At first sight or second glance: clinical presentation of mosaic manifestations of autosomal dominant skin disorders - a case series.

BACKGROUND: Several autosomal dominant disorders may manifest in mosaic patterns with cutaneous involvement. Genomic mosaicism results from postzygotic autosomal mutations, giving rise to clonal proliferation of two genetically distinct cell groups, which clinically present as lesions following the lines of Blaschko. OBJECTIVE: To increase the awareness of the clinical variability of mosaic manifestations in autosomal dominant skin disorders in order to avoid delayed diagnosis. METHODS: Clinicopathologic correlation in a case series including three patients with mosaic manifestations of different autosomal dominant skin diseases. RESULTS: Here, we describe a patient with type 1 segmental mosaicism of epidermolytic ichthyosis (case 1) and two patients with either type 1 (case 2) or type 2 (case 3) segmental neurofibromatosis 1 (NF1). CONCLUSION: Dermatologists should be familiar with mosaic manifestations of autosomal dominant skin diseases to ensure appropriate guidance of the affected patient. Genetic counselling is mandatory as even limited forms of mosaicism may involve the patient's germline with a moderately increased risk to transmit the mutation to their offspring, resulting in a more severe, generalized form of the respective disease.

The dermatology life quality index as a means to assess life quality in patients with different scar types.

BACKGROUND: Measuring quality of life through questionnaires is a common method to evaluate the impact of different afflictions on the patient's well-being, especially in the field of dermatology where appearance changing afflictions are common. OBJECTIVES: A variety of questionnaires has been used to distinguish different skin conditions like psoriasis, atopic dermatitis and scars. Using the Dermatology Life Quality Index (DLQI), we investigated different scar types regarding their impact on quality of life. METHODS: We assessed the quality of life in 130 patients presenting to our outpatient scar clinic for the first time using the DLQI. Scars were analysed according to their clinical appearance (physiological scars, keloids, hypertrophic scars, atrophic scars, self-harm scars). Physiological scars were established as a baseline for further comparison between groups. RESULTS: Patients in the physiological scar group scored a mean DLQI score of 2.07 ± 3.56, patients in the keloid-, hypertrophic scar-, atrophic scar- and self-harm scar group scored values of 6.06 ± 4.00, 2.53 ± 2.48, 7.26 ± 6.72 and 12.00 ± 3.85 respectively. When compared to the baseline group the difference in the overall score for keloids was +3.99 (P < 0.001), hypertrophic scars scored +0.45 (ns), atrophic scars +5.19 (P < 0.01) and self-harm scars +9.93 (P < 0.001). CONCLUSION: Using the DLQI, we could demonstrate that different subsets of pathological scars do affect patients in a different magnitude. The DLQI provides a promising adjunct for quantifying the quality of life in patients suffering from keloids, atrophic- and self-harm scars and may constitute an interesting additional tool for monitoring the progress of scar treatments.

Insulin-like growth factor-I affects amino compounds in the fluids of the chicken embryo.

The concentration differences of more than 40 amino acids and related compounds in the amniotic fluid, allantoic fluid, and plasma of the chicken embryo are maintained by specific barriers. Since the amniotic and allantoic membranes are not innervated, we proposed that these barriers are controlled by hormones. Specific effects of insulin and prolactin on the amino compounds in the three fluids confirmed this hypothesis and raised the question of the possible role of growth factors. Application of insulin-like growth factor-I (IGF-I) to the chorioallantoic membrane of day 13 chicken embryos caused the following concentration changes in 41 amino compounds measured 1 and 2 h later: (1) in the amniotic fluid, an increase of 40 compounds, regardless of the presence or absence of a concomitant stress effect on these compounds; only NH3 was not affected; (2) in the allantoic fluid, a decrease of reduced glutathione (GSH) and anserine, and an increase of NH3; (3) in the plasma, a decrease of 24 compounds. Within the same time frame, stress caused in the amniotic fluid a drop of the concentration of 29, and an increase of 5, amino compounds; IGF-I reversed the stress effect on all 29 compounds the concentrations of which had dropped and enhanced the stress-induced increase of the other 5 compounds. In the allantoic fluid, stress induced an increase of GSH; IGF-I reversed this effect. In the plasma, stress caused an increase of 9 compounds; IGF-I counteracted the increase in 7 cases. These findings indicate new and unexpected roles of IGF-I in the prenatal regulation of amino compounds.

The impact of diets with different magnesium contents on magnesium and calcium in serum and tissues of the rat.

The impact of three different magnesium diets (70, 1,000 and 9,000 ppm) on total, ionized and bound magnesium as well as ionized calcium in serum and total calcium and magnesium in femoral bone, skeletal muscle, heart and liver of male Sprague-Dawley rats was investigated. The percentage of ionized serum magnesium was unproportionally high in rats fed a low magnesium (70 ppm) diet. Femoral magnesium was correlated with ionized and total serum magnesium. In contrast, there was generally no correlation between total serum magnesium and the magnesium fractions in skeletal muscle, heart and liver. In rats fed the magnesium deficient diet, total cardiac concentration of magnesium was even significantly increased along with total calcium content, while there were no effects on total muscle and liver magnesium. Within the single groups, ionized serum calcium was never proportional to dietary magnesium, but in all three magnesium diet groups together, it was inversely correlated with dietary magnesium. Moreover, ionized serum calcium was inversely correlated with both ionized and total serum magnesium. In all 3 groups together, the concentrations of total calcium and magnesium in heart and skeletal muscle were correlated, within the single groups correlation existed only in the 1000 ppm group. Magnesium influx via calcium channels during low magnesium intake has been seen in non cardiac tissues [35,36], but nothing similar is known about non selective channels for divalent cations in the heart [33]. Thus, magnesium uptake by cardiac cells along with calcium seems to be possible, especially at low intracellular magnesium concentrations, but is still poorly investigated. We suggest that the calcium-antagonistic effect of magnesium is related to the turnover rate of magnesium rather than to its tissue concentrations.

Hormonal effects on amino acids and related compounds in plasma, amniotic fluid, and allantoic fluid of the chicken embryo.

So far, more than 40 free amino acids and related compounds have been identified in plasma, amniotic fluid, and/or allantoic fluid of the 13-day chicken embryo. Concentration differences, and greatly varying behavior of these compounds under experimental conditions, revealed the presence of specific barriers among the three fluids. We tested the hypotheses that (1) the absence of an innervation of amnion and allantois indicates a hormonal control of their barriers, and (2) changes in the concentrations of certain amino compounds in the three fluids indicate anabolic or catabolic actions of hormones. Insulin, prolactin, and stress caused complex changes of the concentrations of amino compounds in all three fluids within 30 min. Some of these changes indicated breakdown of embryonic tissues, while others must have been due to transfer of amino compounds among the three fluid compartments. However, there was no significant effect on the glucose concentration in any of the three compartments under any of the experimental conditions. This is the first demonstration of hormonal effects on the amino compounds in the extraembryonic fluids of nonmammalian amniotes.

Impact of exogenous amino acids on endogenous amino compounds in the fluid compartments of the chicken embryo.

Plasma, allantoic and amniotic fluid of the 13-day chicken embryo contain numerous free amino acids and related compounds. Of these, 40 were investigated using an HPLC-fluorometric technique. The concentration differences of the amino compounds between the fluid compartments are maintained by three bidirectional barriers, i.e. a blood/allantoic barrier, a blood/amnion barrier and an allantois/amnion barrier. Intraallantoic injection of 4.5 mumol/egg of asparagine (ASN), aspartic acid (ASP), valine (VAL) or serine (SER) revealed a strong allantois/blood barrier for these compounds. In contrast, there was equilibration between allantoic and amniotic fluid for ASN, ASP and SER, and an upward trend of the VAL concentration in the amniotic fluid, due to an 'overspill' from the allantois. The injections also affected endogenous amino compounds in all three fluid compartments. Asparagine had the most varied effects, including a strong drop of ten plasma amino acids. After all four types of injection, a number of endogenous amino compounds equilibrated between allantois and the normally hyporegulated amnion. Since allantois and amnion are non-innervated, the selective changes of the barriers and the drop of plasma amino acids must be mediated by so far unidentified humoral messengers.

Electrostimulation of catecholamine release in the eel: modulation by antagonists and autocrine agonists.

The innervated chromaffin cells of the eel (Anguilla rostrata) release norepinephrine (NE) and epinephrine (E), while a component of the macrovascular wall releases dopamine (DA). The release of the three catecholamines is governed by complex controls which include adrenergic, nicotinergic, muscarinergic, and opioid mechanisms. To gain insight into the interactions between neural and autocrine factors in stimulated catecholamine release, we investigated the effect of adrenergic (phentolamine and propranolol) and muscarinergic (atropine) receptor antagonists, and of autocrine opioids (met-enkephalin, codeine, and morphine) on electrostimulated catecholamine secretion in situ. The hind brain (close to the root of nerve IX) of anesthetized eels was stimulated at four different time points, and segments of the posterior cardinal vein or the caudal vein were perfused with a saline solution, with or without test substances. Electrostimulation (30 s) four times within a total study duration of 14 min increased the release of DA, NE, and E into the perfusate of the cardinal vein. The vessel contains the innervated adrenomedullary equivalent. In the noninnervated caudal vein electrical stimulation had no impact on total DA release, while there was a slight decrease of NE release and a slight increase of E release. In the cardinal vein, both the alpha-adrenergic receptor antagonist phentolamine and the beta-adrenergic receptor antagonist propranolol strongly reduced the effect of electrostimulation on catecholamine release. Met-enkephalin reduced the release of all three catecholamines to a similar degree; its impact on NE release was especially strong. Codeine reduced the catecholamine release moderately, while morphine had no effect. Atropine reduced the release of all three catecholamines in a pattern similar to that of met-enkephalin. The findings on the posterior cardinal vein indicate that neurally stimulated NE and E release (1) involves autocrine/paracrine adrenergic mechanisms, (2) involves a muscarinergic mechanism, and possibly also endogenous codeine and morphine; and (3) is antagonized by met-enkephalin. The findings on the caudal vein are further evidence that macrovascular DA release is not under direct neural control.

Cholinergic control of catecholamine release in the eel.

The perifused posterior cardinal vein of the American eel (Anguilla rostrata) releases spontaneously dopamine (DA), norepinephrine (NE), and epinephrine (E). NE and E are secreted by innervated chromaffin cells, while DA is most likely released from a component of the vascular wall. Stimulation with acetylcholine strongly enhances the release of DA and E, and to a lesser degree the release of NE. Nicotine stimulates the release of all three catecholamines. Muscarine reduces the basal release of NE. Muscarine does not prevent nicotinic stimulation of NE and E release, but abolishes the nicotine effect on DA release. The muscarinic antagonist atropine stimulates the release of NE, but not of DA and E. The beta-adrenergic receptor antagonist propranolol suppresses the acetylcholine-stimulated release of NE and E, and reduces the DA response. From these findings, it appears that (1) nicotinic receptors regulate NE and E secretion from the chromaffin cells, (2) muscarinic receptors inhibit basal NE release, and (3) acetylcholine-stimulated release of NE and E requires the interaction with adrenergic receptors. On the other hand, DA release involves both nicotinic and adrenergic receptors, while the reduction of nicotine-stimulated (but not basal) DA release involves muscarinic receptors.

Opioid effects on macrovascular dopamine release.

Both alkaloid opiates and met-enkephalin occur in vertebrate chromaffin cells, where they affect catecholamine (CA) secretion. Since the large blood vessels of the eel and the rat release dopamine (DA) from as yet unidentified source(s), we studied the impact of alkaloid opiates and met-enkephalin on the secretion of DA from three macrovessels of the American eel (Anguilla rostrata) in a perifusion system. Codeine, morphine, and met-enkephalin increased the release of DA from both the ventral aorta and the caudal vein. The antagonist naloxone stimulated DA release from the caudal vein, but had no impact on release from the ventral aorta. Only codeine had a significant effect on DA release from the posterior cardinal vein. These findings show that the DA release from the macrovessels is sensitive to opioid substances, and they suggest that the antagonistic effects between alkaloid opiate and opioid peptide, seen in other systems, are absent in large blood vessels. Furthermore, the "unorthodox" stimulatory effect of naloxone in the caudal vein raises the question of as yet unidentified receptor and/or effector systems.

Impact of ethanol stress on components of the allantoic fluid of the chicken embryo.

Recent studies showed that the allantoic fluid of the chicken embryo is a depot for stress-released catecholamines and many free amino acids and related compounds, and that it is separated from plasma and the amniotic fluid by selective barriers. To gain further insights into the functions of the allantois and its barriers, we studied the impact of stress (intra-allantoic injection of 0.1 ml ethanol) on 39 free amino acids and related compounds of the allantoic fluid. Using an HPLC-fluorometric method, we found that the concentration of seven substances was significantly increased 20 min after injection of ethanol, and back to control levels within 40 minutes. Five of these compounds (asparagine, alanine, leucine, tyrosine, lysine) had previously been shown to occur in plasma at concentrations above those in the allantoic fluid. However, taurine and phosphoethanolamine increased in the allantoic fluid even though their concentrations in plasma tended to be lower than in allantoic fluid. These findings (1) reveal the existence of complex embryonic/extraembryonic autoregulations, and (2) raise the question of the regulatory mechanisms involved in the transfer of substances across the allantoic barrier(s).

Regulation of substances in allantoic and amniotic fluid of the chicken embryo.

Traditionally, the avian allantois has been considered a respiratory organ and a dumping ground for metabolic wastes. We tested the hypothesis that the allantoic fluid is also a depot for free amino acids and related compounds. To gain further insight in the specific role of the allantoic fluid, we included plasma and the amniotic fluid in this study. The work was carried out in 13- and 14-day-old chicken embryos. Using an HPLC-fluorometric technique, 40 of the 41 amino acids and related compounds investigated were detected. The amniotic fluid contained 32 compounds, while plasma and allantoic fluid contained 38 and 39 compounds, respectively. The glucose concentration was determined with a hexokinase technique. It was highest in plasma and lowest in the amniotic fluid. We identified three barriers that hyper- and hyporegulate a number of compounds: (1) a blood/allantois barrier, (2) a blood/amnion barrier, and (3) an allantois/amnion barrier. Compared with plasma and allantoic fluid, the amniotic fluid is a mostly hyporegulated environment.

Gracilis muscle dynamic urethral sphincter myoplasty: rat model experience.

PURPOSE: Dynamic urethral sphincter myoplasty (skeletal muscle urinary sphincter reconstruction) using a neurovascularly intact gracilis muscle was investigated in a rat model. MATERIALS AND METHODS: In female Sprague-Dawley rats, a unilateral gracilis anticus muscle flap was dissected from the medial thigh, preserving the medial muscular insertion, vascular flow, and innervation. This muscle graft was used to completely encircle the urethra and was fixed in position. Urodynamic leak point pressure (LPP) and bladder volume at leakage were measured with cystometry after 1 month, using an 18 gauge catheter placed through the bladder dome with a constant infusion rate of 0.2 ml. per minute. In addition, the effect of electrical stimulation of the gracilis myoplasty (current parameters: 1 to 10 mA, 1 to 60 Hz, 0.05 to 1 msec. duration) on intravesical leak point pressure was noted during cystometry. RESULTS: The gracilis muscle measured 3.8 +/- 0.3 cm. in length, 0.5 +/- 0.1 cm. in width and 0.2 +/- 0.1 cm. in thickness. Blood flow rates to the grafted and contralateral gracilis myoplasty were similar at 43 +/- 26 and 51 +/- 30 g.cm.3, respectively (p = 0.46). The leak point pressure (LPP) of control, unstimulated gracilis myoplasty and gracilis myoplasty with electrical stimulation were 28 +/- 8, 32 +/- 12, and 85 +/- 27 mm.Hg (p < 0.01). Bladder volumes at LPP in the 3 respective groups were 0.5 +/- 0.2, 0.6 +/- 0.3 and 1.2 +/- 0.6 ml (p < 0.01). CONCLUSIONS: Gracilis myoplasty is not obstructive, as substantiated by unchanged leak point pressure and leak point capacity. Myoplasty with low current stimulation, however, significantly increased LPP and leak point capacity.

Comparison of bladder rupture pressure after intestinal bladder augmentation (ileocystoplasty) and myomyotomy (autoaugmentation).

OBJECTIVES: To compare the risk of bladder rupture of bladder augmentation using ileocystoplasty versus that of autoaugmentation with myomyotomy in a rat model. METHODS: Bladder rupture pressure and volume of three groups of female Sprague-Dawley rats were determined by cystometry. The first group of 11 rats had undergone ileocystoplasty using a detubularized 1 -cm segment of ileum. A second group of 9 rats had undergone autoaugmentation with myomyotomy. One month after surgery the animals were studied cystometrically to determine the bladder rupture pressure, then killed. A third group, consisting of 10 nonoperated rats, was studied and served as controls. RESULTS: Nonoperated, control rat bladders were able to sustain 154 +/- 43 mm Hg pressure and 2.5 +/- 2.0 mL volume prior to bladder rupture. Conventional ileocystoplasty was noted to increase bladder capacity to 4.0 +/- 1.9 mL, but decrease rupture pressure to 111 +/- 49 mm Hg. Myomyotomy resulted in a mean bladder rupture volume of 1.2 +/- 0.4 mL, with a rupture pressure of 101 +/- 13 mm Hg. The rupture pressure after myomyotomy is significantly lower than that of the native bladder (P < 0.001), whereas the rupture volume after myomyotomy is significantly lower than either after the ileocystoplasty or with the native bladder (P < 0.001). Bladder rupture occurred at the augmented ileal bladder dome in 7 of 11 ileocystoplasty animals and at the anastomotic suture line in 4 animals. Bladder rupture occurred at the area of bladder diverticulum in all 9 myomyotomy animals. Among controls, no specific site pattern of bladder rupture was noted. CONCLUSIONS: Bladder augmentation with myomyotomy increases vulnerability to urinary extravasation, evidenced by a significantly reduced rupture pressure and bladder volume at rupture when compared to the native bladder.

Macrovascular dopamine release.

In an animal model, the American eel, perifused elastic arteries and large veins, but not the heart and organs with extensive microvascular supply (gills and opisthonephric kidney), release spontaneously free dopamine. Only the region of the cardinal vein, which contains the adrenomedullary equivalent, also releases norepinephrine (NE) and epinephrine (E). Ca2+, KCl, and E stimulate dopamine release from the ventral aorta and caudal vein, indicating that this phenomenon is due to secretion and not to washout. E also stimulates NE release from the ventral aorta and caudal vein. In the rat, both aorta and vena cava spontaneously release dopamine and NE. Thus dopamine secretion from large blood vessels may be general in vertebrates. The dopamine response to high physiological concentrations of E in vivo and in vitro suggests that macrovascular dopamine may be involved in local stress responses.

The effect of basic fibroblast growth factor on the blood flow and morphologic features of a latissimus dorsi cardiomyoplasty.

Previous studies designed to determine whether latissimus cardiomyoplasty could be used to revascularize ischemic myocardium showed that after operation the latissimus was ischemic and had severely deteriorated. This study was undertaken to determine whether basic fibroblast growth factor, a potent angiogenic peptide, would improve the vascularity of the latissimus and enhance collateral formation between the muscle of the cardiomyoplasty and ischemic myocardium. In goats, myocardial ischemia was induced with an ameroid constrictor and cardiomyoplasty performed. The latissimus was continuously stimulated electrically at 2 Hz for 6 weeks and given four weekly bolus injections of human recombinant basic fibroblast growth factor (80 micrograms infused into the left subclavian artery). In eight animals, rates of regional blood flow were measured and both the heart and latissimus were evaluated histochemically. The latissimus blood flow rate was 0.114 +/- 0.029 ml/gm per minute, which was three times greater than that of historical controls (chronically stimulated latissimus cardiomyoplasty without basic fibroblast growth factor treatment; 0.042 +/- 0.007 ml/gm per minute, p < 0.05). Associated with the improved blood flow, there was significantly less evidence of skeletal muscle fiber dropout and muscle fibrosis in the animals treated with basic fibroblast growth factor. Latissimus-derived collateral flow to ischemic myocardium developed in five of the eight goats and averaged 0.288 +/- 0.075 ml/gm per minute. This flow was 42.8% +/- 15.7% (n = 5) of the flow required by normal myocardium (which was 0.728 +/- 0.095 ml/gm per minute). This value for latissimus-derived collateral blood flow was almost twice that of the historical controls (24.0% +/- 3.9%), but the increase did not achieve statistical significance (p = 0.08). These results hold the promise that basic fibroblast growth factor treatment might enhance the formation of extramyocardial collaterals to the heart and improve skeletal muscle function.

Release of amino acids and related compounds from the adrenal equivalent and caudal vein of the eel in vitro.

The release of catecholamines and cortisol from the perifused adrenal region and caudal vein of the eel (Anguilla rostrata) was compared with the release of 39 amino acids and related compounds. Dopamine, norepinephrine and epinephrine were present in all perifusates of the adrenal region. Dopamine release from the caudal vein exceeded that from the adrenal region, and norepinephrine and epinephrine were not detected. Cortisol was present in the perifusate of the adrenal region but virtually absent in caudal vein perifusate. Of the six substances with known or suspected neurotransmitter function, taurine, aspartate, glutamate, glycine and alanine were present in all or almost all samples from both the adrenal equivalent and the caudal vein. gamma-aminobutyric acid (GABA) was detected in a few samples from either preparation. The release of taurine and phosphoethanolamine may be linked to that of norepinephrine and epinephrine. Adrenocorticotropic hormone (ACTH) enhanced the release of cortisol, aspartate, valine, leucine and ornithine from the adrenal region, but the release appears to be from differing sources or cellular pools. Overall, the study revealed that both the adrenal region and caudal vein release a large number of amino acids and related substances. The caudal vein, and possibly other blood vessels as well, may be a major source of circulating dopamine.

Temporary increase of plasma epinephrine affects stress responses 24 h later.

The impact of temporary (24 h) implantation of epinephrine tables on catecholamine responses to handling and immobilization 24 h later was investigated in rats. Free plasma epinephrine responded with an increase to both types of stress (77% and 326%, respectively) while controls showed a weaker response to immobilization. The basal level of free plasma norepinephrine was reduced (46% vs. controls) after epinephrine pretreatment, but neither handling nor immobilization had a specific effect on this parameter. In contrast, the basal level of free plasma dopamine was increased after epinephrine pretreatment (183%); however, as with free norepinephrine, there was no specific effect of handling or immobilization. Conjugated plasma epinephrine was significantly lowered after epinephrine pretreatment (44% vs. controls). It did not respond specifically to handling or immobilization except for a stronger response after 20 min of immobilization. Conjugated norepinephrine showed no specific response, but increased nonspecifically after extended immobilization. Conjugated dopamine was lowered (30%-48%) in the E-treated group and did not respond to stress at any time. Thus, a temporary elevation of free plasma epinephrine affected, differentially, basal levels and stress responses of free and conjugated catecholamines 24 h later.

Sulfate conjugates of catecholamines in the allantoic fluid of the chicken embryo.

In addition to free dopamine (DA), norepinephrine (NE), and epinephrine (E), the allantoic fluid of the 13-day-old chicken embryo contains sulfate conjugates of these three catecholamines (CAs). The concentration of DA sulfate is relatively low, while NE and E sulfates occur at levels similar to those of the free fractions. The comparatively low concentration of free CAs in the amniotic fluid, seen in a previous study, is confirmed. However, the amniotic barrier for sulfated CAs is much stronger, possibly absolute. Though some technical difficulties remain to be resolved, the chicken embryo may become a useful model for the study of the prenatal functions of CA conjugates.

Endogenous codeine: autocrine regulator of catecholamine release from chromaffin cells.

In addition to the catecholamines (CAs) dopamine (DA), norepinephrine (NE) and epinephrine (E), perifused chromaffin cells of the eel secrete codeine and morphine. In controls, the release of NE and E is strongly correlated, while there is no correlation with DA. Low, physiological concentrations of codeine (500 pg/ml) reduce the release of NE and E, while 8-fold higher concentrations stimulate an instant, transitory release of all three CAs. Much higher concentration of codeine (100 ng/ml), corresponding to the therapeutically effective range in the human, again reduce the release of NE and E. Physiological and very high concentrations of morphine have no clear effect on CA release, while an intermediate concentration (38 ng/ml) increases the secretion of all three CAs. The opiate antagonist naloxone lowers the basal CA secretion and prevents the morphine-induced CA increase. During naloxone perifusion, a normally non-effective concentration (40 ng/ml) of codeine reduces the CA release. It appears that codeine is an autocrine regulator which suppresses CA release via naloxone-insensitive receptors, and stimulates CA release via opiate receptor(s). Co-released morphine may modulate the action of codeine.