[Therapeutic escalation in a case of nevoid hyperkeratosis of the areola and the nipple]. / Escalade thérapeutique devant un cas d'hyperkératose nævoïde de l'aréole et du mamelon.

Nevoid hyperkeratosis of the nipple areola complex (NAC) is a rare dermatological pathology of unknown etiology, first described in 1923. It is a benign condition characterized by verrucous thickening and brownish discoloration of the NAC. We described the case of a 26-year-old woman with bilateral nevoid hyperkeratosis of the NAC. Several lines of treatment have been used with varying efficacy: conservative (calcipotriol and local retinoids), semi-conservative (CO2 laser) and surgical (excision and total skin graft). The final result is very satisfactory and without recurrence at 1 year follow-up.

[Rose necrosis: Necrotizing granulomatous reaction with infected node at red pigment of a tattoo]. / La nécrose de la rose : réaction granulomateuse et nécrotique avec adénite au pigment rouge d'un tatouage.

INTRODUCTION: Nowadays, necrotizing cutaneous reaction after a tattoo is rare especially with the sterile tattoo equipment and antisepsis rules. We report the rare case of a necrotizing reaction secondary to a granulomatous reaction after a red tattoo, with a satellite node. CASE REPORT: A 40-year-old patient suffering from a granulomatous reaction to red dye of a large pectoral tattoo, with cutaneous and sub-cutaneous necrosis, and an infected axillary node. This pectoral tattoo also triggered a necrotizing granulomatous reaction on red-pigmented areas of other older tattoos. Local treatments (dressings, antibiotics, repeated excisions of necrotizing tissues) did not stop the allergic reaction, and an infectious origin was eliminated. The patient asked for a complete excision of the pectoral tattoo. Black intramacrophagic pigment was found in the black lymph node analysed. We did not experience any complications and the patient is satisfied with the results. DISCUSSION: Very few examples of cutaneous necrotizing secondary to a tattoo have been found in the literature. The hypothesis of a primitive infection that had secondarily led to necrosis is refuted by the lack of infective structures found in the analysed node, and most of all by the same reaction on other older tattoos on red-pigmented areas. This rare complication must be known by plastic surgeons, who will probably be called upon to take care of more and more tattooed patients. CONCLUSION: Even if it's rare, necrosis with a granulomatous reaction to red pigment after a tattoo must be known. This case illustrates a very violent immune reaction where infection was not proved.

[Gorlin syndrome: photodynamic therapy, as a useful adjunct to surgery]. / Syndrome de Gorlin : la photothérapie dynamique, technique complémentaire du traitement chirurgical.

Gorlin syndrome, also called nevoid basal cell carcinoma syndrome, is well known by dermatologists. Since its onset, 10 years ago, photodynamic therapy has found new applications and is now currently used to cure single or multiple basal cell carcinomas, with good results and without residual scars. We recall some of the basic principles of this technique, as well as its indications in Gorlin syndrome, which we illustrate with one case. Plastic surgeons must consider this relatively new technique, developed by dermatologists, as a useful adjunct to surgery in the management of Gorlin syndrome.

Spontaneous pregnancy-induced hypertension and intrauterine growth restriction in rats.

The SHHF/Mcc-fa(cp) (spontaneous hypertension and heart failure) rat is advanced as a novel and suitable non-primate model of pregnancy-associated hypertension and fetal growth restriction because it simultaneously has spontaneous pregnancy-associated hypertension, small for gestational age (SGA) offsprings, and altered placental gene expression. Pregnancy-associated hypertension is a major contributor to maternal and fetal morbidity and mortality with the potential to result in maternal death and the need for iatrogenic preterm delivery. It has been reported to develop spontaneously in humans, but not in animals; consequently, progress in identifying the cause and pathogenesis of this disorder has been hampered. Spontaneous hypertension and heart failure rats develop hypertension spontaneously as they age, therefore we sought to determine whether these rats developed hypertension and SGA offsprings during pregnancy. Our results show that systolic blood pressure (BP) increased >40 mm Hg by the end of the first trimester and remained at this elevated level for the remainder of pregnancy, but decreased after parturition. Placenta weights of SHHF rats (0.60 +/- 0.02 g, n = 36) were significantly higher than Wistar-Kyoto (WKY) rats (0.42 +/- 0.01 g, n = 22, P < .05), but pup weights were significantly lower (2.68 +/- 0.06 g for SHHF rats compared to 3.24 +/- 0.06 g for WKY controls, P < .05). Histologic examination revealed pathologic lesions in neither heart, liver, placenta, nor kidney. L-Arginine administered in drinking water prevented the elevation of BP, particularly during the third trimester. Placentas from SHHF rats displayed altered expression of several genes whose protein products have been implicated in preeclampsia, including serotonin receptor, sodium channel, carbonic anhydrase, estrogen receptor regulator, major histocompatibility complex proteins, superoxide dismutase, and angiotensiogen. In addition, gene expression profiling showed alteration of a number of subcellular putative myristoylproteins not previously associated with preeclampsia, particularly those engaged in post-translational modifications in the placenta. Thus, SHHF rats may be a valuable tool, because it simultaneously has spontaneous pregnancy-associated hypertension, SGA offsprings, and altered placental gene expression.

Hypertension and insulin resistant models have divergent propensities to learned helpless behavior in rodents.

The induction of learned helpless (LH) behavior in rats is a widely used model of unipolar depression. Recent studies have linked depression with hypertension and insulin resistance as observed in obesity, but the propensity of these disorders to manifest depression has not been reported. In this study, the LH behavioral paradigm was exploited in a model of hypertension (Dahl rat) and of insulin resistance (Zucker rat) to determine the propensity of these models to develop depression and to examine the profile of markers for the propensity of the cardiovascular system (plasma renin activity) and of the hypothalamus-pituitary-adrenal axis (corticosterone) in the display of propensity to depression. Results show that Zucker rats displayed the lowest propensity to the development of LH behavior (12%), followed by the control Sprague-Dawley rats (27%), and then Dahl rats (66%). In contrast, congenital learned helpless (cLH) rats, a genetically bred strain for animal depression, had the highest propensity (>90%). A gender effect was observed in the Zucker and cLH rats, with females showing an increased propensity to develop LH behavior. Plasma renin activity in the Dahl and Sprague-Dawley rats after the LH stress paradigm was not significantly different from baseline. In contrast, Zucker rats, with the lowest propensity to LH behavior, demonstrated a threefold increase in plasma renin activity after stress. Congenital LH rats, with the highest propensity to LH behavior, exhibited a significantly lower increase (43%) in plasma renin activity after stress. Hyporesponsive hypothalamus-pituitary-adrenal (HPA) axis functioning correlated with propensity of LH behavior. Stress-induced corticosterone levels increased under twofold in cLH rats, whereas they increased more than sevenfold in Zucker rats. Taken together, these studies suggest that whereas genetically prone hypertensive rats have a very high propensity to depression, insulin-resistant rats have a profound resistance to depression. Moreover, a hyporesponsive HPA axis may be a marker for disorders that are comorbid with depression, whereas a hyperresponsive renin-angiotensin system may be indicative of resilience.

Increased basal activity of the HPA axis and renin-angiotensin system in congenital learned helpless rats exposed to stress early in development.

Learned helpless behavior has been successfully bred in rats and designated as a genetic animal model of human depression and/or anxiety. Since congenital learned helpless animals have an impaired stress response in adulthood, we examined the effects of early stressors (at postnatal day 7, 14 or 21) on the hypothalamic-pituitary-adrenal axis and the renin-angiotensin system. The functioning of the hypothalamic-pituitary-adrenal axis was monitored through changes in corticosterone plasma levels in the adult animals after acute exposure to cold stress and maternal deprivation early in development. Renin-angiotensin system functioning was assessed by plasma renin activity. Unstressed congenital learned helpless rats had corticosterone levels that were similar to control animals (congenital non-learned helpless rats not stressed during development), but unstressed plasma renin activity levels of congenital learned helpless rats were lower than congenital non-learned helpless rats. There was a step-wise increase in corticosterone plasma levels in the congenital learned helpless rats with age of acute presentation of either cold stress or maternal deprivation stress (day 7, 49%; day 14, 84%; and day 21, 543% for cold stress). However, these baseline corticosterone levels were significantly lower in congenital learned helpless rats compared to congenital non-learned helpless controls. Similarly, in response to early exposure to cold stress and maternal deprivation, there was an increase in plasma renin activity levels of congenital learned helpless rats with age of presentation to either stressors. However, this increase in plasma renin activity levels was not evident in congenital non-learned helpless controls. Taken together, these results suggest that exposure to stress early in development has long-term effects on both the hypothalamic pituitary-adrenal axis and the renin-angiotensin system, two neuroendocrine indicators of stress responsivity.

A mental health capitation program: I. Patient outcomes.

OBJECTIVE: The Monroe-Livingston demonstration project's capitation payment system (CPS) was evaluated to determine whether capitated funding of mental health care, compared with fee-for-service funding, could reduce hospitalization rates and improve functioning and symptoms for severely and persistently mentally ill adults without increasing the total cost of care. METHODS: The experiment was a communitywide prerandomized clinical trial involving 422 patients. Patients who were randomized into the experimental group were eligible for enrollment in a capitated funding program administered by one of five community mental health centers. Those randomized into the control group received standard fee-based services. Follow-up interviews with patients one and two years after enrollment in the study assessed changes in symptoms and functioning. Data files of the membership corporation that coordinated community mental health services for the CPS provided measures of study patients' use of inpatient mental health services. RESULTS: During the two-year follow-up period, patients in the experimental group had significantly fewer hospital inpatient days than patients in the control group, but the two groups had no significant differences in functioning or level of symptoms. CONCLUSIONS: The CPS successfully maintained severely ill patients in the community but did not improve their functioning or level of symptoms.

Hydrogen and potassium regulation of (pro)renin processing and secretion.

H and K ions play central roles in prorenin processing and secretion, and prorenin is abnormally expressed in H and K disorders. At the surface membrane of juxtaglomerular (JG) cells, K is sensed and regulated by K channels (coupled to Cl channels and activated by excess Ca), Na-K-adenosinetriphosphatase, and a KCl/H exchange transporter (regulated by Ca). In JG cell granular membrane, K flux is regulated by K channels and a KCl/H exchange transporter (activated by Ca). H channels and a H pump reside in the granular membrane, which maintain H concentration in the granular matrix at least two orders of magnitude greater than in cytosol. The H pump may also be responsible for maintaining the acidic matrix required for maximal prorenin processing to renin by prohormone convertase for human renin (PCren), the prorenin convertase. These molecules form the core of a chemiosmotic system, which appears to regulate both prorenin processing and renin secretion. Renin secretion and prorenin processing appear to be of more than causal significance in clinical disorders characterized by chemiosmotic imbalance. A critical review of the literature supports the following general conclusions. First, hyperrenin state defines the initial phase in the pathogenesis of heart disease, diabetes mellitus, and hypertension. Second, low-renin syndrome defines the transition-to-establish phase in the pathogenesis of heart disease, diabetes mellitus, and hypertension in which the key feature is renin secretory hyporesponsivity. Third, renin disorders are usually associated with other endocrine disorders (polyendocrinopathies types I, II, and III), suggesting that renin may be an important molecule in the processing of chemiosmotic forces. The key chemiosmotic molecules (K and H) are also important in the processing and export of most (if not all) hormones. Thus, by regulating K and H homeostasis, renin may regulate the endocrine system.

Regulation of renin processing and secretion: chemiosmotic control and novel secretory pathway.

The renin-angiotensin-aldosterone system (RAAS) plays an important role in cardiovascular and electrolyte regulation in health and disease. Juxtaglomerular cells in the kidney regulate endocrine RAAS by physiologically controlling conversion of prorenin and secretion of renin. The classical baroceptor, neurogenic, and macula densa mechanisms regulate renin expression at the cellular level by Ca2+, adenosine 3',5'-cyclic monophosphate (cAMP), and chemiosmotic forces (K+, Cl-, and water flux coupled to H+ movement). The baroceptor mechanism (through Ca2+) activates K+ and Cl- channels in the surface membrane and deactivates a KCl-H+ exchange chemiosmotic transporter in the secretory granular membrane. The neurogenic mechanism (through cAMP) promotes prorenin processing to renin. The macula densa mechanism (through K+ and Cl-) involves the processing of prorenin to renin. Ca2+, by inhibiting the KCl-H+ exchange transporter, prevents secretory granules from engaging in chemiosmotically mediated exocytosis. cAMP, on the other hand, by stimulating H+ influx, provides the acidic granular environment for prorenin processing to renin. It is concluded that, in the presence of a favorable chemiosmotic environment, prorenin is processed to renin, which may then be secreted by regulative degranulation or divergence translocation, a novel secretory pathway used by several secretory proteins, including renin.

Chemiosmotic control of renin release from isolated renin granules of rat kidneys.

1. Renin-containing granules were isolated, characterized, and used to gain insight into a possible chemiosmotic mechanism of renin secretion. 2. Renin granules were obtained by a modification of the sucrose gradient method, which yielded a 67-fold purification of renin granules as assessed by marker enzymes, or a modification of the Percoll gradient, which yielded a 230-fold enrichment of renin granules. 3. Granular renin content was increased by chronic sodium deprivation and hypophysectomy. 4. Renin release from granules was inversely related to osmotic strength (150-900 mosmol l-1). pH had a biphasic effect on renin release, with greater stimulation at both acidic (pH 5) and alkaline (pH 8 and 9) pH. The pH effect was dependent on Cl-; raising Cl- stimulated release. This effect was abolished by-oligomycin and N,N'-dicyclohexylcarbodiimide (DCCD) at pH 5, but not at pH 8; the effect was enhanced by NH4+. 5. Either valinomycin or carbonyl cyanide m-chlorophenylhydrazone (CCCP) alone was without effect; but in combination they caused a potent stimulation at all pHs. Nigericin stimulated renin release at all pHs, but its effect required K+. 6. Raising K+ stimulated renin release from granules, whereas raising Na+ was without effect. Lowering Ca2+ below 10(-6) M significantly stimulated renin release. 7. Taken together, the evidence is consistent with the chemiosmotic hypothesis for the control of renin release from granules and may have some implications for the regulation of renin secretion from juxtaglomerular cells.

Stimulation of renin secretion by ethacrynic acid is independent of Na(+)-K(+)-2Cl- cotransport.

This study investigated the cellular mechanism of stimulation of renin secretion by the loop diuretic ethacrynic acid (EA) in rabbit renal cortical slices. The diuretic rapidly stimulated renin secretion reversibly and in a concentration-dependent manner. The stimulation was independent of the presence of Na+, Cl-, Ca2+, or other loop diuretics (furosemide and bumetanide) in the incubation media, suggesting that the stimulation in vitro was not dependent on the inhibitory effect of the diuretic on Na(+)-K(+)-2Cl-cotransport. The findings do not support the macula densa hypothesis. The stimulation by the diuretic was prevented and reversed by thiols such as cysteine and dithiothreitol, which also prevented and reversed the stimulation of renin secretion by the nondiuretic sulfhydryl reagent P-chloromercuriphenyl-sulfonate (PCMPS). These results suggest that EA stimulates renin secretion in vitro via reversible chemical reactions with specific membrane sulfhydryl groups that may have no functional role in the Na(+)-K(+)-2Cl- cotransport.

Mechanism for low renin in blacks: studies in hypophysectomised rat model.

Black people have a lower plasma renin activity (PRA) than is appropriate for the level of blood pressure, but the mechanism remains unknown. Studies in our laboratory, using the hypophysectomised (Hypox) rat model, have provided a partial explanation of the inappropriately low PRA with respect to BP. Kidneys were isolated and perfused and renin secretion responsiveness studied with isoproterenol (Iso) infusion, calcium (Ca) depletion, and pressure reduction; an enriched preparation of juxtaglomerular (JG) cells was prepared for determination of cellular renin content (CRC); and preparations of isolated renin granules (IRG) and plasma membrane vesicles (PMV) from the purified JG cells were used to assess the storage and compartmentalisation of renin. Renin secretion was lower in Hypox than in normal and sodium (Na) deprived rats. On the other hand, CRC, IRG, and PMV were identical (statistically) in Hypox and Na deprived rats. Despite identical content and storage, kidneys from Hypox rats secreted significantly less renin in response to Iso, Ca depletion, and low pressure. One interesting observation is that upon stimulation, PMV of Hypox rats stored a much larger percentage of renin than normal or Na deprived rats, suggesting that the PMV may play a role as a renin sink in the low PRA levels observed in the Hypox rats. Since black people have renin profiles and responsiveness similar to those in Hypox rats, this model may be useful in studying the mechanisms responsible for their lower PRA.