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Digital ulcers (DU) are a common manifestation of systemic sclerosis (SSc) and occur at a variety of locations including the fingertips and over the extensor aspects of the hands. However, most recent clinical trials have included only fingertip DUs as these are believed to be ischaemic in aetiology, and therefore likely to benefit from treatment with vasoactive drug therapies. There is an emerging evidence base to suggest that all DUs in SSc could share an ischaemic component which is potentially responsive to vascular therapy. Our hypothesis is that is that DUs occurring at sites other than the fingertips, in particular, those overlying the extensor aspect of the hands, may also have a potentially reversible ischaemic component. We review the evidence under the headings: 'microvascular imaging', 'structural microvascular' and, 'functional vascular disease', 'macrovascular involvement' and 'vascular associates'. Based upon the current evidence, we would encourage the expert SSc community to reconsider the rationale for including only fingertip DUs in future SSc clinical trials, and suggest an agenda for future research.

Summary A 7-day reduction in duration of common colds was shown by Eby et al. in 1984 using 23 mg zinc gluconate throat lozenges. Over the following 25 years, 14 double-blind, placebo-controlled, randomized clinical trials produced widely differing results with about one-half showing success and the remainder showing failure. Positively charged, ionic zinc (iZn), but not bound zinc, is strongly astringent, antirhinoviral, increases interferon-gamma (IFN-γ) 10-fold, inhibits intercellular adhesion molecule-1 (ICAM-1) and inhibits the release of vasoactive ingredients from mast cell granules. Solution equilibrium chemistry analytical techniques showed lozenge iZn fraction varying from 0% to 100% of total lozenge zinc between trials, with zinc acetate (ZA) releasing 100% iZn, zinc gluconate (ZG) releasing 72% iZn and other zinc compounds releasing much less or none at physiologic pH 7.4. Since only iZn has in vitro benefits, iZn variations are hypothesized to have produced the widely varying clinical results. In support of the iZn hypothesis, lozenge iZn and total daily iZn in trials were found highly correlated with reductions in common cold durations with statistical significance for mean duration (P

Neurogenic pulmonary edema is an acute life-threatening complication following central nervous system injury. The exact pathogenic mechanism leading to its development is still unclear. We introduce a new hypothesis that high levels of anesthesia might protect the organism against the development of neurogenic pulmonary edema due to a more pronounced inhibition of the hypothalamic, brainstem and spinal vasoactive sympathetic centers. On the basis of a more pronounced neuronal inhibition of the vasoactive centers, a severe sympathetic discharge does not occur and neurogenic pulmonary edema does not develop. In contrast, an insufficient anesthesia level is not able to inhibit the sympathetic nervous system during an injury of the central nervous system and thus neurogenic pulmonary edema develops. During experiments with central nervous system injury, low-anesthesia-induced neurogenic pulmonary edema might negatively influence the overall recovery of the animal. More importantly, during a neurosurgical intervention, insufficient anesthesia might similarly lead to neurogenic pulmonary edema development in operated patients. Our hypothesis indicates the necessity of precisely monitoring of the level anesthesia during experimental manipulations of the central nervous system in animals or neurosurgical interventions in humans.

Immune cell cytokines are proposed as the common mediators of headache. This unifying concept can not only account for headache, but also the prostaglandins, leukotrienes, platelet activating and vasoactive substances linked with headache, the varied symptoms associated with headache and the high incidence of headache with depression, infectious disease, trauma and in premenopausal women. The immune system as the central mediator of headache is consistent with the promoting effect of estrogen, the abortive activity of cortisol and the prophylactic properties of fish oil and evening primrose oil. This hypothesis provides a unified mechanism to explain headache triggered by food, infectious disease or trauma.

Platelets have long been implicated in the aetiology of cerebral vasospasm (CV) after subarachnoid haemorrhage (SAH). It was noticed that vasospastic CSF (CSF V ) could be formed in vitro by the mixing of control blood (with platelets) and non-SAH CSF. We also propose a hypothesis for the aetiology of CV after SAH based on this and previous research. This study also aims to determine which blood fraction is responsible for the stimulation of O 2 consumption and vasospasm of blood vessels. Control blood was separated into various fractions and mixed with non-SAH CSF. The activity of the resulting mixture and the blood fraction alone were assessed. Only the fractions containing platelets mixed with CSF showed vasoactivity. These data suggest that platelets plus some component in the CSF produce vasoactive factors with actions similar to CSF V . This study may help to elucidate the aetiology of CV after SAH.

Melatonin has been proposed as a treatment for tinnitus, especially on the basis of its favourable effects on sleep and its vasoactive and antioxidant properties. However, to our knowledge no attempts of interpretation have been advanced through a detailed analysis of the various specific properties of melatonin possibly cooperating in a coincidental way to relieve tinnitus: among these, its modulatory effect on central nervous system resulting in a protective mechanism against an exaggerated sympathetic drive; its capacity to induce a more steady hemodynamic condition, through a multifactorial and multi-organ activity, resulting in a more regular labyrinthine perfusion; a possible action on the skeletal muscle tending to a reduction of the muscular tone, which could relieve tinnitus of muscular origin deriving from tensor tympani tonic contractions; its possible reported antidepressive effect, which could indirectly act on tinnitus; a direct regulation of inner ear immunity as proposed in literature when melatonin was reported to be present in the inner ear. All these observations seem to indicate melatonin as a tool deserving a greater attention than other antioxidants in the attempt of relieving tinnitus, justifying its application from a more precise rationale based on a series of physio-pathological aspects.

In the absence of a satisfactory interpretation, sudden sensorineural hearing loss is often attributed either to infective phenomena or to organic-type circulatory defects. This latter pathogenesis inevitably comes to mind in elderly patients or in the presence of signs of circulatory dysfunction. Nevertheless, the not-infrequent observation of sudden hearing loss in young persons lacking factors predictive of short-term vascular impairment makes us suppose the existence of etiopathogenetic mechanisms of a functional nature. A survey of our cases, matched with a control group, revealed the presence of lower mean blood pressure levels in the group of young patients with 'idiopathic' sudden hearing loss. This finding supports the hypothesis that a condition of haemodynamic imbalance linked to hypotension plays a role in the genesis of cochlear damage in young subjects. Such a mechanism would bear important therapeutic implications: should it be responsible for the damage in at least some cases, vasoactive drugs with a vasodilatative action could have adverse effects on the possibility of recovery.