Simvastatin suppresses LPS-induced Akt phosphorylation in the human monocyte cell line THP-1

BACKGROUND: Activation of the small GTPase, Rac, requires post-translational modification by isoprenylation. Statins interfere with this process by blocking the synthesis of isoprenoid intermediates. The protein kinase Akt is a multifunctional regulator of cell behavior that has been linked to Rac activation. We have shown that lipopolysaccharide (LPS) stimulation leads to Rac activation in THP-1 cells. Therefore, we hypothesized that LPS stimulation would also activate Akt, a downstream effector of Rac, and that this may be blocked by statin pretreatment. MATERIALS AND METHODS: THP-1 cells were maintained in 1% fetal calf serum with or without 20 microM simvastatin for 24 h, followed by LPS stimulation for increasing time. Cytoskeletal changes were observed using Alexa-Phalloidin. Akt was immunoprecipitated from total cell lysate. Activated Akt was detected by immunoblotting with a phospho-Akt antibody and was quantified by image densitometry. RESULTS: LPS stimulation of THP-1 cells results in membrane ruffling and cell polarization. Furthermore, LPS increased Akt activation in THP-1 cells when compared with the nonstimulated controls. Akt phosphorylation peaked after 15 min of LPS stimulation and was suppressed by pretreatment with simvastatin. CONCLUSIONS: These data demonstrate that LPS stimulation leads to increased Akt phosphorylation, which can be suppressed with simvastatin pretreatment. This suggests one possible mechanism through which simvastatin could modulate LPS-induced signaling events in monocytes to improve the host response to Gram-negative infections.     

Port catheter placement by nephrologists in an interventional nephrology training program

We retrospectively reviewed all subcutaneous single- and double-lumen port catheters (PCs) inserted by interventional nephrologists at our institution to determine the success rate, immediate and late complications, and functional life. From January 2000 to August 2002, 187 PCs were placed in 187 patients (42% males, 51% Caucasians, mean age 50 +/- 14 years). There were no immediate complications related to the procedure such as hemorrhage, pulmonary embolism, or pneumothorax. There were a total of 35,078 catheter-days of follow-up. Sixteen catheters were removed during the observation period: three because of infection, seven after completion of chemotherapy, and six for other reasons. The remaining PCs are either functioning or the patients have died. The initial success rate was 100%. Kaplan-Meier analysis showed a 30-day survival of 97% and a 1-year survival of 92%. Interventional nephrologists, who have adequate training in central venous tunneled cuffed catheter placements, can successfully place PCs, with excellent success and minimal complications.     

Botryoid rhabdomyosarcoma of vagina--two case reports

Botryoid rhabdomyosarcoma, previously considered a type of embryonal rhabdomyosarcoma, has clinicopathological features distinctive enough to warrant its classification as a separate entity. It almost always occurs in children under 5 years of age. Two cases of botryoid rhabdomyosarcoma are reported here because of their relative rarity.     

Thymic carcinoma with rhabdoid features

A case of thymic carcinoma with rhabdoid differentiation is presented. A 67-year-old man who presented with chest pain and hemoptysis was referred to The University of Texas M. D. Anderson Cancer Center (Houston, TX). Radiologic studies revealed a large anterior mediastinal mass. After the initial biopsy and preoperative chemotherapy, a radical thymectomy revealed a stage III thymic carcinoma with a rhabdoid component. The rhabdoid component was characterized by large cells with an eccentric nucleus, prominent nucleolus, and typical paranuclear cytoplasmic inclusions. Immunohistochemical and electron microscopic studies confirmed the presence of rhabdoid cells with the paranuclear cytoplasmic inclusions staining for both pancytokeratin and vimentin. The patient was given postoperative chemotherapy and radiation. He has since developed metastases to the pelvis and is alive with disease at 20 months of follow-up. To our knowledge, this is the first reported case of thymic carcinoma with rhabdoid features.     

Polymerisation by the chromate/arsenite system

The aqueous polymerisation of methyl methacrylate initiated by the chromate/arsenite system has been studied. It is observed that the polymerisation by the above redox system is catalysed by OH^? though the parent reaction between chromate and arsenite is catalysed by H^⊕. It is also observed that traces of Cu^2⊕ inhibit both the polymerization reaction as also the parent reaction. From these observations it is concluded (1) intermediate valency states of chromium has no initiating power in alkali solution and (2) the redox reaction between chromate and arsenite is a chain reaction involving single electron transfer and the intermediate As^4⊕ thus produced is the initiating species.     

Duration of US Residence and Obesity Risk in NYC Chinese Immigrants

We evaluated whether duration of time in the US is associated with obesity risk in NYC Chinese immigrants. We analyzed cross-sectional survey data on 2072 men and women. Duration of US residence was categorized into ≤5, 6–15, and 15 years and over. Obesity was defined using WHO Asian standards: BMI of 27.5 kg/m² or greater. Diet and physical activity (PA) were assessed as potential explanatory variables. After adjusting for covariates, increased time in the US was associated with an increased obesity risk (OR 1.49; 95 % CI 1.06, 2.08 for 15 years or more vs. ≤5 years); and in separate analysis, with having reported no work related PA (OR 0.76; 95 % CI 0.59, 0.99). Findings suggest that increased time living in the US is associated with an increased obesity risk, a finding possibly explained by a shift to more sedentary lifestyle characteristic of the transition of immigrants to the US.     

Ocular Disposition of the Hemiglutarate Ester Prodrug of ∆9-Tetrahydrocannabinol from Various Ophthalmic Formulations

Purpose

The overall goal of this project is to enhance ocular delivery of ?⁹-Tetrahydrocannabinol (THC) through the topical route.

Methods

Solubility, stability and in vitro transcorneal permeability of the relatively hydrophilic hemiglutarate ester derivative, THC-HG, was studied in the presence of surfactants. The solutions were characterized with respect to micelle size, zeta potential and solution viscosity. In vivo studies were carried out in New Zealand albino rabbits. A previously reported promising THC-HG ion-pair formulation was also studied in vivo.

Results

Aqueous solubility and stability and in vitro transcorneal permeability of THC-HG was enhanced significantly in the presence of surfactants. THC levels in the ocular tissues (except cornea) were found to be below detection limits from mineral oil, surfactant or emulsion based formulations containing THC. In contrast, micellar and ion pair based THC-HG formulations produced significantly higher total THC concentrations in the anterior ocular chamber.

Conclusion

In this study, although delivery of THC to the anterior chamber ocular tissues could be significantly increased through the prodrug and formulation approaches tested, further studies are needed to increase penetration to the back-of-the eye.     

Toxicokinetic Study of Recombinant Human Heparin-Binding Epidermal Growth Factor-Like Growth Factor (rhHB-EGF) in Female Sprague Dawley Rats

Purpose To determine the toxicity and pharmacokinetics of recombinant heparin-binding epidermal growth factor-like growth factor in female Sprague Dawley rats following intra-bladder and intravenous administration. Materials and Methods rhHB-EGF was administered once daily for 6 or 27 days at doses of 3, 10, or 30 μg/kg. ¹²⁵I-rhHB-EGF was administered on day 7 or 28 for pharmacokinetic analysis. Toxicity was assessed by general appearance and behavior, gross necropsy, blood chemistry and microscopic evaluation. Results Plasma AUCss of [¹²⁵I] rhHB-EGF equivalents following IB administration for 7 days were 4.28 ± 2.29, 7.75 ± 2.70, and 7.11 ± 1.42 ng ml⁻¹ h⁻¹ at doses of 3, 10, and 30 μg/kg, respectively. Following IV administration, the AUCss on day 7 increased from 27.0 ± 2.66 to 124 ± 5.09 and 385.11 ± 7.57 ng ml⁻¹ h⁻¹ with increasing the dose from 3 to 10 and 30 μg/kg. Similar AUCss data was obtained after 28 day administration. No toxicity was evident upon gross examination. Histologic examination revealed subacute inflammation and lymphocytic infiltration of the urinary bladder in animals from all groups dosed by the IB route. Conclusions Plasma and bladder concentrations of recombinant human [¹²⁵I] rhHB-EGF equivalents were significantly lower following the IB route than following IV administration. Histologic tissue examination indicated no toxicity attributable to rhHB-EGF.     

Nanoparticulate drug carriers for delivery of HIV/AIDS therapy to viral reservoir sites

Providing the optimum treatment of AIDS is a major challenge in the 21st Century. HIV is localised and harboured in certain inaccessible compartments of the body, such as the CNS, the cerebrospinal fluid, the lymphatic system and in the macrophages, where it cannot be reached by the majority of therapeutic agents in adequate concentrations or in which the therapeutic agents cannot reside for the necessary duration. Progression in HIV/AIDS treatment suggests that available therapy can lower the systemic viral load below the detection limit. However, on discontinuation of treatment, there is relapse of the infection from the reservoir sites and a potential for resistance development. This review discusses the aetiology and pathology of HIV, with emphasis on the viral reservoirs, current therapy of AIDS, and the opportunity for nanotechnology-based drug delivery systems to facilitate complete eradication of viral load from the reservoir sites. Literature-cited examples of drug delivery systems that are under investigation for the treatment of AIDS are discussed. The article also focuses on the future outlook and strategies for investigational drug formulations that use nanotherapeutic strategy for HIV/AIDS.