Chronic administration of sildenafil improves erectile function in a rat model of chronic renal failure

The relationship between erectile dysfunction (ED) and chronic renal failure (CRF) has been reported in several studies. This study aimed to investigate whether the chronic use of sildenafil could enhance the erectile capacity in CRF-induced rats. In addition, we assessed the effect of that treatment on certain molecules, which have been suggested to play crucial roles in erectile physiology and CRF-related ED as well. Three groups of animals were utilized: (1) age-matched control rats, (2) CRF-induced rats, (3) CRF-induced rats treated with chronic administration of sildenafil (5 mg kg⁻¹ p.o. for 6 weeks [treatment started after 6 weeks of CRF induction]). At 3 months, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue advanced glycation end products (AGE''s)/5-hydroxymethyl-2-furaldehyde, malondialdehyde (MDA), cGMP (ELISA), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) (Western blot) analyses were performed in all rat groups. CRF-induced rats had a significant decrease in erectile function when compared to control rats (P < 0.05). The increase in both intracavernosal pressure (ICP) and area under the curve of CRF-induced rats treated with sildenafil (Group 3) was greater than CRF-induced rats (Group 2). Additionally, sildenafil treatment decreased AGE, MDA and iNOS levels, while it preserved nNOS and cGMP contents in CRF-induced penile tissue. Decreased AGE, MDA, iNOS and increased nNOS, cGMP levels at the sildenafil-treated group increased both ICP and Total ICP to CNS, which led to improve erectile function in CRF-induced rats. The results of the present study revealed the therapeutic effect of chronic sildenafil administration on erectile function in CRF-induced rats.     

Successful Hypothermia Treatment of Hypoxic-Ischemic Encephalopathy in a Neonate with Epidermolysis Bullosa

Despite advances in the neonatal care, hypoxic ischemic encephalopathy in late preterm and term infants remains an important cause of morbidity and mortality. There is lack of data on the application of therapeutic hypothermia in the existence of severe skin lesions. Epidermolysis bullosa is a rare group of inherited conditions which causes blisters in skin and mucosal membranes. In this report, the authors describe a successful whole-body hypothermia treatment of severe hypoxic ischemic encephalopathy in a term newborn with dystrophic epidermolysis bullosa. They observed that therapeutic hypothermia may also be given in newborns with dystrophic epidermolysis bullosa without any complications.     

Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes

Trichothecene mycotoxins are natural contaminants of small grain cereals and are encountered in the environment, posing a worldwide threat to human and animal health. Their mechanism of toxicity is poorly understood, and little is known about cellular protection mechanisms against trichothecenes. We previously identified inhibition of mitochondrial protein synthesis as a novel mechanism for trichothecene-induced cell death. To identify cellular functions involved in trichothecene resistance, we screened the Saccharomyces cerevisiae deletion library for increased sensitivity to nonlethal concentrations of trichothecin (Tcin) and identified 121 strains exhibiting higher sensitivity than the parental strain. The largest group of sensitive strains had significantly higher reactive oxygen species (ROS) levels relative to the parental strain. A dose-dependent increase in ROS levels was observed in the parental strain treated with different trichothecenes, but not in a petite version of the parental strain or in the presence of a mitochondrial membrane uncoupler, indicating that mitochondria are the main site of ROS production due to toxin exposure. Cytotoxicity of trichothecenes was alleviated after treatment of the parental strain and highly sensitive mutants with antioxidants, suggesting that oxidative stress contributes to trichothecene sensitivity. Cotreatment with rapamycin and trichothecenes reduced ROS levels and cytotoxicity in the parental strain relative to the trichothecene treatment alone, but not in mitophagy deficient mutants, suggesting that elimination of trichothecene-damaged mitochondria by mitophagy improves cell survival. These results reveal that increased mitophagy is a cellular protection mechanism against trichothecene-induced mitochondrial oxidative stress and a potential target for trichothecene resistance.Trichothecene mycotoxins are highly toxic secondary metabolites produced by Trichothecium, Myrothecium, Trichoderma, and Fusarium. Fusarium graminearum and Fusarium culmorum cause Fusarium head blight (FHB), which is one of the most damaging diseases of small grain cereals. FHB adversely affects the food supply because trichothecene mycotoxins, such as deoxynivalenol (DON), accumulate in the infected grain, presenting a food safety risk and health hazard to humans and animals (1). Controlling their accumulation in small grains remains a huge challenge. Trichothecenes cause growth retardation, hemorrhagic lesions, immune dysfunction, and emesis (2, 3) and are neurotoxic (4–6). Trichothecene poisoning causes acute gastroenteritis and has been linked to alimentary toxic aleukia (ATA) and Kashin–Beck disease, an endemic and chronic degenerative osteoarthritis (3).Trichothecenes inhibit protein synthesis by targeting ribosomal protein L3 in yeast (7–9). However, their toxicity is not entirely due to inhibition of cytosolic protein synthesis. In mammalian cells, DON induces activation of double-stranded RNA-associated protein kinase (PKR), promotes degradation of 28S rRNA, and up-regulates a number of microRNAs (3, 10). DON exposure stabilizes mRNAs encoding proinflammatory mRNAs (3, 10). In plants, T-2 toxin (T-2) and DON cause oxidative stress damage by increasing reactive oxygen species (ROS) levels (11).Despite the importance of trichothecenes in food safety and chronic environmental exposure, the molecular mechanism of their toxicity is not well-understood and there is a critical gap in our knowledge about the mechanisms that can protect cells against trichothecenes. To understand the trichothecene mechanism of action, we previously carried out a genome-wide screen of Saccharomyces cerevisiae for resistance to trichothecin (Tcin) and showed that the largest group of resistant strains were affected in mitochondrial functions (12). We showed that trichothecenes inhibit mitochondrial translation, before depolarization and fragmentation of the mitochondrial membrane and independent of the cytosolic translation inhibition (12, 13). Previous studies showed a link between ROS generation and mitochondrial translation (14, 15). Yeast mutants with impaired mitochondrial translation exhibited faulty oxidative phosphorylation resulting in toxic levels of ROS, overwhelming the cell’s antioxidant capacity, and causing oxidative stress (14). These results suggested that mitochondrial dysfunction and the resulting oxidative stress might contribute to trichothecene sensitivity. To obtain a comprehensive view of the cellular functions needed for tolerance to trichothecenes, we screened the complete set of viable S. cerevisiae deletion strains for increased sensitivity to Tcin, a representative type B trichothecene that has a similar IC₅₀ for Vero cells (0.5 µM) and yeast grown on nonfermentable media (0.75 µM) (12, 13). Analysis of the identified strains revealed a vital role for mitochondrial oxidative stress in trichothecene sensitivity and provided the first evidence to our knowledge for a prosurvival role for the autophagic degradation of damaged mitochondria or mitophagy in the reduction of trichothecene-mediated mitochondrial oxidative stress.     

Adipokines and Systemic Inflammation in Weight-Losing Lung Cancer Patients

Background  

Cancer cachexia is a devastating condition leading to loss of function and independence, decreased performance status, decreased quality of life, and poor prognosis. Adipokines play a role in a wide variety of physiological or pathological processes, including immunity and inflammation, in addition to having significant effects on metabolism and lipogenesis. The objective of the present study was to investigate the relationship of adipokines and systemic inflammation in weight-losing advanced-stage non-small-cell lung cancer (NSCLC) patients.     

Effects of different surface treatments on shear bond strength in two different ceramic systems

The purpose of this study was to evaluate the influence of different surface treatments (sandblasting, acid etching, and laser irradiation) on the shear bond strength of lithium disilicate-based core (IPS Empress 2) and feldspathic ceramics (VITA VM 9). One hundred ceramic discs were divided into two groups of 50 discs each for two ceramic systems: IPS Empress 2 (group I) and VITA VM 9 (group II). Each of the two groups was further divided into five surface treatment groups (ten each) as follows: group SB, sandblasting with alumina particles (50 μm); group HF, 5 % hydrofluoric acid etching; group L, Er:YAG laser irradiation (distance, 1 mm; 500 mJ; 20 Hz; 10 W; manually, noncontact R14 handpiece); group SB–L, sandblasting + Er:YAG laser; and group HF–L, 5 % hydrofluoric acid + Er:YAG laser. Luting cement (Panavia 2.0) was bonded to the ceramic specimens using Teflon tubes. After 24 h of water storage, a shear bond strength test was performed using a universal testing machine at a crosshead speed of 0.5 mm/min. The data were analyzed with a two-way analysis of variance (ANOVA) and Tukey's honestly significant difference tests (α?=?0.05). The two-way ANOVA indicated that the shear bond strength was significantly affected by the surface treatment methods (p?<?0.05), but there was no significant interaction between the ceramic systems. Group SB–L had the highest mean values for each ceramic system. Sandblasting, followed by Er:YAG laser irradiation, enhanced the bond strength, indicating its potential use as an alternative method. The atomic force microscopic evaluation revealed that group SB had the most distinct sharp peaks among the groups.     

Endoscopic evacuation of cerebellar hematoma in a term newborn

Intracerebellar hemorrhage is very rare in term infants and only severe cases with massive intracranial hemorrhage, posthemorrhagic hydrocephalus and clinical deterioration due to increased intracranial pressure require neurosurgical evacuation. In recent adult studies endoscopic hematoma evacuation has been shown as a rapid, effective, and safe technique. A term newborn hospitalized for meconium aspiration syndrome showed hypertonia, jitteriness and abnormal amplitude integrated electroencephalogram findings. He was diagnosed with cerebellar hematoma which caused hydrocephalus by cranial magnetic resonance imaging (MRI). The hematoma was successfully evacuated neuroendoscopically as the first case in literature to our knowledge. Neurologic, a-EEG and MRI findings resolved.     

Immunohistochemical expression of PTEN in normal, hyperplastic and malignant endometrium and its correlation with hormone receptors, bcl-2, bax, and apoptotic index

PTEN is a tumor suppressor gene that is frequently mutated in type I endometrioid endometrial carcinomas (EECs), and is involved in the control of cell proliferation, differentiation, and apoptosis. In this study, we aimed to assess the relationship between PTEN expression and estrogen, progesterone receptors (PRs), other apoptosis-related proteins, such as bcl-2 and bax, and apoptotic index (AI) in EEC, its precursor lesion hyperplasia, and cyclical endometrium. We also evaluated the relationship between PTEN expression and clinicopathologic parameters. PTEN, estrogen receptor (ER), PR, and bcl-2 and bax expressions were evaluated immunohistochemically, and AI was evaluated in hematoxylin and eosin (HE)-stained slides in 23 cyclical and 37 hyperplastic endometria and in 35 EECs. PTEN expression was higher in cyclical endometrium than in the carcinomas (p<0.05). The PTEN expression level was significantly higher in non-atypical hyperplasias than in EEC, but there were no differences between atypical complex hyperplasia (ACH) and EEC and between hyperplasias. In the carcinomas, there was a negative correlation between grade and PTEN expression (r=-0.338, p=0.047). In conclusion, we presume that PTEN is involved in the early phases of endometrial tumorigenesis, and it can be speculated that decreased PTEN expression with loss of differentiation in carcinoma can contribute to the emergence of tumors with a more aggressive phenotype.