Benefits of Avène thermal hydrotherapy in chronic skin diseases and dermatological conditions: an overview.

The beneficial effects of Avène Thermal Spring Water (TSW), a low mineral content spring water, on chronic skin diseases have been recognized for more than two centuries. This article provides a brief overview of efficacy and tolerance data for Avène TSW from clinical studies conducted at the Avène Hydrotherapy Center in patients with chronic inflammatory skin diseases or temporary skin injuries. Avène TSW hydrotherapy is effective as adjuvant management for chronic skin diseases and dermatological conditions, relieving subjective and physical symptoms with excellent tolerance.

[Preliminary study for the implementation of standardized rounded doses of cytotoxic druqs]. / Etude préliminaire pour l'implémentation d'un dose-banding de chimiothérapie anticancéreuse.

BACKGROUND: "Dose-banding" is a concept of cytotoxic drugs standardization allowing the preparation in advance of standardized rounded doses (SRD covering the most frequently prescribed doses rounded to +/-5%. Standard doses will be prepared in advance by batch in order to increase production capacity and at the same time to regulate pharmacy workflow as well as to reduce patient waiting time. PURPOSE: To identify anticancer drugs suitable for dose banding and to fix standardized doses. METHODS: The interesting molecules are first selected in accordance with several criteria: preparations frequency, long-term physicochemical stability after reconstitution, repetition of the prescribed doses and savings opportunity. The selected molecules were: Carboplatin, Cetuximab, Cisplatin, Cyclophosphamide, Doxorubicin, 5-Fluorouracil, Gemcitabine, Oxaliplatine, Paclitaxel, Rituximab, Trastuzumab and Vinorelbine. We established an inventory of the prescriptions retrospectively for a period of six months in order to highlight the most often prescribed doses. For the analysis, we fixed bands with a standard deviation of +/- 5%, 7% and +/- 10%. RESULTS: Standardization of doses of chemotherapy was deemed interesting if > or =60% of the doses were standardisable with a maximum of five SRD and a minimum of one delivery per week, in order to guarantee a good turnover of the batch. A maximum of 5% standard deviation is added to those three criteria, the deviation currently accepted among our medical staff. After analyzing 3506 prescriptions, 7 molecules are eligible: Doxorubicine, 5-Fluorouracil infusion, 5-Fluorouracil pump, Gemcitabine, Paclitaxel, Rituximab, Trastuzumab and Vinorelbine, with a percentage of standardisation of 77% [SRD: 30 mg), 61% [SRD: 700 mg, 750 mg, 800 mgl, 75% (SRD: 4000 mg, 4500 mg, 5000 mg), 72% [SRD: 1600 mg, 1800 mg, 2000 mg), 61% [SRD: 140 mg, 150 mg, 160 mgl, 64% (SRD: 600 mg, 700 mg, 750 mg], 71% (SRD: 350 mg, 400 mg. 450 mgl et 62% [SRD: 40 mg, 50 mg] respectively. CONCLUSION: This preliminary study allows us to consider implementing the dose banding concept in order to optimize the chemotherapy circuit at our institution.

Oligogalacturonides improve tissue organization of in vitro reconstructed skin.

The aim of this study was to analyse the effects of oligogalacturonides obtained from apple pectin enzymatic hydrolysis (mainly composed of galacturonic acid and oligogalacturonides; OGA) on normal human keratinocytes behaviour using different in vitro models. We demonstrate that 0.01% OGA promotes epidermal growth, organization and stratification in an in vitro reconstructed skin. The presence and the in vivo-like location of epidermal differentiation markers (i.e. keratin 10, involucrin, desmoglein 1 and 3, and cathepsin D) confirms the histological analysis, and underlines the cohesion of the treated epidermis. On the opposite, 0.05% OGA delays epidermal growth and disturbs differentiation, showing that the positive effects of OGA are dependent on its concentration. In parallel, using collagen IV and laminin 332 substrates, two relevant components of dermal-epidermal basement membrane, we demonstrate that the presence of 0.01% OGA clearly stimulates keratinocytes spreading out, paralleled by a well-organized microfilament network. Keratinocytes develop more focal adhesions with the substrates, implicating α6ß4 on laminin 332. Cellular cohesion is also promoted by 0.01% OGA through the over-expression of integrins α2ß1 on collagen IV, and α3ß1 on laminin 332 at cell-cell junctions. Thus, by modulating integrins expression and organization, OGA 0.01% should improve cell-cell interactions and therefore dermal-epidermal cohesion. In conclusion, 0.01% OGA stimulates epidermal spreading and promotes keratinocytes attachment to basement membrane components by reorganizing cytoskeleton and modulating integrins recruitment. Furthermore, 0.01% OGA promotes epidermal differentiation and regulates epidermis homeostasis. Considering that OGA has a beneficial effect on parameters playing a key role in ageing, OGA can be presented as a new anti-ageing active ingredient.

Treatment options for metastatic colorectal cancer in patients with liver dysfunction due to malignancy.

BACKGROUND: The survival of colorectal cancer patients is frequently determined by the extent of metastatic invasion to the liver; in cases of major involvement, therapeutic strategies are limited because the liver is necessary for drug metabolism. MATERIAL AND METHODS: We have reviewed articles about the pharmacokinetic profiles of each drug used in colorectal cancer patients with hepatic dysfunction to determine which of these treatments are most feasible. RESULTS: Some drugs appear to be feasible options for patients with hepatic insufficiency. Agents such as 5-fluorouracil and oxaliplatin, as well as monoclonal antibodies such as bevacizumab, cetuximab, and panitumumab, can potentially be used in these cases. On the other hand, irinotecan and regorafenib cannot be recommended because of the risk of increased toxicity. CONCLUSION: Treatment of patients with colorectal cancer and liver dysfunction represents a major challenge because the prognosis is usually very poor and alteration of liver function is normally an exclusion criterion in clinical trials. In this review, we present evidence regarding the use of each drug in patients with colorectal cancer and hepatic impairment.

Desensitization of carbamylcholine-mediated cyclic GMP accumulation in dog thyroid slices.

Previous studies have shown that carbamylcholine through a muscarinic receptor increases Ca2+ influx and consequently cGMP accumulation in dog thyroid slices. A first exposure to carbamylcholine induced desensitization of the cGMP response to a further exposure to this agent. The aim of this work was to investigate the role of carbamylcholine, extracellular calcium or intracellular cGMP in this desensitization. The effect of various combinations of these factors has been studied. Carbamylcholine in the absence of calcium, with and without cGMP accumulation, did not desensitize. On the other hand, an increase in intracellular calcium and its consequent cGMP accumulation did not desensitize carbamylcholine-induced cGMP accumulation either. Previous exposure of dog thyroid cells to carbamylcholine in the presence of calcium slightly decreased ionophore A23187-induced cGMP accumulation. Carbamylcholine desensitization is thus mainly homologous and bears on a step prior to cGMP synthesis. These data suggest that both carbamylcholine interaction with its receptor and extracellular calcium are necessary for desensitization. cGMP is not sufficient for this effect but its possible role is not excluded.

Effect of thyrotropin-releasing hormone on dog thyroid in vitro.

The in vitro action of thyrotropin-releasing hormone (TRH) on the cyclic AMP level and iodine metabolism in dog thyroid, has been studied. TRH inhibited cyclic AMP accumulation and subsequent secretion in slices stimulated by thyrotropic hormone (TSH), prostaglandin E1, cholera toxin and to a lesser extent forskolin. The effect of TRH was suppressed in a medium deprived of calcium or in the presence of isobutylmethylxanthine. TRH also stimulated iodide binding to proteins, but not cyclic GMP accumulation. Although all these characteristics of TRH action on dog thyroid fit those of prostaglandin F1 alpha in this tissue, TRH effects were not relieved by indomethacine. The possibility of a TRH action through other known inhibitors of the cyclic AMP system in dog thyroid such as: acetylcholine, alpha-adrenergic agents, adenosine, iodide were checked and ruled out. The possible involvement of other neurotransmitters, such as ATP or vasoactive intestinal peptide were studied but could not be substantiated. Our data suggest the existence of a direct negative action of TRH on the thyroid itself besides its stimulatory role at the pituitary level. The great variability of the TRH effect was overcome by pretreatment of the dog by pyridostigmine, an acetylcholinesterase inhibitor.

Effects of prostaglandins F alpha on dog thyroid cyclic AMP level and function.

Prostaglandins F1 alpha and F2 alpha, at high concentrations (greater than or equal to 28 microM) enhanced cyclic AMP accumulation in dog thyroid slices. At lower concentrations, they inhibited the cyclic AMP accumulation induced by thyrotropin (TSH), prostaglandin E1, and cholera toxin. This effect was rapid in onset and of short duration, calcium-dependent and suppressed by methylxanthines. Prostaglandin F alpha also inhibited TSH-induced secretion and activated iodide binding to proteins. These characteristics are similar to those of carbamylcholine action, except that prostaglandins F did not enhance cyclic GMP accumulation. The effect of prostaglandin F alpha was not inhibited by atropine, phentolamine and adenosine deaminase and can therefore not be ascribed to an induced secretion of acetylcholine, norepinephrine or adenosine. It is suggested that prostaglandins F act by increasing influx of extracellular Ca2+. Arachidonic acid also inhibited the TSH-induced cyclic AMP accumulation. However this effect was specific for TSH, it was enhanced in the absence of calcium and was not inhibited by methylxanthines or by indomethacin at concentrations which completely block its conversion to prostaglandin F alpha. Arachidonic acid action is sustained. This suggests that arachidonic acid inhibits thyroid adenylate cyclase at the level of its TSH receptor and that this effect is not mediated by prostaglandin F alpha or any other cyclooxygenase product.

Decreased basal and stimulated thyrotropin secretion in healthy elderly men.

To delineate the effects of aging on basal and stimulated TSH secretion, we studied the 24-h profile of plasma TSH levels and the TSH response to TRH stimulation (200 micrograms TRH, iv) in eight healthy elderly men, aged 67-84 yr, and eight normal young men, aged 20-27 yr. Subjects with thyroid antibodies against microsomal or thyroglobulin antigens were excluded. During the 24-h study, blood was sampled at 15-min intervals. TSH levels were measured by an ultrasensitive immunoradiometric assay. Sleep was polygraphically monitored, and circadian and pulsatile TSH variations were quantified using specifically designed computer algorithms. In older men, the 24-h mean TSH concentration was approximately 50% lower than that in young men (0.78 +/- 0.37 vs. 1.43 +/- 0.41 microU/mL; P less than 0.01), but basal T3 levels were only slightly lower (93 +/- 12 vs. 115 +/- 16 ng/dL; P less than 0.02), while basal T4 levels were normal. The normal diurnal variation of TSH levels, with a nocturnal acrophase and an afternoon nadir, as well as the pulsatile nature of TSH release were preserved in elderly men. When expressed in microunits per mL, the amplitude of these temporal variations was reduced in elderly men compared to that in younger subjects. However, when expressed in relation to the mean TSH levels, the amplitudes of diurnal and pulsatile variations were similar in both groups of subjects. TRH-induced TSH secretion was lower in old than in young men (area under the curve, 15.9 +/- 6.3 microU/mL.10 min in elderly men vs. 42.0 +/- 16.6 microU/mL.10 min in young men; P less than 0.002). However, the TRH-induced elevations of T3 and T4 were of similar magnitude in both groups. These results indicate that in healthy elderly men, the overall 24-h TSH secretion is decreased, and the pituitary is less responsive to stimulation by TRH. However, the chronobiological modulation is preserved. These alterations could reflect an adaptative mechanism to the reduced need for thyroid hormones in old age. The thyroid keeps an intact capacity to respond to acute increases in TSH concentrations.

Nocturnal decrease in glucose tolerance during constant glucose infusion.

Studies comparing glucose tolerance in the morning vs. that in the evening have suggested that time of day may influence glucose regulation. To examine the variation in glucose tolerance throughout the 24-h span, normal subjects were given an iv glucose infusion at a constant rate of either 5 or 8 g/kg.24 h during 30 h, and plasma levels of insulin and glucose were measured at 15-min intervals for the last 24 h of the infusion. The timing of initiation of the infusion was varied to differentiate effects of time of day from effects of duration of the infusion. A nocturnal elevation of glucose levels, culminating around midsleep and corresponding to an increase of about 15% above daytime levels, was observed in all subjects. The timing of this nocturnal maximum was not dependent on the rate of the infusion or on the time elapsed since the beginning of the infusion. Insulin levels did not show a consistent diurnal pattern. Both insulin and glucose exhibited large ultradian oscillations recurring at 100- to 150-min intervals. The amplitude of these oscillations increased with the rate of glucose infusion. These ultradian oscillations of glucose and insulin levels were temporally correlated, with a tendency for glucose pulses to lead insulin pulses by 15-30 min. These results demonstrate in normal subjects the existence of a diurnal variation in glucose tolerance distinct from the dawn phenomenon observed in diabetic subjects and indicate that spontaneous 100- to 150-min oscillations in peripheral glucose and insulin levels characterize stimulated pancreatic function, with the amplitude of the oscillations being dependent on the size of the stimulus.

Thyroglobulin and thyroid hormone release after intravenous administration of bovine thyrotropin in man.

To elucidate the mechanism of thyroglobulin (Tg) release in man, the effects of an iv injection of a submaximal dose of bovine TSH (bTSH) on the serum levels of Tg were compared with the effects on serum T3 and T4. After the administration of bTSH, short term kinetics (0-4 h) were studied in eight subjects receiving 0.5 IU bTSH and seven subjects receiving 1 IU bTSH. Serum Tg did not significantly increase in either of the short term studies. By contrast, serum T3 increased significantly and linearly after the administration of 0.5 and 1 IU bTSH; serum T4 also rose but only after 1 IU bTSH. Long term kinetics (0-120 h) were studied in seven additional subjects after the iv administration of 1 IU bTSH; serum bTSH was no longer detectable after 8 h. Maximum serum concentrations of T3 were obtained at about 4 h, maximum serum concentrations of T4 were obtained between 4-8 h. Serum Tg levels increased linearly with time during the first 24 h. Maximum serum Tg levels correlated well with basal serum Tg values (r = 0.97; P < 0.001). The maximal increment in Tg correlated inversely with the maximal increment in T3 (r = 0.71; P < 0.05). The half-life of Tg was estimated to be approximately 4 days by measuring the disappearance rate of Tg after its peak level was attained.

Periovulatory elevation of angiotensin II in the peritoneal fluid during the human menstrual cycle.

Local variations in the ovarian renin-angiotensin system were investigated in peritoneal fluid (PF) during normal menstrual cycles and after ovarian stimulation with gonadotropins. PF was collected either during laparoscopy or by transvaginal aspiration before ovocyte retrieval for in vitro fertilization. Renin activity (RA) and angiotensin II immunoreactivity (Ang II-ir) were assayed in PF and simultaneously collected blood. The level of Ang II-ir was higher in PF than in plasma throughout the cycle, where as RA was in the same range of magnitude in the two compartments. In PF, Ang II-ir reached levels 2-5 times higher in the periovulatory period (days 12-14 and 15-17 of the cycle) than those found during the other stages of the cycle, whereas plasmatic Ang II-ir remained stable. No significant change could be demonstrated in RA throughout the cycle in either PF or plasma. Ovarian stimulation induced a strong elevation of Ang II-ir in PF, but not in plasma. High performance liquid chromatography revealed that the majority of Ang II-ir in PF was true Ang II. In conclusion, these results show a periovulatory elevation of Ang II in PF during the cycle and a more pronounced rise after treatment with gonadotropins. These observations support the involvement of Ang II in the process of ovulation or fecundation.

Selenium and the thyroid: how the relationship was established.

Several hypotheses concerning consequences of selenium deficiency on iodine metabolism can be proposed on the basis of experimental studies in rats and from epidemiological and experimental studies in humans. By decreasing intracellular GSH peroxidase activity, selenium deficiency may increase hydrogen peroxide (H2O2) supply and lead over several weeks to the thyroid atrophy observed in myxoedematous cretins. By improving thyroid hormone synthesis and by decreasing peripheral thyroxin (T4) deiodination, selenium deficiency could protect fetal brain T4 supply and thus prevent neurologic cretinism. Selenium deficiency may protect against iodine deficiency by decreasing T4 metabolism--and thus iodide leakage and--perhaps also by increasing H2O2 supply and thyroid hormone synthesis and thus thyroid efficiency.

Negative regulation of cyclic-AMP levels by carbamylcholine in dog thyroid is not mediated by cyclic-GMP.

Carbamylcholine, through calcium, enhances cyclic-GMP accumulation and depresses cyclic-AMP accumulation in TSH stimulated dog thyroid. The results presented show that compounds which can be transformed to nitric oxide increase cyclic-GMP accumulation in the dog thyroid. These compounds do not require extracellular calcium for their action. In thyroid stimulated by TSH, these compounds do not depress AMP accumulation. Cyclic-GMP is not the main intracellular signal involved in the negative regulation of cyclic-AMP levels in dog thyroid.

Effects of carbamylcholine and ionophore A-23187 on cyclic 3',5'-AMP and cyclic 3',5'-GMP accumulation in dog-thyroid slices.

Carbamylcholine and acetylcholine through a muscarinic type of receptor, KCl, ionophore A-23187 and NaF increased cyclic GMP accumulation in dog-thyroid slices. These effects were abolished in calcium-depleted slices, which findings confirm that Ca2+ is required for cyclic GMP accumulation. All these agents depressed the accumulation of cyclic AMP in TSH-stimulated slices. KCl and NaF depressed cyclic AMP accumulation in TSH-treated slices even when they had been depleted of Ca2+. This suggests a cyclic GMP- and Ca2+-independent mechanism. The absence of inhibition of the effects of the ionophore, NaF and KCl in the presence of atropine suggests that these drugs do not act by inducing the release of acetylcholine in the slices. The effects of carbamylcholine and ionophore A-23187 on cyclic GMP accumulation and protein iodination were reversible; the inhibitions of TSH-induced cyclic AMP accumulation and secretion were non-competitive and were not accompanied by a depression of ATP levels. All these effects were greatly decreased in the absence of extracellular Ca2+. These data suggest that carbamylcholine and ionophore A-23187 act mainly by increasing the influx of extracellular Ca2+ in thyroid cells. However, the persistence of some carbamylcholine effect in the absence of Ca2+ in the medium suggests that this agent may also trigger the release of Ca2+ from an intrafollicular pool. The kinetics of action of carbamylcholine are compatible with a role of cyclic GMP in the inhibition of cyclic AMP accumulation. However, with the ionophore, the depression of cyclic AMP accumulation was much longer than the rise of cyclic GMP, which suggests a mechanism independent of cyclic GMP.

Human, bovine, canine and rat thyroglobulin promoter sequences display species-specific differences in an in vitro study.

The proximal promoter regions of the thyroglobulin gene from man, beef, dog and rat were compared by transient expression in primary cultured dog thyrocytes. All four promoter regions were able to control properly the expression of a reporter gene in response to cyclic AMP stimulation. Surprisingly, despite extensive sequence conservation, the transcriptional activities of these four mammalian thyroglobulin promoters were differently affected by equivalent mutations. Homologous sequence elements from these promoter regions also exhibited distinct binding characteristics in mobility-shift experiments conducted in the presence of nuclear proteins from bovine thyroids. Our observations show that the highly conserved thyroglobulin promoters may exhibit unexpected functional differences in a specific assay and indicate that some of the molecular mechanisms involved in the control of thyroglobulin gene expression have evolved differently within mammals.

Forearm fullness in Coffin-Lowry syndrome: a misleading yet possible early diagnostic clue.

Two unrelated infants with delayed development and suspected abnormalities of the upper limbs were found to have the Coffin-Lowry syndrome. Both had marked fullness of the forearms in the presence of normal skeletal structures which resulted from increased subcutaneous fat. Although initially misleading, the forearm changes may serve as an early diagnostic clue in this disorder.

Tumor promoters as probes of protein kinase C in dog thyroid cell: inhibition of the primary effects of carbamylocholine and reproduction of some distal effects.

The acute effects of phorbol esters, used as probes of protein kinase C activation, were studied on dog thyroid slices incubated in vitro. The derivatives used were: tetradecanoylphorbol acetate (TPA), phorbol-12,13, didecanoate (PDD), phorbol-12,13-diacetate (PDA), and phorbol dibutyrate (PDBu) and as inactive controls, phorbol itself, phorbol-12, myristate and phorbol-13, acetate, in concentrations ranging from 5.10(-8) to 5.10(-6) mol/L. The active phorbol esters had no effect on basal cyclic AMP concentrations; they inhibited cyclic AMP accumulation induced by prostaglandin E1 but not that induced by thyrotropin (TSH) 1 mU/mL and forskolin 10 mumol/L. Phorbol esters like carbamylcholine acutely stimulated iodide organification and inhibited the stimulation of hormone secretion resulting from TSH, Cholera Toxin, forskolin, and Bu2-cyclic AMP action. These metabolic effects did not require the presence of extracellular Ca++, and could not be antagonized by Ca++ depletion or manganese addition. The active phorbol esters abolished the cyclic AMP independent increased PI turnover induced by TSH 10 mU/mL or carbamylcholine (Cchol) 10(-6) mol/L but did not affect the basal incorporation of 32P into phosphatidylinositol. They reduced the 45Ca efflux from preloaded slices below basal levels and blocked the increased 45Ca release induced by TSH and Cchol. They also inhibited the increase in cyclic GMP concentrations resulting from Cchol action but not the effect of the ionophore A23187 (10(-5) mol/L) nor the basal levels of cyclic GMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II immunoreactivity is elevated in ascites during severe ovarian hyperstimulation syndrome: implications for pathophysiology and clinical management.

OBJECTIVE: To investigate the ovarian renin-angiotensin system (RAS) during severe ovarian hyperstimulation syndrome (OHSS). DESIGN: Simultaneous sampling of blood and ascitic or peritoneal fluid (PF) during therapeutic paracentesis or laparoscopy. SETTING: University Hospital. PATIENTS: Twelve patients were investigated: three patients presenting severe OHSS, three patients with a spontaneous first trimester pregnancy, three normally cycling women during the early luteal phase, and three patients with ascites of nonovarian origin. MAIN OUTCOME MEASURE: Renin-like activity and angiotensin II (ANG II) immunoreactivity were measured simultaneously in the plasma and the ascites or PF. RESULTS: Angiotensin II immunoreactivity was much higher in the ascites or PF than in corresponding plasma during severe OHSS, first trimester pregnancy, and in the early luteal phase, while it was lower in ascites of nonovarian origin. Renin-like activity and ANG II immunoreactivity were the highest in the ascites of severe OHSS and in the PF from part of the patients with a spontaneous first trimester pregnancy. CONCLUSIONS: The present findings argue for the ovarian origin of the elevated renin-like activity and ANG II immunoreactivity in the ascites of severe OHSS and suggest a stimulatory role of hCG on the ovarian RAS whether during severe OHSS or first trimester spontaneous pregnancy. The vasoactive peptide ANG II may contribute to the maintenance of the ascites in severe OHSS but is probably not responsible for the formation of the ascites. The efficiency of paracentesis during severe OHSS could be explained at least partially by the removing of great amounts of ANG II from the peritoneal cavity.