Generalized pustular psoriasis: a review and update on treatment.

Generalized pustular psoriasis (GPP) is a subtype of pustular psoriasis characterized by painful and occasionally disfiguring cutaneous manifestations with sepsis-like systemic symptoms. Affecting any age and race, GPP can occur with other forms of psoriasis or by itself. Stimuli for flares include medications, infections and environmental triggers. The interleukin family and caspase recruitment domain family have been implicated in its pathogenesis. Other forms of pustular psoriasis include impetigo herpetiformis, palmoplantar pustular psoriasis, annular pustular psoriasis and acrodermatitis continua of Hallopeau. Treatment is not well established, but includes the use of retinoids, methotrexate, cyclosporine, corticosteroids, TNF-alpha inhibitors, topical therapy and phototherapy. The use of TNF-alpha inhibitors may result in the formation of antidrug antibodies and should be administered with methotrexate.

Milker's nodule: an occupational infection and threat to the immunocompromised.

Milker's nodule virus, also called paravaccinia virus, is a DNA virus of the parapoxvirus genus transmitted from infected cows to humans. It results from contact with cattle, cattle by-products or fomites. Classified as an occupational disorder, those at risk of exposure include farmers, butchers and agricultural tourists. The viral infection begins 5-15 days after inoculation as an erythematous-purple, round nodule with a clear depressed centre and a surrounding erythematous ring. While familiar to those in farming communities, the presence of the nodule may be concerning to others, particularly the immunosuppressed. Milker's nodules are self-limited in immunocompetent individuals and heal without scarring within 8 weeks. Another member of the Parapoxvirus genus, the orf virus, is also transmitted from animals to humans by direct contact. While complications are rare, haematopoietic stem cell transplant recipients are at risk of graft-versus-host disease, as the parapoxvirus may trigger these complications in immunocompromised individuals. In addition, paravaccinia may serve as the antigen source for the development of erythema multiforme. The unique structure and replication process of viruses in the Poxvirus family, while includes the Parapoxvirus genus, have been a focus for treatment of infections and cancer. Manipulation of these viruses has demonstrated promising therapeutic possibilities as vectors for vaccines and oncologic therapy.

Clinical recurrence and re-resection rates after extensive vs. segmental colectomy in Crohn's colitis: a retrospective cohort study.

BACKGROUND: The aim of the present study was to document long-term clinical recurrence and re-resection rates of segmental and extended colectomy in patients with Crohn's colitis and to identify risk factors causing recurrence. METHODS: Records of patients with isolated colonic Crohn's disease who underwent colectomy between 1995 and 2013 and were followed at our medical center were identified. Data on age at diagnosis, gender, smoking, disease location at diagnosis, perianal and rectal disease, indication for surgery, preoperative disease duration, type of operation, primary anastomosis at first operation, length of resected specimen, recurrence of symptoms, postoperative medication, reoperation, and total follow-up time were retrieved. RESULTS: Thirty-five suitable patients (18 segmental colectomy, 17 extensive colectomy; 17 males; mean age at operation 36.6 years) were identified. Mean age at primary operation was 36 years. The mean preoperative disease duration was 121 months. Postoperative medical treatment was needed in 10 (56 %) patients undergoing segmental colectomy and in 16 (94 %) of those undergoing extensive colectomy (p = 0.01). There was longer reoperation-free survival in the segmental colectomy patient group (p = 0.02) and also a trend toward longer symptom-free survival compared to the extensive colectomy patient group (p = 0.105). There was no correlation between the length of resected bowel and recurrence. Patients operated on at a younger age did not have a higher rate of recurrence of symptoms. Shorter disease duration, smoking, and male gender were risk factors for clinical recurrence. CONCLUSIONS: Segmental resection with primary anastomosis can be safely performed in patients with limited Crohn's colitis with reasonable clinical recurrence rates.

Neonatal leukaemia cutis.

Neonatal leukaemia cutis is a significant neoplasm that may represent a cutaneous manifestation of systemic leukaemia, usually of myeloblastic type. Rarely, it may be or appear to be limited to skin, in which case it is called neonatal aleukaemic leukaemia cutis. By definition, it presents within the first 4 weeks of life and often has a 'blueberry muffin baby' appearance of magenta coloured nodules affecting almost any area of the skin, usually sparing mucous membranes, palms and soles. This clinical pattern is more commonly associated with neonatal infections such rubella and toxoplasmosis, and may be evident with other neonatal neoplasms such as neuroblastoma. Due to the morbidity associated with chemotherapy and reported cases of spontaneous remission without systemic progression in those with neonatal aleukaemic leukaemia cutis without 11q23 translocation, the authors not treating the child with chemotherapy, but to simply monitor for fading of the violaceous nodules, and watch for possible signs of systemic leukaemia.

Alterations of field potentials in isotropic cardiomyocyte cell layers induced by multiple endogenous pacemakers under normal and hypothermal conditions.

The use of autonomous contracting randomly grown cardiomyocyte monolayers cultivated on microelectrode arrays (MEAs) represents an accepted experimental setting for preclinical experimental research in the field of cardiac electrophysiology. A dominant pacemaker forces a monolayer to adhere to a regular and synchronized contraction. Randomly distributed multiple pacemakers interfere with this dominant center, resulting in more or less frequent changes of propagation direction. This study aims to characterize the impact of changing propagation directions at single electrodes of the MEA on the four intrinsic parameters of registered field potentials (FPs) FPrise, FPMIN, FPpre, and FPdur and conduction velocity (CV) under normal and hypothermal conditions. Primary cultures of chicken cardiomyocytes (n = 18) were plated directly onto MEAs and FPs were recorded in a temperature range between 37 and 29°C. The number and spatiotemporal distribution of biological and artificial pacemakers of each cell layer inside and outside of the MEA registration area were evaluated using an algorithm developed in-house. In almost every second myocardial cell layer, interfering autonomous pacemakers were detected at stable temperatures, showing random spatial distributions with similar beating rates. Additionally, a temperature-dependent change of the dominant pacemaker center was observed in n = 16 experiments. A significant spread-direction-dependent variation of CV, FPrise, FPMIN, and FPpre up to 14% could be measured between different endogenous pacemakers. In conclusion, based on our results, disregarding the spatial origin of excitation may lead to misinterpretations and erroneous conclusions of FP parameters in the verification of research hypotheses in cellular electrocardiology.

Platinum stable isotope analysis of geological standard reference materials by double-spike MC-ICPMS.

We report a method for the chemical purification of Pt from geological materials by ion-exchange chromatography for subsequent Pt stable isotope analysis by multiple-collector inductively coupled plasma mass spectrometry (MC-ICPMS) using a 196Pt-198Pt double-spike to correct for instrumental mass bias. Double-spiking of samples was carried out prior to digestion and chemical separation to correct for any mass-dependent fractionation that may occur due to incomplete recovery of Pt. Samples were digested using a NiS fire assay method, which pre-concentrates Pt into a metallic bead that is readily dissolved in acid in preparation for anion-exchange chemistry. Pt was recovered from anion-exchange resin in concentrated HNO3 acid after elution of matrix elements, including the other platinum group elements (PGE), in dilute HCl and HNO3 acids. The separation method has been calibrated using a precious metal standard solution doped with a range of synthetic matrices and results in Pt yields of ≥90% with purity of ≥95%. Using this chemical separation technique, we have separated Pt from 11 international geological standard reference materials comprising of PGE ores, mantle rocks, igneous rocks and one sample from the Cretaceous-Paleogene boundary layer. Pt concentrations in these samples range from ca. 5 ng g-1 to 4 µg g-1. This analytical method has been shown to have an external reproducibility on δ198Pt (permil difference in the 198Pt/194Pt ratio from the IRMM-010 standard) of ±0.040 (2 sd) on Pt solution standards (Creech et al., 2013, J. Anal. At. Spectrom. 28, 853-865). The reproducibility in natural samples is evaluated by processing multiple replicates of four standard reference materials, and is conservatively taken to be ca. ±0.088 (2 sd). Pt stable isotope data for the full set of reference materials have a range of δ198Pt values with offsets of up to 0.4‰ from the IRMM-010 standard, which are readily resolved with this technique. These results demonstrate the potential of the Pt isotope system as a tracer in geochemical systems.

Staphylococcal scalded skin syndrome: diagnosis and management in children and adults.

Staphylococcal scalded skin syndrome is a potentially life-threatening disorder caused most often by a phage group II Staphylococcus aureus infection. Staphylococcal scalded skin syndrome is more common in newborns than in adults. Staphylococcal scalded skin syndrome tends to appear abruptly with diffuse erythema and fever. The diagnosis can be confirmed by a skin biopsy specimen, which can be expedited by frozen section processing, as staphylococcal scalded skin syndrome should be distinguished from life threatening toxic epidermal necrolysis. Histologically, the superficial epidermis is detached, the separation level being at the granular layer. The diffuse skin loss is due to a circulating bacterial exotoxin. The aetiological exfoliating toxin is a serine protease that splits only desmoglein 1. The exfoliative toxins are spread haematogenously from a localized source of infection, causing widespread epidermal damage at distant sites. Sepsis and pneumonia are the most feared complications. The purpose of this review is to summarize advances in understanding of this serious disorder and provide therapeutic options for both paediatric and adult patients. Recent epidemiological studies have demonstrated that paediatric patients have an increased incidence of Staphylococcal scalded skin syndrome during the summer and autumn. Mortality is less than 10% in children, but is between 40% and 63% in adults, despite antibacterial therapy. Previously, intravenous immunoglobulin had been recommended to combat Staphylococcal scalded skin syndrome, but a recent study associates its use with prolonged hospitalization.

Achieving elongated lesions employing cardiac cryoablation: a preclinical evaluation study.

Cardiac cryoablation applied for treating cardiac arrhythmias has shown promising results after intervention, particularly for the creation of elongated lesions. A model for simulating and assessing cryoablation interventions was developed, evaluated and validated with animal experiments. We employed two simulations of different freezing outlet settings for a loop shaped cryocatheter, applying Pennes heat equation for cardiac tissue. Our experiments demonstrated that an equidistantly spaced freezing outlet distribution of 5mm led to an improved formation of lesions, i.e., elongated lesions were observed throughout the transmural cardiac volume and on the epicardial structure. A complete transmural frozen lesion was not achieved with a freezing outlet distance of 10mm. These simulation results could be experimentally verified by morphological and histological examinations. Using our simulation model we were able to optimize the intervention procedure by predicting and assessing the freezing process. This should further increase the success rate of cardiac cryoablation in clinical interventions.

Fitting the determined impedance in the guinea pig inner ear to Randles circuit using square error minimization in the range of 100 Hz to 50 kHz.

Objective. Several lumped and distributed parameter models of the inner ear have been proposed to improve vestibular implant stimulation. The models should account for all significant physical phenomena that influence the current propagation, such as the electrical double layer (EDL) and medium polarization. The electrical properties of the medium are reflected in the electrical impedance; therefore, the study aimed to measure the impedance in the guinea pig inner ear and construct its equivalent circuit.Approach. The electrical impedance was measured from 100 Hz to 50 kHz between a pair of platinum electrodes immersed in 0.9% NaCl saline solution using sinusoidal voltage signals. The Randles circuit was fitted to the measured impedance in the saline solution in order to estimate the EDL parameters (C,W,andRct) of the electrode interface in saline. Then, the electrical impedance was measured between all combinations of the electrodes located in the semicircular canal ampullae and the vestibular nerve in the guinea pigin vitro. The extended Randles circuit considering the medium polarization (Ri,Re,Cm) together with EDL parameters (C,Rct) obtained from the saline solution was fitted to the measured impedance of the guinea pig inner ear. The Warburg element was assumed negligible and was not considered in the guinea pig model.Main results. For the set-up used, the obtained EDL parameters were:C=27.09*10-8F,Rct=18.75kΩ.The average values of intra-, extracellular resistances, and membrane capacitance wereRi=4.74kΩ,Re=45.05kΩ,Cm=9.69*10-8F,respectively.Significance. The obtained values of the model parameters can serve as a good estimation of the EDL for modelling work. The EDL, together with medium polarization, plays a significant role in the electrical impedance of the guinea pig inner ear, therefore, they should be considered in electrical conductivity models to increase the credibility of the simulations.

A Lead Field Two-Domain Model for Longitudinal Neural Tracts-Analytical Framework and Implications for Signal Bandwidth.

Somatosensory evoked potentials are a well-established tool for assessing volley conduction in afferent neural pathways. However, from a clinical perspective, recording of spinal signals is still a demanding task due to the low amplitudes compared to relevant noise sources. Computer modeling is a powerful tool for gaining insight into signal genesis and, thus, for promoting future innovations in signal extraction. However, due to the complex structure of neural pathways, modeling is computationally demanding. We present a theoretical framework which allows computing the electric potential generated by a single axon in a body surface lead by the convolution of the neural lead field function with a propagating action potential term. The signal generated by a large cohort of axons was obtained by convoluting a single axonal signal with the statistical distribution of temporal dispersion of individual axonal signals. For establishing the framework, analysis was based on an analytical model. Our approach was further adopted for a numerical computation of body surface neuropotentials employing the lead field theory. Double convolution allowed straightforward analysis in the frequency domain. The highest frequency components occurred at the cellular membrane. A bandpass type spectral shape and a peak frequency of 1800 Hz was observed. The volume conductor transmitting the signal to the recording lead acted as an additional bandpass reducing the axonal peak frequency from 200 Hz to 500 Hz. The superposition of temporally dispersed axonal signals acted as an additional low-pass filter further reducing the compound action potential peak frequency from 90 Hz to 170 Hz. Our results suggest that the bandwidth of spinal evoked potentials might be narrower than the bandwidth requested by current clinical guidelines. The present findings will allow the optimization of noise suppression. Furthermore, our theoretical framework allows the adaptation in numerical methods and application in anatomically realistic geometries in future studies.

Impedance and conductivity of bovine myocardium during freezing and thawing at slow rates - implications for cardiac cryo-ablation.

Increasing impedance during freezing might be a valuable marker for guiding cardiac cryo-ablation. We provide model based insights on how decreasing temperature below the freezing point of tissue relates to the percentage of frozen water. Furthermore, we provide experimental data for comparing this percentage with the increase in impedance. Measurements were performed on a bovine tissue sample at frequencies between 5 and 80 kHz. Slow cooling and heating rates were applied to minimize temperature gradients in the myocardial sample and to allow accurate assessment of the freezing point. Computer simulation was applied to link impedance with temperature dependent conductivities. The osmotic virial equation was used to estimate the percentage of frozen water. Measurements identified the freezing point at -0.6 ∘C. At -5 ∘C, impedance rose by more than a factor of ten compared to that at the freezing point and the percentage of frozen water was estimated as being 89%. At -49 ∘C impedance had increased by up to three orders of magnitude and ice formation was most pronounced in the extracellular space. Progressive ice formation in tissue is reflected by a large increase in impedance, and impedance increases monotonically with the percentage of frozen water. Its analysis allows for experimental assessment of factors relevant to cell death. Solid ice contributes to the rupture of the micro-vasculature, while phase shifts reflect concentration differences between extra- and intracellular space driving osmotic water transfer across cell membranes.

Presenilin-mediated modulation of capacitative calcium entry.

We studied a novel function of the presenilins (PS1 and PS2) in governing capacitative calcium entry (CCE), a refilling mechanism for depleted intracellular calcium stores. Abrogation of functional PS1, by either knocking out PS1 or expressing inactive PS1, markedly potentiated CCE, suggesting a role for PS1 in the modulation of CCE. In contrast, familial Alzheimer's disease (FAD)-linked mutant PS1 or PS2 significantly attenuated CCE and store depletion-activated currents. While inhibition of CCE selectively increased the amyloidogenic amyloid beta peptide (Abeta42), increased accumulation of the peptide had no effect on CCE. Thus, reduced CCE is most likely an early cellular event leading to increased Abeta42 generation associated with FAD mutant presenilins. Our data indicate that the CCE pathway is a novel therapeutic target for Alzheimer's disease.

APP processing and synaptic plasticity in presenilin-1 conditional knockout mice.

We have developed a presenilin-1 (PS1) conditional knockout mouse (cKO), in which PS1 inactivation is restricted to the postnatal forebrain. The PS1 cKO mouse is viable and exhibits no gross abnormalities. The carboxy-terminal fragments of the amyloid precursor protein differentially accumulate in the cerebral cortex of cKO mice, while generation of beta-amyloid peptides is reduced. Expression of Notch downstream effector genes, Hes1, Hes5, and Dll1, is unaffected in the cKO cortex. Although basal synaptic transmission, long-term potentiation, and long-term depression at hippocampal area CA1 synapses are normal, the PS1 cKO mice exhibit subtle but significant deficits in long-term spatial memory. These results demonstrate that inactivation of PS1 function in the adult cerebral cortex leads to reduced Abeta generation and subtle cognitive deficits without affecting expression of Notch downstream genes.

Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo.

Perlecan, a ubiquitous heparan sulfate proteoglycan, possesses angiogenic and growth-promoting attributes primarily by acting as a coreceptor for basic fibroblast growth factor (FGF-2). In this report we blocked perlecan expression by using either constitutive CMV-driven or doxycycline- inducible antisense constructs. Growth of colon carcinoma cells was markedly attenuated upon obliteration of perlecan gene expression and these effects correlated with reduced responsiveness to and affinity for mitogenic keratinocyte growth factor (FGF-7). Exogenous perlecan effectively reconstituted the activity of FGF-7 in the perlecan-deficient cells. Moreover, soluble FGF-7 specifically bound immobilized perlecan in a heparan sulfate-independent manner. In both tumor xenografts induced by human colon carcinoma cells and tumor allografts induced by highly invasive mouse melanoma cells, perlecan suppression caused substantial inhibition of tumor growth and neovascularization. Thus, perlecan is a potent inducer of tumor growth and angiogenesis in vivo and therapeutic interventions targeting this key modulator of tumor progression may improve cancer treatment.

Thrombin and its precursor in human cerebrospinal fluid.

The blood coagulation cascade proteolytic enzyme, thrombin, affects many cell types, including neurons and astrocytes, in which it prevents process outgrowth and induces significant morphological degeneration and even cell death. Since thrombin may contribute significantly to pathological conditions in the central nervous system (CNS), where it is synthesized locally, we measured the levels of thrombin and its precursor, prothrombin, in the cerebrospinal fluid (CSF) of 67 individuals from 6 groups: non-neurologic controls (NNC); spinal degenerative disease (SDD); peripheral nerve disease (PND); cerebrovascular, neuroimmune and seizure disorders and tumor (CNSD); traumatic brain injury (TBI) and neurodegenerative disorders (NDD). We employed a sensitive chromogenic assay utilizing the thrombin specific tripeptide substrate, S-2238, to evaluate CSF levels of thrombin and prothrombin. The latter estimated after its conversion to active enzyme by the snake venom prothrombinase, ecarin. No measurable active thrombin was detected in these CSF samples. However, activatable prothrombin was measured in all groups. The mean activatable prothrombin concentrations (in nM) were 7.26 +/- 3.39 (NNC); 8.85 +/- 3.09 (SDD); 6.78 +/- 2.58 (PND); 6.33 +/- 3.87 (CNSD); 5.10 +/- 1.86 (TBI), and 7.80 +/- 3.27 (NDD). Duncan's multiple comparison test showed significant reduction (p <0.05) in prothrombin levels of the TBI group. Our data suggests that the prothrombin zymogen gains access to the CSF, likely across either an intact or compromised blood-brain barrier (BBB), in increased amounts with age. Reduced levels in TBI patients may have diagnostic and/or prognostic value.

Role of presenilin-1 in murine neural development.

Our previous studies showed that presenilin-1 (PS1) is required for murine neural and skeletal development. Here we report that the reduction in the neural progenitor cells observed in the PS1-/- mouse brain is due to premature differentiation of progenitor cells, rather than to increased apoptotic cell death or decreased cell proliferation. In the ventricular zone of PS1-/- mice, expression of the Notch1 downstream effector gene Hes5 is reduced, and expression of the Notch1 ligand Dll1 is elevated, indicating reduced Notch signaling. These results provide direct evidence that PS1 is involved in the regulation of neurogenesis and Notch signaling during development.

Detection of pro-opiomelanocortin mRNA in human and rat caudal medulla by RT-PCR.

Pro-opiomelanocortin (POMC) mRNA has been localized in the NTS of the rat, but not in the human or other species. Here, we report that RT-PCR amplification of human caudal medulla RNA generated a distinct band on agarose gels corresponding in size and sequence to the predicted 742-bp POMC PCR product. The 742-bp signal was undetectable following amplification of cortex, amygdala or caudate nucleus RNA. An homologous, 678-bp band was amplified from rat caudal medulla and, unexpectedly, from other brain regions. Competitive RT-PCR demonstrated that POMC cDNA from rat cortex, striatum and cerebellum was 17%, 22% and 45% of caudal medulla levels. These data indicate that the POMC gene is expressed in human caudal medulla and suggest that small amounts of POMC mRNA are present in regions other than the hypothalamus and NTS of rat brain.

MR of spinal cord ganglioglioma.

PURPOSE: Our purpose was to describe the MR imaging features in a series of spinal intramedullary gangliogliomas and to compare these findings with the MR features of intramedullary astrocytomas and ependymomas. METHODS: A retrospective analysis was performed of 76 MR examinations in 27 patients with histologically proved spinal ganglioglioma; these were then compared with imaging findings in a representative sample of histologically proved spinal cord astrocytomas and ependymomas. RESULTS: Statistically significant observations regarding spinal gangliogliomas included young age of the patients (mean, 12 years), long tumor length, presence of tumoral cyst, presence of bone erosion and scoliosis, absence of edema, presence of mixed signal intensity on T1-weighted images, and presence of patchy enhancement and cord surface enhancement. A trend (not statistically significant) was noted for holocord involvement and lack of magnetic susceptibility. CONCLUSION: Spinal ganglioglioma can be strongly suspected if MR images reflect the above criteria; however, the ultimate diagnosis still depends on radical resection and appropriate histopathologic investigation.