Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction.

Deficiency in Sphingosine-1-phosphate lyase (S1P lyase) is associated with a multi-systemic disorder incorporating primary adrenal insufficiency (PAI), steroid resistant nephrotic syndrome and neurological dysfunction. Accumulation of sphingolipid intermediates, as seen with loss of function mutations in SGPL1, has been implicated in mitochondrial dysregulation, including alterations in mitochondrial membrane potentials and initiation of mitochondrial apoptosis. For the first time, we investigate the impact of S1P lyase deficiency on mitochondrial morphology and function using patient-derived human dermal fibroblasts and CRISPR engineered SGPL1-knockout HeLa cells. Reduced cortisol output in response to progesterone stimulation was observed in two patient dermal fibroblast cell lines. Mass spectrometric analysis of patient dermal fibroblasts revealed significantly elevated levels of sphingosine-1-phosphate, sphingosine, ceramide species and sphingomyelin when compared to control. Total mitochondrial volume was reduced in both S1P lyase deficient patient and HeLa cell lines. Mitochondrial dynamics and parameters of oxidative phosphorylation were altered when compared to matched controls, though differentially across the cell lines. Mitochondrial dysfunction may represent a major event in the pathogenesis of this disease, associated with severity of phenotype.

Diagnóstico de endocrinopatía congénita en neonatos con ictericia prolongada e hipoglucemia / Diagnosis of congenital endocrinological disease in newborns with prolonged jaundice and hypoglycaemia

Introducción: La asociación de ictericia neonatal prolongada e hipoglucemia recurrente puede ser secundaria a una patología endocrinológica subyacente. La insuficiencia hipofisaria y la insuficiencia adrenal primaria son las principales patologías que se deben descartar. Material y métodos: Se analizaron retrospectivamente las características clínicas y de laboratorio de 13 pacientes derivados a la división de endocrinología del Hospital de Niños Ricardo Gutiérrez entre los años 2003 y 2008 con ictericia neonatal e hipoglucemia secundaria a insuficiencia hipofisaria en 12 pacientes y en uno a insuficiencia adrenal primaria. Resultados: Todos los pacientes tuvieron hipoglucemia en el periodo neonatal. En 10 pacientes la hiperbilirrubinemia fue de predominio directo y 6 pacientes presentaron elevación de transaminasas. La insuficiencia hipofisaria fue múltiple en los 12 pacientes. El tratamiento de remplazo hormonal normalizó la función hepática, resolvió la ictericia en todos los niños y ninguno requirió biopsia hepática. Los episodios de hipoglucemia también cedieron al iniciar el tratamiento sustitutivo. Conclusiones: El binomio ictericia prolongada o colestásica e hipoglucemia recurrente exige descartar insuficiencia hipofisaria múltiple e insuficiencia suprarrenal primaria. La terapia sustitutiva correspondiente resuelve el problema colestásico en la mayor parte de los casos, así como los problemas derivados de la hipoglucemia recurrente y las deficiencias hormonales(AU)

Introduction: The association of prolonged neonatal jaundice and hypoglycaemia may be secondary to an endocrinological disease. Pituitary insufficiency and primary adrenal insufficiency are the most likely endocrine diseases that need to be ruled out. Material and methods: We retrospectively analysed the clinical and laboratory characteristics of thirteen patients referred to the Hospital de Niños Ricardo Gutiérrez between years 2003 and 2008 due to prolonged neonatal jaundice and hypoglycaemia secondary to pituitary insufficiency in twelve patients, and in one secondary to primary adrenal insufficiency. Results: All patients had a history of neonatal hypoglycaemia. Ten patients had conjugated hyperbilirubinaemia and six also had elevated transaminases. Combined pituitary hormone deficiency was observed in the twelve hypopituitarism patients. Hormonal replacement normalised liver function and resolved the prolonged jaundice in all the patients. None of them underwent liver biopsy. Hypoglycaemia also remitted after hormonal therapy. Conclusions: Prolonged or cholestatic jaundice associated with neonatal hypoglycaemia is highly likely to be due to pituitary hormone deficiency or primary adrenal insufficiency. Early diagnosis and treatment of these children reverts the prolonged jaundice and prevents morbidity and mortality due to recurrent hypoglycaemia and hormone deficiencies(AU)

[Diagnosis of congenital endocrinological disease in newborns with prolonged jaundice and hypoglycaemia]. / Diagnóstico de endocrinopatía congénita en neonatos con ictericia prolongada e hipoglucemia.

INTRODUCTION: The association of prolonged neonatal jaundice and hypoglycaemia may be secondary to an endocrinological disease. Pituitary insufficiency and primary adrenal insufficiency are the most likely endocrine diseases that need to be ruled out. MATERIAL AND METHODS: We retrospectively analysed the clinical and laboratory characteristics of thirteen patients referred to the Hospital de Niños Ricardo Gutiérrez between years 2003 and 2008 due to prolonged neonatal jaundice and hypoglycaemia secondary to pituitary insufficiency in twelve patients, and in one secondary to primary adrenal insufficiency. RESULTS: All patients had a history of neonatal hypoglycaemia. Ten patients had conjugated hyperbilirubinaemia and six also had elevated transaminases. Combined pituitary hormone deficiency was observed in the twelve hypopituitarism patients. Hormonal replacement normalised liver function and resolved the prolonged jaundice in all the patients. None of them underwent liver biopsy. Hypoglycaemia also remitted after hormonal therapy. CONCLUSIONS: Prolonged or cholestatic jaundice associated with neonatal hypoglycaemia is highly likely to be due to pituitary hormone deficiency or primary adrenal insufficiency. Early diagnosis and treatment of these children reverts the prolonged jaundice and prevents morbidity and mortality due to recurrent hypoglycaemia and hormone deficiencies.

La determinación de PTH intraquirúrgica o posquirúrgica por quimioluminiscencia predice la hipocalcemia en el posoperatorio de la tiroidectomía en niños / Determination of PTH during or post surgery for quimioluminiscency can predict hypocalcemy in the post surgery children´s thyroidectomy

Objetivo: Evaluar la eficacia diagnóstica de la determinación de PTH en muestras de plasma tomadas durante la cirugía (intra) y posquirúrgica inmediata para predecir el riesgo de desarrollar hipocalcemia en el postoperatorio de la tiroidectomía total en pacientes pediátricos. Métodos: Se llevó a cabo un estudio de cohortes,prospectivo, longitudinal con 20 pacientes pediátricos en los que se practicó tiroidectomía total. Se determinaron los niveles de PTH preoperatorios, intraoperatorios y en el período posquirúrgico inmediato (basal, 5 y 60 minutos de la remoción de la glándula tiroides) utilizando un ensayo automatizado quimioluminiscente (IMMULITE, Siemens), límite de cuantificación 8 pg/mL, CV intra e interensayos < 5,4%. Para este estudio, la concentración de PTH de cada paciente no fue conocida por el equipo tratante hasta el final del mismo. Además se determinó la concentración en suero de Calcio total (Ca T) y/o Calcio iónico (Cai) regularmente durante las 48 hs posquirúrgicas y se controló la presencia de síntomas o signos de hipocalcemia. Se consideró hipocalcemia Ca T < 8 mg/dl y/o Cai < 0,8 nmol/L. Se realizó un análisis por curva ROC para determinar el nivel de PTH que fuera más eficaz en predecir la aparición de hipocalcemia según su sensibilidad (S), especificidad (E), eficiencia diagnóstica (ED) y Valor Predictivo Positivo (VPP). Resultados: Diez de los 20 pacientes (50%) desarrollaron hipocalcemia y 3 de ellos presentaron síntomas. La presentación de hipocalcemia sucedió: 40% en las primeras 6 hs y 40% a las 24 hs.vel de PTH en la muestra intraoperatoria < 14 pg/ml mostró S: 80%, E: 100%, ED: 90% (IC95%: 73-100) y VPP: 100% para predecir hipocalcemia posquirúrgica. En la muestra posquirúrgica inmediata, la concentración de PTH < 14 pg/ml presentó S: 80%, E: 90%, ED 82% (IC95% 63-100) y VPP 90% para predecir hipocalcemia posquirúrgica. Cuando la PTH intraquirúrgica o posquirúrgica es <14 pg/ml el riesgo relativo de presentar hipocalcemia postiroidectomía es de 9. Conclusiones: La medición de PTH intraquirúrgica y posquirúrgica es una herramienta eficiente para predecir hipocalcemia posquirúrgica por tiroidectomía total en la población pediátrica. Esta detección permite la inmediata decisión sobre el tratamiento suplementario con calcio en los pacientes de riesgo mejorando su evolución y evitando la presentación de tetania y otros síntomas de hipocalcemia. Además, permitiría disminuir los controles en los pacientes que evolucionarán con normocalcemia, reduciendo en ambos grupos de pacientes los costos de internación.

Cervical polyp in the menopause and the need for fractional dilatation and curettage.

OBJECTIVE: To investigate the need for fractional dilatation and curettage following excision of symptomatic versus asymptomatic cervical polyps. STUDY DESIGN: A prospective study was carried out on 467 women who were referred for treatment of symptomatic (accompanied by vaginal bleeding or discharge) or asymptomatic cervical polyps, from January 1, 1990 to December 31, 1992. Of these, 204 were premenopausal and 263 postmenopausal. Every excision of a cervical polyp was followed by a dilatation and curettage. The histological data were evaluated statistically using the chi 2-test. RESULTS: Postmenopausal women had more asymptomatic than symptomatic cervical polyps (P = 0.004). Cervical polyps were associated with more endometrial polyps in the postmenopausal than in the premenopausal women (P = 0.0009). Postmenopausal women with symptomatic cervical polyps had more endometrial abnormalities on histological examination than those with asymptomatic ones (P < 0.0001); this difference was not significant in the premenopausal group (P = 0.49). CONCLUSIONS: While neither symptomatic nor asymptomatic cervical polyps are an indication for dilatation and curettage (following excision) in women in their reproductive years, and do not affect their management or prognosis, this is not the case in postmenopausal women. Symptomatic cervical polyps after the menopause must be excised and followed by mandatory fractional dilatation and curettage, because there is a marked incidence of associated severe pathological conditions in this age group.

[Large loop transformation zone excision in premalignant cervical lesions].

Colposcopic expertise is necessary in cases of cervical intraepithelial neoplasia (CIN) to avoid conservative treatment of microinvasive and invasive lesions. Large loop excision of the transformation zone (LLETZ) enables the pathologist to examine the entire tumor, and especially its margins. We describe this method and its indications, and review the results of our first 100 cases (mean age 28 years, range 19-46). Indications for LLETZ were biopsy findings of CIN III or of a large CIN II, a lesion entering the endocervical canal, and recurrent CIN after CO2-laser treatment. The procedure was performed under local anesthesia in 93 patients; complications were minimal (8 cases of bleeding requiring local tamponade). In 14% marginal involvement was found, but in only 4 was re-treatment necessary during follow-up of 12-33 months. Only 3 developed recurrent CIN, which was again treated by LLETZ. The cure rate of the initial treatment was 97%. This ablative, nondestructive method is easy to perform, requires only local anesthesia, has few, mild complications and gives an accurate histopathological result, including information on margins. The procedure is becoming the method of choice for treating high-grade and recurrent CIN.

Papillary endothelial hyperplasia in the tongue: a benign lesion that may be mistaken for angiosarcoma.

Papillary endothelial hyperplasia is an exuberant, intravascular, endothelial proliferation bearing some similarities to angiosarcoma. To the best of our knowledge, it has never been described in the tongue. A case of such a lesion is herein reported. The lesion, despite its benign nature, may be clinically and histopathologically mistaken for an angiosarcoma and, thus, lead to inappropriate treatment. Papillary endothelial hyperplasia differs from angiosarcoma in its being confined entirely within large vascular lumens and in its lacking of mitosis, necrosis, and true, solid, cellular areas devoid of vascular differentiation.

Metastatic malignant melanoma of the tongue.

The tongue is an unusual site for metastases of cutaneous malignant melanoma. A review of the literature revealed only 16 such cases. The discovery of metastases in the tongue usually indicates widespread dissemination of the melanoma and a terminal phase of the disease. Two patients with metastatic malignant melanoma of the tongue are presented. The primary tumors were excised 10 and four years respectively prior to the discovery of the lingual metastases. In one of the patients the lingual metastasis was the first evidence of a disseminated stage of the disease. The histopathological differentiation between primary and secondary melanoma of the tongue is discussed. Such differentiation may have an important therapeutic implication.

Intravascular papillary endothelial hyperplasia in the maxillary sinus. A benign lesion that may be mistaken for angiosarcoma.

Intravascular papillary endothelial hyperplasia is a vascular benign lesion bearing some similarities to malignant angiosarcoma. To the best of our knowledge, it has never been described within the paranasal sinuses. A case of such a lesion within the maxillary sinus appearing in a 17-year-old boy who presented with unilateral facial pains and proptosis is reported. The lesion, despite its benign nature, extended to the ethmoidal cells and nasal cavity and pressed the floor of the orbit. Clinically and histopathologically it may be mistaken for an angiosarcoma. An awareness of this similarity and the features in which it differs from angiosarcoma will prevent incorrect diagnosis and inappropriate treatment.

Use of modified fine needle aspiration for study of glomerular pathology in human kidneys.

In routine fine needle aspiration (FNA) of the kidney, the glomeruli are seldom visualized. They appear as multi-layered, cellular conglomerates and, therefore, are unsuitable for morphological analysis. A novel plasma-clot technique for collection of glomeruli from FNA samples was used in a study of 6 native and 24 transplanted human kidneys with suspected glomerular lesions. This technique produced a satisfactory yield of well preserved glomeruli and enabled the identification of glomerular pathology with the accuracy comparable to that of renal core biopsy. The FNA plasma clot method may prove useful in the study of glomerular pathology under conditions where the use of percutaneous biopsy is conventionally limited or avoided.

Endometrial laser ablation in rabbits: a comparative study of three laser types.

Endometrial laser ablation is one of the alternatives to hysterectomy in cases of intractable uterine bleeding. It is currently performed using the Nd:YAG laser at 1.06 microns. The aim of this study was to compare the tissue effect of three types of laser irradiation (Nd:YAG laser at 1.06 and 1.32 microns and holmium laser at 2.12 microns) on the rabbit endometrium. Crater formation, coagulation necrosis, and muscle necrosis were evaluated at the time of ablation, as well as at 1 week and 4 weeks postablation. The results were assessed by determining the depth and width of the affected portion in the uterine wall (lumen to serosa). It was shown that Nd:YAG laser at 1.32 microns caused more generalized and extended effects as compared with the other laser types examined. Endometrial regeneration was faster after ablation by the Nd:YAG laser at 1.06 microns and the holmium laser than by the Nd:YAG laser at 1.32 microns. The widest range of "ablation energy" (defined as that causing ablation without muscle damage) was achieved by applying the holmium laser. Further evaluation of the holmium laser for this indication is recommended.

Ultrastructural changes suggestive of focal segmental glomerulosclerosis in atypical minimal change nephrotic syndrome.

In an attempt to recognize early stages of focal segmental glomerulosclerosis (FSGS) in patients with a clinical course suggesting a diagnosis other than minimal change disease (MCD) and normal histology, or minor, nondiagnostic changes on light microscopy (LM), we used a protocol for systematic and extensive electron microscopy (EM) examination of kidney biopsies obtained from such patients. By this method ultrastructural pathology was found in 8 patients. These changes were localized, involving only portions of single glomerular segments. The findings included mild to moderate increase of the mesangial matrix, focal wrinkling of the capillary basement membrane, and early obliteration of the normal architecture of individual capillary loops, as well as electron-dense deposits in a mesangial and subendothelial distribution. Of these 8 patients, 2 are at present in remission without therapy (in 1, following therapy with cyclophosphamide); 3 are in remission on steroid therapy; 1 developed massive proteinuria during pregnancy, after a spontaneous remission lasting almost 2 years; 1 patient advanced to terminal renal failure 3 1/2 years after biopsy; and 1 died of sepsis 1 month after biopsy. We believe that the ultrastructural changes found may represent early or mild FSGS and that the protocol described can add valuable information in clinically worrisome patients in whom renal histology appears normal.

Enterobius (Oxyuris) vermicularis of the pelvic peritoneum--a cause of infertility.

A case of Enterobius (Oxyuris) vermicularis granulomatous disease of the pelvic peritoneum causing pelvic adhesions and infertility is presented and discussed. Since parasitic diseases are common in the developing countries, the infertility team has to bear in mind that a parasitic disease might be the main cause of infertility.

Abdominal splenosis mimicking abdominal carcinomatosis.

Abdominal splenosis is an uncommon condition. Since ovarian abdominal carcinomatosis might be discovered unexpectedly and the finding might be similar to it, the scope of the present paper is to draw attention to such a possibility.

The morphological changes in acute renal failure due to rhamdomyolysis following viral infection.

A case of myoglobinuric renal failure associated with viral rhabdomyolysis is described. Clinical signs of muscle involvement were lacking, but peculiar biochemical abnormalities suggested the diagnosis which was established by renal biopsy. The management required brief supportive hemodialysis, and the patient recovered. The diagnosis of myoglobinuria should be considered when acute renal failure develop subsequently to the onset of viral infection.