Opioid receptor delta as a global modulator of skin differentiation and barrier function repair.

OBJECTIVES: The aims of this study were to confirm the properties of selective agonist peptide (Rubixyl) contained in the spinach towards opioid receptor delta. In fact, agonist properties of both spinach peptides (Rubiscolin-5 and Rubixyl) towards opioid receptor delta were demonstrated by Zang et al., but their effects on the other opioid receptors were not studied [1]. We also studied the expression of opioid receptor delta in epidermis under normal and stress condition (inflammatory) and its role in epidermis homeostasis under stress condition in vitro and in vivo. METHODS: Agonist properties studies were performed using functional agonist cellular model containing human opioid receptors. Opioid receptor delta expression and epidermis homeostasis were studied on human reconstructed epidermis under normal and stress conditions (inflammatory stress) using gene expression (RT-qPCR) and protein expression analysis (immunohistological analysis). Skin repair properties of opioid receptor delta agonist were based on the following parameters TEWL (trans epidermal water loss, hydration and wrinkle depth at periocular and perilabial area) on human volunteers having either intrinsic ageing (more than 40 years old and non-smoker group) and both intrinsic ageing and extrinsic ageing (more than 40 years old and smoker group). RESULTS: We have demonstrated that the Rubixyl peptide is a specific agonist of opioid receptor delta. We have demonstrated that opioid receptor delta expression is modulated under inflammatory condition. The agonist Rubixyl was able to block the depletion of opioid receptor delta seen under inflammatory condition in reconstructed human epidermis. Inflammatory conditions lead to the unbalanced gene and protein expressions of markers involved in epidermis integrity and barrier function properties. The treatment of human reconstructed epidermis with the agonist Rubixyl leads to the normalization of unbalanced gene and protein expressions. In vivo study has confirmed the efficiency of the agonist Rubixyl to repair damaged skin by decreasing TEWL, increasing hydration and decreasing wrinkle depth at the periocular and perilabial area. CONCLUSION: In this research, we have demonstrated in vitro (on inflamed reconstructed human epidermis, RHE) and in vivo (on human aged volunteers) that activation by natural agonist peptide of opioid receptor delta reduces the skin inflammation thus leading to improvement in epidermis differentiation and skin barrier properties.

Skin benefits of a myconoside-rich extract from resurrection plant Haberlea rhodopensis.

Resurrection plant Haberlea rhodopensis develops molecules to survive drought stress. These molecules allow the plant to resurge from a desiccation state. We have extracted a specific fraction from the plant (Haberlea extract) and found it rich, among other molecules, of a caffeoyl phenylethanoid glycoside called myconoside, a molecule extremely abundant in the plant with a potential role in survival. Peroxide-stressed normal human dermal fibroblasts treated with the Haberlea extract, showed increased collagen VI (+822%), collagen XVI (+928%) and elastin (+144%) mRNA synthesis, measured by RT-qPCR. This effect was superior to those obtained with benchmarks retinoic acid and retinol. When used at 3% in human skin biopsies, Haberlea extract protected against UV-induced dermis oxidation by 100% (P < 0.01), as evidenced by immunohistochemistry. Finally, when tested in human volunteers (n = 20) at 3% in a cream against a placebo, Haberlea extract increased skin elasticity (3× placebo, P < 0.0002) and skin radiance (4× placebo, P < 0.05) after only 15 days of treatment, with the effect sustained after 30 and 60 days of treatment. We demonstrated that by using Haberlea extract (particularly rich in glycoside myconoside), it is possible to strongly stimulate antioxidant skin defences and extracellular matrix protein synthesis. This effect, in turn, will further stimulate skin elasticity and skin radiance significantly in human volunteers. The extract can be suggested for anti-ageing treatments, intended for claims such as protection from oxidation, increased skin elasticity and enhanced skin radiance.

A bioactive complex to protect proteins from UV-induced oxidation in human epidermis.

UV light induces multiple damages including protein oxidation on skin. Oxidized proteins if not degraded by the proteasome would eventually accumulate causing metabolic damage, elastosis and pigment formation such as lipofuscin. During ageing, the activity of the proteasome decreases dramatically together with enzymes that protect from oxidation and as a result oxidized proteins accumulate. We have investigated a combination of Panthenyl triacetate and Ethyl linoleate (bioactive complex) to fight against protein oxidation. This complex when tested at 3% on human skin biopsies showed statistically significant protection from UV (UVA + UVB)-induced protein oxidation both in a 24-h pre-treatment before UV irradiation (72% protection, P < 0.05) and immediately after irradiation (78% protection, P < 0.05). UV light also induced a significant decrease of mRNA for protein repairing enzymes, such as Methionine Sulfoxide Reductase (MSR). The complex, given both pre- and post-irradiation, stimulated the repairing enzyme expression. We can suggest utilization of this new complex to prevent accumulation of oxidized protein as a result of skin photo-ageing and to prevent stratum corneum dehydration, skin elastosis and pigmentation formation (age spots).

High-dose rituximab and anti-MAG-associated polyneuropathy.

Rituximab has been administered successfully in patients with polyneuropathy associated with antibodies to myelin-associated glycoprotein (anti-MAG). The authors present a follow-up study with high-dose rituximab. Increase of rituximab from 375 mg/m2 to a dose of 750 mg/m2 was well tolerated and led to clinical improvement in four of eight patients, along with improvement of nerve conduction velocities and a reduction of anti-MAG antibody titers.

[Symptomatic management in amyotrophic lateral sclerosis (ALS)]. / Symptomatische Therapie der amyotrophen Lateralsklerose (ALS).

Although disease-specific treatment of amyotrophic lateral sclerosis is still unsatisfactory, a number of advances have been made in the symptomatic therapy of ALS patients within the last decade. Current data suggest that active and aggressive multidisciplinary management of ALS patients improve their quality of life and prolong their survival. Patient and caregiver communications and decisions are increasingly recognized to be a relevant part of this management. A wide range of supportive and palliative measures, in particular the widely use of symptomatic drugs for pseudobulbar affect, sialorrhea, and sleep disorders is available to relieve patients symptomatology. In addition, patients quality of life has been profoundly improved by the introduction of enteral nutrition and non-invasive ventilation.

Transcranial duplex imaging with a sulfurhexafluoride echocontrast agent: enhancement and diagnostic quality.

BACKGROUND AND PURPOSE: The authors investigate characteristics of ultrasound enhancement and diagnostic quality of a sulfurhexafluorides (SF6)-containing echocontrast agent (SonoVue) in cerebrovascular patients with insufficient temporal bone window by transcranial color-coded duplex (TCCD) sonography. METHODS: Thirty patients (mean age = 62.2 +/- 11.1 years) were enrolled. SF6 was administered intravenously in 4 different doses (0.3, 0.6, 1.2, and 2.4 mL). By videotape analysis, time to contrast appearance, duration of contrast enhancement, and duration of clinically useful signal enhancement were measured. Overall quality of ultrasound investigation was also assessed. RESULTS: Time to contrast appearance ranged from 11 to 74 seconds (mean = 26 seconds). For the 0.3, 0.6, 1.2, and 2.4 mL doses, average times to contrast appearance of 30 +/- 12 seconds, 28 +/- 10 seconds, 23 +/- 8 seconds, and 22 +/- 6 seconds were measured. Duration of TCCD signal enhancement was 438 +/- 169 seconds, 483 +/- 195 seconds, 713 +/- 299 seconds, and 788 +/- 344 seconds for the different doses. Clinically useful enhancement was 160 +/- 124 seconds, 200 +/- 157 seconds, 260 +/- 166 seconds, and 327 +/- 239 seconds. CONCLUSIONS: Administration of SonoVue led to a quality improvement in 21 patients. In TCCD, it optimizes visualization of the cerebral arteries in patients with inadequate bone window. A dose of at least 1.2 mL provides the best enhanced images.

Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Gadolinium MRI Meta-analysis Group.

BACKGROUND: Reliable prognostic factors are lacking for multiple sclerosis (MS). Gadolinium enhancement in magnetic resonance imaging (MRI) of the brain detects with high sensitivity disturbance of the blood-brain barrier, an early event in the development of inflammatory lesions in MS. To investigate the prognostic value of gadolinium-enhanced MRI, we did a meta-analysis of longitudinal MRI studies. METHODS: From the members of MAGNIMS (European Magnetic Resonance Network in Multiple Sclerosis) and additional centres in the USA, we collected data from five natural-course studies and four placebo groups of clinical trials completed between 1992 and 1995. We included a total of 307 patients, 237 with relapsing disease course and 70 with secondary progressive disease course. We investigated by regression analysis the relation between initial count of gadolinium-enhancing lesions and subsequent worsening of disability or impairment as measured by the expanded disability status scale (EDSS) and relapse rate. FINDINGS: The relapse rate in the first year was predicted with moderate ability by the mean number of gadolinium-enhancing lesions in monthly scans during the first 6 months (relative risk per five lesions 1.13, p=0.023). The predictive value of the number of gadolinium-enhancing lesions in one baseline scan was less strong. The best predictor for relapse rate was the variation (SD) of lesion counts in the first six monthly scans which allowed an estimate of relapse in the first year (relative risk 1.2, p=0.020) and in the second year (risk ratio=1.59, p=0.010). Neither the initial scan nor monthly scans over six months were predictive of change in the EDSS in the subsequent 12 months or 24 months. The mean of gadolinium-enhancing-lesion counts in the first six monthly scans was weakly predictive of EDSS change after 1 year (odds ratio=1.34, p=0.082) and 2 years (odds ratio=1.65, p=0.049). INTERPRETATION: Although disturbance of the blood-brain barrier as shown by gadolinium enhancement in MRI is a predictor of the occurrence of relapses, it is not a strong predictor of the development of cumulative impairment or disability. This discrepancy supports the idea that variant pathogenetic mechanisms are operative in the occurrence of relapses and in the development of long-term disability in MS.

[Intensive monitoring of patients with acute cerebral ischemia within the scope of a coordinated stroke treatment concept: initial experiences]. / Intensivmedizinische Uberwachung von Patienten mit akuter zerebraler Ischämie im Rahmen eines koordinierten Hirnschlagbehandlungskonzepts: erste Erfahrungen.

QUESTIONS UNDER STUDY: It has been shown that the prognosis of patients with stroke can be improved by specialized stroke units. Whether any additional benefit can be achieved by use of intensive care resources is unknown. Therefore, it was the purpose of this study to analyze our first experience of management of patients with acute ischaemic stroke in an intensive care unit, as part of a newly implemented coordinated stroke concept. METHODS: A consecutive series of 88 patients with acute ischemic stroke (age 64.4 +/- 14.2 years, 28% females) hospitalized in a medical intensive care unit according to predefined criteria formed the study population. The goals were to monitor vital functions, to complete diagnostic studies in timely fashion and to prevent and treat complications. RESULTS: The patients were hospitalized in the intensive care unit for a mean period of 34.4 +/- 19.5 hours. Relevant pathologic findings included systolic hypertension > 220 mm Hg in 5% and permanent or intermittent relative systolic hypotension < 150 mm Hg in 25% and 98% of patients respectively. One patient (1%) died during the stay. Additional diagnostic studies were performed more often in patients with progressive or fluctuating symptoms (100% of patients in each group) than in those with improving or stable symptoms (50% of patients in each group). Fourteen percent of patients were treated for hypertension and 30% for hypotension. Antithrombotic therapy with aspirin was started in 34%, prophylaxis for venous thrombosis with low dose heparin in 39% and systemic anticoagulation in 40% of patients respectively. No cardiac or pulmonary complications requiring treatment were observed and no specific therapies for neurologic complications were utilized. At the time of discharge from the intensive care unit, 88% of patients showed improved or stable neurologic findings. CONCLUSIONS: In the present analysis, an unexpectedly high incidence of relative arterial hypotension was observed in patients hospitalized in an intensive care unit for acute ischaemic stroke. Therapeutic measures were restricted mainly to blood pressure control and anticoagulation/antithrombotic treatment. Specific therapies for neurologic complications or interventions requiring the resources of an intensive care unit were not used. Whether defined patient groups with ischaemic stroke will benefit from specific treatment in an intensive care unit needs to be tested by controlled, randomized studies.

Fluorinated aldehydes and ketones acting as quasi-substrate inhibitors of acetylcholinesterase.

1. The inhibition of acetylcholinesterase (acetylcholine hydrolase, EC 3.1.1.7) by compounds containing trifluoromethyl-carbonyl groups was investigated and related to the effects observed with structurally similar, non-fluorinated chemicals. 2. Compounds that in aqueous solution readily form hydrates inhibit acetylcholinesterase in a time-dependent process. On the other hand non-hydrated, carbonyl-containing compounds showed rapid and reversible, time-independent enzyme inactivation when assayed under steady state conditions. 3. m-N,N,N-Trimethylammonium-acetophenone acts as a rapid and reversible, time-independent, linear competitive inhibitor of acetylcholinesterase (Ki = 5.0 . 10(-7) M). 4. The most potent enzyme inhibitor tested in this series was N,N,N,-trimethylammonium-m-trifluoroacetophenone. It gives time-dependent inhibition and the concentration which inactivates eel acetylcholinesterase to 50% of the original activity after 30 min exposure is 1.3 . 10(-8) M. The bimolecular rate constant for this reaction is 1.8 . 10(6) 1 . mol-1 . min-1. The enzyme-inhibitor complex is very stable as the inhibited enzyme after 8 days of dialysis is reactivated to 20% only. This compound represents a quasi-substrate inhibitor of acetylcholinesterase.