The impact of abnormalities in IGF and inflammatory systems on the metabolic syndrome

OBJECTIVE: Low plasma levels of IGF-I, particularly when coupled with low levels of the potentially inhibitory IGF binding protein (IGFBP)-1 and higher levels of C-reactive protein (CRP), have been implicated in the pathogenesis of metabolic syndrome X and cardiovascular disease. We report the relative contributions of IGFBP-1 and CRP to the occurrence of the metabolic syndrome in a healthy population cohort to establish the extent to which these factors may contribute to subsequent risk of cardiovascular disease. RESEARCH DESIGN AND METHODS: The volunteers in the study were all participants in the Ely study, a continuing population-based cohort in Ely, Cambridgeshire, U.K. Of 839 individuals studied, 154 (18.4%) fulfilled criteria for the metabolic syndrome. RESULTS: Subjects with the metabolic syndrome had lower IGFBP-1 (14.4 microg/l [95% CI 12.9-16.0] vs. 25.4 [24.1-26.7], P < 0.001) and higher CRP (1.9 mg/l [1.6-2.2] vs. 1.0 [0.9-1.1], P < 0.001). Logistic regression, adjusted for age, sex, fasting insulin, and IGF-I, demonstrated a striking 14-fold increased risk for the metabolic syndrome (odds ratio 14.1 [4.1-48.4], P < 0.001) in individuals with a CRP value in the highest tertile and IGFBP-1 levels below the median. CONCLUSIONS: The combination of a high CRP concentration coupled with a low IGFBP-1 results in a dramatic increase in an individual's risk of having the metabolic syndrome. Further elucidation of the biological processes linking the IGF and inflammatory systems may allow the identification of novel therapeutic targets for cardiovascular risk reduction.     

Cutaneous reactions in patients with solitary cysticercus granuloma on phenytoin sodium

Several medical conditions are believed to be associated with an increased risk of cutaneous adverse reactions to anti-epileptic drugs. The aim of this study was to study the frequency and nature of cutaneous reactions in a cohort of patients being treated with phenytoin sodium for seizures, who were divided into those with a solitary cysticercus granuloma (SCG) and those with a condition other than SCG, to determine if the presence of SCG increases the risk of cutaneous adverse reaction to phenytoin. A cohort of 117, consecutively begun on treatment with phenytoin for seizure control, were followed up prospectively for the development of cutaneous reactions. There were 63 patients with SCG upon imaging and 54 patients to whom phenytoin was administered for seizures due to causes other than SCG or multiple neurocysticercosis. Cutaneous reactions were significantly more common (p = 0.02) in patients with SCG (9/63 patients; 14.3%) than in controls (2/54 patients; 3.7%). The spectrum of skin reactions in patients with SCG included benign skin rash (n = 3), anticonvulsant hypersensitivity syndrome (n = 4), Stevens-Johnson syndrome (n = 1), and urticaria (n = 1). Individuals with seizures due to SCG have a high incidence of cutaneous adverse reactions to phenytoin. This fact should be kept in mind when initiating them on treatment with this anti-epileptic drug.     

Normal flora: living vehicles for non-invasive protein drug delivery

Feasibility to use probiotic bacteria as a living protein delivery system through oral route was assessed in vitro. Lactococcus lactis transformed with a plasmid to express and secret beta-lactamase was used to deliver beta-lactamase through Caco-2 monolayer, an intestine epithelium. Transport of beta-lactamase through Caco-2 monolayer was carried out in the transwells. The viability and integrity of the cell monolayers co-cultured with L. lactis was examined by trypan blue exclusion method and by measuring the transport of mannitol and propranolol as well as the transepithelial electrical resistance (TEER). Results show that it is feasible to use cell culture technique to evaluate the drug delivery by normal flora. The transport rate of beta-lactamase when delivered by L. lactis was 2.0 +/- 0.1 x 10(-2)h(-1) (n = 9) and through free solution form was 1.0 +/- 0.1 x 10(-2)h-1. When co-cultured with L. lactis, Caco-2 cell viability decreased to 98, 96, and 94% at 6, 8, and 10h, respectively. Transport of mannitol through Caco-2 cell monolayer was significantly increased and the transport of propranolol through Caco-2 cell monolayer was significantly decreased in the presence of L. lactis. Increase in the amount of protein delivered is probably due to the concentrate of the protein by L. lactis on the monolayer (absorption surface) and the opening of the tight junction of Caco-2 monolayer by L. lactis.     

Diaper dermatitis — An overview

Diaper dermatitis, also know as nappy rash, is an inflammation of the skin covered by nappy. It probably results due to an interaction of multiple factors like increased wetness, elevated pH due to urine, fecal enzymes and microorganisms under the nappy. It manifests as an erythematous rash occurring on the convex surfaces of skin under the nappy. Rashes resembling nappy dermatitis can also be caused by some diseases which may have serious systemic manifestations. Therefore it is essential to differentiate and treat them. The principle of treatment of diaper dermatitis is to keep the skin in the nappy area as dry as possible with frequent nappy change. The superabsorbent disposable diapers are known to reduce the incidence of diaper dermatitis. Barrier creams to protect the infant’s skin and mild topical corticosteroids to reduce the inflammation are mainstays of therapy. The incidence and severity can be reduced by keeping the skin dry under the nappy and protected from irritants and infections.     

Bone marrow as a cell source for tissue engineering heart valves

Background

This study was designed to assess the feasibility of using ovine bone marrow-derived mesenchymal stem cells to develop a trileaflet heart valve using a tissue engineering approach.

Methods

Bone marrow was aspirated from the sternum of adult sheep. Cells were isolated using a Ficoll gradient, cultured, and characterized based on immunofluorescent staining and the ability to differentiate down a specific cell lineage. Two million cells per centimeter squared were delivered onto a polyglycolic acid (PGA), poly-4-hydroxybutyrate (P4HB) composite scaffold and cultured for 1 week before being transferred to a pulse duplicator for an additional 2 weeks. The tissue-engineered valves were assessed by histology, scanning electron microscopy, and biomechanical flexure testing.

Results

Cells expressed SH2, a marker for mesenchymal stem cells, as well as specific markers of smooth muscle cell lineage including α-smooth muscle actin, desmin, and calponin. These cells could be induced to differentiate down an adipocyte lineage confirming they had not fully committed to a specific cell lineage. Preliminary histologic examination showed patchy surface confluency confirmed by scanning electron microscopy, and deep cellular material. Biomechanical flexure testing of the leaflets showed an effective stiffness comparable to normal valve leaflets.

Conclusions

Mesenchymal stem cells can be isolated noninvasively from the sternum of sheep and can adhere to and populate a PGA/P4HB composite scaffold to form “tissue” that has biomechanical properties similar to native heart valve leaflets. Thus, bone marrow may be a potential source of cells for tissue engineering trileaflet heart valves, particularly in children with congenital heart disease.     

The JNK,ERK and p53 pathways play distinct roles in apoptosis mediated by the antitumor agents vinblastine,doxorubicin, and etoposide

Assessment of specific apoptosis and survival pathways implicated in anticancer drug action is important for understanding drug mechanisms and modes of resistance in order to improve the benefits of chemotherapy. In order to better examine the role of mitogen-activated protein kinases, including JNK and ERK, as well as the tumor suppressor p53, in the response of tumor cells to chemotherapy, we compared the effects on these pathways of three structurally and functionally distinct antitumor agents. Drug concentrations equal to 50 times the concentration required to reduce cell proliferation by 50% were used. Vinblastine, doxorubicin, or etoposide (VP-16) induced apoptotic cell death in KB-3 carcinoma cells, with similar kinetic profiles of PARP cleavage, caspase 3 activation, and mitochondrial cytochrome c release. All three drugs strongly activated JNK, but only vinblastine induced c-Jun phosphorylation and AP-1 activation. Inhibition of JNK by SP600125 protected cells from drug-induced cytotoxicity. Vinblastine caused inactivation of ERK whereas ERK was unaffected in cells exposed to doxorubicin or VP-16. Inhibition of ERK signaling by the MEK inhibitor, U0126, potentiated the cytotoxic effects of vinblastine and doxorubicin, but not that of VP-16. Vinblastine induced p53 downregulation, and chemical inhibition of p53 potentiated vinblastine-induced cell death, suggesting a protective effect of p53. In contrast, doxorubicin and VP-16 induced p53, and inhibition of p53 decreased drug-induced cell death, suggesting a pro-apoptotic role for p53. These results highlight the differential roles played by several key signal transduction pathways in the mechanisms of action of key antitumor agents, and suggest ways to specifically potentiate their effects in a context-dependent manner. In addition, the novel finding that JNK activation can occur without c-Jun phosphorylation or AP-1 activation has important implications for our understanding of JNK function.     

Malignancy in AIDS: institutional management or home care?

In India, the first sero-positive person was reported from Chennai in 1986 and the first case of AIDS from Mumbai 1987. Since then the epidemic is growing steadily and WHO/UNAIDS estimate that by the year 2000 AD India has around 3-5 million people suffering from HIV/AIDS and this is the largest burden of HIV in single country. Over 40% of all patients with HIV infection will develop malignant disease at sometime during their course of illness. AIDS and malignancy together constitute a deadly combination. The authors recommend that the care of patients having malignancy with AIDS should be mainly at home rather than in an oncology center. This will ensure the patient's and family's comfort as most of the specialized cancer centers in India are at a considerable distance away from patient's homes. Frequent visit to a cancer center will exhaust the patient and attendants emotionally, physically and financially. This is especially true because irrespective of the pains taken by the family and the specialists, a cure is an unlikely possibility. Only one specialist from oncology and one primary health physician, who are completely aware of the patient's physical, psychological, financial and social background, should be responsible for the care of a patient having malignancy with AIDS in India. The main advantages of the home care of such patients are: patient's and family's comfort; lesser mental, physical, social, emotional and financial agony; and minimum need for institutional care, which may be instituted as and when necessary.     

Teratomas in infancy and childhood

A 10-year-experience with 42 cases of teratomas in paediatric age group is presented. The commonest type of teratoma was sacrococcygeal²⁵ followed by ovarian⁸ and retroperitoneal teratomas.³ An analysis of clinical profile, malignant potential, management, prognostic factors and follow up is discussed with review of literature.