Congenital Melanocytic Nevus Syndrome: A Case Series. / Síndrome del nevus melanocítico congénito. Serie de casos.

Congenital melanocytic nevus syndrome (CMNS) is the result of an abnormal proliferation of melanocytes in the skin and central nervous system caused by progenitor-cell mutations during embryonic development. Mutations in the NRAS gene have been detected in many of these cells. We present 5 cases of giant congenital melanocytic nevus, 3 of them associated with CMNS; NRAS gene mutation was studied in these 3 patients. Until a few years ago, surgery was the treatment of choice, but the results have proved unsatisfactory because aggressive interventions do not improve cosmetic appearance and only minimally reduce the risk of malignant change. In 2013, trametinib was approved for use in advanced melanoma associated with NRAS mutations. This drug, which acts on the intracellular RAS/RAF/MEK/pERK/MAPK cascade, could be useful in pediatric patients with CMNS. A better understanding of this disease will facilitate the development of new strategies.

Tug-of-war between corrugation and binding energy: revealing the formation of multiple moiré patterns on a strongly interacting graphene-metal system.

The formation of multidomain epitaxial graphene on Rh(111) under ultra-high vacuum (UHV) conditions has been characterized by scanning tunnelling microscopy (STM) measurements and density functional theory (DFT) calculations. At variance with the accepted view for strongly interacting graphene-metal systems, we clearly demonstrate the formation of different rotational domains leading to multiple moiré structures with a wide distribution of surface periodicities. Experiments reveal a correlation between the STM apparent corrugation and the lattice parameter of the moiré unit cell, with corrugations of just 30-40 pm for the smallest moirés. DFT calculations for a relevant selection of these moiré patterns show much larger height differences and a non-monotonic behaviour with the moiré size. Simulations based on non-equilibrium Green's function (NEGF) methods reproduce quantitatively the experimental trend and provide a detailed understanding of the interplay between electronic and geometric contributions in the STM contrast of graphene systems. Our study sheds light on the subtle energy balance among strain, corrugation and binding that drives the formation of the moiré patterns in all graphene/metal systems and suggests an explanation for the success of an effective model only based on the lattice mismatch. Although low values of the strain energy are a necessary condition, it is the ability of graphene to corrugate in order to maximize the areas of favourable graphene-metal interactions that finally selects the stable configurations.

Noise levels and cardiovascular mortality: a case-crossover analysis.

BACKGROUND: The relationship between occupational noise and cardiovascular outcomes has been widely investigated. Regarding environmental noise levels, the attention is focused on road traffic noise due to the large number of exposed persons and the large periods of exposure. There are few studies assessing the short-term effects of traffic noise on cardiovascular outcomes. The aim of this study was to quantify the short-term effects of urban noise levels on age-specific cardiovascular mortality. METHODS: A case-crossover design was used. Daily mortality counts in Madrid city due to cardiovascular causes (ICD codes: 390-459) from 1 January 2003 to 31 December 2005 were obtained. Data noise levels were collected as diurnal equivalent noise (Leqd8-22 h), night equivalent noise (Leqn22-8 h), and daily equivalent noise (Leq24 h). Confounding variables as daily levels of air pollutants, temperature, and relative humidity data were controlled. Overdispersed Poisson regression models were adjusted to control for both seasonality and time trends. Estimated effects are reported as percentage increase in the relative risk (IRR) associated with an increase of 1 dBA. RESULTS: The strongest associations between all noise exposure levels and cardiovascular mortality were reported at lag 1: IRR 4.5% (95% CI 0.6, 8.7%), IRR 3.9% (95% CI 0.6, 7.3%), and IRR 6.2% (95% CI 2.1, 10.6%) for Leqd, Leqn, and Leq24, respectively. Analysing by age-specific groups at lag 1, statistically significant associations were found for those aged ≥65: 4.5% (95% CI 0.3, 8.9%), 3.4% (95% CI 0.1, 6.9%), and 6.6% (95% CI 2.2, 11.1%) for Leqd, Leqn, and Leq24, with no substantial changes in the effects of noise exposure levels at lag 1 after adjusting for PM2.5 and NO2. CONCLUSION: The association found between noise exposure levels and cardiovascular mortality suggests a joint effect of diurnal and night-time noise levels. Our results also reveal independent effects of noise exposure levels and the air pollutants analysed. This strongly suggests the need to seriously consider the high noise exposure levels reported as an important public health issue.

[Results of treatment of scaphoid nonunion with microvascularized bone grafts of the 1, 2 intercompartmental supraretinacular artery and osteosynthesis]. / Resultados del tratamiento de seudoartrosis de escafoides con injerto microvascularizado de arteria 1,2 intercompartimental suprarretinacular y osteosíntesis.

OBJECTIVE: To analyze the results of treatment of scaphoid nonunion with questionable viability of the proximal fragment, but without significant deformity or collapse, using a vascularized bone graft of 1,2 intercompartmental supraretinacular artery (1.2 ICSRA) and subsequent osteosynthesis. MATERIAL AND METHOD: A retrospective study was performed on 10 male patients with a radiographic diagnosis of nonunion. Functionality, pain using Visual Analog Score (VAS), grip strength, patient satisfaction and reintroduction to working life, using QuickDASH and May specific wrist scales were assessed after the treatment. The integration of the graft was checked by radiography. RESULTS: The mean follow-up was 31.4 months, and 90% of the questionnaires were satisfactory. The VAS decreased by 4.6 points and the flexor-extensor mobility gain was 5°. The total graft consolidation rate reached 40% in 5.5 months on average. DISCUSSION: Several studies have demonstrated better results using vascularized bone graft versus non-vascularized. From the description by Zaidemberg in 1991, the vascularized graft with 1.2 ICSRA artery, distal radius, has been the most widely used for the treatment of scaphoid nonunion. CONCLUSIONS: Our results are comparable with the literature reviewed, thus using vascular graft of the 1.2 ICSRA and osteosynthesis with Herbert-type screw, may be an alternative treatment for proximal scaphoid nonunion, without collapse or significant deformity.

Use of biogas for cogeneration of heat and electricity for local application: performance evaluation of an engine power generator and a sludge thermal dryer.

A small unit of cogeneration of energy and heat was tested at the Centre for Research and Training on Sanitation UFMG/COPASA - CePTS, located at the Arrudas Sewage Treatment Plant, in Belo Horizonte, Minas Gerais, Brazil. The unit consisted of an engine power generator adapted to run on biogas, a thermal dryer prototype and other peripherals (compressor, biogas storage tank, air blower, etc.). The heat from engine power generator exhaust gases was directed towards the thermal dryer prototype to dry the sludge and disinfect it. The results showed that the experimental apparatus is self-sufficient in electricity, even producing a surplus, available for other uses. The tests of drying and disinfection of sludge lasted 7 h, leading to an increase in solids content from 4 to 8% (50% reduction in sludge volume). Although the drying of sludge was not possible (only thickening was achieved), the disinfection process proved very effective, enabling the complete inactivation of helminth eggs.

Representation of harmonic complex stimuli in the ventral cochlear nucleus of the chinchilla.

The representation of Schroeder-phase harmonic complex sounds in the ventral cochlear nucleus (VCN) of the anesthetized chinchilla was studied. Stimuli consisted of a series of harmonically related sinusoids, multiples of a fundamental frequency (f0), summed in either negative (-SCHR) or positive (+SCHR) Schroeder phase. Psychoacoustic experiments performed in humans by other investigators have revealed that masking effects of -SCHR stimuli are larger than those found using +SCHR stimuli as maskers. In our laboratory, basilar membrane measurements at the base of the chinchilla cochlea show that responses to -SCHR stimuli are less "peaked," or modulated, than responses to +SCHR stimuli. We also found that suppression of a characteristic-frequency (CF) tone by -SCHR stimuli is larger than that evoked by +SCHR stimuli. Rate-intensity functions display higher firing rates in responses to -SCHR stimuli than in those produced by +SCHR stimuli. Firing rates evoked by either -SCHR or +SCHR stimuli saturate at lower values than those obtained in responses to CF tones. Rate and synchrony suppressions by -SCHR stimuli were larger than those evoked by +SCHR stimuli. Auditory nerve fiber responses to Schroeder complex stimuli share most of the properties of VCN responses, indicating little additional processing by the VCN.

Basilar-membrane response to multicomponent stimuli in chinchilla.

The response of chinchilla basilar membrane in the basal region of the cochlea to multicomponent (1, 3, 5, 6, or 7) stimuli was studied using a laser interferometer. Three-component stimuli were amplitude-modulated signals with modulation depths that varied from 25% to 200% and the modulation frequency varied from 100 to 2000 Hz while the carrier frequency was set to the characteristic frequency of the region under study (approximately 6.3 to 9 kHz). Results indicate that, for certain modulation frequencies and depths, there is enhancement of the response. Responses to five equal-amplitude sine wave stimuli indicated the occurrence of nonlinear phenomena such as spectral edge enhancement, present when the frequency spacing was less than 200 Hz, and mutual suppression. For five-component stimuli, the first, third, or fifth component was placed at the characteristic frequency and the component frequency separation was varied over a 2-kHz range. Responses to seven component stimuli were similar to those of five-component stimuli. Six-component stimuli were generated by leaving out the center component of the seven-component stimuli. In the latter case, the center component was restored in the basilar-membrane response as a result of distortion-product generation in the nonlinear cochlea.

Multicomponent stimulus interactions observed in basilar-membrane vibration in the basal region of the chinchilla cochlea.

Multicomponent stimuli consisting of two to seven tones were used to study suppression of basilar-membrane vibration at the 3-4-mm region of the chinchilla cochlea with a characteristic frequency between 6.5 and 8.5 kHz. Three-component stimuli were amplitude-modulated sinusoids (AM) with modulation depth varied between 0.25 and 2 and modulation frequency varied between 100 and 2000 Hz. For five-component stimuli of equal amplitude, frequency separation between adjacent components was the same as that used for AM stimuli. An additional manipulation was to position either the first, third, or fifth component at the characteristic frequency (CF). This allowed the study of the basilar-membrane response to off-CF stimuli. CF suppression was as high as 35 dB for two-tone combinations, while for equal-amplitude stimulus components CF suppression never exceeded 20 dB. This latter case occurred for both two-tone stimuli where the suppressor was below CF and for multitone stimuli with the third component=CF. Suppression was least for the AM stimuli, including when the three AM components were equal. Maximum suppression was both level- and frequency dependent, and occurred for component frequency separations of 500 to 600 Hz. Suppression decreased for multicomponent stimuli with component frequency spacing greater than 600 Hz. Mutual suppression occurred whenever stimulus components were within the compressive region of the basilar membrane.

Basilar membrane responses to broadband stimuli.

Basilar membrane (BM) responses to two types of broadband stimuli-clicks and Schroeder-phase complexes--were recorded at several sites at the base of the chinchilla cochlea. Recording sites (characteristic frequency, CF, in the range of 5.5-18 kHz) span the 1-4-mm basal region of the basilar membrane. BM responses to clicks consisted of undamped oscillations with instantaneous frequency that increased over time until it reached a value around CF. The time constant of this glide is CF dependent. Throughout the entire region under study, BM vibration exceeded umbo motion by up to 60 dB. Nonlinear properties of BM responses to clicks resemble those found in the more studied 8-10-kHz region. Amplitude spectra of Schroeder-phase complex stimuli, which consist of a series of sinusoidal components summed in negative (-SCHR) and positive Schroeder phase (+SCHR), are flat. The envelope of BM responses to +SCHR stimuli contains valleys, or dips, that are wider than those found in responses to the -SCHR stimuli. Hence, BM responses to the former stimuli are "peakier" than responses to the latter. Differences in response waveforms are less obvious in linear cochleae. Suppression of a near-CF tone by -SCHR stimuli was larger than that evoked by +SCHR stimuli.

Transvenous coil embolization of an intrahepatic portosystemic shunt in a dog.

To treat an intrahepatic portosystemic shunt in a young dog, thrombogenic material was placed into the vessel lumen (transvenous coil embolization) under fluoroscopic control. One coil was placed into the shunt, followed one month later by two additional coils. Transvenous embolization may become a useful method in the treatment of some portosystemic shunts.

Mechanical bases of frequency tuning and neural excitation at the base of the cochlea: comparison of basilar-membrane vibrations and auditory-nerve-fiber responses in chinchilla.

We review the mechanical origin of auditory-nerve excitation, focusing on comparisons of the magnitudes and phases of basilar-membrane (BM) vibrations and auditory-nerve fiber responses to tones at a basal site of the chinchilla cochlea with characteristic frequency approximately 9 kHz located 3.5 mm from the oval window. At this location, characteristic frequency thresholds of fibers with high spontaneous activity correspond to magnitudes of BM displacement or velocity in the order of 1 nm or 50 microm/s. Over a wide range of stimulus frequencies, neural thresholds are not determined solely by BM displacement but rather by a function of both displacement and velocity. Near-threshold, auditory-nerve responses to low-frequency tones are synchronous with peak BM velocity toward scala tympani but at 80-90 dB sound pressure level (in decibels relative to 20 microPascals) and at 100-110 dB sound pressure level responses undergo two large phase shifts approaching 180 degrees. These drastic phase changes have no counterparts in BM vibrations. Thus, although at threshold levels the encoding of BM vibrations into spike trains appears to involve only relatively minor signal transformations, the polarity of auditory-nerve responses does not conform with traditional views of how BM vibrations are transmitted to the inner hair cells. The response polarity at threshold levels, as well as the intensity-dependent phase changes, apparently reflect micromechanical interactions between the organ of Corti, the tectorial membrane and the subtectorial fluid, and/or electrical and synaptic processes at the inner hair cells.

Representation of vowel stimuli in the ventral cochlear nucleus of the chinchilla.

Responses of neurons in the ventral cochlear nucleus (VCN) of anesthetized chinchillas to six synthetic vowel sounds (/a/, /e/, /epsilon/, /i/, /o/ and /u/) were recorded at several intensity levels. Stimuli were synthesized with a fundamental frequency of 100 Hz or 181.6 Hz and had formant values at integer multiples of 100 Hz. Responses came from most neuron types in the VCN (with the exception of onset cells with an I-shaped pattern). Population studies, performed only on primary-like (PL) and chopper neurons, showed that PL neurons provide a better temporal representation than do chopper neurons. At the lowest level of stimulation, all neuron types provide an accurate rate-place representation of vowel spectra. With an increase in stimulus level, the rate-place representation of PL neurons becomes inferior to that of chopper neurons, either sustained choppers or transient choppers.

Study of mechanical motions in the basal region of the chinchilla cochlea.

Measurements from the 1-4-mm basal region of the chinchilla cochlea indicate the basilar membrane in the hook region (12-18 kHz) vibrates essentially as it does more apically, in the 5-9-kHz region. That is, a compressive nonlinearity in the region of the characteristic frequency, amplitude-dependent phase changes, and a gain relative to stapes motion that can attain nearly 10,000 at low levels. The displacement at threshold for auditory-nerve fibers in this region (20 dB SPL) was approximately 2 nm. Measurements were made at several locations in individual animals in the longitudinal and radial directions. The results indicate that there is little variability in the phase of motion radially and no indication of higher-order modes of vibration. The data from the longitudinal studies indicate that there is a shift in the location of the maximum with increasing stimulus levels toward the base. The cochlear amplifier extends over a 2-3-mm region around the location of the characteristic frequency.

A pilot study of systemic corticosteroid administration in conjunction with intrapleural adenoviral vector administration in patients with malignant pleural mesothelioma.

One of the primary limitations of adenoviral (Ad) -mediated gene therapy is the generation of anti-Ad inflammatory responses that can induce clinical toxicity and impair gene transfer efficacy. The effects of immunosuppression on these inflammatory responses, transgene expression, and toxicity have not yet been systematically examined in humans undergoing Ad-based gene therapy trials. We therefore conducted a pilot study investigating the use of systemic corticosteroids to mitigate antivector immune responses. In a previous phase I clinical trial, we demonstrated that Ad-mediated intrapleural delivery of the herpes simplex virus thymidine kinase gene (HSVtk) to patients with mesothelioma resulted in significant, but relatively superficial, HSVtk gene transfer and marked anti-Ad humoral and cellular immune responses. When a similar group of patients was treated with Ad.HSVtk and a brief course of corticosteroids, decreased clinical inflammatory responses were seen, but there was no demonstrable inhibition of anti -Ad antibody production or Ad-induced peripheral blood mononuclear cell activation. Corticosteroid administration also had no apparent effect on the presence of intratumoral gene transfer. Although limited by the small numbers of patients studied, our data suggest that systemic administration of steroids in the context of Ad-based gene delivery may limit acute clinical toxicity, but may not inhibit cellular and humoral responses to Ad vectors.

Frequency tuning of basilar membrane and auditory nerve fibers in the same cochleae.

Responses to tones of a basilar membrane site and of auditory nerve fibers innervating neighboring inner hair cells were recorded in the same cochleae in chinchillas. At near-threshold stimulus levels, the frequency tuning of auditory nerve fibers closely paralleled that of basilar membrane displacement modified by high-pass filtering, indicating that only relatively minor signal transformations intervene between mechanical vibration and auditory nerve excitation. This finding establishes that cochlear frequency selectivity in chinchillas (and probably in mammals in general) is fully expressed in the vibrations of the basilar membrane and renders unnecessary additional ("second") filters, such as those present in the hair cells of the cochleae of reptiles.

A phase II trial and pharmacokinetic analysis of 96-hour infusional paclitaxel in patients with metastatic colorectal cancer.

A phase II study was conducted to evaluate the activity and toxicity of 96-hour infusional paclitaxel in patients with previously untreated metastatic colorectal cancer. Twelve patients were enrolled in this study. The first patient received a total dose of 140 mg/m2 over 96 hours resulting in grade 4 neutropenia, neutropenic fever, and grade 3 stomatitis. Subsequent patients received a total dose of 120 mg/m2 over 96 hours. Grade 3 to 4 neutropenia occurred in four of these patients. No significant thrombocytopenia was observed. Grade 3 to 4 nonhematologic toxicities in the group treated at 120 mg/m2 over 96 hours included nausea/vomiting in one patient, stomatitis in one patient, and diarrhea in two patients. One patient experienced a possible pulmonary hypersensitivity reaction. None of the 12 patients achieved an objective response. Two patients had stable disease and ten had progressive disease. Pharmacokinetic parameters including maximum plasma concentration and area under the concentration time curve were significantly higher in patients with grade 3 to 4 neutropenia than patients who experienced less toxicity. The authors conclude that further study of 96-hour infusional paclitaxel in patients with metastatic colorectal carcinoma is not warranted.

Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma.

Malignant pleural mesothelioma is a fatal neoplasm that is unresponsive to standard modalities of cancer therapy. We conducted a phase I dose-escalation clinical trial of adenoviral (Ad)-mediated intrapleural herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) gene therapy in patients with mesothelioma as a model for treatment of a localized malignancy. The goals of this phase I trial were to assess the safety, toxicity, and maximally tolerated dose of intrapleural Ad.HSVtk, to examine patient inflammatory response to the viral vector, and to evaluate the efficiency of intratumoral gene transfer. Twenty-one previously untreated patients were enrolled in this single-arm, dose-escalation study with viral doses ranging from 1 x 10(9) plaque-forming units (pfu) to 1 x 10(12) pfu. A replication-incompetent recombinant adenoviral vector containing the HSVtk gene under control of the Rous sarcoma virus (RSV) promoter-enhancer was introduced into the pleural cavity of patients with malignant mesothelioma followed by 2 weeks of systemic therapy with GCV at a dose of 5 mg/kg twice a day. The initial 15 patients underwent thoracoscopic pleural biopsy prior to, and 3 days after, vector delivery. The last six patients underwent only the post-vector instillation biopsy. Dose-limiting toxicity was not reached. Side effects were minimal and included fever, anemia, transient liver enzyme elevations, and bullous skin eruptions, as well as a temporary systemic inflammatory response in those receiving the highest dose. Strong intrapleural and intratumoral immune responses were generated. Using RNA PCR, in situ hybridization, immunohistochemistry, and immunoblotting, HSVtk gene transfer was documented in 11 of 20 evaluable patients in a dose-related fashion. This study demonstrates that intrapleural administration of an adenoviral vector containing the HSVtk gene is well tolerated and results in detectable gene transfer when delivered at high doses. Further development of therapeutic trials for treatment of localized malignancy using this vector is thus warranted.

Basilar-membrane responses to clicks at the base of the chinchilla cochlea.

Basilar-membrane responses to clicks were measured, using laser velocimetry, at a site of the chinchilla cochlea located about 3.5 mm from the oval window (characteristic frequency or CF: typically 8-10 kHz). They consisted of relatively undamped oscillations with instantaneous frequency that increased rapidly (time constant: 200 microseconds) from a few kHz to CF. Such frequency modulation was evident regardless of stimulus level and was also present post-mortem. Responses grew linearly at low stimulus levels, but exhibited a compressive nonlinearity at higher levels. Velocity-intensity functions were almost linear near response onset but became nonlinear within 100 microseconds. Slopes could be as low as 0.1-0.2 dB/dB at later times. Hence, the response envelopes became increasingly skewed at higher stimulus levels, with their center of gravity shifting to earlier times. The phases of near-CF response components changed by nearly 180 degrees as a function of time. At high stimulus levels, this generated cancellation notches and phase jumps in the frequency spectra. With increases in click level, sharpness of tuning deteriorated and the spectral maximum shifted to lower frequencies. Response phases also changed as a function of increasing stimulus intensity, exhibiting relative lags and leads at frequencies somewhat lower and higher than CF, respectively. In most respects, the magnitude and phase frequency spectra of responses to clicks closely resembled those of responses to tones. Post-mortem responses were similar to in vivo responses to very intense clicks.

Basilar-membrane responses to tones at the base of the chinchilla cochlea.

Basilar-membrane responses to single tones were measured, using laser velocimetry, at a site of the chinchilla cochlea located 3.5 mm from its basal end. Responses to low-level (< 10-20 dB SPL) characteristic-frequency (CF) tones (9-10 kHz) grow linearly with stimulus intensity and exhibit gains of 66-76 dB relative to stapes motion. At higher levels, CF responses grow monotonically at compressive rates, with input-output slopes as low as 0.2 dB/dB in the intensity range 40-80 dB. Compressive growth, which is significantly correlated with response sensitivity, is evident even at stimulus levels higher than 100 dB. Responses become rapidly linear as stimulus frequency departs from CF. As a result, at stimulus levels > 80 dB the largest responses are elicited by tones with frequency about 0.4-0.5 octave below CF. For stimulus frequencies well above CF, responses stop decreasing with increasing frequency: A plateau is reached. The compressive growth of responses to tones with frequency near CF is accompanied by intensity-dependent phase shifts. Death abolishes all nonlinearities, reduces sensitivity at CF by as much as 60-81 dB, and causes a relative phase lead at CF.