Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR(-/-) mice

Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR(-/-)) mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXRα (Lenti-SP-LXRα) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXRα mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-α. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXRα gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR(-/-) mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis.     

Evaluation of a Prospective Surgical Strategy of Extended Resection to Achieve R0 Status in Gall Bladder Cancer

Introduction

Radical resection to achieve R0 status remains the only potential curative option in patients with gall bladder cancer (GBC). This study was aimed to evaluate the efficacy of an extended criterion of radical resection to achieve R0 status in GBC.

Methods

A triple-phase CT with 3D reconstruction was done in all patients. A standard resectability criterion was followed in all patients. A minimum of liver segment 4B + 5 resection and radical lymphadenectomy including the para-aortic areas were undertaken in all patients. Adjacent organectomy was added as required.

Results

Between November 2008 and April 2011, 59 patients with GBC underwent operation and 40 (resectability, 68 %) underwent resection. The resectional procedures performed were segmentectomy 4B + 5 in 31 (78 %), median sectorectomy in 2 (5 %), extended right hepatectomy in 3 (8 %), and hepatopancreaticoduodenectomy in 4 (10 %) patients. Postoperative complications occurred in 24 (60 %) patients. Two patients died postoperatively. A total of 829 lymph nodes were harvested and the median lymph node count was 18 (4–77). Twenty-three (58 %) patients had lymph node metastases. Twenty-eight of 40 (70 %) had disease limited till N1 nodes. Metastases up to N2 lymph nodes were seen in 12 (30 %). American Joint Committee on Cancer seventh edition stages were I—2 (5 %) patients, II—5 (13 %), III—19 (48 %), and IV—14 (35 %). R0 resection was achieved in 33 (83 %) patients. Four patients had recurrence and one died of recurrence. All other patients are alive till the last follow-up.

Conclusions

Assessment with triple-phase CT with 3D reconstruction can produce high resectability rate in GBC. Extended criterion of radical resection results in R0 status in more than 80 % of patients with GBC.     

Livedo Reticularis Due to Pellagra in a Two Year Old Child

A two-year-old girl child was admitted with complaints of diarrhoea of one week duration in the paediatric ward. She was referred to the skin OPD for gradually progressive skin rashes on both lower limbs noticed since two days. Dermatological examination revealed finding of livedo reticularis. Dietary history revealed maize forming a significant portion of the child''s diet since the age of nine months. The child was treated with a course of Niacin in the form of Nicotinamide 50 mg twice a day for 4 weeks and the parents were advised not to give her maize in the diet. The skin lesions and diarrhoea regressed in duration of two weeks. This is probably the first time that a case of pellagra causing livedo is being reported, that too in a child.     

A Case of Extensive Multifocal Tuberculosis Verrucosa Cutis

Tuberculosis is probably as old as the human race itself. Cutaneous tuberculosis constitutes a very small proportion of extra pulmonary tuberculosis. Extensive, multifocal involvement of cutaneous tuberculosis is a very rare manifestation. We report one such case of extensive, multifocal tuberculosis verrucosa cutis in a 30-year-old immunocompetent male patient in the absence of any primary tubercular focus.     

Cutaneous manifestations of HIV—a detailed study of morphological variants,markers of advanced disease,and the changing spectrum

Background

Cutaneous manifestations are early and easily identifiable markers of human immunodeficiency virus (HIV) infection. They can help in predicting severity and progress of the disease and can be correlated well with CD4 counts. This study was undertaken to study the cutaneous manifestations of HIV infection and to correlate them with CD4 counts. It also aimed to study the changing spectrum of these manifestations and describe cutaneous manifestations seen in advanced disease.

Method

A total of 234 HIV-positive patients not on anti-retroviral therapy, who attended the outpatient department or were admitted as inpatients at Military Hospital, Shillong during the period between May 2008 and October 2009 were included. Cutaneous, mucosal, and genitourinary manifestations in these patients were studied in detail and were correlated with CD4 counts.

Results

Infections were the most common group of mucocutaneous manifestations, while onychomycosis was the commonly observed individual manifestation. A different set of cutaneous markers for advanced HIV disease was observed and new parameters for therapy were also arrived at.

Conclusion

Specific morphological variants of cutaneous markers may provide a better clue to early diagnosis of HIV and can help in diagnosing advanced stages of the disease. Fresh cutaneous markers are required for indicating cut-off levels of CD4 count at 350/μL for starting therapy.     

Macrophage-mediated GDNF Delivery Protects Against Dopaminergic Neurodegeneration: A Therapeutic Strategy for Parkinson's Disease

Glial cell line–derived neurotrophic factor (GDNF) has emerged as the most potent neuroprotective agent tested in experimental models for the treatment of Parkinson''s disease (PD). However, its use is hindered by difficulties in delivery to the brain due to the presence of the blood–brain barrier (BBB). In order to circumvent this problem, we took advantage of the fact that bone marrow stem cell–derived macrophages are able to pass the BBB and home to sites of neuronal degeneration. Here, we report the development of a method for brain delivery of GDNF by genetically modified macrophages. Bone marrow stem cells were transduced ex vivo with lentivirus expressing a GDNF gene driven by a synthetic macrophage-specific promoter and then transplanted into recipient mice. Eight weeks after transplantation, the mice were injected with the neurotoxin, MPTP, for 7 days to induce dopaminergic neurodegeneration. Macrophage-mediated GDNF treatment dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and TH⁺ terminals in the striatum, stimulated axon regeneration, and reversed hypoactivity in the open field test. These results indicate that macrophage-mediated GDNF delivery is a promising strategy for developing a neuroprotective therapy for PD.     

Reactive Bone Marrow Stromal Cells Attenuate Systemic Inflammation via sTNFR1

Excessive systemic inflammation following trauma, sepsis, or burn could lead to distant organ damage. The transplantation of bone marrow stromal cells or mesenchymal stem cells (MSCs) has been reported to be an effective treatment for several immune disorders by modulating the inflammatory response to injury. We hypothesized that MSCs can dynamically secrete systemic factors that can neutralize the activity of inflammatory cytokines. In this study, we showed that cocultured MSCs are able to decrease nuclear factor κ-B (NFκB) activation in target epithelial cells incubated in inflammatory serum conditions. Proteomic screening revealed a responsive secretion of soluble tumor necrosis factor (TNF) receptor 1 (sTNFR1) when MSCs were exposed to lipopolysaccharide (LPS)-stimulated rat serum. The responsive effect was eliminated when NFκB activation was blocked in MSCs. Intramuscular transplantation of MSCs in LPS-endotoxic rats decreased a panel of inflammatory cytokines and inflammatory infiltration of macrophages and neutrophils in lung, kidney, and liver when compared to controls. These results suggest that improvements of inflammatory responses in animal models after local transplantation of MSCs are at least, in part, explained by the NFκB-dependent secretion of sTNFR1 by MSCs.