Overexpression of a mutant form of TGFBI/BIGH3 induces retinal degeneration in transgenic mice.

PURPOSE: Despite ubiquitous expression of the keratoepithelin (KE) protein encoded by the transforming growth factor beta induced/beta induced gene human clone 3 (TGFBI/BIGH3) gene, corneal dystrophies are restricted to the cornea, and no other tissues are affected. We investigated the role of TGFBI/BIGH3 in Groenouw corneal dystrophies by generating transgenic mice overexpressing TGFBI/BIGH3 containing the R555W mutation. METHODS: Transgenic animals expressing the Groenouw mutation of human TGFBI/BIGH3 were generated using lentiviral vectors. The line expressed TGFBI/BIGH3 containing the R555W mutation under the control of the phosphoglycerate kinase (PGK) promoter. Expression of the transgene was monitored by Southern and western blotting and by RT-PCR. Electroretinogram analysis was performed and four mice were subjected to complete necroscopy. RESULTS: Transgene expression was observed in different organs although without specific expression in the cornea. The overall morphology of the transgenic animals was not severely affected by KE overexpression. However, we observed an age-dependent retinal degeneration both functionally and histologically. Female-specific follicular hyperplasia in the spleen and increased levels of lipofuscin in the adrenal gland were also seen in transgenic animals. CONCLUSIONS: Cellular degeneration in the retina of transgenic animals suggest that perturbation of the transforming growth factor beta (TGFbeta) family regulation may affect photoreceptor survival and may induce possible accelerated aging in several tissues. No corneal phenotype could be observed, probably due to the lack of transgene expression in this tissue.

Angiotensin-II mediates norepinephrine and neuropeptide-Y secretion in a human pheochromocytoma.

The potential role of angiotensin-II in mediating catecholamine and neuropeptide-Y release in a human pheochromocytoma has been investigated. Angiotensin-II type I receptors are transcribed and translated into functional proteins in a surgically removed pheochromocytoma. Primary cell culture of the tumor has been studied in a perfused system. Angiotensin-II increased the release of norepinephrine and neuropeptide-Y by the pheochromocytes. Activation of the angiotensin-II type I receptors by angiotensin-II was associated with a rise in cytosolic free calcium. The renin-angiotensin system may, therefore, contribute to the secretion of catecholamines and NPY occurring in patients with pheochromocytoma and when stimulated trigger hypertensive crisis.

Circulating EM66 is a highly sensitive marker for the diagnosis and follow-up of pheochromocytoma.

We have previously demonstrated that measurement of tissue concentration of the novel secretogranin II-derived peptide EM66 may help to discriminate between benign and malignant pheochromocytomas. The aim of the present study was to characterize EM66 in plasma and urine of healthy volunteers and pheochromocytoma patients, in order to further evaluate the usefulness of this peptide as a circulating marker for the management of the tumors. HPLC analysis of plasma and urine samples demonstrated that the EM66-immunoreactive material coeluted with the recombinant peptide. In healthy volunteers, plasma and urinary EM66 levels were, respectively, 2.6 (1.9-3.7) ng/ml and 2.9 (1.9-4.6) ng/ml. In patients with pheochromocytoma, plasma EM66 levels were 10-fold higher than those of healthy volunteers (26.9 (7.3-44) ng/ml), and returned to normal values after removal of the tumor. In contrast, urinary EM66 levels were not significantly different from those of healthy volunteers (3.2 (2.2-3.9) ng/ml). Measurement of total or free plasma metanephrines and 24 hr urinary metanephrines in our series of patients revealed that these tests, taken separately, are less sensitive than the EM66 determination. Pheochromocytes in primary culture secreted high levels of EM66, suggesting that the chromaffin tumor was actually responsible for the increased plasma peptide concentrations in the patients. These data indicate that EM66 is secreted in the general circulation and that elevated plasma EM66 levels are correlated with the occurrence of pheochromocytoma. Thus, EM66 is a sensitive plasma marker that should be considered as a complementary tool in the management of pheochromocytoma.

Xerostomía: diagnóstico y tratamiento

La xerostomía o disminución de la cantidad de saliva en la cavidad bucal suele tener una serie de consecuencias: unas directas, tales como el aumento en la incidencia de caries y enfermedad periodontal, y otras indirectas, como la dificultad en la masticación o la mala adaptación de las prótesis. De ahí la importancia de una correcta lubrificación salival de la cavidad bucal. En el presente trabajo se realiza una revisión de los problemas ocasionados por la xerostomía, así como de su diagnóstico y tratamiento, aspectos éstos un tanto conflictivos, debido a la dificultad de objetivar la sintomatología y de conseguir resultados duraderos.

Malignant pheochromocytoma in a pig

Abstract. Endocrine tumors are rarely observed in pigs, and pheochromocytomas have been only punctually described. The current report describes a white and firm, 15-cm in diameter, neoplastic mass located in the adrenal gland with metastasis to regional lymph nodes in a 2.5-year-old sow. The masses had marked desmoplasia that supported a population of polygonal-tospindle– shaped neoplastic cells arranged into cords and packets within a delicate fibrovascular stroma. Immunohistochemical staining of the tumor was positive for chromogranin and negative for neurofilament protein in adrenal and lymph node masses, which was characteristic of a malignant pheochromocytoma.

Papillary cystoadenoma lymphomatosum (Warthin-like) of minor salivary glands

Papillary cystadenoma lymphomatosum is a benign salivary gland tumor most frequently located in the parotid gland (Warthin"s tumor). Its presentation in other major, or in minor, salivary glands is rare. Clinically, it manifests as a slow growing tumor, fluctuant on palpation due to its cystic morphology. The treatment of choice is complete excision with wide tumor-free margins. We present a 73-year-old female patient with an asymptomatic tumor of 8 years evolution in the right posterior area of the hard palate. We performed surgical excision and a biopsy, which was reported as papillary cystadenoma lymphomatosum. During the post-operative examination carried out after 3 weeks, it was observed that the lesion had recurred. The lesion was re-operated, performing the excision with CO2 laser and including the periosteum to ensure complete resection of the tumor. At 10 months follow-up, there was no recurrence of the lesion. This article includes a review of this condition and discusses its most important clinical and pathologic features and therapeutic approaches.

Treatment of oral mucocele - scalpel versus C02 laser

Objective: To compare the results obtained after oral mucocele resection with the scalpel versus the CO2 laser, based on the complications and recurrences after surgery Patients and Methods: Of the 68 patients we studied who have mucocele, 38 were resected with a scalpel and the remaining 30 with the CO2 laser (5-7 W). Patient sex and age were documented, along with location of the lesion as well as size, symptoms, duration, etiological factors, type of treatment, complications and recurrences after surgical removal. Results: The sample comprised 40 males and 28 females, aged between 6-65 years. The histological diagnosis was extravasation mucocele in 95% of the cases. The most frequent location was the lower lip (73.5%). The mean lesion diameter was 9 mm , and in most cases no evident etiological factor was recorded. The mean duration of the lesion was 4 months. Among the cases of conventional surgical removal of mucocele, recurrence was recorded in 8.8% of the cases, and 13.2% of the patients suffered postoperative complications - the most frequent being the presence of fibrous scars. There were no complications or relapses after a minimum follow-up of 12 months in the cases subjected to CO2 laser treatment. Conclusions: Oral mucocele ablation with the CO2 laser offers more predictable results and fewer complications and recurrences than conventional resection with the scalpel

Pronóstico y tratamiento de la boca seca. Revisión sistemática

No existen protocolos claramente establecidos para el tratamiento de la boca seca. El objetivo de este trabajo es realizar una revisión sistemática de la literatura médica de los últimos 10 años. Hemos utilizado las palabras: «dry mouth», «prognosis», «treatment» y «dentistry». En una primera búsqueda hemos encontrado 1.450 entradas. Con la restricción «clinical trials OR randomized controlled trial OR systemic reviews» se han reducido a 522, de las que 145 eran metaanálisis y revisiones sistemáticas. Se han eliminado las que no eran pertinentes al tema y han quedado reducidas a 53. Posteriormente se descartaron 24 (8 no pertinentes, 7 revisiones y 9 opiniones personales). De los 29 artículos analizados, 15 son ensayos clínicos controlados, 2 ensayos no controlados, 4 estudios observacionales, 2 revisiones sistemáticas y 5 revisiones. Los enfermos mejor estudiados son los pacientes con síndrome de Sjögren y los pacientes irradiados. El tratamiento se centra en el etiológico, preventivo, sintomático, de estimulación salival local y sistémicos. Podemos concluir que el tratamiento debe ser individualizado, pudiéndose aplicar sustitutos salivales y diferentes técnicas de estimulación mecánica. There are no clearly established protocols for the treatment of dry mouth. The aim of this paper is a systematic review of the literature of the past 10 years using the words «dry mouth», «prognosis», «treatment» and «dentistry». The initial search found 1,450 entries and within the restriction «clinical trials OR randomized controlled trial OR systemic reviews» it has been reduced to 522, which 145 were meta-analysis and systematic reviews. Papers not relevant to the issue were removed reducing the entries to 53. Twenty-four were dismissed (8 irrelevant, 7 reviews without adequate information and 9 personal opinions). Of the 29 items tested, 15 were controlled trials, 2 uncontrolled trials, 4 observational studies, 2 systematic reviews and 5 non systematic reviews. The most studied patients were Sjögren's syndrome and the irradiated patients. Treatments are focused on the etiology, prevention, symptomatic, local salivary stimulation and systemic treatments. It can be concluded that treatment must be individualized, salivary substitutes and mechanical stimulation techniques can be applied.

Boca seca y boca ardiente

La saliva es esencial para mantener la salud oral. El 99% de su composición es agua. El desencadenante más común de boca seca es la toma de medicamentos, generalmente acompañada de escasa ingesta de líquidos. Entre sus complicaciones cabe destacar xerostomía, disgeusia y ardor bucal, entre otras. Estos síntomas son tríada frecuente del síndrome de boca ardiente (SBA). Su etiología es imprecisa y multifactorial, sin datos clínicos o de laboratorio específicos. En su patogenia intervienen factores locales, sistémicos y psicológicos. Es común la asociación de hábitos parafuncionales evidentes, dentarios y linguales, con repercusión en tejidos duros (desgaste, ATM) y blandos (lesiones facticias, irritación de papilas linguales). Afecta más a mujeres en edad perimenopáusica, en proporción hasta 7:1 respecto a los hombres. A menudo se asocian ansiedad o depresión. En este trabajo se propone la parafunción deglutoria como parte integrante del síndrome.

Synthetic calibrators for the analysis of total metanephrines in urine: revisiting the conditions of hydrolysis.

BACKGROUND: The quantification of total (free+sulfated) metanephrines in urine is recommended to diagnose pheochromocytoma. Urinary metanephrines include metanephrine itself, normetanephrine and methoxytyramine, mainly in the form of sulfate conjugates (60-80%). Their determination requires the hydrolysis of the sulfate ester moiety to allow electrochemical oxidation of the phenolic group. Commercially available urine calibrators and controls contain essentially free, unhydrolysable metanephrines which are not representative of native urines. The lack of appropriate calibrators may lead to uncertainty regarding the completion of the hydrolysis of sulfated metanephrines, resulting in incorrect quantification. METHODS: We used chemically synthesized sulfated metanephrines to establish whether the procedure most frequently recommended for commercial kits (pH 1.0 for 30 min over a boiling water bath) ensures their complete hydrolysis. RESULTS: We found that sulfated metanephrines differ in their optimum pH to obtain complete hydrolysis. Highest yields and minimal variance were established for incubation at pH 0.7-0.9 during 20 min. CONCLUSION: Urinary pH should be carefully controlled to ensure an efficient and reproducible hydrolysis of sulfated metanephrines. Synthetic sulfated metanephrines represent the optimal material for calibrators and proficiency testing to improve inter-laboratory accuracy.

Response to topical clonazepam in patients with burning mouth syndrome: a clinical study

Burning Mouth Syndrome (BMS) is a difficult disease for patients and clinicians. Moreover, there is not a general consensus on how to treat the disease. The main objective of this paper is to evaluate BMS patients' response to topical clonazepam treatment. A double blind study was performed. Among a total of 66 patients, 33 were treated with tablets of clonazepam and another 33 were treated with a placebo. Symptoms were evaluated after 1 month and 6 months of treatment and scored on an analogical scale from 0 to 10. Among the 33 patients treated with clonazepam, 23 showed at least a 50% reduction in symptoms after 1 month of treatment. On the contrary, only 4 in the placebo group exhibited significant improvement. After 6 months, significant differences were observed again, as 23 of the 33 patients treated with the drug reported at least a 50% reduction in symptoms, whereas only 2 among those treated with the placebo significantly improved. However, when measured in terms of a complete cure (lack of symptoms), the differences were not significant: 5 drug-treated patients and one belonging to the placebo group were asymptomatic after one month of treatment. In summary, it seems that clonazepam applied topically was effective in treating BMS in a large proportion of patients

The CXCR4/CXCR7/CXCL12 Axis Is Involved in a Secondary but Complex Control of Neuroblastoma Metastatic Cell Homing.

Neuroblastoma (NB) is one of the most deadly solid tumors of the young child, for which new efficient and targeted therapies are strongly needed. The CXCR4/CXCR7/CXCL12 chemokine axis has been involved in the progression and organ-specific dissemination of various cancers. In NB, CXCR4 expression was shown to be associated to highly aggressive undifferentiated tumors, while CXCR7 expression was detected in more differentiated and mature neuroblastic tumors. As investigated in vivo, using an orthotopic model of tumor cell implantation of chemokine receptor-overexpressing NB cells (IGR-NB8), the CXCR4/CXCR7/CXCL12 axis was shown to regulate NB primary and secondary growth, although without any apparent influence on organ selective metastasis. In the present study, we addressed the selective role of CXCR4 and CXCR7 receptors in the homing phase of metastatic dissemination using an intravenous model of tumor cell implantation. Tail vein injection into NOD-scid-gamma mice of transduced IGR-NB8 cells overexpressing CXCR4, CXCR7, or both receptors revealed that all transduced cell variants preferentially invaded the adrenal gland and typical NB metastatic target organs, such as the liver and the bone marrow. However, CXCR4 expression favored NB cell dissemination to the liver and the lungs, while CXCR7 was able to strongly promote NB cell homing to the adrenal gland and the liver. Finally, coexpression of CXCR4 and CXCR7 receptors significantly and selectively increased NB dissemination toward the bone marrow. In conclusion, CXCR4 and CXCR7 receptors may be involved in a complex and organ-dependent control of NB growth and selective homing, making these receptors and their inhibitors potential new therapeutic targets.

Catecholamine metabolism in paraganglioma and pheochromocytoma: similar tumors in different sites?

Pheochromocytoma (PHEO) and paraganglioma (PGL) are catecholamine-producing neuroendocrine tumors that arise respectively inside or outside the adrenal medulla. Several reports have shown that adrenal glucocorticoids (GC) play an important regulatory role on the genes encoding the main enzymes involved in catecholamine (CAT) synthesis i.e. tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT). To assess the influence of tumor location on CAT metabolism, 66 tissue samples (53 PHEO, 13 PGL) and 73 plasma samples (50 PHEO, 23 PGL) were studied. Western blot and qPCR were performed for TH, DBH and PNMT expression. We found a significantly lower intra-tumoral concentration of CAT and metanephrines (MNs) in PGL along with a downregulation of TH and PNMT at both mRNA and protein level compared with PHEO. However, when PHEO were partitioned into noradrenergic (NorAd) and mixed tumors based on an intra-tumoral CAT ratio (NE/E >90%), PGL and NorAd PHEO sustained similar TH, DBH and PNMT gene and protein expression. CAT concentration and composition were also similar between NorAd PHEO and PGL, excluding the use of CAT or MNs to discriminate between PGL and PHEO on the basis of biochemical tests. We observed an increase of TH mRNA concentration without correlation with TH protein expression in primary cell culture of PHEO and PGL incubated with dexamethasone during 24 hours; no changes were monitored for PNMT and DBH at both mRNA and protein level in PHEO and PGL. Altogether, these results indicate that long term CAT synthesis is not driven by the close environment where the tumor develops and suggest that GC alone is not sufficient to regulate CAT synthesis pathway in PHEO/PGL.

Pronóstico y tratamiento de la boca seca. Revisión sistemática

No existen protocolos claramente establecidos para el tratamiento de la boca seca. El objetivo de este trabajo es realizar una revisión sistemática de la literatura médica de los últimos 10 años. Hemos utilizado las palabras: «dry mouth», «prognosis», «treatment» y «dentistry». En una primera búsqueda hemos encontrado 1.450 entradas. Con la restricción «clinical trials OR randomized controlled trial OR systemic reviews» se han reducido a 522, de las que 145 eran metaanálisis y revisiones sistemáticas. Se han eliminado las que no eran pertinentes al tema y han quedado reducidas a 53. Posteriormente se descartaron 24 (8 no pertinentes, 7 revisiones y 9 opiniones personales). De los 29 artículos analizados, 15 son ensayos clínicos controlados, 2 ensayos no controlados, 4 estudios observacionales, 2 revisiones sistemáticas y 5 revisiones. Los enfermos mejor estudiados son los pacientes con síndrome de Sjögren y los pacientes irradiados. El tratamiento se centra en el etiológico, preventivo, sintomático, de estimulación salival local y sistémicos. Podemos concluir que el tratamiento debe ser individualizado, pudiéndose aplicar sustitutos salivales y diferentes técnicas de estimulación mecánica. There are no clearly established protocols for the treatment of dry mouth. The aim of this paper is a systematic review of the literature of the past 10 years using the words «dry mouth», «prognosis», «treatment» and «dentistry». The initial search found 1,450 entries and within the restriction «clinical trials OR randomized controlled trial OR systemic reviews» it has been reduced to 522, which 145 were meta-analysis and systematic reviews. Papers not relevant to the issue were removed reducing the entries to 53. Twenty-four were dismissed (8 irrelevant, 7 reviews without adequate information and 9 personal opinions). Of the 29 items tested, 15 were controlled trials, 2 uncontrolled trials, 4 observational studies, 2 systematic reviews and 5 non systematic reviews. The most studied patients were Sjögren's syndrome and the irradiated patients. Treatments are focused on the etiology, prevention, symptomatic, local salivary stimulation and systemic treatments. It can be concluded that treatment must be individualized, salivary substitutes and mechanical stimulation techniques can be applied.