Database of mutations in the p53 and APC tumor suppressor genes designed to facilitate molecular epidemiological analyses

Germline and somatic mutations in the p53 and APC genes contribute to neoplasia. The patterns of these and other acquired mutations in cancers reflect environmental mutagens and endogenous factors that contribute to carcinogenesis. Herein, we describe a database of almost 2,300 mutations in the p53 and APC genes published until September 1, 1993. In addition to cataloging the mutations, multiple fields of information have been added to facilitate future molecular epidemiological analyses of human cancer. The accuracy of the database has been checked by the present authors and, by soliciting feedback from the original corresponding authors. The strengths and limitations of the primary literature are discussed. © 1996 Wiley-Liss, Inc.     

Vertical banded gastroplasty as an antireflux procedure

Vertical banded gastroplasty creates a channel by two applications of the TA-90 stapler from an end-to-end anastomosis window above the crow's foot to the angle of His, against a 32 F. tube along the lesser curvature. The caudad end of the channel is restricted by a 5 cm collar. Thirty-one obese patients more than 45 kg overweight were studied by interview, barium swallow, endoscopy, and manometry. These procedures were repeated 13 +/- 5.5 weeks postoperatively, after resolution of operative edema and before extensive weight loss. Preoperative symptoms included heartburn in 24 patients, regurgitation in 17 patients, and aspiration in 2 patients, and barium swallow demonstrated hiatal hernia in 7 patients and reflux in 7 patients (5 with hiatal hernia). In addition, endoscopy detected mild esophagitis in 3 patients, and hiatal hernia in 11 patients. Postoperatively, the incidence of heartburn decreased in all patients, barium swallow showed slow channel emptying but no hiatal hernia or reflux, and endoscopy did not identify any esophagitis. Preoperative lower esophageal sphincter pressure was 14.5 +/- 7.2 mm Hg. Postoperatively, the vertical banded gastroplasty channel had an initial peak (collar) pressure of 19.2 +/- 7.8 mm Hg (p less than 0.01 compared with preoperative lower esophageal sphincter pressure), a channel pressure of 9.5 +/- 6 mm Hg, a lower esophageal sphincter pressure of 20.1 +/- 7.7 mm Hg (p less than 0.005), and a channel length of 6.8 +/- 1.4 cm. Vertical banded gastroplasty creates a high pressure channel, inhibiting reflux of gastric juice without the need for any additional procedure.     

S1 guidelines for the diagnosis and treatment of ichthyoses – update

Ichthyoses are a group of rare genetic skin disorders that pose numerous clinical challenges, in particular with respect to the correct diagnosis and appropriate management. The present update of the German ichthyosis guidelines addresses recent diagnostic advances that have resulted in the Sorèze consensus classification. In this context, we provide an updated diagnostic algorithm, taking into account clinical features as well as the molecular genetic basis of these disorders. Moreover, we highlight current therapeutic approaches such as psychosocial support, balneotherapy, mechanical scale removal, topical therapy, and systemic retinoid therapy. General aspects such as the indication for physical therapy, ergotherapy, or genetic counseling are also discussed. The present update was consented by an interdisciplinary consensus conference that included dermatologists, pediatricians, human geneticists, and natural scientists as well as representatives of the German patient support organization Selbsthilfe Ichthyose e. V.     

Rapid mobilization of intracellularly stored RANTES in response to interferon-gamma in human eosinophils.

The CC chemokine RANTES is synthesized, stored, and upregulated in response to interferon-gamma (IFN-gamma) in human peripheral blood eosinophils. In this report, we propose that RANTES is rapidly mobilized from eosinophil crystalloid granules during agonist-induced degranulation. We stimulated purified eosinophils (>99%) from atopic asthmatics with 500 U/mL IFN-gamma to analyze the kinetics of mobilization and release of RANTES (0 to 240 minutes). We used subcellular fractionation, immunogold analysis, two-color confocal laser scanning microscopy (CLSM), and enzyme-linked immunosorbent assay (ELISA) to trace the movement of eosinophil-derived RANTES from intracellular stores to release. RANTES was rapidly mobilized (10 minutes) and released after 120 minutes of stimulation (80 +/- 15 pg/mL per 2 x 10(6) cells). RANTES appeared to be stored in at least two intracellular compartments: the matrix of crystalloid granules, detected by major basic protein and eosinophil peroxidase activities, and a specialized small secretory vesicle present in light membrane fractions. The extragranular RANTES was mobilized more rapidly than that of crystalloid granules during IFN-gamma stimulation. This effect was not observed in eosinophils treated with IFN-alpha, interleukin-3 (IL-3), IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), or genistein followed by IFN-gamma. Our findings suggest that RANTES may be mobilized and released by piecemeal degranulation upon stimulation, involving transport through a putative pool of small secretory vesicles.     

Visuomotor processing as reflected in the directional discharge of premotor and primary motor cortex neurons

Premotor and primary motor cortical neuronal firing was studied in two monkeys during an instructed delay, pursuit tracking task. The task included a premovement "cue period," during which the target was presented at the periphery of the workspace and moved to the center of the workspace along one of eight directions at one of four constant speeds. The "track period" consisted of a visually guided, error-constrained arm movement during which the animal tracked the target as it moved from the central start box along a line to the opposite periphery of the workspace. Behaviorally, the animals tracked the required directions and speeds with highly constrained trajectories. The eye movements consisted of saccades to the target at the onset of the cue period, followed by smooth pursuit intermingled with saccades throughout the cue and track periods. Initially, an analysis of variance (ANOVA) was used to test for direction and period effects in the firing. Subsequently, a linear regression analysis was used to fit the average firing from the cue and track periods to a cosine model. Directional tuning as determined by a significant fit to the cosine model was a prominent feature of the discharge during both the cue and track periods. However, the directional tuning of the firing of a single cell was not always constant across the cue and track periods. Approximately one-half of the neurons had differences in their preferred directions (PDs) of >45 degrees between cue and track periods. The PD in the cue or track period was not dependent on the target speed. A second linear regression analysis based on calculation of the preferred direction in 20-ms bins (i.e., the PD trajectory) was used to examine on a finer time scale the temporal evolution of this change in directional tuning. The PD trajectories in the cue period were not straight but instead rotated over the workspace to align with the track period PD. Both clockwise and counterclockwise rotations occurred. The PD trajectories were relatively straight during most of the track period. The rotation and eventual convergence of the PD trajectories in the cue period to the preferred direction of the track period may reflect the transformation of visual information into motor commands. The widely dispersed PD trajectories in the cue period would allow targets to be detected over a wide spatial aperture. The convergence of the PD trajectories occurring at the cue-track transition may serve as a "Go" signal to move that was not explicitly supplied by the paradigm. Furthermore, the rotation and convergence of the PD trajectories may provide a mechanism for nonstandard mapping. Standard mapping refers to a sensorimotor transformation in which the stimulus is the object of the reach. Nonstandard mapping is the mapping of an arbitrary stimulus into an arbitrary movement. The shifts in the PD may allow relevant visual information from any direction to be transformed into an appropriate movement direction, providing a neural substrate for nonstandard stimulus-response mappings.     

Mechanism of Oleogel‐S10: A triterpene preparation for the treatment of epidermolysis bullosa

Epidermolysis bullosa (EB) is a group of rare heterogeneous, genetic disorders. Currently, there is no effective pharmacological or genetic therapy for all EB subtypes. Dry extract from birch bark and betulin upregulate some pro‐inflammatory mediators and downregulate others. The increase in pro‐inflammatory cytokines is temporary and attenuated over long‐term treatment. This inflammatory stimulus is thought to be prerequisite for a secondary anti‐inflammatory response. Dry extract from birch bark and its active marker substances have also been shown to increase the migration of primary human keratinocytes, accelerate wound closure, and promote differentiation of keratinocytes in vitro and in vivo—processes that are essential for reepithelialization and maintenance of the skin barrier. Comprehensive clinical data are available to support the use of Oleogel‐S10 in the treatment of partial thickness wounds of different etiologies, and a proof‐of‐concept Phase 2 study in patients with dystrophic EB has suggested the potential for faster reepithelialization of wounds treated with Oleogel‐S10.     

Multidisciplinary long‐term care and modern surgical treatment of congenital melanocytic nevi – recommendations by the CMN surgery network

In recent years, our knowledge of congenital melanocytic nevi (CMN) has greatly expanded. This has led to a paradigm shift. The present article represents a commentary by an interdisciplinary group of physicians from German‐speaking countries with extensive experience in long‐term care and surgical treatment of children and adults with CMN (CMN surgery network, “Netzwerk Nävuschirurgie”, NNC). The authors address aspects such as the indication for treatment as well as treatment planning and implementation under these new premises. Adequate counseling of parents on conservative and/or surgical management requires an interdisciplinary exchange among physicians and individualized planning of the intervention, which frequently involves a multi‐stage procedure. Today, the long‐term aesthetic outcome is at the center of any therapeutic endeavor, whereas melanoma prevention plays only a minor role. The premise of “removal at any cost” no longer holds. Potential treatment‐related adverse effects (hospitalization, wound healing disorders, and others) must be carefully weighed against the prospects of a beneficial outcome. In this context, the use of dermabrasion in particular must be critically evaluated. At a meeting of the NNC in September 2018, its members agreed on a consensus‐based position on dermabrasion, stating that the procedure frequently leads to impaired wound healing and cosmetically unfavorable or hypertrophic scarring. Moreover, dermabrasion is considered to be commonly associated with considerable repigmentation that usually occurs a number of years after the procedure. In addition, the NNC members saw no benefit in terms of melanoma prevention. In the future, physicians should therefore thoroughly caution about the potential risks and often limited cosmetic benefits of dermabrasion.