1,25(OH)2Vitamin D3 induces elevated expression of the cell cycle inhibitor p18 in a squamous cell carcinoma cell line of the head and neck

BACKGROUND: 1Alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2) Vitamin D(3)] induces growth inhibition in squamous cell carcinoma (SCC) cell lines of the head and neck by arresting the cells in the G0/G1 phase of the cell cycle, probably due to an enhanced expression of p21, which could be demonstrated in other cell lines (JPPA, SCC9) before. In SCC25, a SCC cell line isolated from tongue, growth inhibition but no overexpression of p21 was detected. The retinoblastoma gene, as a direct target of G1 cyclin-CDK complexes, showed an obvious shift from the hyperphosphorylated to the hypophosphorylated form under 1,25(OH)(2)Vitamin D(3), which indicates that the growth inhibition takes place in the G0/G1 phase. To explore the possible pathway of growth inhibition in SCC25 we investigated other cell cycle inhibitors (p18, p19, p27). METHODS: Synchronized cells were treated with 1,25(OH)(2)Vitamin D(3) over 96 h. The cell cycle status and expression of cell cycle-regulating proteins was determined by fluorescence-activated cell sorting (FACS) and Western blotting. An overexpression of p18 in 1,25(OH)(2)Vitamin D(3) vs. ethanol-treated cells was determined until 30 h in SCC25. No influence was detectable on the expression of p27 and p19. CONCLUSION: One mechanism by which 1,25(OH)(2)Vitamin D(3) controls cell growth might be the upregulation of p21. As p21 was unsusceptible to 1,25(OH)(2)Vitamin D(3) in SCC25, other inhibiting proteins were necessary to be tested. The proven upregulation of p18 seems to be the responsible step for growth inhibition of 1,25(OH)(2)Vitamin D(3) in SCC25.     

Kardiale Manifestationen der HIV-Infektion

Zusammenfassung. Die Infektion mit dem humanen Immundefizienzvirus (HIV) betrifft nicht nur das Immunsystem des menschlichen Organismus, sondern schließt vielmehr eine Reihe weiterer Organsysteme mit ein. Es wird angenommen, dass bei 5-15% der HIV-positiven Patienten kardiale Manifestationen auftreten. Zu den häufigsten HIV-assoziierten kardialen Manifestationen gehören der Perikarderguss und die chronisch aktive, fokale oder diffuse Myokarditis. Endokardiale Manifestationen bei HIV-positiven Patienten treten in Form der infektiösen Endokarditis und der nichtbakteriellen thrombotischen Endokarditis auf. In der Regel weisen HIV-assoziierte kardiale Manifestationen einen langsam progredienten Krankheitsverlauf auf. Komplikationen sind Folge eines langfristig unentdeckten Fortschreitens der Erkrankung, aber auch schnell progredienter Verlaufsformen. Aufgrund der Vielzahl HIV-assoziierter kardialer Manifestationen und deren möglicher Komplikationen ist daher neben der Früherkennung ein effektives diagnostisches und therapeutisches Vorgehen erforderlich. Seit Einführung der Proteaseinhibitoren in den 90er Jahren und der Anwendung der hochaktiven antiretroviralen Kombinationstherapie (HAART) konnten sowohl Mortalität als auch Morbidität der HIV-Infektion deutlich gesenkt werden. Die Auswirkungen der HAART auf das kardiovaskuläre System sind bisher nur in Ansätzen bekannt. Als Nebenwirkungen wurden metabolische Veränderungen in Form von Hyperlipoproteinämie und Insulinresistenz bei einer Vielzahl HIV-positiver Patienten beobachtet. Es kann davon ausgegangen werden, dass durch den Anstieg der kardiovaskulären Risikofaktoren unter der HAART in den nächsten Jahren eine erhöhte Rate kardialer Erkrankungen bei HIV-positiven Patienten auftreten wird. In dem vorliegenden Übersichtsartikel wird ein Überblick über die häufigsten kardialen Erkrankungen bei HIV-Infektionen gegeben. Zusätzlich werden Vorschläge zu Diagnostik und Therapie unterbreitet und eine Einschätzung über Veränderungen der HIV-assoziierten kardialen Manifestationen nach Einführung der HAART vorgenommen. Abstract. The human immunodeficiency virus (HIV) does not only affect the immune system. Other organs including the cardiovascular system are influenced by the HIV as well. Most common HIV-associated cardiac manifestations are pericardial effusion and chronic active, focal or diffuse myocarditis. In addition to peri- and myocardial disease, endocardiac manifestations occur as infective endocarditis and nonbacterial thrombotic endocarditis in HIV-infected patients. Although most of the cardiac manifestations associated with HIV-infection exhibit a slow progression, rapid courses may lead to fatal complications. Early screening of HIV-infected patients will identify the potentially fatal complications of HIV disease and permit efficient treatment. The use of highly active antiretroviral therapy (HAART) significantly reduced the mortality and morbidity of HIV-infected patients. However, the impact that HAART will have on the incidence and prevalence of cardiac complications in HIV-infected patients is still unknown. It can be predicted, that the long-term viral infection and the increase of cardiovascular risk factors by HAART will probably lead to an increased prevalence of HIV-infected individuals with cardiac complications in the next decade. The present review describes the most frequent HIV-associated cardiac manifestations including diagnostic and therapeutic perspectives.     

ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels.

The tarantula venom peptides ProTx-I and ProTx-II inhibit voltage-gated sodium channels by shifting their voltage dependence of activation to a more positive potential, thus acting by a mechanism similar to that of potassium channel gating modifiers such as hanatoxin and VSTX1. ProTx-I and ProTx-II inhibit all sodium channel (Nav1) subtypes tested with similar potency and represent the first potent peptidyl inhibitors of TTX-resistant sodium channels. Like gating modifiers of potassium channels, ProTx-I and ProTx-II conform to the inhibitory cystine knot motif, and ProTx-II was demonstrated to bind to sodium channels in the closed state. Both toxins have been synthesized chemically, and ProTx-II, produced by recombinant means, has been used to map the interaction surface of the peptide with the Nav1.5 channel. In comparison, beta-scorpion toxins activate sodium channels by shifting the voltage dependence of activation to more negative potentials, and together these peptides represent valuable tools for exploring the gating mechanism of sodium channels.     

Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg

To cover intermediate sensitive Candida glabrata in ICU patients,fluconazole plasma peak levels at least in the range of 16–32µg/ml appear necessary for treatment. Previous studiesdid not reach these fluconazole levels under continuous veno-venoushaemofiltration (CVVHF) with dosages of 200–600 mg fluconzoledaily. In the present study, nine patients simultaneously requiringCVVHF for treatment of acute oligoanuric renal failure and antimycotictherapy of Candida septicemia received fluconazole 800 mg/day.Fluconazole plasma levels were determined to evaluate whetherthis dosage is adequate to reach the advised fluconazole levels.Patients were dialysed on two consecutive days with an ultrafiltrationrate (UF) of 1000 ml/h or 2000 ml/h, respectively, in a randomizedorder. The predilution was 800 ml/h and 1800 ml/h, respectively.The treatment was tolerated without adverse effects. All patientsreached plasma fluconazole concentrations between 16 and 32µg/ml, remaining in this range for a minimum of 1 up to24 h with a mean of 9.6 h and a UF rate of 2000 ml/h, and 15.7h with a UF rate of 1000 ml/h. So far, there are no in vivodata on the fluconazole plasma concentrations required for effectivetreatment. However, our data demonstrate, that at least thefluconazole concentrations desirable on the basis of in vitrosusceptibility testing can be reached in critically ill patientson CVVHF in an ICU setting. However, in these patients, 800mg fluconazole/day are necessary to achieve fungicidal drugconcentrations.     

Prefrontal cortex dysfunction and depression in atypical parkinsonian syndromes.

Depressive symptoms are common in patients with neurodegenerative disorders. Imaging studies suggest that a disruption of frontal-subcortical pathways may underlie depression associated with basal ganglia disease. This pilot study tested the hypothesis that frontal dysfunction contributes to depression associated with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Depressed patients with MSA (n = 11), PSP (n = 9), and age-matched controls (n = 25) underwent measures of cerebral glucose metabolism applying positron emission tomography with (18)F-fluorodeoxyglucose. Regional metabolism in the patient groups was compared to the normal subjects using the voxel-based statistical parametric mapping. Depressive symptom severity (Hamilton Depression Rating) and degree of locomotor disability (Hoehn & Yahr) were assessed in the patient groups. The association between prefrontal metabolism and the occurrence of depressive symptoms and the degree of locomotor disability was investigated. When compared to controls, MSA patients revealed significant metabolic decreases in bilateral frontal, parietal, and cerebellar cortex and in the left putamen. In PSP patients, significant hypometabolism was demonstrated in bilateral frontal cortex, right thalamus, and midbrain. Depression severity but not the patients' functional condition was significantly associated with dorsolateral prefrontal glucose metabolism in both patient groups. The findings of this pilot study support the hypothesis that depressive symptoms in MSA and PSP are associated with prefrontal dysfunction.