Prurigo nodularis: a physician survey to evaluate current perceptions of its classification, clinical experience and unmet need.

BACKGROUND: Prurigo nodularis (PN) is a chronic skin condition characterized by intensely pruritic, hyperkeratotic papulonodular lesions that dramatically impairs patients' quality of life. Management of the condition is challenging, and there is no approved therapy in the United States or in Europe. OBJECTIVE: The key aim of this survey was to examine current perceptions of PN diagnosis and management among members of the European Academy of Dermatology and Venereology (EADV). METHODS: The survey comprised 29 questions, including multiple choice and open responses, and was sent to clinicians via e-mail during December 2016. The survey results were collected and analysed. RESULTS: Responses were received from 30 participants from 14 countries, of whom 22 (73.3%) were members of the EADV Task Force Pruritus. The majority (73.3%) considered PN to be a distinct condition, and the preferred description to explain the most common pathogenesis was 'chronic pruritus leading to chronic scratching' (80.0%). Pruritic nodules (n = 23/30, 76.7%) and scratching (n = 12/30, 40.0%) were the most common descriptors used to characterize PN. Most respondents (60.0%) reported seeing ≤5 unique PN patients per month, the majority of whom (68.8%) visited a physician ~2-4 times per year. PN patients reported to the respondents that they experienced persistent, severe pruritus, with a mean ± SD numeric rating scale score of 7.8 ± 1.2, lasting for >6 months in 82.3% of patients and >2 years in 51.0%. The most frequently prescribed therapies by survey respondents for PN symptoms were antihistamines (90.0%), antidepressants (90.0%), gabapentinoids (86.7%) and immunosuppressants (86.7%). Respondents agreed upon the need for new PN therapies (56.7%), revised PN classification and terminology (23.3%) and better understanding of PN pathophysiology (20.0%). CONCLUSION: EADV Task Force Pruritus notes several challenges that must be met to improve symptoms and quality of life for patients with PN.

Pathologic and Environmental Studies Provide New Pathogenetic Insights Into Ringtail of Laboratory Mice.

Ringtail is a pathologic condition of laboratory rodents characterized by annular constrictions of the tail. Traditionally, it is classified as an environmental disorder caused by low relative humidity, but other factors (temperature, dietary deficiencies, genetic susceptibility, and caging type) have also been proposed. Twenty litters of mice with ringtail lesions occurred from September 2010 to August 2013 in a facility located in the northern Italy. Mice were maintained under controlled environmental conditions and fed a standard diet. Retrospective analysis of environmental data (relative humidity, temperature) was carried out. Gross, histopathologic, scanning, and transmission electron microscopy examination of tails and limbs was performed. The incidence of ringtail was 0.075% (20/26 800) of all weaned litters over the 3-year period of examination. Temperature and relative humidity remained within accepted limits in all cases except one. We observed annular constrictions in tail, digits of pes, crus, and antebrachium in 116 (100.0%), 47 (40.5%), 11 (9.5%), and 2 (1.7%) of 116 affected mice, respectively. Histologic and ultrastructural examination revealed abnormal keratin desquamation and presence of a keratin ring encircling the tail, causing progressive strangulation of the growing tail with subsequent compression and ulceration of underlying soft tissues, resulting in circulatory changes (edema, hyperemia, thrombosis, hemorrhages), ischemic necrosis, and eventually auto-amputation distal to the constriction. On the basis of our findings, we suggest a disorder of cornification as the primary lesion of ringtail in mice. The cause of these cases, however, remained undetermined, even though traditional etiologic factors (relative humidity, temperature, diet, caging type) were reasonably excluded.

A novel influenza A virus mitochondrial protein that induces cell death.

While searching for alternative reading-frame peptides encoded by influenza A virus that are recognized by CD8+ T cells, we found an abundant immunogenic peptide encoded by the +1 reading frame of PB1. This peptide derives from a novel conserved 87-residue protein, PB1-F2, which has several unusual features compared with other influenza gene products in addition to its mode of translation. These include its absence from some animal (particularly swine) influenza virus isolates, variable expression in individual infected cells, rapid proteasome-dependent degradation and mitochondrial localization. Exposure of cells to a synthetic version of PB1-F2 induces apoptosis, and influenza viruses with targeted mutations that interfere with PB1-F2 expression induce less extensive apoptosis in human monocytic cells than those with intact PB1-F2. We propose that PB1-F2 functions to kill host immune cells responding to influenza virus infection.

Concentration-dependent interaction of theophylline with d-tubocurarine.

The interaction of theophylline with d-tubocurarine chloride (dTC) was examined in rabbits. After steady-state subtherapeutic (less than 10 mg/l), therapeutic (10-20 mg/l), and toxic (greater than 20 mg/l) concentrations of theophylline, dose-response curves for dTC were determined and compared with controls that received no theophylline. At therapeutic concentrations of theophylline the effective dose for 50% inhibition of twitch (ED50) for dTC (mean +/- SE, 0.115 +/- 0.016 mg/kg) was significantly shifted to the left in comparison with the control (0.165 +/-0.008 mg/kg). The ED50 of dTC for the subtherapeutic group was 0.143 +/- 0.011 mg/kg, which was less than the control but not of statistical significance (P = 0.1). The ED50 for the toxic theophylline group was 0.168 +/- 0.003 mg/kg, which was not significantly different from controls but significantly different from the theophylline therapeutic and subtherapeutic groups. Thus, toxic concentrations of theophylline reversed the potentiating effects of therapeutic and subtherapeutic concentrations of dTC dose-response curves. Therefore, depending on concentration, theophylline exhibits a biphasic interaction with dTC. Surgical patients on theophylline may require less dTC intraoperatively. More importantly, the use of theophylline in the postoperative period to reverse anesthetic effects may result in recurarization.

Effects of paralysis with pancuronium on chest wall statics in awake humans.

The influence of tonic inspiratory muscle activity on the relaxation characteristics of the chest wall, rib cage (RC), and abdominal wall (ABW) has been investigated in four highly trained subjects. Chest wall shape and volume were estimated with magnetometers. Pleural pressure (Pes) and abdominal pressure were measured with esophageal and gastric balloons, respectively. Subjects were seated reclining 30 degrees from upright, and respiratory muscle weakness was produced by pancuronium bromide until RC inspiratory capacity was decreased to 60% of control. Only minor changes were observed for Konno-Mead relaxation characteristics (RC vs. ABW) between control and paralysis. Similarly, although RC relaxation curves (RC vs. Pes) during paralysis were significantly different from control (P less than 0.05), the changes were small and not consistent. The differences between paralysis-induced changes in resting end-expiratory position of the chest wall and helium-dilution functional residual capacity (FRC) suggested changes in volume of blood within the chest wall. We conclude that 1) although tonic inspiratory activity of chest wall muscles exists, it does not significantly affect the chest wall relaxation characteristics in trained subjects; 2) submaximal paralysis produced by pancuronium bromide is likely to modify either spinal attitude or the distribution of blood between extremities and the thorax; these effects may account for the changes in FRC in other studies.

Iontophoretic administration of 2% lidocaine HCl and 1:100,000 epinephrine in humans.

OBJECTIVE: The primary objective was to evaluate the clinical safety and effectiveness of the iontophoretic administration of lidocaine HCl 2% and epinephrine 1:100,000 to induce local dermal anesthesia before intravenous (i.v.) cannulation. DESIGN: Section I: Open, nonblinded. Section II: Randomized, double-blind, placebo-controlled. SETTING: Section I: Healthy adult volunteers. Section II: Patients presenting for scheduled outpatient eye surgery. PATIENTS: Section I: Seven healthy adult volunteers. Section II: Forty-four patients requiring i.v. cannulation before scheduled eye surgery. INTERVENTIONS: Section I: Volunteers received iontophoresis of lidocaine HCl 2% with epinephrine 1:100,000 for a total delivery current of 40 mA min. Section II: Patients received iontophoresis for a total delivery current of 40 mA min of lidocaine HCl 2% with epinephrine 1:100,000 (active) or saline (control) immediately before intravenous cannulation with a 20-gauge i.v. catheter. MAJOR OUTCOME MEASURES: Section I: Venous blood plasma lidocaine levels, adverse events associated with iontophoresis. Section II: Patient and investigator assessment of analgesia, patient acceptance of iontophoresis, adverse events associated with iontophoresis. RESULTS: Section I: No detectable levels of lidocaine were identified in any blood plasma sample. Adverse effects were minimal and transitory. Section II: Pain was decreased following lidocaine iontophoresis in comparison with controls, as determined by the patients and investigators. Iontophoresis was well accepted by the patients. Adverse effects were minimal and transitory. CONCLUSIONS: Iontophoresis of lidocaine 2% with 1:100,000 epinephrine for short delivery times does not lead to delivery of clinically important systemic levels of lidocaine in healthy adults. Iontophoresis of lidocaine 2% with 1:100,000 epinephrine provides adequate skin anesthesia for placement of peripheral small-gauge i.v. catheters.

Evaluating skin anesthesia after administration of a local anesthetic system consisting of an S-Caine patch and a controlled heat-aided drug delivery (CHADD) patch in volunteers.

OBJECTIVE: The objective of this study was to evaluate the depth and duration of skin anesthesia after the administration of a local anesthetic system consisting of an S-Caine (Zars, Salt Lake City, UT) patch coupled with a controlled heat-aided drug delivery (CHADD; Zars) patch. DESIGN: The study design was a randomized, double-blind, placebo-controlled, two-period crossover trial. PATIENTS: Twelve healthy adult volunteers between the ages of 18 and 50 years were enrolled. INTERVENTIONS AND OUTCOME MEASURES: After administration of the study drug or placebo, vital signs (blood pressure, pulse, respiratory rate) were monitored and recorded, and depth and duration of anesthesia were determined and recorded at defined intervals for 10 to 120 minutes after treatment. Depth of anesthesia was measured with a 21-gauge short-bevel needle attached to a depth gauge, and duration was measured using a 0 to 2 (0 = no sensation, 1 = dull sensation, 2 = sharp scratching sensation) verbal report scale. RESULTS: Statistically significant differences were noted in both depth and duration of anesthesia between the active and placebo groups. The posttreatment mean for anesthetic depth in the active group was 6.8 mm compared with 4.7 mm for control group (p = 0.050). The median anesthetic duration was greater than 120 minutes for the active group compared with less than 10 minutes for the placebo group (p = 0.001). CONCLUSIONS: The local anesthetic system consisting of a combination of S-Caine and CHADD patches provided a statistically significant dermal anesthesia effect compared with placebo in this volunteer study. If confirmed in other studies, this system has promise as a noninvasive method of producing dermal anesthesia for minor surgical procedures or intravenous insertion.

Porcine alveolar macrophages: poor accessory or effective suppressor cells for T-lymphocytes.

Porcine Alv-Mphi from bronchoalveolar lavages were tested for their function in an in vitro foot-and-mouth disease virus (FMDV)-specific lymphoproliferative recall response. The Alv-Mphi were seen to be poor accessory cells when compared with peripheral blood monocytes. This poor capacity was evident despite an efficient expression of SLA-DR region antigens, and other co-stimulatory adhesion molecules. It was noted that Alv-Mphi secrete relatively little interleukin 1 (IL-1beta), with or without LPS induction, even though mRNA for the cytokine could be detected. In contrast, blood monocytes with their effective accessory activity were potent secretors of IL-1. Although this IL-1beta would be important with respect to the accessory capacity of monocytic cells, it was noted that the absence of bioactive IL-1 from the Alv-Mpi cultures was not solely responsible for their poor accessory function. In fact, the Alv-Mphi produced factors which not only inhibited IL-1 bioactivity, but were also responsible for a clear suppression of lymphoproliferation. This suppressor activity was dependent on the type of monocytic cell present in the culture, being more prominent when "scavenger" phagocytes were present. Thus, the major role of Alv-Mphi s not as an accessory cell akin to monocytes, but as both a scavenger cell, related to Mphi derived from monocytes in the absence of inflammatory signals, and an immunoregulatory cell.

Perpetrator status and the personality characteristics of molested children.

The personality and intellectual characteristics of three groups of children, one molested by a teacher (n = 16), a second group (n = 16) where the offender was a member of the child's family, and a non-molested control group (n = 16) were contrasted. The children were evaluated using the Personality Inventory for Children (PIC), the Children's Personality Questionnaire (CPQ), and the Wechsler Intelligence Scale for Children (WISC-R). There were few differences between the two molested groups or between boys and girls. However, comparisons of molested and non-molested children showed significant differences on 23 of 34 scales on the PIC and CPQ combined. WISC-R verbal IQs were also lower for the molested groups. While the lack of differences between the two molested groups may have been due to the parent-like relationship between the teacher and the children he molested, the results suggest that a relatively noncoercive style of abuse can still produce significant psychological impairment.

Mothers of molested children: some comparisons of personality characteristics.

The Clinical Analysis Questionnaire (CAQ) was used to study the personality characteristics of three groups of mothers: one whose children had been molested by a family member (n = 13), a second group whose children had been molested by a teacher (n = 15), and a group of control mothers whose children had not been molested (n = 12). There were few disparities between the two groups of mothers of molested children. When the molested groups were combined and compared to controls, they differed on only one scale measuring normal personality functioning. Significant differences between mothers of molested children and control mothers were found on 7 of the 12 scales measuring abnormal functioning. In addition, significant correlations were obtained between mother's scores and children's scores on the Adjustment scale of the Personality Inventory for Children (PIC). Results were discussed in terms of the lack of differences between the two molested groups, the role of mothers in sexual abuse, and the relationship of maternal clinical symptoms to child maladjustment.

Clinical pharmacology of mivacurium chloride: a review.

Mivacurium chloride (Mivacron) is a new benzylisoquinolinium choline-like diester neuromuscular blocking drug with an onset of action at equipotent doses that is comparable to atracurium and vecuronium but slower than succinylcholine. Its clinical duration (injection-25% recovery and injection-95% recovery) is twice that of succinylcholine but one-half to one-third that of atracurium and vecuronium. Mivacurium is easy to use as a continuous infusion and when used this way its recovery characteristics are unchanged. It is readily antagonized by anticholinesterase drugs. The ED95 in adults under narcotic-based anesthesia is 0.07-0.08 mg/kg. At twice the ED95 (0.15 mg/kg) onset time is about 2 to 3 minutes, duration to 25% recovery is 15 to 20 minutes, and 5-95% recovery time about 14 minutes. The mean infusion rate in adults is 6 micrograms/kg/min (range 2-15) with a 5-95% recovery time of 14 minutes. Enflurane and isoflurane require a 20-30% decrease in dosage; halothane, enflurane, and isoflurane prolong the duration of mivacurium 25-30%. The ED95 in children 2 to 12 years of age is slightly higher (0.09-0.11 mg/kg) with a faster onset and shorter duration. In these young patients, a dose of 0.2 mg/kg has an onset comparable to succinylcholine. Being chemically related to atracurium, mivacurium may cause histamine release. When administered rapidly at doses of 0.2 mg/kg or greater in adults, histamine release and transient hypotension have been observed. Doses of 0.2 mg/kg or higher are not recommended by the manufacturer. Mivacurium is metabolized by plasma cholinesterase. In vitro, the rate is about 70% that of succinylcholine. In patients with normal or slightly less than normal plasma cholinesterase activity, no prolonged durations of action have been observed. In patients heterozygous for the atypical gene and at a dose of 0.2 mg/kg, 50% prolongation has been shown. Those individuals homozygous for the atypical gene are exquisitely sensitive to mivacurium and have a markedly prolonged blockade that is readily reversible. In these patients and those with acquired deficiencies, mivacurium should not be used. The duration of action in elderly patients is comparable to that in the young, while in prerenal transplant patients, its duration is prolonged by about 50%, and in prehepatic transplant patients, duration of block is increased threefold. Mivacurium possesses the advantages of short duration, unchanged recovery characteristics following infusions (without phase II block or tachyphylaxis), and precise control.(ABSTRACT TRUNCATED AT 250 WORDS)

Pressure sore prevention education with the spinal cord injured.

The purpose of this qualitative single case study was to explore and describe the various formal and informal pressure sore prevention (PSP) educational encounters that occurred with an adolescent spinal cord injured client during his initial admission in an inpatient rehabilitation facility. Data collection supported the conclusion that nurses engaged most frequently in educational encounters with the client. Based on study findings, nurses should consider the following in planning client teaching: (a) assessing a client's learning style on admission and considering this when choosing teaching methods; (b) timing the delivery of PSP education to coincide with times when the information and skills would be most immediately applicable and relevant for the client; and (c) clarifying PSP measures of highest priority with clients while educating them. It also is suggested that rehabilitation nurses consider striking a balance between modeling important PSP measures in earlier phases of a rehabilitation program and encouraging client independence in these behaviors in later program phases.

The cross-priming pathway: a portrait of an intricate immune system.

Antigen presentation by professional antigen-presenting cells (pAPCs) to cytotoxic CD8(+) T cells can occur via two processing routes - the direct and cross-presentation pathways. Cross-presentation of exogenous antigens in the context of major histocompatibility complex (MHC) class I molecules has recently attracted a lot of research interest because it may prove crucial for vaccine development. This alternative pathway has been implicated in priming CD8(+) T-cell responses to pathogens as well as tumours in vivo (cross-priming). In cross-presentation, the internalized antigens can be processed through diverse intracellular routes. As many unresolved questions regarding the molecular basis that controls the cross-priming process still exist, it is essential to explore the various elements involved therein, to better elucidate this pathway. In this review, we summarize current data that explore how the source and nature of antigens could affect their cross-presentation. Moreover, we will discuss and outline how recent advances regarding pAPCs' properties have increased our appreciation of the complex nature of the cross-priming pathway in vivo. In conclusion, we contemplate how the direct and cross-presentation pathways can function to allow the immune system to deal efficiently with diverse pathogens.

Lipopolysaccharide and phorbol 12-myristate 13-acetate both impair monocyte differentiation, relating cellular function to virus susceptibility.

Both lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA) impeded monocyte to macrophage differentiation with respect to typical phenotypic modulation and certain phagocyte-related processes. The down-regulation of the porcine monocyte marker SWC1, and up-regulation of the SWC9 macrophage marker were retarded, but not inhibited, as was the differentiation-associated down-regulation of p53 and myeloperoxidase. Despite this clear impairment of macrophage differentiation, not all cellular functions were equally susceptible. Both agents inhibited phagocytosis, but not low-density lipoprotein receptor-associated endocytosis. Only LPS inhibited tartrate-resistant acid phosphatase up-regulation. In contrast, increase of vacuolar acidification rates was more susceptible to PMA. The activity of certain endosomal/lysosomal enzymes - esterase, nucleotidase, peroxidase and cathepsins - was generally enhanced by both LPS and PMA. This contrasted with autophagosomal activity, detected through the induction of an antiviral state. Disruption of autophagosomes and lysosomes (methionine-O-methyl ester), but not lysosomes alone (glycyl-L-phenylalanine) reversed LPS-induced inhibition of virus replication, without influencing the PMA-induced antiviral effect. Thus, PMA is similar to LPS in inhibiting monocyte to macrophage differentiation, when primary blood monocytes are employed, but not all pathways are equally susceptible. The analyses demonstrate that the pathways modulated during monocyte differentiation function somewhat independently. Moreover, certain functions of monocytic cells are more important with respect to the outcome of virus infection, with autophagosomal activities in particular favouring cell survival.

Dietary protein intake and skeletal-muscle protein metabolism in rats. Studies with salt-washed ribosomes and transfer factors.

1. Aspects of skeletal muscle protein synthesis in vitro were studied in young rats given a low-protein diet for up to 10 days and during re-feeding with an adequate diet. 2. Partially purified muscle transfer factors (transferases I and II), crude and purified (NH(4)Cl-washed) ribosomes and a pH5 enzyme fraction were prepared for this purpose. 3. A marked decrease in the capacity of crude ribosomes to carry out cell-free polypeptide synthesis occurred within 4 days of feeding the low-protein diet. 4. The capacity of salt-washed ribosomes to promote amino acid polymerization, in the presence of added transfer factors and aminoacyl-tRNA, was only slightly decreased by the dietary treatment. 5. However, the capacity of salt-washed ribosomes to bind (14)C-labelled aminoacyl-tRNA was decreased by feeding the low-protein diet. 6. The capacity of the pH5 enzyme fraction to promote amino acid incorporation in a complete cell-free system was decreased within 2 days of feeding the low-protein diet. There is no evidence that the change is associated with aminoacyl-tRNA synthetase or binding enzyme activities of the pH5 fractions. 7. These changes are discussed in relation to the diminished rate of protein synthesis in the intact muscle cell when rats are given a low-protein diet.

Evaluation of cumulative properties of three new nondepolarizing neuromuscular blocking drugs BW A444U, atracurium and vecuronium.

Comparative patterns of recovery during successive doses of three new, relatively non-cumulative, intermediate-duration non-depolarizing neuromuscular blocking drugs, BW A444U, atracurium (BW33A) and vecuronium (Org NC 45), were studied in 94 surgical patients during thiopentone in nitrous oxide and oxygen with narcotic anaesthesia. The train-of-four (TOF) pattern of nerve stimulation was used. The spontaneous 5-25% recovery time of the first twitch of TOF showed a statistically significant difference between the initial dose and the fifth incremental dose in the cases of atracurium and vecuronium, but not in the case of BW A444U. The 25-75% recovery times for the final doses were significantly longer than the corresponding times for each drug after the initial doses. The percent TOF ratio at the point of recovery of the first twitch to 95% of the control height was compared for the initial and final doses in a series of doses of each drug. The difference was significant only when the final dose of vecuronium was compared with the initial dose (TOF ratio 79.3 +/- 2.3% v. 64.3 +/- 4.4%; P less than 0.005). Analysis of variance indicates that the TOF ratio at 95% recovery of the first twitch of TOF after the final dose of vecuronium (64.3%) is significantly smaller (P less than 0.001) than that of either BW A444U (78%) or atracurium (84%), indicating that vecuronium appears to show more residual fade and greater cumulative effect after incremental doses than BW A444U or atracurium. The data suggest that the cumulative properties of the new drugs may be ranked as follows: atracurium less than BW A444U less than vecuronium.

An anatomic and mechanical study of the interosseous membrane of the forearm: pathomechanics of proximal migration of the radius.

The interosseous membrane of the forearm of 12 fresh cadaver specimens was studied anatomically and mechanically to better understand its role in stabilization of the radius after radial head excision. A central band of ligamentous tissue, approximately twice the thickness of the membrane on either side was identified in all specimens. Mechanical studies determined the relative contribution to longitudinal stiffness of the forearm. The central band was responsible for 71% of the longitudinal stiffness of the interosseous membrane after radial head excision. The contribution of the triangular fibrocartilage complex was 8%. Silicone radial head implants were much less stiff than the intact interosseous membrane. Injury to the central band of the interosseous membrane may be crucial to the development of proximal migration of the radius after radial head excision.