Diagnosis of Birt-Hogg-Dube syndrome in a patient with spontaneous pneumothorax

Birt-Hogg-Dube syndrome refers to a dermatologic syndrome, consisting of small papular skins lesion distributed on the scalp, forehead, face and neck, which is autosomal dominantly inherited. Subsequently patients may develop concomitant renal and thoracic pathology. We report the case of a patient with Birt-Hogg-Dube syndrome diagnosed after spontaneous pneumothorax.

Selective ion changes during spontaneous mitochondrial transients in intact astrocytes.

The bioenergetic status of cells is tightly regulated by the activity of cytosolic enzymes and mitochondrial ATP production. To adapt their metabolism to cellular energy needs, mitochondria have been shown to exhibit changes in their ionic composition as the result of changes in cytosolic ion concentrations. Individual mitochondria also exhibit spontaneous changes in their electrical potential without altering those of neighboring mitochondria. We recently reported that individual mitochondria of intact astrocytes exhibit spontaneous transient increases in their Na(+) concentration. Here, we investigated whether the concentration of other ionic species were involved during mitochondrial transients. By combining fluorescence imaging methods, we performed a multiparameter study of spontaneous mitochondrial transients in intact resting astrocytes. We show that mitochondria exhibit coincident changes in their Na(+) concentration, electrical potential, matrix pH and mitochondrial reactive oxygen species production during a mitochondrial transient without involving detectable changes in their Ca(2+) concentration. Using widefield and total internal reflection fluorescence imaging, we found evidence for localized transient decreases in the free Mg(2+) concentration accompanying mitochondrial Na(+) spikes that could indicate an associated local and transient enrichment in the ATP concentration. Therefore, we propose a sequential model for mitochondrial transients involving a localized ATP microdomain that triggers a Na(+)-mediated mitochondrial depolarization, transiently enhancing the activity of the mitochondrial respiratory chain. Our work provides a model describing ionic changes that could support a bidirectional cytosol-to-mitochondria ionic communication.

Systematic review of delayed postoperative hemorrhage after pancreatic resection.

This review assesses the presentation, management, and outcome of delayed postpancreatectomy hemorrhage (PPH) and suggests a novel algorithm as possible standard of care.An electronic search of Medline and Embase databases from January 1990 to February 2010 was undertaken. A random-effect meta-analysis for success rate and mortality of laparotomy vs. interventional radiology after delayed PPH was performed.Fifteen studies comprising of 248 patients with delayed PPH were included. Its incidence was of 3.3%. A sentinel bleed heralding a delayed PPH was observed in 45% of cases. Pancreatic leaks or intraabdominal abscesses were found in 62%. Interventional radiology was attempted in 41%, and laparotomy was undertaken in 49%. On meta-analysis comparing laparotomy vs. interventional radiology, no significant difference could be found in terms of complete hemostasis (76% vs. 80%; P = 0.35). A statistically significant difference favored interventional radiology vs. laparotomy in term of mortality (22% vs. 47%; P = 0.02).Proper management of postoperative complications, such as pancreatic leak and intraabdominal abscess, minimizes the risk of delayed PPH. Sentinel bleeding needs to be thoroughly investigated. If a pseudoaneurysm is detected, it has to be treated by interventional angiography, in order to prevent a further delayed PPH. Early angiography and embolization or stenting is safe and should be the procedure of choice. Surgery remains a therapeutic option if no interventional radiology is available, or patients cannot be resuscitated for an interventional treatment.

An immune-competent model of spontaneous breast cancer metastasis to the brain

In breast cancer, brain metastases are often seen as late complications of recurrent disease and represent a particularly serious condition, since there are limited therapeutic options and patients have an unfavorable prognosis. The frequency of brain metastases in breast cancer is currently on the rise. This might be due to the fact that adjuvant chemotherapeutic and targeted anticancer drugs, while they effectively control disease progression in the periphery, they only poorly cross the blood-brain barrier and do not reach effectively cancer cells disseminated in the brain. It is therefore of fundamental clinical relevance to investigate mechanisms involved in breast cancer metastasis to the brain. To date experimental models of breast cancer metastasis to the brain described in literature are based on the direct intracarotid or intracardiac injection of breast cancer cells. We recently established a brain metastasis breast cancer model in immunocompetent mice based on the orthotopic injection of 4T1 murine breast carcinoma cells in the mammary gland of syngeneic BALB/c mice. 4T1-derived tumors recapitulate the main steps of human breast cancer progression, including epithelial-to-mesenchymal transition, local invasion and metastatic spreading to lung and lymph nodes. 4T1 cells were engineered to stably express firefly Luciferase allowing noninvasive in vivo and ex vivo monitoring of tumor progression and metastatic spreading to target organs. Bioluminescence imaging revealed the appearance of spontaneous lesions to the lung and lymph nodes and, at a much lower frequency, to the brain. Brain metastases were confirmed by macroscopic and microscopic evaluation of the brains at necropsy. We then isolated brain metastatic cells, re-injected them orthotopically in new mice and isolated again lines from brain metastases. After two rounds of selection we obtained lines metastasizing to the brain with 100% penetrance (named 4T1-BM2 for Brain Metastasis, 2nd generation) compared to lines derived after two rounds of in vivo growth from primary tumors (4T1-T2) or from lung metastases (4T1-LM2). We are currently performing experiments to unravel differences in cell proliferation, adhesion, migration, invasion and survival of the 4T1-BM2 line relative to the 4T1-T2 and 4T1-LM2 lines. Initial results indicate that 4T1-BM2 cells are not more invasive or more proliferative in vitro and do not show a more mesenchymal phenotype. Our syngeneic (BALB/c) model of spontaneous breast carcinoma metastasis to the brain is a unique and clinically relevant model to unravel the mechanisms of metastatic breast cancer colonization of the brain. Genes identified in this model represent potentially clinically relevant therapeutic targets for the prevention and the treatment of brain metastases in breast cancer patients.

Hémorragie intra-alvéolaire [Alveolar hemorrhage].

Diffuse alveolar hemorrhage (DAH) is defined by the presence of red blood cells originating from the lung capillaries or venules within the alveoli. The diagnosis is established on clinical features, radiological pattern, and especially bronchoalveolar lavage. Diffuse alveolar hemorrhage may have many immune or non-immune causes. Immune causes of DAH include vasculitides, connective tissue diseases, especially systemic lupus erythematosus, and antiglomerular basement membrane antibody disease (Goodpasture's syndrome). Treatment is both supportive and causal, often based on high dose corticosteroids and immunosuppressive therapy (especially intravenous cyclophosphamide). Plasma exchanges are performed in antiglomerular basement membrane antibody disease and systemic lupus erythematosus, and are considered in systemic vasculitis. Non-immune causes of DAH mainly include heart diseases, coagulation disorders, infections, drug toxicities and idiopathic DAH. Treatment of non-immune DAH is that of its cause. Whatever the cause, DAH is an emergency requiring prompt assessment and early treatment.

Symptomatic intracranial hemorrhage after stroke thrombolysis: comparison of prediction scores.

BACKGROUND AND PURPOSE: Several prognostic scores have been developed to predict the risk of symptomatic intracranial hemorrhage (sICH) after ischemic stroke thrombolysis. We compared the performance of these scores in a multicenter cohort. METHODS: We merged prospectively collected data of patients with consecutive ischemic stroke who received intravenous thrombolysis in 7 stroke centers. We identified and evaluated 6 scores that can provide an estimate of the risk of sICH in hyperacute settings: MSS (Multicenter Stroke Survey); HAT (Hemorrhage After Thrombolysis); SEDAN (blood sugar, early infarct signs, [hyper]dense cerebral artery sign, age, NIH Stroke Scale); GRASPS (glucose at presentation, race [Asian], age, sex [male], systolic blood pressure at presentation, and severity of stroke at presentation [NIH Stroke Scale]); SITS (Safe Implementation of Thrombolysis in Stroke); and SPAN (stroke prognostication using age and NIH Stroke Scale)-100 positive index. We included only patients with available variables for all scores. We calculated the area under the receiver operating characteristic curve (AUC-ROC) and also performed logistic regression and the Hosmer-Lemeshow test. RESULTS: The final cohort comprised 3012 eligible patients, of whom 221 (7.3%) had sICH per National Institute of Neurological Disorders and Stroke, 141 (4.7%) per European Cooperative Acute Stroke Study II, and 86 (2.9%) per Safe Implementation of Thrombolysis in Stroke criteria. The performance of the scores assessed with AUC-ROC for predicting European Cooperative Acute Stroke Study II sICH was: MSS, 0.63 (95% confidence interval, 0.58-0.68); HAT, 0.65 (0.60-0.70); SEDAN, 0.70 (0.66-0.73); GRASPS, 0.67 (0.62-0.72); SITS, 0.64 (0.59-0.69); and SPAN-100 positive index, 0.56 (0.50-0.61). SEDAN had significantly higher AUC-ROC values compared with all other scores, except for GRASPS where the difference was nonsignificant. SPAN-100 performed significantly worse compared with other scores. The discriminative ranking of the scores was the same for the National Institute of Neurological Disorders and Stroke, and Safe Implementation of Thrombolysis in Stroke definitions, with SEDAN performing best, GRASPS second, and SPAN-100 worst. CONCLUSIONS: SPAN-100 had the worst predictive power, and SEDAN constantly the highest predictive power. However, none of the scores had better than moderate performance.

Detection of hemorrhage source: the diagnostic value of post-mortem CT-angiography.

The aim of this study was to compare the diagnostic value of post-mortem computed tomography angiography (PMCTA) to conventional, ante-mortem computed tomography (CT)-scan, CT-angiography (CTA) and digital subtraction angiography (DSA) in the detection and localization of the source of bleeding in cases of acute hemorrhage with fatal outcomes. The medical records and imaging scans of nine individuals who underwent a conventional, ante-mortem CT-scan, CTA or DSA and later died in the hospital as a result of an acute hemorrhage were reviewed. Post-mortem computed tomography angiography, using multi-phase post-mortem CTA, as well as medico-legal autopsies were performed. Localization accuracy of the bleeding was assessed by comparing the diagnostic findings of the different techniques. The results revealed that data from ante-mortem and post-mortem radiological examinations were similar, though the PMCTA showed a higher sensitivity for detecting the hemorrhage source than did ante-mortem radiological investigations. By comparing the results of PMCTA and conventional autopsy, much higher sensitivity was noted in PMCTA in identifying the source of the bleeding. In fact, the vessels involved were identified in eight out of nine cases using PMCTA and only in three cases through conventional autopsy. Our study showed that PMCTA, similar to clinical radiological investigations, is able to precisely identify lesions of arterial and/or venous vessels and thus determine the source of bleeding in cases of acute hemorrhages with fatal outcomes.

A novel approach to characterize clonality and differentiation of human melanoma-specific T cell responses: spontaneous priming and efficient boosting by vaccination.

Despite major progress in T lymphocyte analysis in melanoma patients, TCR repertoire selection and kinetics in response to tumor Ags remain largely unexplored. In this study, using a novel ex vivo molecular-based approach at the single-cell level, we identified a single, naturally primed T cell clone that dominated the human CD8(+) T cell response to the Melan-A/MART-1 Ag. The dominant clone expressed a high-avidity TCR to cognate tumor Ag, efficiently killed tumor cells, and prevailed in the differentiated effector-memory T lymphocyte compartment. TCR sequencing also revealed that this particular clone arose at least 1 year before vaccination, displayed long-term persistence, and efficient homing to metastases. Remarkably, during concomitant vaccination over 3.5 years, the frequency of the pre-existing clone progressively increased, reaching up to 2.5% of the circulating CD8 pool while its effector functions were enhanced. In parallel, the disease stabilized, but subsequently progressed with loss of Melan-A expression by melanoma cells. Collectively, combined ex vivo analysis of T cell differentiation and clonality revealed for the first time a strong expansion of a tumor Ag-specific human T cell clone, comparable to protective virus-specific T cells. The observed successful boosting by peptide vaccination support further development of immunotherapy by including strategies to overcome immune escape.

Systematic review of delayed postoperative hemorrhage after pancreatic resection

Objective:This review assesses the presentation,management, and outcome of delayed postpancreatectomy hemorrhage (PPH) and suggests a novel algorithm as possible standard of care.Methods: An electronic search of Medline and Embase databases from January 1990 to February 2010 was undertaken. A random-effect meta-analysis for success rate and mortality of laparotomy vs. interventional radiology after delayed PPH was performed.Results: Fifteen studies including 248 patients with delayed PPH were included. Its incidence was 3?3%. A sentinel bleed heralding a delayed PPH was observed in 45% of cases. Pancreatic leaks or intraabdominal abscesses were found in 62%. Interventional radiology was attempted in 41%, and laparotomy was undertaken in 49%. On meta-analysis comparing laparotomy vs. interventional radiology, no significant difference could be observed in term of complete hemostasis (76% vs. 80%; P = 0?35). A statistically significant difference favored interventional radiology vs. laparotomy in term of mortality (22% vs. 47%; P = 0?02).Conclusion: Proper and early management of postoperative complications, such as pancreatic leak and intraabdominal abscess, minimizes the risk of delayed PPH. Sentinel bleeding needs to be thoroughly investigated. If a pseudoaneurysm is detected, it has to be treated by interventional angiography, in order to prevent a further delayed PPH. Early angiography and embolization or stenting is safe and should be the procedure of choice. Surgery remains a therapeutic option if no interventional radiology is available, or patients cannot be resuscitated for an interventional treatment.

Spontaneous 24-h GHRELIN secretion pattern in fasting subjects : maintenance of a meal-related pattern

RESUME OBJECTIF: Outre la stimulation de la sécrétion d'hormone de croissance, la ghréline cause une prise pondérale par augmentation de l'assimilation d'aliments et réduction de la consommation lipidique. Il a été décrit que les taux de ghréline augmentent durant la phase pré-prandiale et diminuent juste après un repas, ceci suggérant qu'elle puisse jouer un rôle d'initiateur de la prise du repas. Cependant, la sécrétion de ghréline chez des sujets à jeun n'a pas encore été étudiée en détail. DESSIN: Les profils de sécrétion de ghréline pendant 24 heures ont été étudiés chez six sujets volontaires sains (3 femmes, 3 hommes; 25.5 ans; BMI 22.8 kg/m2) et comparés aux profils plasmatiques de l'hormone de croissance, de l'insuline et du glucose. METHODE: Des échantillons sanguins ont été prélevés toutes les 20 minutes pendant 24 heures et les taux de ghréline ont été mesurés par radio-immuno essai, utilisant un anticorps polyclonal de lapin. Le profil circadien de la sécrétion de ghréline (cluster analysis) a été évalué. RESULTATS: Une augmentation puis une diminution spontanée des taux de ghréline ont été observées aux moments où les sujets auraient habituellement mangé. La ghréline a été sécrétée de façon pulsatile avec approximativement 8 pics par 24 heures. Une diminution générale des taux de ghréline a également été observée durant la période d'étude. Aucune corrélation n'a pu être observée entre les taux de ghréline, d'homione de croissance, d'insuline et de glucose. CONCLUSIONS: Cette étude montre que pendant une période de jeûne les taux de ghréline suivent un profil similaire à ceux décrits chez des sujets mangeant 3 fois par jour. Durant le jeûne, l'hormone de croissance, l'insuline et le glucose ne semblent pas être impliqués dans la régulation de la sécrétion de ghréline. En outre, nous avons observé que la sécrétion de ghréline est pulsatile. La variation des taux de ghréline, indépendamment des repas, chez des sujets à jeun, renforce les observations préalables selon lesquelles le système nerveux central est primairement impliqué dans la régulation de la prise alimentaire. ABSTRACT: OBJECTIVE: Ghrelin stimulates GH release and causes weight gain through increased food intake and reduced fat utiIization. Ghrelin levels were shown to rise in the preprandial period and decrease shortly after meal consumption, suggesting a role as a possible meal initiator. However, ghrelin secretion in fasting subjects has not yet been studied in detail. DESIGN: 24-h ghrelin profiles were studied in six healthy volunteers (three females; 25.5 years; body mass index 22.8 kg/m2) and compared with GH, insulin and glucose levels. METHODS: Blood samples were taken every 20 min during a 24-h fasting period and total ghrelin levels were measured by RIA using a polyclonal rabbit antibody. The circadian pattern of ghrelin secretion and pulsatility (Cluster analysis) were evaluated. RESULTS: An increase and spontaneous decrease in ghrelin were seen at the timepoints of customary meals. Ghrelin was secreted in a pulsatile manner with approximately 8 peaks/24 h. An overall decrease in ghrelin levels was observed during the study period. There was no correlation of ghrelin with GH, insulin or blood glucose levels. CONCLUSIONS: This pilot study indicates that fasting ghrelin profiles display a circadian pattern similar to that described in people eating three times per day. In a fasting condition. GH, insulin and glucose do not appear to be involved in ghrelin regulation. In addition, we round that ghrelin is secreted in a pulsatile pattern. The variation in ghrelin independently of meals in fasting subjects supports previous observations that it is the brain that is primarily involved in the regulation of meal initiation.

Fatal intrahepatic hemorrhage after nadroparin use for total hip arthroplasty.

Low-molecular-weight heparins have become the predominant choice for deep venous thrombosis prophylaxis and treatment. However, their use may cause bleeding complications. Intrahepatic bleeding is exceptional and only very few cases have been described. The authors present a unique case of fatal intrahepatic hematoma complicating nadroparin use in a 65-year-old woman with a hepatic cyst who was admitted to hospital for unilateral total hip arthroplasty. At autopsy, hemoperitoneum (2,000 ml of blood and clots) was evident. A ruptured sub-capsular hematoma involving the right lobe of the liver was observed. The hemorrhage within the cyst induced by the nadroparin use was likely responsible for the subsequent hepatic hematoma, liver rupture, and death. This case highlights the need for pathologists and surgeons to be aware of the possibility of intrahepatic hematoma in patients who have received low-molecular-weight heparins, undergone major surgery and present postoperative hemodynamic instability, especially in those with preoperative diagnosis of hepatic cyst.