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Surgical resection is the treatment for early cutaneous melanoma and is often curative. Some patients, however, will subsequently relapse. High-risk features in the primary tumor and regional lymph node metastasis highlight patient subsets that are at increased risk for recurrent disease. Immunotherapy in the form of checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab have been shown to improve recurrence-free survival for node-positive melanoma in the adjuvant setting and will be the focus of this review.

Purpose Technetium-99m (99m Tc) is the radioisotope most widely used in diagnostic nuclear medicine. It is readily available from 99 Mo/99m Tc generators as the β- decay product of the 99 Mo (Tf = 66 h) parent nuclide. This latter is obtained as a fission product in nuclear reactors by neutron-induced reactions on highly enriched uranium. Alternative production routes, such as direct reactions using proton beams on specific target materials [100 Mo(p,2n)99m Tc], have the potential to be both reliable and relatively cost-effective. However, results showed that the 99m Tc extracted from proton-bombarded 100 Mo-enriched targets contains small quantities of several Tc radioisotopes (93m Tc, 93 Tc, 94 Tc, 94m Tc, 95 Tc, 95m Tc, 96 Tc, and 97m Tc). The aim of this work was to estimate the dose increase (DI) due to the contribution of Tc radioisotopes generated as impurities, after the intravenous injection of four radiopharmaceuticals prepared with cyclotron-produced 99m Tc (CP-99m Tc) using 99.05% 100 Mo-enriched metallic targets. Methods Four 99m Tc radiopharmaceuticals (pertechnetate, sestamibi (MIBI), hexamethylpropylene-amine oxime (HMPAO) and disodium etidronate (HEDP)) were considered in this study. The biokinetic models reported by the International Commission on Radiological Protection (ICRP) for each radiopharmaceutical were used to define the main source organs and to calculate the number of disintegrations per MBq that occurred in each source organ (Nsource ) for each Tc radioisotope present in the CP-99m Tc solution. Then, target organ equivalent doses and effective dose were calculated for each Tc radioisotope with the OLINDA/EXM software versions 1.1 and 2.0, using the calculated Nsource values and the adult male phantom as program inputs. Total effective dose produced by all Tc isotopes impurities present in the CP-99m Tc solution was calculated using the fraction of total activity corresponding to each radioisotope and compared with the effective dose delivered by the generator-produced 99m Tc. Results In all cases, the total effective DI of CP-99m Tc radiopharmaceuticals calculated with either versions of the OLINDA software was less than 10% from 6 up to 12 h after EOB. 94m Tc and 93m Tc are the Tc radioisotopes with the highest concentration in the CP-99m Tc solution at EOB. However, their contribution to DI 6 h after EOB is minimal, due to their short half-lives. The radioisotopes with the largest contribution to the effective DI are 96 Tc, followed by 95 Tc and 94 Tc. This is due to the types of their emissions and relatively long half-lives, although their concentration in the CP-99m Tc solution is five times lower than that of 94m Tc and 93m Tc at the EOB. Conclusions The increase in the radiation dose caused by other Tc radioisotopes contained in CP-99m Tc produced as described here is quite low. Even though the concentrations of the 94 Tc and 95 Tc radioisotopes in the CP-99m Tc solution exceed the limits established by the European Pharmacopoeia, CP-99m Tc radiopharmaceuticals could be used in routine nuclear medicine diagnostic studies if administered from 6 to 12 h after the EOB, thus maintaining the effective DI within the 10% limit.

Many prior studies have uncovered evidence for local adaptation using reciprocal transplant experiments. However, these studies are rarely conducted for a long enough time to observe succession and competitive dynamics in a community context, limiting inferences for long-lived species. Furthermore, the genetic basis of local adaptation and genetic associations with climate has rarely been identified. Here, we report on a long-term (6-year) experiment conducted under natural conditions focused on Andropogon gerardii, the dominant grass of the North American Great Plains tallgrass ecosystem. We focus on this foundation grass that comprises 80% of tallgrass prairie biomass and is widely used in 20,000 km2 of restoration. Specifically, we asked the following questions: (a) Whether ecotypes are locally adapted to regional climate in realistic ecological communities. (b) Does adaptive genetic variation underpin divergent phenotypes across the climate gradient? (c) Is there evidence of local adaptation if the plants are exposed to competition among ecotypes in mixed ecotype plots? Finally, (d) are local adaptation and genetic divergence related to climate? Reciprocal gardens were planted with 3 regional ecotypes (originating from dry, mesic, wet climate sources) of Andropogon gerardii across a precipitation gradient (500-1,200 mm/year) in the US Great Plains. We demonstrate local adaptation and differentiation of ecotypes in wet and dry environments. Surprisingly, the apparent generalist mesic ecotype performed comparably under all rainfall conditions. Ecotype performance was underpinned by differences in neutral diversity and candidate genes corroborating strong differences among ecotypes. Ecotype differentiation was related to climate, primarily rainfall. Without long-term studies, wrong conclusions would have been reached based on the first two years. Further, restoring prairies with climate-matched ecotypes is critical to future ecology, conservation, and sustainability under climate change.

Objectives Humanly induced modifications on human and non-human bones from four archaeological sites of known funerary rituals (one interpreted as cannibalism and three interpreted as funerary defleshing and disarticulation after a period of decay) were analyzed to ascertain whether macromorphological and micromorphological characteristics of cut marks can be used to distinguish cannibalistic from secondary burial practices. Material and methods Four collections were analyzed: the Magdalenian assemblage from Gough's Cave (UK) and the Mesolithic-Neolithic bone samples from Lepenski Vir, Padina and Vlasac (Serbia). A total of 647 cut marks (345 on human and 302 on non-human remains) were imaged and measured using an optical surface measurement system, the Alicona InfiniteFocus, housed at the Natural History Museum (London, UK). Results The frequency of cut marks at Gough's Cave exceeds 65%, while it is below 1% in the Serbian sites, and no human tooth marks and only one case of percussion damage have been observed on the three Serbian collections. The distribution of cut marks on human bones is comparable in the four assemblages. Cannibalized human remains, however, present a uniform cut mark distribution, which can be associated with disarticulation of persistent and labile articulations, and the scalping and filleting of muscles. For secondary burials where modification occurred after a period of decay, disarticulation marks are less common and the disarticulation of labile joints is rare. The micromorphometric analyses of cut marks on human and non-human remains suggest that cut marks produced when cleaning partially decayed bodies are significantly different from cut marks produced during butchery of fresh bodies. Conclusions A distinction between cannibalism and secondary treatment of human bodies can be made based on frequency, distribution and micromorphometric characteristics of cut marks.

SUMMARY 1. Stream fish can regulate their environment through direct and indirect pathways, and the relative influence of communities with different taxonomic and functional richness on ecosystem properties likely depends on habitat structure. Given this complexity, it is not surprising that observational studies of how stream fish communities influence ecosystems have shown mixed results. 2. In this study, we evaluated the effect of an observed gradient of taxonomic (zero, one, two or three species) and functional (zero, one or two groups) richness of fishes on several key ecosystem properties in experimental stream mesocosms. Our study simulated small (less than two metres wide) headwater prairie streams with a succession of three pool-riffle structures (upstream, middle and downstream) per mesocosm. Ecosystem responses included chlorophyll a from floating algal mats and benthic algae, benthic organic matter, macroinvertebrates (all as mass per unit area), algal filament length and stream metabolism (photosynthesis and respiration rate). Ecosystem responses were analysed individually using general linear mixed models. 3. Significant treatment (taxonomic and functional richness) by habitat (pools and riffles) interactions were found for all but one ecosystem response variable. After accounting for location (upstream, middle and downstream) effects, the presence of one or two grazers resulted in shorter mean algal filament lengths in pools compared to no-fish controls. These observations suggest grazers can maintain short algal filaments in pools, which may inhibit long filaments from reaching the surface. Accordingly, floating algal mats decreased in mid- and downstream locations in grazer treatment relative to no-fish controls. 4. At the scale of the entire reach, gross primary productivity and respiration were greater in treatments with two grazer species compared to mixed grazer/insectivore or control treatments. 5. The distribution of stream resources across habitat types and locations within a reach can therefore be influenced by the taxonomic and functional composition of fishes in small prairie streams. Thus, disturbances that alter diversity of these systems might have unexpected ecosystemlevel consequences.

We investigated by computational means the kinetics and stationary behavior of stochastic dynamics on an ensemble of rough two-dimensional energy landscapes. There are no obvious separations of temporal scales in these systems, which constitute a simple model for the behavior of glasses and some biomaterials. Even though there are significant computational challenges present in these systems due to the large number of metastable states, the Milestoning method is able to compute their kinetic and thermodynamic properties exactly. We observe two clearly distinguished regimes in the overall kinetics: one in which diffusive behavior dominates and another that follows an Arrhenius law (despite the absence of a dominant barrier). We compare our results with those obtained with an exactly-solvable one-dimensional model, and with the results from the rough one-dimensional energy model introduced by Zwanzig. © 2015 Wiley Periodicals, Inc.

SummaryReasons for performing study Protection from infectious disease requires antigen-specific immunity. In foals, most vaccine protocols are delayed until 6 months to avoid maternal antibody interference. Susceptibility to disease may exist prior to administration of vaccination at age 4–6 months. Objectives The aim of this investigation was to characterise immune activation among healthy foals in response to a multivalent vaccine protocol and compare immune responses when foals were vaccinated at age either 90 or 180 days. Study design Randomised block design. Methods Twelve healthy foals with colostral transfer were blocked for age and randomly assigned to vaccination at age 90 days (treatment) or at age 180 days (control). Vaccination protocols included a 3-dose series and booster vaccine administered at age 11 months. Results Immune response following vaccination at age 90 or 180 days was comparable for several measures of cellular immunity. Antigen specific CD4+ and CD8+ expression of interleukin-4, interferon-γ and granzyme B to eastern equine encephalomyelitis, western equine encephalomyelitis, West Nile virus, tetanus toxoid, equine influenza and equine herpesvirus-1/4 antigens were evident for both groups 30 days after initial vaccine and at age 344 days. Both groups showed a significant increase in antigen-specific immunoglobulin G expression following booster vaccine at age 11 months, thereby indicating memory immune responses. Conclusions The data presented in this report demonstrate that young foals are capable of immune activation following a 3-dose series with a multivalent vaccine, despite presence of maternal antibodies. Although immune activation does not automatically confer protection, several of the immune indicators measured showed comparable expression in foals vaccinated at 3 months relative to control foals vaccinated at age 6 months. In high-risk situations where immunity may be required earlier than following a conventional vaccine series, our data provide evidence that foals respond to immunisation initiated at 3 months in a comparable manner to foals initiated at an older age.

Big bluestem (Andropogon gerardii) is an ecologically dominant grass with wide distribution across the environmental gradient of U.S. Midwest grasslands. This system offers an ideal natural laboratory to study population divergence and adaptation in spatially varying climates. Objectives were to: (i) characterize neutral genetic diversity and structure within and among three regional ecotypes derived from 11 prairies across the U.S. Midwest environmental gradient, (ii) distinguish between the relative roles of isolation by distance (IBD) vs. isolation by environment (IBE) on ecotype divergence, (iii) identify outlier loci under selection and (iv) assess the association between outlier loci and climate. Using two primer sets, we genotyped 378 plants at 384 polymorphic AFLP loci across regional ecotypes from central and eastern Kansas and Illinois. Neighbour-joining tree and PCoA revealed strong genetic differentiation between Kansas and Illinois ecotypes, which was better explained by IBE than IBD. We found high genetic variability within prairies (80%) and even fragmented Illinois prairies, surprisingly, contained high within-prairie genetic diversity (92%). Using Bayenv2, 14 top-ranked outlier loci among ecotypes were associated with temperature and precipitation variables. Six of seven BayeScanFST outliers were in common with Bayenv2 outliers. High genetic diversity may enable big bluestem populations to better withstand changing climates; however, population divergence supports the use of local ecotypes in grassland restoration. Knowledge of genetic variation in this ecological dominant and other grassland species will be critical to understanding grassland response and restoration challenges in the face of a changing climate.

Background Left atrial size is prognostically important in dogs with myxomatous mitral valve disease (MMVD). Hypothesis/Objectives To compare the level of agreement in identification of left atrial enlargement (LAE) between the left atrial-to-aortic root ratio (LA : Ao) and left atrial volume using the biplane area-length method indexed to body weight (LA Vol/BW). Animals Sixty dogs with MMVD and 22 normal dogs were prospectively studied with 2-dimensional echocardiography. Methods The upper limit of normal for LA Vol/BW was defined as 1.1 mL/kg. LA : Ao was deemed normal if ≤1.5. To define overall disease severity, each dog was assigned a mitral regurgitation severity score (MRSS) based on echocardiographic parameters that did not include left atrial size. ACVIM staging also was utilized. Results Of 60 affected dogs, 20 were ACVIM Stage B1, 25 were Stage B2, and 15 were Stage C. LA Vol/BW identified LAE in 12 cases in which LA : Ao was normal; 7 of these were Stage B1 and 5 were Stage B2. This diagnostic disagreement was significant (P = .00012). Of the 12 cases in which diagnostic discrepancies were identified, 5/5 of the B2 dogs and 3/7 B1 dogs had a moderate MRSS, whereas 4/7 B1 dogs had a mild MRSS. No diagnostic discrepancies between LA : Ao and LA Vol/BW were apparent in dogs with a severe MRSS. Conclusions and Clinical Importance This study shows evidence of diagnostic disagreement between LA : Ao and LA Vol/BW for assessment of LAE. LA Vol/BW may be superior to LA : Ao for identification of mild LAE.

Objective To assess intraocular pressure (IOP) in conditioned equine athletes and document changes with exercise. A secondary objective was to assess associations between IOP and heart rate, as well as with other subjective physical parameters. Sample population Horses were evaluated during 50 mile endurance ride competitions. Data were collected on 69 horses during five different competitions at three different locations with 59 horses ridden once, nine horses ridden in two competitions, and one horse ridden in three competitions for a total of 80 horse-ride combinations. Procedures Intraocular pressure was measured using a TonoVet® tonometer in both eyes of each horse prior to, at two time points during, and immediately after endurance competitions. Heart rates and subjective veterinary scores were recorded on ride cards at each time point. Results For horses with shorter finishing times (≤400 min), IOP decreased by at least 3.1 ± 0.9 mmHg (least square mean estimate ± SEM) from baseline to the end of endurance exercise (P

This study assessed the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 2,3,7,8 tetrachlorodibenzofuran (TCDF) on the incidence of jaw lesions and on hepatic cytochrome P4501A (CYP1A) endpoints in mink (Mustela vison). Adult female mink were assigned randomly to one of 13 dietary treatments (control and four increasing doses of TCDD, PeCDF, or TCDF) and provided spiked feed for approximately 150 d (60 d prior to breeding through weaning of offspring at 42 d post-parturition). Offspring were maintained on their respective diets for an additional 150 d. Activity of hepatic CYP1A enzymes in adult and juvenile mink exposed to TCDD, PeCDF, or TCDD was generally greater compared with controls, but changes in other CYP1A endpoints were less consistent. Histopathology of the mandible and maxilla of juvenile mink suggested a dose-related increase in the incidence of jaw lesions. The dietary effective doses (ED) for jaw lesions in 50% of the population (ED50) were estimated to be 6.6, 14, and 149 ng/kg body weight (bw)/d for TCDD, PeCDF, and TCDF, respectively. The relative potencies of PeCDF and TCDF compared with TCDD based on ED10, ED20, and ED50 values ranged from 0.5 to 1.9 and 0.04 to 0.09, respectively. These values are within an order of magnitude of the World Health Organization toxic equivalency factor (TEFWHO) values of 0.3 and 0.1 for PeCDF and TCDF, respectively. Environ. Toxicol. Chem. 2012; 31: 2545–2556. © 2012 SETAC

An isolated adult human ulna fragment recovered from the ‘black mould’ layer of Kent's Cavern by William Pengelly in 1866 exhibits a series of stone tool cut marks. The specimen has been directly AMS 14C-dated to 7314–7075 cal bc (OxA-20588: 8185 ± 38 bp) and may be from the same individual as a maxilla fragment dated to the same period. The cut marks are located on the olecranon process, in a position indicative of dismemberment, whereas the fracture characteristics of the bone furthermore suggest peri-mortem breakage, typical of butchery for the extraction of marrow. We here present and discuss the specimen and consider both ritual mortuary treatment and anthropophagy as possible explanations. Although it is difficult to interpret a single element in isolation, the latter scenario seems to be better supported and is not without parallel in prehistoric Europe, as indicated by a review of the available literature. Copyright © 2012 John Wiley & Sons, Ltd.

Background Opening glass jars has been noted to be particularly problematic for consumers, leading to many studies related to the opening process. However, most studies place restrictions on jar opening by forcing the jar to remain on the counter or by requiring a specific hand on the closure. Objective The objectives of this research were (i) to evaluate the effect of restrained and unrestrained conditions on kinematics of jar opening, (ii) to evaluate the effects of jar diameter on kinematics and (iii) to evaluate how user characteristics (e.g. hand size) are associated with kinematics. Methods Kinematic data were collected from 21 participants during two opening conditions using jars with two diameters. Condition 1 restrained the participant by requiring that the jar maintain contact with the counter during the opening procedure. Condition 2 was termed unrestrained and allowed the user to open the jar with no requirements on jar or hand location. Results When restrained to a counter, the closure hand produced significantly more rotation compared with the closure hand in the unrestrained condition. Differences were not found in the opening motions when comparing jar diameters. However, hand breadth and length were related to the magnitude of rotation of the closure hand. Conclusions Placing restrictions on the participant, the orientation or location of the jar aids data analysis but may yield results that are not indicative of the user's actual jar opening process. Impositions on user positioning should be carefully considered in studies investigating the opening process of glass jars. Copyright © 2012 John Wiley & Sons, Ltd.

The augmentation of categorical outcomes with underlying Gaussian variables in bivariate generalized mixed effects models has facilitated the joint modeling of continuous and binary response variables. These models typically assume that random effects and residual effects (co)variances are homogeneous across all clusters and subjects, respectively. Motivated by conflicting evidence about the association between performance outcomes in dairy production systems, we consider the situation where these (co)variance parameters may themselves be functions of systematic and/or random effects. We present a hierarchical Bayesian extension of bivariate generalized linear models whereby functions of the (co)variance matrices are specified as linear combinations of fixed and random effects following a square-root-free Cholesky reparameterization that ensures necessary positive semidefinite constraints. We test the proposed model by simulation and apply it to the analysis of a dairy cattle data set in which the random herd-level and residual cow-level effects (co)variances between a continuous production trait and binary reproduction trait are modeled as functions of fixed management effects and random cluster effects.

Commonly used clinical indicators of renal disease are either insensitive to early dysfunction or have delayed results. Decreased glomerular filtration rate (GFR) indicates renal dysfunction before there is a loss of 50% of functional nephrons. Most tests evaluate global rather than individual kidney function. Dynamic computed tomography (CT) and Patlak plot analysis allows for individual GFR to be tested. Our objectives were to establish a procedure and provide reference values for determination of global GFR in 10 healthy cats using dynamic CT (CTGFR). This method of GFR determination was compared against serum iohexol clearance (SIC). A single CT slice centered on both kidneys and the aorta was acquired every fifth second during and after a bolus injection of iohexol (240 mgI/ml; 300 mgI/kg) for 115 s. Using data from this dynamic acquisition, Patlak plots were obtained, GFR was calculated, and results were compared to global GFR determined by iohexol clearance. The average global CTGFR estimate was 1.84 ml/min x kg (SD = 0.43; range = [1.22, 2.45]). The average global GFR measured using SIC was 2.45 ml/min x kg (SD = 0.58; range = [1.72, 3.69]). GFR measurements estimated by both dynamic CT and SIC were positively associated (estimated Spearman rank correlation coefficient = 0.72; P = 0.0234). The CTGFR method consistently underestimated GFR with a bias of -0.62 (SE = 0.1307) when compared to SIC (P = 0.0011). In healthy cats, CTGFR was capable of determining individual kidney function and appears clinically promising.

BACKGROUND: Secondary acute myeloid leukemia (AML) from an antecedent myelodysplastic syndrome (MDS)/myeloproliferative neoplasm is associated with a poor prognosis. The authors evaluated predictive factors in patients with secondary AML treated with anthracycline-based induction therapy. METHODS: This was a retrospective review of secondary AML patients treated with induction therapy. Age, International Prognostic Scoring System, Eastern Cooperative Oncology Group performance status, cytogenetics, duration of MDS/myeloproliferative neoplasm, and prior MDS/myeloproliferative neoplasm treatment were evaluated for their impact on complete response (CR), CR with low platelets, and overall survival (OS). RESULTS: The authors evaluated 61 secondary AML patients who received induction chemotherapy; 59% (36 patients) achieved CR/CR with low platelets (95% confidence interval [CI], 46%-71%), and median OS was 6.5 (95% CI, 3.9-8.1) months. Three factors were associated with lower CR/CR with low platelets and OS: poor risk cytogenetics, prior treatment with hypomethylating agents or lenalidomide, and longer time to transformation to AML. Of those treated with hypomethylating agents or lenalidomide, 32% achieved CR/CR with low platelets versus 78% in the group not treated with a hypomethylating agent or lenalidomide (odds ratio [OR], 0.13; 95% CI, 0.04-0.42). Median OS for those treated with a hypomethylating agent or lenalidomide was 3.7 versus 10.5 months for those not treated with a hypomethylating agent or lenalidomide (P < .0001). The CR/CR with low platelets rate for those with intermediate risk cytogenetics was 70% versus 35% for those with poor risk (OR, 4.33; 95% CI, 1.38-13.6). Those with poor risk cytogenetics had a median OS of 2.8 versus 7.5 months for those with intermediate risk (P = .01). CONCLUSIONS: Prior treatment with hypomethylating agents or lenalidomide, poor risk cytogenetics, and longer time to transformation to AML are independent negative predictive factors for response and OS in patients with secondary AML after induction therapy. Cancer 2011. © 2010 American Cancer Society.

This study introduces the use of change detection, a technique used in cognitive psychology to measure attentional scan paths, as a way to objectively evaluate the prominence of varied label elements. There are two major objectives related to this work: (a) to develop change detection software and methodology for label use; and (b) to compare the relative prominence of different label elements on a beverage container. Six label elements (i.e. treatments) were analysed, namely: the manufacturer name, the product name and a warning dot with text in three colours. Study results suggest that experimental set-up can significantly impact results, specifically the position of the change (p = 0.0078) and the order of appearance (p = 0.069). This is not only important from an experimental design perspective, but also could lead to insights regarding the attentive behaviours of people as they purchase, select and use products. With regard to the elements of the labels tested, we identified a significant difference on time to detect a change (p < 0.0001). Time required for the manufacturer's name, Asahi Breweries, was significantly longer than for any of the other label elements (p < 0.0001). Pairwise comparisons indicated that for the warning dot, red text was located marginally faster than the warning printed in black (p = 0.0566). Change detection offers the promise to objectively evaluate the relative prominence of a label (or a scene) but is quicker and cheaper than other methods, such as eye tracking, that are currently utilized for this purpose. Copyright © 2010 John Wiley & Sons, Ltd.

Bivariate mixed effects models are often used to jointly infer upon covariance matrices for both random effects (u) and residuals (e) between two different phenotypes in order to investigate the architecture of their relationship. However, these (co)variances themselves may additionally depend upon covariates as well as additional sets of exchangeable random effects that facilitate borrowing of strength across a large number of clusters. We propose a hierarchical Bayesian extension of the classical bivariate mixed effects model by embedding additional levels of mixed effects modeling of reparameterizations of u-level and e-level (co)variances between two traits. These parameters are based upon a recently popularized square-root-free Cholesky decomposition and are readily interpretable, each conveniently facilitating a generalized linear model characterization. Using Markov Chain Monte Carlo methods, we validate our model based on a simulation study and apply it to a joint analysis of milk yield and calving interval phenotypes in Michigan dairy cows. This analysis indicates that the e-level relationship between the two traits is highly heterogeneous across herds and depends upon systematic herd management factors.

A 71-year-old man presented with an asymptomatic lesion on the arm. He was born in rural West Virginia, spent several years in military service in the South Pacific, and is a long-term resident of Maine. He has chronic obstructive pulmonary disease, coronary artery disease, and noninsulin-dependent diabetes melitus. He was evaluated for episodes of hemoptysis by bronchoscopy in 1980 and 1984, but no cause was established. His usual medications included prednisone 10 mg daily. One month prior to the dermatology consultation the patient had been admitted to another hospital because of a flare-up of his lung disease. He was treated for 10 days with intravenous steroids and bronchodilators, resulting in improvement of his respiratory status. A cardiac pacemaker was inserted because of arrythmias. By the time of discharge, 1 week later, the prednisone dose had been tapered to his usual 10 mg daily. One week prior to the dermatology consultation, he was admitted to this institution for evaluation of recurrent atrial fibrillation. On admission, his chest X-ray revealed a pulmonary nodule which had not been present 1 month previously (Fig. la). The dermatology service was asked to evaluate an enlarging lesion on the right arm. The arm lesion began 2 weeks earlier as a group of papules which grew and coalesced. Two days prior to evaluation, the lesion had spontaneously drained purulent material. There was no pruritus or pain. The patient did not recall any similar skin problem in the past and had no history of trauma to the area. He reported a 30 Ib weight loss in the 2 months prior to admission despite a good appetite. There was no history of fever or malaise. On examination, a 3.3 × 1.5 cm plaque was noted on the right extensor forearm just above the wrist (Fig. 2). The plaque was erythematous with a shiny atrophic epidermis and fine scale. One portion of the plaque had a red-yellow hue and was indurated while the other had a grey-blue pigmented appearance. The remainder of his skin examination was unremarkable. There was no adenopathy or hepatosplenomegaly. Routine laboratory tests were significant for hyperglycemia, a mildly elevated white blood cell count of 11.5 K/UL with a normal differential; lactate dehydrogenase was 325 U/ L (normal, 88–196) and alkaline phosphatase 113 U/L (normal, 16–95). CT scan of the chest revealed emphysema and multiple bilateral pulmonary nodules with cavitation (Fig. 1b). A low attenuation region in the spleen was interpreted as representing an inflammatory or infectious focus, or, less likely, a cyst. CT scan of the abdomen revealed a normal liver and no abdominal adenopathy. Bone scan and ophthalmologic examination revealed no evidence of bony or ocular involvement. A 4-mm punch biopsy from the plaque on the wrist revealed suppurative granulomatous inflammation extending from the lower papillary dermis down to the deep dermis at the base of the biopsy specimen (Fig. 3a). Many multinucleated giant cells were observed. The overlying epidermis showed slight acanthosis with compaction and focal parakeratosis of the stratum corneum. In the dermis, numerous rounded structures and septate hyphae, measuring 5–9 microns in diameter, were present both within giant cells and extracellularly (Fig. 3b). These structures were stained by a Grocott methenamine silver stain, consistent with fungi (Fig. 3c). These findings, and the lack of encapsulation typically seen in subcutaneous phaeohyphomycosis, suggest a systemic fungal disease rather than direct cutaneous inoculation.8 A second specimen was sent for culture to the University of Texas Health Science Center in San Antonio and grew Alternaria alternata (no further description is available). In retrospect, the pigment seen clinically may have resulted either from the fungus, which is typically pigmented, or from an ecchymosis. Sensitivity testing revealed that the fungus was susceptible to amphotericin 0.29 μg/mL, itraconazole 0.07 μg/mL, and ketoconazole 0.1 μg/mL. Serum titers for complement-fixing antibodies to aspergillus and blastomyces were negative. Although no specific antifungal therapy was started, follow-up chest X-rays showed a dramatic decrease in the size of the pulmonary nodules (Fig. 1c). During the same week, the plaque on the arm also decreased in size to 2.7 × 1.4 cm. The alkaline phosphatase decreased to normal and the lactate dehydrogenase decreased to 261. The patient was discharged home without antifungal therapy, and prednisone was discontinued 10 days after discharge. The skin lesion resolved spontaneously, in the 2 years since presentation there has not been a recurrence of skin or lung lesions.

Aconitum roots are traditionally prescribed for the management of different types of painful affections in Asiatic countries. A quantitative structure-activity relationship (QSAR) analysis was performed to study the effect of chemical substitutes in the analgesic potency of alkaloids available in Chinese Aconitum roots. Using the CAChe program package for biomolecules, molecular modelling was performed in 12 alkaloids previously tested in a model of acetic acid-induced writhing in rats. The ED50 (micromol/kg) was used as the activity parameter. Structural parameters were compared between alkaloids with an aroyl/aroyloxy group at R14 and alkaloids with the aroyloxy group at R4. Single linear regression analyses were performed in order to find the parameters explaining activity. Alkaloids with an aroyl/aroyloxy group at R14 exhibited the highest potency (significantly less ED50). The stability parameters were different between groups, e.g. total energy was -8.0 +/- 0.4 in the potent analgesic alkaloids and -6.7 +/- 0.3 in the weak analgesic alkaloids (P = 0.001). The reactivity index of C2', C3' and C5' of the aromatic ring was also different between groups, e.g. the reactivity index of C5' was 40.8 +/- 0.6 in potent analgesic alkaloids and 48.1 +/- 0.6 in weaker analgesic alkaloids (P < 0.001). Several structural parameters explained analgesic activity of alkaloids, being the reactivity index of C5' on the aromatic group the most important factor (r = 0.89; P < 0.001).

Summary: Purpose: Differences in potency among valproate (VPA) metabolites could be explained by structural properties. Therefore, a quantitative structure–activity relation (QSAR) analysis was performed to study the relation between structural parameters and the effect of the following VPA metabolites: 4-en-VPA, 2-en-VPA, 3-en-VPA, 2,4'-dien-VPA, 4,4'-dien-VPA, 4-hydroxy-VPA, 3-ceto-VPA, 3-hydroxy-VPA, 5-hydroxy-VPA, and propylglutaric acid. Methods: By using the CAChe program package for biomolecules (Oxford Molecular, Ltd), we performed molecular modeling. The anticonvulsant activity determined on the threshold for maximal electroconvulsions in mice was obtained from a study of Loscher and Nau. Structural parameters were compared between metabolites with a double bond and metabolites with oxygen at either side chain (unpaired Student's t test). A single linear regression analysis between each structural parameter and the relative anticonvulsant potency was also performed. Results: Similar parameters were found between the cis and trans and R and S isomers. Biologic activity and most of the structural parameters were significantly different between metabolites with a double bond and metabolites with oxygen at either side chain. Activity was directly related to log Poct (r2 = 0.77) and to reactivity parameters and was inversely related to stability parameters and to molecular weight and surface. The most potent metabolites had a log Poct value of higher than 2 units. Conclusions: Similar data were identified between cis and trans, and R and S isomers of VPA metabolites. Anticonvulsant activity was mainly related to log Poct, probably reflecting the ability of VPA metabolites to cross the blood–brain barrier.

Background Eating disorders are increasing and show a variety of symptoms. They mainly include anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not specified (EDNOS). They predominate in females and represent an important danger, especially in teenagers. In serious cases, they may be life-threatening. Objective To determine the prevalence of cutaneous findings in patients with eating disorders and to compare the results with those found in the literature. Methods An observational, transverse, and prospective study was performed. Two hundred patients of recent admission to ALUBA (association that fights against BN and AN), a psychiatric unit for eating disorders, were included: 122 BN; 62 AN; 16 EDNOS. Results Patients with eating disorders show dermatologic manifestations (alopecia, xerosis, hypertrichosis, caries, nail fragility) that are secondary to starvation. Russell's sign, seen as calluses on the dorsal aspect of the hands, is a consequence of self-induced vomiting and the local trauma of the superior incisors. This sign represents a compensatory behavior to overeating and predominates in the BN group. Conclusion The recognition of dermatologic signs could be of immense value and could lead to the early diagnosis and treatment of these eating disorders.

1. Drugs administered into the epidural space by caudal block are cleared by means of a process potentially affected by the lipophilic character of the compounds. 2. In the present study, we examined the relationship between the octanol-water partition coefficient (log Poct) and the time to reach the maximum plasma drug concentration (tmax) of lignocaine, bupivacaine and ropivacaine administered by caudal block in paediatric patients. We also examined the relationship between log Poct and the toxicity of these local anaesthetic agents in experimental models. The tmax and toxicity data were obtained from the literature. 3. Ropivacaine, with a log Poct of 2.9, exhibited a tmax of 61.6 min. The tmax of lignocaine, with a log Poct of 2.4, and bupivacaine, with a log Poct of with 3.4, were approximately 50% shorter than ropivacaine. At log Poct of approximately 3.0, the toxicity of these local anaesthetic agents was substantially increased. The relationship between log Poct and the convulsive effect in dogs was similar to the relationship between log Poct and the lethal dose in sheep. 4. With local anaesthetic agents, it appears that the relationship between log Poct and drug transfer from the epidural space to the blood stream is parabolic, being the slowest rate of transference at log Poct 3.0. Toxicity, due to plasma availability of these local anaesthetic agents, seems to be increased at log Poct equal or higher than 3.0 secondary to the highest transfer from plasma into the central nervous system.

Surface-enhanced Raman scattering (SERS) spectra of vitamin B complex extracted in ethanol were analyzed using a silver-coated alumina substrate. The SERS effect appears to enhance selectively the spectrum of p-aminobenzoic acid (PABA) from among the complex constituents of the vitamin B complex tablet. A calibration graph of SERS signal intensity versus concentration of PABA was constructed for quantitative analysis. With such a graph it is possible to detect PABA down to low parts per million levels. The potential of the SERS technique in other analytical and biomedical areas is discussed.