Molecular signalling of a novel curcumin derivative versus Tadalafil in erectile dysfunction

The efficacy of a novel curcumin derivative (NCD) versus tadalafil in erectile signalling was assessed. Ten control male rats and 50 diabetic male rats were used and divided into the following: diabetic (DM), curcumin (CURC), NCD, tadalafil and NCD combined with tadalafil rat groups. Cavernous tissue gene expression of heme oxygenase‐1 (HO‐1), Nrf2, NF‐B and p38, enzyme activities of heme oxygenase (HO) and nitric oxide synthase (NOS), cGMP and intracavernosal pressure (ICP)/mean arterial pressure (MAP) were assessed. Results showed that 12 weeks after induction of diabetes, erectile dysfunction (ED) was confirmed by the significant decrease in ICP/MAP, a significant decrease in cGMP, NOS, HO enzyme activities, a significant decrease in HO‐1 gene and a significant increase in NF‐?β, p38 genes. Administration of all therapeutic interventions led to a significant increase in ICP/MAP, cGMP levels, a significant increase in HO‐1 and NOS enzymes, a significant increase in HO‐1, and Nrf2 gene expression, and a significant decrease in NF‐?β, p38 gene expression. NCD or its combination with tadalafil showed significant superiority and more prolonged duration of action. In conclusion, a tendency was observed that CURC and NCD have high efficacy and more prolonged duration of action in enhancing erectile function.     

Thymoquinone therapy abrogates toxic effect of cadmium on rat testes

The protective effect of thymoquinone was investigated against cadmium‐induced testicular toxicity in rats. Testicular toxicity was induced by a single intraperitoneal (i.p.) injection of cadmium chloride (2 mg kg^?1). Thymoquinone treatment (10 mg kg^?1 day^?1, i.p.) was applied for five consecutive days, starting 3 days before cadmium administration. Thymoquinone significantly attenuated the cadmium‐induced decreases in serum testosterone, and testicular reduced glutathione and superoxide dismutase activity and significantly decreased the elevations of testicular malondialdehyde, nitric oxide and cadmium ion levels resulted from cadmium chloride administration. Also, thymoquinone ameliorated the cadmium‐induced testicular tissue injury observed by histopathological examination. In addition, thymoquinone significantly decreased the cadmium‐induced expression of inducible nitric oxide synthase, tumour necrosis factor‐α, cyclooxygenase‐2, nuclear factor‐κB and caspase‐3 in testicular tissue. It was concluded that thymoquinone, through its antioxidant and anti‐inflammatory activities, may represent a potential candidate to protect the testes against the detrimental effect of cadmium exposure.     

Mutation in Osteoactivin Decreases Bone Formation in Vivo and Osteoblast Differentiation in Vitro

We have previously identified osteoactivin (OA), encoded by Gpnmb, as an osteogenic factor that stimulates osteoblast differentiation in vitro. To elucidate the importance of OA in osteogenesis, we characterized the skeletal phenotype of a mouse model, DBA/2J (D2J) with a loss-of-function mutation in Gpnmb. Microtomography of D2J mice showed decreased trabecular mass, compared to that in wild-type mice [DBA/2J-Gpnmb⁺/SjJ (D2J/Gpnmb⁺)]. Serum analysis showed decreases in OA and the bone-formation markers alkaline phosphatase and osteocalcin in D2J mice. Although D2J mice showed decreased osteoid and mineralization surfaces, their osteoblasts were increased in number, compared to D2J/Gpnmb⁺ mice. We then examined the ability of D2J osteoblasts to differentiate in culture, where their differentiation and function were decreased, as evidenced by low alkaline phosphatase activity and matrix mineralization. Quantitative RT-PCR analyses confirmed the decreased expression of differentiation markers in D2J osteoblasts. In vitro, D2J osteoblasts proliferated and survived significantly less, compared to D2J/Gpnmb⁺ osteoblasts. Next, we investigated whether mutant OA protein induces endoplasmic reticulum stress in D2J osteoblasts. Neither endoplasmic reticulum stress markers nor endoplasmic reticulum ultrastructure were altered in D2J osteoblasts. Finally, we assessed underlying mechanisms that might alter proliferation of D2J osteoblasts. Interestingly, TGF-β receptors and Smad-2/3 phosphorylation were up-regulated in D2J osteoblasts, suggesting that OA contributes to TGF-β signaling. These data confirm the anabolic role of OA in postnatal bone formation.Osteoporosis is a growing public health problem, in part because of the increasing numbers of people living beyond the age of 65 years.¹ It is characterized by low bone mass due to increased bone resorption by osteoclasts and decreased bone formation by osteoblasts, with significant deterioration in the bone microarchitecture leading to high bone fragility and increased fracture risk.^1,2 The net effect of osteoporosis is low bone mass.¹ There is an increasing demand for identifying novel bone anabolic factors with potential therapeutic benefits in treating generalized bone loss, such as osteoporosis and/or major skeletal fracture.Osteoactivin is a novel glycoprotein first identified in natural mutant osteopetrotic rats.³ The same protein has been identified and named separately in several other species: as dendritic cell heparan sulfate proteoglycan integrin dependent ligand (DCHIL) in mouse dendritic cells,⁴ as transmembrane glycoprotein NMB (GPNMB) in human melanoma cell lines and melanocytes,⁵ and as hematopoietic growth factor inducible neurokinin (HGFIN) in human tumor cells.⁶ The current recommended name for the protein encoded by Gpnmb in mouse is transmembrane glycoprotein NMB (http://www.ncbi.nlm.nih.gov/protein/Q99P91.2); here, we continue to use osteoactivin (OA) for the protein and Gpnmb for the gene. OA is a type I transmembrane protein that consists of multiple domains, including an extracellular domain, transmembrane domain, and protein sorting signal sequence.⁷ Within the C-terminal domain, OA has an RGD motif, predicting an integrin attachment site.^3,7–9Our research group initially reported on the novel role of OA in osteoblast differentiation and function.^7–10 We demonstrated that OA expression has a temporal pattern during osteoblast differentiation, being highest during matrix maturation and culture mineralization in vitro.^7–11 Using loss-of–function and gain-of–function approaches in osteoblasts, we reported that OA overexpression increases osteoblast differentiation and function and that OA down-regulation decreases nodule formation, alkaline phosphatase (ALP) activity, osteocalcin (OC) production, and matrix mineralization in vitro.⁷ We also reported on the positive role of OA in mesenchymal stem cell (MSCs) differentiation into osteoblasts in vitro.¹² In another study, we showed that recombinant OA protein induces higher osteogenic potential of fetal-derived MSCs, compared with bone marrow–derived MSCs¹³ and its osteogenic effects in the mouse C3H10T1/2 MSC cell line were similar to those of recombinant BMP-2.¹² We also localized OA protein as associated predominately with osteoblasts lining trabecular bones in vivo,¹¹ and showed that local injection of recombinant OA increased bone mass in a rat model.¹⁴ Moreover, in a fracture repair model OA expression increased over time, reaching a maximum 2 weeks after fracture.¹¹ In a parallel study, recombinant OA supported bone regeneration and formation in a rat critical-size calvarial defect model.¹⁵ Others have shown that OA is highly expressed by osteoclasts in vitro, suggesting that it may regulate osteoclast formation and activity.¹⁶There is urgent need for an animal model to fully examine the role of OA in osteogenesis. Interestingly, a natural mutation of the Gpnmb gene has been identified in the DBA/2J (D2J) mouse strain.¹⁷ These mice exhibit high-frequency hearing loss, which begins at the time of weaning and becomes severe by 2 to 3 months of age.^18,19 Aged D2J mice also develop progressive eye abnormalities that closely mimic human hereditary glaucoma. The onset of disease symptoms falls roughly between 3 and 4 months of age, and disease becomes severe by 6 months of age.^5,20 D2J mice are homozygous for a nonsense mutation in the Gpnmb gene sequence that induces an early stop codon, generating a truncated protein sequence of 150 amino acids (aa) instead of the full-length 562-aa OA protein.⁵ The control for the D2J mouse is the wild-type DBA/2J-Gpnmb⁺/SjJ mouse (D2J/Gpnmb⁺), homozygous for the wild-type Gpnmb gene.²¹ These Gpnmb wild-type mice do not develop glaucoma, as D2J mice do, although they exhibit mild iris stromal atrophy.²¹In the present study, we used Gpnmb mutant (D2J) and Gpnmb wild-type (D2J/Gpnmb⁺) mice to gain insight into the role of OA in osteogenesis and in osteoblast differentiation and function. Here, we report that loss-of–function mutation of Gpnmb suppresses bone formation by directly affecting osteoblast proliferation and survival, leading to a decreased number of differentiated osteoblasts with suppressed activity in bone mineralization. Thus, our data point to OA as a novel and positive regulator of postnatal bone formation.     

Marginal bone loss adjacent to conventional and immediate loaded two implants supporting a ball-retained mandibular overdenture: a 3-year randomized clinical trial

Objectives: The aim of this study was to evaluate and compare marginal bone loss and clinical outcomes of conventionally and immediately loaded two implants supporting a ball‐retained mandibular overdenture. Materials and methods: Thirty six completely edentulous patients (22 males and 14 females) were randomly assigned into two groups. Each patient received two implants in the canine area of the mandible after a minimal flap reflection. Implants were loaded by mandibular overdentures either 3 months (conventional loading group) or the same day (immediate loading group) after implant placement. Ball attachments were used to retain all overdentures to the implants. Vertical and horizontal alveolar bone losses were evaluated in both groups 1 and 3 years after implant placement using multislice computed tomography, which allow evaluation of peri‐implant buccal and lingual alveolar bone. Plaque scores, gingival scores, probing depths and periotest values (PTVs) were evaluated at 4 months (baseline), 1 and 3 years after implant placement. Clinical and radiographic evaluations were performed at distal, labial, mesial and lingual peri‐implant sites. Results: After 3 years of follow‐up period, the immediate loading group recorded significant vertical bone loss at distal and labial sites than the conventional loading group and no significant differences in horizontal bone loss between groups were observed. Probing depth at distal and labial sites in the immediate loading group were higher than the conventional loading group, while plaque scores, gingival scores and PTVs showed no significant differences between the two groups. A low level of positive correlation between plaque scores, gingival scores, probing depths and vertical bone loss was noted. Conclusion: Immediately loaded two implants supporting a ball‐retained mandibular overdenture are associated with more marginal bone resorption and increased probing depths when compared with conventionally loaded implants after 3 years. The bone resorption and probing depths at distal and labial sites are significantly higher than those at mesial and lingual sites. Clinical outcomes do not differ significantly between loading protocols. To cite this article :
Elsyad MA, Al‐Mahdy YF, Fouad MM. Marginal bone loss adjacent to conventional and immediate loaded two implants supporting a ball‐retained mandibular overdenture: a 3‐year randomized clinical trial.
Clin. Oral Impl. Res. 23 , 23, 2012 496‐503.
doi: 10.1111/j.1600‐0501.2011.02173.x     

Traumatismos torácicos en niños: experiencia de un centro

Trauma is the leading cause of mortality in children over one year of age in industrialized countries. In this retrospective study we reviewed all chest trauma in pediatric patients admitted to Mansoura University Emergency Hospital from January 1997 to January 2007. Our hospital received 472 patients under the age of 18. Male patients were 374 with a mean age of 9.2 ± 4.9 years. Causes were penetrating (2.1%) and blunt trauma (97.9%). The trauma was pedestrian injuries (38.3%), motor vehicle (28.1%), motorcycle crash (19.9%), falling from height (6.7%), animal trauma (2.9%), and sports injury (1.2%). Type of injury was pulmonary contusions (27.1%) and lacerations (6.9%), rib fractures (23.9%) and flail chest (2.5%), hemothorax (18%), hemopneumothorax (11.8%), pneumothorax (23.7%), surgical emphysema (6.1%), tracheobronchial injury (5.3%), and diaphragm injury (2.1%). Associated lesions were head injuries (38.9%), bone fractures (33.5%), and abdominal injuries (16.7%). Management was conservative (29.9%), tube thoracostomy (58.1%), and thoracotomy (12.1%). Mortality rate was (7.2%) and multiple trauma was the main cause of death (82.3%) (P < .001). We concluded that blunt trauma is the most common cause of pediatric chest trauma and often due to pedestrian injuries. Rib fractures and pulmonary contusions are the most frequent injuries. Delay in diagnosis and multiple trauma are associated with high incidence of mortality.     

Overexpression of FoxM1 offers a promising therapeutic target in diffuse large B-cell lymphoma

Background

FoxM1 has been shown to play a critical role in the pathogenesis of various epithelial malignancies. However, its role in lymphoid malignancies has not been fully clarified. We, therefore, investigated the role of FoxM1 expression in a large cohort of diffuse large B-cell lymphoma samples and panel of cell lines.

Design and Methods

FoxM1 expression was investigated in a large series of diffuse large B-cell lymphoma tissues in a tissue microarray format by immunohistochemistry. Apoptosis was measured by flow cytometry and protein expression was detected by immunoblotting using diffuse large B-cell lymphoma cell lines following treatment with either pharmacological inhibitor of FoxM1 or small interference RNA knockdown strategy. Invasion/migration and soft agar colony assays were also performed following treatment with FoxM1 inhibitor.

Results

FoxM1 expression was detected in 84.6% of diffuse large B-cell lymphoma tumors and found to be significantly associated with proliferative tumor marker Ki67 (P<0.0001), matrix metalloproteinases-2 (P=0.0008), matrix metalloproteinases-9 (P=0.0002), S-phase kinase associated protein-2 (P<0.0001) and inversely associated with p27 expression (P=0.0215). Expression of small interference RNA targeted against FoxM1 or treatment of diffuse large B-cell lymphoma cells with thiostrepton caused its downregulation accompanied by decreased expression of matrix metalloproteinases-2 and matrix metalloproteinases-9. Inhibition of FoxM1 in diffuse large B-cell lymphoma cells also decreased invasive and migratory capability, and induced caspase dependent apoptosis via activation of the mitochondrial apoptotic pathway. Finally, combined thiostrepton and bortezomib at sub-toxic doses led to efficient apoptosis in diffuse large B-cell lymphoma cells.

Conclusions

Altogether, these results suggest that FoxM1 is over-expressed in the majority of diffuse large B-cell lymphoma samples. These data also indicate that targeting FoxM1 signaling can serve as a potential therapeutic modality in the management of diffuse large B-cell lymphoma.     

A case report of cecal plasmablastic lymphoma in a HIV-negative patient

Plasmablastic lymphoma (PBL) is a unique type of diffuse proliferation of large neoplastic lymphoid cells most of which resemble B immunoblasts, but all tumor cells show the immunophenotype of plasma cells. It has a strong predilection for jaw and oral cavity in HIV-positive patients. Incidences of extraoral location of this tumor is increasingly being recognized especially in HIV-negative patients for example, stomach, jejunum, omentum, anorectum, lungs, testes, soft tissues, lymph nodes, bone marrow, skin, and central nervous system. We present a case of PBL found in cecum in an HIV-negative patient. It was accompanied by lung and lymph node involvement and presented as abdominal mass. This is only the second reported case of PBL originating in cecum.