Geometric, elastic and contractile-relaxation changes in coronary arterioles induced by Vitamin D deficiency in normal and hyperandrogenic female rats.

Vitamin D (VitD) hypovitaminosis and androgen excess (AE) are both risk factors for cardiovascular diseases in fertile women. However, the possible early interaction between AE and VitD status is not clear. Our goal was to describe how VitD status influences early changes in the biomechanical reactivity of small coronary arterioles in adult female rats after transdermal testosterone treatment. Forty-six adolescent, 90-110-gram-weighed female Wistar rats were randomly grouped into 4 groups. Twenty-four animals received an optimal VitD-supplemented diet, from which 12 animals underwent transdermal testosterone treatment. Twenty-two animals received a VitD-deficient diet, from which 11 were treated with testosterone. At 8 weeks of treatment, invasive arterial blood pressure was registered after in vivo cannulation of carotid artery. Arteriolar end and side branches (200 µm diameter) of the left anterior descendent coronary artery (LAD) were obtained and examined with pressure arteriography in vitro. Similar segments were removed for histological examination. The inner and outer radii of the arterioles were measured using video-microscopy. Normal myogenic tone, maximal passive vasorelaxation and vasoconstriction of the arterioles were measured and statistically analyzed. The vessels' maximal smooth muscle relaxant potential, thromboxane-induced contraction capacity and normal myogenic tone were significantly influenced by actual VitD status. A lower relaxation capacity and increased wall thickness were observed in VitD-deficient groups, which could cause rigidity of the coronary arterioles and elevate cardiovascular risk. Supplementation of VitD could improve myogenic tone and relaxation and hold cardiovascular benefits.

Treatment of pseudoxanthoma elasticum-like papillary dermal elastolysis with nonablative fractional resurfacing laser resulting in clinical and histologic improvement in elastin and collagen.

OBJECTIVE: Pseudoxanthoma elasticum-like papillary dermal elastolysis (PXE-PDE) is a rare skin condition seen predominantly in elderly females. These asymptomatic lesions are brought to the dermatologist's attention due to patient's displeasure in their appearance. We report a case of a 28-year-old female with PXE-PDE on the right neck treated with nonablative fractional resurfacing (NAFR). CASE: The patient on examination had yellow-to-skin-colored papules that coalesced into a cobblestone-appearing plaque on her lateral neck. The area was treated with NAFR to improve texture and cosmesis. After three treatments, the patient noted at least a 50% improvement of appearance and texture in the affected skin. Adverse effects were mild without development of serious side effects, such as scarring and/or permanent dyspigmenation. CONCLUSION: Established therapies for elastin disorders like PXE-PDE have yielded unsatisfactory results by patient and clinician standards. Positive results with NAFR, illustrated in our PXE-PDE case, further provides a role for NAFR in elastin disorders.

Treatment of fibroelastolytic papulosis with fractionated carbon dioxide laser.

Fibroelastolytic papulosis (FEP) is an acquired elastic tissue disorder that presents as white-to-yellow papules and plaques usually occurring on the neck. Although the lesions are often asymptomatic, their appearance may be distressing to patients. FEP has been treated with topical tretinoin in one case report ( 1 ). Other reports have not mentioned treatment for this rare disorder ( 1-6 ). We present a case of FEP successfully treated with a fractionated carbon dioxide (CO2) laser.

Vitamin E attenuates homocysteine and cholesterol induced damage in rat aorta.

BACKGROUND: The aim of this study was to investigate the effect of vitamin E on homocysteine and cholesterol-induced damage of rat aorta. METHODS: Wistar rats (all fed with a vitamin E poor diet) were divided into five groups. Control group was fed with the diet only, the second group received 1 mg kg(-1) day(-1) L-methionine in drinking water, the third group was fed with 2% cholesterol containing diet, the fourth group received L-methionine and cholesterol together, and the fifth group was fed with L-methionine and cholesterol and received intramuscular injections of vitamin E. After 4 weeks serum homocysteine, cholesterol and vitamin E levels were measured; aortas were removed; collagen and elastin and the major extracellular matrix components were evaluated microscopically as indicators of aortic degeneration. Aortic collagen content was measured by a colorimetric hydroxyproline assay. RESULTS: Four-week diet supplementation with methionine and cholesterol caused a twofold increase in serum homocysteine and 22% increase in serum cholesterol levels; endothelial damage and degenerative alterations in the aortic media were observed, as indicated by the dissociation of elastic fibers and accumulation of collagen. Vitamin E completely prevented the accumulation of collagen and largely prevented aorta damage as shown by the morphological data. CONCLUSION: The results indicate that, even moderate increases in homocysteine and cholesterol levels are sufficient to induce vascular degeneration that may be prevented by vitamin E supplementation.

Chondroitinase injection improves keloid pathology by reorganizing the extracellular matrix with regenerated elastic fibers.

Keloids are a proliferative fibrotic disease characterized by abnormal accumulation of extracellular matrix in the dermis. Keloid lesions lack skin plasticity due to deficiencies in elastic fiber formation in the extracellular matrix. The loss of elastic fiber is caused by excessive accumulation of chondroitin sulfate (CS), a sulfated glycosaminoglycan. However, there is no radical cure for keloids. Using a model system, we show herein that treatment of keloid tissues with chondroitinase ABC, an enzyme that specifically digests CS, improves clinical features of keloids. Keloid tissues obtained from patients were grafted on nude mice, and chondroitinase ABC was injected into the grafted keloid tissues. Chondroitinase ABC treatment significantly reduced the volume of keloid implants concomitant with recovery of elastic fiber formation. These results suggest that chondroitinase ABC injection is an effective therapy for keloid.

Effect of vitamin D on aortic remodeling in streptozotocin-induced diabetes.

BACKGROUND: Diabetes mellitus is associated with micro- and macrovascular complications and increased cardiovascular risk. Elevated levels of serum asymmetric dimethylarginine (ADMA) may be responsible for endothelial dysfunction associated with diabetes-induced vascular impairment. Vitamin D may have potential protective effects against arterial stiffening. This study aimed to examine both the effects of diabetes on the functional/structural properties of the aorta and the endothelial function and the effects of vitamin D supplementation. METHODS: Male Wistar rats (n = 30) were randomly assigned to control untreated, diabetic untreated, and diabetic + cholecalciferol groups. Diabetes was induced by intraperitoneal injection of streptozotocin, followed by oral administration of cholecalciferol (500 IU/kg) for 10 weeks in the treatment group. Aortic pulse wave velocity (PWV) was recorded over a mean arterial pressure (MAP) range of 50 to 200 mmHg using a dual pressure sensor catheter. Intravenous infusion of phenylephrine and nitroglycerine was used to increase and decrease MAP, respectively. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured using a radioimmune assay. ADMA levels in serum were measured by enzyme-linked immunoassay. Aortic samples were collected for histomorphometrical analysis. RESULTS: PWV up to MAP 170 mmHg did not reveal any significant differences between all groups, but in diabetic rats, PWV was significantly elevated across MAP range between 170 and 200 mmHg. Isobaric PWV was similar between the treated and untreated diabetic groups, despite significant differences in the levels of serum 25(OH)D (493 ± 125 nmol/L vs 108 ± 38 nmol/L, respectively). Serum levels of ADMA were similarly increased in the treated and untreated diabetic groups, compared to the control group. The concentration and integrity of the elastic lamellae in the medial layer of the aorta was impaired in untreated diabetic rats and improved by vitamin D supplementation. CONCLUSION: PWV profile determined under isobaric conditions demonstrated differential effects of uncontrolled diabetes on aortic stiffness. Diabetes was also associated with elevated serum levels of ADMA. Vitamin D supplementation did not improve the functional indices of aortic stiffness or endothelial function, but prevented the fragmentation of elastic fibers in the aortic media.

[Annular elastolytic giant cell granuloma]. / Granulome élastolytique annulaire à cellules géantes.

BACKGROUND: Annular elastolytic giant cell granuloma (AEGCG) is a rare form of granulomatous dermatosis. It is characterised histologically by phagocytosis of elastic fibres by multinucleated cells. We report a favourable outcome in a case of AEGCG following PUVA therapy and treatment with synthetic antimalarials. PATIENTS AND METHODS: A 67-year-old retired wine grower presented with highly pruritic annular lesions with raised borders on the shoulders and trunk that had been present for several months. Histological examination of a biopsy sample from the erythematous border was characteristic of AEGCG. Various topical treatments proved ineffective and systemic corticosteroids attenuated the patient's pruritus but had no effect on the skin lesions. PUVA therapy resulted in regression of lesions on the trunk, but the rash spread to the patient's arms and was covered with epidermal microcysts. PUVA therapy was discontinued and treatment with a synthetic antimalarial (hydroxychloroquine 400mg/d) was initiated, resulting in complete regression of the lesions. DISCUSSION: AEGC was isolated in 1979 by Hanke et al. on the basis of five cases seen in females. This is a rare form of dermatosis with some 30 cases being reported in the English literature. The clinical aspect is fairly evocative, with erythematous papular lesions, either alone or in groups, with a raised border and a lighter centre tending towards atrophy. In most cases, the lesions are found predominantly in areas exposed to sunlight. The histological appearance is characteristic, with an image of giant cell elastophagic granuloma from which the name of the disease is taken. This appearance allows the disease to be differentiated from a number of other granulomatous diseases. The aetiology is unknown and treatment is empirical. Spontaneous cure can occur and consistent results have not been obtained with any treatments. In our case, PUVA was partly successful, and the synthetic antimalarials resulted in complete regression of residual lesions.

New clinical outcomes utilizing a 1064-nm Nd:YAG laser for lipolysis of the torso oblique region.

OBJECTIVES: The safety and efficacy of a 1064-nm Nd:YAG laser (Cynosure, Westford, USA) utilizing a 300-microm optical fiber and a 1-mm diameter micro-cannula were evaluated as a treatment for reduction in the appearance or elimination of unwanted fat in the lower back/flanks ('love handles'). In addition, the use of the laser for tightening the skin and collagen regeneration in the area of lipolysis was assessed through biopsies. METHODS: Ten subjects with unwanted flaccidity and fat deposits in the oblique region of the torso were enrolled in the study. Subjects underwent a single laser lipolysis treatment followed by aspiration of the treatment area. The total tumescence used, laser energy delivered, and tissue removed was recorded for each subject. All subjects had baseline photographs taken and their weight recorded prior to treatment. Pregnancy tests (if applicable) were performed prior to treatment as well. Three subjects had 4-mm biopsies taken at baseline and 6 months to evaluate collagen regeneration. Collagen and elastic tissue fibers were evaluated using special routine stains and histochemical stains designed to highlight these dermal components. Follow-up visits were conducted at 1 week, 1 month, 3 months and 6 months following treatment to evaluate side effects, weight loss and laxity. Additionally, patients kept an evaluation log for each of the first 7 days following treatment. At the 6-month conclusion, patient satisfaction was recorded. RESULTS: Laser lipolysis procedures with subsequent aspiration were performed bilaterally on the flanks of 10 subjects. At 1-week post-treatment, 80% of the subjects demonstrated reduction in laxity. Similarly, 100% of patients showed visible skin improvement at 1 month, with 70% recording a score of 2 (good improvement). Three-month evaluations yielded one patient (10%) with a score of 3 (excellent improvement) and seven patients (70%) with a score of 2. Histology reports confirmed the visual clinical outcomes, describing thicker collagen bundles at 6 months, as well as coagulation of blood vessels and adipocytes. Side effects were mild and transient in nature, and the majority of discomfort, redness, bruising, swelling, and tingling experienced was resolved within 1 week post-procedure. The treatment was well tolerated and efficacious, with 90% of patients rating their results as good or excellent and 100% of patients reporting that they would recommend the procedure. CONCLUSION: The use of the 1064-nm Nd:YAG laser with a 300-microm fiber demonstrated the ability to treat adipose tissue in the highly vascular flank area with favorable efficacy and safety. Patients exhibited a quick recovery time and excellent tolerance, as well as visually improved skin.

Evaluation of an onion extract, Centella asiatica, and hyaluronic acid cream in the appearance of striae rubra.

This study evaluated the effect of an onion extract cream with Centella asiatica and hyaluronic acid in improving the appearance of striae rubra (SR). Women participants with bilateral, outer aspect of the thigh SR were randomized to apply a quarter-sized amount of the onion extract cream twice daily for 12 weeks to the randomized left or right, outer aspect of the thigh. No treatment was administered to the contralateral side. Participants were evaluated at weeks 2, 4, 8, and 12. Primary efficacy endpoints included color, texture, softness, and overall appearance of SR by the participant and investigator at week 12. The treated thigh demonstrated a statistically significant difference in the mean change in participant and investigator evaluations in overall appearance, texture, color, and softness compared with the untreated thigh at week 12. No adverse events occurred during the study. The onion extract cream was well tolerated and significantly improved the appearance of SR in women.

Prevention of aortic elastic lamina defects by losartan in apolipoprotein(E)-deficient mouse.

1. In a previous study, we identified prevalent internal elastic lamina (IEL) defects in the aorta of hyperlipidaemic apolipoprotein E (ApoE)-deficient mice that are thought to provide a structural basis for the development of atherosclerosis and intimal thickening. In the present study, we examined the effects of losartan, an angiotensin AT1 receptor antagonist, on the development of IEL defects. 2. Male 18-week-old ApoE-deficient mice (maintained on a normal diet) were treated with losartan (3 or 30 mg/kg per day) for 10 weeks via the drinking water. The IEL defects were quantified histologically by measuring the continuity of the IEL within the inner curvature of the aortic arch. 3. In untreated animals, there was an age-dependent increase in IEL defects from 7.2 ± 2.1% at 18 weeks to 13.8 ± 4.0% at 28 weeks. Treatment with the high dose of losartan significantly prevented the development of IEL defects (4.7 ± 1.3% at 28 weeks; P < 0.05 vs untreated). This effect was independent of changes in blood pressure or plasma lipid levels. Using quantitative real-time polymerase chain reaction, we found that the effects of losartan were not associated with changes in levels of matrix metalloproteinase (MMP)-2 and MMP-9, tissue inhibitor of matrix metalloproteinase-1 or inflammatory markers in the aorta. 4. The results suggest that the renin-angiotensin system may contribute to the development of aortic IEL defects in a blood pressure-independent manner.

Bipolar fractional radiofrequency treatment induces neoelastogenesis and neocollagenesis.

BACKGROUND: We recently introduced Renesis, a novel minimally invasive radiofrequency (RF) device, for the treatment of human skin. The wound healing response post-fractional RF (FRF) treatment was examined in human subjects. STUDY DESIGN: The FRF system delivered RF energy directly within the dermis via 5 micro-needle electrode pairs. Tissue temperature was held at 72 degrees C for 4 seconds using an intelligent feedback system. The wound healing response was evaluated histologically and by RT-PCR up to 10 weeks post-RF treatment. Neoelastogenesis and the role of heat shock proteins (HSPs) were assessed by immunohistochemistry. RESULTS: FRF treatment generated a RF thermal zone (RFTZ) pattern in the reticular dermis that consisted of zones of denatured collagen separated by zones of spared dermis. RFTZs were observed through day 28 post-treatment but were replaced by new dermal tissue by 10 weeks. HSP72 expression rapidly diminished after day 2 while HSP47 expression increased progressively through 10 weeks. Reticular dermal volume, cellularity, hyaluronic acid, and elastin content increased. RT-PCR studies revealed an immediate increase in IL-1beta, TNF-alpha, and MMP-13 while MMP-1, HSP72, HSP47, and TGF-beta levels increased by 2 days. We also observed a marked induction of tropoelastin, fibrillin, as well as procollagens 1 and 3 by 28 days post-treatment. CONCLUSION: Our study revealed a vigorous wound healing response is initiated post-treatment, with progressive increase in inflammatory cell infiltration from day 2 through 10 weeks. An active dermal remodeling process driven by the collagen chaperone HSP47 led to complete replacement of RFTZs with new collagen by 10 weeks post-treatment. Furthermore, using both immunohistochemical and PCR studies, we successfully demonstrated for the first time evidence of profound neoelastogenesis following RF treatment of human skin. The combination of neoelastogenesis and neocollagenesis induced by treatment with the FRF system may provide a reliable treatment option for skin laxity and/or rhytids.

The effect of aqueous ethanolic extract of Alchornea cordifolia leaf on the histology of the aorta of Wistar rats.

Sixteen Wistar rats weighing 160-180 g were used in this research work. The rats were divided into three groups, designated A, B, and C. Group A served as the control and consisted of four rats, whereas groups B and C consisted of six rats each and served as the experimental groups. A. cordifolia leaf extract was administered to the experimental groups B and C orally at a dose of 250 mg/kg/day and 500 mg/kg/day respectively. The control group received 0.5 ml of normal saline. The administration lasted for fourteenth days. All the animals were given feed and water freely. The rats were sacrificed after the fourteenth day of administration of herbal extract and the aortae harvested and processed histologically using haematoxylin and eosin staining technique. Tissue sections revealed that A. cordifolia is capable of inducing elastogenesis in the aorta. This attribute of the herb may be beneficial in increasing elastic recoil of the aortic wall and may reduce blood pressure.

Different solutions used for submucosal injection influenced early healing of gastric endoscopic mucosal resection in a preclinical study in experimental pigs.

BACKGROUND: We hypothesised that different solutions for submucosal injection may influence early healing of endoscopic mucosal resection (EMR). The aim of this study was to evaluate histological and immunological changes after EMR in experimental pigs. MATERIALS AND METHODS: Two parallel EMRs on the anterior and posterior wall of the gastric body were performed by means of the cap technique in 21 female pigs. A glycerol-based solution (anterior EMR) and hydroxypropyl methylcellulose solution (posterior EMR) were applied for submucosal injection. The animals were sacrificed 7 days later, and tissue sections of all EMRs were stained using combined trichrome. Computer image analysis was used for objective evaluation of elastic and collagen fibres content. Two-colour indirect immunophenotyping of blood and gastric samples were performed using mouse anti-pig monoclonal antibodies. RESULTS: The values of collagen fibre content 7 days after EMR were significantly higher in lesions after the use of solution A in comparison with solution B (2.10 +/- 0.25% versus 1.57 +/- 0.25%, p = 0.009). Concordant results were found in elastic fibres (3.23 +/- 0.49% versus 2.93 +/- 0.61%, p = 0.018). No systemic changes in major leukocyte subpopulations were found. In gastric tissue, lymphocyte subsets exhibited only minor changes. CD4(+) T-lymphocytes were increased in the healing tissue after EMR using solution A (17.08 +/- 9.24% versus 9.76 +/- 7.97%, p = 0.011). Significant increase of SWC3(+) leukocytes was observed after EMR using solution B (47.70 +/- 25.41% versus 18.70 +/- 12.16%, p = 0.001). CONCLUSIONS: The use of glycerol-based solution for submucosal injection was associated with more pronounced histological signs of early healing of EMRs compared with hydroxypropyl methylcellulose.

Disabling pansclerotic morphea of childhood--unusual case and management challenges.

Morphea, also known as localized scleroderma is a chronic disease of unknown etiology, characterized by fibrous deposition and obliteration of vessels in the skin. This disease has a wide clinical spectrum, ranging from mild hyperpigmented plaques to severe, invalidating generalized and pansclerotic forms. Disabling pansclerotic morphea of childhood is a rare and debilitating variant of localized scleroderma, characterized by a rapid progression of deep cutaneous fibrosis that involves the dermis and the subcutaneous adipose tissue but also fascia, muscles, and bone. Contractures and musculoskeletal atrophy develop and the disease has an invalidating and even fatal course. We present an unusual case of severe morphea in a 19-year-old girl, with a polymorphous clinical picture consisting of plaques, linear and pansclerotic, circumferential lesions, with symmetric, invalidating involvement of all limbs and explosive evolution with centripetal progression. This case emphasizes the unpredictable character of morphea evolution, the possible severe prognosis and the therapeutic challenges raised by the generalized, disabling forms of this disease.

Análise mecânica e histológica do tegumento facial com seqüela de queimadura após tratamento tópico com tretinoína / Mechanical and histological analysis of the facial skin with burn sequelae after tretinoin topical treatment

Pacientes vítimas de queimaduras convivem com seqüelas que podem diminuir sua auto-estima e qualidade de vida. Vítimas de queimaduras faciais são excluídos social e profissionalmente solicitando ao cirurgião plástico tratamentos complementares aos cirúrgicos para melhoria da aparência e qualidade da pele. Quinze pacientes do sexo feminino, vítimas de queimadura facial por álcool com mais de dois anos de evolução, foram submetidas a tratamento tópico com tretinoína 0,05% durante um ano, com exceção da região pré-auricular. Após este período, duas biópsias faciais, uma na região pré-auricular e outra um centímetro abaixo do lóbulo da orelha, foram realizadas para comparar áreas não tratadas e tratadas. Os fragmentos biopsiados foram submetidos à análise mecânica e histológica. Medidas de resistência e elastância foram significativamente menores nas áreas tratadas (resistência p=0,03 e elastância p<0,05). Não houve diferença estatística entre as densidades de fibras colágenas totais e de colágeno tipo III, fibras elásticas e versicam nas áreas tratadas e não tratadas...

Patients that are victims of burns live with sequelae that may decrease their self-esteem and quality of life. Victims of facial burns are excluded from social and professional life. They request the plastic surgeon to provide complementary treatment to the surgical one, so as to improve their appearance and the quality of the skin. Fifteen female patients, victims of facial burns caused by alcohol with more than two years of evolution, underwent topical treatment with 0.05% tretinoin during one year. During this period, a small area at the pre-auricular region was spared from the treatment. After this period two facial biopsies, one in the pre-auricular area and the other one, 1 cm below the ear lobe, were performed to compare treated and non treated areas. Skin strips underwent a mechanical and histological analysis. Measurements of resistance and elasticity were significantly lower in the treated skin as compared with non-treated skin (resistance, p=0.03 and elasticity, p<0.05). The density of collagen and collagen type III fibers, elastic fibers and versican was not significantly different between treated and non-treated skins...

Inhibition of ultraviolet-B-induced wrinkle formation by an elastase-inhibiting herbal extract: implication for the mechanism underlying elastase-associated wrinkles.

BACKGROUND: Previously, we have demonstrated that fibroblast-derived elastase plays an essential role in the increased three-dimensional tortuosity of elastic fibers, contributing to the loss of skin elasticity in UV-B-exposed skin. This decrease in skin elasticity is closely associated with the formation of wrinkles induced by UV exposure. OBJECTIVE: To further clarify the role of elastase in the formation of wrinkles induced by UV exposure, we assessed the effects of an extract of Zingiber officinale (L.) Rose (which inhibits fibroblast-derived elastase) on the wrinkle formation induced by chronic UV-B irradiation. RESULTS: Topical application of an extract of Zingiber officinale (L.) Rose to rat or hairless mouse skin significantly inhibited the wrinkle formation induced by chronic UV-B irradiation at a suberythemal dose, which was accompanied by a significant prevention of the decrease in skin elasticity in both types of animal skin. In the rat hind limb skin, consistent with the inhibition of reduced skin elasticity, wrinkle prevention occurred concomitantly with a significant decrease in the curling and three-dimensional tortuosity of dermal elastic fibers. CONCLUSION: Our results indicate that herbal extracts with an ability to inhibit fibroblast-derived elastase may prove to be effective as anti-wrinkling agents, confirming the important role of elastase in UV-B-induced wrinkle formation.

[Granular media calcinosis of the aorta. Structural findings, historical review and pathogenetic significance]. / Granuläre Mediakalzinose der Aorta. Strukturelle Befunde, historischer Rückblick und pathogenetische Bedeutung.

Granular mediacalcinosis of the aorta seems to be a forgotten phenomenon that had been intensively investigated at the beginning of the past century. Without knowledge of this older literature we were, first of all, astonished to find in histological sections from aortic aneurysms, appearing "normal" in the H&E stain, severe calcifications of the media in von Kóssa and Alizarin red S stained sections. Therefore, 24 operation specimens of aneurysms were investigated with several morphological methods. In all cases, light microscopy exhibited granular medial calcification with a slight increase of the severity in specimens from older patients. Scanning electron microscopy on paraffin sections revealed calcified globules with diameters of about 1 micron localized between the elastic laminae. By transmission electron microscopy these calcospherites occupied the space between the elastic laminae. X-ray microanalysis exhibited high amounts of calcium and phosphorus and a smaller amount of magnesium. This atomic composition supports the findings of Reid and Andersen (69) indicating that these calcifications are due to the deposition of whitlockite. These morphological findings are supplemented by a review of the older literature. The biological significance of this calcification remains unknown. On the one hand, it may be responsible for the increasing stiffness of the aorta in older age groups--and, on the other hand, a pathogenetic role for the development of dissecting aneurysms cannot be excluded. This may be supported by the effect of beta-aminopropionitril in lathyric rats with destruction of the interlaminar fibers, described by Nakashima and Sueishi (65): it seems possible that a focal increased calcification in the human aorta may disturb the connection between the elastic laminae, thus, facilitating their separation.

Aortic wall damage in mice unable to synthesize ascorbic acid.

By inactivating the gene for L-gulono-gamma-lactone oxidase, a key enzyme in ascorbic acid synthesis, we have generated mice that, like humans, depend on dietary vitamin C. Regular chow, containing about 110 mg/kg of vitamin C, is unable to support the growth of the mutant mice, which require L-ascorbic acid supplemented in their drinking water (330 mg/liter). Upon withdrawal of supplementation, plasma and tissue ascorbic acid levels decreased to 10-15% of normal within 2 weeks, and after 5 weeks the mutants became anemic, began to lose weight, and die. Plasma total antioxidative capacities were approximately 37% normal in homozygotes after feeding the unsupplemented diet for 3-5 weeks. As plasma ascorbic acid decreased, small, but significant, increases in total cholesterol and decreases in high density lipoprotein cholesterol were observed. The most striking effects of the marginal dietary vitamin C were alterations in the wall of aorta, evidenced by the disruption of elastic laminae, smooth muscle cell proliferation, and focal endothelial desquamation of the luminal surface. Thus, marginal vitamin C deficiency affects the vascular integrity of mice unable to synthesize ascorbic acid, with potentially profound effects on the pathogenesis of vascular diseases. Breeding the vitamin C-dependent mice with mice carrying defined genetic mutations will provide numerous opportunities for systematic studies of the role of antioxidants in health and disease.

Arterial elastorrhexis: manifestation of a generalized elastic tissue disorder in beta-thalassaemia major.

Pseudoxanthoma elasticum-like lesions of the eye and skin are frequently observed in beta-thalassaemia, and there has been speculation about associated vascular lesions. This led to our study of histopathological material from thalassaemic patients. Histological re-examination was made of a series of 45 spleens and 45 surgical liver biopsies from 45 patients with beta-thalassaemia major, aged 6-25 yr and treated over the 20-yr period 1975-95. Correlations between clinical, laboratory and histological findings were demonstrated by statistical analysis. Arteriopathy characterized by fragmentation and multiple defects of the internal elastic lamina ('arterial elastorrhexis'), with deposits of iron and calcium salts, was found in the hilar arteries of the spleen with a frequency of 96%. Similar lesions were observed in the parenchymal arteries and the stromal elastic tissue ('stromal elastorrhexis') of the spleen, liver and lymph nodes. Arterial and elastic tissue alterations appear in the first decade of life and become generalized over the course of the disease, independent of the time of onset of transfusion and iron chelation therapy. Arterial elastorrhexis is the earliest and most frequent manifestation of a systemic elastic tissue disorder in beta-thalassaemia major. It appears to be an acquired pseudoxanthoma elasticum-like syndrome, related primarily to tissue hypoxia and disturbance of elastin metabolism.