Assessment of the dissimilarities of totally 186 countries and regions according to COVID-19 indicators at the end of March 2020.

Background: This study is aimed at evaluating the relationship between the number of days elapsed since a country's first case(s) of coronavirus disease 2019 (COVID-19), the total number of tests conducted, and outbreak indicators such as the total numbers of cases, deaths, and patients who recovered. The study compares COVID-19 indicators among countries and clusters them according to similarities in the indicators. Methods: Descriptive statistics of the indicators were computed and the results were presented in figures and tables. A fuzzy c-means clustering algorithm was used to cluster/group the countries according to the similarities in the total numbers of patients who recovered, deaths, and active cases. Results: The highest numbers of COVID-19 cases were found in Gibraltar, Spain, Switzerland, Liechtenstein and Italy were also of that order with about 1500 cases per million population. Spain and Italy had the highest total number of deaths, which were about 140 and 165 per million population, respectively. In Japan, where exposure to the causative virus was longer than in most other countries, the total number of deaths per million population was less than 0.5. According to cluster analysis, the total numbers of deaths, patients who recovered, and active cases were higher in Western countries, especially in central and southern European countries, which had the highest numbers when compared with other countries. Conclusion: There may be various reasons for the differences between the clusters obtained by fuzzy c-means clustering. These include quarantine measures, climatic conditions, economic levels, health policies, and the duration of the fight against the outbreak.

Possible antiapoptotic and neuroprotective effects of magnesium sulphate on retina in a preterm hypoxic-ischemic rat model

Background/aim: The effects of systemic magnesium sulfate (MgSO4) on retina in preterm hypoxic-ischemic (HI) rat model are not known. Our aim was to investigate the effects of MgSO4 on retinal ganglion cell (RGC) count, retinal ganglion cell (RGC) apoptotic index, retinal vascular endothelial growth factor receptor-2 (VEGFR-2), and glial fibrillary acidic protein (GFAP) expressions in preterm HI rat model. Materials and methods: Fifteen, postnatal day (PND) 7 rat pups were divided into 3 groups: 1. Sham-operated group, 2. HI group, and 3. MgSO4-treated HI group. The second and third groups underwent ischemia followed by exposure to hypoxia for 2 h (Vannucci model). The first and second groups received intraperitoneal saline and the third group received intraperitoneal MgSO4. On PND 10, eyes of the pups were evaluated for RGC count, apoptotic index, VEGFR-2, and GFAP expressions. Results: In both HI and MgSO4-treated HI group, the mean total RGC counts were found to be significantly decreased. However, the mean total RGC count in the MgSO4-treated HI group was significantly higher than that of the HI group. The mean apoptotic index was found to be significantly increased in the HI group. Retinal VEGFR-2 and GFAP expressions were found to be significantly higher in the HI group. Conclusions: Magnesium sulfate preconditioning and treatment in preterm HI rat model might diminish apoptosis, relatively preserve RGCs, and reduce retinal VEGFR-2 and GFAP expressions.

In vitro tooth-shaped scaffold construction by mimicking late bell stage.

Neogenesis of osseous and ligamentous interfacial structures is essential for the regeneration of large oral or craniofacial defects. However, current treatment strategies are inadequate in renewing supporting tissues of teeth after trauma, chronic infections or surgical resection. Combined use of 3D scaffolds with stem cells became a promising treatment option for these injuries. Matching different scaffolding materials with different tissues can induce the correct cytokines and the differentiation of cells corresponding to that particular tissue. In this study, a hydroxyapatite (HA) based scaffold was used together with human adipose stem cells (hASCs), human bone marrow stem cells (hBMSCs) and gingival epithelial cells to mimic human tooth dentin-pulp-enamel tissue complexes and model an immature tooth at the late bell stage in vitro. Characteristics of the scaffold were determined via SEM, FTIR, pore size and density measurements. Changes in gene expression, protein secretions and tissue histology resulting from cross-interactions of different dental tissues grown in the system were shown. Classical tooth tissues such as cementum, pulp and bone like tissues were formed within the scaffold. Our study suggests that a HA-based scaffold with different cell lineages can successfully mimic early stages of tooth development and can be a valuable tool for hard tissue engineering.

A New Perspective in Comparing Injuries Caused by Short-Duration External and Internal Forces in Saphenous Vein.

BACKGROUND: Great saphenous vein (GSV) graft failure is one of the major reasons for repeat bypass grafting. A comparison of the effects of simultaneous, short-duration, externally squeezing and internally distending forces on the same segment of ex-vivo human GSV has not yet been published, although similar studies have compared the experimental injury of different ex-vivo human veins. METHODS: Approximately 8-cm-long segments of GSV were harvested from each of the 15 patients. For each specimen, one end of the vein piece was occluded at a distance of 1 cm with an external cross-clamp for 5 min and the other end was similarly occluded at a distance of 1 cm by an endoluminal balloon. The middle sections of the veins, which were not occluded by any means, were taken as the control group. Two histologists, who were blinded to the groups, graded the hematoxylin and eosin (H&E) and Weigert-Van Gieson (WVG) stained sections semi-quantitatively and performed the histomorphometric measurements. RESULTS: The result of the histopathological evaluation of the intima layer showed that the microscopic scoring of lesions in the balloon group was significantly higher than that in the clamp and control groups (5.16 ± 1.32, 3.83 ± 0.75, and 1.00 ± 1.09, respectively; P < .001). In the adventitia layer, this level of scoring increased more in the clamp group than in the balloon and control groups (5.16 ± 1.16, 3.00 ± 0.89, and 0.16 ± 0.40, respectively, P < .001). CONCLUSION: Both the endoluminal balloon and external clamp techniques have harmful effects on the vein wall. Studying different kind of forces on different veins cannot provide us with reliable comparisons.

The effect of 1,25 dihydroxyvitamin D3 on HCl/Ethanol-induced gastric injury in rats.

This study evaluated ulceroprotective and antioxidant effect of 1,25 dihydroxyvitamin D3 against gastric damage in rats. Rats were treated intraperitoneally with either 1,25 dihydroxyvitamin D3 (0.25 µg/kg) or saline for 14 days. On day-15, the non-selective cyclooxygenase inhibitor indomethacin (10 mg/kg; subcutaneously), the inhibitor of sulfhydryl groups N-ethylmaleimide (10 mg/kg; intraperitoneally) or ATP-sensitive K+ channel blocker glibenclamide (10 mg/kg; orally) was given prior to 1,25 dihydroxyvitamin D3. Animals were euthanized at 60 min post ulcerogenic challenge (0.3 M HCl and 60% ethanol (0.2 mL; orally). Stomach and blood were collected for biochemical and histological evaluations. HCl/Ethanol group revealed severely damaged mucous and glandular epithelium with diffuse hemorrhage and inflammatory cell infiltration (microscopic score: 10.67 ±â€¯0.67 and ulcer index: 33.13 ±â€¯5.09). 1,25 dihydroxyvitamin D3 decreased the extent of damage (microscopic score: 6.80 ±â€¯0.02 and ulcer index: 19.00 ±â€¯4.34; p < 0.05), and the elevations in gastric malondialdehyde level (p < 0.001), myeloperoxidase activity (p < 0.001), nuclear factor-κB expression (p < 0.05), and apoptotic index (p < 0.05) following HCl/Ethanol challenge. Decreased gastric glutathione following HCl/Ethanol administration was restored by 1,25 dihydroxyvitamin D3 (p < 0.01). These findings demonstrated protection of the gastric mucosa against HCl/Ethanol-induced injury by 1,25 dihydroxyvitamin D3 via attenuation of inflammatory reaction, oxidative stress and apoptosis.

The effects of bevacizumab treatment in a rat model of retinal ischemia and perfusion injury.

Purpose: To create a model of an ischemic retina with temporary ischemia and reperfusion (IR) and to examine the possible antiapoptotic and neurodegenerative effects of a vascular endothelial growth factor (VEGF) antagonist. Methods: Three groups were formed. Rats were subjected to continued ischemia for 45 min, and then reperfusion was allowed for 2 days. For the first group, ischemia was induced, but an anti-VEGF agent was not administered. For the second group, 2 days before ischemia, 0.005 ml (0.125 mg) of bevacizumab was administered intravitreally, and then the ischemic model was created. The last group's intraocular pressure was not increased as in the control group, and only a cannula was introduced into the anterior chamber through the cornea. Six animals from each group were subjected to histomorphometry, and four were subjected to immunohistochemical and histopathologic examinations. For a histomorphometric examination, the number of cells in the retinal ganglion cell (RGC) layer was counted using the optical dissector method. For immunohistochemistry, the vascular endothelial growth factor receptor-2 (VEGFR-2) levels and apoptosis were examined in the retinal and choroidal tissue. Results: It was observed that in an IR injury, bevacizumab reduces the death and apoptosis of cells in the RGC layer. It was also identified that although bevacizumab is a large molecule, the agent affects the choroid and reduces the amount of VEGFR-2 in this tissue. Conclusions: IR may be used as a model of ischemic retinopathy that includes VEGF-dependent vascular permeability and neurodegeneration. Although VEGF is a neurotrophic molecule, in IR injury, treatment with bevacizumab, which is an anti-VEGF agent, decreases apoptosis, showing that excess function of this molecule can be hazardous.

Preventive Effect of Phosphodiesterase Inhibitor Pentoxifylline Against Medication-Related Osteonecrosis of the Jaw: An Animal Study.

PURPOSE: The aim of this experimental study was to investigate the prophylactic effect of pentoxifylline (PTX) on medication-related osteonecrosis of the jaw (MRONJ). MATERIALS AND METHODS: Female Sprague-Dawley rats (n = 33) received zoledronic acid (ZA) for 8 weeks to create an osteonecrosis model. The left mandibular second molars were extracted and the recovery period lasted 8 weeks before sacrifice. PTX was intraperitoneally administered to prevent MRONJ. The specimens were histopathologically and histomorphometrically evaluated. RESULTS: Histomorphometrically, between the control and ZA groups, there was no statistically significant difference in total bone volume (P = .999), but there was a statistically significant difference in bone ratio in the extraction sockets (P < .001). A comparison of the bone ratio of the ZA group with the ZA/PTX group (PTX administered after extraction) showed no statistically significant difference (P = .69), but there was a statistically significant difference with the ZA/PTX/PTX group (PTX administered before and after extraction; P = .008). Histopathologically, between the control and ZA groups, there were statistically significant differences for inflammation (P = .013), vascularization (P = .022), hemorrhage (P = .025), and regeneration (P = .008). Between the ZA and ZA/PTX groups, there were no statistically significant differences for inflammation (P = .536), vascularization (P = .642), hemorrhage (P = .765), and regeneration (P = .127). Between the ZA and ZA/PTX/PTX groups, there were statistically significant differences for inflammation (P = .017), vascularization (P = .04), hemorrhage (P = .044), and regeneration (P = .04). CONCLUSION: In this experimental model of MRONJ, it might be concluded that although PTX, given after tooth extraction, improves new bone formation that positively affects bone healing, it is not prophylactic. However, PTX given before tooth extraction is prophylactic. Therefore, PTX might affect healing in a positive way by optimizing the inflammatory response.

Effects of local platelet-rich plasma injection on the rate of orthodontic tooth movement in a rat model: A histomorphometric study.

INTRODUCTION: The aims of this study were to determine the effects of different concentrations of platelet-rich plasma (PRP) on alveolar bone density and orthodontic tooth movement. METHODS: Seventy-six rats were divided into 2 groups: a moderate concentration PRP injection group (n = 38) and a high concentration PRP injection group (n = 38). In each group, 5 time points were studied: 3, 7, 14, 21, and 60 days. Before orthodontic mesialization of the maxillary first molars, moderate and high concentrations of PRP were injected on the right sides of the molar buccal sulcus, and the left sides served as the controls. Tooth movements were measured on 3-dimensional digital models. Alveolar bone volume density and osteoclastic activity in the first molar intraradicular areas were evaluated by histomorphometric analysis. RESULTS: Alveolar bone density was decreased in the experimental groups compared with the control groups (P = 0.0001) at 3, 7, 14, and 21 days. On day 3, osteoclastic activity of the experimental groups was higher than that of the controls (P = 0.044, P = 0.0001). On day 21, the amounts of tooth movement in the high-concentration experimental group were 1.7 times greater than in the high-concentration control group and 1.4 times greater than in the moderate-concentration experimental group (P = 0.001). On day 60, alveolar bone density increased to the original levels in all groups. CONCLUSIONS: Injection of both moderate and high concentrations of PRP may accelerate orthodontic tooth movement by decreasing alveolar bone density on paradental tissues by enhancing osteoclastic activity in a transient way.

Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction.

OBJECTIVE: The goal of the present study was to investigate the effects of 5-lipoxygenase (5-LOX) inhibition, alone and with cyclooxygenase (COX) inhibitors, on inflammatory parameters and apoptosis in ischemia/reperfusion (I/R)-induced myocardial damage in rats. For this purpose, zileuton, a selective and potent inhibitor of 5-LOX, resulting in suppression leukotriene production, was used. METHODS: Male Wistar rats (200-250 g; n=12 per group) were used in the study. I/R was performed by occluding the left coronary artery for 30 minutes and 2 hours of reperfusion of the heart. Experimental groups were I/R group, sham I/R group, zileuton (5 mg/kg orally, twice daily)+I/R group, zileuton+indomethacin (5 mg/kg intraperitoneally)+I/R group, zileuton+ketorolac (10 mg/kg subcutaneously)+I/R group, and zileuton+nimesulide (5 mg/kg subcutaneously)+I/R group. Following I/R, blood samples were collected to measure tumor necrosis factor alpha (TNF-α), and left ventricles were excised for evaluation of microscopic damage; malondialdehyde (MDA), glutathione, nuclear factor (NF)-κB assays; and evaluation of apoptosis. RESULTS: Left ventricle MDA in I/R group was higher compared to sham group; however, it did not show significant change with zileuton. Although tissue injury in I/R group was less severe in all treatment groups, it was not statistically significant. NF-κB H-score and apoptotic index, which were higher in I/R group compared to sham I/R, were decreased with application of zileuton (H-score: p<0.01; apoptotic index: p<0.001). Zileuton had no significant effect on increased serum TNF-α levels in I/R group. CONCLUSION: 5-LOX inhibition in rat myocardial infarction model attenuated increased left ventricle NF-κB expression and apoptosis and these actions were not modulated by COX inhibitors.

Sodium pentaborate pentahydrate and pluronic containing hydrogel increases cutaneous wound healing in vitro and in vivo.

After a disruption of skin integrity, the body produces an immediate response followed by a functional and comparable regeneration period, referred to as wound healing. Although normal wounds do not need much attention during the healing period, chronic (non-healing) wounds are the major challenge of current dermatological applications. Therefore, developing new, safe, and effective wound healing drugs has always been an attractive area of international research. In the current study, sodium pentaborate pentahydrate (NaB), pluronics (Plu; F68 and F127), and their combinations were investigated for their wound healing activities, using in vitro and in vivo approaches. The results revealed that NaB significantly increased migration capacity and superoxide dismutase activity in primary human fibroblasts. Combinations of optimized concentrations for pluronic block co-polymers further increased cell migration, and the messenger RNA (mRNA) expression levels of important growth factor and cytokines (vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-ß), and tumor necrosis factor alpha (TNF-α)). NaB containing hydrogel co-formulated with pluronics was also investigated for their wound healing activities using a full thickness wound model in rats. Macroscopic and histopathological analysis confirmed that wounds in combination gel-treated groups healed faster than those of control groups. NaB/Plu gel application was found to increase wound contraction and collagen deposition in the wound area. Therefore, our results suggest that NaB, and its pluronics combination, could be used in dermatological clinics and be a future solution for chronic wounds. However, further studies should be conducted to explore its exact action of mechanism and effects of this formulation on chronic wounds.

The role of cholinergic anti-inflammatory pathway in acetic acid-induced colonic inflammation in the rat.

The "cholinergic anti-inflammatory pathway" provides neurological modulation of cytokine synthesis to limit the magnitude of the immune response. This study aimed to evaluate the impact of the cholinergic anti-inflammatory pathway on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of acetic acid-induced colitis. Colitis was induced by intrarectal administration of 5% acetic acid (1ml) to Sprague-Dawley rats (200-250g; n=7-8 per group). Control group received an equal volume of saline intrarectally. The rats were treated with either nicotine (1mg/kg/day) or huperzine A (0.1mg/kg/day) intraperitoneally for 3 days. After decapitation, the distal colon was scored macroscopically and microscopically. Tissue samples were used for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity. Formation of reactive oxygen species was monitored by using chemiluminescence (CL). Nuclear factor (NF)-κB expression was evaluated in colonic samples via immunohistochemical analysis. Trunk blood was collected for the assessment of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-10, resistin and visfatin levels. Both nicotine and huperzine A reduced the extent of colonic lesions, increased colonic MDA level, high MPO activity and NF-κB expression in the colitis group. Elevation of serum IL-1ß level due to colitis was also attenuated by both treatments. Additionally, huperzine A was effective to reverse colitis-induced high lucigenin-enhanced CL values and serum TNF-α levels. Colitis group revealed decreased serum visfatin levels compared to control group which was completely reversed by nicotine. In conclusion, modulation of the cholinergic system either by nicotine or ACh esterase inhibition improved acetic acid-induced colonic inflammation as confirmed by macroscopic and microscopic examination and biochemical assays.

The effect of phosphodiesterase-5 inhibition by sildenafil citrate on inflammation and apoptosis in rat experimental colitis.

AIMS: To investigate the effect of sildenafil citrate (SIL) on the extent of tissue integrity, oxidant-antioxidant status and apoptosis in rats with colitis. MAIN METHODS: Colitis was induced by trinitrobenzenesulphonic acid (TNBS) in 40% ethanol (30 mg/ml; 0.8 ml) given intrarectally to Sprague-Dawley rats. Sildenafil (25 mg/kg/day) was administered after the induction of colitis and the treatment was continued for 7 days. Other groups received subcutaneously either N(G)-nitro- L-arginine methyl ester (l-NAME; 25 mg/kg) or N(G)-nitro-d-arginine methyl ester (d-NAME; 25 mg/kg) before SIL. After decapitation, the distal colon was scored and stored for the measurement of malondialdehyde (MDA) level, glutathione (GSH) content, myeloperoxidase (MPO) activity and apoptosis. Oxidant generation was monitored by using chemiluminescence (CL). Blood was collected for tumor necrosis factor (TNF)-α and interleukin (IL)-10 assays. KEY FINDINGS: The macroscopic lesion score of the colitis group was reduced by SIL (p < 0.01) and this effect was abolished by l-NAME (p < 0.01). Increase in colonic MDA along with a concomitant decrease in GSH of the colitis group was reversed by SIL (p < 0.01 and p < 0.001, respectively). l-NAME prevented the effect of SIL on GSH content (p < 0.001). Sildenafil also reduced the elevated MPO of the colitis group (p < 0.001) and this effect was reversed by L-NAME (p < 0.01). Increase in lucigenin CL and serum TNF-α levels in the colitis group were also prevented by SIL (p < 0.001 and p < 0.01, respectively). SIGNIFICANCE: Sildenafil is beneficial in TNBS-induced rat colitis partially by nitric oxide-dependent mechanisms via the maintenance of oxidant-antioxidant status, prevention of apoptosis, superoxide production and cytokine release.

An immunohistochemical analysis of the neuroprotective effects of memantine, hyperbaric oxygen therapy, and brimonidine after acute ischemia reperfusion injury.

PURPOSE: This study applies treatment methods to rat retinas subjected to acute ischemia reperfusion injury and compares the efficacy of memantine, hyperbaric oxygen (HBO) therapy, and brimonidine by histopathological examination. METHODS: Thirty adult Wistar albino rats were divided into five groups after retinal ischemia was induced by elevating the intraocular pressure to 120 mmHg. The groups were as follows: group 1: control; group 2: acute retinal ischemia (ARI) model but without treatment group; group 3: memantine (MEM) treatment group; group 4: HBO therapy group; and group 5: brimonidine treatment (BRI) group. In the control group, right eyes were cannulated with a 30-gauge needle and removed without causing any intraocular pressure change. The ARI group was an acute retinal ischemia model, but without treatment. In the MEM group, animals were given a unique dose of intravenous 25 mg/kg memantine by the tail vein route after inducing ARI. In the HBO group, at 2 h following ARI, HBO treatment was applied for nine days. In the BRI group, a 0.15% brimonidine tartrate eye drop treatment was applied twice a day (BID) for seven days before ARI. Twenty-one days after establishing ischemia reperfusion, the right eyes were enucleated after the cardiac gluteraldehyde perfusion method, and then submitted to histological evaluation. RESULTS: On average, the total retinal ganglion cell number was 239.93 ± 8.60 in the control group, 125.14 ± 7.18 in the ARI group, 215.89 ± 8.36 in the MEM group, 208.69 ± 2.05 in the HBO group, and 172.27 ± 8.16 in the BRI group. Mean apoptotic indexes in the groups were 1.1 ± 0.35%, 57.71 ± 0.58%, 23.57 ± 1.73%, 15.63 ± 0.58%, and 29.37 ± 2.55%, respectively. CONCLUSIONS: The present study shows that memantine, HBO, and brimonidine therapies were effective in reducing the damage induced by acute ischemia reperfusion in the rat retina. Our study suggests that these treatments had beneficial effects due to neuroprotection, and therefore may be applied in clinical practice.

Effects of the gonadotropin-releasing hormone antagonist cetrorelix in the early postimplantation period on rat pregnancy.

OBJECTIVE: The effect of cetrorelix given in the early implantation period on rat pregnancy was investigated. STUDY DESIGN: Forty-nine virgin Sprague-Dawley rats were randomized into six groups. At the 4th or 8th days of sperm plug, groups received 15, 75, 150 µg/kg cetrorelix or saline. Three subjects were randomly selected from each group and sacrificed at 11th gestational day for histomorphometric analysis. The remaining subjects were allowed to complete their pregnancy period. Volumes of total conceptus, labyrinth zone, transitional zone, giant cell zone, and exocoelomic cavity were calculated according to Cavalieri's principle. RESULTS: Subjects receiving cetrorelix at 15 or 150 µg doses at the 4th day (D4) and those receiving cetrorelix at 150 µg dose at the 8th day (D8) of pregnancy delivered later than the controls. On necropsy examination at the 11th day, mean embryo weights of the cetrorelix 15 D4, 150 D4, 15 D8 and 75 D8 groups were found to be significantly lower than that of the controls (p<0.05). On histomorphometric evaluation, volumes of the fetuses and the amniotic sacs were decreased by cetrorelix at all doses studied dose dependently. Gross congenital anomalies were observed in the pups of three rats of the cetrorelix 150 D4 and D8 groups. CONCLUSION: The results of this study suggest that cetrorelix in the early post-implantation period may lead to serious side effects in the rat.

Microsurgical and histomorphometric study of the occipital sinus: quantitative measurements using a novel approach of stereology.

Quantitative descriptions of the occipital sinus are lacking in the extant medical literature. Posterior fossa duras with the superior sagittal sinus, the inferior and superior petrosal sinuses were dissected and taken out from fresh human cadavers by cutting at the superior sagittal sinus, the marginal sinuses and the petrosal sinuses bilaterally. The length of the occipital sinuses was measured using calipers. A 0.5-cm section of the occipital sinus was cut out at its midpoint and prepared for measurements of the perimeter and diameter using a stereology workstation. The sinuses were also examined qualitatively using a surgical microscope. There was no occipital sinus in 6.6% of total 30 cases. Multiple occipital sinuses were seen in 10%. In one specimen, the sinus seemed incomplete, failing to reach the marginal sinuses. Some specimens gave the impression that more than one occipital sinus was present, nevertheless, careful dissection showed connections. The breadth of the sinus steadily narrowed downward in direction of foramen magnum. The inner wall with many fibrous bridges was tight, except the lateral parts that were easily separated into two dural sheets. The length of the sinus varied from 10 to 37 mm. The inner diameter (feret maximum) varied from 0.33 to 7.06 mm at midpoint. The breadth of the multiple sinuses did not exceed the mean of our series except in one case. The occipital sinus, which is generally ellipsoid in shape, functions in the majority of cases as a thin, single midline sinus. It may have less resistant recesses laterally.

Role of Nogo-A in neuronal survival in the reperfused ischemic brain.

Nogo-A is an oligodendroglial neurite outgrowth inhibitor, the deactivation of which enhances brain plasticity and functional recovery in animal models of stroke. Nogo-A's role in the reperfused brain tissue was still unknown. By using Nogo-A(-/-) mice and mice in which Nogo-A was blocked with a neutralizing antibody (11C7) that was infused into the lateral ventricle or striatum, we show that Nogo-A inhibition goes along with decreased neuronal survival and more protracted neurologic recovery, when deactivation is constitutive or induced 24 h before, but not after focal cerebral ischemia. We show that in the presence of Nogo-A, RhoA is activated and Rac1 and RhoB are deactivated, maintaining stress kinases p38/MAPK, SAPK/JNK1/2 and phosphatase-and-tensin homolog (PTEN) activities low. Nogo-A blockade leads to RhoA deactivation, thus overactivating Rac1 and RhoB, the former of which activates p38/MAPK and SAPK/JNK1/2 via direct interaction. RhoA and its effector Rho-associated coiled-coil protein kinase2 deactivation in turn stimulates PTEN, thus inhibiting Akt and ERK1/2, and initiating p53-dependent cell death. Our data suggest a novel role of Nogo-A in promoting neuronal survival by controlling Rac1/RhoA balance. Clinical trials should be aware of injurious effects of axonal growth-promoting therapies. Thus, Nogo-A antibodies should not be used in the very acute stroke phase.

Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycin-induced lung fibrosis.

Sildenafil, a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)5, has a relaxant effect on the smooth muscle cells of the arterioles supplying the human corpus cavernosum acting via nitric oxide (NO)-dependent mechanism. This study aimed to investigate the possible protective effect of sildenafil citrate on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of bleomycin-induced lung fibrosis. Lung fibrosis was induced by intratracheal administration of 0.1 ml of bleomycin hydrochloride (5 mg/kg in 0.9% NaCl) under anesthesia to Sprague-Dawley rats (200-250 g; n = 7-8 per group). Control rats received an equal volume of saline intratracheally. In the treatment groups, the rats were treated with either sildenafil citrate (10 mg/kg per day; subcutaneously) or saline for 14 days. Another group of rats were administered subcutaneously with N(G)-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg in 0.9% NaCl) 5 min after sildenafil injections. After decapitation, the lungs were excised and taken for microscopic evaluation or stored for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity, and for the assessment of apoptosis. Trunk blood was collected for the assessment of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels. In the group with lung fibrosis, the lung tissue was characterized by microscopic lesions, increased lipid peroxidation with a concomitant reduction in GSH content, increased MPO activity and apoptosis. Serum TNF-alpha and IL-1beta levels were higher in the lung fibrosis group compared to control values. Sildenafil reversed tissue MDA levels, MPO activity and serum pro-inflammatory cytokine levels, and preserved GSH content although its effect on the extent of tissue lesion and apoptosis was not statistically significant. Treatment with l-NAME reversed the effect of sildenafil on GSH content. In conclusion, sildenafil citrate administration to rats with bleomycin-induced lung fibrosis seems to be beneficial via prevention of lipid peroxidation, cytokine production and/or release and neutrophil accumulation.