Reduced mitochondrial Ca(2+) transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase.

Mitochondrial disorders are a group of pathologies characterized by impairment of mitochondrial function mainly due to defects of the respiratory chain and consequent organellar energetics. This affects organs and tissues that require an efficient energy supply, such as brain and skeletal muscle. They are caused by mutations in both nuclear- and mitochondrial DNA (mtDNA)-encoded genes and their clinical manifestations show a great heterogeneity in terms of age of onset and severity, suggesting that patient-specific features are key determinants of the pathogenic process. In order to correlate the genetic defect to the clinical phenotype, we used a cell culture model consisting of fibroblasts derived from patients with different mutations in the mtDNA-encoded ND5 complex I subunit and with different severities of the illness. Interestingly, we found that cells from patients with the 13514A>G mutation, who manifested a relatively late onset and slower progression of the disease, display an increased autophagic flux when compared with fibroblasts from other patients or healthy donors. We characterized their mitochondrial phenotype by investigating organelle turnover, morphology, membrane potential and Ca(2+) homeostasis, demonstrating that mitochondrial quality control through mitophagy is upregulated in 13514A>G cells. This is due to a specific downregulation of mitochondrial Ca(2+) uptake that causes the stimulation of the autophagic machinery through the AMPK signaling axis. Genetic and pharmacological manipulation of mitochondrial Ca(2+) homeostasis can revert this phenotype, but concurrently decreases cell viability. This indicates that the higher mitochondrial turnover in complex I deficient cells with this specific mutation is a pro-survival compensatory mechanism that could contribute to the mild clinical phenotype of this patient.

TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis.

Transmembrane BAX inhibitor motif-containing (TMBIM)-6, also known as BAX-inhibitor 1 (BI-1), is an anti-apoptotic protein that belongs to a putative family of highly conserved and poorly characterized genes. Here we report the function of TMBIM3/GRINA in the control of cell death by endoplasmic reticulum (ER) stress. Tmbim3 mRNA levels are strongly upregulated in cellular and animal models of ER stress, controlled by the PERK signaling branch of the unfolded protein response. TMBIM3/GRINA synergies with TMBIM6/BI-1 in the modulation of ER calcium homeostasis and apoptosis, associated with physical interactions with inositol trisphosphate receptors. Loss-of-function studies in D. melanogaster demonstrated that TMBIM3/GRINA and TMBIM6/BI-1 have synergistic activities against ER stress in vivo. Similarly, manipulation of TMBIM3/GRINA levels in zebrafish embryos revealed an essential role in the control of apoptosis during neuronal development and in experimental models of ER stress. These findings suggest the existence of a conserved group of functionally related cell death regulators across species beyond the BCL-2 family of proteins operating at the ER membrane.

Fine needle aspiration cytology of basal cell adenoma of the salivary gland: a cytohistological correlation study of 35 cases.

OBJECTIVE: In order to evaluate the possibility of a specific cytological recognition of basal cell adenoma (BCA) we reviewed our experience with 35 histologically proven cases. Few series describing cytological features of BCA are available and diagnostic cytological criteria are not well established. METHODS: This study was based on 41 cytology samples from 35 patients with BCA. Thirty-five aspiration procedures were performed pre-operatively and six on tumour recurrence. Nineteen of the 35 patients were men and 16 women. The mean age at diagnosis was 55 years old (range 24-92). The series includes one non-representative case. Except for one tumour located in the upper lip, all of them involved the parotid gland. RESULTS: Aspirates were cellular, showing groups with dense, homogeneous metachromatic stroma and single cells. Relevant features were the trident-like configuration of groups, intimate relationship between neoplastic cells and stroma and cellular polymorphism. In approximately half of the cases a precise diagnosis was given. Most of the remaining tumours were diagnosed as benign but they were difficult to differentiate from pleomorphic adenoma. Regarding malignancy, there were two misdiagnoses of acinic cell carcinoma, due to high epithelial cellularity along with scarcity of stroma, and one case was considered to be suspicious of malignancy. CONCLUSION: BCA shows characteristic cytological features that allow a precise diagnosis. The main differential diagnosis is epithelial-rich pleomorphic adenoma, while acinic cell carcinoma is a potential false positive.

Acute rheumatic fever in a grown up with repaired tetralogy of Fallot: the role of acquired diseases in patients with congenital heart diseases.

We report a 20 year old patient with repaired Tetralogy of Fallot who presented with acute right side heart failure. The echocardiogram showed severe mitral regurgitation which was not present one year before. Because of mitral insufficiency, pulmonary pressure increased and it was nearby 70% systemic pressure. Pulmonary regurgitation got worse, and the patient came to the hospital in a state of anasarca. After valve replacement, histopathological study of the mitral valve and the aortic valve revealed Aschoff nodules and rheumatic fever was confirmed.

[The impact of Glut-1 marker application on the diagnosis and treatment of congenital vascular anomalies]. / Impacto de la aplicación del marcador GLUT-1 en el diagnóstico y tratamiento de las anomalías vasculares congénitas.

Hemangiomas of infancy have a unique vascular phenotype demonstrated by glucose transporter 1 (GLUT-1) staining marker. Since its first description by P. E. North in 2000 its use has become widely spread by clinicians and researchers in the field of vascular anomalies. We prospectively and retrospectively used GLUT-1 marker on 90 patients divided in five groups over a two years period. Grupo I: Hemangiomas under 1 year of age. Grupo II: Hemangiomas between 1 and 15 years of age. Grupo III: Misdiagnosed angiomas in patients older than 15 years. Grupo IV: Patients with low and high flow vascular malformations Grupo V: Vascular tumors other than hemangiomas. As a result of the study, significant improvement has been noticed by the authors in appropiate vascular anomalies classification by primary care physicians involved in the study. Angioma is not anymore synonym of vascular birthmark. In addition the management of the newborn with a vascular tumour benefit from a more appropriate antiangiogenic therapy. Patients with RICH (rapidly involuting congenital hemangioma) or NICH (non involuting congenital hemangioma) pattern after biopsy and inmunohistochemical study did not receive any pharmacological agent as a part of their treatment. Finally GLUT-1 helped multidisciplinary vascular anomalies team development by promoting clinical, radiological and histopathologic correlations between different specialists.

[Diagnosis of intracranial facial schwannoma: clinical, and radiological factors, and the value of immunohistochemistry]. / Diagnóstico del schwannoma intracraneal del nervio facial. Factores clínicos, radiológicos y valor de la inmunohistoquímica.

OBJECTIVE: To analyze the clinical, radiological, and pathological features which may be useful to differentiate intracranial schwannomas of the facial nerve from vestibular schwannomas. MATERIAL AND METHODS: A retrospective study of 91 patients undergoing surgery with a clinical suspicion of vestibular schwannoma is presented. Clinical and radiological features are analyzed. Immunohistochemistry for neurofilaments was performed in selected cases of unilateral vestibular schwannomas, bilateral vestibular schwannomas, and facial nerve schwannomas. RESULTS: Facial function was normal in 83% of patients with vestibular schwannoma. Both patients with facial schwannomas had preoperative House-Brackmann grade II facial function. MRI showed no main differences between facial and vestibular schwannomas. A positive immunostaining was found in unilateral vestibular schwannomas, bilateral vestibular schwannomas, and facial nerve schwannomas. CONCLUSION: There are no specific clinical, radiological, or pathological factors to accurately differentiate schwannomas of the facial nerve from vestibular schwannomas.

HIV-1 (p24)-positive multinucleated giant cells in HIV-associated lymphoepithelial lesion of the parotid gland. A report of two cases.

BACKGROUND: Cystic benign lymphoepithelial lesion (CBLL) is a well-recognized parotid disorder the diagnosis of which can be made on the basis of clinical findings, human immunodeficiency virus (HIV) testing, image studies and fine needle aspiration (FNA). Most aspirations are cystic, and the lesion can be recognized if the triad of foamy macrophages, lymphoid and epithelial (squamous) cells is observed. CASES: The authors recently observed FNA cytologic features of two HIV-associated cases that exhibited numerous multinucleated giant cells (MGCs) but failed to show the epithelial component. A subsequent surgical resection was performed in one patient. Similarly to what has been described for nasopharyngeal (adenoid and tonsil) lymphoid tissue of HIV-positive patients, intense immunoexpression of S-100 and p24 (HIV-1) protein was present in MGC. CONCLUSION: The diagnosis of HIV-associated CBLL should always be considered if a parotid cystic lesion presents with numerous MGCs. Immunocytochemical detection of p24 (HIV-1) protein in MGC becomes a very useful diagnostic aid and extends to parotid CBLL many of those pathogenic features of HIV-1 infection already noted in other HIV-1-infected, lymphoid oropharyngeal lesions.

Post-kala-azar dermal leishmaniasis with mucosal involvement in a kidney transplant recipient: treatment with liposomal amphotericin B.

Post-kala-azar dermal leishmaniasis (PKDL) is a rare clinical variant of cutaneous leishmaniasis. It is very common in the Indian subcontinent and less frequent in East Africa, but exceptional in the American and European continents. We have observed a case of PKDL in a renal transplant recipient. No systemic symptoms were present. The patient was treated with liposomal amphotericin B. We emphasize the unusual aspects of this case: the appearance of PKDL in Europe, its relationship with immunosuppression, the severe mucosal involvement and the excellent response to liposomal amphotericin B, a newly described treatment for the disease.

[Sinus bradycardia secondary to systemic pentamidine]. / Bradicardia sinusal secundaria a pentamidina sistémica.

Systemic side effects caused by parenteral pentamidine are frequent. They can be severe and life-threatening. Intravenous pentamidine may cause a variety of abnormalities in the cardiac conduction system as tachyarrhythmias, hypotension and/or non-specific ECG changes (a long corrected QT interval). There is only one case of previously reported bradyarrhythmias in an HIV-infected patient. We present a new adverse effect associated with intravenous pentamidine therapy, and to the best of our knowledge, this is the first reported case of sinus bradycardia in a patient who is not HIV-infected.

[Goodpasture's syndrome with negative renal immunofluorescence]. / Síndrome de Goodpasture con inmunofluorescencia renal negativa.

The diagnosis of Goodpasture's syndrome is established by the clinical setting of diffuse alveolar hemorrhage and glomerulonephritis, and the demonstration of circulating or tissue-bound antibasement membrane antibodies. However, cases of Goodpasture's syndrome limited either to the lungs or kidneys have been reported. The absence of immune deposits from renal biopsy specimens of a patient with Goodpasture's syndrome, even with normal renal function, is exceptional. We report here a case of Goodpasture's syndrome characterized by direct immunofluorescence staining of the transbronchial biopsy specimen, and with direct negative immunofluorescence on renal biopsy specimen.

Tuberous sclerosis associated with histologically confirmed ocular and cerebral tumors.

The clinical, neuroradiologic, and pathologic features of an unusual retinal and cerebral giant cell astrocytoma in a 24-year-old man with tuberous sclerosis are reported. The patient was referred at 3 years of age because of partial seizures from the first months of life, severe mental retardation, and left microphthalmos. The microphthalmic eye presented slow growth from 9 years of age and was enucleated at age 18 years because of exophthalmos and pain. At age 23 years, the patient experienced sudden and severe headache. Magnetic resonance imaging revealed a voluminous cystic tumor in the region of the foramen of Monro, lateral ventricle, and basal ganglia of the right cerebral hemisphere. Pathologic examination of the enucleated eye and of the cerebral tumor disclosed the same histologic findings in both locations, a giant cell astrocytoma.

[Bronchiectasis associated with human immunodeficiency virus infection]. / Bronquiectasias asociadas a infección por el virus de la inmunodeficiencia humana.

The precise incidence of bronchiectasis (BCH) in individuals infected by human immunodeficiency virus (HIV) is unknown. Because such knowledge can imply different diagnostic procedures, prognosis and treatment, we report a relevant case in which clinical and radiological signs led to suspicion of BCH which was confirmed by high resolution computerized axial tomography. As life expectancy improves for HIV-infected patients, the incidence of BCH may rise. We therefore believe it is important to include BCH in the spectrum of likely pulmonary radiological signs in the HIV-infected population, though further studies must be done to assess the epidemiology, etiology, pathogenesis and prognosis of BCH.

Polymorphous low-grade adenocarcinoma of the oral cavity: a report of 14 cases.

The clinicopathologic characteristics of 14 new cases of low-grade polymorphous adenocarcinoma of the oral cavity are presented. Tumors were located in the palate in 10 cases, and in one case each in the base of the tongue, buccal mucosa, tonsil, and retromolar pad. Nine cases were previously diagnosed as other categories of benign and malignant tumors. The tumors were classified as terminal-duct and low-grade papillary adenocarcinomas. Three cases developed local recurrence and four cases had lymph nodes metastasis, two on admission and two during the course of the disease. Two of the local recurrences and all cases with metastasis were salvaged with further surgery with or without irradiation. Recurrence and metastasis occurred only with the terminal duct adenocarcinoma. There was no death related to the neoplasm, although one patient is living with advanced disease.