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.

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.

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.

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.

Time to stop counting the tablets?

We attempted to assess compliance using both a pharmacologic indicator (low-dose phenobarbital) and a return tablet count in 225 patients who were taking part in three separate studies. There were 216 patients (96%) who kept a follow-up appointment after 28 days; 161 patients appeared to have good compliance (90% to 109%) by return tablet count. Of these 161 patients, 51 (32%) had plasma phenobarbital concentrations (corrected for dose and weight) that were less than 90% of the lowest value previously found in normal volunteers, which suggested poorer compliance. When compared with the age-related volunteer values, 77 (48%) had values that were less than 90% of the lowest volunteer value. There were 6 of 10 patients with apparently excessive (greater than or equal to 110%) compliance by return tablet count and 4 of 12 who failed to return their container who also had phenobarbital concentrations that were less than 90% of the lowest volunteer value. We concluded that return tablet count grossly overestimates compliance.

Measuring compliance in methadone maintenance patients: use of a pharmacologic indicator to "estimate" methadone plasma levels.

A quantitative indicator of compliance is not available for methadone--the drug of choice for the treatment of opioid addiction. We successfully used low-dose phenobarbital (a valid pharmacologic indicator) to measure compliance by incorporating the drug into the methadone medication of patients attending an addiction unit. Plasma phenobarbital and methadone concentrations were measured in 20 (11 clinic-based and 9 community-based) patients receiving long-term treatment with the phenobarbital level-to-dose ratio, together with interviews, to validate methadone measurements and to monitor compliance. Patients attending the unit on a daily basis and who consumed their medication in the clinic were substantially more compliant than community-based patients. Laboratory measurements of phenobarbital and methadone helped to identify the use of illicit methadone, as well as incorrect self-administration, such as the consumption of several days' dosage at one time.

Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or three times daily.

By use of an interview, return tablet count, and a pharmacologic indicator (low-dose phenobarbital), we compared compliance with tablets prescribed to be taken once, twice, or three times daily. One hundred seventy-nine patients with type II diabetes were randomly allocated to take one 2 mg phenobarbital tablet once, twice, or three times daily for 28 days. Phenobarbital level/dose ratios indicated that compliance was similar with once- and twice-daily regimens, and both were better than thrice-daily dosing. Mean return tablet counts suggested that compliance was best with the once-daily regimen; both twice- and thrice-daily regimens were similarly inferior. This difference between the techniques may be explained by the inadequacies of the residual tablet count, which identified only 13% of cases identified by phenobarbital. We conclude that compliance with the once-daily regimen was best, but that compliance with a twice-daily regimen was very similar, and both were superior to dosing three times a day.

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.

Poor compliance is a major factor in unstable outpatient control of anticoagulant therapy.

Control of oral anticoagulant therapy in outpatients is often unsatisfactory. The contribution of poor compliance with prescribed warfarin to unstable anticoagulant control was investigated prospectively using low-dose phenobarbitone as an indicator of compliance in 30 out-patients, 15 with stable and 15 with unstable control. Following entry to the study, there was no significant change in anticoagulation (p = 0.36) in the group with stable control. In the group who previously had unstable control, there was a significant change in INR (p = 0.0045) and anticoagulant control greatly improved. It appears that the considerable fluctuation in INR seen in many of the latter patients before the study was due to poor compliance and that entering them into the study modified their behavior. Two patients in this group who continued to have unstable anticoagulant control were shown to be poorly compliant using the phenobarbitone indicator. The results suggest that, in outpatients, poor compliance is the major cause of unstable anticoagulation with warfarin.

Comparison of lisinopril versus atenolol for mild to moderate essential hypertension.

The antihypertensive effects and safety profiles of lisinopril (10 to 40 mg) and atenolol (50 to 100 mg) were compared in a randomized, double-blind, parallel group trial in 144 patients with essential hypertension. After 8 weeks of therapy, seated blood pressure (BP) decreased by 26/15 mm Hg with lisinopril and by 19/14 mm Hg with atenolol. Lisinopril produced a greater reduction (p less than 0.05) in sitting systolic BP than did atenolol. Standing BP decreased by 25/15 mm Hg with lisinopril and by 19/14 mm Hg with atenolol. No important changes in hematologic and biochemical profiles were seen with either drug. Eleven patients, 7 receiving lisinopril and 4 receiving atenolol, were withdrawn because of adverse experiences; another 3 patients defaulted during treatment, 1 in the lisinopril group and 2 in the atenolol group. Both drugs were well-tolerated and are therefore suitable for first-line therapy in essential hypertension.

Studies on the clinical pharmacokinetics of imidazopyrazole.

Plasma decay kinetics were analyzed for seven patients (400-5700 mg) during a Phase I clinical trial of imidazopyrazole. A two-compartment open pharmacokinetic model was able to account for the data. The median alpha-phase half-life was found to be 0.65 hour, with a median beta-phase half-life of 23.1 hours. Twelve per cent of the administered drug was excreted unchanged in 72 hours, whereas the total amount of imidazopyrazole equivalents excreted in that period was 38.6%. The median plasma equivalent space was found to be 15.9 l./m2, and volume of distribution at steady state was 40.2 l./m2. Renal and plasma clearance for imidazopyrazole was found to be 0.2 and 1.7 l./m2/hr, respectively.

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).

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.

RO 16-6028, a benzodiazepine receptor partial agonist, does not exhibit anticonvulsant tolerance in mice.

The development of anticonvulsant tolerance with RO 16-6028, a benzodiazepine receptor partial agonist, was assessed in mice using an i.v. infusion of pentylenetetrazol as the convulsive stimulus. In contrast to other benzodiazepines tested previously in this seizure model the anticonvulsant protection afforded by RO 16-6028 did not change significantly during 10 days treatment (2 mg/kg b.i.d.). This result supports the hypothesis that partial agonists at the benzodiazepine receptor may induce less tolerance and/or dependence than full agonists.

Benzodiazepine cross-tolerance in mice extends to sodium valproate.

Slow intravenous infusion of pentylenetetrazol was used to measure the convulsive threshold in mice. The anticonvulsant effects of clobazam, clonazepam, diazepam, lorazepam, sodium phenobarbitone and sodium valproate were assessed in naive animals and compared with the effects of the same compounds in animals which had been pretreated (twice daily for 3 days) with one of the benzodiazepines or sodium valproate. Cross-tolerance was observed between all the benzodiazepines but not between benzodiazepines and sodium phenobarbitone. Animals pretreated with the benzodiazepines were cross-tolerant to valproate, but the converse was not true; nor did sodium valproate induce tolerance to itself.

Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?

The development of anticonvulsant tolerance with three benzodiazepines was assessed in mice using a slow intravenous infusion of pentylenetetrazol as the convulsive stimulus. Chlordiazepoxide (12.5 mg/kg b.d.) and midazolam (0.75 mg/kg b.d.) induced a slowly evolving tolerance over 15 days whereas nitrazepam (0.6 mg/kg b.d.) induced a very marked rapid tolerance which developed no further during 6 days treatment. Tolerance appeared to be incomplete with all three benzodiazepines. Possible explanations for the differences in tolerance profile are discussed and an alternative basis for the classification of benzodiazepines is suggested.

Lack of anticonvulsant tolerance with RU 32698 and Ro 17-1812.

Possible development of anticonvulsant tolerance to three benzodiazepine receptor ligands was assessed in mice using an i.v. infusion of pentylenetetrazol as the convulsive stimulus. Extensive tolerance developed rapidly in the case of diazepam (0.35 mg/kg b.d. or 1.5 mg/kg b.d.). No significant tolerance was seen with the imidazopyrimidine derivative RU 32698 (9 mg/kg b.d.) or the partial agonist benzodiazepine Ro 17-1812 (1 mg/kg b.d.) These results provide further support for the hypothesis that partial agonists at the benzodiazepine receptor induce less tolerance than full agonists.

Cerebellar infarction.

Cerebellar infarction has been inadequately recognized by clinicians. A review of 75 cases showed that in 55 of them the infarct acted as an expanding mass lesion and compressed the brain stem. Once this occurred, the mortality without operation was very high. With surgical treatment, the mortality was reduced considerably. The computerized tomographic scan is the diagnostic test of choice.