Atopic dermatitis: pathomechanisms and lessons learned from novel systemic therapeutic options.

Atopic dermatitis (AD) is a chronic, heterogenous, inflammatory skin disorder associated with a high skin-related health burden, typically starting in childhood and often persisting into adulthood. AD is characterized by a wide range of clinical phenotypes, reflecting multiple underlying pathophysiological mechanisms and interactions between genetics, immune system dysregulation and environmental factors. In this review, we describe the diverse cellular and molecular mechanisms involved in AD, including the critical role of T-cell-driven inflammation, primarily via T helper (Th) 2- and Th17-derived cytokines, many of which are mediated by the Janus kinase (JAK) signaling pathway. These local inflammatory processes interact with sensory neuronal pathways, contributing to the clinical manifestations of AD, including itch, pain and sleep disturbance. The recent elucidation of the molecular pathways involved in AD has allowed treatment strategies to evolve from broad-acting systemic immunosuppressive therapies to more targeted agents, including JAK inhibitors and cytokine-specific biologic agents. Evidence from the clinical development of these targeted therapies has reinforced and expanded our understanding of the pathophysiological mechanisms underlying AD and holds promise for individualized treatment strategies tailored to specific AD subtypes.

Depression: a psychiatric nursing theory of connectivity.

This paper presents a theory of connectivity, which was formulated from the findings of a Classical Grounded Theory study that was designed to capture a sample of people's perceptions of living with depression or caring for individuals with depression. Data were collected from: (1) a focus group consisting of people with depression (n = 7), of which five were patients in the community and two were nurses; (2) one-to-one interviews with patients in the community (n = 5) and nurses (n = 5), three of whom had experienced depression from both sides of the caring process; and (3) two 'happy accident' focus groups (n = 25; n = 18) comprising of healthcare workers with a shared understanding of depression. Purposeful sampling was used initially. Thereafter, in keeping with one of the key tenets of grounded theory, theoretical sampling was used until theoretical saturation occurred. Data were analysed using the constant comparative approach together with the NVivo qualitative analysis software package. The core category that emerged was 'connectivity' relating to the connections and disconnections, which people make in their lives. Six key categories emerged all of which were integrated with the core category. Hence, connectivity provided a significant platform for understanding and responding to the life experience of depression. They were: (1) life encounters on the journey to naming; (2) depression: What's in a name? The silent thief; (3) tentative steps to health care; (4) connective encounters and challenges; (5) connecting with self; and (6) self-connection maintenance. Subsequently, a theory, 'Depression: a psychiatric nursing theory of connectivity', surfaced from the overall findings. We argue that this theory of connectivity provides a framework that people working in the field of holistic treatment and care could use to better understand and respond to the life experience of people living with depression.

Seaweed attachment to bedrock: biophysical evidence for a new geophycology paradigm.

Seaweeds are amongst the most obvious and ecologically important components of rocky shore communities worldwide but until now little has been known about the processes involved in their attachment. This multidisciplinary study investigated for the first time the interactions between marine macroalgal holdfasts and their underlying substrata, requiring the development of specialized sample preparation techniques to maintain the structural integrity of the holdfast-bedrock interface. Transmitted plane polarized light microscopy, scanning electron microscopy with energy dispersive spectroscopy and structured light illumination microscopy were used in the examination of the interface between Ascophyllum nodosum (Fucales, Heterokontophyta) and crustose red algae Lithothamnion sp. (Corallinales, Rhodophyta) on granite and limestone substrates. The new evidence presented here represents a paradigm shift in the way we view seaweed attachment because results show that the holdfasts exploit the physical characteristics of the rock-forming minerals in order to penetrate the bedrock and thus facilitate the attachment process. Mineral cleavage planes together with intercrystalline and intracrystalline boundaries and fractures provide penetration pathways for the holdfast tissue. This process causes disaggregation of rock-forming minerals to depths <10 mm and therefore assists in the bioerosion of coastal bedrock. It is concluded that seaweeds are able to cause weathering of natural rock and the term 'geophycology' is introduced to describe seaweed-bedrock interactions, including seaweed-induced weathering.

Early life experiences and their impact on our understanding of depression.

This paper presents part of a larger Grounded Theory study, which was designed to capture a sample of people's perceptions of living with or, caring for, individuals with depression. Data were collected from a focus group consisting of people with depression (n = 7). In-depth one-to-one interviews were undertaken with eight further respondents (n = 8). Purposeful sampling was used initially. Thereafter, in keeping with one of the key tenets of grounded theory, theoretical sampling was used. The emergent concepts were pursued until saturation occurred. The constant comparative approach was used to analyse the data together with the NVivo qualitative analysis software package. This paper focuses on the respondents' perceptions of the pre-diagnosis, depression encounter. The key category that emerged was 'the pre-diagnosis phase of depression and the now experience'. Five key themes surfaced within this category: (1) negative impact significant life events; (2) self-blame; (3) personal characteristics; (4) pre-diagnosis, depression unknowingness; and (5) pre-help seeking. The findings suggest that those in the field of human services need to better understand the lived experience of people with depression, in order to provide holistic treatment and care.

Naming of depression: nursing, social and personal descriptors.

This paper explores descriptors of depression and begins by exploring nursing descriptors including the nature of assessment and nursing diagnosis and progresses to underpin these major processes by considering social descriptors such as cultural and spiritual constructs. The role and influence of stigma is discussed and an examination of gender influences and experiences is undertaken. The paper concludes by examining personal descriptors in the literature. The overall aim of the paper is (1) to add to nursing knowledge by depicting the grounded realities of the experience of depression and (2) stimulate discussion on the need to provide holistic care pathways that are responsive to the uniqueness of this lived experience and finally to (3) encourage further research on key psycho-social factors associated with depression and the concurring advancement of nursing care. This paper has been completed in the context of an ongoing study into the grounded experience of 'Depression' and the development of a psychiatric nursing theory of connectivity.

Immune responses to AAV in a phase I study for Canavan disease.

BACKGROUND: Canavan disease is a rare leukodystrophy with no current treatment. rAAV-ASPA has been developed for gene delivery to the central nervous system (CNS) for Canavan disease. This study represents the first use of a viral vector in an attempt to ameliorate a neurodegenerative disorder. METHODS: Subjects received intracranial infusions via six cranial burr holes. Adeno-associated virus, serotype 2 (AAV2), mediated intraparenchymal delivery of the human aspartoacylase cDNA at a maximum dose of 1 x 10(12) vector genomes per subject. The immune response and safety profiles were monitored in the follow-up of ten subjects. RESULTS: Following rAAV2 administration, we found no evidence of AAV2 neutralizing antibody titers in serum for the majority of subjects tested (7/10). In a subset (3/10) of subjects, low to moderately high levels of AAV2 neutralizing antibody with respect to baseline were detected. In all subjects, there were minimal systemic signs of inflammation or immune stimulation. In subjects with catheter access to the brain lateral ventricle, cerebrospinal fluid was examined and there was a complete absence of neutralizing antibody titers with no overt signs of brain inflammation. CONCLUSIONS: rAAV2 vector administration to the human CNS appears well tolerated. The low levels of immune response to AAV2 detected in 3/10 subjects in this study suggest at this dose and with intraparenchymal administration this approach is relatively safe. Long-term monitoring of subjects and expansion to phase II/III will be necessary in order to make definitive statements on safety and efficacy.

New standardised texts for assessing reading performance in four European languages.

AIMS: To develop standardised texts for assessing reading speed during repeated measurements and across languages for normal subjects and low vision patients. METHODS: 10 texts were designed by linguistic experts in English, Finnish, French, and German. The texts were at the level of a sixth grade reading material (reading ages 10-12 years) and were matched for length (830 (plus or minus 2) characters) and syntactic complexity, according to the syntactic prediction locality theory of Gibson. 100 normally sighted native speaking volunteers aged 18-35 years (25 per language) read each text aloud in randomised order. The newly designed text battery was then applied to test the reading performance of 100 normally sighted native speaking volunteers aged 60-85 years (25 per language). RESULTS: Reading speed was not significantly different with at least seven texts in all four languages. The maximum reading speed difference between texts, in the same language was 6.8% (Finnish). Average reading speeds (SD) in characters per minute are, for the young observer group: English 1234 (147), Finnish 1263 (142), French 1214 (152), German 1126 (105). The group of older readers showed statistically significant lower average reading speeds: English 951 (97), Finnish 1014 (179), French 1131 (160), German 934 (117). CONCLUSION: The authors have developed a set of standardised, homogeneous, and comparable texts in four European languages (English, Finnish, French, German). These texts will be a valuable tool for measuring reading speed in international studies in the field of reading and low vision research.

Are there potential problems with generic substitution of antiepileptic drugs? A review of issues.

In response to increasing cost pressures, healthcare systems are encouraging the use of generic medicines. This review explores potential problems with generic substitution of antiepileptic drugs (AEDs). A broad search strategy identified approximately 70 relevant articles. Potential problems with generic substitution included: The limited evidence (mainly case reports with some pharmacokinetic studies) appears to support these concerns for older AEDs. As a result, restrictions on use of specific generic AEDs are in place in some countries and recommended by some lay epilepsy organisations. As more AEDs lose patent protection, it is important to examine the question of whether generic substitution may pose problems for patients with epilepsy, and whether there should be safeguards to ensure that both physician and patient are informed when generic substitution occurs.

Characterization of crude oils using fluorescence lifetime data.

The average fluorescence lifetimes of nine North Sea crude oils with API gravities of between 20 and 51 were measured using a modular, filter based, instrument developed in-house. Two pulsed light emitting diode (LED) excitation sources (460 and 510 nm) were used to excite fluorescence, the lifetime of which was measured at a range of emission wavelengths. Fluorescence lifetimes were found to vary from 1.8 to 8.2 ns with confidence intervals of +/- 0.11 ns. The average lifetimes at all emission wavelengths were linearly correlated with API gravity and with aromatic concentration with the best results being obtained with the 460 nm excitation source. Predictive models with an accuracy of +/- 7.6 API degrees were generated using partial least-squares methods from average fluorescence lifetimes measured at an emission wavelength of 500 nm using 460 nm excitation. A better correlation was found between the aromatic concentration of the oils and the ratio of the average fluorescence lifetimes at measured at 550 and 650 nm using 460 nm excitation. This led to a quantitative model with an accuracy of +/- 5.4% for aromatic concentration.

Human hypertension caused by mutations in WNK kinases.

Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.

Cytogenetic instability, predominantly involving chromosome 1, is characteristic of elastofibroma.

Elastofibroma, an unusual pseudotumor composed of excessive collagen and abnormal elastic fibers, has rarely been subjected to cytogenetic analysis. Only two cases have been previously defined, both of which demonstrated nonclonal abnormalities. In the present study, three cases of elastofibroma were cytogenetically analyzed. Abnormalities of the short arm of chromosome 1 were seen in all three cases (either clonally or as the most frequently involved region among nonclonal aberrations). In addition, a translocation involving chromosomes 8 and 12 was detected as a clonal rearrangement in one of the three cases. The observation of clonal abnormalities in elastofibroma suggests that this lesion may represent a neoplastic rather than a reactive process.

Primary malignant neuroepithelial tumors of the kidney: a clinicopathologic analysis of 146 adult and pediatric cases from the National Wilms' Tumor Study Group Pathology Center.

Primary malignant neuroepithelial tumors of the kidney (NETKs) comprise a group of primitive, highly malignant neoplasms that histologically and clinically are not well characterized. A large cohort of 146 of these tumors, occurring in adults and children, has been collected at a single depository site, the National Wilms' Tumor Study Group (NWTSG) Pathology Center. The authors undertook a systematic retrospective review of the histologic, ultrastructural, and clinical features of these tumors, based on materials collected by the NWTSG and the consultation files of one of the authors (J.B.B.). Histologic features were generally those of primitive neural tumors with varying amounts of rosettes and neuropil; however, a large proportion of cases displayed unusual features such as spindle cells, ganglion cells, clear cell sarcoma-like foci, rhabdoid cells, epithelioid cells, and organoid foci. CD99 staining had been performed on 69 cases and showed membranous staining in 65. The NETKs were present in patients with a wide age spectrum, ranging from 1 month to 72 years (median, 18 years). EWS/FLI1 fusion analysis using reverse transcriptase-polymerase chain reaction and immunohistochemical stains for cytokeratin, chromogranin, and epithelial membrane antigen were performed successfully on a subset of 45 cases with available paraffin blocks. Only 13 of the 45 were fusion-positive, and there was no correlation between fusion status and histology, presence of rosettes, ultrastructural features, or cytokeratin positivity. CD99-negative cases were usually fusion-negative (six of seven cases), and all three chromogranin-positive cases were fusion-negative. Tumor staging, performed on 72 clearly defined and quantifiable cases by using NWTSG criteria, indicated that these are aggressive tumors, because only six were Stage 1, compared with 16 Stage 2, 31 Stage 3, and 19 Stage 4 lesions. The authors conclude that NETKs are a somewhat diverse group of generally aggressive, high-grade lesions that may present in a wide age range and are difficult to characterize without immunohistochemistry and cytogenetics/molecular biology.

Cytogenetic findings in a case of epithelioid sarcoma and a review of the literature.

Cytogenetic studies of epithelioid sarcoma, a rare malignant soft tissue neoplasm of adolescents and young adults, are few. A characteristic anomaly has not yet been identified for this sarcoma. In this study, cytogenetic studies of a primary epithelioid sarcoma of a 15-year-old male revealed the following abnormalities: t(6;8)(p25;q11.2) and add(7)(p15).

Once a day is best: evidence or assumption? The relationship between compliance and dosage frequency in older people.

To rationalise medication in the elderly, physicians often change multiple dose regimens to once daily in the belief that this improves compliance. Effective methods for measuring compliance have only come into use during the last decade. Partly as a result of this, high quality studies comparing once daily with other regimens in the elderly, are lacking. What evidence there is, from investigations which used suboptimum methods and/or mixed (elderly/younger) patient groups, does not justify the widely held view that 'once a day is best', particularly when compared with twice daily regimens.

Initial evaluation of low-dose phenobarbital as an indicator of compliance with antimalarial drug treatment.

Since poor compliance with antimalarial therapy is often suspected but difficult to prove, this study attempted to establish a model for predicting the plasma concentration of phenobarbital (given in low doses in conjunction with the drug) as an indicator of compliance. Phenobarbital was chosen because its value had been demonstrated as a marker of compliance in long-course therapies, any significant departure from steady-state concentrations (achieved with full compliance) indicating one or more missed doses. Therapy for uncomplicated malaria varies from 5 days with artesunate to 7 days with quinine + tetracycline. Volunteers with confirmed falciparum malaria were randomized into 5 groups and given malaria therapy as well as phenobarbital daily for 3-7 days. Plasma samples for determination of phenobarbital concentrations were taken just prior to the daily dose of phenobarbital. Although there was a clear and predictable individual pattern of blood concentrations following each dose of phenobarbital, inter-individual variation in blood levels was significant and reduced their predictive value beyond the second day's dose. The cause of the variations is not clear; it could be attributable to different sources of the drug, previous intake of phenobarbital by the patient, or differences in drug absorption and disposition in malaria patients. Results for the 5-day artesunate regimen suggest that phenobarbital may be useful as a marker of compliance if the patient stops medication after 3 days; clear differences were evident at the end of the course of treatment between plasma phenobarbital concentrations in individuals completing the 5-day course and those who stopped after 3 days. For the quinine-tetracycline regimen, results suggest that it may be possible to discriminate between subjects where there is a 3-day difference in treatment. Phenobarbital is a better discriminant when dosing is every 24 hours as with artesunate, rather than the 8-hourly regimen for quinine-tetracycline. When measuring compliance for malaria treatment, if it is important to know what proportion of patients reach 3, 5 or 7 days of compliance, then phenobarbital might have a role to play in this assessment, but further investigations in more patients would be required. Alternatively, different markers could be used for the doses to be given on these days and, as long as the patient does not mix the doses for the different days, sequential doses and determination of compliance could be based on an "all or none" detection of the marker rather than on drug levels.

Prescribing of anti-epileptic drugs in the northern and Yorkshire region: 1992-1995.

Epilepsy is a condition for which regular drug treatment is normally prescribed. We have examined the primary care prescribing rates for anti-epileptic drugs (AEDs) in a region of northern England with a population of 6.8 million. Over the 4-year period 1992-1995 the number of AED prescription items issued rose by 15%. A third of this rise is accounted for by increased prescribing of the new anticonvulsants, vigabatrin, lamotrigine and gabapentin, which are primarily indicated for adjunct use. Prescribing of phenytoin and barbiturates fell over the same period, but this reduction was more than compensated for by increased prescribing of carbamazepine and sodium valproate. There were notable differences in both the overall volume and the choice of AEDs used in different health authority areas and these are probably attributable to the influence of the local secondary-care sector on the therapeutic regimens adopted by general practitioners in the area.

The pharmacokinetics of methadone in healthy subjects and opiate users.

AIMS: There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. METHODS: Single oral doses of rac-methadone were given to 13 drug-naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P-Pharm software. RESULTS: Comparison of kinetic models incorporating mono- or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9+/-1.5 s.d. l h(-1) (5.3+/-1.2 s.d. l h(-1) using 0-24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2+/-0.3 s.d. l h(-1), P<0.001); 95% CI for the difference = -3 to -6 l h(-1) and no difference in the population mean values of V/F (212+/-27 s.d. l and 239+/-121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V/F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half-life of methadone in healthy subjects was 33-46 h depending on the method used to calculate this parameter. CONCLUSIONS: Estimates of the long terminal elimination half-life of methadone (33-46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).

Using Peplau's theory in nurse-patient relations.

In caring for a person suffering from depression, Peplau's theory of "Interpersonal Relations" was found to be both effective and representative of what psychiatric nurses do. Peplau's work, initially published in 1952, continues to make a major contribution to nursing knowledge and deserves the significance that it is being given in the 1990s. Below, a report on the learning experience for both the patient and the carer.