an established clinical procedure, but the mechanisms conferring tissue protection are still incompletely understood. To elucidate the role of heme oxygenase-1 [HO-1 or heat shock protein-32 (HSP-32)] in delay, we examined in the skin-flap model of the ear of the hairless mouse, 1) whether chronic ischemia (delay) is capable to induce expression of HO-1, and 2) whether delay-induced HO-1 affects skin-flap microcirculation and survival by either its carbon monoxide-associated vasodilatory action or its biliverdin-associated anti-oxidative mechanism. Chronic ischemia was induced by transsection of the central feeding vessel of the ear 7 days before flap creation. The flap was finally raised by an incision through four-fifths of the base of the ear. Microcirculatory dysfunction and tissue necrosis were studied with the use of laser Doppler fluxmetry and intravital fluorescence microscopy. HO-1 protein expression was determined with Western blot analysis. Seven days of chronic ischemia (delay) induced a marked expression of HO-1. This was paralleled by a significant improvement (P <0.05) of microvascular perfusion and a reduction (P <0.05) of flap necrosis when compared with nondelayed controls. Importantly, blockade of HO-1 activity by tin protoporhyrin-IX completely blunted the protection of microcirculation and the improvement of tissue survival. Additional administration of the vitamin E analog trolox after blockade of HO-1 to mimic exclusively the anti-oxidative action of the heat shock protein did not restore the HO-1-associated microcirculatory improvement and only transiently attenuated the manifestation of flap necrosis. Thus our data indicate that the delay-induced protection from tissue necrosis is mediated by HO-1, predominantly through its carbon monoxide-associated action of adequately maintaining nutritive capillary perfusion.     

Ablastin: The phenomenon

A brief report is made of a conference held on the subject of ablastic immunity. Included are the background of the meeting, its organization, and its purpose, which was to summarize our knowledge of the subject and to consider future research plans. A list of some of the research problems discussed by the participants and possible experimental approaches for their resolution are presented. The report also serves as an introduction to a series of papers by the participants of the conference published concurrently.     

Study of the delay phenomenon in axial pattern flaps in pigs.

A technique, using radioactively-tagged microspheres to measure the blood flow in delayed axial pattern flaps in the pig, is presented. The blood flow was significantly (p less than 0.01) increased in the delayed portion of these flaps, reaching maximal levels after 4 to 12 days of delay. Also, the blood flow to these flaps correlated with tissue survival during the first week after the delay (p less than 0.001).     

Tissue oxygen measurements in delayed skin flaps: a reconsideration of the mechanisms of the delay phenomenon

The delay phenomenon was studied by measuring tissue oxygen tension (PsqO2) for 3 weeks in delayed flaps and normal adjacent contralateral skin in seven mongrel dogs. The PsqO2 fell after elevation of a bipedicle flap and rose again to normal by day 14. Delivery of oxygen to this flap was improved by surgical delay, so that when the bipedicle flap was reelevated on day 14 and its distal pedicle divided, minimal changes in PsqO2 occurred. When the control area was elevated on day 14 as a random-pattern flap, it had higher PsqO2 values than measured in the bipedicle flap on day 0, and therefore, it too had participated in the delay phenomenon, even though only its midline edge had been incised. An anatomic explanation for the findings was sought in wounds made in 10 rabbit ear chambers. After injury, blood flow was seen to be rerouted parallel to the incision line and was increased first by vasodilation and then also by angiogenesis until about day 14. Rerouting of blood by injury, inflammation, and angiogenesis due to repair appears to account for a significant portion of the delay phenomenon.