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OBJECTIVE: Theophylline is a phosphodiesterase inhibitor that is being used clinically for asthma therapy. In addition, it is recognized as a cosmetic agent with possible anti-ageing and anti-oxidative properties. Nevertheless, how it affects human skin is still poorly examined. METHODS: Theophylline (10 or 100 µM) was administered to the culture medium of full-thickness human skin ex vivo for 24 or 72 h. RESULTS: Theophylline stimulated protein expression of the anti-oxidant metallothionein-1 and mRNA levels of collagen I and III. Assessment of fibrillin-1 immunohistology revealed enhanced structural stability of dermal microfibrils. Theophylline also exerted extracellular matrix-protective effects by decreasing MMP-2 and MMP-9 mRNA levels, partially antagonizing the effects of menadione, the potent, toxic ROS donor. In addition, it decreased menadione-stimulated epidermal keratinocytes apoptosis. Interestingly, theophylline also increased the level of intracutaneously produced melatonin, that is the most potent ROS-protective and DNA damage repair neuromediator, and tendentially increased protein expression of MT1, the melatonin receptor. Theophylline also increased the expression of keratin 15, the stem cell marker, in the epidermal basal layer but did not change mitochondrial activity or epidermal pigmentation. CONCLUSION: This ex vivo pilot study in human skin shows that theophylline possesses several interesting complex skin-protective properties. It encourages further examination of theophylline as a topical candidate for anti-ageing treatment.

OBJECTIF: la théophylline est un inhibiteur de la phosphodiestérase actuellement utilisée en clinique pour le traitement de l'asthme. En outre, elle est reconnue comme étant un agent cosmétique ayant des propriétés potentiellement anti-âge et antioxydantes. Cependant, la manière dont elle affecte la peau chez l'homme est encore très peu étudiée. MÉTHODES: de la théophylline (10 ou 100 µM) a été ajoutée dans le milieu de culture d'un échantillon de peau humaine d'épaisseur totale ex vivo pendant 24 ou 72 h. RÉSULTATS: la théophylline a stimulé l'expression de la métallothionéine-1, une protéine antioxydante, et les taux d'ARNm du collagène I et III. L'évaluation immunohistologique de la fibrilline-1 a révélé une meilleure stabilité structurale des microfibrilles du derme. La théophylline a également exercé des effets protecteurs sur la matrice extracellulaire en diminuant les taux d'ARNm des métalloprotéinases matricielles MMP-2 et MMP-9, neutralisant en partie les effets de la ménadione, puissant donneur d'espèces réactives de l'oxygène (ROS) toxiques. En outre, elle a diminué l'apoptose des kératinocytes épidermiques stimulés par la ménadione. Fait intéressant, la théophylline a également augmenté le taux de mélatonine produite de manière intra-cutanée, la mélatonine étant le plus puissant neuromédiateur protecteur contre les ROS et réparateur des lésions de l'ADN. Elle a augmenté de façon tendancielle l'expression de la protéine MT1, récepteur de la mélatonine. La théophylline a également augmenté l'expression de la kératine 15, marqueur de cellules souches, dans la couche basale épidermique, mais n'a pas modifié l'activité mitochondriale ou la pigmentation épidermique. CONCLUSION: cette étude pilote ex vivo réalisée sur de la peau humaine montre que la théophylline a plusieurs propriétés protectrices de la peau complexes et intéressantes. Ces résultats encouragent à poursuivre l'étude de la théophylline en tant que candidat à un traitement local anti-âge.

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BACKGROUND: There has been recent concern about long-term morbidity associated with arthroscopic co-planing of the acromioclavicular joint in the treatment of impingement syndrome. OBJECTIVE: The purpose of this study was to assess the results of the co-planing procedure, special attention being paid to acromioclavicular joint morbidity. METHODS: The study included 56 patients who were operated on by the senior author. Outcomes were evaluated both objectively and subjectively through physical examinations and telephone surveying. Each patient had subacromial decompression at the time of the index surgery. Other concomitant arthroscopic procedures included rotator cuff repair and labral debridement or repair. RESULTS: Average follow-up was 4 years (range, 2-7 years). Thirty-five (95%) of 37 patients had no subjective pain and no objective tenderness to direct palpation or compression of the acromioclavicular joint. The joint was not clinically hypermobile in comparison with that on the opposite side in any patient. In all, 95% of patients had good or excellent results in terms of the University of California at Los Angeles Shoulder Score. Of the 2 patients who did have pain and tenderness at the acromioclavicular joint, both had had multiple operations on their shoulders before the index procedure. Nineteen patients were not examined clinically but did complete a telephone survey; these 19 patients were not symptomatic at the acromioclavicular joint. CONCLUSIONS: To fully treat impingement syndrome, the surgeon should remove osteophytes under the lateral clavicle and medial acromion. With good technique, the surgeon can leave the anterior, posterior, and superior acromioclavicular joint capsule intact. We conclude that for appropriate clinical indications, beveling the inferior 20% to 25% of the clavicle to make it co-planar with the decompressed acromion is safe and is not an etiologic factor in acromioclavicular joint pain or instability.

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Cell migration plays a major role during wound healing and is tightly controlled by a variety of growth factors and extracellular matrix proteins. The experiments reported here have been designed to study whether defined beta 1 integrins are involved in the platelet-derived growth-factor-AB (PDGF-AB)-modulated migratory response to collagen type I and to fibronectin. Preincubation of fibroblasts with PDGF-AB resulted in an up to 2.5-fold increase in the migratory response to collagen type I as well as fibronectin and to enhanced synthesis and cell surface expression of the alpha 2, alpha 3, alpha 5, and beta 1 integrin subunits. Function-blocking monoclonal antibodies against the common beta 1 integrin subunit dose-dependently inhibited the PDGF-AB-augmented migration of fibroblasts to collagen type I and fibronectin. The PDGF-AB-induced migration to collagen type I was also inhibited by antibodies against the alpha 2 integrin subunit, whereas the corresponding migration to fibronectin was almost completely blocked by the combined application of antibodies against the alpha 3 and the alpha 5 integrin subunits. Taken together, up-regulation of integrin synthesis and expression by human recombinant PDGF-AB correlate with an increase in the migratory response of dermal human fibroblasts to various extracellular matrix proteins and thus may contribute to an efficient regulation of cell migration during wound healing and tissue repair.

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We developed a reproducible muscle contusion injury and studied its effect on contractile function, histology, and passive failure. An instrumented drop-mass technique (mass, 171 g; height, 102 cm; spherical radius, 6.4 mm) delivered a single impact to the posterior surface of the gastrocnemius muscle in one limb of 40 male Wistar rats. On Day 0, the impact significantly (N = 12, P < 0.01) decreased maximum tetanic tension to 63% of the contralateral control value. Histologic examination demonstrated extravasation of erythrocytes, edema, myofiber disruption, and vacuolation of myofibers. Passive failure initiated at the site of injury. At 2 days, tetanic tension was 75% of controls (N = 11, P < 0.01). Histologically, acute inflammation and phagocytosis were noted. Tetanic tension at 7 days was 81% of controls (N = 8, P < 0.01). Vimentin staining indicated a dramatic increase in myoblast activity. Contractile strength was near normal at 24 days. Histologic examination showed complete regeneration of normal striated muscle fibers. No vimentin activity was found. No passive failures initiated at the injury site. Contusion injury produced a significant deficit in contractile function that continually diminished with gross histologic evidence of degeneration, regeneration, and normalization at the injured muscle fibers.

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Previous work has shown that fibroblast-derived collagenase/matrix-metalloproteinase-1 (MMP-1), responsible for the breakdown of dermal interstitial collagen, was dose-dependently induced in vitro and in vivo by UVA irradiation and this induction was at least partly mediated by interleukin-6 (IL-6). We here provide evidence that UVA-induced IL-1 alpha and IL-1 beta play a central role in the induction of the synthesis both of IL-6 and collagenase/MMP-1. In contrast to the late increase of IL-1 alpha and IL-1 beta mRNA levels at 6 h postirradiation, bioactivity of IL-1 is already detectable at 1 h postirradiation. This early peak of IL-1 bioactivity appears to be responsible for the induction of IL-6 synthesis and together with IL-6 lead to an increase of the steady-state mRNA level of collagenase/MMP-1 as deduced from studies using IL-1 alpha and IL-1 beta antisense oligonucleotides or neutralizing antibodies against IL-1 alpha and IL-1 beta. Besides the early posttranslationally controlled release of intracellular IL-1, a latter pretranslationally controlled synthesis and release of IL-1 perpetuates the UV response. From these data we suggest a UV-induced cytokine network consisting of IL-1 alpha, IL-1 beta and IL-6, which via interrelated autocrine loops induce collagenase/MMP-1 and thus may contribute to the loss of interstitial collagen in cutaneous photoaging.

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In hypertensive diabetics a strict blood pressure control may decrease the incidence of cardiovascular and diabetic complications. Long-term experience with the use of calcium antagonists is still limited. The metabolic and renal effects of long-term (8 months) therapy with amlodipine, 5 to 10 mg daily, were studied in 15 hypertensive patients with uncomplicated diabetes mellitus as compared with 15 patients with essential hypertension. After a 4 week placebo phase, the diabetics and essential hypertensive patients did not differ in mean blood pressure (156/93 +/- 16/7 v 150/95 +/- 9/5 mm Hg), body weight, creatinine clearance, microalbumin excretion, and C-peptide and lipid levels, while serum fructosamine was higher in the diabetics. In both groups, amlodipine caused a significant and long-lasting decrease of arterial pressure (8%), but did not modify creatinine clearance, microalbumin excretion, and serum lipid levels. In diabetics indices of diabetic control and the insulin and glucose response to an oral glucose tolerance test were unchanged, whereas in essential hypertension the insulin response to a glucose load was decreased (P = .033). Amlodipine exerts a comparable and long-lasting antihypertensive effect in hypertensive diabetics and patients with essential hypertension. Despite the significant decrease in arterial pressure, there was no change in urinary microalbumin excretion. Lipid metabolism, quality of diabetic control, and the insulin response to a glucose load were not affected unfavorably.

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Recent publications report increased cardiovascular morbidity and mortality after transurethral prostatic resection (TURP). Repeated breath-ethanol monitoring with a new infrared device permits a highly sensitive peroperative registration of fluid absorption. A prospective study in 52 patients revealed surprisingly high rates of intravascular fluid loads without clinical manifestations. Only 4 patients developed clinical signs of the TUR syndrome. Immunological work-up in 41 patients demonstrated circulating endotoxins and significant rise of endogenous tumour necrosis factor (TNF) in 3 of these patients. In 11 patients transient endotoxins could be detected during resection under prophylactic parenteral antibiosis. In the face of less invasive approaches to benign prostatic hyperplasia, close intraoperative monitoring and antibiotic coverage should be demanded as a routine procedure during TURP. Elective surgery should be delayed until appropriate antibiotic therapy has been given.

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Calcium entry blockade may affect the pressor reactivity to vasoconstrictors. The pressor response to norepinephrine and angiotensin II, as well as several other blood pressure modulating factors, were studied in normal subjects (n = 9) and patients with essential hypertension (n = 10) before and after 8 weeks of treatment with the long-acting dihydropyridine amlodipine. In control subjects, calcium entry blockade did not modify blood pressure, the pressor and aldosterone response to angiotensin II, the activity of the renin-angiotensin and sympathetic nervous systems, or urinary dinoprostone (prostaglandin E2) excretion; however, the pressor response to norepinephrine was significantly decreased (p less than 0.01). In patients with hypertension, amlodipine decreased blood pressure (p less than 0.01) and the pressor response to both norepinephrine and angiotensin II (p less than 0.01), without changes in body weight, plasma renin, angiotensin II and catecholamine levels, dinoprostone excretion, or aldosterone responsiveness to angiotensin II. These findings suggest that calcium entry blockade modifies sympathetic-dependent vasoconstriction in both normal subjects and in patients with hypertension. Angiotensin II pressor response may be selectively decreased in essential hypertension.

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The migratory response of the human keratinocyte cell line HaCaT to collagen type I and the molecular mechanism underlying collagen-mediated migration have been analyzed. The migratory response of HaCaT cells to collagen type I consisted of a dose-dependent migration to insoluble step gradients of substratum-bound collagen (haptotaxis) and to gradients of soluble collagen (chemotaxis). Checkerboard analysis demonstrated a minor chemokinetic component. Denatured collagen type I was less chemoattractive than the native triple-helical form. Pre-treatment of cells with 25-250 micrograms/ml of synthetic peptides containing the fibronectin cell-recognition sequence RGD (Arg-Gly-Asp) resulted in a concentration-dependent inhibition of fibronectin-mediated chemotaxis, whereas chemotaxis to collagen was not affected. We then investigated the role of VLA/collagen-receptors for collagen type I-induced chemotaxis. Monoclonal antibody (MoAb) 5E8, which selectively blocks function of the alpha 2 subunit of the VLA-2/collagen receptor, dose-dependently inhibited the chemotactic response of HaCaT cells to collagen. This effect was specific for collagen-mediated chemotaxis because the chemotactic response to fibronectin remained unaffected. In contrast, a function blocking MoAb directed to the alpha 3 subunit of the coexpressed VLA-3 receptor, which is also capable of binding collagen, had no effect. However, function blocking MoAb directed to the beta 1-chain of integrins completely inhibited chemotaxis to collagen type I. Based on our results, we propose that the chemotactic migration of the human keratinocyte cell line (HaCaT) to collagen type I is specifically mediated by the RGD independent VLA-2/collagen receptor (alpha 2 beta 1) of the integrin family.

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For data acquisition intensive care neurosurgery increasingly has recourse to modern electronics, which have become an integral part of many aspects of present-day neurosurgery. Despite their high technical standard, the devices in common use often lack flexibility. Their range of possible applications is defined by the manufacturer, and the user has little or no influence on them. Moreover, there are often no adequate interfaces to peripherals, and the storage capacity is limited. We would like to present a data acquisition system on a PC/AT basis, which operates up to 64 channels allowing parallel registration, storage, analysis, and of decisive importance, also various computations, i.e. correlation. Computation is rarely feasible on commercial devices, but it is essential for specific demands, such as implementation of PA/PM diagrams to determine intracranial compliance. In addition, the pertinent software permits implementation of Fourier analyses, offers separate statistical functions, and transfers data to other programs. The program is capable of automatic batch-processing, which greatly facilitates its use.

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A report about the treatment of 85 women in the premenopause during 387 cycles is given. The treatment consisted in sequential therapy in form of conjugated Estrogens (Presomen) and a new synthetic Gestagen, which was given in three different modifications: from the fifth to the 24-th day of the cycle 1,25 mg Presomen a day, additionally on the last five, seven or ten days, during each period 6 respectively 5 mg Gestagen a day. It proved that both, the disfunctional haemorrhages as well as the climacteric syndrome, were favourably influenced. The mode 10+10, that is, 10 days Estrogens alone + 10 days combined with ;estagen, proved best. A sufficiently secure contraception is not guaranteed. This can be recognized by the occurence of biphasic basal temperature curves.

PIP: The treatment of 85 women in the premenopause during 387 cycles is reported. Sequential therapy in the form of conjugated Estrogens (Presomen) and a new synthetic Gestagen, was given in 3 different modifications: from the 5th to the 24th day of the cycle 1.25 mg Presomen a day, additionally on the last 5, 7, or 10 days, during each period 6, respectively, 5 mg Gestagen a day. Both the dysfunctional hemorrhages as well as the climacteric syndrome, were favorably influenced. The mode 10 + 10 days, i.e., 10 days Estrogens alone + 10 days combined with Gestagen, proved best. A sufficiently secure contraception is not guaranteed. This can e recognized by the occurrence ob biphasic basal temperature curves.

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