Heme oxygenase overexpression attenuates glucose-mediated oxidative stress in quiescent cell phase: linking heme to hyperglycemia complications

Heme oxygenase (HO-1) is a stress protein, which has been suggested to participate in defense mechanisms against glucose induced oxidative injury. The purpose of this study was to examine the role of human HO-1 in attenuating glucose-mediated oxidative stress. We investigated the effect of high ambient glucose (15, 33 and 66 mM) on HO-1 gene expression in endothelial cells grown in a serum deprived media compared to the effect of glucose on exponentially grown cells (10% FBS). High glucose at 15 and 33 mM caused significant inhibition of HO-1 protein and activity in G0/G1 and in cells exponentially grown. Glucose concentration at 66 mM caused a significant increase in HO-1. Addition of heme (10 microM) increased HO-1 protein and bilirubin formation in G0/G1, in a time dependent manner peaking at 16 h. Glucose attenuated heme mediated increase in HO-1 proteins. RT-PCR demonstrated that glucose decreased the levels of HO-1 mRNA in both G0/G1 or cells grown in 10% FBS. The rate of HO-1 induction in response to heme was several fold higher in serum-starved cells compared to cells cultured in 10% FBS. Cells exposed to high glucose for up to 24 h had a significant increase in cellular heme and potentiated heme-mediated increase in generation of superoxide anion and 8-epi-isoprostane PGF(2alpha). HO-1 gene transduction prevented glucose-mediated elevation of 8-epi-isoprostane PGF(2alpha). These results imply that expression of HO-1 in G0/G1 cells may be a key player in decreasing cellular heme, associated with increased generation of bilirubin, and in attenuating glucose mediated oxidative stress.     

Relationships between total and unbound propofol in plasma and CSF during continuous drug infusion

BACKGROUND: Propofol is one of the most frequently applied intravenous anesthetics. Although it has been used for a long period, its pharmacokinetics, especially central nervous system pharmacokinetics, are not fully recognized. OBJECTIVE: Investigation of the relationships between total propofol concentration in blood, total propofol concentration in cerebrospinal fluid (CSF), free propofol concentration in blood, and free anesthetic concentration in CSF in patients undergoing elective neurosurgery and anesthetized with propofol. METHODS: Eleven patients scheduled for elective intracranial procedures were studied. Propofol was applied in the form of target control infusion. During anesthesia, fractional doses of fentanyl and cisatracurium were administered as necessary. After tracheal intubation the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (Fi O2 = 0.33). CSF and blood were taken at the moment of intraventricular drainage application. RESULTS: The unbound propofol concentration in plasma is 1.12% (SD 0.61%; SEM 0.18%) of the total concentration in plasma, and the free propofol concentration in plasma is 71.6% (SD 61.0%; SEM 18.4%) of the total CSF propofol concentration. The free anesthetic concentration in CSF is 30.9% (SD 15.7%; SEM 4.7%) of the total CSF propofol concentration, and 61.8% (SD 34.9%; SEM 10.5%) of the free propofol concentration in plasma. CONCLUSION: The relationship between unbound drug concentrations in plasma and in CSF determined in this study leads to the postulate that propofol is transported from blood to CSF by passive diffusion.     

1H-MR spectroscopy of normal brain tissue before and after postoperative radiotherapy because of primary brain tumors

PURPOSE: Brain metabolism after surgery and postoperative radiotherapy (pRT) because of primary brain tumors was assessed by proton magnetic resonance spectroscopy ((1)H-MRS) in vivo. The study was designed to reveal the impact of pRT on normal brain tissue metabolism, which may potentially help in delineating the target volumes for reirradiated patients. METHODS AND MATERIALS: Spectra of 43 patients ages 16-63 years treated with pRT for primary glial tumors in the Center of Oncology Maria Curie Memorial Institute Branch in Gliwice were analyzed. The control group consisted of spectra acquired for 30 healthy volunteers. All patients were treated with 3D conformal techniques using 6-20 MV photons to total doses of 60 Gy. Spectra were acquired from the control region before pRT and from three uninvolved regions 9-12 months after the end of pRT. Voxels were located in the region of low (<6 Gy), medium (29-39 Gy), and high radiation dose ( approximately 60 Gy). Relative intensities of the signals relating to N-acetyl-aspartate (NAA), choline-based compounds, creatine and phosphocreatine (Cr), mio-Inositol, lactate, and lipids were obtained. RESULTS: The spectra of "normal brain" taken 9 months after pRT are significantly different from those obtained for control volunteers and from the spectra acquired before radiotherapy. The lactate and lipids signals are very strong; however, they are not correlated with absorbed dose. NAA/Cr ratios are significantly lower than before radiotherapy even for the low-dose regions. Differences increase with radiation dose: the NAA/Cr ratio is significantly lower for the regions of brain receiving a high dose of radiation than for the low-dose areas. CONCLUSION: Combined treatment of primary brain tumors (surgery + postoperative radiotherapy) causes alteration of brain metabolism, even in regions of the brain far from the postoperative tumor bed and receiving relatively low total doses of radiation. Single voxel MRS spectroscopy in vivo cannot help in delineating target volumes for secondary irradiation.     

GDNF increases the survival of developing oculomotor neurons through a target-derived mechanism

Glial cell line-derived neurotrophic factor (GDNF) is the most potent motoneuron survival factor. We show here that in the chick oculomotor system, endogenous GDNF is derived largely from extraocular muscle but less from glial cells and not from muscle spindles. Increased levels of GDNF exclusively in the target rescued 30% of oculomotor neurons that would normally die during developmental cell death, a rate of rescue similar to that with systemic GDNF application. Thus, GDNF supports motoneuron survival in a retrograde, target-derived fashion, as opposed to a local paracrine route or an indirect route via sensory afferents. Persephin, another member of the GDNF family, did not increase survival with target delivery, despite its retrograde transport from the target. Unlike GDNF, however, persephin increased neurite outgrowth from oculomotor nuclei in vitro. Thus, one GDNF family member acts as a muscle-derived retrograde survival factor, whereas another one has distinct functions on neurite outgrowth.     

Hymenal anomalies in twins—review of the literature and case report

Subocclusive hymenal variants, such as microperforate or septate hymen, impair somatic functions (e.g., vaginal intercourse or menstrual hygiene) and can negatively impact the quality of life of young women. We know little about the prevalence and inheritance of subocclusive hymenal variants. So far, eight cases of familial occurrence of occlusive hymenal anomalies (imperforate hymen) have been reported. In one of these cases, monozygotic twins were affected. We are reporting the first case of subocclusive hymenal variants (microperforate hymen and septate hymen) in 16-year-old white dizygotic twins. In addition, we review and discuss the current evidence. Conclusion: The mode of inheritance of hymenal variants has not been determined so far. Because surgical corrections of hymenal variants should be carried out in asymptomatic patients (before menarche), gynecologists and pediatricians should keep in mind that familial occurrences may occur.     

Urethral length in girls with lower urinary tract symptoms and forme fruste of female epispadias

PurposeTo investigate systematically the length of the urethra in girls with lower urinary tract symptoms.Materials and methodsIn a group of 121 consecutive girls presented at a tertiary referral clinic for urinary incontinence or recurrent urinary tract infections, urethral length was measured by perineal ultrasound. The urethra was measured with the patient in supine position without anesthesia. Mean age of the patients was 7.8 (0–15) years.ResultsAverage urethral length was 26 mm. Minimum length was 12 mm, measured in a 5-year-old girl with dribbling incontinence. Maximum measured length was 40 mm in a 15-year-old girl. In four girls (3.3%), aged 1–10 years (mean 6.3), a short urethra was detected, with measured lengths of 12 and 14 mm. All four had normal genitalia, and were referred with therapy-resistant urinary incontinence or urinary tract infections. A gradual increase in average urethral length was measured from 23 mm at birth to 32 mm at 15 years.ConclusionUrethral length can be measured accurately by ultrasound. Although a short urethral length is rarely detected by ultrasound in girls with incontinence, it may be associated with therapy-resistant incontinence. In such cases, different treatment options are available.     

Expression profiling after retinal detachment and reattachment: a possible role for aquaporin-0

PURPOSE: Retinal detachment (RD) is associated with acute visual loss caused by anatomic displacement of the photoreceptors and with chronic visual loss/disturbance caused by retinal remodeling and photoreceptor cell death, which may occur even after successful reattachment. The P2Y(2) receptor agonist INS37217 improves the rate of retinal reattachment in animal models of induced RD, and has been shown to also significantly enhance the rate of ERG recovery in a mouse model of RD. The identification of genes modulated by INS37217 may allow further drug discovery for treating RD and edema. METHODS: To identify genes involved in RD and subsequent reattachment, a retinal microarray screen was performed using a mouse model of RD in the presence or absence of INS37217. RESULTS: Ninety-two genes were identified as differentially expressed across three time points, most of which were upregulated in the presence of this agonist. Furthermore, it was shown that RD alters the expression of aquaporin-0 (AQP-0), and this modulation is prevented by treatment with INS37217. The presence of AQP-0 in retinal bipolar cells was also demonstrated, whereas it was previously thought to be specific to the lens. Mice lacking functional alleles of AQP-0 had a phototransduction deficit as assessed by electroretinography; however, their photoreceptor structure was normal, indicative of a problem with signal transmission between neurons. CONCLUSIONS: This study establishes the genes involved in RD and reattachment, and also demonstrates for the first time a physiologically significant role for AQP-0 in retinal function.     

Synthesis and antinociceptive activity of cyclic endomorphin-2 and morphiceptin analogs

Cyclic analogs of the opioid peptides endomorphin-2 and morphiceptin of the type Tyr-X-Phe-Phe-Y-NH2 and Tyr-X-Phe-D-Pro-Y-NH2 (X = Lys or Asp and Y = Lys or Asp), respectively, were synthesized in order to test their structure-activity relationships. Antinociceptive activity of the new analogs was assessed in the hot-plate test after intracerebroventricular administration in mice. The strong analgesic effect was observed for the analogs with Asp in position 2, while the analogs with Lys in the second position were inactive. Antinociception caused by Asp2 analogs was dose-dependent and reversed by the concomitant administration of the universal opioid antagonist naloxone and by the selective kappa antagonist, nor-BNI. However, receptor binding studies revealed poor affinity of all cyclic analogs at the mu-opioid receptor and no affinity at delta- and kappa-opioid receptors. It is most likely that the new cyclic analogs produced their antinociception by the release of dynorphin A, which subsequently acted on the kappa-opioid receptor.