Regulation of phosphorylase kinase by low concentrations of Ca ions upon muscle contraction: the connection between metabolism and muscle contraction and the connection between muscle physiology and Ca-dependent signal transduction

It had long been one of the crucial questions in muscle physiology how glycogenolysis is regulated in connection with muscle contraction, when we found the answer to this question in the last half of the 1960s. By that time, the two principal currents of muscle physiology, namely, the metabolic flow starting from glycogen and the mechanisms of muscle contraction, had already been clarified at the molecular level thanks to our senior researchers. Thus, the final question we had to answer was how to connect these two currents. We found that low concentrations of Ca ions (10−7–10−4 M) released from the sarcoplasmic reticulum for the regulation of muscle contraction simultaneously reversibly activate phosphorylase kinase, the enzyme regulating glycogenolysis. Moreover, we found that adenosine 3′,5′-monophosphate (cyclic AMP), which is already known to activate muscle phosphorylase kinase, is not effective in the absence of such concentrations of Ca ions. Thus, cyclic AMP is not effective by itself alone and only modifies the activation process in the presence of Ca ions (at that time, cyclic AMP-dependent protein kinase had not yet been identified). After a while, it turned out that our works have not only provided the solution to the above problem on muscle physiology, but have also been considered as the first report of Ca-dependent protein phosphorylation, which is one of the central problems in current cell biology. Phosphorylase kinase is the first protein kinase to phosphorylate a protein resulting in the change in the function of the phosphorylated protein, as shown by Krebs and Fischer. Our works further showed that this protein kinase is regulated in a Ca-dependent manner. Accordingly, our works introduced the concept of low concentrations of Ca ions, which were first identified as the regulatory substance of muscle contraction, to the vast field of Ca biology including signal transduction

The diagnosis and management of 689 chronic leg ulcers in a single-visit assessment clinic

AbstractObjectives: accurate diagnosis is essential if patients with chronic leg ulceration are to receive optimal treatment. This prospective study describes the findings of a standardised assessment protocol and the initial management of a consecutive series of patients with chronic leg ulceration presenting to a single-visit leg ulcer assessment clinic. Methods: between January 1993 and January 1999, a total of 555 patients (220 men and 335 women of median age 73, range 28-95 years) with 689 chronic leg ulcers were assessed. Full clinical assessment, ankle:brachial pressure index and lower limb venous duplex scan were performed according to a standardised protocol and diagnostic and management data were recorded prospectively on a computerised database. Results: venous disease alone was responsible for 496 of 689 (72%) ulcers. Isolated superficial venous reflux (SVR) was identified in 52% of limbs and two-thirds of these had superficial venous surgery. Combined SVR and segmental deep venous reflux (DVR) was present in 13%, and full-length DVR was present in 33% of limbs. Nineteen (4%) limbs had deep venous stenosis or obstruction. Overall, superficial venous surgery was performed in 43% and compression bandages or hosiery alone were applied in 52% of limbs. Mixed arteriovenous ulceration was present in 100 (14.5%) limbs of which 56 had arterial revascularisation, 38 had superficial venous surgery and 23 had compression alone. Fifteen limbs with pure arterial ulceration had angioplasty (n = 13) or simple dressings alone (n = 2). Ulceration due to lymphoedema (n = 17), mixed lymphoedema and venous reflux (n = 11) and other causes (n = 50) were managed by compression, dressings or skin grafting. Conclusions: a standardised protocol of clinical and duplex assessment can lead to a diagnosis in 97% of chronic leg ulcers. Duplex is essential to confirm or exclude potentially correctable venous disease and allow tailored surgical intervention for those patients who many benefit.Eur J Vasc Endovasc Surg 25, 462-468 (2003