Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy

Familial amyloid polyneuropathy (FAP) is a progressive systemic autosomal dominant disease caused by pathogenic mutations in the transthyretin (TTR) gene. We studied clinical, electrophysiological, histopathological, and genetic characteristics in 15 (13 late-onset and two early-onset) patients belonging to 14 families with polyneuropathy and mutations in TTR. In comparison, we analysed the features of nine unrelated patients with an idiopathic polyneuropathy, in whom TTR mutations have been excluded. Disease occurrence was familial in 36 % of the patients with TTR-associated polyneuropathy and the late-onset type was observed in 86 % (mean age at onset 65.5 years). Clinically, all late-onset TTR-mutant patients presented with distal weakness, pansensory loss, absence of deep tendon reflexes, and sensorimotor hand involvement. Afferent-ataxic gait was present in 92 % leading to wheelchair dependence in 60 % after a mean duration of 4.6 years. Autonomic involvement was observed in 60 %, and ankle edema in 92 %. The sensorimotor polyneuropathy was from an axonal type in 82 %, demyelinating or mixed type in 9 % each. Compared to the TTR-unmutated idiopathic polyneuropathy patients, we identified rapid progression, early ambulatory loss, and autonomic disturbances, associated with a severe polyneuropathy as red flags for TTR–FAP. In 18 % of the late-onset TTR-FAP patients, no amyloid was found in nerve biopsies. Further diagnostic pitfalls were unspecific electrophysiology, and coincident diabetes mellitus (23 %) or monoclonal gammopathy (7 %). We conclude that a rapid disease course, severely ataxic gait, hand involvement, and autonomic dysfunction are diagnostic hallmarks of late-onset TTR–FAP. Genetic analysis should be performed even when amyloid deposits are lacking or when polyneuropathy-causing comorbidities are concomitant.     

Sensitivity of prostate cells to TRAIL-induced apoptosis increases with tumor progression: DR5 and caspase 8 are key players

BACKGROUND: As advanced prostate cancers are resistant to currently available chemotherapies, we evaluated the cytotoxic effect of TNF-related apoptosis-inducing ligand (TRAIL) and characterized the involvement of its five receptors DR4, DR5, DcR1, DcR2, and osteoprotegerin (OPG) and of the death-inducing signaling complex (DISC)-forming proteins caspase 8 and c-FLIP in prostate cell lines. METHODS: We used six prostate cell lines, each corresponding to a particular stage in prostate tumorigenesis, and analyzed TRAIL sensitivity in relation to TRAIL receptors' expression. RESULTS: TRAIL sensitivity was correlated with tumor progression and DR5 expression levels and apoptosis was exclusively mediated by DR5. DcR2 was significantly more abundant in tumor cells than in non-neoplastic ones and may contribute to partial resistance to TRAIL in some prostate tumor cells. Conversely, non-tumoral cells secreted high levels of OPG, which can protect them from apoptosis. Finally, caspase 8 expression levels were as DR5 directly correlated to TRAIL sensitivity in prostate tumor cells. CONCLUSION: TRAIL-induced apoptosis is closely related to the balanced expression of its different receptors in prostate cancer cells and their modulation could be of potential clinical value for advanced tumor treatment.     

Laparoscopic cholecystectomy in cirrhotic patients

Since 1992, laparoscopic cholecystectomy has been the treatment of choice for symptomatic gallstones. The advantages of laparoscopic cholecystectomy for most patients have been extensively published. However, its benefits and successful use in patients with cirrhosis are less well documented. The aim of this study was to determine the efficacy and safety of laparoscopic cholecystectomy in cirrhotic patients. We did a retrospective review of the records of 26 consecutive laparoscopic cholecystectomy procedures performed on cirrhotic patients between January 1992 and September 2000. Twenty-two patients were classified as having Child's class A cirrhosis, and 4 patients were classified as having Child's class B. No patients were classified as having Child's class C cirrhosis. There were 20 men and 6 women, with a mean age of 57 years (range, 37-76). All procedures were completed laparoscopically. There was histologic confirmation of cirrhosis in all patients. The mean operative time was 126 minutes (range, 60-184). The mean estimated blood loss was 110 mL (range, 40-380). Complications occurred in 7 patients (27%). No operative mortality occurred in this study. The mean length of hospital stay was 5 days (range, 3-14). Our results and the results of others show that laparoscopic cholecystectomy in cirrhotic patients seems to be safe in selected Child-Pugh class A and B patients with compensated cirrhosis. Cholecystectomy remains a high-risk procedure in cirrhotic patients, and indications for cholecystectomy should be evaluated carefully. Controlled trials are required to confirm the safety of this procedure, and further studies are also required to evaluate the management of gallbladder disease in patients with Child-Pugh class C cirrhosis.     

Elderly-onset rheumatoid arthritis

The treatment of elderly-onset rheumatoid arthritis pursues the same objectives as in younger patients: to control the clinical manifestations, to prevent structural damage, to preserve function, and to decrease excess mortality. In the elderly, the presence of co-morbidities and increased rate of drug-related adverse effects raise specific therapeutic challenges. Nonsteroidal anti-inflammatory drugs are associated with cardiovascular, gastrointestinal, and renal adverse events. The role for corticosteroid therapy remains controversial. Although glucocorticoids provide a short-term decrease in clinical activity and probably a medium-term decrease in structural damage, these benefits are offset by numerous adverse effects. Methotrexate was effective in clinical trials and observational studies and did not produce a higher adverse event rate compared to younger patients, provided renal function was normal. Data on the efficacy of TNFα antagonists in therapeutic trials are available only for etanercept. Disease activity decreased and function improved. The adverse event rate was higher in older patients, but this was also true of the conventional drugs used as comparators. Registry data confirm that TNFα antagonist therapy is effective in RA. An increased rate of infections was found only in some registries. To combat the 2-fold cardiovascular risk increase associated with RA, disease activity should be stringently controlled and all cardiovascular risk factors managed aggressively.     

Modulation by the noble gas argon of the catalytic and thrombolytic efficiency of tissue plasminogen activator

Argon has been shown to provide cortical as well as, under certain conditions, subcortical neuroprotection in all models so far (middle cerebral artery occlusion, trauma, neonatal asphyxia, etc.). This has led to the suggestion that argon could be a cost-efficient alternative to xenon, a metabolically inert gas thought to be gold standard in gas pharmacology but whose clinical development suffers its little availability and excessive cost of production. However, whether argon interacts with the thrombolytic agent tissue plasminogen activator, which is the only approved therapy of acute ischemic stroke to date, still remains unknown. This latter point is not trivial since previous data have clearly demonstrated the inhibiting effect of xenon on tPA enzymatic and thrombolytic efficiency and the critical importance of the time at which xenon is administered, during or after ischemia, in order not to block thrombolysis and to obtain neuroprotection. Here, we investigated the effect of argon on tPA enzymatic and thrombolytic efficiency using in vitro methods shown to provide reliable prediction of the in vivo effects of both oxygen and the noble inert gases on tPA-induced thrombolysis. We found that argon has a concentration-dependent dual effect on tPA enzymatic and thrombolytic efficiency. Low and high concentrations of argon of 25 and 75 vol% respectively block and increase tPA enzymatic and thrombolytic efficiency. The possible use of argon at low and high concentrations in the treatment of acute ischemic stroke if given during ischemia or after tPA-induced reperfusion is discussed as regards to its neuroprotectant action and its inhibiting and facilitating effects on tPA-induced thrombolysis. The mechanisms of argon–tPA interactions are also discussed.     

Chronic stress induces transient spinal neuroinflammation,triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia

Chronic stressful events induce biochemical, physiological and psychological changes, resulting in stress-related neuropsychiatric disorders, such as anxiety or depression. Using repeated social defeat as a stressful event model, we show that this preclinical paradigm induces a transient increase in the expression of the genes encoding the pro-inflammatory molecules iNOS and COX-2. We provide the first demonstration that chronic stress affects spinal plasticity through a mechanism involving local neuroinflammation. The functional consequences of such neuroinflammation are associated with a transient decrease in the mechanical nociceptive threshold. Administration of the cholecystokinin(CCK)-2 receptor antagonist, CI-988, directly into the Rostral Ventromedial Medulla reverses the chronic stress-induced decrease in the nociceptive threshold. These data strongly suggest that chronic stress induces a spinal neuroinflammation associated with transient sensory hypersensitivity involving the activation of CCK-dependent nociceptive descending facilitatory pathways. Pharmacological data show that chronic social stress-induced long-lasting state of anxiety is not responsible for maintaining the spinal neuroinflammation and, therefore, for the associated sensory hypersensitivity. Conversely, an evaluation of pain-related behavior in the formalin model indicates that anxiety is directly related to prolonged hyperalgesia prevented by systemic benzodiazepine or CCK-2 receptor antagonist treatments. The present study highlights the adverse effects of chronic stress on spinal neuroinflammation triggering sensory hypersensitivity. Exploration of this phenomenon points out the divergence between pain sensitivity and anxiety-induced hyperalgesia, which is in agreement with clinical observations. Altogether, these data open up new perspectives for clinical research devoted to the evaluation and treatment of pain in anxio-depressive patients.     

An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma.

PURPOSE: A topical Toll-like receptor 7 (TLR7) agonist induces regression of cutaneous melanocytic neoplasms. We explored antitumor activity of a systemically administered TLR7 agonist, 852A, in patients with metastatic melanoma. EXPERIMENTAL DESIGN: We undertook a phase II, multicenter, open-label study in patients with chemotherapy-refractory metastatic melanoma. Patients received i.v. 852A, starting at 0.6 mg/m(2) and increasing to 0.9 mg/m(2) based on tolerance, thrice per week for 12 weeks. Clinical response was determined by Response Evaluation Criteria in Solid Tumors. Immune effects of 852A were monitored by measuring serum type I IFN and IP-10 together with assessment of immune cell markers in peripheral blood. RESULTS: Twenty-one patients were enrolled. Thirteen patients completed the initial 12-week treatment cycle, with two discontinuing for adverse events considered to be possibly related to study drug. Four (19%) patients had disease stabilization for >100 days. One patient had a partial remission after two treatment cycles, but progressed during the third. Dose-limiting toxicity was observed in two patients. Serum type I IFN and IP-10 increased in most patients on 852A administration. Serum type I IFN increases were greater after dosing with 852A 0.9 mg/m(2) than after 0.6 mg/m(2) (P = 0.009). The maximal increase in IP-10 compared with baseline correlated with the maximal increase in type I IFN (P = 0.003). In the eight patients with immune cell marker data, CD86 expression on monocytes increased significantly post-first dose (P = 0.007). CONCLUSION: Intravenous 852A was well tolerated and induced systemic immune activation that eventually resulted in prolonged disease stabilization in some patients with stage IV metastatic melanoma who had failed chemotherapy.     

Expression of mage genes in transitional-cell carcinomas of the urinary bladder

Human genes MAGE-1 and MAGE-3 code for distinct antigens, which are recognized on melanoma cells by autologous cytolytic T lymphocytes (CTL). These antigens may constitute useful targets for anti-cancer immunotherapy, since no expression of MAGE genes has been observed in normal tissues other than testis. Out of 57 samples of primary transitional-cell carcinomas of the bladder, 12 (21%) expressed MAGE-1 and 20 (35%) expressed MAGE-3. All but one of the tumors expressing MAGE-1 also expressed MAGE-3. Genes MAGE-2 and MAGE-4, which are closely related to MAGE-1 and MAGE-3, were expressed by 30% and 33% of the tumors respectively. MAGE expression was more frequent in advanced tumor stages: 61% of the invasive tumors (stage ± T2) were positive for expression of at least one of the four genes, whereas only 28% of the superficial tumors (stages Ta and Tl) expressed these genes. © 1995 Wiley-Liss, Inc.     

Morphometric evaluation of the microvillous surface enlargement factor in the human placenta from mid-gestation to term

The factor by which the villous surface area is enlarged owing to the presence of microvilli has been evaluated with quantitative analyses in human placental tissues from mid-gestation to term. It has shown that, between 25 and 36 weeks of gestation, the peripheral villous surface area is enlarged by a constant factor of approximately 9.47 +/- 0.28 (mean +/- s.d.). Then, from 36 weeks to term, it has shown a significant decrease in the microvillous surface enlargement factor (9.44 to 7.67; P less than 0.01). Consequently, the actual surface area of exchange between mother and fetus was shown to be significantly decreased during that same period (93.91 to 67.02 m2; P less than 0.01). On a functional basis, these findings support the theory that, during that last four weeks of pregnancy, the increasing physiological needs of the fetus are probably met by profound functional changes in the permeability and transfer functions of the cells that constitute the placental barrier.