CO2 flux from Javanese mud volcanism.

Studying the quantity and origin of CO2 emitted by back-arc mud volcanoes is critical to correctly model fluid-dynamical, thermodynamical, and geochemical processes that drive their activity and to constrain their role in the global geochemical carbon cycle. We measured CO2 fluxes of the Bledug Kuwu mud volcano on the Kendeng Fold and thrust belt in the back arc of Central Java, Indonesia, using scanning remote sensing absorption spectroscopy. The data show that the expelled gas is rich in CO2 with a volume fraction of at least 16 vol %. A lower limit CO2 flux of 1.4 kg s-1 (117 t d-1) was determined, in line with the CO2 flux from the Javanese mud volcano LUSI. Extrapolating these results to mud volcanism from the whole of Java suggests an order of magnitude total CO2 flux of 3 kt d-1, comparable with the expected back-arc efflux of magmatic CO2. After discussing geochemical, geological, and geophysical evidence we conclude that the source of CO2 observed at Bledug Kuwu is likely a mixture of thermogenic, biogenic, and magmatic CO2, with faulting controlling potential pathways for magmatic fluids. This study further demonstrates the merit of man-portable active remote sensing instruments for probing natural gas releases, enabling bottom-up quantification of CO2 fluxes.

How staging of thin melanoma is changed after the introduction of TNM 7th edition: a population-based analysis.

INTRODUCTION: In 2009, the American Joint Committee on Cancer (AJCC) incorporated the tumor mitotic rate in the melanoma pathological TNM staging system. To investigate the effect of this change on the pT1 substaging of primary cutaneous melanomas, we reclassified the cases collected by a cancer registry according to the 6th and the 7th editions of AJCC melanoma staging. METHODS: Patients with pathological T1 melanoma diagnosed in the period 2000-2008 were selected from Tuscan Cancer Registry. The histological reports were reviewed and pT1 melanomas classified according to both the 6th and the 7th editions of the AJCC staging system. The shift of melanomas between pT1 substages was analyzed. RESULTS: Among the 242 pT1 melanomas collected in the study period and with mitotic index available, there were 202 (83 % of all pT1) and 175 (72 %) pT1a, according to the 6th and the 7th editions of the AJCC melanoma staging, respectively. When the 7th edition was used, 20 % of all pT1a melanomas shifted to pT1b, and 32 % of all pT1b melanomas shifted to pT1a. A poor level agreement between the two TNM staging systems, measured by the Cohen's kappa coefficient, was found (K = 0.37). CONCLUSIONS: The addition of mitotic activity to the pathological staging resulted in an increase in pT1b proportion and in a change in the classification of some cases. This modification could influence the clinical approach, with a different use of the sentinel lymph node biopsy, and underlines the role of mitosis evaluation in the management of thin melanoma patients.

Differences in clinicopathological features and distribution of risk factors in Italian melanoma patients.

BACKGROUND: No studies are available in the literature on the distribution of different melanoma features and risk factors in the Italian geographical areas. OBJECTIVE: To identify the differences in clinical-pathological features of melanoma, the distribution of risk factors and sun exposure in various Italian macro-areas. METHODS: Multicentric-observational study involving 1,472 melanoma cases (713 north, 345 centre, 414 south) from 26 referral centres belonging to the Italian Multidisciplinary Group for Melanoma. RESULTS: Melanoma patients in northern regions are younger, with thinner melanoma, multiple primaries, lower-intermediate phototype and higher counts of naevi with respect to southern patients; detection of a primary was mostly connected with a physician examination, while relatives were more involved in the south. Northern patients reported a more frequent use of sunbeds and occurrence of sunburns before melanoma despite sunscreen use and a lower sun exposure during the central hours of the day. CONCLUSIONS: The understanding of differences in risk factors distribution could represent the basis for tailored prevention programmes.

Long-term suppression of EAE relapses by pharmacological impairment of epitope spreading.

BACKGROUND AND PURPOSE: Immune events sustaining dendritic cell (DC)-dependent epitope spreading (ES) are of key relevance to the development of relapses during multiple sclerosis (MS). Although no drugs are currently available to target ES, its inhibition would represent a major advancement in MS therapy. Inhibitors of the enzyme PARP-1 afford protection in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE). These drugs epigenetically impair antigen presentation by DCs, but whether these drugs affect ES is unknown. Here, we investigated whether short-term treatments with these compounds would impair ES, thereby preventing EAE relapses. EXPERIMENTAL APPROACH: We used a model of relapsing EAE in SJL mice and also adopted in vivo and ex vivo models of DC-dependent T-cell polarization. The effect of PARP-1 inhibitors on ES was evaluated at the humoral and cellular level. KEY RESULTS: Short-term treatments with PARP-1 inhibitors during the acute phase of relapsing EAE of mice induced, at later times, more tolerogenic DCs, increased numbers of Treg cells and impairment of ES at the humoral and cellular level. These effects are followed by long-lasting reduction of relapse severity and incidence, although drug treatment had been discontinued for several weeks. PARP-1 inhibitors also induced tolerogenic DCs and increased Treg cells number and function in a model of ovalbumin immunization. CONCLUSIONS AND IMPLICATIONS: Our data emphasize the therapeutic potential of PARP-1 inhibitors in the treatment of relapsing-remitting MS and additional ES-driven autoimmune disorders.

Dermoscopic features of cutaneous melanoma are associated with clinical characteristics of patients and tumours and with MC1R genotype.

BACKGROUND: Several algorithms are available for the dermoscopic diagnosis of pigmented skin lesions. The MC1R gene is a key determinant of pigmentation characteristics that are established host-related melanoma risk factors. OBJECTIVES: To investigate the association of dermoscopic features of sporadic cutaneous melanomas with clinical characteristics of patients and corresponding tumours and with genetic changes in the MC1R and BRAF genes. METHODS: A total of 64 dermoscopic images of 62 patients were scored by ABCD rule and modified pattern analysis. Detailed patients' and melanomas' characteristics were collected. Patients were screened for germline MC1R variants and related melanomas for somatic V600 BRAF mutations. RESULTS: A lower total dermoscopic score (TDS) was observed in melanomas of patients with red hair (P = 0.019), due to reduced dermoscopic structures (P < 0.0001). Thicker melanomas showed higher TDS values (P = 0.021) due to sharper borders (P < 0.0001) and higher number of colors (P = 0.004). An atypical pigment network was prevalent in superficial spreading melanomas (P = 0.010), in individuals with dark skin (P = 0.043) and hair color (P = 0.001). An atypical vascular pattern was more frequent in nodular (P < 0.0001) and thick (P < 0.0001) melanomas, in individuals with skin type I-II (P = 0.037), blond or red hair color (P = 0.032) and blue or green eyes (P = 0.014). Melanomas of MC1R R carriers showed lower TDS value (P = 0.037), reduced dermoscopic structures (P = 0.001) and lower prevalence of atypical pigment network (P = 0.001). No differences were identified between BRAF-mutated or wild-type melanomas. CONCLUSIONS: We suggest a phenotypic/MC1R profile for melanoma patients and their tumours. Melanomas of MC1R R carriers show a significant lower TDS value, with reduced dermoscopic structures, and a lower prevalence of an atypical pigment network. Non-carriers of MC1R R variants develop melanomas dermoscopically characterized by an atypical pigment network which is prevalent in superficial spreading melanomas, in patients with dark complexion and less frequent in red-haired individuals.

Caspase inhibition augments Dichlorvos-induced dopaminergic neuronal cell death by increasing ROS production and PARP1 activation.

Numerous epidemiological studies have shown an association between pesticide exposure and the increased risk of developing Parkinson's disease. Previously we have reported that Dichlorvos exposure can induce oxidative stress, resulting in over-expression of pro-apoptotic genes and finally caspase-dependent nigrostriatal dopaminergic neuronal cell death in rat brain. Here, we examined the effect of caspase inhibition on PC12 cell death induced by Dichlorvos (30 µM). Reactive oxygen species (ROS) generation followed by protein carbonylation, lipid peroxidation, decreased antioxidant defenses (decreased Mn-superoxide dismutase (MnSOD) activity and decreased glutathione levels) and subsequent caspase activation mediated the apoptosis. Inhibition of caspase cascade with Boc-aspartyl(OMe)-fluoromethylketone (BAF) enhanced the Dichlorvos-induced PC12 cell death, as assessed by the increased cellular efflux of lactate dehydrogenase (LDH). This increase in cell death was accompanied by a marked increase in poly(ADP-ribose) polymerase-1 (PARP1) activity, increased oxidative stress, a reduction in the mitochondrial membrane potential and reduced cellular NAD and ATP levels. Pretreatment of cells with PJ34, a PARP1 inhibitor prevented the cells from undergoing cell death and preserved intracellular NAD and ATP levels. Subsequent release of the apoptosis-inducing factor (AIF) from mitochondria and its translocation into the nucleus was also prevented by PJ34 pretreatment. In conclusion, the results of the present study show that caspase inhibition without concurrent inhibition of PARP1 is unlikely to be effective in preventing cell death because in the presence of the caspase inhibitor, caspase-independent cell death predominates due to PARP activation. These results suggest that combined therapeutic strategies directed at multiple cell death pathways may provide superior neuroprotection than those directed at a single mechanism.

Topical mannitol reduces inflammatory edema in a rat model of arthritis.

The hexahydric alcohol mannitol is widely used to shift fluids from the intracellular to the extracellular compartments, to increase diuresis and improve mucus clearance in the airways. In principle, because of its physicochemical properties, topical mannitol might also draw fluids out of epidermis or mucosa. Here, we report that topical mannitol applications on the hind paws of rats with adjuvant-induced arthritis reduced paw thickness and tissue edema without affecting the inflammatory infiltrates. Of note, the anti-edema effects of acute (4 h) mannitol application occurred earlier than those prompted by a similar treatment with classic anti-inflammatory drugs such as diclofenac or ketoprofen. Yet, the extent of edema reduction was higher with diclofenac or ketoprofen than with mannitol when the drugs were applied in a chronic (16 h) paradigm. Together, data demonstrate that topical application of mannitol exerts potent and fast anti-edema effects in a rat model of joint inflammation, suggesting a possible utilization in patients affected by osseo-arthritic disorders.

Long-lasting neuroprotection and neurological improvement in stroke models with new, potent and brain permeable inhibitors of poly(ADP-ribose) polymerase.

BACKGROUND AND PURPOSES: Thienyl-isoquinolone (TIQ-A) is a relatively potent PARP inhibitor able to reduce post-ischaemic neuronal death in vitro. Here we have studied, in different stroke models in vivo, the neuroprotective properties of DAMTIQ and HYDAMTIQ, two TIQ-A derivatives able to reach the brain and to inhibit PARP-1 and PARP-2. EXPERIMENTAL APPROACH: Studies were carried out in (i) transient (2 h) middle cerebral artery occlusion (tMCAO), (ii) permanent MCAO (pMCAO) and (iii) electrocoagulation of the distal portion of MCA in conjunction with transient (90 min) bilateral carotid occlusion (focal cortical ischaemia). KEY RESULTS: In male rats with tMCAO, HYDAMTIQ (0.1-10 mg·kg(-1)) injected i.p. three times, starting 4 h after MCAO, reduced infarct volumes by up to 70%, reduced the loss of body weight by up to 60% and attenuated the neurological impairment by up to 40%. In age-matched female rats, HYDAMTIQ also reduced brain damage. Protection, however, was less pronounced than in the male rats. In animals with pMCAO, HYDAMTIQ administered 30 min after MCAO reduced infarct volumes by approximately 40%. In animals with focal cortical ischaemia, HYDAMTIQ treatment decreased post-ischaemic accumulation of PAR (the product of PARP activity) and the presence of OX42-positive inflammatory cells in the ischaemic cortex. It also reduced sensorimotor deficits for up to 90 days after MCAO. CONCLUSION AND IMPLICATIONS: Our results show that HYDAMTIQ is a potent PARP inhibitor that conferred robust neuroprotection and long-lasting improvement of post-stroke neurological deficits.

Familial and sporadic melanoma: different clinical and histopathological features in the Italian population - a multicentre epidemiological study - by GIPMe (Italian Multidisciplinary Group on Melanoma).

BACKGROUND: Having a familial member affected by cutaneous melanoma is a risk factor for this neoplasm. Only a few epidemiological case-control studies have been carried out to investigate whether familial and sporadic melanomas show different clinical and histopathological features. OBJECTIVE: The aim of this study was to evaluate eventual different features and risk factors in subjects affected by familial and sporadic cutaneous melanoma. METHODS: A case-control multicentre study interesting 1407 familial (n = 92) and sporadic (n = 1315) melanomas in the Italian population. The analysis was made using t-test for continuous variables and chi-squared test for categorized ones. The variables which have shown statistically significant differences in the two groups in the univariate analysis were included in a multivariate model. RESULTS: The results showed some main significantly clinical differences between the two groups investigated: earlier age at diagnosis, a greater proportion of sunburns and a higher number of naevi were observed for the familial cases compared with sporadic ones. Nevertheless, we did not find a diagnostic anticipation in familial melanomas, in fact the invasion level and the thickness of melanomas was similar in the two groups. CONCLUSION: Some relevant clinical differences are observed between the two groups examined. The familial melanoma members, although carriers of constitutional risk factors, are not careful enough to primary and secondary prevention.

The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury.

The activation of nuclear factor kappa B (NF-κB) p50/RelA is a key event in ischemic neuronal injury, as well as in brain ischemic tolerance. We tested whether epigenetic mechanisms affecting the acetylation state of RelA might discriminate between neuroprotective and neurotoxic activation of NF-κB during ischemia. NF-κB activation and RelA acetylation were investigated in cortices of mice subjected to preconditioning brain ischemia or lethal middle cerebral artery occlusion (MCAO) and primary cortical neurons exposed to preconditioning or lethal oxygen-glucose deprivation (OGD). In mice subjected to MCAO and in cortical neurons exposed to lethal OGD, activated RelA displayed a high level of Lys310 acetylation in spite of reduced total acetylation. Also, acetylated RelA on Lys310 interacted strongly with the CREB-binding protein (CBP). Conversely, RelA activated during preconditioning ischemia appeared deacetylated on Lys310. Overexpressing RelA increased Bim promoter activity and neuronal cell death both induced by lethal OGD, whereas overexpressing the acetylation-resistant RelA-K310R, carrying a mutation from Lys310 to arginine, prevented both responses. Pharmacological manipulation of Lys310 acetylation by the sirtuin 1 activator resveratrol repressed the activity of the Bim promoter and reduced the neuronal cell loss. We conclude that the acetylation of RelA in Lys310 dictates NF-κB-dependent pro-apoptotic responses and represents a suitable target to dissect pathological from neuroprotective NF-κB activation in brain ischemia.

Selective PARP-2 inhibitors increase apoptosis in hippocampal slices but protect cortical cells in models of post-ischaemic brain damage.

BACKGROUND AND PURPOSE: Poly(ADP-ribose) polymerases (PARP)-1 and PARP-2 play complementary tasks in the maintenance of genomic integrity, but their role in cell death or survival processes is rather different. A recently described series of selective PARP-2 inhibitors (UPF-1035, UPF-1069) were used to study the role of PARP-1 and PARP-2 in post-ischaemic brain damage. EXPERIMENTAL APPROACH: We evaluated post-ischaemic brain damage in two different in vitro models: rat organotypic hippocampal slices exposed to oxygen-glucose deprivation (OGD) for 20-30 min, a model characterized by apoptosis-like cell death and mouse mixed cortical cell cultures exposed to 60 min OGD, a model in which cells die with mostly necrosis-like features. KEY RESULTS: In organotypic hippocampal slices, PARP-2 inhibition with UPF-1069 (0.01-1 micromolxL(-1)) caused a concentration-dependent exacerbation (up to 155%) of OGD-induced CA1 pyramidal cell death. Higher concentrations, acting on both PARP-1 and PARP-2, had no effect on OGD injury. In mouse mixed cortical cells exposed to OGD, on the contrary, UPF-1069 (1-10 micromolxL(-1)) significantly reduced post-ischaemic damage. CONCLUSION AND IMPLICATIONS: Selective PARP-2 inhibitors increased post-OGD cell death in a model characterized by loss of neurons through a caspase-dependent, apoptosis-like process (hippocampal slice cultures), but they reduced post-OGD damage and increased cell survival in a model characterized by a necrosis-like process (cortical neurons). UPF-1069 may be a valuable tool to explore the function of PARP-2 in biological systems and to examine the different roles of PARP isoenzymes in the mechanisms of cell death and survival.

Sensitivity to ultraviolet B is a risk factor for cutaneous melanoma in a Mediterranean population: results from an Italian case-control study.

BACKGROUND: Sun sensitivity is one of the predictors of melanoma risk, together with other individual characteristics such as skin and eye colour and number of naevi. However, it is unclear how best to measure sun sensitivity in order to quantify the individual risk of melanoma. OBJECTIVES: In this case-control study, the relationship between minimal erythema dose (MED) and skin colour (both instrumentally assessed) was investigated, and their possible role as independent risk factors for melanoma in a Mediterranean population evaluated. METHODS: In total, 143 patients with cutaneous melanoma and 102 controls were enrolled in the study. Skin colour was assessed using a Minolta CR-200 chromameter. For MED calculation, a fluorescent lamp (Philips TL 4W/12) was used as a source of ultraviolet B light. MED was defined as the lowest dose that produced an increase of 2.5 in the redness value, expressed by the parameter a* of the Commission Internationale d'Eclairage (CIE) L*a*b* colour space (Deltaa* = 2.5). RESULTS: A significant excess of risk was associated with increasing L* values of skin colour (P < 0.05; OR = 1.12; 95% CI 1.01-1.24) for each unit of change. Low MED values were also associated with an increasing risk of melanoma, with an excess of risk of 18% (OR = 1.18, 95% CI 1.04-1.35) for every 10 mJ/cm(2) of MED reduction. Compared with the highest MED values (> 97.7 mJ/cm(2)), subjects with MED values 2-fold increased risk of melanoma (OR = 2.37, 95% CI 1.05-5.38). The effect of decreasing MED value as a melanoma risk factor persisted after adjustment for skin colour and atypical naevi in a multivariate model. CONCLUSIONS: In conclusion, both instrumentally assessed skin colour and MED are significant risk factors for malignant melanoma in a Mediterranean population. MED seems be an independent variable in establishing the subject's risk profile.

Mono-galloyl glucose derivatives are potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors and partially reduce PARP-1-dependent cell death.

BACKGROUND AND PURPOSE: Maintenance of poly(ADP-ribose) (PAR) polymers at homoeostatic levels by PAR glycohydrolase (PARG) is central in cell functioning and survival. Yet the pharmacological relevance of PARG inhibitors is still debated. Gallotannin, a complex mixture of hydrolysable tannins from oak gall, inhibits PARG but which of its constituents is responsible for the inhibition and whether the pharmacodynamic properties are due to its antioxidant properties, has not yet been established. EXPERIMENTAL APPROACH: A structure-activity relationship study was conducted on different natural and synthetic tannins/galloyl derivatives as potential PARG inhibitors, using a novel in vitro enzymic assay. Cytotoxicity was assayed in cultured HeLa cells. KEY RESULTS: Mono-galloyl glucose compounds were potent inhibitors of PARG, with activities similar to that of ADP-(hydroxymethyl) pyrrolidinediol, the most potent PARG inhibitor yet identified. When tested on HeLa cells exposed to the PAR polymerase (PARP)-1-activating compound 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), 3-galloyl glucose weakly inhibited PAR degradation. Conversely, the more lipophilic, 3-galloyl-1,2-O-isopropylidene glucose, despite being inactive on the pure enzyme, efficiently prolonged the half-life of the polymers in intact HeLa cells. Also, PARG inhibitors, but not radical scavengers, reduced, in part, cell death caused by MNNG. CONCLUSIONS AND IMPLICATIONS: Taken together, our findings identify mono-galloyl glucose derivatives as potent PARG inhibitors, and emphasize the active function of this enzyme in cell death.

High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo.

High mobility group proteins are chromatin binding factors with key roles in maintenance of nuclear homeostasis. The evidence indicates that extracellularly released high mobility group box 1 (HMGB1) protein behaves as a cytokine, promoting inflammation and participating to the pathogenesis of several disorders in peripheral organs. In this study, we have investigated the expression levels and relocation dynamics of HMGB1 in neural cells, as well as its neuropathological potential. We report that HMGB1 is released in the culture media of neurons and astrocytes challenged with necrotic but not apoptotic stimuli. Recombinant HMGB1 prompts induction of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2, interleukin-1beta, and tumor necrosis factor alpha, and increases excitotoxic as well as ischemic neuronal death in vitro. Dexamethasone reduces HMGB1 dependent immune glia activation, having no effect on the protein's neurotoxic effects. HMGB1 is expressed in the nucleus of neurons and astrocytes of the mouse brain, and promptly (1 h) translocates into the cytoplasm of neurons within the ischemic brain. Brain microinjection of HMGB1 increases the transcript levels of pro-inflammatory mediators and sensitizes the tissue to the ischemic injury. Together, data underscore the neuropathological role of nuclear HMGB1, and point to the protein as a mediator of post-ischemic brain damage.

Predictors of skin self-examination in subjects attending a pigmented lesion clinic in Italy.

BACKGROUND: Skin self-examination (SSE) is associated with thinner melanomas in both North American and Italian patients. The knowledge of conditions associated with SSE may help in refining educational strategies for the prevention of melanoma. OBJECTIVE: The aim of the study was to investigate the frequency of SSE and the factors associated with SSE in subjects followed at a specialized pigmented lesion clinic (PLC) in Italy. PATIENTS/METHODS: A series of 299 consecutive subjects who visited the Florence PLC was investigated by means of a self-administered questionnaire regarding SSE habits. The statistical association between SSE and selected variables was examined by univariate and multivariate analyses. RESULTS: In the univariate analysis, variables significantly associated with SSE were: green/blue eyes, phototype I/II, the presence of large numbers of common acquired and atypical melanocytic naevi, sunscreen use, having had a previous PLC examination, and having received a leaflet explaining SSE. SSE was less frequent in women using sunbeds and more frequent in those performing breast self-examination. Using the multivariate model, which included all the variables associated with SSE in the previous analysis, we found that, among males, the only variable significantly associated with SSE was the report of having received a leaflet explaining SSE [odds ratio (OR) 3.02, 95% confidence interval (CI) 1.24-7.38]. Among females, having had a previous consultation at a PLC was significantly associated with SSE (OR 4.84, 95%CI 1.57-14.93); this might be because of the explanation and advice about skin cancer prevention customarily provided as a part of the PLC consultation at our department. CONCLUSION: Educational tools, including a leaflet explaining SSE and counselling given within previous PLC visits, seem to play a crucial role in promoting SSE habits in subjects followed at a specialized PLC consultation.

Comparison of risk patterns in carcinoma and melanoma of the skin in men: a multi-centre case-case-control study.

We directly compared risk factors between 214 histologically confirmed melanomas (CMM), 215 basal-cell carcinomas (BCC) and 139 squamous-cell carcinomas (SCC) in a multiple case-case-control study with 349 controls from patients without dermatological disease admitted to the same hospitals. Subjects with fair hair had a significant risk increase for all types of tumours at a comparable level (OR(adj) for blonde hair: CMM 2.3; SCC 2.4; BCC 2.3). The effect of pale eyes was significant and similar for CMM and BCC (OR(adj) 2.6). Intermittent sun exposure measured in hours spent at beach during holidays was significant for both CMM (OR(adj) 2.6 for more than 7000 lifelong hours) and BCC (OR(adj) 2.1 for more than 7000 lifelong hours), while SCC exhibited a significant risk increase for chronic exposure to sunlight measured in hours of outdoor work (OR(adj) 2.2 for more than 6000 lifelong hours). In the case-case comparison using a multinomial logistic regression model, we found a statistically significant risk difference for pale eyes, and number of naevi in the CMM group, compared to other skin cancers. For intermittent sun exposure, there was a significant risk difference of BCC when compared to the risk of SCC. Factors influencing risk of SCC are different, with chronic exposure to sun playing a major role in causing this type of carcinoma.

Improvement of malignant/benign ratio in excised melanocytic lesions in the 'dermoscopy era': a retrospective study 1997-2001.

BACKGROUND: Because of the many limitations of studies based on the diagnostic setting of excised lesions, the impact of dermoscopy (epiluminescence microscopy, dermatoscopy) in melanoma screening during practice remains to be established. OBJECTIVES: We assumed that effects of the use of dermoscopy on some indicators of diagnostic performance in melanoma screening should be traceable retrospectively; therefore, we analysed the impact of routine dermoscopy use on the malignant/benign ratio in excised melanocytic lesions. METHODS: Preoperative and histological diagnosis of 3053 melanocytic lesions [319 melanomas (10.4%)] consecutively diagnosed and excised at the Department of Dermatology, University of Florence in the period 1997-2001 inclusive were retrieved. Six dermatologists who selected the lesions to excise and who performed preoperative diagnosis were divided into two groups according to their use of dermoscopy in routine activity (n = 2 dermoscopy users and n = 4 nonusers). The study period was divided into a predermoscopy period (1997), a shift phase (1998) and a dermoscopy period (1999-2001). RESULTS: During the study period, the malignant/benign ratio improved in dermoscopy users only (from 1 : 18 to 1 : 4.3, P = 0.037). No significant difference was found for nonusers (from 1 : 11.8 to 1 : 14.4). Dermoscopy users were more likely to have a melanoma diagnosed within a series of excised lesions than nonusers, even taking into account potential confounders such as sex, age and study period by means of multivariate analysis (odds ratio 1.55, 95% confidence interval 1.17-2.01). The percentage of 'problem' naevi (naevi with architectural disorder with or without cytological atypia and Spitz or Reed naevi) over the total number of excised lesions was higher in dermoscopy users than in nonusers (year 2001, 51.6% vs. 40.9%, P = 0.014). Similar findings were obtained after exclusion from the data set of lesions excised for cosmetic reasons. CONCLUSIONS: The adoption of dermoscopy in routine melanoma screening is followed by an improvement of the malignant/benign ratio in excised lesions, suggesting a more appropriate selection of pigmented lesions referred to surgery. Because of the possible limitations of a retrospective study design, future confirmation of this finding by means of a prospective, randomized study is advisable. The introduction of dermoscopy in routine practice may have major implications in large-scale melanoma screening with cost savings and a reduction of the dermosurgery workload.

BID mediates neuronal cell death after oxygen/ glucose deprivation and focal cerebral ischemia.

Mitochondria and cytochrome c release play a role in the death of neurons and glia after cerebral ischemia. In the present study, we investigated whether BID, a proapoptotic promoter of cytochrome c release and caspase 8 substrate, was expressed in brain, activated after an ischemic insult in vivo and in vitro, and contributed to ischemic cell death. We detected BID in the cytosol of mouse brain and primary cultured mouse neurons and demonstrated, by using recombinant caspase 8, that neuronal BID also is a caspase 8 substrate. After 2 h of oxygen/glucose deprivation, BID cleavage was detected in neurons concurrent with caspase 8 activation but before caspase 3 cleavage. Bid(-/-) neurons were resistant to death after oxygen/glucose deprivation, and caspase 3 cleavage was significantly reduced; however, caspase 8 cleavage did not differ from wild type. In vivo, BID was cleaved 4 h after transient middle cerebral artery occlusion. Infarct volumes and cytochrome c release also were less in Bid(-/-) mice (-67% and -41%, respectively) after mild focal ischemia. These findings suggest that BID and the mitochondrial-amplification pathway promoting caspase activation contributes importantly to neuronal cell death after ischemic insult.

Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages.

We studied the regulation of the kynurenine pathway of tryptophan metabolism in human monocyte-derived macrophages (MDM) with the aim of evaluating macrophage involvement in inflammatory neurological disorders. Cultured MDM metabolized tryptophan and released kynurenine metabolites, including the excitotoxin quinolinic acid (QUIN). Lipopolysaccharides (LPS) or the pro-inflammatory cytokines INFgamma and TNFalpha increased, while IL 4 or IL 10 inhibited the rate of tryptophan metabolism and the release of QUIN. The incubation media of INFgamma-exposed MDM caused neuronal death in primary cultures of mixed cortical cells. Glutamate receptor antagonists or poly(ADP-ribose) polymerase inhibitors significantly reduced this death, thus suggesting new possibilities for the treatment of neuronal damage in neuroinflammatory disorders.