Inhibition of murine embryonic development by α-difluoromethylornithine,an irreversible inhibitor of ornithine decarboxylase

The activities of ornithine decarboxylase (ODC) and S-adenosyl-L-methionine decarboxylase (SAMDC) and the concentrations of putrescine, spermidine and spermine were measured in mouse uterus, placenta and foetus during gestation. The prominent post-implantation biochemical changes in the intact uterus were associated mainly with the deciduomata and significant ODC activity was located in theembryo. Administration of the irreversible inhibitor of ODC, α-difluoromethylornithine, DFMO, 2% in the drinking water during days 5–8 of gestation, abolished the increases in uterine ODC activity, putrescine and spermidine concentrations and enhanced the activity of SAMDC. Treated animals showed no signs of pregnancy when autopsied on day 18. The alterations in deciduomal weight and the changes in uterine DNA, RNA and protein content indicated that decidualization following DFMO took place normally but that embryonic growth was arrested. Treatment on single days with DFMO, 200 mg/kg every six h, revealed optimal contragestational effects on day 8 which corresponded exactly to the time of the peak in deciduomal ODC activity. Treatment with DFMO at times other than during the vulnerable period of days 5–8 has less prominent effects on gestation. An increase in ODC activity appears to be an essential factor during a short, but critical, period after implantation for continued murine embryonal growth.     

Immaturity of IL-18 gene expression and protein production in cord blood (CB) versus peripheral blood (PB) mononuclear cells and differential effects in natural killer (NK) cell development and function

We have previously demonstrated dysregulation of IL-12 and IL-15 gene and protein expression between activated cord blood (CB) versus peripheral blood (PB) mononuclear cells (MNCs). In the present study, we compared IL-18 gene expression and protein production and IL-18 mRNA half-life in basal versus activated CB versus PB MNCs, the effects of IL-18 +/- IL-12 on MNCs IFN-gamma protein production and ex vivo expansion and activation of CB with IL-12 + IL-2 + anti-CD3 +/- IL-18. Basal and activated levels of IL-18 were significantly higher in PB versus CB MNCs (P < 0.05). IL-18 mRNA was coincidental with protein levels and significantly lower in CB (P < 0.05) and its half-life significantly shorter in CB versus PB MNCs (P < 0.05). IL-18 synergistically with IL-12 induced IFN-gamma production from PB greater than CB MNCs (P < 0.05). NK cells expansion (P < 0.001) and cytotoxicity (P < 0.01) was significantly increased with IL-12 + IL-2 + anti-CD3 and IL-18. In summary IL-18 gene expression and protein production are significantly decreased in activated CB versus PB MNCs, in part secondary to increased degradation of CB IL-18 mRNA. These results may have implications for the mechanism(s) in part responsible for the immaturity of CB T-cell immunity.     

Dyslipidemia and lipid-lowering therapy in the elderly

According to the current evidence, the fastest growing proportion of patient populations seeking healthcare is those over 65 years of age. Coronary artery disease and subclinical atherosclerosis are highly prevalent in this group of patients and are strongly linked to dyslipidemia, a well-established risk factor for atherosclerosis. Treating dyslipidemia in this group of patients requires specific knowledge and understanding of common dyslipidemias and the relative safety of various pharmacologic agents in the presence of possible multiple comorbidities. Lifestyle modification remains the first step in the treatment of dyslipidemia; however, it can be difficult to sustain and achieve acceptable compliance in the elderly and it is best used in combination with drug therapy. Statins are widely accepted as the first-line therapy. Several recent studies have demonstrated that statins are safe and effective in the elderly. However, it is important to note that there is very limited data regarding the effects of dyslipidemia treatment on morbidity and mortality in patients over 85 years of age. In summary, the clinicians must recognize that the presence of dyslipidemia in the elderly poses substantial risk of coronary events and stroke. The available evidence has demonstrated that in most elderly patients who are at increased risk for cardiovascular morbidity and mortality, treatment of dyslipidemia with appropriate therapy reduces the risk, and when used carefully with close monitoring for safety, the treatment is generally well tolerated. With increasing life expectancy, it is critical for physicians to recognize the importance of detection and treatment of dyslipidemia in the elderly.     

Head and neck squamous cell carcinoma: the role of post-operative adjuvant radiotherapy

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the leading cancers in India. Since a large majority present in loco-regionally advanced stages, surgery followed by adjuvant post-operative radiotherapy (PORT) has been the mainstay of treatment for resectable HNSCC. AIM: To identify clinico-pathologic factors that could have an impact on outcome in HNSCC in the postoperative setting. MATERIALS AND METHODS: A retrospective review of 348 previously untreated patients with HNSCC who received PORT following curative surgery. The outcome measures were local control, loco-regional control, and disease free survival (DFS). RESULTS: With a median follow-up of 36 months (range: 2-127 months) for surviving patients, the 5-year local control, loco-regional control, and DFS was 79%, 63%, and 56%, respectively for all patients. On univariate analysis, site of primary was an independent prognostic factor for all the outcome measures (P = 0.005, 0.02, and 0.04, respectively) with oral cavity lesions faring the worst. Peri-nodal extension (PNE) affected loco-regional control (P = 0.002) and DFS (P = 0.0005), but was not predictive for local control (P = 0.9852). Cut margin positivity predicted for inferior local control alone (P = 0.03), the significance of which was lost on multivariate analysis. Cox regression analysis however confirmed the significance of primary site and PNE as independent prognostic factors. CONCLUSION: Primary site and PNE are independent factors predicting outcome in the postoperative radiotherapeutic management of HNSCC.     

Polymorphisms in DNA repair gene <Emphasis Type="Italic">XRCC1</Emphasis> and increased genetic susceptibility to breast cancer

X-ray repair cross-complementing 1 (XRCC1) gene encodes for a scaffolding protein, which plays an important role in base excision DNA repair by bringing together DNA polymerase beta, DNA ligase III and poly(ADP-Ribose) polymerase (PARP) at the site of DNA damage. Three polymorphisms of the XRCC1 gene at codons 194, 280 and 399 leading to a mino acid changes at evolutionary conserved regions are found to alter the efficiency of the resulting protein and may therefore constitute potential breast cancer risk. In the present study we sought to determine whether these genetic variants of the XRCC1 gene was associated with any increased risk of breast cancer among the South Indian women in a hospital based case control study using PCR-RFLP and DNA sequencing techniques. Our data showed a positive association between the polymorphisms of codons 194 (OR=1.98, 95% CI=1.13--3.48 for Trp allele) and 399 (OR=2.14, 95% CI=1.29--3.58 for Gln allele) and breast cancer risk. However, XRCC1 codon 280 genotype analysis showed no evidence for an association with increased risk of breast cancer. A combined analysis of the effect of XRCC1 codon 194 and 399 revealed the highest risk (OR=3.64, 95% CI=1.57--8.46) for carriers of the polymorphic alleles in both these codons. In conclusion, the present study suggested involvement of XRCC1 codon 194 and 399 polymorphisms in the genetic predisposition to breast cancer among South Indian women. Our preliminary results based on the analysis of functionally relevant polymorphisms in XRCC1 low penetrance gene may provide a better model that would exhibit additive effects on individual susceptibility to breast cancer.     

Development of three layered buccal compact containing metoprolol tartrate by statistical optimization technique

The objective of this work to evaluate the effect of formulation variables on release properties and bioadhesive strength in development of three layered buccal compact containing highly water-soluble drug metoprolol tartrate (MT) by statistical optimization technique. Formulations were prepared based on rotatable central composite design with peripheral polymer ratio (carbopol 934P: HPMC 4KM) and core polymer ratio (HPMC 4KM: sodium alginate) as two independent formulation variables. The three layered buccal compact comprises a peripheral layer, core layer and backing layer. Four dependent (response) variables were considered: bioadhesion force, percentage MT release at 8 h, T50% (time taken to release 50% of drug) and release exponent (n). The release profile data was subjected to curve fitting analysis for describing the release mechanism of MT from three layered buccal compact. The main effects and interaction terms was quantitatively evaluated by quadratic model. The decrease in MT release was observed with an increase in both the formulation variables and as the carbopol: HPMC ratio increases the bioadhesive strength also increases. The desirability function was used to optimize the response variables, each having a different target and the observed responses were highly agreed with experimental values. The results demonstrate the feasibility of the model in the development of three layered buccal compact containing highly water-soluble drug MT.