Repinotan, a selective 5-HT1A-R-agonist, antagonizes morphine-induced ventilatory depression in anesthetized rats.

BACKGROUND: Spontaneous breathing during mechanical ventilation improves arterial oxygenation and cardiovascular function, but is depressed by opioids during critical care. Opioid-induced ventilatory depression was shown to be counteracted in anesthetized rats by serotonin(1A)-receptor (5-HT(1A)-R)-agonist 8-OH-DPAT, which cannot be applied to humans. Repinotan hydrochloride is a selective 5-HT(1A)-R-agonist already investigated in humans, but the effects on ventilation and nociception are unknown. In this study, we sought to establish (a) the effects of repinotan on spontaneous breathing and nociception, and (b) the interaction with the standard opiate morphine. METHODS: The dose-dependent effects of repinotan, given alone or in combination with morphine, on spontaneous minute ventilation (MV) and nociceptive tail-flick reflex latencies (TFLs) were measured simultaneously in spontaneously breathing anesthetized rats. An additional series with NaCl 0.9% and the 5-HT(1A)-R-antagonist WAY 100 135 served as controls. RESULTS: (a) Repinotan dose-dependently activated spontaneous breathing (MV, mean [95% confidence interval]; 53% [29%-77%]) of pretreatment level) and suppressed nociception (TLF, 91% maximum possible effect [68%-114%]) with higher doses of repinotan (2-200 µg/kg). On the contrary, nociception was enhanced with a small dose of repinotan (0.2 µg/kg; TFL, -47% maximum possible effect [-95% to 2%]). Effects were prevented by 5-HT(1A)-antagonist WAY 100 135. (B) Morphine-induced depression of ventilation (MV, -72% [-100% to -44%]) was reversed by repinotan (20 µg/kg), which returned spontaneous ventilation to pretreatment levels (MV, 18% [-40% to 77%]). The morphine-induced complete depression of nociception was sustained throughout repinotan and NaCl 0.9% administration. Despite a mild decrease in mean arterial blood pressure, there were no serious cardiovascular side effects from repinotan. CONCLUSIONS: The 5-HT(1A)-R-agonist repinotan activates spontaneous breathing in anesthetized rats even in morphine-induced ventilatory depression. The potency of 5-HT(1A)-R-agonists to stimulate spontaneous breathing and their antinociceptive effects should be researched further.

Understanding international differences in terminology for delirium and other types of acute brain dysfunction in critically ill patients.

BACKGROUND: Delirium (acute brain dysfunction) is a potentially life threatening disturbance in brain function that frequently occurs in critically ill patients. While this area of brain dysfunction in critical care is rapidly advancing, striking limitations in use of terminology related to delirium internationally are hindering cross-talk and collaborative research. In the English literature, synonyms of delirium such as the Intensive Care Unit syndrome, acute brain dysfunction, acute brain failure, psychosis, confusion, and encephalopathy are widely used. This often leads to scientific "confusion" regarding published data and methodology within studies, which is further exacerbated by organizational, cultural and language barriers. OBJECTIVE: We undertook this multinational effort to identify conflicts in terminology and phenomenology of delirium to facilitate communication across medical disciplines and languages. METHODS: The evaluation of the terminology used for acute brain dysfunction was determined conducting communications with 24 authors from academic communities throughout countries/regions that speak the 13 variants of the Romanic languages included into this manuscript. RESULTS: In the 13 languages utilizing Romanic characters, included in this report, we identified the following terms used to define major types of acute brain dysfunction: coma, delirium, delirio, delirium tremens, délire, confusion mentale, delir, delier, Durchgangs-Syndrom, acute verwardheid, intensiv-psykose, IVA-psykos, IVA-syndrom, akutt konfusion/forvirring. Interestingly two terms are very consistent: 100 % of the selected languages use the term coma or koma to describe patients unresponsive to verbal and/or physical stimuli, and 100% use delirium tremens to define delirium due to alcohol withdrawal. Conversely, only 54% use the term delirium to indicate the disorder as defined by the DSM-IV as an acute change in mental status, inattention, disorganized thinking and altered level of consciousness. CONCLUSIONS: Attempts towards standardization in terminology, or at least awareness of differences across languages and specialties, will help cross-talk among clinicians and researchers.

Hydrophilic silica aerogels as dermal drug delivery systems--dithranol as a model drug.

A special class of porous silica materials, silica aerogels, was recently shown to be a potential candidate for oral drug delivery systems. It was demonstrated, that stability of drugs and their dissolution rate can essentially be improved through the adsorption on to these materials. In this work, drug loaded silica aerogels are firstly applied as dermal drug delivery systems. Dithranol is used as a representative drug since there is a need to enhance its dermal availability. The unstable and nearly water-insoluble drug exhibits a poor penetration. Release of dithranol from aerogels into various semi-solid formulations and its dissolution as well as the release and penetration into artificial membranes were investigated by Fourier-transform infrared attenuated total reflection (FTIR-ATR) spectroscopy. Two model membranes (one hydrophilic and one lipophilic) were applied. Several formulations were tested and the most promising one was used in order to study the penetration of dithranol into human stratum corneum (SC). Dithranol adsorbed on hydrophilic silica aerogels exhibited superior penetration behaviour compared to that of the standard ointment (dithranol in white soft paraffin).

[Distal spinal-muscular atrophy 1 (DSMA1 or SMARD1)]. / L'amyotrophie spinale distale de type 1 (DSMA1 ou SMARD1).

In this article, we review the clinical, neuropathological and genetic aspects of distal spinal-muscular atrophy 1 (DSMA1; MIM#604320), formerly designated as autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) and also known as distal hereditary-motor neuropathy type 6 (dHMN6 or HMN6).

[Nursing workload indices TISS-10, TISS-28, and NEMS : Higher workload with agitation and delirium is not reflected]. / Pflegeaufwandsindizes TISS-10, TISS-28 und NEMS : Erhöhter Arbeitsaufwand bei Agitation und Delir wird nicht erfasst.

BACKGROUND: Financial resources for the treatment of ICU patients requiring high nursing workload are allocated within the German diagnostic-related groups (DRG) system in part through the Therapeutic Intervention Scoring System-10 (TISS-10). TISS-10, however, has never been validated. This study evaluated whether delirium and agitation in ICU were reflected by TISS-10, and also by the established workload indices TISS-28 and Nine Equivalents of Nursing Manpower (NEMS). Secondary aims were if indices correlated, and what effects delirium and agitation had on financial balances. MATERIALS AND METHODS: Analyses were performed retrospectively in 521 datasets from 152 patients. Nursing workload was assessed with TISS-28, TISS-10, and NEMS, delirium with the Confusion Assessment Method for Intensive Care Units (CAM-ICU), and vigilance with the Richmond Agitation-Sedation Scale (RASS). Revenues were retrieved from the institution's patient data management system, and costs calculated with the Budget Calculation Tool 2007 provided by the German Society of Anaesthesiologists. RESULTS: Delirium was found in 36.2 % of patients (n = 55). TISS-28, TISS-10, and NEMS were not higher in patients with delirium, if corrected for mechanical ventilation. TISS-28, TISS-10, and NEMS were significantly higher in deeply sedated and comatose patients (RASS ≤ - 3, p < 0.001), but not in agitated (RASS ≥ 1) and lightly sedated patients (RASS - 1/- 2). TISS-10 and TISS-28 had a linear correlation (r (2) = 0.864). Median financial balances were negative, but much more pronounced in patients with delirium that without (- 3174 € with delirium vs. - 1721 € without delirium, p = 0.0147). CONCLUSION: The standard workload-scores (TISS-10, TISS-28, NEMS) do not reflect higher daily workload associated with patients with delirium and agitation.

A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is an inherited disorder of the elastic tissue with characteristic progressive calcification of elastic fibers in skin, eye, and the cardiovascular system. Recently mutations in the ABCC6 gene, encoding a transmembrane transporter protein, were identified as cause of the disease. Surprisingly, sequence and RFLP analysis for exon 9 with primers corresponding to flanking intronic sequence in diseased and haplotype negative members from all of our families and in a control population revealed either a homozygous or heterozygous state for the Q378X (1132C-->T) nonsense mutation in all individuals. With the publication of the genomic structure of the PXE locus we had identified the starting point of a large genomic segmental duplication within the locus in the cytogenetic interval defined by the Cy19 and Cy185 somatic cell hybrid breakpoints on chromosome 16p13.1. By means of somatic cell hybrid mapping we located this starting point telomeric to exon 10 of ABCC6. The duplication, however, does not include exon 10, but exons 1-9. These findings suggest that one or several copies of an ABCC6 pseudogene (psiABCC6) lie within this large segmental duplication. At least one copy contains exons 1-9 and maps to the chromosomal interval defined by the Cy163 and Cy11 breakpoints. Either this copy and/or an additional copy of psiABCC6 within Cy19-Cy183 carries the Q378X mutation that masks the correct identification of this nonsense mutation as being causative in pseudoxanthoma elasticum. Long-range PCR of exon 9 starting from sequence outside the genomic replication circumvents interference from the psiABCC6 DNA sequences and demonstrates that the Q378X mutation in the ABCC6 gene is associated with PXE in some families. These findings lead us to propose that gene conversion mechanisms from psiABCC6 to ABCC6 play a functional role in mutations causing PXE.

[Delirium on the ICU: clinical impact, diagnostic workup, and therapy]. / Delir auf der Intensivstation : Klinische Wertigkeit, Diagnostik und Therapie.

Delirium is an acute, potentially life-threatening organ dysfunction with an incidence reported to range between 10 and 92 %. Delirium is potentially preventable and has a great impact on patients' outcomes, even beyond their stay in the hospital. It was found to be associated with persisting cognitive deficits, increased physical dependence, institutionalization, and increased mortality. Delirium is the result of the complex interplay of predisposing and hospital-associated precipitating risk factors, some of which are potentially preventable and modifiable.Delirium is frequently not or incorrectly diagnosed. Subtype, severity, and duration are associated with prognosis. Both prevention and treatment necessitate implementation of daily structured delirium screening. Prevention requires risk assessment: predisposing and precipitating factors should be recognized and treated, if modifiable. Prevention and treatment options include behavioral, cognitive training programs and possibly anti-inflammatory and antipsychotic drugs. Delirium requires search for underlying illness, intoxication or drug side effects.This review summarizes recent work from the last two years, giving a brief overview and background information with regard to risk factors, impact on outcome parameters, mechanisms of pathophysiology, non-pharmacological and pharmacological prevention and treatment strategies of delirium in critically ill patients.

Collagen type XVIII/endostatin is differentially expressed in primary and metastatic colorectal cancers and ovarian carcinomas.

Collagen type XVIII (C18) is a nonfibrillar collagen of basement membranes. Its C-terminal fragment, endostatin, has been identified as an inhibitor of angiogenesis. C18 is predominantly expressed by hepatocytes of normal, cirrhotic and neoplastic liver. We compared the patterns of C18 RNA-expression in colonic adenocarcinoma metastases, which represent the most frequently occurring liver tumours, to normal colon mucosa, to primary colon cancers and to ovarian cancers which are often morphologically similar to colonic cancer or metastasis. Two C18-specific RNA-probes were generated to perform in situ hybridization combined with immunohistochemistry for cytokeratin, vimentin and the endothelial marker CD31, in order to characterize the C18-expressing cells. C18/endostatin protein was localized by immunohistology. In colorectal carcinomas and their liver metastases high levels of C18 transcripts were observed in endothelial cells and fibroblasts/myofibroblasts, whereas C18 RNA was virtually absent from carcinoma cells. Ovarian carcinomas displayed high C18 RNA expression both in carcinoma and stromal cells, indicating that induction of C18 transcription in tumour stromal cells is independent of the ability of carcinoma cells to express C18. While the role of tumour cell derived C18 in cancer growth regulation remains unknown, stimulation of proteolysis of the locally strongly expressed C18 to endostatin could offer an attractive approach for a targeted antineoplastic therapy.