From bench to bedside: evolving therapeutic targets in autoimmune blistering disease.

Autoimmune blistering diseases comprise a group of heterogenous conditions characterized by the loss of tolerance and subsequent development of autoantibodies targeting epidermal and subepidermal adhesion proteins. Blisters and erosions form on the skin and mucous membranes leading to significant morbidity and mortality. Traditional therapies rely on systemic immunosuppression. Advancements in our understanding of the pathophysiology of pemphigus and pemphigoid have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. In this review, we outline the novel therapeutic strategies including B-cell depletion, T-regulatory cell repletion, cell signalling inhibitors and small molecular inhibitors, inhibitory monoclonal antibodies, as well as complement inhibition. We additionally review their current level of clinical evidence. We lastly review therapeutics targets gleaned from the experimental epidermolysis bullosa acquisita mouse model. These emerging treatments offer an exciting progression from basic science discoveries that have the potential to transform the treatment paradigm in autoimmune blistering diseases.

Gastrointestinal symptoms, gastrointestinal bleeding and the role of diet in patients with autoimmune blistering disease: a survey of the International Pemphigus and Pemphigoid Foundation.

BACKGROUND: Autoimmune blistering diseases are a group of severe mucocutaneous conditions that typically require the use of prolonged corticosteroids and immunosuppression. Properly managing associated comorbidities is an integral part of these patients' care. The frequency of gastrointestinal symptoms, particularly gastrointestinal bleeding in these patients, is not known. Likewise, the effect of diet on disease is unknown. OBJECTIVE: To determine the incidence of gastrointestinal comorbidities and the role of diet in patients with autoimmune blistering disease. METHODS: We distributed an e-survey to patients with autoimmune blistering disease utilizing the International Pemphigus and Pemphigoid Foundation's listserv. The incidence of gastrointestinal symptoms and gastrointestinal bleeding were recorded, as were foods avoided and those noted to be beneficial in patients' disease. Historical incidences in the general population were used as controls. RESULTS: A total of 200 responses were collected. 30.3% of patients experienced gastroesophageal reflux following treatment of their autoimmune blistering disease, with 51.7% utilizing some form of gastrointestinal symptomatic treatment. The incidence of gastrointestinal bleeding following an autoimmune blistering diagnosis was 2.1%, which remained significant despite correction for non-steroidal anti-inflammatory use (NSAID), but not corticosteroid use. 65.2% of patients reported dietary limitations because of their autoimmune blistering disease. Significant intolerances after correction for multiple comparisons included alcohol, citrus and spicy foods. Greater than 10% of patients reported improvements in their disease with vegetables and dairy. CONCLUSIONS: Gastrointestinal comorbidities are common in patients with autoimmune blistering diseases, with gastrointestinal bleeding occurring in 2.1% of patients following a diagnosis of autoimmune blistering disease. While further work is needed to determine the relative risk of routine gastrointestinal prophylaxis in this population, gastrointestinal bleeding prophylaxis should be considered in patients receiving corticosteroids, particularly those taking NSAIDs. Dietary limitations are additionally frequent in this population. Patients should be cautious of alcohol, citrus and spicy foods.

Edge scanning reflectometry for density profile measurement on the SPARC tokamak.

Edge scanning reflectometry (ESRL) on the SPARC tokamak aims to measure the electron density profile from the far scrape-off layer to the top of the typical H-mode pedestal and provide real-time data for plasma control. ESRL uses a standard frequency-modulated continuous wave technique from 18 to 90 GHz. By implementing both the O-mode and left-hand-cutoff X-mode, it covers densities from ∼4 × 1018 to ∼4 × 1020 m-3 at B0 ∼12 T. A voltage-controlled oscillator acts as the frequency sweep source. Phase-locked dielectric resonator oscillators and bandpass filters generate base signals ∼9-15 GHz. The signals are then frequency multiplied and amplified to reach the K (18-26 GHz), Ka (26-40 GHz), U (40-60 GHz), and E (60-90 GHz) bands. Multi-band signals are combined via the quasi-optical technique. ESRL plans to use oversized waveguides (∼20 m one-way) and a bi-static arrangement to minimize signal losses and distortions while allowing system flexibility. A COMSOL Multiphysics RF model in 2D has been set up to simulate the reflectometry process and help decide the layout of the horn antennas. Engineering analyses of the key parts of the system have been carried out in support of its preliminary design.

Effect of sire type and a by-product based diet on performance and meat quality in growing-finishing pigs.

For many years, pig production has focused on maximizing performance by selecting for maximal muscle growth and feeding diets that allow the animals to express their genetic potential. However, it is unclear whether this selection for muscle deposition has affected the capacity of pigs to cope with by-product-based diets, which rely on fat as the primary energy source instead of starches and sugars. Therefore, an experiment was set up to investigate if different types of boars affect how their progeny cope with alternative ingredients in the diet, with a possible need for adapted breeding schemes. Two types of boars within the Piétrain sire line were used based on either a high or low estimated breeding value for daily feed intake (HFI: high feed intake, low feed intake). When their progeny reached 14 weeks of age, two dietary strategies were compared: a control (CON) vs a by-product-based diet high in fat and fiber (HFF). The CON diet was mainly based on cereals (corn, wheat, barley) and soybean meal. The HFF diet was formulated to contain the same net energy, CP and digestible amino acid levels without any cereals or soybean meal. In total 192 animals were included in the experiment (48 animals/type of boar/diet) and performance, digestibility, carcass and meat quality were compared. None of the parameters showed a significant interaction (P < 0.05) between the type of boar and diet, suggesting that shifting to diets that are less prone to feed-food competition is equally feasible in different types of pigs. Type of boar did affect performance, carcass quality and intramuscular fat content. HFI pigs showed higher daily feed intake (DFI) and daily gain (P < 0.001), with no significant difference in feed conversion ratio (P = 0.205), lower carcass quality (P < 0.001) and higher intramuscular fat content (P = 0.030). For both boar types, pigs fed the CON diet performed better, with a higher daily gain (P = 0.028), DFI (P = 0.011) and dressing yield (P = 0.009) and better digestibility (P < 0.001), but without differences in feed conversion ratio or meat quality. In conclusion, there was no indication that pigs differing in feed intake capacity cope differently with a high-fat, high-fiber diet based on by-products. Different types of pigs may cope well with diets that are less prone to feed-food competition.

Quality characteristics of fresh loin and cooked ham muscles as affected by genetic background of commercial pigs.

This study was performed to investigate meat quality traits of loin and ham of commercial pigs as affected by genetic differences in carcass and growth traits of the parent lines. Three hybrid sow lines were crossbred with two types of Belgian Piétrain with different breeding goals (BPgrowth and BPcarcass emphasizing daily growth and carcass conformation, respectively). Pig live performance and carcass quality of 270 offspring were measured, and meat quality of the loin and (cooked) ham was evaluated on 216 animals. Despite the differences in pig live performance and carcass quality for sow line, little effect on meat quality was observed. Only a lower (p < 0.05) intramuscular fat content of ham and a tendency (p < 0.1) toward lower cooking yield was observed in offspring of the sow line with the highest versus the lowest carcass lean content. Loin traits were only weakly associated with fresh and cooked ham quality traits.

Effect of terminal sire line and timing second vaccination on effectiveness of immunocastration, performance, and carcass and meat quality.

Performance (from 10 weeks until slaughter), carcass and meat quality, and effectiveness of immunocastration was compared in crossbred offspring of stress positive (BP+) and negative (BP-) Belgian Piétrain and Canadian Duroc (CD) given the second vaccination of Improvac® at different times (4, 6, 8 weeks before slaughter). CD offspring had a significantly higher daily gain (DG) and feed intake (DFI), and lower predicted lean meat percentage (LMP) and dressing yield compared to BP+ and BP-, while feed conversion ratio (FCR) did not differ. CD offspring had significantly lower drip loss and higher pHi, intramuscular fat content than BP+ and BP- (except for pHi). No significant effect of vaccination time on DG nor FCR was observed. Predicted LMP tended to increase as time-post injection decreased, while meat quality was minor affected. Earlier vaccination had no effect on the effectiveness of immunocastration based on testosterone and GnRH-binding.

Performance and carcass, loin and ham quality in crossbreds from three terminal sire lines.

This study was designed to compare performance, carcass and meat quality of crossbred of a hybrid sow x three sire lines, i.e. stress positive Belgian Piétrain (BP), stress negative French Piétrain (FP) and Canadian Duroc (CD). BP offspring had a significantly higher carcass yield (p < .001) and lean meat content (p < .001) in comparison with FP, which was higher than CD. BP offspring had significantly lower pH (p < .05), water-holding capacity (WHC) (p < .001) and intramuscular fat (IMF) (p < .001) content in the loin compared to FP and CD, but these meat quality parameters, with the exception of pH, were superior for CD as compared to FP. In accordance with loin quality, pHi, pHu, WHC and IMF of BP were significantly lower (p < .05) compared to CD in the fresh and cooked ham. Most often, FP offspring could not be differentiated from the other offspring, with the exception of cooking loss of the cooked ham. Trained and consumer taste panels resulted in no significant differences (p > .1) in sensory attributes, however, consumers preffered CD based on ranking.

Monitoring of behavior, sex hormones and boar taint compounds during the vaccination program for immunocastration in three sire lines.

Immunocastration (vaccination against boar taint) is an alternative method to prevent boar taint without the need for surgical castration. This study investigates the evolution of boar taint compounds in serum and fat, serum steroid compounds as well as behavior in immunocastrated pigs from 3 sire lines: 15 stress positive Belgian Piétrain (BP), 20 stress negative French Piétrain (FP), and 20 stress negative Canadian Duroc (CD). Hormone and boar taint compounds in serum were determined at 4 time points; boar taint compounds in fat were determined at 3 time points. Behavior, skin lesions, animal and pen fouling were also recorded before the first vaccination (V2). Aggressiveness, eating and drinking and general activity behavior declined from  V2 for all sire lines. Pigs from BP were cleaner than FP and CD pigs. Even though immunocastration was effective in general (reduced testosterone, estradiol as well as androstenone in serum) for all sire lines, some individual pigs showed either androstenone or skatole levels in fat above cutoff values. While the immunocastration mechanism works as intended for androstenone, and also for skatole for the three sire lines, the risk of carcasses with boar taint compounds above cutoff levels (respectively 1.9 and 3.7%) still remains to some extent.

Prevalence of hypertension in a hemodialysis population.

BACKGROUND: Accurate information on prevalence and status of blood pressure (BP) control in hemodialysis patients is lacking. Our Hemodialysis Quality Improvement Program, sought to determine: 1) The extent and control of hypertension (HTN), 2) whether Erythropoietin (EPO) dose or intradialytic fluid loss had any effect on BP and 3) a means to follow the severity of HTN. PATIENTS AND METHODS: The pre/post mid-week dialysis BP readings of 190 patients (64+/-14.1 years, 53% males, 77% whites) were evaluated over a 3 month period. HTN was defined as BP >150/90. Hypertension was further characterized according to whether the patients had normal or elevated pre-dialysis systolic, pre-dialysis diastolic, post-dialysis systolic or post-diastolic BP readings on more than 6 of the possible 13 recordings. The average EPO dose and weight loss during dialysis was correlated with BP. To better understand the extent of HTN, systolic and diastolic pressures were separately graded from 0 to 3 and a number designated as hypertension sensitivity index (HSI) was assigned to each patient. RESULTS: Of the 190 patients, 146 (76.8%) were hypertensive. 117 out of 146 hypertensive patients (80.1%) had persistent elevation of BP despite being on one or more antihypertensive medications. Most patients were on calcium channel blockers (39%) with 27% being on beta-blockers and 14% on Angiotensin converting enzyme inhibitors. There was no correlation between the number of medications used and the control of HTN. The dose of EPO also had no effect on the degree of HTN. 69.8% of all HTN was systolic. Of this, 64.7% was pre-dialysis and 35.3% post-dialysis. Multiple regression analysis demonstrated a significant correlation with loss of weight during dialysis and lowering of systolic BP (r = 0.33, p = 0.0001). The mean HSI for this population was 2.3+/-1.8. CONCLUSION: HTN was a frequent finding in our hemodialysis population and it was controlled in only 19.9% of hypertensive patients. Most of this HTN was pre-dialysis systolic. There was a significant correlation between fluid loss during dialysis and lowering of blood pressure. The use of the HSI has proven to be helpful in differentiating type and severity of HTN.

[The application of biodegradable anastomosis ring Valtrac for intestinal anastomosis]. / Zastosowanie biorozpadalnego pierscienia zespoleniowego Valtrac do zespolen jelitowych.

UNLABELLED: In 1985 a biofragmentable anastomosis ring (BAR) Valtrac was introduced for intestinal anastomoses. From August 1994 trough March 1998, 49 intestinal anastomoses were performed in 44 patients: there were 28 jejunoileostomies, 8 colocolostomies and 3 gastrojejunostomies. In 5 patients after total gastrectomy, two anastomoses with the use of Valtrac ring were made during the same operation. The patient group consisted of 26 women and 18 men, aged 14 to 81 years (mean age: 54 years); there were 13 emergency and 31 elective procedures. The reasons for the operations were: cancer--35 cases, pancreatic cyst drainage--4 cases and reconstructive procedures in the digestive tract--5 cases. First intestinal gas passage and defecation were monitored in all patients; control X-ray was performed on the 10th postoperative day. No mortality nor serious complications were observed in the postoperative period. In an 81-year old patient, an inconsiderable leakage was found at the anastomotic site. This was successfully managed in the second operation. CONCLUSIONS: 1. Valtrac is an alternative method for intestinal anastomoses. 2. The anastomotic technique is atraumatic and easy even for an unexperienced surgeon.